melphalan and Lymphoma

Patients suffering from refractory aggressive B-cell lymphoma not responding to salvage chemotherapy have a dismal prognosis. CAR T-cells or allogeneic stem cell transplantation (SCT) are potentially curative approaches. However, obtaining a remission, and lowering tumor burden before consolidation seems crucial for long-term efficacy of both treatment modalities.. In this retrospective analysis, we reviewed patients with chemoresistant aggressive B-cell lymphoma, defined as being refractory or progressive to at least second line salvage chemotherapy including the regimen immediately preceding autologous stem cell transplantation (ASCT), treated at 2 tertiary centers, who were eligible for intensive treatment using single agent high-dose (HD) melphalan to obtain a remission before consolidating therapy.. We identified 36 patients that received single agent HD melphalan and ASCT as remission induction followed by CAR T-cells or allogeneic stem cell transplantation (SCT). Thirteen of the evaluable patients (39.4%) achieved a partial remission and 9 patients (27.73%) a complete remission, resulting in an overall response rate (ORR) of 66.7%. High remission rates were seen across all subgroups including patients with primary refractory lymphoma (ORR 58.3%), uncontrolled disease and high tumor burden as indicated by increased LDH levels (ORR 66.7% for patients with elevated LDH above 2 times upper limit of norm). 22 patients proceeded to allogeneic SCT and 5 to CAR T-cell therapy. Treatment related mortality of ASCT was 5.5% (2 patients, both due to infections). Two-year overall survival of all patients was 15.8%, primarily due to a high non-relapse mortality (45.5%) of allogeneic SCT patients treated with myeloablative conditioning chemotherapy.. Single agent HD melphalan produces high remission rates in patients with chemoresistant, uncontrolled aggressive B-cell lymphoma and provides a window of opportunity for consolidation therapy.. Patient with refractory/relapsed aggressive B-cell lymphoma after salvage therapy are an unmet medical need because of their very poor prognosis. In our retrospective analysis of 36 patients we showed that single agent high-dose melphalan can achieve high response rates (ORR 66.7%) even in uncontrolled disease enabling consolidation therapy e.g. with allogeneic stem cell transplantation or CAR T-cell therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Consolidation Chemotherapy; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Lymphoma, B-Cell; Melphalan; Neoplasm Recurrence, Local; Retrospective Studies; Salvage Therapy; Stem Cell Transplantation; Transplantation, Autologous

To review the clinical pharmacology and clinical trials that have used intravenous (IV) high-dose melphalan (HDM).. We reviewed the mechanism of action, clinical pharmacology, and clinical studies of HDM with and without autologous bone marrow support (ABMT) or peripheral-blood progenitor cells (PBPCs) in the following disease areas: myeloma, ovarian cancer, malignant lymphoma, breast cancer, neuroblastoma, Ewing's sarcoma, and acute leukemia.. HDM has a distribution half-life (t1/2 alpha) of 5 to 15 minutes and an elimination half-life (t1/2 beta) of 17 to 75 minutes at doses of 140 to 180 mg/m2, with significant intrapatient variability. At these doses, a wide range of areas under the concentration/time curve (AUC) have been reported, ie, 146 to 1,515 mg/min/mL. HDM has significant clinical activity in patients with multiple myeloma in relapse or when used as consolidative therapy in relapsed ovarian cancer, relapsed Hodgkin's disease, breast cancer, and relapsed neuroblastoma. Additional studies are required to determine the activity of HDM in Ewing's sarcoma or acute leukemia. Toxicities of HDM include myelosuppression, moderate nausea and vomiting, moderate to severe mucositis and diarrhea, and, infrequently, hepatic venoocclusive disease.. HDM has become an established and effective salvage regimen for children with relapsed neuroblastoma, as well as an effective consolidative treatment for children with high-risk disease (stage IV). HDM is emerging as an active and effective mode of treatment in patients with stage II and III myeloma. The favorable toxicity profile of HDM and the availability of PBPCs allows for repetitive therapy.

Topics: Acute Disease; Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Forecasting; Half-Life; Humans; Infusions, Intravenous; Leukemia; Lymphoma; Melphalan; Multiple Myeloma; Neuroblastoma; Ovarian Neoplasms; Sarcoma, Ewing

MOPP chemotherapy was the significant breakthrough that improved the outlook for patients with advanced Hodgkin's disease. Results with alternating potentially non-cross-resistant drug combinations, including MOPP/ABVD, CAD/MOPP/ABV, and MOPP/ABV, are similar and seem to be slightly superior to those with MOPP alone. Limited adjuvant RT does not seem to add appreciably to the morbidity of chemotherapy, although its role in improving on results with chemotherapy alone has not been well studied in prospective, randomized, controlled clinical trials. There are two major challenges for the future. The first is to improve the outcome for advanced Hodgkin's disease patients, perhaps with more intensive chemotherapy and RT with use of cytokines such as the colony-stimulating factors or interleukin-1 or with rescue employing autologous bone marrow transplantation or both. The second challenge is to reduce the morbidity but not the effectiveness of treatment for advanced Hodgkin's disease patients without adverse prognostic factors.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Clinical Trials as Topic; Combined Modality Therapy; Dacarbazine; Doxorubicin; Female; Hodgkin Disease; Humans; Leukemia; Lomustine; Lymphoma; Male; Mechlorethamine; Melphalan; Middle Aged; Neoplasms, Multiple Primary; Prednisone; Procarbazine; Remission Induction; Vinblastine; Vincristine; Vindesine

Topics: Adrenal Cortex Hormones; Animals; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Breast Neoplasms; Cyclophosphamide; Dacarbazine; Doxorubicin; Drug Therapy, Combination; Dyspnea; Fluorouracil; Hodgkin Disease; Humans; Hypercalcemia; Leukemia; Leukemia, Lymphoid; Lymphoma; Mechlorethamine; Melphalan; Methotrexate; Multiple Myeloma; Palliative Care; Prednisone; Procarbazine; Receptors, Glucocorticoid; Vinblastine; Vincristine; Vomiting

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Drug Evaluation; Drug Resistance; Etoposide; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Melphalan; Neoplasm Recurrence, Local; Neoplasms; Thioguanine; Transplantation, Autologous

There has been a striking improvement in the overall numbers of children and adolescents who become disease-free and remain disease-free as a result of intensive therapy as defined today, for the following cancers: acute nonlymphocytic leukemia (ANLL), non-Hodgkin's lymphoma (NHL), poor risk acute lymphocytic leukemia (ALL), osteosarcoma, and Ewing's sarcoma. The therapy for each of these tumors, with the exception of osteosarcoma, consisted of combination chemotherapy with or without radiotherapy and was started as soon after diagnosis as possible. Aggressive therapy of osteosarcoma has consisted of surgical removal of lung metastases and chemotherapy. Intensive chemotherapy recently has included the use of high doses of certain drugs such as cytosine arabinoside (Ara-C), methotrexate, VP-16-213 and melphalan in the treatment of patients with tumors that are currently difficult to treat.

Topics: Acute Disease; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Etoposide; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Melphalan; Methotrexate; Neoplasms; Osteosarcoma; Risk; Sarcoma, Ewing

Prognostic factors in patients with Hodgkin's disease and the non-Hodgkin lymphomas are reviewed and discussed since they form the basis of the therapeutic approach to these conditions. Hodgkin's disease is treated according to stage, histology and other prognostic criteria and the appropriate management is presented in tabular form. In the non-Hodgkin lymphomas, prospective studies using the Kiel classification indicated that these lymphomas could be subdivided into types of low-, intermediate- and high-grade malignancy, each requiring different treatment modalities. An expectative approach is often, but not always, recommended in lymphomas of low malignancy. The natural history of lymphomas of high-grade malignancy is unfavourable and, usually, prolonged survival is observed only in those cases in which a complete remission is achieved. Our therapeutic approach to the various forms of these lymphomas is based on the stage of the disease and the respective schedules are summarized for lymphomas of low- and high-grade malignancy. Finally, the chances of cure in Hodgkin's disease and in the non-Hodgkin lymphomas are discussed and recent developments are mentioned.

Topics: Adolescent; Adult; Age Factors; Aged; Antineoplastic Agents; Child; Child, Preschool; Drug Therapy, Combination; Hodgkin Disease; Humans; Lymphoma; Melphalan; Middle Aged; Neoplasm Staging; Procarbazine; Prognosis; Radiotherapy Dosage; Vinblastine

Topics: Adult; Aged; Arsenic; Benzene; Bone Marrow; Breast Neoplasms; Female; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Mycosis Fungoides; Ovarian Neoplasms; Paraproteinemias; Waldenstrom Macroglobulinemia

Although cytotoxic immunosuppressive agents play an unquestionably useful role in treating many neoplastic and non-neoplastic disorders, there is accumulating evidence that the toxicity associated with their use is considerable. The therapeutic successes obtained with antitumor agents have led to increases in the life span of cancer patients, but have also provided the opportunity for this toxicity to become manifest. A search of the available literature was carried out, with emphasis on cases in which a malignancy developed in patients following chemotherapy for either neoplastic or non-neoplastic (e.g., renal transplantation, psoriasis) conditions; particular focus was given to the incidence of acute myelogenous leukemia in various groups of Hodgkin's disease and multiple myeloma patients. That patients with nonmalignant conditions treated with cytotoxic immunosuppressive agents are also at increased risk of developing a malignancy raises the possibility that these agents may have oncogenic potential. Therefore, one may be faced with the paradox that the patients benefiting most from chemotherapy may be at highest risk of suffering its consequences.

Topics: Alkylating Agents; Animals; Antineoplastic Agents; Azathioprine; Burkitt Lymphoma; Choriocarcinoma; Cyclophosphamide; Dactinomycin; Female; Hodgkin Disease; Humans; Immunosuppressive Agents; Kidney Neoplasms; Leukemia, Myeloid, Acute; Lymphoma; Mechlorethamine; Melphalan; Mercaptopurine; Methotrexate; Mice; Multiple Myeloma; Neoplasms; Prednisone; Pregnancy; Procarbazine; Time Factors; Vincristine

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Anemia; Anemia, Hemolytic, Autoimmune; Blood Urea Nitrogen; Glucocorticoids; Humans; Hypercalcemia; Immunoglobulins; Leukemia; Lymphoma; Melphalan; Multiple Myeloma; Myeloma Proteins; Prednisone; Waldenstrom Macroglobulinemia

Topics: Adenocarcinoma; Alkylating Agents; Antineoplastic Agents; Breast Neoplasms; Carcinoma; Carcinoma, Bronchogenic; Carmustine; Cyclohexanes; Cyclophosphamide; Cytarabine; Drug Therapy, Combination; Hodgkin Disease; Humans; Hydroxyurea; Leukemia, Lymphoid; Leukemia, Myeloid; Lymphoma; Melanoma; Melphalan; Multiple Myeloma; Nitrosourea Compounds; Prednisone; Vincristine

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Bone Marrow; Bone Marrow Cells; Cell Division; Cyclophosphamide; Cytarabine; Female; Fluorouracil; Humans; Leukemia L1210; Leukemia, Lymphoid; Lymphoma; Melphalan; Mercaptopurine; Methotrexate; Mice; Multiple Myeloma; Neoplasms; Nitrogen Mustard Compounds; Prednisone; Pregnancy; Time Factors; Trophoblastic Neoplasms; Vinblastine

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard management for relapsed or high-risk non-Hodgkin's lymphoma (NHL). We reported the busulfan, melphalan, and etoposide (BuME) conditioning regimen was effective in patients with relapsed or high-risk NHL. Moreover, the busulfan, cyclophosphamide, and etoposide (BuCE) conditioning regimen has been used widely in ASCT for NHL. Therefore, based on these encouraging results, this randomized phase II multicenter trial compared the outcomes of BuME and BuCE as conditioning therapies for ASCT in patients with NHL.. Patients were randomly assigned to receive either BuME (n=36) or BuCE (n=39). The BuME regimen was comprised of busulfan (3.2 mg/kg/day, intravenously) administered on days -7, -6, and -5, etoposide (400 mg/m2 intravenously) on days -5 and -4, and melphalan (50 mg/m2/day intravenously) on days -3 and -2. The BuCE regimen was comprised of busulfan (3.2 mg/kg/day intravenously) on days -7, -6, and -5, etoposide (400 mg/m2/day intravenously) on days -5 and -4, and cyclophosphamide (50 mg/kg/day intravenously) on days -3 and -2. The primary endpoint was 2-year progression-free survival (PFS).. Seventy-five patients were enrolled. Eleven patients (30.5%) in the BuME group and 13 patients (33.3%) in the BuCE group had disease progression or died. The 2-year PFS rate was 65.4% in the BuME group and 60.6% in the BuCE group (p=0.746). There were no non-relapse mortalities within 100 days after transplantation.. There were no significant differences in PFS between the two groups. Therefore, busulfan-based conditioning regimens, BuME and BuCE, may be important treatment substitutes for the BCNU-containing regimens.

Topics: Antineoplastic Combined Chemotherapy Protocols; Behavior Therapy; Busulfan; Cyclophosphamide; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Lymphoma, Non-Hodgkin; Melphalan; Transplantation, Autologous

The aim of this study was to prospectively compare the MIFAP protocol, which had been shown to be effective in patients with relapsed and refractory Hodgkin's lymphoma (HL) or aggressive non-Hodgkin's lymphoma (NHL), to an established regimen like Dexa-BEAM.. Seventy-three adult patients with HL (N = 25) or aggressive NHL (N = 48) suffering from relapse or refractory disease were randomly allocated to receive two cycles of Dexa-BEAM (dexamethasone, carmustine, etoposide, cytarabine, melphalan; N = 37) or MIFAP (mitoxantrone, fludarabine, cytarabine, cisplatin; N = 36) prior to a consolidating high-dose therapy and hematopoietic cell transplantation (HCT). Primary endpoint was the overall response rate (ORR) [complete response (CR) and partial response (PR)] after two courses of salvage chemotherapy.. The ORR was 51% (CR 38%) and 53% (CR 36%) in the Dexa-BEAM arm and in the MIFAP arm (both not significant), respectively. There was a significantly higher grade 3-4 toxicity after MIFAP compared to Dexa-BEAM. Thirty-five patients were consolidated by autologous (N = 29), allogeneic (N = 1) or sequential autologous/allogeneic (N = 5) HCT. No significant differences were found in progression-free survival (PFS) and overall survival (OS) between the Dexa-BEAM and the MIFAP arms.. Compared to Dexa-BEAM, MIFAP is associated with a higher toxicity and does not improve the outcome of patients with recurrent HL or aggressive NHL. For those patients, innovative treatment concepts like recently developed immunotherapies are necessary.. EudraCT number 2021-001937-38.. 7 April 2021, retrospectively registered.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Dexamethasone; Etoposide; Follow-Up Studies; Hodgkin Disease; Humans; Lymphoma; Lymphoma, Non-Hodgkin; Melphalan; Neoplasm Recurrence, Local; Prospective Studies; Salvage Therapy

Most studies addressing the impact of hematopoietic stem cell transplantation (SCT) on pulmonary function test (PFT), and the various factors affecting that impact have been performed on the allogenic type. Few have addressed PFT changes in autologous SCT. This study describes PFT changes seen in autologous SCT recipients and addresses the various factors impacting these changes.. We reviewed the medical records of 223 consecutive adult autologous SCT recipients. We collected pre-transplant and post-transplant data, as well as PFT data and long-term mortality.. A total of 123 patients with lymphoma receiving the BEAM (carmustine, etoposide, aracytin, and melphalan) conditioning regimen had a significant 5% drop in mean forced vital capacity and total lung capacity but no significant change in forced expiratory volume in one second/forced vital capacity ratio nor in diffusion lung capacity of carbon monoxide adjusted to volume. Fifteen percent of the patients with lymphoma had a clinically significant drop of 15% in their lung volume parameters. The patients with multiple myeloma receiving the melphalan conditioning regimen had no significant change in any of the PFT parameters. Smoking, baseline PFT parameters, and radiation did not affect lung function or mortality.. Autologous SCT impact on lung function depends on the disease and conditioning regimen. It leads to a drop in lung volumes but no obstruction or decrease in diffusion in patients with lymphoma receiving the BEAM regimen. Autologous SCT did not affect lung functions in patients with multiple myeloma, and these patients may not need screening PFTs.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Autografts; Carmustine; Cytarabine; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Lung; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Podophyllotoxin; Respiratory Function Tests; Retrospective Studies; Survival Rate; Transplantation Conditioning

The current standard of care for patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) is high-dose conditioning followed by autologous stem cell transplantation (ASCT). For some patients (ie, those with highest-risk disease, insufficient stem cell numbers after mobilization, or bone marrow involvement) allogeneic hematopoietic cell transplantation (alloHCT) offers the potential for cure. However, the majority of patients undergoing alloHCT receive reduced-intensity conditioning as a preparative regimen, and studies assessing outcomes of patients after alloHCT with myeloablative conditioning are limited. In this retrospective study, we reviewed outcomes of 22 patients with recurrent and refractory NHL who underwent alloHCT with myeloablative BEAM conditioning and received tacrolimus/sirolimus as graft-versus-host disease (GVHD) prophylaxis at City of Hope between 2005 and 2018. With a median follow-up of 2.6 years (range, 1.0 to 11.2 years), the probabilities of 2-year overall survival and event-free survival were 58.3% (95% confidence interval [CI], 35.0% to 75.8%) and 45.5% (95% CI, 24.4% to 64.3%), respectively. The cumulative incidence of grade II to IV acute GVHD was 45.5% (95% CI, 23.8% to 64.9%), with only 1 patient developing grade IV acute GVHD. However, chronic GVHD was seen in 55% of the patients (n = 12). Of the 22 eligible patients, 2 had undergone previous ASCT and 2 had undergone previous alloHCT. Both patients with previous ASCT developed severe regimen-related toxicity. Patients who underwent alloHCT with chemorefractory disease had lower survival rates, with 1-year OS and EFS of 44.4% and 33.0%, respectively. In conclusion, alloHCT with a BEAM preparative regimen and tacrolimus/sirolimus-based GVHD should be considered as an alternative option for patients with highest-risk lymphoma whose outcomes are expectedly poor after ASCT.

Topics: Adolescent; Adult; Allografts; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Disease-Free Survival; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Lymphoma; Male; Melphalan; Middle Aged; Podophyllotoxin; Sirolimus; Survival Rate; Tacrolimus; Transplantation Conditioning

Topics: Adult; Aged; Allografts; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Obesity; Podophyllotoxin; Prospective Studies; Transplantation Conditioning

Busulfan, cyclophosphamide, and etoposide (BuCyE) is a commonly used conditioning regimen for autologous stem cell transplantation (ASCT). This multicenter, phase II study examined the safety and efficacy of BuCyE with individually adjusted busulfan based on preconditioning pharmacokinetics. The study initially enrolled Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients ages 18 to 80 years but was amended due to high early treatment-related mortality (TRM) in patients > 65 years. BuCyE outcomes were compared with contemporaneous recipients of carmustine, etoposide, cytarabine, and melphalan (BEAM) from the Center for International Blood and Marrow Transplant Research. Two hundred seven subjects with HL (n = 66) or NHL (n = 141) were enrolled from 32 centers in North America, and 203 underwent ASCT. Day 100 TRM for all subjects (n = 203), patients > 65 years (n = 17), and patients ≤ 65 years (n = 186) were 4.5%, 23.5%, and 2.7%, respectively. The estimated rates of 2-year progression-free survival (PFS) were 33% for HL and 58%, 77%, and 43% for diffuse large B cell lymphoma (DLBCL; n = 63), mantle cell lymphoma (MCL; n = 29), and follicular lymphoma (FL; n = 23), respectively. The estimated rates of 2-year overall survival (OS) were 76% for HL and 65%, 89%, and 89% for DLBCL, MCL, and FL, respectively. In the matched analysis rates of 2-year TRM were 3.3% for BuCyE and 3.9% for BEAM, and there were no differences in outcomes for NHL. Patients with HL had lower rates of 2-year PFS with BuCyE, 33% (95% CI, 21% to 46%), than with BEAM, 59% (95% CI, 52% to 66%), with no differences in TRM or OS. BuCyE provided adequate disease control and safety in B cell NHL patients ≤ 65 years but produced worse PFS in HL patients when compared with BEAM.

Topics: Adult; Aged; Busulfan; Carmustine; Cyclophosphamide; Cytarabine; Drug Combinations; Etoposide; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Lymphoma; Lymphoma, Non-Hodgkin; Melphalan; Middle Aged; North America; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous

Topics: Adolescent; Adult; Aged; Carmustine; Cytarabine; Etoposide; Female; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Myeloablative Agonists; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Young Adult

Conditioning therapy with fludarabine and melphalan 140 mg/m(2) has been widely used before allogeneic hematopoietic cell transplantation (HCT) for lymphoma. A lower dose of melphalan might result in lower mortality and morbidity without compromising engraftment.. In our phase II trial, we investigated a conditioning regimen of fludarabine (30 mg/m(2)/day for 5 days on days -6 to -2) and melphalan (100 mg/m(2) on day -2). Antithymocyte globulin was added to fludarabine and melphalan for unrelated or mismatched familial donor HCT. The present study included 26 patients with lymphoma (B-cell in 10, T-cell in 11, and natural killer/T-cell lymphoma in 2).. An objective tumor response after HCT was observed in 18 patients (75.0%; complete in 14 and partial in 4). Acute and chronic graft-versus-host disease (GVHD) occurred in 23.1% and 55.0% of the assessable patients, respectively. The 5-year overall survival, nonrelapse mortality, progression-free survival, and event-free survival rate was 40.4%, 21.6%, 39.2%, and 30.8%, respectively. Donor lymphocyte infusions were given to 3 patients who had developed a relapse or progression after HCT, and 2 of whom had a showed partial response. Patients with severe chronic GVHD had greater overall survival than those with no, mild, or moderate chronic GVHD.. Conditioning therapy with a lower dose of melphalan, combined with fludarabine, appears to be promising in allogeneic HCT for lymphoma. The Clinicaltrials.gov identification number for the present study is NCT00772811.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Prognosis; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine; Young Adult

In this retrospective study, a chemotherapy protocol using dexamethasone, melphalan, actinomycin D, and cytosine arabinoside (DMAC) was evaluated for efficacy and adverse event profile as a first line rescue protocol in 86 client-owned dogs previously treated with a CHOP-based protocol. Forty-three dogs (43%) achieved remission (16% complete remission, 27% partial remission), and 57% were non-responders. The median overall progression-free survival (PFS) was 24 days. Adverse events included thrombocytopenia in 41% of dogs, neutropenia in 17% of dogs, and gastrointestinal toxicity in 13% of dogs. Overall, 16% (13/79) dogs experienced grade III to IV thrombocytopenia, 8% (6/74) dogs grade III to IV neutropenia and 1% (1/79) dogs grade III to IV gastrointestinal toxicity. The efficacy of the DMAC protocol is similar to that of other rescue protocols in dogs with relapsed lymphoma but is associated with shorter PFS. The main toxicity is thrombocytopenia, which may limit treatment.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Dactinomycin; Dexamethasone; Dog Diseases; Dogs; Female; Lymphoma; Male; Melphalan; Recurrence; Retrospective Studies

Allogeneic stem cell transplant (SCT) after high-dose conditioning with BEAM/fludarabine/total body irradiation (TBI) in patients with relapsed or refractory lymphoma has shown promising results in a pilot study. In this trial, we treated 50 consecutive patients with refractory or relapsed lymphoma or chronic lymphocytic leukemia (CLL). The patients included were considered to have poor-prognosis disease (eg, one-third was chemo-refractory at transplantation and more than one-half had failed previous autologous or allogeneic SCT). All patients engrafted and achieved full donor chimerism. Grade II-IV acute graft-versus-host disease (aGVHD) occurred in 64% of patients (95% confidence interval [CI], 52% to 79%), and chronic GVHD (cGVHD) in 51% (95% CI, 36% to 66%). At 3 years, overall survival was 61% (95% CI, 46% to 75%). Progression-free survival was 55% (95% CI, 40% to 70%), with 30% (95% CI, 19% to 47%) transplantation-related mortality and a relapse incidence of 15% (95% CI, 7% to 32%). Disease classification and stage as well as remission status at transplantation and type of previous treatment (including previous SCT) had no significant impact on transplantation outcome. In conclusion, allogeneic SCT after BEAM/fludarabine/TBI provides excellent tumor control with complete and durable remissions in patients with poor-prognosis lymphoma and CLL. High rates of GVHD and GVHD-related mortality associated with this regimen are a major concern and warrant modification of the regimen in the future.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Disease-Free Survival; Female; Graft vs Host Disease; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Melphalan; Middle Aged; Myeloablative Agonists; Podophyllotoxin; Recurrence; Stem Cell Transplantation; Survival Rate; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Whole-Body Irradiation

Plerixafor in combination with granulocyte-colony-stimulating factor (G-CSF) has been shown to enhance stem cell mobilization in patients with multiple myeloma, non-Hodgkin's lymphoma, and Hodgkin's disease who demonstrated with previous mobilization failure. In this named patient program we report the Austrian experience in insufficiently mobilizing patients.. Twenty-seven patients from eight Austrian centers with a median (range) age of 58 (19-70) years (18 female, nine male) were included in the study. Plerixafor was limited to patients with previous stem cell mobilization failure and was given in the evening of Day 4 of G-CSF application.. A median increase of circulating CD34+ cells within 10 to 11 hours from administration of plerixafor by a factor of 4.7 over baseline was noted. Overall, 20 (74%) patients reached more than 10 × 10(6) CD34+ cells/L in the peripheral blood, resulting in 17 (63%) patients collecting at least 2 × 10(6) CD34+ cells/kg body weight (b.w.; median, 2.6 × 10(6) CD34+ cells/kg b.w.; range, 0.08 × 10(6) -8.07 × 10(6) ). Adverse events of plerixafor were mild to moderate and consisted of gastrointestinal side effects and local reactions at the injection site. Thirteen (48%) patients underwent autologous transplantation receiving a median of 2.93 × 10(6) CD34+ cells/kg (range, 1.46 × 10(6) -5.6 × 10(6) ) and showed a trilinear engraftment with a median neutrophil recovery on Day 12 and a platelet recovery on Day 14.. Our study confirms previous investigations showing that plerixafor in combination with G-CSF is an effective and well-tolerated mobilization regimen with the potential of successful stem cell collection in patients with previous mobilization failure.

Topics: Adolescent; Adult; Aged; Antigens, CD34; Austria; Benzylamines; Combined Modality Therapy; Cyclams; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Heterocyclic Compounds; Humans; Immunoglobulin G; Leukapheresis; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Receptors, CXCR4; Transplantation, Autologous; Young Adult

With the eventual goal of reducing relapse and thus improving overall survival in selected lymphoma patients, a Phase I study was performed using the cytoprotectant amifostine to permit safe dose-augmentation of melphalan in the carmustine (BCNU), etoposide, cytarabine (arabinosylcytosine), and melphalan (BEAM) regimen before autologous hematopoietic stem cell transplantation. Between 30 July 2003 and 25 November 2008, a total of 32 lymphoma patients were entered, of which 28 were evaluable. We found the melphalan dose in BEAM could be safely escalated to at least 260 mg/m², a substantial increase from the usual dose of 140 mg/m² in BEAM while the trial was terminated early due to poor accrual, no maximal tolerated dose or dose-limiting toxicity was found. A Phase II trial is planned.

Topics: Adult; Aged; Amifostine; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Carmustine; Combined Modality Therapy; Cytarabine; Cytoprotection; Dose-Response Relationship, Drug; Etoposide; Female; Humans; Lymphoma; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Mucositis; Pancytopenia; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Transplantation Conditioning; Transplantation, Autologous; Young Adult

The individual risk of infection and requirements for medical treatment after high-dose chemotherapy have been unpredictable. In this prospective, multicenter, open-label study we investigated the potential of granulocyte colony-stimulating factor (G-CSF) responsiveness as a predictor. A total of 168 patients with multiple myeloma or lymphoma received a single dose of subcutaneous G-CSF (lenograstim, 263 μg) after high-dose chemotherapy. Highly variable leukocyte peaks were measured and grouped as low (quartile 1; leukocytes 100-10 100/μL), medium (quartile 2; leukocytes > 10 100-18 300/μL), and high (quartiles 3/4; leukocytes > 18 300-44 800/μL). G-CSF responsiveness (low vs medium vs high) was inversely correlated with febrile neutropenia (77% vs 60% vs 48%; P = .0037); the rate of infection, including fever of unknown origin (91% vs 67% vs 54%; P < .0001); days with intravenous antibiotics (9 vs 6 vs 5; P < .0001); and antifungal therapy (P = .042). In multivariate analysis, G-CSF responsiveness remained the only factor significantly associated with infection (P = .016). In addition, G-CSF responsiveness was inversely correlated with grade 3/4 oral mucositis (67% vs 33% vs 23%; P < .0001). G-CSF responsiveness appears as a signature of the myeloid marrow reserve predicting defense against neutropenic infection after intensive chemotherapy. This study is registered at http://www.clinicaltrials.gov as NCT01085058.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Female; Granulocyte Colony-Stimulating Factor; Humans; Infections; Lenograstim; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Multivariate Analysis; Neutropenia; Peripheral Blood Stem Cell Transplantation; Predictive Value of Tests; Prognosis; Prospective Studies; Recombinant Proteins; Risk Factors; Young Adult

BEAM is a widely used conditioning regimen for relapsed/refractory lymphoma patients undergoing auto-SCT. We conducted a multicenter study with an alternative regimen (fotemustine plus etoposide, cytarabine and melphalan (FEAM)) in which BCNU was substituted by the chloroethylnitrosourea fotemustine (FTM). Eighty-four patients with relapsed/refractory Hodgkin's (n=20) and non-Hodgkin's lymphoma (n=64) were conditioned with a FEAM regimen (FTM 150 mg/m(2) on days -7, -6, etoposide 200 mg/m(2) and cytarabine 400 mg/m(2) on days -5, -4, -3, -2 and melphalan 140 mg/m(2) on day -1). Patients were evaluated for toxicity and engraftment parameters. Median times to neutrophil (>500 x 10(9)/l) and plt (>20 000 x 10(9)/l) engraftment were 11 and 13 days, respectively. Grade 3 mucositis occurred in 19 patients (23%), while G3 nausea/vomiting and G3 diarrhea were observed in 13 (15%) and 6 (7%) patients, respectively. No severe hepatic, renal or pulmonary toxicity was detected. Seven patients (7%) experienced G4 mucositis, while no other G4 toxicities or unexpected adverse events of any grade were recorded. Transplant-related mortality was 2.4%. We conclude that a FEAM regimen is feasible and safe. Although toxicity and engraftment times compared favorably with BEAM, longer follow-up is needed to evaluate fully its efficacy and long-term safety.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Etoposide; Feasibility Studies; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Kinetics; Lymphoma; Male; Melphalan; Middle Aged; Nitrosourea Compounds; Organophosphorus Compounds; Survival Rate; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Young Adult

ATL-104 is a potent mitogen for epithelial cells of the gastrointestinal tract. In animal models, ATL-104 aids regeneration of the gastrointestinal tract after treatment with chemotherapeutic agents. The effect of ATL-104 on mucositis in patients requiring high-dose melphalan or BEAM before peripheral blood SCT (PBSCT) was investigated in a randomized, placebo-controlled, double-blind, two-part study. Patients were randomized to ATL-104 (50, 100 or 150 mg) or placebo once daily for 3 days before chemotherapy and 3 days after PBSCT. Part one of the study was a dose-escalation design; part two was a parallel group design using all three ATL-104 doses. Patients were followed up for 28 days post-treatment. Severity of signs and symptoms were assessed and used to calculate scores for standard toxicity rating scales (WHO, Western Consortium for Cancer Nursing Research (WCCNR)). Sixty-three patients were treated. Treatment with ATL-104 substantially reduced the median duration of severe oral mucositis (WHO grade 3 or 4) compared with placebo (median duration: ATL-104 groups 2 or 3 days, placebo 10.5 days). The effect of ATL-104 on the incidence of severe oral mucositis was inconclusive. Similar results were obtained using the WCCNR Scale. Adverse events (AEs) were predominantly mild or moderate in intensity. Gastrointestinal AE were most common.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Double-Blind Method; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Mouthwashes; Phytohemagglutinins; Pilot Projects; Placebos; Recombinant Proteins; Stomatitis

High-dose chemotherapy (HD-CT) with autologous stem cell transplantation is considered to be the treatment of choice for relapsed high-grade non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL) patients, but the optimal treatment has not yet been defined. We evaluated a salvage treatment regimen consisting of conventional cycles with ifosfamide, etoposide, cytarabine, and dexamethasone (IVAD) followed by two cycles of HD-CT consisting of cyclophosphamide, melphalan, and etoposide (CMV) with autologous stem cell support in patients with relapsed or refractory NHL (n = 59) and HL (n = 16). Response to IVAD was complete remission (CR) in 16 patients (21%), partial remission (PR) in 39 patients (52%), stable disease (SD) in 18 patients (24%), and progressive disease (PD) in two patients (2.7%). Of 70 patients treated with HD-CT, 41 patients (59%) showed a CR, 20 patients a PR (29%), eight patients a SD (11%), and one patient a PD (1.4%). The 5-yr overall survival for the entire group of patients was 29%, and for patients with NHL and HL 25%, and 38%, respectively. The respective event-free survival probabilities at 5 yr were 22%, 16%, and 31%. Seven treatment-related deaths due to septicemia (three), cardiac arrhythmia (one), pneumonia (one), pneumonitis (one), and toxic epidermal necrolysis (one) were observed. In multivariate analysis, an International Prognostic Index of > or = 2 and resistant disease to first-line chemotherapy were poor independent prognostic factors for the subgroup of patients with NHL. In conclusion, these results indicate that IVAD/CMV is feasible as a salvage therapy for lymphoma patients. This treatment is currently evaluated with the addition of rituximab.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Dexamethasone; Drug Resistance, Neoplasm; Etoposide; Female; Follow-Up Studies; Gastrointestinal Diseases; Hodgkin Disease; Humans; Ifosfamide; Kaplan-Meier Estimate; Lymphoma; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Neutropenia; Peripheral Blood Stem Cell Transplantation; Recurrence; Remission Induction; Salvage Therapy; Sepsis; Survival Rate; Transplantation, Autologous; Treatment Outcome

Patients with refractory/relapsing lymphoma are rarely cured by chemotherapy. High-dose chemotherapy (HDC) for tumor debulking followed by reduced-intensity conditioning (RIC) hematopoietic stem-cell transplantation (HSCT) has been advocated as a concept. We previously treated 10 patients (group A) with BEAM chemotherapy followed by delayed RIC HSCT at day 28. We now report on the subsequent 11 patients receiving BEAM followed immediately by fludarabine/total body irradiation and allogeneic HSCT (group B), and compare the outcome to group A patients. Non-hematological toxicity before engraftment was comparable, only gut toxicity was higher in group B. Days in aplasia, days on antibiotics and length of hospital stay were significantly longer in group A. Cumulative incidence of acute (GvHD) >or=grade II and incidence of chronic GvHD were lower in group B. At last follow-up, seven patients in group A were alive, with six of them in complete remission. In group B, nine patients were alive, seven of them in complete remission. No significant difference in estimated 3-year overall survival was seen. These data challenge the initial concept of debulking first and delaying allogeneic RIC HSCT. Allogeneic HSCT with standard BEAM conditioning is a valid alternative for patients with resistant/relapsed lymphoma, which might be considered earlier in the disease course.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Etoposide; Female; Graft vs Host Disease; Graft vs Tumor Effect; Hematopoietic Stem Cell Transplantation; Humans; Kaplan-Meier Estimate; Lymphoma; Male; Melphalan; Remission Induction; Transplantation Conditioning; Transplantation, Homologous

A single injection of pegfilgrastim has been shown to be equivalent to daily filgrastim in enhancing neutrophil recovery after chemotherapy, whereas the experiences with pegfilgrastim in mobilization of peripheral blood progenitor cells (PBPCs) are limited.. Forty unselected patients with lymphoma or multiple myeloma were treated with different chemotherapy regimens followed by 6 mg of pegfilgrastim for mobilization of autologous PBPCs. Patients with an inadequate mobilization (blood CD34+ cells

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Dexamethasone; Etoposide; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Polyethylene Glycols; Recombinant Proteins; Remission Induction; Transplantation, Autologous; Treatment Outcome

Although high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has become the standard approach for patients with relapsed/refractory Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL), more than 50% of patients will experience relapse following ASCT. High-dose sequential chemotherapy (HDSC) can intensify the conventional salvage treatment and improve the outcome of ASCT by maximal debulking of the tumor load with the use of non-cross resistant drugs, each at their maximal tolerated doses. We conducted a phase II study in 40 patients with relapsed/refractory HD (n = 18) and NHL (n = 22) using HDSC followed by ASCT. Only patients sensitive to salvage chemotherapy were eligible for the protocol, consisting of three phases. Phase I consisted of cyclophosphamide (4.5 g/m2) followed by G-CSF and peripheral blood stem cell (PBSC) collection. Phase II consisted of etoposide (2 g/m2). The transplant phase consisted of mitoxantrone (60 mg/m2) and melphalan (180 mg/m2) followed by PBSC infusion. Eleven out of nineteen patients with B-cell lymphoma received rituximab. Prior to HDSC, 45% of the patients were in complete remission (CR) and 55% were in partial remission (PR). After completion of all phases of the protocol, 35 out of 39 evaluable patients achieved CR (90%) and this was durable in 30 (75%) patients with a projected progression-free survival (PFS) rate at 4 years of 71.7%. Treatment-related mortality rate at day +100 was 2.5% (n = 1). At a median follow-up of 32 months (range, 3 - 61), nine patients relapsed/progressed and eleven patients died. The estimated 4-year PFS and overall survival (OS) were 72.2% and 47.6% in HD patients and 70.3% and 69.4% in NHL patients, respectively. Factors predicting OS were response to conventional salvage therapy and stage prior to salvage therapy. When compared to patients achieving PR, patients who attained CR prior to HDSC had a significantly higher probability of 4-year OS (78.4% vs 31.3%, p = 0.02). Three prognostic subgroups were defined according to the score determined by stage prior to initiation of salvage chemotherapy, remission duration prior to salvage (refractory/early relapse vs. late relapse) and response to salvage. Prognostic score was found to predict OS, PFS and event free survival (EFS). In conclusion, HDSC followed by ASCT is an effective salvage therapy with acceptable toxicity, allowing further consolidation of response attained by conventional salvage therapy.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Etoposide; Female; Humans; Lymphoma; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Mitoxantrone; Peripheral Blood Stem Cell Transplantation; Prognosis; Remission Induction; Salvage Therapy; Survival Analysis; Transplantation, Autologous

In an effort to improve the outcome of poor-risk lymphoma patients, we evaluated a novel regimen of tandem high-dose chemotherapy (THDC) with autologous stem cell transplantation. A total of 41 patients (median age 40 years, range 15-68 years) with poor-risk non-Hodgkin's lymphoma and Hodgkin's disease were enrolled. THDC consisted of melphalan (180 mg/m2) and escalating dose mitoxantrone (30-50 mg/m2) (MMt) for the first conditioning regimen, and thiotepa (500 mg/m2), carboplatin (800 mg/m2), and escalating dose etoposide phosphate (400-850 mg/m2), (ETCb) as the second regimen. In all, 31 patients (76%) completed both transplants, with a median time between transplants of 55 days (range 26-120). The maximum tolerated dose was determined as 40 mg/m2 for mitoxantrone and 550 mg/m2 for etoposide phosphate. The overall toxic death rate was 12%. Following high-dose chemotherapy, 10 of 24 evaluable patients (42%) were in CR. The two-year overall survival and event-free survival is 67% (95% CI, 52-81%) and 45%, (95% CI, 29-61%) for the 41 patients enrolled; and 69% (95% CI, 525-586%) and 48% (95% CI, 30-67%) for the 31 patients completing both transplants. This THDC regimen is feasible but with notable toxicity in heavily pretreated patients; its role in the current treatment of high-risk lymphoma remains to be determined.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Mitoxantrone; Pilot Projects; Risk; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous

The treatment of primary central nervous system lymphoma (PCNSL) has been considerably improved over recent years. In this article, we report six cases of PCNSL treated by first-line induction chemotherapy followed by intensive chemotherapy and autologous stem cell transplantation (ASCT). Six immunocompetent patients presenting with a PCNSL, confirmed by thoraco-abdomino-pelvic computer tomography scan and bone marrow biopsy, were treated with induction chemotherapy followed by BEAM intensive chemotherapy and ASCT and radiotherapy. At the end of the treatment, all the patients were in complete remission. After a median follow-up of 41.5 months (17-70 months), four patients were alive without signs of relapse (median survival: 35.5 months). Two patients died from relapse at 19 and 23 months. The neurotoxicity was low with epilepsy in one patient and persistent left side dysesthesia in another one. These results are fairly encouraging. Other studies with greater numbers of patients and longer follow-up are needed to confirm this study.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Central Nervous System Neoplasms; Combined Modality Therapy; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunocompetence; Lymphoma; Male; Melphalan; Middle Aged; Neurotoxicity Syndromes; Radiotherapy, Adjuvant; Recurrence; Remission Induction; Survival Rate; Transplantation, Autologous

The efficacy of first-line intensive chemotherapy plus transplantation of autologous hematopoietic stem cells in adults with disseminated aggressive lymphoma is unknown.. We compared high-dose therapy plus autologous stem-cell support with the standard regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in a randomized trial. The patients were 15 to 60 years of age, had untreated aggressive lymphoma, and were at low, low intermediate, or high intermediate risk of death (i.e., a maximum of two adverse prognostic factors) according to the age-adjusted International Prognostic Index. The primary outcome was event-free survival at five years.. Of 207 consecutive patients, 197 underwent randomization; 99 were assigned to receive CHOP, and 98 to receive high-dose chemotherapy plus stem-cell transplantation. Overall, 78 percent of the patients completed the assigned treatment; the median follow-up was four years. The estimated event-free survival rate (+/-SD) at five years was significantly higher among patients who received high-dose therapy than among patients who received CHOP (55+/-5 percent vs. 37+/-5 percent, P=0.037). Among patients with a high intermediate risk of death, according to the age-adjusted International Prognostic Index, the five-year survival rate was significantly higher after high-dose therapy than after CHOP (74+/-6 percent vs. 44+/-7 percent, P=0.001).. High-dose chemotherapy with autologous stem-cell support is superior to CHOP in adults with disseminated aggressive lymphoma.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Doxorubicin; Epirubicin; Female; Humans; Lymphoma; Male; Melphalan; Methotrexate; Middle Aged; Prednisone; Remission Induction; Stem Cell Transplantation; Survival Analysis; Transplantation, Autologous; Vincristine; Vindesine

We have undertaken a retrospective sequential-cohort analysis of 131 lymphoma patients treated with the BEAM regimen and autologous stem cell transplantation, to compare BEAM at standard doses (sBEAM; n = 67 from May 1990 to April 1995) and BEAM with escalated etoposide dose from 800 to 1600 mg/m(2) (eBEAM; n = 64 from May 1995 to June 1999). Transplant-related mortality and incidence of secondary malignancies were similar in both groups. Disease progression was significantly lower in indolent lymphoma (IL) patients receiving eBEAM (7 vs 43%), although survival was comparable due to a higher toxic mortality in the eBEAM group. The 5-year event-free survival and overall survival were better in Hodgkin's disease (HD) patients treated with eBEAM (70 and 77%, respectively) compared to sBEAM (58 and 69%, respectively), but the difference was not statistically significant. In aggressive lymphomas, no difference was detected between groups. Our results indicate that while escalation of the etoposide doses in the BEAM conditioning regimen does not appear to improve outcome, encouraging results in IL and HD may warrant further studies.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cohort Studies; Cytarabine; Disease Progression; Disease-Free Survival; Dose-Response Relationship, Drug; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Lymphoma; Male; Melphalan; Middle Aged; Multivariate Analysis; Retrospective Studies; Time Factors; Transplantation Conditioning; Transplantation, Autologous

To evaluate the impact of ex vivo expanded megakaryocyte (MK) progenitors on high-dose chemotherapy-induced thrombocytopenia, we conducted a phase II study in 10 patients with relapsed lymphoma. Two fractions of peripheral blood progenitor cells (PBPC) were cryopreserved, one with enough cells for at least 2 x 10(6) CD34+ cells/kg and a second obtained after CD34+ selection. Ten days before autologous stem cell transplantation, the CD34+ fraction was cultured with MGDF+SCF for 10 days. After BEAM (BCNU, cyclophosphamide, cytarabine, and melphalan) chemotherapy, patients were reinfused with standard PBPC and ex vivo expanded cells. No toxicity was observed after reinfusion. The mean fold expansion was 9.27 for nucleated cells, 2 for CD34+ cells, 676 for CD41+ cells, and 627 for CD61+ cells. The median date of platelet transfusion independence was day 8 (range: 7-12). All patients received at least one platelet transfusion. In conclusion, ex vivo expansion of MK progenitors was feasible and safe, but this procedure did not prevent BEAM-induced thrombocytopenia. Future studies will determine if expansion of higher numbers of CD34+ cells towards the MK-differentiation pathway will translate into a functional effect in terms of shortening of BEAM-induced thrombocytopenia.

Topics: Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cell Culture Techniques; Cells, Cultured; Cyclophosphamide; Cytarabine; Erythroid Precursor Cells; Humans; Integrin beta3; Lymphoma; Megakaryocytes; Melphalan; Peripheral Blood Stem Cell Transplantation; Platelet Membrane Glycoprotein IIb; Platelet Transfusion; Salvage Therapy; Thrombocytopenia; Thrombopoietin; Transplantation, Autologous; Treatment Outcome

We and others have previously shown that the use of amifostine (Ethyol; MedImmune Inc, Gaithersburg, MD) can ameliorate certain regimen-related toxicities of high-dose melphalan (HD-MEL) in the autologous hematopoietic stem cell transplant setting. Our recent experience indicated that the maximum tolerated dose of HD-MEL plus autologous hematopoietic stem cell transplant could be increased from approximately 200 mg/m2 to at least 280 mg/m2 with amifostine. Although a dose-limiting toxicity was not clearly identified, atrial fibrillation was noted in several patients. Phase II trials using this regimen have been reported in lymphoma and myeloma. Nonetheless, it is unlikely that single agent therapy, regardless of dose, will be highly curative in advanced hematologic malignancy. Thus, we used amifostine to permit dose escalation of HD-MEL within the BEAM (BCNU/etoposide/arabinosylcytosine/HD-MEL) combination chemotherapy regimen before autologous hematopoietic stem cell transplant in selected patients with lymphoma. Patient entry at the starting dose (ie, HD-MEL 140 mg/m2) has been completed without the development of severe regimen-related toxicities. This trial is ongoing.

Topics: Adult; Amifostine; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cytarabine; Cytoprotection; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Melphalan; Middle Aged; Radiation-Protective Agents; Transplantation, Autologous

The pharmacokinetics of two etoposide (E) formulations were evaluated in patients with refractory hematologic malignancies receiving high-dose conditioning with autologous stem cell transplantation. Patients were randomized to either E at 800 mg/m(2) (containing polysorbate 80 and polyethylene glycol) or etoposide phosphate (EP) at 910 mg/m(2) on days -7 and -5, prior to melphalan, 80 mg/m(2) on day -5. On day -3, EP was repeated. Plasma E was analyzed after each formulation on days -7 and -5 to compare intrapatient pharmacokinetics. In total, 10 patients were treated: four each with multiple myeloma or Hodgkin's disease and two with non-Hodgkin's lymphoma. Mucositis was the major toxicity with seven patients. EP first produced grade 3 mucositis. There was no procedure-related mortality and eight patients remained alive 1 year post-transplant. Cumulative etoposide exposure (AUC) was slightly greater with EP (P=0.056). Conversely, the volume of distribution was slightly, 33%, larger (P=0.052) and clearance was increased with the E infusion (P=0.14). As none of the differences reached statistical significance, both E formulations appear to be pharmacokinetically equivalent in the high-dose transplant setting. The combination of high-dose EP with melphalan is an active preparative regimen prior to ABMT for hematologic malignancies.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Chromatography, High Pressure Liquid; Etoposide; Hodgkin Disease; Humans; Life Expectancy; Lymphoma; Lymphoma, Non-Hodgkin; Melphalan; Middle Aged; Multiple Myeloma; Organophosphorus Compounds; Stem Cell Transplantation; Time Factors; Transplantation, Autologous

We performed a phase II study to determine the efficacy of maximal cytoreductive therapy with up to five cycles of Dexa-BEAM (dexamethasone, carmustine [BCNU], etoposide, cytarabine, and melphalan) followed by high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) for patients with advanced relapsed or refractory indolent lymphoma. Thirty-two patients with primary refractory or relapsed indolent lymphoma were treated with the Dexa-BEAM regimen. Thirteen patients had primary refractory disease, 4 patients partial remission, and 15 patients first or subsequent relapse. Patients achieving PR or CR received HDCT with ASCT. The conditioning regimen used was BEAM (carmustine [BCNU], etoposide, cytarabine, and melphalan). Twenty-two patients responded to Dexa-BEAM resulting in a response rate of 78%. Maximum response was observed after 3.2 (range 2-5) courses. One patient with progressive disease died in septic shock during neutropenia. Nineteen patients with partial or complete remission after Dexa-BEAM received HDCT. Hematopoietic stem cells (HSC) were collected after two cycles of Dexa-BEAM. The median number of CD34+ HSC reinfused was 3.1 x 10(6)/kg (range 1.6-8.2 x 10(6)/kg). There was no transplantation-related death. All patients receiving HDCT achieved complete remission. Overall survival (OS) and freedom from treatment failure (FFTF) for all patients are estimated to be 68% and 65% at two years, respectively. With a mean follow-up of 20 months (range 8-42 months), 16/19 patients receiving HDCT are in continuous complete remission. The Dexa-BEAM regimen is effective in overcoming drug resistance in patients with indolent lymphoma who failed to respond to conventional treatment or who relapsed. The CR rate of 100% of those patients receiving HDCT and ASCT after maximal cytoreductive treatment with Dexa-BEAM suggests the use of HDCT at the time of maximal response.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Dexamethasone; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Remission Induction; Salvage Therapy; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous

The aim of this study was to compare antiemetic efficacy of three serotonin antagonists, granisetron, tropisetron and ondansetron, during conditioning for autologous stem cell transplantation (ASCT). Forty-five malignant lymphoma patients (mean age 38 years, M:F 30:15), undergoing the highly emetogenic regimen BEAM prior to ASCT, were randomized to receive IV granisetron (G) 3 mg once a day, IV tropisetron (T) 5 mg once a day, or IV ondansetron (0) 8 mg twice daily, for six days. The treatment groups were comparable with respect to age, sex and previous experience of nausea and/or vomiting. Nausea and/or emesis control failure was defined as a nausea lasting > or = 4 hours and/or > or = 3 episodes of vomiting/24 h, emesis control failure as > or = 3 episodes of vomiting/24 h. Both the period of chemotherapy (6 days) and the whole period of observation (10 days) were evaluated. Nausea and/or emesis control failure occurred in 24% of patients during the period of chemotherapy and in 51% of patients throughout the whole period of observation, while emesis control failed in 2% and 27% of patients, respectively. The efficacy of three serotonin antagonists was comparable during the chemotherapy period (5 patients with nausea and/or emesis control failure in the granisetron group, 2 in the tropisetron group and 4 in the ondansetron group,p = 0.40). When evaluating the whole period of observation, the antiemetic response to G and T was significantly better than to O, nausea and/or emesis control failure having occurred in 7 (47%) patients treated with G, 5 (33%) patients treated with T, and 12 (80%) patients treated with O, p = 0.03. The results concerning emesis control failures were similar, G 4 (27%), T 1 (7%), O 7 (47%), p = 0.04. Headache was the only frequent side effect of serotonin antagonists (30% incidence). All three serotonin antagonists sufficiently controlled nausea and vomiting during high-dose chemotherapy (BEAM) administration in 67-87% of patients. In comparison with ondansetron, both tropisetron and granisetron proved to be more effective after ASCT, when emetogenic factors other than chemotherapy alone participated.

Topics: Adult; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cytarabine; Etoposide; Female; Granisetron; Hematopoietic Stem Cell Transplantation; Humans; Indoles; Lymphoma; Male; Melphalan; Nausea; Ondansetron; Serotonin Antagonists; Transplantation, Autologous; Tropisetron; Vomiting

The purpose of this study was to determine the toxicities and potential effectiveness of high-dose busulfan, melphalan and thiotepa (Bu/Mel/TT) followed by autologous peripheral blood stem cell (PBSC) infusion in patients with a variety of diseases. A phase II clinical trial of Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) followed by PBSC infusion in 104 patients with breast cancer (n = 48), malignant lymphoma (n = 25), ovarian cancer (n = 13), multiple myeloma (n = 7) and other malignancies (n = 11) was performed. Sixty-two patients were treated in an academic medical center and 42 in a community cancer center. Grade 3-4 regimen-related toxicities occurred in 14% of patients, causing regimen-related mortality in six (6%) patients with an overall transplant-related mortality of 9%. Transplant-related deaths occurred in 6/62 patients (10%) treated in an academic medical center and in 3/42 (7%) treated in a community cancer center. Complete remissions (CR) were achieved in 1/17 (6%) patients with refractory stage IV breast cancer, 4/4 patients with responsive stage IV breast cancer, 6/13 (46%) with more-advanced lymphoma and 4/4 with less-advanced lymphoma. These patients are alive and disease-free a median of 712, 279, 461 and 404 days after transplant, respectively. Nineteen of 22 patients with stage II-III breast cancer remain alive and disease-free a median of 365 days after transplant. Complete remissions were also seen in 4/9 patients with ovarian cancer and 3/7 with multiple myeloma. The Bu/Mel/TT regimen followed by autologous PBSC infusion is associated with acceptable morbidity and mortality, appears to have significant activity in patients with breast cancer and is well tolerated in the adjuvant setting of stage II-III breast cancer. Bu/Mel/TT also appears to have significant activity in patients with lymphoma, multiple myeloma and possibly ovarian cancer. Further phase II-III studies are warranted in patients with these and other malignancies.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Busulfan; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Neoplasms; Ovarian Neoplasms; Thiotepa; Transplantation, Autologous

High-dose chemotherapy followed by autologous peripheral blood progenitor cell transplantation (PBPCT) is increasingly applied in patients with relapsed, poor risk malignant lymphomas. Different strategies for progenitor cell mobilization using cytoreductive chemotherapy, hematopoietic growth factors, or both have been described. We studied the safety and efficacy of a modified DexaBEAM regimen (dexamethasone, BCNU [carmustine], etoposide, ara-C, melphalan) followed by granulocyte-colony stimulating factor (G-CSF) that was administered in order to minimize any residual disease and to obtain a sufficient amount of progenitor cells in the autografts. Until now, 16 patients at poor risk (8 with Hodgkin's disease, 8 with non-Hodgkin's lymphoma) entered the study. All the 12 patients with measurable disease at study entry responded to DexaBEAM. Median time of subsequent leukopenia (leukocytes < 1.000/microL) was 6 days (range 5-8 days). Peak numbers of CD34+ hematopoietic progenitor cells appeared in the peripheral blood after a median of 20 days (range 18-22 days) after onset of therapy. At that time, peripheral mononuclear cells were collected for autografting. Thereafter, the leukapheresis products were frozen until the day of transplantation, either unpurged in the case of Hodgkin's disease or purged with the ether lipid edelfosine in cases of non-Hodgkin's lymphoma. After high-dose chemotherapy with the CBV regimen (cyclophosphamide, BCNU, etoposide) the patients received their autografts, followed again by G-CSF treatment. A stable hematopoietic recovery was reached with granulocytes > 2.000/muL within 11 days (range 8-17 days), and platelets > 50.000/microL within 15 days (range 10-31 days), respectively, without significant differences between the purged and unpurged transplants. After a median follow-up of 28 months (range 1-40 months) 7 patients are alive without signs of recurrent disease, while 1 patient has died due to acute treatment related toxicity. Three patients had refractory disease, and 5 have relapsed of whom 4 have died. In summary, the DexaBEAM/G-CSF/CBV strategy appears to be safe and effective for salvage treatment in patients with poor risk malignant lymphomas.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Carmustine; Cell Movement; Cyclophosphamide; Cytarabine; Dexamethasone; Dose-Response Relationship, Drug; Etoposide; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Leukapheresis; Lymphoma; Melphalan; Middle Aged; Phospholipid Ethers; Risk Factors; Transplantation Conditioning

We have previously demonstrated a dose response relationship in Hodgkin's disease for the combination of BCNU, VP16, Ara C and Melphalan, with the superior efficacy of the BEAM regimen requiring haemopoietic support, compared with miniBEAM. To further exploit this, we have attempted to escalate the VP16 dose in BEAM. The standard etoposide dose is 200 mg/m2 IV for four days. Thirty seven patients with refractory lymphoma received 400 mg/m2/day of etoposide, and 13 patients 600 mg/m2/day, in addition to BCNU, cytarabine, and melphalan. Toxicity and outcome parameters were compared in the preceding 40 patients, who received 200 mg/m2/day etoposide. The toxic mortality with 400 mg/m2/day of etoposide (3%) was identical to that for the standard BEAM regimen (5%). Two procedure related deaths occurred in the highest VP16 dose group (15%). The morbidity of the lower etoposide dose regimens was comparable, but 600 mg/m2/day induced significantly greater gastrointestinal toxicity. Twelve of the 13 patients receiving this dose suffered grade II-IV mucositis, with stomatitis, dysphagia and prolonged diarrhoea; 5 haemodynamically significant gastrointestinal haemorrhage, and 1 fatal toxic colitis. Granulocyte colony stimulating factor did not influence the nonhaematological toxicity. The three month response rates were similar (91%) in all dose cohorts. The maximum tolerable etoposide dose within the BEAM regimen is thus 400 mg/m2 for four days.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Combined Modality Therapy; Cytarabine; Dose-Response Relationship, Drug; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Humans; Lymphoma; Male; Melphalan; Middle Aged

Since December 1987, we have examined the use of high-dose chemotherapy and unpurged bone marrow rescue in 31 patients with advanced or refractory lymphoma. Twenty-one patients had Hodgkin's disease (HD) and 10 had Non-Hodgkin's lymphoma (NHL). At ABMT, 22 patients had relapsed or resistant disease. All patients, excluding 3 early deaths, engrafted. There was no relationship between cell numbers harvested, CFU-GM and bone marrow recovery. The mean times to 0.5 x 10(9)/l neutrophils and 50 x 10(9)/l platelets were 20 d and 43 d respectively. However, 5 patients with HD had a significantly slower platelet recovery time of up to 203 days (p = 0.05). Disease-free survival was 72% for HD and 40% for NHL at 40 months. Relapsed or refractory disease at ABMT, bulky disease, extensive salvage therapy and Karnofsky scores below 80% were all associated with a poorer outcome. The most striking observation has been the dramatic radiological response of some patients with advanced/refractory disease.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Combined Modality Therapy; Cytarabine; Etoposide; Female; Humans; Lymphoma; Male; Melphalan; Middle Aged; Survival Rate; Transplantation, Autologous

MOPP chemotherapy was the significant breakthrough that improved the outlook for patients with advanced Hodgkin's disease. Results with alternating potentially non-cross-resistant drug combinations, including MOPP/ABVD, CAD/MOPP/ABV, and MOPP/ABV, are similar and seem to be slightly superior to those with MOPP alone. Limited adjuvant RT does not seem to add appreciably to the morbidity of chemotherapy, although its role in improving on results with chemotherapy alone has not been well studied in prospective, randomized, controlled clinical trials. There are two major challenges for the future. The first is to improve the outcome for advanced Hodgkin's disease patients, perhaps with more intensive chemotherapy and RT with use of cytokines such as the colony-stimulating factors or interleukin-1 or with rescue employing autologous bone marrow transplantation or both. The second challenge is to reduce the morbidity but not the effectiveness of treatment for advanced Hodgkin's disease patients without adverse prognostic factors.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Clinical Trials as Topic; Combined Modality Therapy; Dacarbazine; Doxorubicin; Female; Hodgkin Disease; Humans; Leukemia; Lomustine; Lymphoma; Male; Mechlorethamine; Melphalan; Middle Aged; Neoplasms, Multiple Primary; Prednisone; Procarbazine; Remission Induction; Vinblastine; Vincristine; Vindesine

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Drug Evaluation; Drug Resistance; Etoposide; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Melphalan; Neoplasm Recurrence, Local; Neoplasms; Thioguanine; Transplantation, Autologous

With the advent of new cellular and targeted therapies, treatment options for relapsed and refractory (r/R) lymphomas have multiplied, and the optimal approach offering the best outcomes remains a matter of passionate debate. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is still considered a treatment option for patients with chemosensitive lymphoma when cure is the expected goal. The myeloablative conditioning regimen preceding the stem cell infusion is considered the effective component of this approach. Carmustine (BCNU)-based preparative regimens, such as BEAM and BEAC, are considered the standard of care and have shown efficacy and low nonrelapse mortality (NRM). Comparative studies between conditioning regimens have failed to identify a better option. After a BCNU drug shortage in Canada followed by a steep increase in price, we elected to substitute BCNU for bendamustine (benda) in the preparative regimen. The purpose of this substitution was to improve response while preserving safety and controlling costs. From May 2015 to May 2018, a total of 131 consecutive lymphoma patients received benda-EAM conditioning. These patients were compared with 96 consecutive patients who received BCNU-based conditioning from January 2012 to May 2015. Apart from conditioning, supportive care measures were the same in the 2 groups. Patients receiving benda were older (55.7 years versus 51.1 years; P = .002). The development of grade ≥3 mucositis was more frequent with benda conditioning (39.5% versus 7.8%; P < .001) leading to a greater requirement for parenteral nutrition (48.9% versus 21.9%; P < .001). A transient creatinine increase >1.5 times the upper limit of normal (15.3% versus 4.2%; P < .008) and intensive care unit admission (6.9% versus 1.1%; P < .029) were more frequent with benda; however, there were no between-group differences in cardiac, pulmonary, or liver toxicity and NRM. With a median follow-up of 48 months for the benda group and 60 months for the BCNU group, benda was associated with significantly better progression-free survival (71% versus 61%; P = .040; hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.0 to 2.7) and overall survival (86% vs 71%; P = .0066; HR, 2.6; 95% CI, 1.3 to 5.4) compared with BCNU-based conditioning regimens. While novel therapies emerge, our study demonstrates that benda-EAM is safe and effective and should be considered a valid alternative to BCNU conditioning to improve outcom

Topics: Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Carmustine; Cytarabine; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Melphalan; Retrospective Studies; Transplantation, Autologous

Autologous stem cell transplantation (ASCT) remains a cornerstone in the treatment of both Hodgkin lymphoma (HL) and various non-Hodgkin lymphoma (NHL) subtypes. BEAM (carmustine, etoposide, cytarabine, and melphalan) is the most frequently used conditioning regimen; however, owing due to limited availability and toxicity of carmustine, thiotepa-containing regimens have been suggested. We previously reported encouraging results in ASCT with a TECAM (thiotepa, etoposide, cyclophosphamide, cytarabine, and melphalan) conditioning regimen from 2000 to 2013. We aimed to update our experience with the TECAM regimen by adding our experience from 2013 to 2020 to the previously reported cohort. Moreover, we aimed to use the detailed data for the 2 transplant cohorts to identify improvements in ASCT outcomes in the recent era. We retrospectively analyzed all lymphoma patients who underwent ASCT at our center between January 2000 and December 2020. A total of 353 lymphoma patients were included (142 in the newer cohort added to 211 previously reported patients), all of whom were treated with our standard TECAM conditioning regimen. The cohort included 127 patients with HL, 107 with DLBCL, and 119 with other NHL subtypes. The newer cohort was characterized by significantly poorer Eastern Cooperative Oncology Group Performance Status (ECOG-PS) prior to ASCT (45.7% versus 19.3% with ECOG-PS ≥1; P < .01), whereas a higher proportion of patients entered transplantation in complete response (CR) (71.9% versus 47.8%; P < .01). The median follow-up after ASCT was 136.4 months (95% confidence interval [CI], 91.4 to 181.4 months). The 3-year progression-free survival (PFS) and overall survival (OS) rates post-ASCT for the entire cohort were 59.8% and 79.3%, respectively. Evaluating the 303 of 353 patients (86.4%) who entered ASCT with a responsive disease-a population that represents today's approach to the selection of patients for ASCT-the 3-year PFS and OS rates were 61.5% and 81.9%, respectively. In this population, the 3-year PFS rate was 62.2% for HL, 62.6% for DLBCL, 64.3% for primary central nervous system lymphoma (PCNSL), and the 3-year OS rate were 90.1%, 75.2%, and 78.6%, respectively. OS was significantly better in the newer cohort (P < .01), but not when evaluating only patients who entered ASCT with responsive disease. Dose reductions, poor disease status, and poor ECOG-PS at ASCT entry were associated with worse outcomes across all lymphoma subtypes. In accord

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Etoposide; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Lymphoma; Lymphoma, Non-Hodgkin; Melphalan; Retrospective Studies; Thiotepa; Transplantation, Autologous

Neutropenia postchemotherapy is associated with favorable outcomes, which was attributed to optimal dosing. However, little is known about the neutrophil decline rate as a predictor of cancer outcomes, which may reflect a dynamic marker of chemosensitivity. We assessed the association between the neutrophil decline rate and disease outcomes in a known cohort of 212 lymphoma patients, treated with thiotepa, etoposide, cyclophosphamide, cytarabine, and melphalan (TECAM) conditioning followed by autologous transplant in our center between 2000 and 2013. Slower neutrophil decline rate was correlated with worse overall survival, mediated not by shorter time to progression (TTP), but rather by worse survival post-progression, possibly pointing to chemosensitivity at each line of therapy as the responsible mechanism. The effect was seen across histologies and was independent of stronger predictors of outcome like performance status (PS) and response before transplant. Prospective research is needed to confirm our results and expand their validity to other clinical scenarios.

Topics: Antineoplastic Combined Chemotherapy Protocols; Autografts; Cytarabine; Etoposide; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Lymphoma; Lymphoma, Non-Hodgkin; Melphalan; Neoplasm Recurrence, Local; Neutrophils; Prospective Studies; Transplantation Conditioning; Transplantation, Autologous

Topics: Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Melphalan; Transplantation Conditioning; Transplantation, Autologous

The aim of this retrospective study was to evaluate the safety and efficacy of SEAM regimen followed by auto-SCT in lymphoma.. We retrospectively reviewed the records of patients with lymphoma who underwent auto-SCT with SEAM conditioning regimen from January 2010 to June 2018 at our centre. In total, 97 patients were analysed.. The median time to neutrophil engraftment and platelet engraftment was 9.5 days (range, 7-15 days) and 12 days (range, 7-25 days), respectively. Grade 3-4 nausea/vomiting, mucositis and diarrhoea were observed in 21.6%, 36.1%, and 11.3% of patients, respectively. Treatment-related mortality at 100 days occurred in 2 patients (2.1%). After a median follow-up time of 53.9 months, the 3-year incidence of disease relapse or progression was 34%. The estimated progression-free survival and overall survival at 3 years were 62% and 75%, respectively. Compared with previous studies using BEAM as the conditioning regimen, this study shows that the SEAM regimen has a comparable efficacy and safety profile.. The SEAM regimen is feasible and might be an ideal alternative to BEAM regimen for lymphoma auto-SCT.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Melphalan; Retrospective Studies; Semustine; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous

High-dose melphalan (HD-Mel) has been successfully employed in autografting patients with multiple myeloma. An advantage of this regimen is that the total dose of Mel can be delivered in a single day, being particularly useful when non-frozen hematopoietic stem cells are employed in the autograft.. Twenty-five R/R HL/NHL patients were prospectively accrued in the study. There were 8 (32%) females, 13 (52%) patients had at least 1 adverse effect: 7 (28%) developed mucositis, 5 (20%) neutropenic fever, and 6 (24%) grade IV nausea. In the HD-Mel group, median overall survival (OS) was not achieved and OS at 36 months was 71%, the transplant-related mortality being 0%. In the control group, median OS was not achieved and the 36-month OS was 76%, results not statistically significant (. HD-Mel alone is non-inferior to a BEAM-like regimen as a preparative regimen for autografting patients with R/R HL and NHL. The regimen is adequate to graft persons with non-frozen stem cells.

Topics: Antineoplastic Combined Chemotherapy Protocols; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Melphalan; Transplantation Conditioning; Transplantation, Autologous

High-dose melphalan is one of the main cytotoxic DNA alkylating agents and is used in many transplantation conditioning regimens. Studies have shown a wide range of drug exposure when a traditional weight-based dose of melphalan is used. The optimal melphalan dose in BEAM (carmustine, etoposide, cytarabine, and melphalan), which results in maximum efficacy with acceptable toxicity, is unknown. In this pharmacokinetic (PK) analysis of 105 patients with lymphoma undergoing treatment with BEAM and autologous hematopoietic cell transplantation, we initially estimated melphalan exposure as area under the curve (AUC) by a noncompartmental analysis and subsequently compared it with a newly developed 2-compartment population-PK model. The 2 models correlated closely with each other. We found that the traditional fixed weight-based dosing of propylene glycol-free (captisol-enabled) melphalan in BEAM results in a wide variation in exposure as estimated by both models. Higher melphalan exposure was significantly associated with increased metabolic toxicities but did not seem to impact progression-free survival. Although our study suggests a melphalan AUC of 8 mg·h/L as a potential target in BEAM, larger prospective studies using personalized PK-directed melphalan dosing are needed to determine the optimal melphalan exposure in lymphomas.

Topics: Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Melphalan; Prospective Studies; Transplantation, Autologous

Chemotherapy-induced nausea and vomiting (CINV) is common in patients with lymphoma and multiple myeloma (MM) receiving high-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT). Despite a standard triple antiemetic regimen of a neurokinin-1 (NK1) receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone is recommended, how to control the protracted CINV in ASCT setting remains an intractable problem. Here, we retrospectively analyze CINV data of 100 patients who received either SEAM (semustine, etoposide, cytarabine, melphalan) or MEL140-200 (high-dose melphalan) before ASCT, evaluate the efficacy and safety of multiple-day administration of fosaprepitant combined with tropisetron and olanzapine (FTO), and compare the results to those of patients who received a standard regimen of aprepitant, tropisetron, and dexamethasone (ATD). The overall rate of complete response (CR), defined as no emesis and no rescue therapy, is 70% in the FTO group compared to 36% in the ATD group. Although CR rates are comparable in the acute phase between the two groups, significantly more patients treated by FTO achieve CR in the delayed phase than those treated by ATD (74% vs. 38%, p < 0.001). Moreover, FTO treatment significantly reduced the percentage of patients who are unable to eat, as well as the requirement for rescue medications. Both regimens are well tolerated and most adverse events (AEs) were generally mild and transient. In conclusion, the antiemetic strategy containing multiple-day administration of fosaprepitant is safe and effective for preventing CINV in lymphoma and MM patients, particularly in the delayed phase.

Topics: Antiemetics; Antineoplastic Agents; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Melphalan; Morpholines; Multiple Myeloma; Nausea; Olanzapine; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous; Tropisetron; Vomiting

Lymphoma is seen as a highly treatable and curable malignancy with aggressive treatment methods. Efficacy is often limited by toxicity and many patients need alternative treatment strategies as they cannot tolerate existing high cytotoxic approaches. Our aim is to compare BEAM [carmustine (BCNU), etoposide, cytarabine (ARA-C, cytosine arabinoside), and melphalan] and mitoxantrone-melphalan (Mx-Mel) regimens utilized in our patients with a diagnosis of lymphoma who underwent autologous stem cell transplantation (ASCT), and to demonstrate that the Mx-Mel regimen has similar but less toxic results than the BEAM regimen we have been using frequently as standard conditioning regimen.. A total of 101 patients with lymphoma who underwent ASCT were included in our study. The BEAM regimen included BCNU, etoposide, ARA-C, and melphalan. The Mx-Mel regimen included mitoxantrone and melphalan.. Of 101 patients included in the study, 60 (59.4%) received BEAM and 41 (40.6%) received Mx-Mel (40.6%) conditioning regimen. The median time to neutrophil engraftment was 10 (range: 9-20) days and 12 (range: 9-12) days in the BEAM and Mx-Mel arms, respectively; it was statistically significantly shorter in the BEAM arm (p = .001).. This study demonstrates that the Mx-Mel regimen has similar efficacy and toxicity compared with the BEAM regimen. Although time to neutrophil engraftment was shorter in the BEAM arm, it did not result as significant transplant-related complications between the two regimens. The Mx-Mel regimen is seen as a good alternative with low toxicity and high efficacy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Melphalan; Mitoxantrone; Transplantation Conditioning; Transplantation, Autologous

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Etoposide; Humans; Lomustine; Lymphoma; Melphalan; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Melphalan; Progression-Free Survival; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous

The aim of this study is to determine whether the modified BuCy (semustine, cytarabine, busulfan, and cyclophosphamide, mBuCy) conditioning regimen can be safely used as an alternative to the SEAM (semustine, etoposide, cytarabine, and melphalan) regimen by comparing the efficacy and toxicity of the mBuCy and SEAM regimens. We matched 34 pairs of patients with regard to disease status at the time of autologous stem cell transplantation (auto-SCT). We found no significant difference in the time of platelet engraftment between the two groups. Furthermore, neutrophil engraftment was somewhat faster in the mBuCy group than in the SEAM group (median: 9 days vs 10 days, p = 0.015). With regard to toxicity, the incidence of nausea/vomiting, hepatic impairment, renal impairment, pulmonary infection, and treatment-related mortality (TRM) was similar between the two groups. In addition, compared to patients conditioned with SEAM, patients conditioned with mBuCy were less likely to develop mucositis and diarrhea (p = 0.027; p = 0.050). The 2-year progression-free survival (PFS) rates in the mBuCy and SEAM groups were 79% and 70% (p = 0.378), respectively, and the 2-year overall survival (OS) rates were 81% and 78.0%, respectively (p = 0.789). These analyses showed that the mBuCy conditioning regimen was well tolerated and can be used as an alternative to the SEAM regimen for lymphoma.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Autografts; Busulfan; Cyclophosphamide; Cytarabine; Disease-Free Survival; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Semustine; Survival Rate; Transplantation Conditioning

High-dose chemotherapy before autologous transplantation is a therapeutic option as consolidation in primary or relapsed lymphoma. Even if BEAM conditioning is generally used, alternative conditioning regimens have been published. The purpose of this study was to assess the outcome of 177 adult patients with lymphoma whose conditioning treatment included a BAM (busulfan, aracytine, and melphalan) regimen. With a median follow-up of 17.4 months, 2-year estimates of overall survival and progression-free survival for the entire group were 87% and 70.5%, respectively. Mucositis was the main reported complications and infectious episodes were described in 80.2% of patients. According to multivariate analysis, high performance status and age at diagnosis were adverse factors for survival and increased the risk of disease relapse and death. Despite its limitations, this retrospective study suggests that BAM combination is a valid conditioning regimen in lymphoma patients, with an acceptable rate of toxicity.

Topics: Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Cytarabine; Female; France; Humans; Lymphoma; Male; Melphalan; Middle Aged; Mucositis; Multivariate Analysis; Prognosis; Retrospective Studies; Risk Factors; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has become the\ standard approach for patients with relapsed/refractory Hodgkin’s lymphoma (HL) or non-Hodgkin’s lymphoma (NHL).\ In this study, we report the outcome of the mitoxantrone-melphalan conditioning regimen for lymphoma.. The study group included 53 patients who were relapsed/refractory HL (n = 14) and NHL (n =\ 39) and received mitoxantrone and melphalan followed by ASCT. The transplant regimen consisted of mitoxantrone (60\ mg/m2) and melphalan (180 mg/m2) followed by peripheral blood stem cell infusion (PBSC).. Prior to high-dose chemotherapy, 37.7% of the patients were in complete remission (CR) and 45.3% were in\ partial remission (PR), and 17% had stable or progressive disease. After high-dose chemotherapy and PBSC, 44 out of 51\ patients achieved CR (86.2%). CR was achieved in 24 out of 33 patients (72.7%) who were transplanted in a marginally\ active phase of the disease. At a median followup of 25.4 months (1.8–131.3 months) after ASCT, 13 patients relapsed/\ progressed and 8 patients died. The estimated 2-year overall survival (OS) was 81.9%, and event-free survival (EFS) was\ 59.3%.. High-dose chemotherapy followed by ASCT is an effective conditioning regimen in relapsed/refractory\ lymphoma patients who are undergoing ASCT.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Mitoxantrone; Recurrence; Retrospective Studies; Young Adult

Topics: Administration, Oral; Animals; Antineoplastic Agents, Alkylating; Dog Diseases; Dogs; Female; Lymphoma; Male; Melphalan; Recurrence; Retrospective Studies

Nineteen cats with relapsed high-grade/large-cell lymphoma were treated with dexamethasone, melphalan, actinomycin-D and cytarabine (DMAC). All cats had received Cyclophosphamide, Vincristine, Prednisolone (COP) as first-line chemotherapy and most cats had received at least 2 prior rescue agents with 14 of 19 having received both epirubicin and lomustine. Five cats (26%) exhibited a response (defined as an improvement or resolution of tumour-associated clinical signs/tumour volume, or complete/partial response) to chemotherapy though no patients received more than 2 cycles of DMAC. Most cats tolerated the protocol well though 3 patients exhibited Veterinary Cooperative Oncology Group (VCOG) grade 4 neutropenia and 1 patient exhibited grade 4 thrombocytopenia. The median progression-free survival and overall survival from starting DMAC were 14 and 17 days respectively. There is still an unmet need for successful rescue chemotherapy protocol for cats with relapsed lymphoma. [Correction added on 02 November 2017, after first online publication: The expansion for the term DMAC was previously incorrect and has been corrected in this current version.].

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cat Diseases; Cats; Cytarabine; Dactinomycin; Dexamethasone; Female; Lymphoma; Male; Melphalan; Salvage Therapy

Objectives The goals of this retrospective study were to evaluate the use of mechlorethamine, vincristine, melphalan and prednisolone (MOMP) chemotherapy for rescue of feline lymphoma, to describe the protocol's toxicity and to determine prognostic indicators for progression-free survival. Methods The medical records of 12 cats treated with MOMP chemotherapy at the University of Tennessee Veterinary Medical Center between 2007 and 2017 were evaluated. Parameters assessed included lymphoma cell size, anatomical location, number of previous chemotherapy drugs and number of previous rescue protocols received. Chemotherapy-related toxicity was also described. Results Seven of 12 cats responded to this rescue protocol. Three cats experienced complete response and four cats achieved partial response for a median duration of 39 days (range 14-345 days). Cats that achieved complete response had a significantly longer median progression-free survival than cats that did not respond to treatment. Five of 12 cats developed hematologic toxicity (neutropenia) and one cat developed gastrointestinal toxicity. Toxicity was mild in most cases; no cats needed to be hospitalized. Neutropenia was associated with increased progression-free survival. Conclusions and relevance MOMP is a safe and effective rescue chemotherapy protocol for cats with relapsing and refractory lymphoma.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cat Diseases; Cats; Disease-Free Survival; Female; Lymphoma; Male; Mechlorethamine; Melphalan; Neoplasm Recurrence, Local; Prednisolone; Records; Retrospective Studies; Tennessee; Treatment Outcome; Vincristine

Based on experience with comprehensive patient involvement, we present data from implementation of portable, programmable infusion pumps (PPP) for home-based chemotherapy administration in patients with acute leukaemia and in lymphoma patients receiving (carmustine, etoposide, cytarabine, melphalan) BEAM regimen. Data from 84 patients, receiving 177 cycles of PPP administered chemotherapy, showed convincing safety with minor equipment errors encountered and with high patient satisfaction. In-hospital days could be reduced with 52% out of a total of 1197 treatment days. Homebased PPP has several advantages from a patient perspective and furthermore frees up in-hospital beds for patients in need of them.

Topics: Acute Disease; Adult; Aged; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Female; Humans; Infusion Pumps; Leukemia; Lymphoma; Male; Melphalan; Middle Aged; Outpatients; Podophyllotoxin

Autologous stem cell transplantation (ASCT) following BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning is standard of care in relapsed low- and high-grade B-cell lymphoma (DLBCL) and other lymphoproliferative disorders, but BCNU is associated with interstitial pneumonia and an increased mortality. A less toxic regimen might improve the outcome of patients with lymphoma after transplantation.. We investigated the role of bendamustine replacing BCNU in the BEAM regimen in patients with lymphoma undergoing ASCT.. The conditioning regimen BendaEAM consisted of bendamustine, cytarabine, etoposide, and melphalan and was used in patients with Hodgkin's disease (HD) and Non-Hodgkin lymphoma (NHL).. Forty-one patients with HD (n = 9) or NHL (n = 32) were consecutively treated with Benda-BEAM replacing BCNU. No pulmonary or renal toxicities occurred, and no patient died related to transplant. After a median follow-up of 55 months, CR rate was 56%, 18 patients (44%) showed progression after a median time of 7 months after transplantation (range: 2-29 months), and 11 patients (24%) have died, all due to lymphoma progression. The 1-, 2-, and 4-year PFS are 73.2%, 58.6%, and 55.6% and the 1-, 2-, and 4-year OS 85.4%, 78.0%, and 72.6%, respectively.. BendaEAM seems to be feasible with a promising response rate and acceptable toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Carmustine; Combined Modality Therapy; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Young Adult

BEAM (carmustine [bis-chloroethylnitrosourea (BCNU)]-etoposide-cytarabine-melphalan) chemotherapy is the standard conditioning regimen for autologous stem cell transplantation (ASCT) in lymphomas. Owing to BCNU shortages, many centers switched to fotemustine-substituted BEAM (FEAM), lacking proof of equivalence. We conducted a retrospective cohort study in 18 Italian centers to compare the safety and efficacy of BEAM and FEAM regimens for ASCT in lymphomas performed from 2008 to 2015. We enrolled 1038 patients (BEAM = 607, FEAM = 431), of which 27% had Hodgkin lymphoma (HL), 14% indolent non-Hodgkin lymphoma (NHL), and 59% aggressive NHL. Baseline characteristics including age, sex, stage, B-symptoms, extranodal involvement, previous treatments, response before ASCT, and overall conditioning intensity were well balanced between BEAM and FEAM; notable exceptions were median ASCT year (BEAM = 2011 versus FEAM = 2013, P < .001), Sorror score ≥3 (BEAM = 15% versus FEAM = 10%, P = .017), and radiotherapy use (BEAM = 18% versus FEAM = 10%, P < .001). FEAM conditioning resulted in higher rates of gastrointestinal and infectious toxicities, including severe oral mucositis grade ≥3 (BEAM = 31% versus FEAM = 44%, P < .001), and sepsis from Gram-negative bacteria (mean isolates/patient: BEAM = .1 versus FEAM = .19, P < .001). Response status at day 100 post-ASCT (overall response: BEAM = 91% versus FEAM = 88%, P = .42), 2-year overall survival (83.9%; 95% confidence interval [CI], 81.5% to 86.1%) and progression-free survival (70.3%; 95% CI, 67.4% to 73.1%) were not different in the two groups. Mortality from infection was higher in the FEAM group (subhazard ratio, 1.99; 95% CI, 1.02 to 3.88; P = .04). BEAM and FEAM do not appear different in terms of survival and disease control. However, due to concerns of higher toxicity, fotemustine substitution in BEAM does not seem justified, if not for easier supply.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cohort Studies; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Italy; Lymphoma; Male; Melphalan; Middle Aged; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Cell Line, Tumor; Cell Proliferation; Cell Survival; Deoxycytidine; DNA Damage; DNA Repair; Drug Synergism; Gemcitabine; Humans; Lymphoma; Male; Melphalan; Middle Aged; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Reactive Oxygen Species; Tumor Cells, Cultured

Haploidentical transplantation (Haplo-SCT) with post-transplantation cyclophosphamide (PTCy) is increasingly utilized for the treatment of lymphoma and almost exclusively with the nonmyeloablative fludarabine (Flu)/cyclophosphamide/total body irradiation (TBI) conditioning regimen. We present early results of a reduced-intensity (RIC) regimen utilizing fludarabine and melphalan (FM) for the treatment of advanced lymphoma. All patients with a diagnosis of lymphoma or chronic lymphocytic leukemia (CLL) who received Haplo-SCT at the University of Texas MD Anderson Cancer Center between 2009 and 2014 were reviewed (N = 22). Patients received Flu 160 mg/m(2) and melphalan 100 mg/m(2) to 140 mg/m(2) with thiotepa 5 mg/kg or 2 Gy TBI. Because of concerns of increased treatment-related mortality (TRM) with the melphalan 140 mg/m(2) regimen (FM140), a RIC regimen with melphalan 100 mg/m(2) (FM100) was devised. Rituximab was included for CD20(+) disease. Graft-versus-host disease prophylaxis consisted of PTCy 50 mg/kg on days +3 and + 4, tacrolimus, and mycophenolate mofetil. Sixty-eight percent of all patients were not in complete remission at the time of transplantation. The 2-year progression-free survival (PFS) and overall survival (OS) for the entire cohort were 54%, 1-year TRM was 19%, and the cumulative incidence of relapse at 2 years was 27%. Two-year PFS for Hodgkin lymphoma, non-Hodgkin lymphoma, and CLL/small lymphocytic lymphoma were 57%, 51%, and 75%. Patients treated with FM100 compared to FM140 had equivalent PFS (71% versus 37%, P = .246) and OS (71% versus 58%, P = .32). These early results establish Flu and melphalan 100 mg/m(2) with 2 Gy TBI or thiotepa 5 mg/kg as a very promising conditioning regimen for the treatment of advanced lymphoma with Haplo-SCT and PTCy.

Topics: Adult; Allografts; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Male; Melphalan; Middle Aged; Rituximab; Transplantation Conditioning

Clinical information about thiotepa-based autologous stem cell transplantation (auto-SCT) outside the primary central nervous system lymphoma (PCNSL) field is sparse. In this registry-based retrospective study, we evaluated potential risks and benefits of thiotepa-based preparative regimens compared with BEAM (carmustine, etoposide, cytarabine, melphalan) in auto-SCT for diffuse large B-cell lymphoma (DLBCL, excluding PCNSL), follicular lymphoma (FL) or Hodgkin lymphoma (HL). A total of 14 544 patients (589 thiotepa and 13 955 BEAM) met the eligibility criteria, and 535 thiotepa- and 1031 BEAM-treated patients were matched in a 1:2 ratio for final comparison. No significant differences between thiotepa and BEAM groups for any survival end point were identified in the whole sample or disease entity subsets. For a more detailed analysis, 47 TEAM (thiotepa, etoposide, cytarabine, melphalan)-treated patients were compared with 75 matched BEAM patients with additional collection of toxicity data. Again, there were no significant differences between the two groups for any survival end point. In addition, the frequency of common infectious and non-infectious complications including secondary malignancies was comparable between TEAM and BEAM. These results indicate that thiotepa-based high-dose therapy might be a valuable alternative to BEAM in DLBCL, HL and FL. Further evaluation by prospective clinical trials is warranted.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Autografts; Carmustine; Cytarabine; Disease-Free Survival; Female; Humans; Lymphoma; Male; Melphalan; Middle Aged; Podophyllotoxin; Registries; Retrospective Studies; Stem Cell Transplantation; Survival Rate; Thiotepa

There is currently minimal data on fertility outcomes in premenopausal women undergoing autologous stem cell transplant (ASCT) with carmustine, etoposide, cytarabine and melphalan (BEAM) conditioning. A retrospective analysis of fertility outcomes in premenopausal females aged between 18 and 40 yr who underwent BEAM/ASCT for lymphoma between 1995 and 2011 was performed at four transplant centres. Of 41 premenopausal women who underwent BEAM conditioning, 25 met the inclusion criteria with the main exclusion criterion being inadequate documentation. Eighteen had Hodgkin lymphoma, and seven had non-Hodgkin lymphoma. Median number of chemotherapy regimens pretransplant was 2 (1-3). Seventeen women (68%) with a median age at transplant of 25 yr (range 17-33) recovered their menses. The comparative group without recovery was older with a median age of 34 yr (range 20-40) (P = 0.007). Ten patients, with a median age at transplant of 22 yr (range 17-30), had 15 naturally conceived pregnancies. Chemotherapy regimens and lymphoma type did not obviously influence the incidence of menses recovery or conception. The incidence of recovery of menses and fertility in premenopausal women undergoing BEAM/ASCT for lymphoma is substantial. Younger age at transplant correlates with superior fertility outcomes.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Female; Fertility; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Melphalan; Podophyllotoxin; Premenopause; Retrospective Studies; Transplantation Conditioning; Young Adult

Melphalan has been used in the treatment of various hematologic malignancies for almost 60 years. Today it is part of standard therapy for multiple myeloma and also as part of myeloablative regimens in association with autologous allogenic stem cell transplantation. Melflufen (melphalan flufenamide ethyl ester, previously called J1) is an optimized derivative of melphalan providing targeted delivery of active metabolites to cells expressing aminopeptidases. The activity of melflufen has compared favorably with that of melphalan in a series of in vitro and in vivo experiments performed preferentially on different solid tumor models and multiple myeloma. Melflufen is currently being evaluated in a clinical phase I/II trial in relapsed or relapsed and refractory multiple myeloma.. Cytotoxicity of melflufen was assayed in lymphoma cell lines and in primary tumor cells with the Fluorometric Microculture Cytotoxicity Assay and cell cycle analyses was performed in two of the cell lines. Melflufen was also investigated in a xenograft model with subcutaneous lymphoma cells inoculated in mice.. Melflufen showed activity with cytotoxic IC50-values in the submicromolar range (0.011-0.92 μM) in the cell lines, corresponding to a mean of 49-fold superiority (p < 0.001) in potency vs. melphalan. In the primary cultures melflufen yielded slightly lower IC50-values (2.7 nM to 0.55 μM) and an increased ratio vs. melphalan (range 13-455, average 108, p < 0.001). Treated cell lines exhibited a clear accumulation in the G2/M-phase of the cell cycle. Melflufen also showed significant activity and no, or minimal side effects in the xenografted animals.. This study confirms previous reports of a targeting related potency superiority of melflufen compared to that of melphalan. Melflufen was active in cell lines and primary cultures of lymphoma cells, as well as in a xenograft model in mice and appears to be a candidate for further evaluation in the treatment of this group of malignant diseases.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; G2 Phase Cell Cycle Checkpoints; Humans; Lymphoma; Melphalan; Mice; Multiple Myeloma; Phenylalanine; Xenograft Model Antitumor Assays

More active high-dose chemotherapy (HDC) regimens are needed for refractory lymphomas. The authors previously combined infusional gemcitabine with busulfan and melphalan (Gem/Bu/Mel) pursuing DNA damage repair inhibition. Subsequently, they combined Gem/Bu/Mel with vorinostat, which facilitates chemotherapy access to DNA. The resulting regimen was safe and synergistic. However, vorinostat induced DNA methyltransferase up-regulation, which could be preclinically abrogated by azacitidine, increasing tumor-cell kill. Those observations led to a clinical combination of azacitidine with vorinostat/Gem/Bu/Mel.. Patients ages 12 to 65 years with refractory or poor-risk relapsed lymphomas were eligible. They received intravenous azacitidine on days -11 through -3 at doses from 15 to 35 mg/m(2) daily (dose levels 1-3), followed by oral vorinostat (1000 mg once daily on days -11 through -3), gemcitabine (2775 mg/m(2) over 4.5 × 2), busulfan (at an area under the receiver operating characteristic curve of 4000 daily × 4), and melphalan (60 mg/m(2) × 2). Patients who had tumors that were positive for CD20 (cluster of differentiation 20; B-lymphocyte antigen) received rituximab on day -9.. In total, 60 patients were enrolled, including 26 with diffuse large B-cell lymphoma (DLBCL) (10 double hit/double expressors), 21 with Hodgkin lymphoma, 8 with T-cell lymphoma, and 5 with other B-cell lymphomas. The median patient age was 41 years (range, 16-65 years), patients had received a median of 3 prior lines of chemotherapy (range, 2-7 lines of chemotherapy); and 32% of tumors were positive on positron emission tomography studies at the time of HDC. Two patients died from treatment complications (respiratory syncytial virus pneumonia and sepsis, respectively). The maximum tolerated dose of azacitidine was encountered at dose level 1 (15 mg/m(2) daily). The toxicity profile (mainly mucositis and dermatitis) was manageable and was identical to that of vorinostat/Gem/Bu/Mel. Neutrophils and platelets engrafted promptly. At a median follow-up of 15 months (range, 8-27 months), the event-free and overall survival rates were 65% and 77%, respectively, among patients with DLBCL; 76% and 95%, respectively, among patients with Hodgkin lymphoma; and 88% for both among patients with T-cell lymphoma.. Double epigenetic modulation of Gem/Bu/Mel with azacitidine/vorinostat is feasible and highly active in patients with refractory/poor-risk relapsed lymphomas, warranting further evaluation. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2680-2688. © 2016 American Cancer Society.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Busulfan; Child; Deoxycytidine; Drug Resistance, Neoplasm; Epigenesis, Genetic; Female; Follow-Up Studies; Gemcitabine; Humans; Hydroxamic Acids; Lymphoma; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Survival Rate; Vorinostat; Young Adult

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Lomustine; Lymphoma; Male; Melphalan; Middle Aged; Retrospective Studies; Salvage Therapy; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous

The BEAM regimen consisting of carmustine (BCNU), etoposide, cytarabine, and melphalan (MEL) is widely used before autologous hematopoietic stem cell transplantation (auto-HSCT) for lymphoma. However, intravenous BCNU is not available in Japan, and therefore, ranimustine (MCNU) has been used instead of BCNU (the MEAM regimen). We retrospectively analyzed the outcome of 79 adult patients who underwent auto-HSCT for lymphoma using this regimen in two centers, with 1- and 2-day dosing of MEL, respectively. Three-year overall survival (OS) and progression-free survival (PFS) probabilities were 77.3 and 56.5 % in the entire population and 71.7 and 58.0 % in patients with diffuse large B cell lymphoma. These outcomes were at least equivalent to those with the BEAM regimen. There was no regimen-related pulmonary toxicity. In a multivariate analysis, older age was the only factor that was significantly associated with for OS. In a comparison of the two MEL dosing schedules, while there was no significant differences in either OS or PFS, diarrhea was observed more frequently with 1-day dosing of MEL. In conclusion, the MEAM regimen appeared to be a promising conditioning regimen in auto-HSCT for lymphoma. A large prospective study is warranted to confirm the current findings.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Disease-Free Survival; Dose-Response Relationship, Drug; Etoposide; Febrile Neutropenia; Female; Humans; Lymphoma; Male; Melphalan; Middle Aged; Nausea; Nitrosourea Compounds; Peripheral Blood Stem Cell Transplantation; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Young Adult

There is at present little data to guide the choice of conditioning for patients with lymphoma undergoing reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (SCT). In this study, we compared the outcomes of patients undergoing RIC SCT who received fludarabine and melphalan (FluMel), the standard RIC regimen used by the Spanish Group of Transplantation, and fludarabine and busulfan (FluBu), the standard RIC regimen used by the Dana-Farber Cancer Institute/Brigham and Women's Hospital. We analyzed 136 patients undergoing RIC SCT for lymphoma with either FluBu (n = 61) or FluMel (n = 75) conditioning between 2007 and 2014. Median follow-up was 36 months. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 13% with FluBu and 36% with FluMel (P = .002). The cumulative incidence of nonrelapse mortality (NRM) at 1 year was 3.3% with FluBu and 31% with FluMel (P < .0001). The cumulative incidence of relapse at 1 year was 29% with FluBu and 10% with FluMel (P = .08). The 3-year disease-free survival rate was 47% with FluBu and 36% with FluMel (P = .24), and the 3-year overall survival rate was 62% with FluBu and 48% with FluMel (P = .01). In multivariable analysis, FluMel was associated with a higher risk of acute grades II to IV GVHD (HR, 7.45; 95% CI, 2.30 to 24.17; P = .001) and higher risk of NRM (HR, 4.87; 95% CI, 1.36 to 17.44; P = .015). The type of conditioning was not significantly associated with relapse or disease-free survival in multivariable models. However, conditioning regimen was the only factor significantly associated with overall survival: FluMel conditioning was associated with a hazard ratio for death of 2.78 (95% CI, 1.23 to 6.27; P = .014) compared with FluBu. In conclusion, the use of FluBu as conditioning for patients undergoing SCT for lymphoma was associated with a lower risk of acute GVHD and NRM and improved overall survival when compared with FluMel in our retrospective study. These results confirm the differences between these RIC regimens in terms of toxicity and efficacy and support the need for comparative prospective studies.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Survival Rate; Transplantation Conditioning; Vidarabine

High-dose BEAM chemotherapy (BCNU, etoposide, Ara-C, and melphalan) followed by autologous hematopoietic stem cell transplantation is frequently used as consolidative therapy for patients with recurrent or refractory Hodgkin or non-Hodgkin lymphoma. The BEAM regimen has traditionally been administered over 6 days in the hospital, with patients remaining hospitalized until hematologic recovery and clinical stability. In an effort to reduce the length of hospitalization for these patients, our institution has transitioned from inpatient (IP) to outpatient (OP) administration of BEAM conditioning. Here, we report the results of an analysis of the feasibility, cost, complications, and outcomes for the initial group of patients who received OP BEAM compared to a prior cohort of patients who received IP BEAM. Patient and disease characteristics were comparable for the two cohorts, as were engraftment kinetics. Length of hospital stay was reduced by 6 days for the OP cohort (P < 0.001), resulting in a cost savings of more than $17,000 per patient. Fewer complications occurred in the OP cohort, including severe enteritis (P = 0.01), organ toxicities (P = 0.01), and infections (P = 0.04). Overall survival rate up to 3 years posttransplant was better for the OP cohort (P = 0.02), likely due to differences in posttransplant therapies. We conclude that OP administration of BEAM conditioning is safe and may offer significant advantages, including decreased length of hospitalization, reduced costs, decreased risks for severe toxicities and infectious complications, and likely improvement in patient satisfaction and quality of life.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cost-Benefit Analysis; Cytarabine; Female; Follow-Up Studies; Health Care Costs; Hematopoietic Stem Cell Transplantation; Humans; Infections; Kaplan-Meier Estimate; Lymphoma; Male; Melphalan; Middle Aged; Outpatients; Podophyllotoxin; Transplantation Conditioning; Transplantation, Autologous; Young Adult

Eighty-eight dogs with relapsed lymphoma were treated with the MOMP (mechlorethamine, vincristine, melphalan and prednisone) protocol on a 28-day treatment cycle. The overall response rate (ORR) to the MOMP protocol was 51.1% for a median of 56 days (range 7-858 days). Twelve percent of dogs experienced a complete response for a median of 81 days (range 42-274 days) and 38.6% experienced a partial response for a median of 49 days (range 7-858 days). Dogs with T-cell lymphoma had an ORR of 55% for a median of 60 days (range 49-858 days) while those with B-cell lymphoma had an ORR of 57% for a median of 81 days (range 7-274 days) (P = 0.783). The overall survival time for all dogs was 183 days (range 17-974 days). Fifty-four percent of dogs experienced toxicity with the majority classified as grade I. The MOMP protocol seems well-tolerated and is an option for dogs with relapsed lymphoma.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Dog Diseases; Dogs; Female; Lymphoma; Lymphoma, B-Cell; Lymphoma, T-Cell; Male; Mechlorethamine; Melphalan; Prednisone; Recurrence; Survival Analysis; Vincristine

Autologous stem cell transplant (ASCT) after high-dose chemotherapy (HDT) increases overall survival when used in relapsed non-Hodgkin lymphoma (NHL) in patients under 65 years old. Limited experience is available for older patients. We present a retrospective analysis of 73 consecutive patients aged over 65 years treated for aggressive or relapsed lymphoma by HDT with carmustine, etoposide, cytarabine and melphalan (BEAM) at full dosage followed by ASCT. Patient data were obtained from medical charts from two institutions. Median age was 67 years (65-74). Significant comorbidities were present in 24.7% of patients. The median number of days for grade 4 neutropenia was 9 (5-18). The early treatment-related mortality rate (<100 days) was 2.7%. The estimated 2-year progression-free survival and overall survival rates were 67.2% and 78.5%, respectively. In conclusion, the full-dose HDT-ASCT regimen is feasible, safe and efficient in selected patients over 65 years old.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Disease Progression; Etoposide; Female; France; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Prognosis; Recurrence; Retrospective Studies; Survival Analysis; Transplantation, Autologous; Treatment Outcome

Autologous stem-cell transplantation (ASCT) has shown to provide curative benefit in patients with relapsed lymphoma and multiple myeloma (MM), often requiring hematopoietic support until marrow engraftment. Because of Jehovah's Witnesses' (JW) refusal of blood products, treatment challenges arise. This study represents 125 JWs with lymphoma (n = 55), MM (n = 68), or amyloidosis (n = 2), treated with high-dose chemotherapy (HDC) and ASCT without transfusions.. Priming with intravenous iron and erythropoietin occurred to increase hemoglobin (Hb) pretransplantation. Cytokine mobilization of stem-cells was used. Delay to HDC was done to allow Hb and platelets to approach 11 g/dL and 100 × 10(3)/μL, respectively. Patients with MM received a standard dose of melphalan 200 mg/m(2), with dose reduction for severe kidney dysfunction. Patients with lymphoma received carmustine 300 mg/m(2), cyclophosphamide 1,500 mg/m(2) on days 2 through 5 (total 6 g/m(2)), and etoposide 700 mg/m(2) per day on days 2 through 4 (total 2,100 mg/m(2)). Post-transplantation, a combination of granulocyte colony-stimulating factor, erythropoietin, aminocaproic acid, and phytonadione was administered.. There were two major and 15 minor bleeding complications, none occurring at platelets less than 5.0 × 10(3)/μL, with six (4.8%) treatment-related mortalities. The median decrease in Hb was 5.0 g/dL, with median Hb nadir of 7.0 g/dL. The median number of days with platelet count less than 10 × 10(3)/μL was 3, with median platelet nadir of 5.0 × 10(3)/μL. Cardiac complications occurred in 40 patients (32%).. ASCT can safely be performed without transfusion support. A platelet transfusion trigger of ≤ 5 × 10(3)/μL may be appropriate in select patients. Pharmacotherapy and cardiac monitoring are effective in the management of cardiac complications.

Topics: Adult; Aged; Aminocaproic Acid; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Carmustine; Combined Modality Therapy; Cyclophosphamide; Erythropoietin; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hemoglobins; Humans; Iron; Jehovah's Witnesses; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Recurrence; Stem Cell Transplantation; Transplantation, Autologous; Vitamin K 1; Young Adult

Few studies have evaluated the role of antibacterial prophylaxis during neutropenia in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation (HSCT). At our center, levofloxacin prophylaxis was initiated in June 2006 in patients with myeloma who were undergoing autologous HSCT. We compared the incidence of bloodstream infection (BSI) and fever and neutropenia (FN) within 30 days of transplantation before (January 2003 to May 2006) and after (June 2006 to April 2010) the initiation of levofloxacin prophylaxis in patients undergoing autologous HSCT for myeloma. We also compared rates of BSI and FN during the same time periods in autologous HSCT recipients with lymphoma who did not receive antibacterial prophylaxis during either time period. After the initiation of levofloxacin prophylaxis, the BSI rate decreased from 41.2% (49 of 119) to 14.7% (23 of 156) and the rate of FN decreased from 91.6% to 60.9% in patients with myeloma (P < .001, for each). In contrast, rates of BSI (43.1% versus 47.3%; P = .50) and FN (98.8% versus 97.1%; P = .63) did not change in patients with lymphoma. Levofloxacin prophylaxis was independently associated with decreased odds of BSI (odds ratio, .27; 95% confidence interval, .14 to .51; P < .001) and FN (odds ratio, .18; 95% confidence interval, .09 to .36; P < .001) in multivariate analysis. Patients with myeloma had a nonsignificant increase in the risk of BSI due to levofloxacin-resistant Enterobacteriaceae (5% versus 1%, P = .08) and Clostridium difficile infection (7% versus 3%, P = .12) after the initiation of levofloxacin prophylaxis but did not have higher rates of BSI due to other resistant bacteria. Levofloxacin prophylaxis is associated with decreased risk of BSI and FN in patients with myeloma undergoing autologous HSCT.

Topics: Antibiotic Prophylaxis; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Bacteremia; Clostridioides difficile; Clostridium Infections; Combined Modality Therapy; Drug Resistance, Microbial; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Febrile Neutropenia; Female; Filgrastim; Guideline Adherence; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Incidence; Levofloxacin; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Practice Guidelines as Topic; Retrospective Studies; Risk Factors; Transplantation Conditioning; Transplantation, Autologous

Novel clusters of 3,5-bis(benzylidene)-4-oxo-1-piperidinyl dimers 3-5 were evaluated against human Molt4/C8 and CEM T-lymphocytes and human HeLa cervix adenocarcinoma cells as well as murine L1210 leukemia neoplasms. Several of these compounds demonstrated IC50 values in the submicromolar and low micromolar range and compounds possessing 4-fluoro, 4-chloro and 3,4,5-trimethoxy substituents in the series 3 and 4 were identified as potent molecules. A heat map revealed the very high cytotoxic potencies of representative compounds against a number of additional leukemic and lymphoma cell lines and displayed greater toxicity to these cells than nonmalignant MCF10A and Hs-27 neoplasms. These dienones are more refractory to breast and prostate cancers. The evaluation of representative compounds in series 3-5 against a panel of human cancer cell lines revealed them to be potent cytotoxins with average IC50 values ranging from 0.05 to 8.51 μM. In particular, the most potent compound 4g demonstrated over 382-fold and 590-fold greater average cytotoxic potencies in this screen than the reference drugs, melphalan and 5-fluorouracil, respectively. A mode of action investigation of two representative compounds 3f and 4f indicated that they induce apoptosis which is due, at least in part, to the activation of caspase-3 and depolarization of the mitochondrial membrane potential.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Dimerization; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HeLa Cells; HL-60 Cells; Humans; Leukemia; Lymphoma; Molecular Structure; Piperidines; Structure-Activity Relationship

Topics: Amifostine; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Melphalan; Outpatients; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

This was an Australasian Bone Marrow Transplant Recipient Registry (ABMTRR)-based retrospective study assessing the outcome of Fludarabine Melphalan (FluMel) reduced-intensity conditioning between 1998 and 2008. Median follow-up was 3.4 years. There were 344 patients with a median age of 54 years (18-68). In all, 234 patients had myeloid malignancies, with AML (n=166) being the commonest indication. There were 110 lymphoid patients with non-hodgkins lymphoma (NHL) (n=64) the main indication. TRM at day 100 was 14% with no significant difference between the groups. OS and disease-free survival (DFS) were similar between myeloid and lymphoid patients (57 and 50% at 3 years, respectively). There was no difference in cumulative incidence of relapse or GVHD between groups. Multivariate analysis revealed four significant adverse risk factors for DFS: donor other than HLA-identical sibling donor, not in remission at transplant, previous autologous transplant and recipient CMV positive. Chronic GVHD was associated with improved DFS in multivariate analysis predominantly due to a marked reduction in relapse (HR:0.44, P=0.003). This study confirms that FluMel provides durable and equivalent remissions in both myeloid and lymphoid malignancies. Disease stage and chronic GVHD remain important determinants of outcome for FluMel allografting.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Australia; Bone Marrow Transplantation; Disease-Free Survival; Female; Follow-Up Studies; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphoma; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Multivariate Analysis; Myeloablative Agonists; New Zealand; Recurrence; Remission Induction; Retrospective Studies; Risk Factors; Transplantation Conditioning; Treatment Outcome; Vidarabine; Young Adult

In recent years, immune-based therapies have become an increasingly attractive treatment option for patients with cancer. Cancer immunotherapy is often used in combination with conventional chemotherapy for synergistic effects. The alkylating agent cyclophosphamide (CTX) has been included in various chemoimmunotherapy regimens because of its well-known immunostimulatory effects. Paradoxically, cyclophosphamide can also induce suppressor cells that inhibit immune responses. However, the identity and biologic relevance of these suppressor cells are poorly defined. Here we report that cyclophosphamide treatment drives the expansion of inflammatory monocytic myeloid cells (CD11b(+)Ly6C(hi)CCR2(hi)) that possess immunosuppressive activities. In mice with advanced lymphoma, adoptive transfer (AT) of tumor-specific CD4(+) T cells following cyclophosphamide treatment (CTX+CD4 AT) provoked a robust initial antitumor immune response, but also resulted in enhanced expansion of monocytic myeloid cells. These therapy-induced monocytes inhibited long-term tumor control and allowed subsequent relapse by mediating functional tolerization of antitumor CD4(+) effector cells through the PD-1-PD-L1 axis. PD-1/PD-L1 blockade after CTX+CD4 AT therapy led to persistence of CD4(+) effector cells and durable antitumor effects. Depleting proliferative monocytes by administering low-dose gemcitabine effectively prevented tumor recurrence after CTX+CD4 AT therapy. Similarly, targeting inflammatory monocytes by disrupting the CCR2 signaling pathway markedly potentiated the efficacy of cyclophosphamide-based therapy. Besides cyclophosphamide, we found that melphalan and doxorubicin can also induce monocytic myeloid suppressor cells. These findings reveal a counter-regulation mechanism elicited by certain chemotherapeutic agents and highlight the importance of overcoming this barrier to prevent late tumor relapse after chemoimmunotherapy.

Topics: Animals; Antineoplastic Agents, Alkylating; B7-H1 Antigen; CD4-Positive T-Lymphocytes; Cell Line, Tumor; Cell- and Tissue-Based Therapy; Combined Modality Therapy; Cyclophosphamide; Deoxycytidine; Doxorubicin; Female; Gemcitabine; Immunosuppression Therapy; Immunosuppressive Agents; Immunotherapy, Adoptive; Lymphocyte Activation; Lymphoma; Melphalan; Mice; Mice, Inbred BALB C; Myeloid Cells; Programmed Cell Death 1 Receptor; Receptors, CCR2

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Lomustine; Lymphoma; Male; Melphalan; Middle Aged; Transplantation Conditioning; Young Adult

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Etoposide; Female; Humans; Lymphoma; Male; Melphalan; Middle Aged; Stem Cell Transplantation; Survival Analysis; Transplantation, Autologous; Waldenstrom Macroglobulinemia

Oral mucositis (OM) is a common complication of conditioning regimens with high-dose melphalan (HDmel). This retrospective cohort study analyzes the impact of oral cryotherapy (OC) or room temperature saline rinses on the prevention of OM in patients with multiple myeloma (MM) or lymphoid neoplasias submitted to autologous stem cell transplantation (ASCT) in a single center.. From August 2006 to July 2011, 134 consecutive patients were enrolled. Two consecutive groups were included: Non-OC (August 2006 to April 2009, 68 patients) and OC (May 2009 to July 2011, 66 cases). MM cases (78, 58%) received HDmel as the conditioning regimen and 56 patients (42%) with lymphoma received BEAM.. The non-OC and OC groups were comparable for the main clinicobiologic features and type of neoplasia. OM was more frequent and severe in patients receiving BEAM as the conditioning therapy. The group of OC showed less frequent and less severe mucositis and fewer days on antibiotics. No differences were observed in the duration of OM, need for parenteral nutrition and narcotics, and the length of hospital stay on comparison with the OC and non-OC groups. By multivariate analyses, OC was an independent favorable prognostic factor for OM development.. This study shows that OC is more effective than saline rinses in the prevention of OM in patients with lymphoma and myeloma receiving conditioning regimens with HDmel for ASCT.

Topics: Adult; Aged; Female; Hematopoietic Stem Cell Transplantation; Humans; Hypothermia, Induced; Incidence; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Prognosis; Retrospective Studies; Stomatitis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Young Adult

Hodgkin lymphoma (HL) is cured in the majority of children and adolescents. However, there remains a group of patients with primary refractory or relapsed disease for whom cure is more difficult to achieve. Most of these patients receive high-dose chemotherapy followed by auto-SCT, with expected cure rates ranging from 40 to 60%. Conditioning regimens often consist of multiple non-cross-resistant agents, with well-described risks of morbidity and mortality. The use of single-agent high-dose melphalan (HDM) as conditioning, before autologous rescue, has been described in adult patients at our center, with comparable efficacy and less morbidity. We present a series of eight pediatric patients conditioned with single-agent HDM before autologous stem cell rescue for relapsed and primary refractory HL. All patients engrafted with a median of 12 days to neutrophil engraftment. Two patients subsequently relapsed. Seven patients are currently alive, and seven of eight patients have no evidence of disease (one in CR3). Toxicities included grade 4 hematologic in 8/8, grade 3 mucositis in 3/8, grade 3 infectious in 2/8 and grade 4 infectious in 1/8. Our analysis suggests that this regimen is feasible in pediatric patients with acceptable engraftment and toxicity.

Topics: Adolescent; Canada; Child; Drug Resistance, Neoplasm; Female; Hodgkin Disease; Humans; Lymphoma; Male; Melphalan; Myeloablative Agonists; Recurrence; Retrospective Studies; Stem Cell Transplantation; Transplantation Conditioning

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Melphalan; Middle Aged; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

We developed a new high-dose combination of infusional gemcitabine with busulfan and melphalan for lymphoid tumors. Gemcitabine dose was escalated by extending infusions at a fixed rate of 10 mg/m(2)/min in sequential cohorts, in daily, 3-dose or 2-dose schedules. Each gemcitabine dose immediately preceded busulfan (adjusted targeting area under the curve 4,000 μM/min(-1)/day × 4 days) or melphalan (60 mg/m(2)/day × 2 days). We enrolled 133 patients (80 Hodgkin lymphoma [HL], 46 non-Hodgkin lymphoma [NHL], 7 myeloma), median 3 prior regimens; primary refractory disease in 63% HL/45% NHL and positron emission tomography positive tumors at transplantation in 50% patients. Two patients died from early posttransplantation infections. The major toxicity was mucositis. The daily and 3-dose schedules caused substantial cutaneous toxicity. In contrast, the 2-dose schedule was better tolerated, which allowed us to extend the infusions from 15 to 270 minutes. Pretransplantation values of C-reactive protein, B-type natriuretic peptide, ferritin, or haptoglobin did not correlate with toxicity. Overall response and complete response rates were 87%/62% (HL), 100%/69% B large-cell lymphoma (B-LCL), 66%/66% (T-NHL), and 71%/57% (myeloma). At median follow-up of 24 months (range, 3-63 months), the event-free/overall survival rates were 54%/72% (HL), 60%/89% (B-LCL), 70%/70% (T-NHL), and 43%/43% (myeloma). In conclusion, gemcitabine/busulfan/melphalan is a feasible regimen with substantial activity against a range of lymphoid malignancies. This regimen merits further evaluation in phase II and III trials.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Deoxycytidine; Drug Administration Schedule; Female; Follow-Up Studies; Gemcitabine; Hematopoietic Stem Cell Transplantation; Humans; Infusions, Intravenous; Lymphoma; Male; Melphalan; Middle Aged; Mucositis; Recurrence; Survival Rate; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Hematopoietic stem cell transplantation is used for treatment of lymphoma. In an attempt to design an efficacious and safe prehematopoietic stem cell transplantation conditioning regimen, we investigated the cytotoxicity of the combination of busulfan (B), melphalan (M), and gemcitabine (G) in lymphoma cell lines in the absence or presence of drugs that induce epigenetic changes. Cells were exposed to drugs individually or in combination and analyzed by the MTT proliferation assay, flow cytometry, and Western blotting. We used ~IC(10) drug concentrations (57 μM B, 1 μM M and 0.02 μM G), which individually did not have major effects on cell proliferation. Their combination resulted in 50% inhibition of proliferation. Reduction to almost half concentration (20 μM B, 0.7 μM M and 0.01 μM G) did not have significant effects, but addition of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (0.6 μM) to this combination resulted in a marked (~65%) growth inhibition. The cytotoxicity of these combinations correlates with the activation of the ataxia telangiectasia mutated-CHK2 pathway, phosphorylation of KRAB-associated protein-1, epigenetic changes such as methylation and acetylation of histone 3, and activation of apoptosis. The relevance of epigenetic changes is further shown by the induction of DNA methyltransferases in tumor cells with low constitutive levels of DNMT3A and DNMT3B. The addition of 5-aza-2'-deoxycytidine to (BMG+suberoylanilide hydroxamic acid) further enhances cell killing. Overall, BMG combinations are synergistically cytotoxic to lymphoma cells. Epigenetic changes induced by suberoylanilide hydroxamic acid and 5-aza-2'-deoxycytidine further enhance the cytotoxicity. This study provides a rationale for an ongoing clinical trial in our institution using (BMG+suberoylanilide hydroxamic acid) as pre-hematopoietic stem cell transplantation conditioning for lymphoma.

Topics: Antineoplastic Agents, Alkylating; Ataxia Telangiectasia Mutated Proteins; Azacitidine; Busulfan; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Checkpoint Kinase 2; Cytotoxins; Decitabine; Deoxycytidine; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; DNA Methyltransferase 3B; DNA-Binding Proteins; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug Synergism; Epigenesis, Genetic; Gemcitabine; Hematopoietic Stem Cell Transplantation; Humans; Hydroxamic Acids; Lymphoma; Melphalan; Protein Serine-Threonine Kinases; Transplantation Conditioning; Transplantation, Homologous; Tumor Suppressor Proteins

NGR-TNF is a derivative of TNF-α that targets tumor blood vessels and enhances penetration of chemotherapeutic drugs. Because of this property, NGR-TNF is being tested in combination with chemotherapy in various phase II and III clinical trials. Here we report that chromogranin A (CgA), a protein present in variable amounts in the blood of normal subjects and cancer patients, inhibits the synergism of NGR-TNF with doxorubicin and melphalan in mouse models of lymphoma and melanoma. Pathophysiologically relevant levels of circulating CgA blocked NGR-TNF-induced drug penetration by enhancing endothelial barrier function and reducing drug extravasation in tumors. Mechanistic investigations done in endothelial cell monolayers in vitro showed that CgA inhibited phosphorylation of p38 MAP kinase, disassembly of VE-cadherin-dependent adherence junctions, paracellular macromolecule transport, and NGR-TNF-induced drug permeability. In this system, the N-terminal fragment of CgA known as vasostatin-1 also inhibited drug penetration and NGR-TNF synergism. Together, our results suggest that increased levels of circulating CgA and its fragments, as it may occur in certain cancer patients with nonneuroendocrine tumors, may reduce drug delivery to tumor cells particularly as induced by NGR-TNF. Measuring CgA and its fragments may assist the selection of patients that can respond better to NGR-TNF/chemotherapy combinations in clinical trials.

Topics: Antineoplastic Agents; Cell Membrane Permeability; Chromogranin A; Doxorubicin; Drug Synergism; Humans; Lymphoma; Melanoma; Melphalan; Recombinant Fusion Proteins; Tumor Necrosis Factor-alpha

An 8-year-old miniature dachshund presented with a right femoral muscle mass and anorexia. Cytology of the mass revealed a number of small-sized lymphoid cells containing a pleomorphic-shaped dense nucleus and narrow pale cytoplasm. Histopathology indicated that neoplastic lymphoid cells proliferated in skeletal muscles and replaced the muscular architecture. Immunohistochemical and genetic examinations confirmed the diagnosis of primary skeletal muscle lymphoma classified as the pleomorphic small cell type and T-cell low-grade. Although the dog suffered at least three relapses by combination chemotherapy, the dog survived 713 days after the initial presentation.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Dacarbazine; Dogs; Female; Femoral Neoplasms; Lymphoma; Melphalan; Muscle Neoplasms; Ovariectomy; Prednisolone; Survivors; Tomography, X-Ray Computed

To investigate the relationship between TNFalpha and tumor rejection induced by a single dose of melphalan in C57BL/6 mice.. Different gene type mice (TNFR1(+/+), TNFR1(+/-) and TNFR1(-/-)) with the same genetic background of C57BL/6 were used in this experiment. Murine lymphoma EL4 cells were inoculated subcutaneously into the different gene type mice simultaneously. Twelve days later, 7.5 mg/kg melphalan was used intraperitoneally to treat the tumor-bearing mice with TNFR1(+/+), TNFR1(+/-) and TNFR1(-/-). The tumors in the different gene type mice were observed and recorded every one to three day.. After the treatment of 7.5 mg/kg melphalan during the first week, the tumors in the different gene type mice shrank at a similar rate. In the following 2 months, the tumors in the TNFR1(+/+) and TNFR1(+/-) C57BL/6 mice gradually shrank and were cured but most tumors in the TNFR1(-/-) C57BL/6 mice relapsed after melphalan treatment.. TNFalpha plays an important role in melphalan-induced tumor rejection. The anti-tumor effect of melphalan has no relationship with the expression of tumor necrosis factor 1 in tumor-bearing mice. TNFR1 is required to prevent or avoid the relapse of tumors in mice instead of tumor cells.

Topics: Animals; Antineoplastic Agents, Alkylating; Disease Models, Animal; Genotype; Lymphoma; Melphalan; Mice; Mice, Inbred C57BL; Random Allocation; Receptors, Tumor Necrosis Factor, Type I; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Recently, the standard treatments for hematological malignancies have shown dramatic improvement. For chronic myeloid leukemia, imatinib has become the treatment of choice in initial treatment, and its long-term effectiveness and safety have been confirmed. For acute myelogenous leukemia, cytarabine with anthracycline agent is believed to be the standard treatment in first remission induction therapy. To improve the efficacy of the first remission induction chemotherapy, the addition of gemutuzumab ozogamicin has been investigated intensively all over the world. However, there are many obstacles to conducting its clinical trial in Japan. The addition of rituximab to CHOP improves the survival of patients with diffuse large B-cell lymphoma. For follicular lymphoma patients, rituximab with conventional chemotherapies are considered the standard treatments, but the question of which conventional chemotherapy is better is unsolved. MP therapy had long been the standard treatment for elderly patients with multiple myeloma, but MP therapy plus thalidomide with MP therapy has been found to be superior. In patients who are candidates for autologous stem-cell transplantation, VAD therapy or high-dose dexamethasone therapy followed by autologous stem-cell transplantation is considered the treatment of choice. But the number of transplantations and the timing of second transplantation need more investigation. Considering the overall situation with regard to the standard treatments of hematological malignancies in Japan, there is little difference in practice from western countries. However, the framework of conducting clinical trials to investigate standard treatment in Japan is unsatisfactory.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Administration Schedule; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Melphalan; Multiple Myeloma; Prednisone; Rituximab; Survival Rate; Vincristine

To study the relationship of the sensitivity of tumor cells to chemotherapeutic agent between in vivo and in vitro.. Mouse lymphoma cells of the line E14 were cultured and melphalan resistant EL4 cell line (EL4/melphalan) was established by culturing EL4 cells with continuous low-concentration and intermittent gradually-increasing-concentration of melphalan in vitro. MTT assay was used to evaluate the drug sensitivity and the resistance index of the EL4/melphalan cells to melphalan was calculated. EL4/melphalan and EL4 cells of the concentration of 5 x 10(8)/L were inoculated separately into 20 C57BL/6 mice subcutaneously. 12 days later, the EL4 and EL4/melphalan tumor-bearing mice were randomly divided into 2 groups respectively, 5 mice in each group. Treatment groups were given 7.5 mg/kg melphalan intraperitoneally, and control groups were given the same volume of normal saline. The tumor size was observed every other day.. Compared with the EL4 cells, the EL4/melphalan cells had no obvious changes morphologically. They could grow in RPMI 1640 medium containing 5 mg/ml melphalan. The resistance index was 2.87 against melphalan. After the treatment of melphalan of the dose 7.5 mg/kg, the tumor sizes of the treatment groups and control groups inoculated with both EL4 cells and the EL4/melphalan cells gradually decreased at the similar speed, and about one week later all tumors disappeared. However, the tumors of the control groups grew progressively and all the mice died at last.. The chemotherapeutic effects of tumors in vivo have nothing to do with the effects of the chemotherapeutic agents on tumor cells in vitro. The tumor cells resistant to melphalan in vitro remain sensitive to the drug in vivo.

Topics: Animals; Antineoplastic Agents, Alkylating; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Lymphoma; Melphalan; Mice; Mice, Inbred C57BL; Random Allocation; Time Factors; Tumor Burden

Chemotherapy-susceptive multiple myeloma (MM) has an indication for high-dose melphalan (HDM) followed by autologous stem cell transplantation (auto-SCT). HDM was a most simple and convenient regimen among various preparatory regimens, because of rapid infusion divided over 2 days. In order to assess the potential of auto-SCT by HDM in a outpatient setting, we evaluated the toxicities of HDM compared with the ICE regimen generally applied to patients with refractory or relapsed lymphoma. We reviewed 27 cases of auto-SCT from April 2003 to December 2004. The preparatory regimen was HDM (melphalan 200 mg/m(2)) for 18 cases of multiple myeloma and ICE therapy (ifosfamide 12 g/m (2), carboplatin 1,200 mg/m(2), etoposide 800 mg/m2) for 9 malignant lymphomas. Gastrointestinal (GI) adverse events for a patient per hospital day were 0.93 for myeloma and 0.95 for lymphoma (no significant differences), with GI toxicity of more than grade 3, 0.08 and 0.12, respectively (p=0.07). Hematological toxicity was not significantly different between the 2 therapies. The clinical toxicity of HDM was milder compared to ICE, especially regarding the speculated GI-associated nutritional disorders. We thus concluded that outpatient auto-SCT could be validated first in myeloma patients treated by HDM with careful supportive treatments, thereby avoiding regimen-related severe adverse events.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Etoposide; Female; Humans; Ifosfamide; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Stem Cell Transplantation; Transplantation, Autologous

We retrospectively evaluated early and long-term complications of an intensified conditioning regimen consisting of busulfan and etoposide in combination with either nimustine hydrochloride (ACNU) (BVA regimen, n = 18) or melphalan (BVL regimen, n = 34) in 52 children with acute leukemia or non-Hodgkin's lymphoma. With a median follow-up of 13.2 years after the BVA regimen and 8.1 years after the BVL regimen, 61% and 76% of patients, respectively, are in continuous complete remission. Transplantation-related mortality was 17% and 6% after the BVA and BVL regimens, respectively, and the corresponding relapse rates were 17% and 15%. The most common and severe toxicity was pulmonary complication in the BVA regimen, which was seen in 67% of patients and was life-threatening in 20%. Thirty-three percent of patients after the BVA regimen and 24% after BVL died of relapse or disease progression (n = 9), interstitial pneumonia (n = 2), fungal pneumonia (n = 1), or chronic graft-versus-host disease (n = 2). One of the long-term survivors developed secondary leukemia. A significant decrease in the height standard deviation score of more than 2 SD from diagnosis to the last follow-up was seen in 17% of the patients, with hypothyroidism in 15%, and alopecia in 42%. Because our experience is limited to a small heterogeneous population of patients who mainly underwent transplantation in the first remission, we cannot draw conclusions on the treatment's effectiveness. The BVL regimen is tolerable, however, because no regimen-related death was observed, whereas the BVA regimen is not recommended because of the high incidence of pulmonary complications. The effectiveness of the BVL regimen requires further study.

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Disease-Free Survival; Etoposide; Female; Follow-Up Studies; Humans; Infant; Leukemia; Lymphoma; Lymphoma, Non-Hodgkin; Male; Melphalan; Nimustine; Recurrence; Retrospective Studies; Stem Cell Transplantation; Survival Rate; Transplantation Conditioning; Transplantation, Homologous

To establish mouse lymphoma EL4 tumor-bearing mouse models in wild type C57BL/6 mice and nude C57BL/6 mice respectively, and to further investigate the immunological mechanisms of anti-tumor effect of melphalan.. Mouse lymphoma EL4 cells were inoculated subcutaneously into wild type C57BL/6 mice (immune-competent mice). Twelve days later, melphalan of different doses were administered intraperitoneally to treat these wild type C57BL/6 tuomr-bearing mice. Tumor sizes were observed and recorded subsequently to find out the minimal dose of melphalan that could cure the tuomr-bearing mice. Then the same amount of EL4 tumor cells were inoculated subcutaneously into wild type C57BL/6 mice and nude C57BL/6 mice (T cell-deficient mice) simultaneously, which had the same genetic background of C57BL/6. Twelve days later, melphalan of the minimal dose was given intraperitoneally to treat both the wild type and nude C57BL/6 tuomr-bearing mice. Tumor sizes were observed and recorded in these two different types of mice subsequently.. A single dose of melphalan (7.5 mg/kg) could cure EL4 tumor-bearing wild type C57BL/6 mice, but could not induce tumor regression in EL4 tumor-bearing nude C57BL/6 mice.. A single dose of melphalan has obvious anti-tumor effect on mouse lymphoma EL4 tumor-bearing wild type C57BL/6mice, which requires the involvement of T lymphocytes in the host probably related to their killing functions.

Topics: Animals; Antineoplastic Agents, Alkylating; Disease Models, Animal; Lymphoma; Melphalan; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Xenograft Model Antitumor Assays

To investigate the relationship between IFN-gamma and anti-tumor effects of melphalan in vivo.. Different gene-type mice (IFN-gamma(+/+), IFN-gamma(+/-) and IFN-gamma(-/-)), which had the same genetic background of C57BL/6, were used in this experiment. Murine lymphoma EL4 cells were inoculated subcutaneously into different gene-type mice simultaneously. Twelve days later, 7.5 mg/kg melphalan was used intraperitoneally to treat all these IFN-gamma(+/+), IFN-gamma(+/-) and IFN-gamma(-/-) tumor-bearing mice. Tumor size was observed and recorded every one to three days in these different gene-type mice subsequently.. After melphalan (7.5 mg/kg) treatment, tumor size decreased at a similar rate in IFN-gamma(-/-), IFN-gamma(+/-) and IFN-gamma(+/+) mice within the first 3 d. Tumors shrank further or completely disappeared in most of IFN-gamma(+/-) and IFN-gamma(+/+) mice, whereas tumors grew gradually in all IFN-gamma(-/-) mice.. 7.5 mg/kg melphalan has obvious anti-tumor effects on tumor-bearing IFN-gamma(+/+) and IFN-gamma(+/-) mice, but little effects on IFN-gamma(-/-) mice. These data suggest that IFN-gamma is required for the anti-tumor effects of melphalan on tumor-bearing mice in vivo.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Genotype; Interferon-gamma; Lymphoma; Melphalan; Mice; Mice, Inbred C57BL; Survival Rate; Time Factors

We prospectively assessed the effectiveness of cryotherapy after high-dose L-PAM to prevent oral mucositis. Cryotherapy with ice tips was commenced 15 minutes before L-PAM administration, and continued until the end of administration. Twenty-six patients were enrolled in this study. Thirteen patients with myeloma were treated with 200 mg/m2 L-PAM followed by autologous peripheral blood stem cell transplantation, and 13 patients (4 AML, 4 MDS, 2 ALL, 2 lymphoma and 1 CML) were treated with 140 mg/m2 L-PAM followed by allogeneic stem cell transplantation. Grade 1 mucositis occurred in four of 13 patients (31%) with 200 mg/m2 L-PAM, and 2 of 13 patients (16%) with 140 mg/m2 L-PAM. Only one patient had grade 2 mucositis, and no grade 3 mucositis were observed. The procedure was well tolerated in all patients. These data suggest that cryotherapy is effective to minimize L-PAM-induced oral mucositis.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Cryotherapy; Female; Humans; Leukemia; Lymphoma; Male; Melphalan; Middle Aged; Stem Cell Transplantation; Stomatitis

It has recently been demonstrated that autologous bone-marrow transplantation (ABMT) is feasible in heavily pretreated patients who do not mobilize peripheral blood progenitor cells (PBPC), suggesting that bone marrow (BM) progenitor-cells are not as sensitive to chemotherapy as are PBPC. However, information regarding the impact of previous chemotherapy on the performance of BM grafts is scanty.. We have retrospectively analyzed 40 consecutive lymphoma patients treated with the BEAM regimen and ABMT at our institution. The impact of the chemotherapeutic drugs (individual cumulative doses) received before transplant on stem-cell yield and hematologic recovery was investigated. Univariate analysis failed to identify any variable that significantly affected progenitor-cell content.. Regarding the impact of pre-transplant chemotherapy on early engraftment, only cumulative doses of cytarabine (r=0.28, p=0.04) and cisplatin (r=0.32,p=0.02) had a negative influence on neutrophil recovery (to >0.5x10(9)/L), but the significance of this was not maintained in multivariate analysis. We did not find any chemotherapeutic drug that negatively affected platelet recovery (to >20x10(9)/L). By contrast, administration of several drugs, including doxorubicin, procarbazine, nitrogen mustard, cytarabine and cisplatin, significantly delayed complete trilineage reconstitution. In multivariate analysis, only previous doxorubicin retained statistical significance (p=0.014).. Our results show that pre-transplant chemotherapy has little or no influence on progenitor-cell yield and short-term engraftment after ABMT. In contrast, we found that cumulative doxorubicin doses have an independent influence on long-term engraftment. In heavily pretreated lymphoma patients in whom poor PBPC mobilization is expected, BMT may represent an attractive option.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Bone Marrow; Bone Marrow Transplantation; Carmustine; Chemotherapy, Adjuvant; Cytarabine; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Humans; Lymphoma; Male; Melphalan; Middle Aged; Multivariate Analysis; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous

Topics: Adult; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Disease Progression; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Prognosis; Remission Induction; Time Factors; Transplantation Conditioning; Treatment Outcome

Between January 1996 and July 2002, 72 patients with non-Hodgkin's lymphoma or Hodgkin's disease underwent high-dose chemotherapy with autologous stem cell transplant conditioned with either cyclophosphamide, etoposide, carmustine (CEB) or carmustine, etoposide, cytarabine, melphalan (BEAM) at a single institution. In all, 52 patients received CEB and 20 patients received the BEAM regimen. Patient characteristics that were significantly different between the two groups are tumor grade and extranodal involvement (P = 0.0196, 0.0341, respectively). Regimen-related toxicities examined yielded only diarrhea occurring at a higher rate in the BEAM group (81 vs 51%, P = 0.0026), although cases were milder (92 vs 57%). Patients treated with CEB developed mucositis at a slightly higher rate (79%) than patients treated with BEAM (75%), but this difference did not reach statistical significance. However, the mucositis that occurred within the BEAM group was predominately mild (67%) in contrast to the predominance of moderate to severe cases in the CEB group (74%). In addition, patients treated with CEB required growth factor support for a longer time than patients treated with BEAM (P = 0.0399). Response rates were high in both groups, with trends favoring the BEAM group. Overall survival was higher after treatment with BEAM than with CEB (84 vs 60%).

Topics: Adolescent; Adult; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Length of Stay; Lymphoma; Male; Melphalan; Middle Aged; Podophyllotoxin; Prognosis; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

The purpose of this evaluation was to investigate the efficacy of high-dose chemotherapy with thiotepa, melphalan, and carboplatin (TMCb), and of autologous peripheral blood stem cell (PBSC) infusion in patients with aggressive non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD). A total of 42 patients, 23 with intermediate-grade NHL and 19 with HD, received thiotepa (500 mg/m2), melphalan (100 mg/m2), and carboplatin (1050-1350 mg/m2) followed by autologous PBSC infusion. Of 21 patients with more advanced disease, four had primary refractory disease, one was in complete remission (CR)-2, 11 were in first refractory relapse, and five were beyond first relapse. Of 21 patients with less advanced disease, two were in CR-1, four were in CR-2, and 15 were in first responding relapse. In all, 14 patients (33%) had received prior radiotherapy prohibiting a total-body irradiation (TBI)-based conditioning regimen. The projected 2-year probabilities of survival, event-free survival (EFS), and relapse for all patients were 0.65, 0.60, and 0.21 (0.85, 0.80, and 0.10 for patients with less advanced disease and 0.47, 0.42, and 0.33 for patients with more advanced disease). The probability of nonrelapse mortality in the first 100 days was 0.12. Grade 3-4 regimen-related toxicities (RRT) occurred in five of 42 (12%) patients and death due to grade-4 RRT occurred in only one (2.5%) patient. These preliminary data suggest that 0.42% EFS in this study for advanced disease patients is highly encouraging and high-dose TMCb followed by autologous PBSC transplantation is well tolerated as well as an effective regimen in patients with intermediate-grade NHL or HD, and may be comparable to some previously used regimens including TBI-based regimens.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Combined Modality Therapy; Female; Humans; Lymphoma; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Retrospective Studies; Stem Cell Transplantation; Survival Analysis; Thiotepa; Transplantation, Autologous; Treatment Outcome

Five lymphoma patients relapsed from allogeneic hematopoietic stem cell transplantation (HSCT). Three patients who received myeloablative conditioning had full donor chimerism at relapse, whereas two who received nonmyeloablative conditioning had partially or completely lost the graft. All received mini-BEAM [carmustine (BCNU), etoposide, cytarabine (AraC), melphalan], followed by infusion of HSC (four peripheral blood, one marrow) from the initial donor. Neutropenia and thrombocytopenia were brief, and full donor chimerism was established in all cases. There were four complete and one partial remissions. Graft-versus-host disease occurred in three cases, all with full donor chimerism at relapse. Two patients died subsequently of disease relapse or progression. Another two patients died from fungal infection, one of whom was still in remission at death. One patient had remained in remission 47 months after treatment. Mini-BEAM/HSC is an effective treatment for lymphoma relapses after allogeneic HSCT, but optimal strategies of remission consolidation and prevention of treatment-related complications are needed to improve outcome.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Etoposide; Female; Graft vs Host Disease; Graft vs Tumor Effect; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Neutropenia; Recurrence; Remission Induction; Thrombocytopenia; Tomography, X-Ray Computed; Transplantation Chimera; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome

Drug delivery and penetration into neoplastic cells distant from tumor vessels are critical for the effectiveness of solid-tumor chemotherapy. We have found that targeted delivery to tumor vessels of picogram doses of TNF-alpha (TNF), a cytokine able to alter endothelial barrier function and tumor interstitial pressure, enhances the penetration of doxorubicin in tumors in murine models. Vascular targeting was achieved by coupling TNF with CNGRC, a peptide that targets the tumor neovasculature. This treatment enhanced eight- to tenfold the therapeutic efficacy of doxorubicin, with no evidence of increased toxicity. Similarly, vascular targeting enhanced the efficacy of melphalan, a different chemotherapeutic drug. Synergy with chemotherapy was observed with 3-5 ng/kg of targeted TNF (intraperitoneally), about 10(6)-fold lower than the LD(50) and 10(5)-fold lower than the dose required for nontargeted TNF. In addition, we have also found that targeted delivery of low doses of TNF to tumor vessels does not induce the release of soluble TNF receptors into the circulation. The delivery of minute amounts of TNF to tumor vessels represents a new approach for avoiding negative feedback mechanisms and preserving its ability to alter drug-penetration barriers. Vascular targeting could be a novel strategy for increasing the therapeutic index of chemotherapeutic drugs.

Topics: Animals; Antineoplastic Agents; Blood Vessels; Capillary Permeability; Dose-Response Relationship, Drug; Doxorubicin; Drug Delivery Systems; Drug Synergism; Drug Therapy, Combination; Lymphoma; Melanoma, Experimental; Melphalan; Mice; Mice, Inbred C57BL; Models, Biological; Neoplasms, Experimental; Receptors, Tumor Necrosis Factor; Recombinant Fusion Proteins; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

We have determined the predictive value of [18F]2-fluoro-2-deoxy-glucose (FDG-PET) in patients with Hodgkin's disease (HD) and aggressive non-Hodgkin's lymphoma (NHL) scheduled for high-dose therapy with stem cell transplantation (HDT/SCT). Inclusion criteria were the presence of an FDG-PET scan after chemotherapy (ChT) within 8 weeks prior to HDT/SCT and available follow-up data. Sixteen patients (10 NHL and six HD) were observed during a follow-up period of 4 to 28 months (median 13 months). Before SCT, five patients had a negative PET, three were weakly positive, two moderately positive, and six strongly positive. None of the five patients with a negative PET before HDT/SCT relapsed and two of three patients with a weakly positive scan are still in remission after HDT/SCT. Of eight patients with a moderate or high positive PET before HDT/SCT, seven relapsed and one died of early HDT/SCT related complications (P< 0.01). Three of eight relapsing patients died of lymphoma 5 to 10 months after SCT and in one additional patient not responding to HDT/SCT, the main cause of death was chronic toxicity 4 months after transplantation. After 12 months, in PET-negative patients the overall and relapse-free survival was 100%, in PET-positive patients 55% and 18%, respectively. In NHL, two patients with negative PET, but with an age-adjusted international prognostic index (AaIPI) of 2 and one with AaIPI = 1 are still in remission. In the seven PET-positive subjects, one patient with AaIPI = 0, three with AaIPI = 1, and two with AaIPI = 2 relapsed. We conclude that FDG-PET is accurate in the prediction of relapse prior to HDT/SCT in patients with lymphoma. It provides additional information when compared with the AaIPI.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Disease-Free Survival; Etoposide; Female; Fluorodeoxyglucose F18; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Lymphoma; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Podophyllotoxin; Prognosis; Radiopharmaceuticals; Survival Analysis; Survival Rate; Tomography, Emission-Computed; Transplantation Conditioning; Treatment Outcome; Whole-Body Irradiation

Hematological and extrahematological toxicity of high-dose (hd) mitoxantrone (MITO) and melphalan (L-PAM) as conditioning regimen prior to peripheral blood progenitor cell (PBPC) autograft was evaluated in 113 lymphoma patients (87 at disease onset). Autograft was the final part of a hd-sequential (HDS) chemotherapy program, including a debulkying phase (1-2 APO +/- 2 DHAP courses) and then sequential administration of hd-cyclophosphamide, methotrexate (or Ara-C) and etoposide, at 10 to 30 day intervals. Autograft phase included: (1) hd-MITO, given at 60 mg/m2 on day -5; (2) hd-L-PAM, given at 180 mg/m2 on day -2; (3) PBPC autograft, with a median of 11 x 10(6) CD34+/kg, or 70 x 10(4) CFU-GM/kg, on day 0. A rapid hematological recovery was observed in most patients, with ANC >500/microL and Plt >20,000/microl values reached at a median of 11 and 10 days since autograft, respectively. The good hemopoietic reconstitution allowed the delivery of consolidation radiotherapy (RT) to bulky sites in 53 out of 57 candidate patients, within 1 to 3 months following autograft; five of these patients required back-up PBPC re-infusion due to severe post-RT pancytopenia. Few severe infectious complications were recorded. There was one single fatal event due to severe pancytopenia following whole abdomen RT. Cardiac toxicity was evaluated as left ventricular ejection fraction (LVEF), monitored by cardiac radionuclide scan. LVEF prior to and after autograft was significantly reduced (median values: 55% vs 46%) in 58 evaluated patients; however, a significant increase to a median value of 50% was observed in 45 patients evaluated at 1 to 3 years since autograft. At a median follow-up of 3.6 years, 92 patients are alive, with a 7-year overall survival projection and 6.7-year failure-free survival projection of 77% and 69%, respectively. We conclude that a conditioning regimen with hd-MITOIL-PAM fits well within the HDS program. It implies good tolerability and reversible cardiotoxicity and it may have contributed to the good long-term outcome observed in this series of patients.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Female; Heart Ventricles; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Mitoxantrone; Retrospective Studies; Transplantation Conditioning; Treatment Outcome

There are several reports describing acute liver decompensation in chronic carriers of HBsAg after withdrawal of chemotherapy or immunosuppressive therapy; recently the same was also reported for chronic HCV-RNA carriers. We retrospectively evaluated hepatic toxicity in eleven patients (6 carriers of HCV-RNA and 5 of HBsAg) autotransplanted at our Institution between March '92 and June '98. Male/female ratio was 7/4, median age 41 years (26-56). Nine patients (4 HBsAg) were affected by non-Hodgkin's lymphoma, 1 (HCV-RNA) by chronic myelogenous leukaemia and 1 (HBsAg) by breast cancer. In the immediate post-transplant period in only 1 patient (HBsAg carrier and affected by breast cancer) was hepatitis documented (at about 1 month from transplant) with an elevation of transaminase levels (x20-40 n.v.). Neither other complications, nor toxic deaths were observed. During the post-transplant follow-up (median 31 months, range 9-83) no hepatic abnormalities were observed. All patients are alive at 56 months (20-122) from diagnosis. Currently 10/11 patients are in complete remission, while 1 patient, affected by follicular centre lymphoma, is alive with disease 52 months from autologous stem cell transplantation. Our study shows that both conventional therapy and high-dose chemotherapy can be performed safely in chronic hepatitis B and C virus carriers.

Topics: Adult; Antineoplastic Agents, Alkylating; Busulfan; Carrier State; Feasibility Studies; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Liver; Lymphoma; Male; Melphalan; Middle Aged; Transplantation Conditioning; Transplantation, Autologous

Autologous transplantation has an established role in the treatment of lymphoproliferative disorders, but allogeneic transplantation remains controversial. In an attempt to reduce the high procedure-related mortality reported with allografting in lymphoma, we have used BEAM (BCNU, etoposide, cytarabine and melphalan), a standard conditioning regimen for autologous transplantation. As BEAM may be insufficiently immunosuppressive to permit durable engraftment in the allogeneic setting, patients received additional pretransplant immunosuppression with the anti-CD52 antibody CAMPATH-1G from day -5 to day -1. Twelve patients (median age 46 years) underwent allogeneic transplantation for lymphoma (n = 11) or chronic lymphocytic leukaemia (n = 1) from HLA-identical (n = 9) or mismatched (n = 3) sibling donors. Cyclosporin A and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. One patient died of progressive lymphoma at day +12, the remaining 11 patients engrafted rapidly, with eight demonstrating full donor chimerism. One patient had an episode of rejection and received a further stem cell infusion with sustained recovery. Only one patient developed GVHD (grade I). The low incidence of acute GVHD may be in part related to persisting levels of in vivo CAMPATH-IG at the time of transplantation. Of 11 evaluable patients, nine achieved complete remission (CR), and a further patient achieved CR after donor lymphocyte infusion at 5 months. Our preliminary experience is that this regimen was well tolerated with a low risk of GVHD and appears no more toxic than a BEAM autograft. Further follow-up is required to see whether the low incidence of GVHD impacts upon relapse risk.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclosporine; Cytarabine; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Lymphoproliferative Disorders; Male; Melphalan; Methotrexate; Middle Aged; Podophyllotoxin; Transplantation Conditioning; Transplantation, Homologous

The traditional indicators of engraftment following PBSC transplantation (PBSCT) are the rising total WBC count and ANC. Reticulocytes may be an earlier indicator, since as reticulocytes mature, there is a gradual loss of cellular RNA, which can be measured using methylene blue and light scatter with an Abbott CD 3500 automated counter (Abbott Laboratories, Maidenhead, U.K.). Reticulocytes can be divided into three fluorescence ratios depending on the amount of light scatter generated, high, medium, and low. The most immature are the high fluorescence reticulocytes (HFR). Standard engraftment parameters together with HFR were measured in a homogeneous group of 25 patients with lymphoma after PBSCT using a standard conditioning protocol. An ANC of 0.5 x 10(9)/L was achieved after a median of 10 days (mean 11.2 days, range 9-22). The recovery of the HFR to 2% of the total reticulocytes was significantly shorter, with a median of 8 days (mean 7.5 days, range 6-10) (p < 0.0001). The values of HFR to 2% preceded the ANC of 0.5 x 10(9)/L in 24 of the 25 patients by a median of 3 days (mean 3.8 days, range 2-12 days). On this basis, it can be determined that in 96% of cases, engraftment was indicated earlier by HFR measurement. The HFR to 2% even preceded the ANC of 0.1 x 10(9)/L in 23 of the 25 patients, showing that engraftment was indicated earlier in 92% of patients. Immature reticulocytes appearing in peripheral blood can be reliably measured by automated cytometers, and HFR can, therefore, be used as an earlier indicator of engraftment following PBSCT. This information provides the opportunity for earlier cessation of antibiotics and growth factors and could lead to earlier discharge from hospital, with cost savings.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Automation; Biomarkers; Carmustine; Cytarabine; Female; Flow Cytometry; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Neutrophils; Podophyllotoxin; Predictive Value of Tests; Reticulocyte Count; Reticulocytes; Time Factors; Transplantation, Autologous

The combination of carmustine, etoposide, cytarabine and melphalan (BEAM) is an effective autologous transplantation preparative regimen for lymphoma and has little toxicity, but the feasibility and tolerance of BEAM as a preparative regimen for allogeneic transplantation has not been established.. Thirty adults with primary refractory or recurrent intermediate- or low-grade lymphoma were treated on a prospective phase II study with carmustine 300 mg/m2 i.v. day -6, etoposide 200 mg/m2 i.v. followed by cytarabine 200 mg/m2 i.v. twice daily days -5 to -2, melphalan 140 mg/m2 i.v. day -1, and marrow or blood stem cells from an HLA-identical donor on day 0. Tacrolimus and methotrexate were used to prevent graft-vs.-host disease (GVHD).. Median time from transplantation was 20 mos (range 6-32 months). Median maximal regimen-related toxicity grade was 2, and four patients (13%) had a grade 3-4 regimen-related toxicity. Two patients had idiopathic interstitial pneumonitis. One patient had primary graft failure, and a second had autologous reconstitution documented at three months posttransplant. Grades 2-4 acute GVHD occurred in 31%, grades 3-4 in 16%, and chronic GVHD in 54%. Day-100 survival was 70%. Twenty-three patients achieved a complete response. The two-year relapse rate was 23%, survival was 48%, and disease-free survival (DFS) was 42%.. BEAM supports engraftment of allogeneic transplants and is a tolerable preparative regimen for allogeneic transplantation for lymphoma.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Podophyllotoxin; Survival Rate; Transplantation Conditioning; Transplantation, Homologous

The purpose of this study was to determine the effectiveness of second mobilization strategies in patients who yielded < 2.5 x 10(6) CD34+ PBSC/kg after initial mobilization. Repeat mobilization attempts were made with chemotherapy and G-CSF (n = 61) or G-CSF alone (n = 58) in patients who failed initial mobilization with chemotherapy and G-CSF (n = 92) or G-CSF alone (n = 27). A median of 0.27 x 10(6) CD34+ cells/kg per apheresis was collected after the second mobilization, compared with 0.16 with initial harvests (p = 0.0001). Forty-eight percent achieved a target CD34+ cell dose > or = 2.5 x 10(6)/kg when harvests from the first and second mobilizations were combined. Fifteen of 17 patients (88%) with > or = 1.5 x 10(6) CD34+ cells/kg harvested after first mobilization had > or = 2.5 x 10(6) CD34+ cells/kg collected when first and second harvests were combined, as compared with 42 of 102 (41%) achieving < 1.5 x 10(6) CD34+ cells/kg with first PBSC harvests (p = 0.0001). Second mobilizations with chemotherapy and G-CSF or G-CSF alone resulted in similar CD34+ cell yields. Toxicities of second mobilizations were comparable with those of first mobilizations. Seventy-nine patients (66%) received high-dose chemotherapy with PBSC support, with recovery of neutrophils and platelets in a median of 11 and 15 days, respectively. Transplant-related mortality was 4%, and event-free survival at 2 years was 0.34. It was concluded that second mobilization attempts in patients who fail to achieve > or = 2.5 x 10(6) CD34+ cells/kg on initial mobilization were successful in 48% of patients. G-CSF alone was as effective as chemotherapy plus G-CSF in mobilizing CD34+ cells and was associated with less morbidity.

Topics: Adult; Antigens, CD; Antigens, CD34; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Cytapheresis; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cells; Hodgkin Disease; Humans; Lymphoma; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging

We compared retrospectively the efficacy of granulocyte colony stimulating factor (G-CSF) alone with chemotherapy plus G-CSF in mobilizing CD34-positive cells in patients with malignant lymphoma. 35 patients underwent peripheral blood stem cell (PBSC) collection following mobilization either with 24 microg/kg G-CSF for 4 consecutive days (n = 18) or Dexa-BEAM chemotherapy plus 5 microg/kg G-CSF (n = 17). High-dose G-CSF was well tolerated with only slight bone pain and/or myalgia. The Dexa-BEAM therapy required hospitalization with a median duration of 21 d. The median number of apheresis procedures in both groups was two (range two to four), resulting in a median of 5.3 and 5.1 x 10(6) CD34+ cells/kg. No patients in the G-CSF group, but one in the Dexa-BEAM group, failed to reach the target of collecting >2.0 x 10(6) CD34+ cells/kg. The number of CFU-GM (10.4 v 6.0 x 10(5)/kg) and of BFU-E (10.6 v 4.5 x 10(5)/kg; P = 0.04) was higher in the G-CSF group than in the Dexa-BEAM group. A subset analysis of CD34+ cells was performed in 16 patients showing a higher mean of Thy-1 (CD90w) coexpression in the G-CSF than in the Dexa-BEAM group (4.8 v 1.8%, P = 0.12). Additionally the percentage of CD34+/CD38- cells was higher in the G-CSF group (10.66% v 8.8%). However, these differences were not statistically significant. The median time to leucocyte and platelet engraftment after high-dose chemotherapy was slightly shorter in the G-CSF than in the Dexa-BEAM group (9 v 10 and 12 v 13.5 d, respectively). These results demonstrate that high-dose G-CSF is as effective as Dexa-BEAM plus G-CSF in mobilizing peripheral blood stem cells and produces prompt engraftment. The major advantages of G-CSF mobilization were the safe outpatient self-application and the fixed-day apheresis.

Topics: Adolescent; Adult; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Colony-Forming Units Assay; Cytarabine; Dexamethasone; Etoposide; Female; Filgrastim; Graft Survival; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hospitalization; Humans; Lymphoma; Male; Melphalan; Middle Aged; Recombinant Proteins; Retrospective Studies

The high-dose sequential regimen developed by Gianni et al. in Milan is a novel concept in which five active drugs are administered sequentially at their maximum tolerated dosages. In previous studies this treatment was efficacious in relapsed Hodgkin's disease and in "de novo" high-risk high-grade NHL. We tested the feasibility, toxicity and efficacy of this approach, administered with simplified supportive measures, as salvage regimen for patients with relapsed (n = 17) or resistant (n = 3) lymphoma (9 high-grade NHL, 4 low-grade NHL and 7 Hodgkin's disease). The regimen included sequential administration of cyclophosphamide (7 g/m2), methotrexate (8 g/m2), etoposide (2 g/m2), mitoxantrone (60 mg/m2) and melphalan (180 mg/m2) over a period of 8 weeks in an effort to reduce hospitalisation to a minimum. Of the 20 initial patients, 15 completed the planned programme. The regimen was subjectively well tolerated despite frequent hospital stays (median 44 days). Recovery of absolute neutrophil and platelet counts after transplantation occurred on the average on days 13 and 11 respectively. A second neutrophil and platelet nadir was seen 7-8 weeks after transplantation. Long-term side effects were a severe stenosing postactinic oesophagitis and a secondary subacute monoblastic leukaemia. At a median follow-up of 24 months, the 2 years disease-free and overall survival are 27% and 60% respectively. Of the 15 patients actually transplanted, 7 (47%) are alive disease-free. Although as feasible and effective as other high-dose regimens, this regimen requires longer hospital stays and its costs may be higher than those of other high-dose programmes.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Drug Resistance, Neoplasm; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Methotrexate; Middle Aged; Mitoxantrone; Neoplasm Recurrence, Local; Stem Cells

ID50 and ID90 values for L-prolyl-L-m-[bis(chloroethyl)amino]-phenylalanyl-L-norvaline ethyl ester HCl (MF13), were determined in four murine (leukemia, lymphoma, melanoma, and lung) and eight human cancer cell lines (two leukemia, prostate, kidney, colon, two melanoma, and breast). Cytotoxic activity was 2-5 times higher than that of sarcolysin [(L-3-[bis(2-chloroethyl)amino]-L-phenylalanine] against all leukemias and lymphomas, ID50 0.5-0.9 microM, and against human solid tumors, ID50 0.4-2.1 microM. Sensitivities of L-phenylalanine mustard-resistant and methotrexate-resistant L1210 cells were the same as the naive lines, ID50 0.5 microM. Apoptosis was confirmed by: (a) morphology, revealing chromatin condensation and nuclear fragmentation; (b) flow cytometry, showing changes in cell size and DNA integrity; and (c) DNA electrophoresis, demonstrating multiples of 180-200-bp DNA units. MF13 had no cytotoxicity against human peripheral blood lymphocytes at concentrations lethal to tumor cells (ID50, 13.3 microM without and 11 microM with phytohemagglutinin stimulation) and failed to induce apoptosis. s.c. MF13 treatment of mice with advanced EL4 leukemic ascites yielded extensive apoptosis, with DNA degradation identical to that seen in vitro, and resulted in complete tumor regression in all treated mice. These results suggest MF13 as a potential chemotherapeutic agent.

Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Cell Survival; DNA Fragmentation; DNA, Neoplasm; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Flow Cytometry; Humans; Lethal Dose 50; Leukemia; Leukemia L1210; Lymphoma; Melphalan; Methotrexate; Mice; Neoplasms; Oligopeptides; Tumor Cells, Cultured

We have investigated the toxicity of dose-escalation of BCNU, etoposide and melphalan ('BEM') chemotherapy with autologous stem cell transplantation in patients with haematological malignancies. Seventy-two patients with haematological malignancies were treated with BCNU (600 mg/m2, 450 mg/m2 or 300 mg/m2), etoposide 2 g/m2 and melphalan 140 mg/m2 followed by autologous bone marrow transplantation (ABMT), n = 51, or autologous peripheral blood progenitor cell transplantation (APBPCT), n = 21. Liver and pulmonary function was monitored pretransplant and at regular intervals post-transplant. Mucositis was graded daily during in-patient stay. There was a significantly higher incidence of symptomatic pulmonary toxicity in the patients who received BCNU at 600 mg/m2 than in the other two groups, and there was a significant increase in the incidence of asymptomatic decrease in carbon monoxide (KCO) in the patients who received BCNU 450 mg/m2. There was no significant difference between the three groups in the incidence and severity of mucositis or in the incidence of transiently abnormal liver function. We conclude that etoposide at 2 g/m2 can be used without unacceptable mucositis. BCNU at 600 mg/m2 is associated with an unacceptably high incidence of lung toxicity, but at 450 mg/m2 there is minimal symptomatic lung toxicity.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Dose-Response Relationship, Drug; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Liver Function Tests; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Respiratory Function Tests; Retrospective Studies; Transplantation, Autologous

We report that in cancer patients a dramatic reduction in infection rate, days of isolation, oral mucositis and hospitalization due to high-dose chemotherapy is achievable by autografting with haematopoietic progenitor cells (CPCs) circulating in peripheral blood following cancer therapy with high-dose cyclophosphamide (HD-CTX) and administration of recombinant haematopoietic cytokines. Thirty patients (29 lymphomas, one breast cancer) were treated with total body irradiation and high-dose melphalan followed by either: (i) bone marrow transplant (Group A); (ii) bone marrow plus HD-CTX-mobilized CPC transplant (Group B); or (iii) bone marrow plus HD-CTX- and cytokine-mobilized CPC transplant (Group C). Nursing care load was remarkably higher in Group A patients compared to Group B and C patients, thus demonstrating clinical advantages of transplantation of HD-CTX-f and cytokine-mobilized CPCs.

Topics: Adolescent; Adult; Antineoplastic Agents, Alkylating; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; Erythroid Precursor Cells; Female; Humans; Lymphoma; Male; Melphalan; Middle Aged; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation; Workload

The purpose of this study was to demonstrate the reconstitutive potential of granulocyte colony-stimulating factor (G-CSF) (filgrastim; Neupogen-primed unprocessed whole blood after myelotoxic therapy in bad-risk lymphoma. Nine patients with resistant lymphoma were treated with BAM: a BEAM regimen modified to a 72 h course consisting of BCNU 300 mg/m2 i.v. (day 1), Ara-C 3000 mg/m2 i.v. q 12 h (day 2) and melphalan 140 mg/m2 i.v. (day 3). After 5 days stimulation with G-CSF (10 micrograms/kg) 1l of blood was drawn, kept unprocessed for 3 days and reinfused 24 h after completion of chemotherapy. Back-up peripheral stem cells were available for all patients. The neutrophil count reached 0.5 x 10(9)/l at a median of 16 days (range 11-25) and a platelet count of 10 x 10(9)/l was reached at a median of 20 days (range 11-NR (not reached)). The median length of hospital stay was short in these patients with a median of 19 days (range 17-33). In three patients platelet transfusion independence did not occur before day 28. Those patients received their back-up stem cells. Antibiotics had to be used in two patients. The median number of reinfused CD34+ cells was 0.28 x 10(6)/kg (range 0.01-0.59). When more than 0.2 x 10(6)/kg CD34+ cells were reinfused the time to recovery was comparable to that observed after 'classical PBSCT'. In conclusion, the use of G-CSF-stimulated unprocessed whole blood is easy to perform and a cheap technique to mobilize and collect stem cells that can serve as a stem cell source after severe myelotoxic therapy in bad-risk malignant lymphoma.

Topics: Adult; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cold Temperature; Combined Modality Therapy; Cytarabine; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Podophyllotoxin

Intermediate-dose salvage therapy is frequently given for relapsed and resistant lymphomas and is usually intensely myelosuppressive. In an attempt to reduce the haematological toxicity of miniBEAM, one of the commonly used salvage regimens, peripheral blood stem cell (PBSC) support was given to 21 consecutive patients who received miniBEAM chemotherapy. The outcome was compared with a non-randomised control group of consecutive patients who were similar to the supported group apart from the fact that it was not possible to collect PBSC before miniBEAM therapy. Apart from a small, marginally significant difference between the supported and unsupported groups in the number of days for which intravenous antibiotics were required, there were no other differences between the two groups in supportive care required and times to haematological recovery. In conclusion, PBSC support does not accelerate haematological recovery from miniBEAM therapy.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Etoposide; Female; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged

Bone marrow transplant (BMT) complications such as graft-versus-host disease (GVHD), veno-occlusive disease (VOD) and cytomegalovirus (CMV) infection are associated with high levels of circulating tumour necrosis factor-alpha (TNF), much of which may be monocyte derived. We therefore studied monocyte activation after BMT in 36 patients (18 allografts and 18 autografts); plasma neopterin and in vitro secretion of superoxide, neopterin and TNF by peripheral blood monocytes were assessed. Monocyte respiratory burst was raised at regeneration but returned to near-normal within 7 days. Plasma neopterin, and in vitro secretion of neopterin and TNF, were greater than twice normal at regeneration and remained raised for up to 6 weeks after BMT. Plasma neopterin was higher following allogeneic BMT than autologous BMT and was independent of GVHD or VOD. Low levels were seen in one patient who failed to engraft. There is evidence of increased activation of monocytes at the time of and for several weeks after engraftment post-BMT. Abnormal monocyte activation may predispose to, rather than result from, the development of complications in the early post-transplant period.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Biopterins; Bone Marrow Transplantation; Busulfan; Carmustine; Cells, Cultured; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Disease Susceptibility; Female; Graft vs Host Disease; Hepatic Veno-Occlusive Disease; Humans; Leukemia; Lymphoma; Male; Melphalan; Middle Aged; Monocytes; Neopterin; Podophyllotoxin; Respiratory Burst; Superoxides; Tumor Necrosis Factor-alpha; Whole-Body Irradiation

We have assessed the potential use of the mononuclear cell (MNC) content as the sole assessment of graft quality in 35 patients receiving BEAM (carmustine, etoposide, cytosine arabinoside, melphalan) chemotherapy and autologous peripheral blood progenitor cell (PBPC) transplantation for malignant lymphoma. PBPCs were mobilized with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF), and each patient underwent two (n = 20) or three (n = 15) apheresis procedures. Median cell yields were 5.08 x 10(8) MNC/kg (range 1.59-15.70 x 10(8)) and 73.10 x 10(4) CFU-GM/kg (range 0.09-346.72 x 10(4)). All patients achieved hematologic recovery. Median days to neutrophils > or = 0.1 x 10(9)/L, neutrophils > or = 0.5 x 10(9)/L, and platelets > or = 25 x 10(9)/L were 11 (range 8-15), 13 (range 10-37), and 11 (range 7-41), respectively. A close correlation was observed between the MNC and CFU-GM dose (r = 0.79, p < 0.0001). We have previously defined a minimum threshold CFU-GM dose of 20 x 10(4)/kg for patients undergoing high-dose therapy. This corresponds with an MNC dose of 3 x 10(8)/kg. Comparison of engraftment in patients receiving 3 x 10(8) MNC/kg with those receiving lower doses demonstrated significantly longer times to recovery of neutrophils to > or = 0.5 x 10(9)/L and platelets to > or = 25 x 10(9)/L. All patients receiving an MNC dose of > or = 3 x 10(8)/kg achieved neutrophil and platelet recovery by days 12 and 24, respectively. These preliminary data demonstrate that for patients with lymphoma undergoing PBPC mobilization according to this protocol and treatment with BEAM chemotherapy, assessment of MNC dose alone is sufficient to predict early hematologic recovery. Additional assays such as CFU-GM or CD34+ cell counts may not be necessary if this MNC dose is reinfused.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Cytarabine; Etoposide; Female; Graft Survival; Granulocyte Colony-Stimulating Factor; Granulocytes; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Leukapheresis; Leukocyte Count; Leukocytes, Mononuclear; Lymphoma; Lymphoma, Non-Hodgkin; Macrophages; Male; Melphalan

Seventy-three BMT procedures (42 allogeneic-BMT, 30 autologous-BMT, 1 syngeneic transplant) were undertaken at the Shariati Hospital in Tehran between March 1991 and November 1993. Allogeneic-BMT was performed for thalassaemia major (n = 23), AML in complete remission (n = 3), severe aplastic anaemia (n = 7), CML (n = 7), dyskeratosis congenita (n = 2) and Fanconi anaemia (n = 1). Conditioning regimens comprised busulphan (BU) plus cyclophosphamide (CY) or CY only. Thirty-two (78%) of the 43 patients remain alive 1-34 months after BMT. Twelve patients died: the causes of death were haemorrhagic cystitis (n = 1), CMV pneumonitis (n = 1), GVHD (n = 3), infection (n = 3), rejection (n = 1), VOD (n = 2) and hepatitis (n = 1). Autologous-BMT was performed for patients with AML in CR (n = 16), ALL in CR (n = 9), lymphoma in relapse (n = 3), Ewing sarcoma (n = 1) and multiple myeloma (n = 1). The median age was 18 years. Conditioning regimens were Ara C plus CY, etoposide plus CY and high-dose melphalan. Sixteen (54%) of the 30 patients survive, 14 in continuous complete remission. The causes of death were relapse (AML (n = 7), ALL (n = 4), lymphoma (n = 1)), VOD (n = 1) and infection (n = 1).

Topics: Adolescent; Adult; Anemia, Aplastic; beta-Thalassemia; Bone Marrow Transplantation; Busulfan; Child; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Drug Therapy, Combination; Female; Financing, Personal; Graft vs Host Disease; Humans; Insurance, Health, Reimbursement; Iran; Lymphoma; Male; Melphalan; Middle Aged; Transplantation, Autologous; Transplantation, Homologous

We have previously reported that the rate of haematopoietic recovery following Autologous Blood Stem Cell Transplantation (ABSCT) could be influenced by the type of conditioning regimen or by the underlying disease. Furthermore, Peripheral Blood Stem Cell (PBSC) growth was found to be sensitive to stimulation by irradiated allogeneic stromal layers. In the present study, we used the long term culture system (LTC) to investigate the quality of the bone marrow (BM) microenvironment from patients who had undergone ABSCT for either Malignant Lymphoma (ML, 13 patients) or Multiple Myeloma (MM, 8 patients) after conditioning regimens comporting myeloablative chemotherapy (CT) or Total Body Irradiation (TBI). Among the 13 ML patients, 10 received CT conditioning and 9 of the 10 BM samples developed a complete confluent stromal layer. The remaining 3 ML patients received TBI prior to ABSCT and 2 of the 3 samples developed confluent stroma. In contrast, when LTC were established with BM from the 8 MM patients, all of whom were treated with TBI prior to ABSCT, only 3 of the 8 marrow samples developed a complete confluent stromal layer. Thus BM from patients who had received CT conditioning therapy tended to form confluent stroma more often than BM from those who had received TBI (p = 0.08). CFU-GM production was also evaluated for the stromal layers derived from all transplanted patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Bone Marrow; Carmustine; Cells, Cultured; Colony-Forming Units Assay; Connective Tissue; Cyclophosphamide; Cytarabine; Etoposide; Graft Survival; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Melphalan; Multiple Myeloma; Transplantation, Autologous; Whole-Body Irradiation

Thirteen post-pubertal male patients aged 17-25 years were assessed for pituitary-gonadal function 0-3 months prior to and 2-3 months post-bone marrow transplantation for haematological malignancy. All patients had multiagent cytotoxic treatment prior to transplantation and 30% were found to have germ cell dysfunction with abnormal semen parameters before high-dose therapy indicating damage to the germinal epithelium. They also had evidence of reduced Leydig cell reserve even before transplantation. During transplantation all patients sustained sustained gonadal injury, the effect on their germ cells being more pronounced than on the Leydig cells. Fifty per cent had reduction in testicular volume and all had azoospermia 2-3 months post-transplantation. Our results indicate that short-term chemoradiotherapy causes profound damage to the germ cell compartment of the testis, with less severe damage to the Leydig cells, but no overt injury to the anterior pituitary gland. The changes appeared to be identical in patients conditioned with total body irradiation-based protocols and those who received only high-dose chemotherapy prior to bone marrow transplantation.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Combined Modality Therapy; Cytarabine; Etoposide; Follicle Stimulating Hormone; Humans; Leydig Cells; Luteinizing Hormone; Lymphoma; Male; Melphalan; Spermatozoa; Transplantation, Autologous

The mini-BEAM regimen (BCNU, etoposide, cytarabine, melphalan) and its modification 'Dexa-BEAM' are effective salvage protocols for relapsed Hodgkin's disease and non-Hodgkin's lymphoma. Since many patients with relapsed lymphoma are eligible for high-dose chemotherapy with autologous stem cell rescue, we were interested in the suitability of these second line regimens for mobilising peripheral blood progenitor cells (PBPC). The kinetics of PBPC were studied in 15 patients treated with Dexa-BEAM and granulocyte colony-stimulating factor (G-CSF). Leukocytes started to rise from < 0.5 nL-1 on day 18 (16-22) after Dexa-BEAM, and exceeded 10 nL-1 on day 20 (18-28). Peripheral blood CFU-GM peaked on day 21 (19-28) and declined slowly thereafter; the median leukocyte count was 18.7 nL-1 (12.2-60) on the day of CFU-GM-peak. The maximum number of CFU-GM circulating in peripheral blood was inversely correlated to the duration of leukopenia after Dexa-BEAM. Measurement of CD34+ cells with the monoclonal antibody 8G12-PE (HPCA-2) predicted the number of CFU-GM precisely in both peripheral blood and leukapheresis products (r = 0.90-0.95). Two to six leukapheresis procedures yielded 6.39 x 10(8) mononuclear cells kg-1 (1.82-13.49) containing 44.4 x 10(4) CFU-GM kg-1 (2.2-213.8). Immunophenotypical analysis revealed that the percentage of CD19+ B cells was very low in all collection products (less than 1%). Nine patients were autografted with PBPC (15.4-213.8 x 10(4) CFU-GM kg-1) after myeloablative chemotherapy and experienced rapid and sustained engraftment (Platelets > 50 nL-1 on day +13 [9-22]). We conclude that PBPC can be mobilised effectively by Dexa-BEAM plus G-CSF. An adequate timing of PBPC collection (when the leukocyte count has exceeded 10 nL-1) and evaluation of the progenitor content of the leukapheresis products with 8G12-PE will allow to minimise the number of leukaphereses.

Topics: Adult; Antigens, CD; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Cytarabine; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Leukapheresis; Lymphoma; Male; Melphalan; Middle Aged; Salvage Therapy; Time Factors

The two monoclonal antibodies (mAb), L6 (anti-carcinoma), and 1F5 [anti-(B-cell-lymphoma)], were chemically linked to the enzyme penicillin-V amidase (PVA), which hydrolyzes phenoxyacetamides, to explore the potential of using mAb-enzyme conjugates for the localization of chemotherapeutic drugs at tumor cells. The phenoxyacetamide derivatives of doxorubicin and melphalan were prepared, yielding the less toxic amides, doxorubicin-N-p-hydroxyphenoxyacetamide (DPO) and melphalan-N-p-hydroxyphenoxyacetamide (MelPO). These were hydrolyzed by PVA to doxorubicin and melphalan respectively. In vitro studies with the L6-positive lung carcinoma cell line, H2981, and the 1F5-positive B-cell lymphoma line, Daudi, showed that DPO was 80-fold less toxic to H2981 cells and 20-fold less toxic to Daudi cells than doxorubicin, and its toxicity was substantially increased when the H2981 cells were pretreated with L6-PVA or the Daudi cells were pretreated with 1F5-PVA. The cytotoxic effect was antigen-specific, since only the binding mAb-enzyme conjugate increased the cytotoxicity of the prodrug. MelPO was more than 1000-fold less toxic than melphalan to H2981 cells and more than 100-fold less toxic than melphalan to Daudi cells. Pretreatment with the mAb-PVA conjugates did not enhance the toxicity of MelPO in either cell line, because PVA hydrolyzes the phenoxyacetamide bond of MelPO too slowly to generate a toxic level of melphalan.

Topics: Amidohydrolases; Antibodies, Monoclonal; Antigens, Neoplasm; Carcinoma; Doxorubicin; Humans; Immunotoxins; Lymphoma; Melphalan; Penicillin Amidase; Penicillin V; Prodrugs; Tumor Cells, Cultured

We have previously demonstrated that depletion of CD8+ T-cells by the use of a monoclonal anti-Lyt-2.2 antibody abolishes the curative effectiveness of low-dose melphalan (L-phenylalanine mustard; L-PAM) therapy for BALB/c mice bearing a large (greater than or equal to 20 mm) s.c. MOPC-315 tumor and extensive metastases (Mokyr et al., Cancer Res., 49: 4597-4606, 1989). Here we show that as a consequence of low-dose L-PAM therapy, CD8+ T-cells accumulate in the s.c. tumor nodules of MOPC-315 tumor bearers. Specifically, an 80-fold increase in the number of CD8+ T-cells was seen within 5 days after the chemotherapy. Treatment of MOPC-315 tumor bearers with low-dose L-PAM in conjunction with monoclonal anti-Thy-1.2 or anti-Lyt-2.2 antibody, in contrast to treatment with monoclonal anti-L3T4 antibody, prevented the appearance of the massive CD8+ T-cell infiltrate in the s.c. tumor nodules. Fresh CD8+ T-cells derived from s.c. MOPC-315 tumor nodules that were regressing as a consequence of low-dose L-PAM therapy exhibited a potent direct lytic activity against the MOPC-315 plasmacytoma in a short-term in vitro assay. The specificity of the lytic activity exhibited by the CD8+ T-cells was illustrated not only by the inability of the CD8+ T-cells to lyse two antigenically unrelated thymomas (the WEHI 22.1 and the EL-4) and a natural killer-sensitive lymphoma (the YAC-1), but also by their relatively weak lytic activity against an antigenically related plasmacytoma (the MOPC-104E). Thus, CD8+ T-cells that infiltrate the s.c. tumor nodules of MOPC-315 tumor bearers following low-dose L-PAM therapy most likely exploit a CTL-type lytic mechanism to eradicate at least part of the large tumor burden not eliminated by the direct antitumor effects of the drug.

Topics: Animals; Antibodies, Monoclonal; Antigens, Differentiation, T-Lymphocyte; CD8 Antigens; Female; Immunohistochemistry; In Vitro Techniques; Lymphoma; Melphalan; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Plasmacytoma; T-Lymphocytes, Cytotoxic; Thymoma

The pharmacokinetics and systemic availability of melphalan after high-dose oral administration with and without 1,3-bis(2-Chloroethyl)-1-nitrosourea (BCNU) or etoposide were examined in three patients undergoing autologous bone marrow transplantation. Patient 1 (advanced melanoma) received melphalan at 80 mg/m2/day p.o. on days -6, -5, and -4, followed by BCNU at 300 mg/m2/day i.v. on days -3, -2, and -1 prior to bone marrow transplantation. Patient 2 (advanced colon carcinoma) received melphalan at 75 mg/m2/day p.o. on days -3, -2, and -1. Patient 3 (advanced refractory lymphoma) received etoposide at 800 mg/m2/day i.v. on days -7, -5, and -3, followed by melphalan at 157 mg/m2/day p.o. on days -2 and -1. Melphalan was administered as a bolus oral dose, using 2-mg tablets. Blood samples were collected at 0, 5, 10, 15, 30, and 45 min and 1, 2, 3, 4, 6, 8, 12, and 24 h after each dose of melphalan. Peak plasma melphalan concentrations in the three patients ranged from 0.354 (patient 2) to 1.768 micrograms/ml (patient 1). Plasma melphalan concentration X time products (C x Ts) showed extreme variability in one patient (patient 2), ranging from 0.76 to 4.48 micrograms.h/ml. To determine the relative systemic availability of orally administered melphalan, i.v. C X Ts proportional to the p.o. doses were extrapolated from previously reported i.v. bolus pharmacokinetic data. The p.o.:i.v. plasma C X T ratios for high-dose melphalan ranged between 0.09 (patient 3) and 0.58 (patient 2). Although these C X T data suggest a dose-response for orally administered melphalan, the systemic availability of these high p.o. melphalan doses was extremely variable, both within and between study patients. Thus, we cannot recommend the use of high-dose p.o. melphalan regimens in patients undergoing autologous bone marrow transplantation.

Topics: Adenocarcinoma; Administration, Oral; Adult; Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Bone Marrow Transplantation; Carmustine; Etoposide; Female; Humans; Injections, Intravenous; Lymphoma; Male; Melanoma; Melphalan; Middle Aged; Time Factors

Topics: Animals; Biological Transport; Humans; Lymphoma; Melphalan; Mice; Multiple Myeloma; Tumor Cells, Cultured

Mice cured from large MOPC-315 tumors by a single dose of melphalan, 7.5 mg/kg, were examined for up to 60 days after the drug treatment (71 days after the tumor inoculation) for their ability to respond to mitogenic stimulation, specific and nonspecific antigenic stimulation and for their susceptibility to inoculation with an unrelated tumor, L10 lymphoma. The response of spleen cells from cured mice to mitogenic stimulation by phytohemagglutinin or concanavalin A was slightly depressed at an early stage after the drug treatment. The allogeneic response against C57BL spleen cells and the antibody response against sheep red blood cells (SRBC) of spleen cells from cured mice remained below normal levels during the whole observation period. The deficiency in response to antigenic stimulation was found to be due to impairment in T-cell function. Cured mice were also deficient in their response to SRBC immunization (antibody and delayed-type hypersensitivity responses) and were more susceptible to inoculation with an unrelated tumor, L10 lymphoma, than normal, noninoculated mice. On the other hand, spleen cells of cured mice developed a highly specific cytotoxic response against target MOPC-315 tumor cells and the cured mice were resistant to challenge with an otherwise highly tumorigenic dose of MOPC-315. Thus, cured mice remained deficient for a long period of time in their response to MOPC-315-unrelated antigens but, at the same time, they showed a potent specific antitumor immunity potential in vivo and in vitro.

Topics: Animals; Antibody Formation; B-Lymphocytes; Cytotoxicity, Immunologic; Dose-Response Relationship, Immunologic; Hypersensitivity, Delayed; Immunity; Lymphocyte Activation; Lymphoma; Melphalan; Mice; Mitogens; Plasmacytoma; Spleen; T-Lymphocytes

Chromosome lesions detected in lymphocytes from 14 patients previously treated with melphalan, a bifunctional alkylating agent, have been analyzed on R-banded preparations. In comparison to controls, there was no significant increase of chromatid-type lesions, but chromosome-type lesions were quite frequent, affecting 21.5% of metaphases, on the average. Reciprocal translocations represent 54%, unbalanced translocations 15%, deletions 19% and inversions 6% of all rearrangements. Most of these would not have been detected without the use of chromosome banding. The distributions of affected chromosomes and chromosome bands were not random. Almost all imbalances resulting from rearrangements lead to losses but not to gains. The distribution of the abnormal chromosomes has been compared to that observed in controls and in in vitro experiments, and to the characteristic pattern of malignant cells from patients affected by secondary acute leukemia (ANLL).

Topics: Breast Neoplasms; Chromosome Aberrations; Chromosome Banding; Chromosome Deletion; Chromosome Inversion; Humans; Lymphocytes; Lymphoma; Melphalan; Translocation, Genetic

Twenty-six patients (median age 33 years) with poor-risk malignancies were treated with high-dose combination chemotherapy associating BCNU-etoposide-cytosine arabinoside and melphalan (BEAM) followed by autologous bone marrow transplantation (ABMT). Twenty-one patients had malignant lymphomas, three, acute lymphoblastic leukemia (ALL), and two, malignant thymomas. Eleven patients (group 1) were not in complete remission (CR) at the time of BEAM, and fifteen patients (group 2) were in CR. Hematological recovery occurred in all patients. The duration of aplasia and the non-hematological toxicities were similar in both groups. Ten of the eleven patients (group 1) evaluable for response achieved CR and one achieved partial remission (PR). Five patients relapsed, and five are in continuous CR with a short follow-up (median 8 months). Among the fifteen patients in CR at the time of BEAM (group 2), four patients relapsed and ten patients are in unmaintained continuous CR with a median follow-up of 15 months (one patient died in CR). The disease-free survival is 53%, with 29% for patients receiving BEAM while in relapse (group 1) and 65% for patients receiving BEAM while in CR (group 2). These data indicate that BEAM followed by ABMT can produce a high antitumor response with an acceptable toxicity in patients with poor-risk malignancies.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Etoposide; Female; Hematologic Diseases; Humans; Leukemia, Lymphoid; Lymphoma; Male; Melphalan; Middle Aged; Recurrence; Remission Induction; Thymoma; Thymus Neoplasms

Eighteen patients with high-grade malignant lymphoma were treated with ifosfamide-VP16213 combinations after failing to respond completely or after relapsing on CHOP-like therapy. Responders to the salvage therapy were subsequently treated with ablative chemotherapy (BCNU, VP-16213, Ara-C and melfalan) and autografted. Of these 18 patients six were in relapse, six were partial responders and six failed CHOP-like therapy. There were two complete remissions and seven partial responses to the ifosfamide-VP-16213 combinations. Of them, eight patients were transplanted, together with one non-responder. Four of these nine patients were disease-free survivors 18-34 months after autografting. There were two early deaths: one before and one during the autografting procedure. Using one of the best salvage therapy combinations followed by high-dose chemotherapy and autografting is feasible. The results in this pilot study suggest that an appreciable number of patients may be cured by this procedure.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Combined Modality Therapy; Cytarabine; Etoposide; Humans; Ifosfamide; Lymphoma; Melphalan; Methotrexate; Middle Aged; Mitoguazone; Podophyllotoxin

To increase the accessibility of drug-antibody complexes to tumours and to decrease non-specific binding via Fc receptors N-acetyl-melphalan (N-AcMEL) was conjugated to F(ab')2 fragments. These fragments were synthesised by pepsin degradation of IgG MoAb. Up to 20 molecules of N-AcMEL could be successfully coupled to each F(ab')2 fragment (compared with 25 molecules/intact IgG) with retention of both drug and antibody activity. The N-AcMEL-F(ab')2 conjugates demonstrated specific cytotoxicity in vitro however despite the absence of non specific Fc receptor binding and greater permeability when using F(ab')2 fragments, the N-AcMEL-F(ab')2 and N-AcMEL-IgG conjugates had similar anti-tumour activity in vivo. Conjugates made with whole IgG and F(ab')2 were equally effective in eradicating subcutaneous solid tumours in mice when injected intravenously. The lower immunogenicity of F(ab')2 fragments compared with whole IgG and the similar cytotoxicity of their conjugates, suggests that the F(ab')2 conjugate has greater clinical utility.

Topics: Animals; Antibodies, Monoclonal; Antigens, Ly; Antineoplastic Agents; Immunoglobulin Fab Fragments; Lymphoma; Melphalan; Mice; Mice, Inbred Strains; Neoplasms, Experimental; Thymoma; Thymus Neoplasms

Seventeen patients with advanced lymphoma were treated with high-dose chemotherapy with autologous bone marrow rescue. In 11 patients with non-Hodgkin's lymphoma (NHL) there were 2 complete remissions (CRs) and 2 partial remissions (PRs), and in 6 patients with Hodgkin's disease there were 5 CRs. Three patients remain well in unmaintained remission (days 874, 446 and 351), and a further 2 are alive and still receiving treatment (days 650 and 558). This type of therapy appears useful and should now be considered earlier in the course of the disease.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Cyclophosphamide; Cytarabine; Female; Hodgkin Disease; Humans; Lymphoma; Male; Melphalan; Methotrexate; Middle Aged; Podophyllotoxin

We investigated if high dose melphalan and total body irradiation could be administered to adult patients with acceptable toxicity. Nineteen adult patients with relapsed disease, 15 of them having hematologic malignancies, were treated with high-dose melphalan (100 mg/m2-140 mg/m2) divided over 2 consecutive days followed by a rest period of 4 days before receiving total body irradiation, 850 rad administered in five fractionated doses over 3 days. Subsequently 11 patients received autologous, seven allogeneic and one syngeneic, bone marrow transplantation. All patients had severe myelosuppression and the major extramedullary toxicity was mucositis. There were three early deaths, two related to septicemia and one to graft-versus-host disease with associated cytomegalovirus pneumonitis. All patients were heavily pretreated, and 16 were demonstrating progressive disease on alternative salvage therapies at the time of bone marrow transplantation. Two of the 16 evaluable patients (12.5%) achieved complete remissions, and 10 (63%) achieved partial remissions for a total response rate of 75%. One patient is a long-term disease-free survivor (over 1 yr). An occasional patient may be cured by this approach. The combination of melphalan, an alternative alkylating agent to cyclophosphamide and total body irradiation are associated with moderate gastrointestinal toxicity in heavily pretreated adult patients. The combination warrants further investigation in a less heavily pretreated population to determine more accurately the complete response rate.

Topics: Adult; Bone Marrow Transplantation; Combined Modality Therapy; Female; Graft vs Host Disease; Humans; Lymphoma; Male; Melphalan; Middle Aged; Neoplasms; Platelet Count; Whole-Body Irradiation

Experience with 19 autologous bone marrow transplantations shows that this approach may produce a high proportion of complete remissions in otherwise resistant tumours. Although most responses are of short duration, they suggest that longterm disease-free survival may be achieved in patients with poor prognosis if treated earlier in the course of disease.

Topics: Adult; Bone Marrow Transplantation; Child; Cyclophosphamide; Female; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphoma; Male; Melphalan; Middle Aged; Postoperative Complications; Remission Induction

Adherence to the dose or the need for dose reduction and the duration of treatment intervals were determined retrospectively for 1446 chemotherapy courses in 291 patients with malignant lymphoma and breast cancer. In patients over 60 years of age treated with the COP and COPP regimes there was a significantly higher frequency of deviation from the standard regime than in younger patients; a similar situation was seen in patients with breast cancer. The cause in the elderly patients was presumably due to the higher incidence of non-oncological diseases. In a group treated using the CHOP-scheme there was no difference in comparison with the reference group. In this group patients with severe pre-existent diseases were excluded before treatment. The results indicate that age itself is not a major risk factor for a combination chemotherapy. Pre-existent diseases play a substantial role in the toxicity of cytostatics.

Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Dactinomycin; Doxorubicin; Female; Fluorouracil; Humans; Lymphoma; Male; Melphalan; Methotrexate; Middle Aged; Multiple Myeloma; Prednisolone; Prednisone; Procarbazine; Risk; Vincristine

Topics: Adolescent; Adult; Bone Marrow Transplantation; Cyclophosphamide; Female; Humans; Leukemia; Lymphoma; Male; Melphalan

Eleven adult patients with poor-risk non-Hodgkin's lymphoma were treated with high-dose melphalan (140 mg/m2) or high-dose combination chemotherapy (BCNU, Ara-C, vindesine and melphalan) followed by autologous bone marrow transplantation. Six of the eight patients evaluable for response achieved complete remission and one achieved partial remission. Response duration ranged from 1.5 to 12 months (median 2 months). Prompt hematological recovery occurred in all patients. The duration of aplasia and the extrahematological toxicity were similar in both groups. High-dose melphalan alone or associated with other drugs followed by marrow infusion appears to produce a high response rate and demonstrates the potential for salvaging patients with refractory lymphoma.

Topics: Adult; Bone Marrow Transplantation; Combined Modality Therapy; Drug Evaluation; Female; Humans; Lymphoma; Male; Melphalan; Middle Aged; Risk

58 consecutively referred, previously untreated patients with nodular lymphomas (stages III and IV) were treated with two different combination chemotherapy regimens-(cyclophosphamide, vincristine and prednisone (COP), and BCNU , cyclophosphamide, vincristine, melphalan and prednisone (M-2) - to compare remission induction and duration as well as survival. The two groups were comparable for age, stage IV and histology. The complete response for each combination was greater than 80%. Median duration of remission for the COP-treated patients is 18 months. Remission duration and survival are superior for M-2-treated patients. The difference in remission duration and survival advantage is statistically significant for the M-2 protocol compared with COP at 5 years (p less than 0.01).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Carmustine; Cyclophosphamide; Humans; Lymphoma; Melphalan; Middle Aged; Neoplasm Staging; Prednisone; Probability; Time Factors; Vincristine

Topics: Animals; Cell Line; Cell Survival; Cisplatin; DNA Replication; Dose-Response Relationship, Drug; Humans; Kinetics; Leukemia L1210; Lymphoma; Melphalan; Mice

Topics: Adult; Chlorambucil; Female; Humans; Lupus Erythematosus, Systemic; Lymphoma; Melphalan

Topics: Cells, Cultured; Cytarabine; DNA, Neoplasm; Humans; Lymphoma; Melphalan; Prednimustine; Thymidine; Vincristine

Topics: Bone Neoplasms; Breast Neoplasms; Cyclophosphamide; Humans; Lymphoma; Melphalan; Multiple Myeloma; Neoplasm Metastasis; Palliative Care; Prednisone; Vincristine

Topics: Animals; Antineoplastic Agents; Caffeine; Carcinoma 256, Walker; Cells, Cultured; Drug Synergism; Lymphoma; Mechlorethamine; Melphalan; Rats; Time Factors

Centrophenoxine, without antitumor activity itself, enhanced the cytotoxic action of melphalan and "activated" cyclophosphamide against mouse P388 lymphoma and rat W256 carcinosarcoma cells growing in static suspension culture. The concentration of alkylating agent required for 99% cell-kill was approximately halved when centrophenoxine was also present during exposure to the antitumor drug. Maximum potentiation by centrophenoxine of the cytotoxic action of melphalan occurred when cells were exposed to the two agents simultaneously; little or no potentiation was observed when cells were exposed to centrophenoxine before or after exposure to the alkylating agent.

Topics: Animals; Antineoplastic Agents; Carcinoma 256, Walker; Cell Division; Cells, Cultured; Chlorpromazine; Cyclophosphamide; Drug Synergism; Glycolates; In Vitro Techniques; Lymphoma; Meclofenoxate; Melphalan; Neoplasms, Experimental; Time Factors

Mechanism of transport of the alkylating agent [14C]melphalan was investigated in L5178Y lymphoblasts in vitro. A time course of melphalan uptake was approximately linear for 5 to 10 min and thereafter entered a plateau region. Evidence that unidirectional influx of melphalan is carrier mediated was that uptake obeyed simple Michaelis-Menten kinetics, that it demonstrated chemical specificity, and that the cell/medium distribution ratio of drug decreased with increasing extracellular drug concentration. The kinetic parameters for melphalan transport consisted of a Km (mean +/- S.E.) of 1.53 +/- 0.18 X 10(-4) M and a transport capacity (Vmax) of 3.48 +/- 0.31 X 10(-17) mole/min/cell. Findings suggesting that transport was at least in part energy dependent and not simply a passive process were that drug uptake was temperature sensitive and sodium dependent. Analysis of cell sap constituents indicated the presence of intact drug within the cell. The percentage of radioactivity (mean +/- S.D.) found in the cell sap fraction was 95.8 +/- 2.2% of total cell activity, and 92.6 +/- 4.1% of this was trichloroacetic acid soluble. Thin-layer chromatography of the cell sap fraction and medium each revealed that the majority of radioactivity migrated as a single peak with an RF value identical with that obtained for free drug. The alkylating potential of intact drug complicated interpretation of the finding of apparent uphill transport against a concentration gradient. This observation, together with the relatively low cell-medium ratio (mean +/- S.D.) of 3.07 +/- 1.07, favors the concept that melphalan transport occurs by a facilitated diffusion process, although an active transport system has not been entirely excluded. The relative insensitivity of melphalan uptake to a wide range of metabolic inhibitors also suggests that transport is by a facilitated diffusion mechanism rather than an active process. Other alkylating agents and several amino acids including the L and D isomers of phenylalanine did not inhibit melphalan transport; thus a native substrate was not identified for the melphalan carrier and transport was by a mechanism separate from that of other alkylating agents.

Topics: Antimetabolites; Biological Transport, Active; Carrier Proteins; Cells, Cultured; Kinetics; Lymphocytes; Lymphoma; Melphalan; Neoplasms, Experimental; Phenylalanine; Sodium; Temperature

Topics: Asparaginase; Child; Cyclophosphamide; Cytosine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Hodgkin Disease; Humans; Infant; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphoma; Melphalan; Mercaptopurine; Methotrexate; Neoplasms; Nitrogen Mustard Compounds; Osteosarcoma; Prednisone; Procarbazine; Prognosis; Remission, Spontaneous; Rhabdomyosarcoma; Teniposide; Thioguanine; Vincristine; Wilms Tumor

Topics: Alkylating Agents; Animals; Carcinoma 256, Walker; Cells, Cultured; Chlorambucil; Cyclic AMP; Drug Resistance; Electrophoresis; Female; Kinetics; Lymphoma; Male; Melphalan; Mice; Mice, Inbred BALB C; Mice, Inbred CBA; Neoplasm Proteins; Neoplasm Transplantation; Neoplasms, Experimental; Phosphoric Diester Hydrolases; Plasmacytoma; Rats; Time Factors; Transplantation, Homologous

Topics: Animals; Antibodies, Neoplasm; Antibody Formation; Antigens, Neoplasm; Bone Marrow; Bone Marrow Cells; Graft vs Host Reaction; Hybridization, Genetic; Immunosuppression Therapy; Leukemia, Experimental; Lymphoma; Melphalan; Mice; Mice, Inbred AKR; Mice, Inbred C57BL; Neoplasm Transplantation; Spleen; Transplantation, Homologous

Rabbit anti-mouse tumour cell serum can be made tumour specific by absorption with normal mouse cells and in an in vivo protection test can be shown to have a measurable protective effect on mice against a given number of lethal doses of a lymphoma. Some drugs have been evaluated in this system. When drug treatment is combined with antibody treatment much greater protection can be obtained than when the same amounts of drug or antibody are used alone. It is preferable to administer drug before antibody and with the combined schedule it is possible in the test model to protect all mice from tumour growth, even allowing the tumour up to 48 h "get-away" time before starting treatment.

Topics: Animals; Antibodies, Neoplasm; Antineoplastic Agents; Carcinoembryonic Antigen; Cell Line; Chlorambucil; Cyclophosphamide; Immunization, Passive; Immunodiffusion; Lymphoma; Melphalan; Mice; Mice, Inbred C57BL; Models, Biological; Neoplasms, Experimental; Rabbits; Time Factors

Topics: Chlorambucil; Cyclophosphamide; Dermatitis, Exfoliative; Humans; Keratoderma, Palmoplantar; Lymphatic Diseases; Lymphoma; Melphalan; Methotrexate; Nitrogen Mustard Compounds; Prednisone; Pruritus; Remission, Spontaneous; Syndrome; Time Factors; Triethylenemelamine; Vinblastine

Topics: Animals; Antibodies, Neoplasm; Chlorambucil; Cytarabine; Immune Sera; Immunotherapy; Lymphoma; Melphalan; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Rabbits; Time Factors

Topics: Animals; Antineoplastic Agents; Biological Assay; Carmustine; Cyclohexanes; Cyclophosphamide; Cytarabine; Daunorubicin; Disease Models, Animal; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Fluorouracil; Hodgkin Disease; Humans; Leukemia; Leukemia L1210; Leukemia, Experimental; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphoma; Male; Mechlorethamine; Melphalan; Mice; Mice, Inbred AKR; Multiple Myeloma; Nitrosourea Compounds; Prednisone; Remission, Spontaneous; Vinblastine; Vincristine

Topics: Alkylating Agents; Animals; Cell Line; Cell Survival; Chlorambucil; Clone Cells; Cyclophosphamide; Female; Hematopoietic Stem Cells; Lethal Dose 50; Lymphoma; Mechlorethamine; Melphalan; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Nitrosourea Compounds; Thiotepa; Triethylenemelamine

Topics: Adrenal Cortex Hormones; Adult; Age Factors; Blood Protein Disorders; Chlorambucil; Humans; Immunity, Cellular; Immunoelectrophoresis; Immunoglobulin G; Immunoglobulins; Intestinal Absorption; Intestine, Small; Jejunum; Lymphoma; Malabsorption Syndromes; Male; Melphalan; Microscopy, Electron; Racial Groups; Saliva

Topics: Animals; Blood Cell Count; Immunization; Lymphocytes; Lymphoma; Melphalan; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Rats; Spleen; Transplantation Immunology; Transplantation, Heterologous; Transplantation, Homologous

Topics: Adult; Antineoplastic Agents; Busulfan; Chlorambucil; Hodgkin Disease; Humans; Leukemia; Lymphoma; Male; Mechlorethamine; Melphalan; Vinblastine

Topics: Animals; Carcinoma, Ehrlich Tumor; Lymphoma; Melphalan; Mice; Neoplasms, Experimental; Nitrogen Mustard Compounds; Sarcoma 180

Topics: Antineoplastic Agents; Burkitt Lymphoma; Cyclophosphamide; Follow-Up Studies; Humans; Lymphoma; Melphalan; Vinblastine

Topics: Abdominal Neoplasms; Angiography; Breast Neoplasms; Geriatrics; Gold; Humans; Injections; Iodine Isotopes; Leukemia; Lymphatic Metastasis; Lymphatic System; Lymphography; Lymphoma; Lymphoma, Non-Hodgkin; Melanoma; Melphalan; Methotrexate; Neoplasms; Radioisotopes; Radionuclide Imaging; Retroperitoneal Neoplasms; Scandium; Thiotepa; Yttrium

Topics: Alkaloids; Antineoplastic Agents; Ascites; Cyclophosphamide; Electrons; Lymphoma; Mannomustine; Melphalan; Mice; Microscopy; Microscopy, Electron; Neoplasms; Neoplasms, Experimental; Pharmacology; Research

Topics: Breast Neoplasms; Carcinoma, Bronchogenic; Dysgerminoma; Female; Gastrointestinal Neoplasms; Hodgkin Disease; Humans; Liver Neoplasms; Lymphoma; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melanoma; Melphalan; Multiple Myeloma; Neoplasms; Ovarian Neoplasms; Sarcoma

Topics: Adolescent; Alkylating Agents; Antineoplastic Agents; Aziridines; Black People; Burkitt Lymphoma; Child; Cyclophosphamide; Dactinomycin; Epidemiology; Humans; Kenya; Lymphoma; Mandibular Neoplasms; Maxillary Neoplasms; Melphalan; Neoplasms; Oncogenic Viruses

Topics: Anti-Bacterial Agents; Antineoplastic Agents; Drug Therapy; Hodgkin Disease; Lymphatic System; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mannomustine; Melphalan; Neoplasms; Piperazines; Sarcoma

Topics: Alkylating Agents; Aziridines; Child; Cyclophosphamide; Dactinomycin; Humans; Jaw; Lymphoma; Mechlorethamine; Melphalan

Topics: Adolescent; Child; Geriatrics; Head and Neck Neoplasms; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mandibular Neoplasms; Maxillary Neoplasms; Melanoma; Melphalan; Multiple Myeloma; Neoplasms; Orbital Neoplasms; Plasmacytoma; Sarcoma; Sarcoma, Kaposi

Topics: Antineoplastic Agents; Genetic Diseases, X-Linked; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Hairy Cell; Lymphatic Diseases; Lymphoma; Melphalan; Nitrogen Mustard Compounds; Severe Combined Immunodeficiency

Topics: Aminopterin; Antineoplastic Agents; Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Chlorambucil; Dactinomycin; Fibrosarcoma; Fluoresceins; Humans; Infusions, Parenteral; Injections, Intra-Arterial; Lymphoma; Lymphoma, Non-Hodgkin; Melanoma; Melphalan; Neoplasms; Pharmacology; Thiotepa; Toxicology