melphalan and Lymphoma--Large-B-Cell--Diffuse

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard therapy in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are chemosensitive. The combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) is commonly used as a conditioning regimen. The addition of yttrium-90 ((90) Y)-ibritumomab tiuxetan (Zevalin(®)) to BEAM (Z-BEAM) is increasingly being used to improve outcomes and overcome refractory disease. We conducted a literature review and meta-analysis in order to evaluate the clinical effects of Z-BEAM followed by ASCT in patients with DLBCL. A literature search was conducted for randomized controlled trials and observational studies of Z-BEAM as a conditioning regimen for ASCT in adult patients with DLBCL. Extracted data included baseline patient demographics, overall response (ORR), complete response (CR), overall survival (OS), progression-free survival (PFS), nonrelapse mortality (NRM), median time to ANC and platelet engraftment, and rate of myelodysplastic syndrome. Mixed-effects models were used to determine estimates. Ten studies (N = 328) were included in the meta-analysis. The 2-year OS and PFS were 84.5% (n = 328) and 67.2% (n = 285), respectively. Outcomes were superior in patients with nontransformed lymphoma. Posttransplant, ORR and CR rates were 72.6% and 68.5%, respectively. The NRM rate was 6.3% and the incidence rate of myelodysplastic syndrome was 2.5%. Two-year OS was significantly associated with pretransplant ORR (P = 0.008, τ(2) = 0). There was no significant association between PFS and pretransplant response. Z-BEAM is safe and effective as a conditioning regimen in relapsed/refractory DLBCL.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Chemoradiotherapy; Cytarabine; Disease-Free Survival; Etoposide; Humans; Lymphoma, Large B-Cell, Diffuse; Melphalan; Radiopharmaceuticals; Treatment Outcome

Drug resistance in cancer refers to recurrent or primary refractory disease following drug therapy. At the cellular level, it is a consequence of molecular functions that ultimately enable the cell to resist cell death-one of the classical hallmarks of cancer. Thus, drug resistance is a fundamental aspect of the cancer cell phenotype, in parallel with sustained proliferation, immortality, angiogenesis, invasion, and metastasis. Here we present a preclinical model of human B-cell cancer cell lines used to identify genes involved in specific drug resistance. This process includes a standardized technical setup for specific drug screening, analysis of global gene expression, and the statistical considerations required to develop resistance gene signatures. The state of the art is illustrated by the first-step classical drug screen (including the CD20 antibody rituximab, the DNA intercalating topoisomerase II inhibitor doxorubicin, the mitotic inhibitor vincristine, and the alkylating agents cyclophosphamide and melphalan) along with the generation of gene lists predicting the chemotherapeutic outcome as validated retrospectively in clinical trial datasets. This B-cell lineage-specific preclinical model will allow us to initiate a range of laboratory studies, with focus on specific gene functions involved in molecular resistance mechanisms.

Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; B-Lymphocytes; Cell Line, Tumor; Cyclophosphamide; Doxorubicin; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, Large B-Cell, Diffuse; Melphalan; Models, Biological; Multiple Myeloma; Neoplasm Proteins; Rituximab; Vincristine

The primary cardiac lymphoma (PCL) is an extremely infrequent tumor suffered by immunocompetent patients with a difficult diagnosis and slow progress leading to a serious prognosis and few therapeutically possibilities. It's a primary-cardiac non-Hodgkin's lymphoma (NHL) in a patient of 46-year-old, immunocompetent, who started with a congestive heart failure and atrial flutter. Some examinations were carried out such as a transesophageal echocardiography (TEE), a computed tomography (TC) and a magnetic resonance imaging (MRI) and an intracardiac tumor placed in the interauricular septum was detected. The diagnosis was based on a pleural fluid cytological examination. It was decided to follow a chemotherapy treatment and the autologous peripheral blood stem cells transplantation was carried out. The patient remains in full remission thirty-six months after diagnosis and twenty-nine months after the autotransplant. Our clinical experience indicated that an early and accurate diagnosis combined with the appropriate and aggressive antilymphoma therapy can thus help in obtaining a long survival in patients with PCL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Atrial Flutter; Carmustine; Cyclophosphamide; Cytarabine; Doxorubicin; Echocardiography, Transesophageal; Etoposide; Heart Failure; Heart Neoplasms; Heart Septum; Hematopoietic Stem Cell Transplantation; Humans; Hydrocortisone; Immunocompetence; Injections, Spinal; Lymphoma, Large B-Cell, Diffuse; Magnetic Resonance Imaging; Male; Melphalan; Methotrexate; Middle Aged; Pleural Effusion; Prednisone; Remission Induction; Tomography, X-Ray Computed; Transplantation Conditioning; Transplantation, Autologous; Vincristine

The case of a patient with the diagnosis of essential thrombocythemia is presented. Following treatment with melphalan during three years the patient presented clinical and radiologic data of pulmonary fibrosis. Thoracotomy with lung biopsy histologically proving fibrosis was performed. The patient developed a true histiocytic lymphoma afterwards. The rarity of pulmonary fibrosis induced by melphalan and the exceptional association of essential thrombocythemia and histiocytic lymphoma is emphasized. The characteristics of the latter disease, diagnostic difficulties and possible treatment are commented upon.

Topics: Adult; Biopsy; Female; Humans; Lung; Lymphoma, Large B-Cell, Diffuse; Melphalan; Pulmonary Fibrosis; Thoracic Neoplasms; Thrombocythemia, Essential; Time Factors

Topics: Amyloid; Amyloidosis; Anemia; Antineoplastic Agents; Clinical Trials as Topic; Cyclophosphamide; Hodgkin Disease; Humans; Immunodiffusion; Immunoelectrophoresis; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Infections; Leukemia, Lymphoid; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Multiple Myeloma; Prognosis; Pyelonephritis

In the treatment of diffuse large B-cell lymphoma, a persistently positive [

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carmustine; Cyclophosphamide; Cytarabine; Doxorubicin; Etoposide; Female; Fluorodeoxyglucose F18; Humans; Ifosfamide; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Podophyllotoxin; Positron-Emission Tomography; Prednisone; Retreatment; Rituximab; Treatment Outcome; Vincristine; Young Adult

More active high-dose regimens are needed for refractory/poor-risk relapsed lymphomas. We previously developed a regimen of infusional gemcitabine/busulfan/melphalan, exploiting the synergistic interaction. Its encouraging activity in refractory lymphomas led us to further enhance its use as a platform for epigenetic modulation. We previously observed increased cytotoxicity in refractory lymphoma cell lines when the histone deacetylase inhibitor vorinostat was added to gemcitabine/busulfan/melphalan, which prompted us to clinically study this four-drug combination. Patients ages 12 to 65 with refractory diffuse large B cell lymphoma (DLCL), Hodgkin (HL), or T lymphoma were eligible. Vorinostat was given at 200 mg/day to 1000 mg/day (days -8 to -3). Gemcitabine was infused continuously at 10 mg/m(2)/minute over 4.5 hours (days -8 and -3). Busulfan dosing targeted 4000 μM-minute/day (days -8 to -5). Melphalan was infused at 60 mg/m(2)/day (days -3 and -2). Patients with CD20(+) tumors received rituximab (375 mg/m(2), days +1 and +8). We enrolled 78 patients: 52 DLCL, 20 HL, and 6 T lymphoma; median age 44 years (range, 15 to 65); median 3 prior chemotherapy lines (range, 2 to 7); and 48% of patients had positron emission tomography-positive tumors at high-dose chemotherapy (29% unresponsive). The vorinostat dose was safely escalated up to 1000 mg/day, with no treatment-related deaths. Toxicities included mucositis and dermatitis. Neutrophils and platelets engrafted promptly. At median follow-up of 25 (range, 16 to 41) months, event-free and overall survival were 61.5% and 73%, respectively (DLCL) and 45% and 80%, respectively (HL). In conclusion, vorinostat/gemcitabine/busulfan/melphalan is safe and highly active in refractory/poor-risk relapsed lymphomas, warranting further evaluation. This trial was registered at ClinicalTrials.gov (NCI-2011-02891).

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Deoxycytidine; Drug Administration Schedule; Female; Follow-Up Studies; Gemcitabine; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Hydroxamic Acids; Lymphoma, Large B-Cell, Diffuse; Lymphoma, T-Cell; Male; Melphalan; Middle Aged; Recurrence; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Vorinostat

Lymphoma patients with persistent disease undergoing autologous transplantation have a very poor prognosis in the rituximab era. The addition of radioimmunotherapy to the conditioning regimen may improve the outcome for these patients. In a prospective, phase 2 study, we evaluated the safety and efficacy of the addition of (90)Y-ibritumomab tiuxetan to the conditioning chemotherapy in patients with refractory diffuse large B-cell lymphoma. Thirty patients with induction failure (primary refractory; n=18) or refractory to salvage immunochemotherapy at relapse (n=12) were included in the study. The median age of the patients was 53 years (range, 25-67). All patients were given (90)Y-ibritumomab tiuxetan at a fixed dose of 0.4 mCi/kg (maximum dose 32 mCi) 14 days prior to the preparative chemotherapy regimen. Histological examination showed that 22 patients had de novo diffuse large B-cell lymphoma and eight had transformed diffuse large B-cell lymphoma. All patients had persistent disease at the time of transplantation, with 25 patients considered to be chemorefractory. The median time to neutrophil recovery (>500 white blood cells/μL) was 11 days (range, 9-21), while the median time to platelet recovery (>20,000 platelets/μL) was 13 days (range, 11-35). The overall response rate at day +100 was 70% (95% CI, 53.6-86.4) with 60% (95% CI, 42.5-77.5) of patients obtaining a complete response. After a median follow-up of 31 months for alive patients (range, 16-54), the estimated 3-year overall and progression-free survival rates are 63% (95% CI, 48-82) and 61% (95% CI, 45-80), respectively. We conclude that autologous transplantation with conditioning including (90)Y-ibritumomab tiuxetan is safe and results in a very high response rate with promising survival in this group of patients with refractory diffuse large B-cell lymphoma with a very poor prognosis. Study registered at European Union Drug Regulating Authorities Clinical Trials (EudraCT) N. 2007-003198-22.

Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Neoplasm Staging; Podophyllotoxin; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

We conducted a multicentre, phase II study of interim positron emission tomography (PET) as a guide to risk-adapted therapy in high-risk patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients achieving negative fluorodeoxyglucose (FDG)-PET after three courses of R-MegaCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) received three additional courses, whereas PET-positive patients received two courses of R-IFE (rituximab, ifosfamide, etoposide) followed by BEAM (BCNU, etoposide, cytarabine, melphalan) and autologous stem-cell transplantation. The primary endpoint was progression-free survival (PFS). 71 patients (median age 55 years, range 25-69) were enrolled. With a median follow-up of 42·8 months (range 7·2-58·4), the estimated 4-year PFS and overall survival (OS) were 67% and 78%, respectively, for the global series. Patients in complete remission after interim PET (N = 36) had significantly better 3-year PFS than those with partial response (N = 30) [81% vs. 57%, Hazard ratio (HR) = 2·6, 95% confidence interval (CI) = 1·02-6·65] but not a statistically significant longer OS. A retrospective PET central review was done for 51 patients. According to semiquantitative analysis, 3-year PFS (81% vs. 33%; HR = 6·9, 95% CI = 2·35-20·6) and OS (95% vs. 33%, HR = 19·4, 95% CI = 3·89-97·0) were significantly better for negative than for positive interim PET patients. Early PET assessment is valuable for risk stratification in DLBCL; for this purpose semiquantitative evaluation is a better predictor than visual criteria.

Topics: Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Disease-Free Survival; Doxorubicin; Etoposide; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Humans; Ifosfamide; Kaplan-Meier Estimate; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Positron-Emission Tomography; Prednisone; Prognosis; Prospective Studies; Radiopharmaceuticals; Remission Induction; Rituximab; Transplantation, Autologous; Treatment Outcome; Vincristine

We evaluated the safety and efficacy of standard-dose yttrium-90 (Y(90)) ibritumomab tiuxetan combined with high-dose BEAM (carmustine, etoposide, cytarabine, and melphalan) after first-line induction treatment in young patients with poor prognoses diffuse large B cell lymphoma (DLBCL) (clinicaltrials.gov: NCT00689169). Seventy-five high-risk (≥2 International Prognostic Index [IPI] factors) consecutive DLBCL patients (≤65 years old) in complete remission (CR) or partial remission (PR) after rituximab chemotherapy were treated with Y(90) ibritumomab tiuxetan and BEAM regimen followed by autologous stem cell transplantation (ASCT). The median follow-up was 34 months. Of the 75 patients, 71 underwent ASCT and were eligible for analysis. Median time to reach a neutrophil count of >500/μL and platelet count of >20,000/μL was 11 days. Mucositis ≥3 (51%) occurred in most patients. Other adverse events were similar to those seen with BEAM alone. The overall response rate was 86%; 59 patients (83%) achieved a CR or unconfirmed CR. The 2-year event-free survival (EFS), overall survival (OS), and disease-free survival were 79%, 83%, and 91%, respectively. Disease status (CR/PR) and positron emission tomography (PET) findings before transplantation did not predict treatment failure. The IPI (2 versus >2) and maximum tumor diameter of ≥10 cm at diagnosis appeared to be prognosis factors for OS but not for EFS. Adding Y(90) ibritumomab tiuxetan to BEAM is safe and does not increase transplantation-related toxicity. First-line consolidation with Y(90) ibritumomab tiuxetan and high-dose chemotherapy induced high rates of EFS and OS in poor-prognosis patients with DLBCL, regardless of PET status after induction treatment and warrants a randomized study.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Autografts; Carmustine; Consolidation Chemotherapy; Cytarabine; Disease-Free Survival; Female; Follow-Up Studies; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Podophyllotoxin; Prospective Studies; Risk Factors; Rituximab; Stem Cell Transplantation; Survival Rate

This clinical trial evaluated standard-dose radioimmunotherapy with a chemotherapy-based transplantation regimen followed by autologous hematopoietic cell transplantation versus rituximab with the same regimen in patients with relapsed diffuse large B-cell lymphoma (DLBCL).. Patients with chemotherapy-sensitive persistent or relapsed DLBCL were randomly assigned to receive iodine-131 tositumomab (dosimetric dose of 5 mCi on day -19 and therapeutic dose of 0.75 Gy on day -12), carmustine 300 mg/m(2) (day -6), etoposide 100 mg/m(2) twice daily (days -5 to -2), cytarabine 100 mg/m(2) twice daily (days -5 to -2), and melphalan 140 mg/m(2) (day -1; B-BEAM) or rituximab 375 mg/m(2) on days -19 and -12 and the same chemotherapy regimen (R-BEAM).. Two hundred twenty-four patients were enrolled, with 113 patients randomly assigned to R-BEAM and 111 patients assigned to B-BEAM. Two-year progression-free survival (PFS) rates, the primary end point, were 48.6% (95% CI, 38.6% to 57.8%) for R-BEAM and 47.9% (95% CI, 38.2% to 57%; P = .94) for B-BEAM, and the 2-year overall survival (OS) rates were 65.6% (95% CI, 55.3% to 74.1%) for R-BEAM and 61% (95% CI, 50.9% to 69.9%; P = .38) for B-BEAM. The 100-day treatment-related mortality rates were 4.1% (95% CI, 0.2% to 8.0%) for R-BEAM and 4.9% (95% CI, 0.8% to 9.0%; P = .97) for B-BEAM. The maximum mucositis score was higher in the B-BEAM arm (0.72) compared with the R-BEAM arm (0.31; P < .001).. The B-BEAM and R-BEAM regimens produced similar 2-year PFS and OS rates for patients with chemotherapy-sensitive relapsed DLBCL. No differences in toxicities other than mucositis were noted.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cytarabine; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Large B-Cell, Diffuse; Melphalan; Middle Aged; Prospective Studies; Radioimmunotherapy; Recurrence; Rituximab; Transplantation, Autologous; Young Adult

The purpose of this study was to evaluate the standard outpatient dose of 131-Iodine tositumomab (75 cGy) combined with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem cell rescue for the treatment of chemotherapy-sensitive relapsed or refractory, or high-risk first complete remission (CR) patients with diffuse large B cell non-Hodgkin's lymphoma (DLBCL). Forty patients with chemotherapy-sensitive persistent or relapsed or high/intermediate or high international prognostic index DLCBL were treated in a phase II trial combining 75 cGy 131-Iodine tositumomab with high-dose BEAM followed by autologous stem cell transplantation. The CR rate after transplantation was 78%, and the overall response rate was 80%. Short-term and long-term toxicities were similar to historical control patients treated with BEAM alone. With a median follow-up of 6 years (range, 3-10 years), the 5-year overall survival (OS) was 72% (95% confidence interval [CI], 55%-83%), and the 5-year progression-free survival (PFS) rate was 70% (95% CI, 53%-82%). The PFS and OS were encouraging in this group of chemotherapy-sensitive persistent, relapsed, or high-risk patients with DLBCL. A follow-up phase III trial with 131-Iodine tositumomab/BEAM vs rituximab/BEAM was planned based on this information.

Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Disease-Free Survival; Follow-Up Studies; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Podophyllotoxin; Recurrence; Stem Cell Transplantation; Survival Rate; Transplantation, Autologous

Approximately 5-10% of diffuse large B-cell lymphomas (DLBCL) harbor a 8q24/MYC rearrangement (MYC(+)). We determined the prognostic significance of MYC rearrangement in patients with relapsed/refractory DLBCL prospectively treated by R-ICE or R-DHAP followed by high-dose therapy and autologous stem cell transplantation. Twenty-eight (17%) of the 161 patients analyzed presented a MYC(+) rearrangement, targeted as either simple hit (25%) or complex hits (n=75%) including MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6. Results were statistically highly concordant in matched primary and relapsed biopsies (n = 45). Compared to the MYC(-) DLBCL patients, the MYC(+) DLBCL patients presented with a more elevated lactico-deshydrogenase level (P = .0006) and a more advanced age adjusted international prognostic index (P = .0039). The 4-year PFS and OS were significantly lower in the MYC(+) DLBCL patients than those in the MYC(-) DLBCL patients, with rates of 18% vs 42% (P = .0322), and of 29% vs 62% (P = .0113), respectively. Type of treatment, R-DHAP or R-ICE, had no impact on survivals, with 4-year PFS rates of 17% vs 19% and 4-year OS rates of 26% vs 31%. In conclusion, MYC rearrangement is an early event in DLBCL. MYC(+) DLBCL patients have a significant inferior prognosis than MYC(-) DLBCL patients. Their outcome was not influenced by the proposed salvage therapy.

Topics: Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Cytarabine; Dexamethasone; Etoposide; Female; Genes, myc; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Immunotherapy; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Podophyllotoxin; Rituximab; Salvage Therapy; Transplantation, Autologous; Treatment Failure; Young Adult

This trial involved 457 patients and sought to assess the value of early intensification with autologous transplantation in patients with poor prognosis histologically aggressive non-Hodgkin lymphoma (NHL) showing a response to initial CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy. Randomization was made at the time of diagnosis with 223 assigned to continuing CHOP and 234 to 3 cycles of CHOP followed by a BEAM (carmustine, etoposide, cytarabine, melphalan) autograft. Analysis was on an intention to treat basis. After the initial three cycles of CHOP 19% of the whole group were in complete response (CR) and 53% in partial remission (PR). At the end of treatment 86% of patients in the CHOP arm had responded with 58% in CR. In the high-dose therapy arm the overall response rate was 83% with 64% in CR (difference between arms not significant). The progression-free survival (PFS) and overall survival at 5 years for the continuing CHOP arm were 38% and 50% respectively, and for the autograft arm were 44% and 50% (differences not significant). Of the patients who attained CR and subsequently relapsed, there were no long-term survivors in the autograft recipients compared to 46% of the continuing CHOP recipients (P = 0.0008). In conclusion, no survival benefit was demonstrated for an early autograft in first response.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Neoplasm Staging; Prednisolone; Prognosis; Recurrence; Survival Analysis; Transplantation Conditioning; Treatment Outcome; Vincristine; Young Adult

Limited data exist about the role of second-line chemotherapy response assessed by positron emission tomography (PET) as a prognostic factor in patients with aggressive non-Hodgkin Lymphoma (NHL) who undergo autologous stem cell transplantation (ASCT). The objective of this analysis was to investigate the main determinants of prognosis in patients with aggressive B-cell NHL who undergo ASCT, focusing on the impact of pretransplantation PET, secondary age-adjusted International Prognostic Index (sAA-IPI) score, histology, and previous response to first-line chemotherapy.. Seventy-five patients with diffuse, large B-cell lymphoma or grade 3 follicular lymphoma who were treated at the author' institution with second-line chemotherapy (combined ifosfamide, etoposide, and epirubicin [IEV]) followed by ASCT between September 2002 and September 2006 were included. All patients were evaluated by PET after 1 to 3 courses of IEV chemotherapy before ASCT, and all patients received a conditioning regimen of combined carmustine, etoposide, cytosine arabinoside, and melphalan. The prognostic impact of pretransplantation PET, sAA-IPI score, histology, and previous response to first-line chemotherapy was evaluated by univariate and multivariate analyses.. Seventy-two of 75 patients underwent ASCT. In a univariate analysis for progression-free survival (PFS) and overall survival (OS), a significant association was observed with pretransplantation PET (PFS, P< .00001; OS, P< .01) and previous first-line response (PFS, P= .02; OS, P= .04). In the multivariate framework, pretransplantation PET was identified as the only independent prognostic factor (PFS, P< .001; OS, P= .01).. The current data indicated that pretransplantation PET is the main prognostic predictor in patients with aggressive B-cell NHL who are scheduled for ASCT.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Cytarabine; Etoposide; Female; Fluorodeoxyglucose F18; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Positron-Emission Tomography; Predictive Value of Tests; Prognosis; Prospective Studies; Radiopharmaceuticals; Remission Induction; Salvage Therapy; Survival Analysis; Transplantation, Autologous; Vincristine

This phase II trial evaluated the safety and efficacy of combining yttrium-90 (90Y) ibritumomab tiuxetan with high-dose carmustine, cytarabine, etoposide, and melphalan (BEAM) and autologous stem-cell transplantation in patients with non-Hodgkin's lymphoma who were considered ineligible for total-body irradiation because of older age or prior radiotherapy.. Between May 2002 and January 2006, 14 days before autologous stem-cell transplantation, 41 patients with non-Hodgkin's lymphoma received standard-dose 90Y ibritumomab tiuxetan (14.8 MBq/kg [0.4 mCi/kg]) followed by high-dose BEAM.. The median age was 60 years (range, 19 to 78 years), and the median number of previous therapies was two (range, one to six). Disease histologies were diffuse large B-cell (n = 20), mantle cell (n = 13), follicular (n = 4), and transformed lymphoma (n = 4). With a median follow-up of 18.4 months (range, 5.5 to 53.3 months) the estimated 2-year overall and progression-free survival were 88.9% (95% CI, 75.3% to 95.2%) and 69.8% (95% CI, 56.4% to 79.7%). The median time to WBC engraftment was 11 days (range, 9 to 26 days) and time to platelet engraftment was 12 days (range, 3 to 107 days). Adverse events were similar to those seen historically with high-dose BEAM alone, and included grade 3 or 4 pulmonary toxicity in 10 patients.. Adding 90Y ibritumomab tiuxetan to high-dose BEAM with autologous stem-cell transplantation is feasible and has a toxicity and tolerability profile similar to that observed with BEAM alone. Rates of progression-free survival seen in these patients are promising and warrant additional study.

Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cytarabine; Disease-Free Survival; Female; Humans; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Podophyllotoxin; Radioimmunotherapy; Stem Cell Transplantation; Treatment Outcome; Yttrium Radioisotopes

The role of high-dose therapy and autologous stem-cell transplantation (HDT/ASCT) in the up-front treatment of poor-risk aggressive lymphoma is still unknown. We conducted a prospective multi-centre trial with dose-escalated CHOP (MegaCHOP) and tailored intensification prior to HDT/ASCT according to early response assessed by CT and gallium scan (Ga67S).. Eighty-six patients with newly diagnosed and Ga-67 avid aggressive B-cell lymphoma received MegaCHOP for three courses and were evaluated for response by CT and Ga67S. Patients with CT response and negative Ga67S received another MegaCHOP cycle followed by BEAM and ASCT. Those patients with positive Ga67S or without CT response received salvage treatment with two courses of ifosfamide and etoposide (IFE) followed, whenever response had been achieved, by BEAM and ASCT.. Response rate before HDT/ASCT was 85% and, with 34 months of median follow-up, progression-free survival (PFS), overall survival (OS) and treatment-related mortality were 56%, 64% and 7%, respectively. For transplanted patients (81% of the whole series), PFS and OS were 67% and 74%, respectively. No different outcomes were observed between patients achieving an early negative Ga67S response treated with MegaCHOP and BEAM/ASCT and patients with mid-treatment positive Ga67S who received IFE prior BEAM/ASCT.. This response-adapted strategy including early treatment modifications prior HDT/ASCT have yielded encouraging PFS and OS in patients with poor-risk B aggressive non-Hodgkin's lymphoma.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Follow-Up Studies; Humans; Ifosfamide; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Podophyllotoxin; Prednisone; Prognosis; Prospective Studies; Risk Assessment; Stem Cell Transplantation; Survival Analysis; Transplantation, Autologous; Vincristine

The multicentre phase III CORAL study aims to guide choice of salvage chemotherapy in diffuse large B-cell lymphoma (DLBCL) and assess the role of rituximab maintenance after autologous stem cell transplantation (ASCT). Patients are first randomised between ICE (ifosfamide, carboplatin, etoposide) and DHAP (dexamethasone, ara-C and cisplatin), both combined with rituximab (R-ICE or R-DHAP). After three courses, responders are treated by ASCT with BEAM. A second randomisation then allocates patients to maintenance treatment with rituximab 375 mg/m(2), one injection every 2 months six times, or observation. Accrual to the study is now proceeding well and the planned 400 patients are likely to be enrolled within the next 1.5 years. Results to date are very preliminary but suggest encouraging rates of response. However, they also indicate that initial exposure to rituximab may increase the difficulty of salvaging patients who fail first-line therapy.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carmustine; Cisplatin; Combined Modality Therapy; Cytarabine; Dexamethasone; Disease-Free Survival; Dose-Response Relationship, Drug; Etoposide; Hodgkin Disease; Humans; Ifosfamide; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Podophyllotoxin; Remission Induction; Rituximab; Salvage Therapy; Stem Cell Transplantation; Survival Rate; Transplantation, Autologous; Treatment Outcome

Poor prognosis diffuse large cell lymphoma (DLCL) responds poorly to standard chemotherapy. Randomized studies comparing high-dose chemotherapy with autologous stem-cell transplantation (ASCT) against standard chemotherapy have produced conflicting results. Dose-dense chemotherapy with granulocyte colony-stimulating factor (G-CSF) support seems to hold promise. The purpose of this multicenter, randomized trial was to compare failure-free and overall survival in patients with poor prognosis DLCL treated with high-dose sequential (HDS) chemotherapy followed by ASCT or an outpatient dose-dense chemotherapy regimen (MegaCEOP).. Between 1996 and 2001, 130 DLCL patients, aged < or = 60 years, with intermediate-high or high-risk disease, according to the International Prognostic Index score, and/or bone marrow involvement were enrolled. Sixty were randomized to HDS chemotherapy plus high-dose mitoxantrone and melphalan with ASCT (arm A) and 66 to the MegaCEOP regimen (6-8 courses of an escalated dose of cyclophosphamide and epirubicin plus vincristine and prednisone with G-CSF every 2-weeks) (arm B); 4 patients were considered ineligible.. The complete remission rate was 59% in arm A and 70% in arm B (p = 0.18). After a median follow-up of 78 months, the 6-year failure-free survival was 45% in arm A and 48% in arm B (hazard ratio = 1.15, 95% confidence intervals = 0.72-1.84, p = 0.56). The 5-year overall survival was 49% in arm A and 63% in arm B (hazard ratio = 1.67, 95% confidence interval = 0.98-2.85, p = 0.06). Two cases of secondary acute myeloid leukemia were observed after treatment in group A.. HDS and ASCT as initial therapy for patients with poor-prognosis DLCL does not provide a benefit over that of outpatient dose-dense MegaCEOP chemotherapy.

Topics: Adolescent; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease-Free Survival; Epirubicin; Female; Granulocyte Colony-Stimulating Factor; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Mitoxantrone; Prednisone; Prognosis; Transplantation, Autologous; Vincristine

Autologous stem cell transplantation (ASCT) in the front line treatment of non-Hodgkin's lymphoma (NHL) remains controversial. Anaplastic large-cell lymphoma (ALCL) is known to have its own clinical and biological features. The outcome of ALCL patients treated with high-dose chemotherapy and ASCT as part of their first-line therapy was analysed in 202 intermediate or high-grade NHL patients in a prospective randomized trial. First-line chemotherapy comprised two alternating anthracycline-containing regimens. Responding patients were autografted after a BEAM (BCNU, cytarabine, etoposide and melphalan) regimen. Patients with bulky or residual masses were irradiated. Fifteen patients with ALCL were identified by morphological and immunological features (CD30 was expressed in 14 out of 15 patients, three patients expressed B-cell markers, five patients expressed T-cell markers and seven patients did not express cell markers). Anaplastic lymphoma kinase (ALK) expression was confirmed in seven cases. The median age was 39 years with a predominant male sex ratio (2.75). Thirteen patients were stage >/= III and six presented with two or more adverse prognostic factors. According to the international age-adjusted prognostic index, the expected complete remission (CR), event-free survival (EFS) and overall survival (OS) rates were 69%, 71% and 69%. Two deaths were observed (one due to interstitial pneumonitis, one due to pulmonary carcinoma). All patients entered CR, no relapse occurred and EFS and survival reached 87% with a follow-up of more than 5 years. These results differ significantly from those observed in the other 176 lymphoma patients: event-free survival was only 53 +/- 5% and OS reached 60 +/- 4% with a median follow-up of 56 months (P = 0.006). Intensified chemotherapy with autologous stem cell support appeared effective in the treatment of ALCL, offering patients the real chance of a cure.

Topics: Adolescent; Adult; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cytarabine; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Podophyllotoxin; Prospective Studies; Survival Rate; Transplantation, Autologous

The survival of two cohorts of patients with stage III/IV large-cell lymphomas treated by CHOP has been compared. In the first cohort of 88 patients (1974-1982), high-dose therapy with autologous bone marrow transplantation (ABMT) was not available as salvage therapy and in the second cohort of 87 patients (1987-1992), this was the recommended salvage for patients with disease that was still chemosensitive to conventional-dose therapy. The actuarial overall survivals at five years were 40% and 44% in the first and second cohorts, respectively, indicating that the availability of ABMT had made little impact. Of the 62 patients in the second cohort who failed CHOP therapy, 8 died before second-line chemotherapy could be given, 1 refused more therapy, and 8 were considered unsuitable for further combination chemotherapy. Seven patients with localized disease remaining received local radiotherapy. Of the 38 patients given salvage therapy, 14 had chemoresistant disease. Only 9 patients received high-dose BEAM chemotherapy and ABMT, and 7 remain disease-free. ABMT was restricted to a highly select patient group, and as a result more widespread application of this strategy might result in only a modest further improvement.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Cohort Studies; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Dose-Response Relationship, Drug; Doxorubicin; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Large-Cell, Immunoblastic; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Neoplasm Staging; Podophyllotoxin; Prednisone; Salvage Therapy; Treatment Outcome; Vincristine

Topics: Amyloid; Amyloidosis; Anemia; Antineoplastic Agents; Clinical Trials as Topic; Cyclophosphamide; Hodgkin Disease; Humans; Immunodiffusion; Immunoelectrophoresis; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Infections; Leukemia, Lymphoid; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Multiple Myeloma; Prognosis; Pyelonephritis

Topics: Adolescent; Adult; Child; Clinical Trials as Topic; Dysgerminoma; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Neoplasms; Osteosarcoma; Sarcoma, Kaposi

Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon, aggressive type of non-Hodgkin lymphoma. Rituximab-containing chemoimmunotherapy with or without radiation therapy (RT) is standard first-line treatment. Relapsed or refractory (R/R) disease has long been treated with salvage chemotherapy followed by high-dose chemotherapy (HDC), with autologous stem cell transplantation (ASCT) in appropriate patients. We retrospectively analyzed all patients with R/R PMBCL treated with HDC/ASCT at our center between January 2000 and August 2022. The 60 study patients received either rituximab-BEAM (n = 37) or rituximab-gemcitabine/busulfan/melphalan (R-GemBuMel) with or without vorinostat (n = 23), followed by ASCT. Forty-six patients received mediastinal RT, either as prior consolidation of frontline therapy or following ASCT. At median follow-up of 6 years (range, .3 to 21 years), the 5-year progression-free survival (PFS) and overall survival (OS) rates of the whole group were 58% and 77%, respectively, for the entire cohort, 51% and 65% for the R-BEAM recipients, and 69% and 82% for R-vorinostat/GemBuMel recipients. Multivariable analyses showed that a negative positron emission tomography scan at ASCT (hazard ratio [HR], .28) and involvement of only 1 organ (HR, .33) were independently associated with improved PFS. In addition, receipt of R-vorinostat/GemBuMel (HR, .23) was an independent favorable predictor of OS. Our data indicate that HDC/ASCT is effective in R/R PMBCL, with improved outcomes in patients receiving R-vorinostat/GemBuMel.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Large B-Cell, Diffuse; Melphalan; Neoplasm Recurrence, Local; Retrospective Studies; Rituximab; Thymus Neoplasms; Transplantation, Autologous; Vorinostat

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Immunological; Biological Products; Clinical Trials as Topic; Drug Discovery; Humans; Lymphoma, Large B-Cell, Diffuse; Melphalan; Multiple Myeloma; Phenylalanine; Receptors, Antigen, T-Cell

Secondary central nervous system lymphoma (SCNSL) affects approximately 5% of patients with aggressive large B-cell lymphoma (LBCL) and is associated with poor outcomes. This retrospective, multicenter study included 62 consecutive patients with SCNSL intended for transplant with high-dose methotrexate (HD-MTX)-based induction followed by high-dose thiotepa, busulfan, melphalan, rituximab (TBMR) conditioning and autologous stem cell transplantation (ASCT). Median age was 58 years (range 20-75) and 52 (84%) patients had ECOG performance status >1 at diagnosis of SCNSL. Fifty-two (84%) patients completed induction and proceeded to TBMR/ASCT. With median follow-up 5.7 years, 5-year progression-free and overall survival rates were 53% (95% CI 39-65%) and 65% (95% CI 51-76%) for all patients and 62% (95% CI 45-74%) and 73% (95% CI 57-84%) for those undergoing TBMR/ASCT, respectively. Despite a historically poor prognosis, HD-MTX-based induction followed by TBMR/ASCT has the potential to achieve long-term survival in a substantial proportion of patients with SCNSL.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Autografts; Busulfan; Central Nervous System Neoplasms; Combined Modality Therapy; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Large B-Cell, Diffuse; Melphalan; Methotrexate; Middle Aged; Neoplasms, Second Primary; Retrospective Studies; Rituximab; Thiotepa; Transplantation, Autologous; Treatment Outcome; Young Adult

We report a case of donor-derived diffuse large B-cell lymphoma (DLBCL), which developed 5 years after stem cell transplantation from a human leukocyte antigen (HLA)-haploidentical donor for acute myeloid leukemia (AML). A 51-year-old male was diagnosed with AML with variant KMT2A translocation involving t(6;11)(q13;q23). After 12 cycles of azacitidine treatment, fluorescence in situ hybridization (FISH) for KMT2A split signal indicated that 94% of his bone marrow (BM) cells were positive. He underwent peripheral blood stem cell transplantation (PBSCT) from his HLA-haploidentical son. The preconditioning regimen consisted of fludarabine, busulfan, melphalan, and antithymocyte globulin (ATG). The graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and short-term methotrexate. On day 28, KMT2A FISH analysis indicated that he had achieved a complete response (CR). He continued to receive tacrolimus for the limited type of cutaneous chronic GVHD. Five years after the transplantation, positron emission tomography/computed tomography (PET/CT) showed an abdominal tumor. The tumor was diagnosed as DLBCL without Epstein-Barr virus. BM aspiration revealed the infiltration of lymphoma cells with t(8;14)(q24;q32). Chimerism analysis showed that both the peripheral blood (PB) and abdominal lymphoma cells were of donor origin. After 4 cycles of salvage chemotherapy, PET/CT showed that a CR had been achieved. He underwent a second PBSCT from an HLA-identical unrelated donor. The preconditioning regimen and GVHD prophylaxis were the same as those for the first PBSCT without ATG. The patient's PB revealed complete second donor-type chimerism, and the patient has maintained a CR since the second transplantation.

Topics: Antilymphocyte Serum; Azacitidine; Busulfan; Epstein-Barr Virus Infections; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; HLA Antigens; Humans; In Situ Hybridization, Fluorescence; Leukemia, Myeloid, Acute; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Methotrexate; Middle Aged; Positron Emission Tomography Computed Tomography; Tacrolimus; Transplantation Conditioning

Topics: Adrenal Cortex Hormones; Allografts; Anemia, Aplastic; Antibodies, Monoclonal, Humanized; Antigens, CD19; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Deoxycytidine; Doxorubicin; Etoposide; Gemcitabine; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Oxaliplatin; Prednisone; Recurrence; Rituximab; Salvage Therapy; Transplantation, Autologous; Vincristine

Although rituximab-based high-dose therapy is frequently used in diffuse large B cell lymphoma (DLBCL) patients undergoing autologous hematopoietic cell transplantation (auto-HCT), data supporting the benefits are not available. Herein, we report the impact of rituximab-based conditioning on auto-HCT outcomes in patients who have DLBCL.. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, 862 adult DLBCL patients undergoing auto-HCT between 2003 and 2017 using BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning regimen were included. All patients received frontline rituximab-containing chemoimmunotherapy and had chemosensitive disease pre-HCT. Early chemoimmunotherapy failure was defined as not achieving complete remission (CR) after frontline chemoimmunotherapy or relapse within 1 year of initial diagnosis. The primary outcome was overall survival (OS).. The study cohort was divided into 2 groups: BEAM (n = 667) and R-BEAM (n = 195). On multivariate analysis, no significant difference was seen in OS (P = .83) or progression-free survival (PFS) (P = .61) across the 2 cohorts. No significant association between the use of rituximab and risk of relapse (P = .15) or nonrelapse mortality (P = .12) was observed. Variables independently associated with lower OS included older age at auto-HCT (P < .001), absence of CR at auto-HCT (P < .001) and early chemoimmunotherapy failure (P < .001). Older age (P < .0002) and non-CR pre-HCT (P < .0001) were also associated with inferior PFS. There was no significant difference in early infectious complications between the 2 cohorts.. In this large registry analysis of DLBCL patients undergoing auto-HCT, the addition of rituximab to the BEAM conditioning regimen had no impact on transplantation outcomes. Older age, absence of CR pre auto-HCT, and early chemoimmunotherapy failure were associated with inferior survival.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cohort Studies; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Multivariate Analysis; Registries; Rituximab; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Failure; Treatment Outcome; Young Adult

Intravascular large B-cell lymphoma (IVLBCL) is a rare subset of extranodal non-Hodgkin lymphoma characterized by neoplastic lymphocytes within the lumina of small to medium-sized blood vessels. IVLBCLs are B-cell tumors that can present in essentially any organ system, including the skin. Cutaneous manifestations vary greatly and can mimic other skin disease which may delay diagnosis; in the absence of skin lesions, blind skin biopsies can be utilized for diagnosis. Early studies suggested that IVLBCL is a very aggressive lymphoma with high overall mortality rate and short survival times. However, earlier diagnosis and use of new treatment modalities have shown promise in recent studies. This case series illustrates the heterogeneity of clinical and pathologic presentations of this uncommon lymphoma.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Blood Vessels; Carmustine; Cyclophosphamide; Cytarabine; Delayed Diagnosis; Diagnosis, Differential; Doxorubicin; Early Detection of Cancer; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Podophyllotoxin; Prednisone; Rituximab; Skin; Skin Neoplasms; Treatment Outcome; Vincristine

High-grade B cell lymphoma with MYC and BCL2 rearrangements (double hit) has a poor prognosis with standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). We report here a treatment algorithm of DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) followed by BEAM (carmustine, etoposide, cytarabine, melphalan) autologous transplant in 36 cases of previously untreated double hit lymphoma (DHL) from 2010 to 2015. A high risk International Prognostic Index (IPI) was present in 42% of cases. At median follow-up of 38 months, the 2-year progression free survival (PFS) and overall survival (OS) were 69% (95% CI 54-84%) and 71% (95% CI 56-86%). Eight cases were refractory to induction with 1-year OS 20%, and no factors were predictive for primary refractory disease. Of 28 responders, 17 proceeded to transplant while 11 were observed, primarily due to age and co-morbidities. By 24-week landmark analysis after diagnosis, the 2-year PFS and OS were both 94% (95% CI 83-100%) vs 79% (95% CI 52-100%) for transplant vs observation (p = .59 for both PFS and OS). There was no significant benefit to consolidative transplant in our series, and primary refractory DHL needs novel approaches.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Disease-Free Survival; Doxorubicin; Etoposide; Gene Rearrangement; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Large B-Cell, Diffuse; Melphalan; Middle Aged; Prednisone; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Rituximab; Transplantation, Autologous; Treatment Outcome; Vincristine

High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) improves outcomes in relapsed lymphoma, but the relative efficacy of different preparative regimens is not well defined. We included patients undergoing autologous HCT using BEAM (carmustine, 300 mg/m(2), etoposide, cytarabine, and melphalan) or BEP (carmustine 600 mg/m(2), etoposide, and cisplatin) between January 2004 and December 2013; 65 patients received BEP and 64 patients BEAM. Both cohorts were similar for advanced-stage disease, extranodal and bulky disease, and prior therapies. Median neutrophil and platelet engraftment was 10 and 20 days for both regimens, respectively. Febrile neutropenia, serum creatinine concentration increase, and electrolyte abnormalities were more frequent with BEP. Incidence of carmustine pneumonitis was not higher with BEP, likely the result of corticosteroid prophylaxis, although 2 cases of fatal pneumonitis were observed after BEP. One-year nonrelapse mortality was 6.8% after BEP and 0% after BEAM (P = .379). After a median follow-up of 39.4 months (range, 1 to 128), 4-year rates of overall survival (OS) after BEP and BEAM were 80.4% and 72.3%, respectively (P = .611). Diffuse large B cell lymphoma patients transplanted after early relapse post-rituximab-based first-line therapy presented 3-year rates of OS and progression-free survival (PFS) of 73.8% and 65%, respectively. There were no statistically significant differences in the OS and PFS of follicular lymphoma, mantle cell lymphoma, or Hodgkin lymphoma. BEP is a valid alternative to BEAM in autologous HCT. Although associated with more renal and electrolytic toxicities, BEP results in similar disease control and long-term survival as BEAM. Prospective studies are needed to confirm whether intensification of conditioning regimens for autologous HCT can improve disease control in high-risk relapsed lymphoma patients.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cisplatin; Cytarabine; Etoposide; Female; Graft Survival; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Recurrence; Retrospective Studies; Risk; Rituximab; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous

Topics: Adult; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Brain; Carmustine; Central Nervous System Neoplasms; Cesarean Section; Cytarabine; Dexamethasone; Drug Administration Schedule; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Large B-Cell, Diffuse; Magnetic Resonance Imaging; Melphalan; Methotrexate; Podophyllotoxin; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Rituximab; Transplantation, Autologous; Treatment Outcome

We retrospectively examined the outcomes of 56 patients with diffuse large B-cell lymphoma (DLBCL) who underwent autologous stem cell transplant (ASCT) with BEAM/BEAC (carmustine, etoposide, cytarabine, melphalan/cyclophosphamide) or busulfan (Bu)-containing conditioning regimens. The Bu group had lower disease-related mortality and more frequent achievement of complete remission (CR) after ASCT from partial remission (PR) or refractory status before ASCT compared with the BEAM/BEAC group. The estimated 2-year EFS (59.3% vs. 15.0%) and overall survival (OS) (70.2% vs. 42.0%) in pre-ASCT rituximab-exposed patients with DLBCL were higher in the Bu group. In patients with high-risk DLBCL exposed to rituximab with first remission, the Bu group had better EFS (p = 0.004) and OS (p = 0.053) rates, while survival rates for relapsed/refractory patients did not differ between groups. Bu regimens are highly effective for preparing patients with DLBCL with previous exposure to rituximab for ASCT, especially in high-risk patients who achieved a first remission.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Busulfan; Carmustine; Cyclophosphamide; Cytarabine; Disease-Free Survival; Etoposide; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Remission Induction; Retrospective Studies; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Young Adult

The number of elderly patients with diffuse large B cell lymphoma (DLBCL) continues to increase but the data regarding autologous stem cell transplantation (ASCT) for elderly patients are limited. We analyzed 484 patients, ages 60 years or over, diagnosed with relapsed/refractory DLBCL who received ASCT from 1993 to 2010 in the Japan Society for Hematopoietic Cell Transplantation database. Median age was 64 years (range, 60 to 78). To evaluate the impact of age at ASCT, patients were classified into 3 groups: those between the ages of 60 to 64, 65 to 69, and 70 years or over. Overall nonrelapse mortality (NRM) at day 100, 1 year, and 2 years was 4.1%, 5.9% and 7.7%, respectively. NRM did not significantly differ among age groups (P = .60). Two-year progression-free survival (PFS) and overall survival (OS) were 48% and 58%, respectively. PFS and OS were significantly longer in patients 60 to 64 years old; however, the survival rate was acceptable even in those 70 or over, with a 2-year OS of 46%. ASCT is feasible in selected elderly patients and age alone should not be a contraindication for ASCT. Eligibility should be individualized and identification of a subset of elderly patients at high risk of treatment-related morbidity or mortality warrants investigation.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cyclophosphamide; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Nitrosourea Compounds; Recurrence; Retrospective Studies; Survival Analysis; Transplantation, Autologous

Treatment of primary central nervous system lymphoma (PCNSL) improved in recent years. However, the high neurotoxicity and low survival rates associated with this condition remain unresolved. We report 13 consecutive patients with PCNSL for whom upfront melphalan, cyclophosphamide, etoposide, and dexamethasone (known as LEED) followed by autologous stem-cell transplantation (ASCT) was planned at the Anjo Kosei Hospital. All patients were pathologically diagnosed with diffuse large B-cell lymphoma and were negative for human immunodeficiency virus. All patients were to receive three cycles of high-dose methotrexate-based induction chemotherapy, two cycles of high-dose AraC-based chemotherapy, and LEED followed by ASCT. All 13 patients achieved a partial response, and the 3-year overall survival (OS) rate was 76.2 %. Seven of the 13 patients were alive at the last follow-up, without any adverse events, including neurotoxicity. Six of the 13 (46.2 %) patients underwent ASCT and the 3-year OS rate was 80.0 %. Although this study included only a limited number of patients, these preliminary signs of efficacy and tolerability merit further consideration. To make further improvements in survival, the rate of patients undergoing ASCT should be increased. Other prospective studies involving greater numbers of patients are required to confirm these findings.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Cyclophosphamide; Cytarabine; Dexamethasone; Etoposide; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Methotrexate; Middle Aged; Remission Induction; Retrospective Studies; Stem Cell Transplantation; Survival Analysis; Transplantation, Autologous; Treatment Outcome

This sixteenth biannual report of the Cochrane Haematological Malignancies Group highlights recently published randomized controlled trials (RCTs) in the field of hemato-oncology, with special focus on non-Hodgkin's lymphoma. The report covers the publication period June 2012 to July 2013. Trials are selected regarding their methodology and implication for clinical practice. Studies were identified by electronic search of MEDLINE using a broad search filter that covers all topics in hemato-oncology combined with a highly sensitive search filter for randomized trials (Cochrane Handbook for Systematic Reviews of Interventions). Four RCTs are presented in detail, followed by two further RCTs of high importance in a short version. The report is finalized with an overview of new and updated Cochrane Reviews.

Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Boronic Acids; Bortezomib; Carmustine; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Administration Schedule; Etoposide; Hematologic Neoplasms; Humans; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Melphalan; Nitriles; Nitrogen Mustard Compounds; Prednisone; Primary Myelofibrosis; Pyrazines; Pyrazoles; Pyrimidines; Quality of Life; Randomized Controlled Trials as Topic; Rituximab; Vincristine

Patients with relapsed or refractory lymphoma can be cured with stem cell transplantation if they are shown to have disease that is responsive to salvage chemotherapy. Patients who fail to respond to first-line salvage chemotherapy tend to do very poorly. Here we report on 39 such patients who received mini-BEAM (carmustine, etoposide, cytarabine, melphalan) chemotherapy as second or subsequent-line salvage chemotherapy. Fifty-six percent of these patients had primary refractory disease and a further 28% had responses to first-line therapy that lasted <12 months. Seventy-two percent had progressive disease following the salvage chemotherapy administered immediately prior to mini-BEAM and the remaining 28% had stable disease. Overall there was a 38% response to mini-BEAM (complete response = 28%, partial response = 10%). Patients with Hodgkin lymphoma (HL) had a higher response rate compared to those with diffuse large B cell lymphoma (DLBCL) (63% vs. 20%). Seventy-four percent of HL patients were able to proceed to transplantation compared with 30% of patients with DLBCL. Mini-BEAM is a very effective bridge to transplantation in very poor risk patients with HL who have failed to respond to first-line salvage chemotherapy. Its efficacy in non-Hodgkin lymphoma is more modest.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Recurrence; Salvage Therapy; Survival Analysis; Transplantation Conditioning; Treatment Outcome; Young Adult

Recent reports indicate that in vitro drug screens combined with gene expression profiles (GEP) of cancer cell lines may generate informative signatures predicting the clinical outcome of chemotherapy. In multiple myeloma (MM) a range of new drugs have been introduced and now challenge conventional therapy including high dose melphalan. Consequently, the generation of predictive signatures for response to melphalan may have a clinical impact. The hypothesis is that melphalan screens and GEPs of B-cell cancer cell lines combined with multivariate statistics may provide predictive clinical information.. Microarray based GEPs and a melphalan growth inhibition screen of 59 cancer cell lines were downloaded from the National Cancer Institute database. Equivalent data were generated for 18 B-cell cancer cell lines. Linear discriminant analyses (LDA), sparse partial least squares (SPLS) and pairwise comparisons of cell line data were used to build resistance signatures from both cell line panels. A melphalan resistance index was defined and estimated for each MM patient in a publicly available clinical data set and evaluated retrospectively by Cox proportional hazards and Kaplan-Meier survival analysis.. Both cell line panels performed well with respect to internal validation of the SPLS approach but only the B-cell panel was able to predict a significantly higher risk of relapse and death with increasing resistance index in the clinical data sets. The most sensitive and resistant cell lines, MOLP-2 and RPMI-8226 LR5, respectively, had high leverage, which suggests their differentially expressed genes to possess important predictive value.. The present study presents a melphalan resistance index generated by analysis of a B-cell panel of cancer cell lines. However, the resistance index needs to be functionally validated and correlated to known MM biomarkers in independent data sets in order to better understand the mechanism underlying the preparedness to melphalan resistance.

Topics: Antineoplastic Agents; B-Lymphocytes; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Least-Squares Analysis; Lymphoma, Large B-Cell, Diffuse; Melphalan; Multiple Myeloma; Oligonucleotide Array Sequence Analysis; Plasmacytoma

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leg; Lymphoma, Large B-Cell, Diffuse; Melphalan; Middle Aged; Recurrence; Remission Induction; Skin Neoplasms

The role of allogeneic transplantation with reduced-intensity conditioning in diffuse large B-cell lymphoma (DLBCL) is currently unclear, with relatively little published data. We report the outcome of reduced-intensity transplantation (RIT) in a cohort of 48 consecutive patients with relapsed/refractory DLBCL (30 patients with de novo disease and 18 patients with transformed follicular lymphoma) who underwent transplantation with an alemtuzumab-containing regimen, with a median follow-up of 52 months.. Patients had experienced treatment failure with a median of five lines of prior therapy, including autologous transplantation in 69%, and 17% of patients were chemotherapy refractory at transplantation. Median age was 46 years, and 38% of patients had matched/mismatched unrelated donors. Conditioning was with alemtuzumab, fludarabine, and melphalan, and additional graft-versus-host disease (GVHD) prophylaxis was with cyclosporine.. All patients were successfully engrafted. Only 17% of patients developed grade 2 to 4 acute GVHD, with 13% experiencing extensive chronic GVHD. Four-year estimated nonrelapse mortality was 32%, and relapse risk was 33%. Twelve patients received donor lymphocyte infusions +/- chemoimmunotherapy for relapse, and five patients obtained durable remissions, giving current progression-free survival (PFS) and overall survival (OS) rates at 4 years of 48% and 47%, respectively. Patients who had chemotherapy-sensitive disease before RIT had current PFS and OS rates at 4 years of 55% and 54%, respectively. Chemotherapy-refractory patients had a poor outcome.. The encouraging survival rates with extended follow-up suggest a role for RIT in chemotherapy-sensitive relapsed DLBCL, even in patients who have previously experienced treatment failure with autologous transplantation. Future studies will be required to determine whether any subset of patients with relapsed DLBCL should be considered for RIT versus autologous transplantation.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Agents; Bone Marrow Transplantation; Graft vs Host Disease; Humans; Lymphoma, Large B-Cell, Diffuse; Melphalan; Middle Aged; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

Topics: Acyclovir; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Carmustine; Cisplatin; Colitis; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Dexamethasone; Doxorubicin; Etoposide; Hematopoietic Stem Cell Transplantation; Herpes Zoster; Herpesvirus 3, Human; Humans; Immunocompromised Host; Immunoglobulins, Intravenous; Intestinal Pseudo-Obstruction; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Postoperative Complications; Prednisolone; Rituximab; Transplantation, Autologous; Vincristine; Virus Activation

The purpose of this study was to evaluate the ability of biomarkers to predict 5-year event-free survival (EFS) of poor prognosis patients with diffuse large B-cell lymphoma (DLBCL) who were treated on a prospective clinical trial with upfront high dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). We previously reported 51 patients with DLBCL treated with one cycle each of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP), dose-intensive cyclophosphamide, etoposide, cisplatin (DICEP), and carmustine, etoposide, Ara-C, and melphalan (BEAM)/ASCT. Of these patients, 33 had DLBCL and suitable tissue for immunohistochemical (IHC) biomarker evaluation. We found no statistically significant association between EFS and age adjusted International Prognostic Index (IPI) score, bulk over 10 cm, germinal center B-cell phenotype, or expression of BCL-2 or BCL-6 biomarkers. However, the detection of pY-STAT3 expression was associated with improved 5-year EFS (93%versus 47%, p = 0.006), and p53 expression was associated with lower 5-year EFS (47%versus 83%, p = 0.025). Predictive ability was improved by combining pY-STAT3 and p53 expression. Specifically, 5-year EFS rates were 93% for pY-STAT3+, 77% for pY-STAT3-/p53-, and 20% for pY-STAT3-/p53+ patients (p = 0.0002). In conclusion, pY-STAT3 and p53 expression may help predict outcome of HDCT for DLBCL, and further study of these biomarkers is warranted.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Disease-Free Survival; Doxorubicin; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Neoplasm Proteins; Phosphorylation; Phosphotyrosine; Podophyllotoxin; Prednisone; Prognosis; Prospective Studies; Protein Processing, Post-Translational; STAT3 Transcription Factor; Transplantation, Autologous; Tumor Suppressor Protein p53; Vincristine

High-dose chemotherapy supported by autologous peripheral blood stem cell transplantation (PBSCT) is beneficial for patients with relapsed or refractory but chemosensitive diffuse large B-cell lymphoma (DLBCL). However, most elderly patients are not indicated for that therapy and receive supportive treatment only. We describe here two elderly patients with relapsed or refractory DLBCL who achieved prolonged disease-free survival after undergoing intermediate-dose melphalan therapy supported by PBSCT (MEL100) three times. Case 1 was an early relapse (within one year) after the first remission and case 2 was a second relapse. Both cases are currently alive without relapse and have maintained a good performance status for 41 months and 32 months, respectively, after MEL100. Febrile neutropenia and herpes zoster as non-hematological toxicities (grade > or = 3) occurred only in case 1. Considering the benefits vs. toxic effects, this regimen may improve the prognosis of elderly patients with relapsed or refractory DLBCL by MEL100.

Topics: Aged; Antineoplastic Agents, Alkylating; Disease-Free Survival; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Neoplasm Recurrence, Local; Peripheral Blood Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome

High-dose chemotherapy and haematopoietic stem cell (HSC) transplantation is considered standard therapy in patients with chemosensitive relapsed diffuse large B cell lymphoma (DLBCL). BCNU (carmustine), etoposide, cytarabine and melphalan (BEAM) is a widely used standard DLBCL conditioning regimen. The practice of basing chemotherapy doses on body surface area (BSA) is empirical and the best biometric parameter to dose chemotherapy is unknown. Weight-based dosing has been suggested to better predict toxicity of the conditioning regimen. We correlated the dose/weight ratio with toxicity and overall outcome in a uniform cohort of 80 consecutive patients receiving HSC transplant for relapsed DLBCL at Mayo Clinic, Rochester, MN following BSA-dosed BEAM conditioning chemotherapy. Melphalan dose was used as surrogate for the entire regimen. Median age at the time of transplant was 62 (26-77) years; 65% were males. The median melphalan dose was 3.2 mg/kg (range 2.2-4.5). Patients who received >3.6 mg/kg of melphalan were more likely to have grade 3 or 4 mucositis (44.4% vs. 9.8%, P = 0.001) and prolonged hospitalization (median 13 vs. 7 d; P = 0.04). Dose/weight ratio did not correlate with cumulative incidence of relapse (P = 0.3) or survival (P = 0.8). Transplant physicians should consider limiting the dose of BEAM to the equivalent of 3.6 mg/kg of melphalan.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Carmustine; Chi-Square Distribution; Cohort Studies; Cytarabine; Drug Administration Schedule; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Length of Stay; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Mucositis; Recurrence; Risk; Statistics, Nonparametric; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

To investigate the impact of adding rituximab to intensive chemotherapy with peripheral-blood progenitor cell (PBPC) autograft for high-risk diffuse large B-cell lymphoma (DLB-CL) and follicular lymphoma (FL).. Data were collected from 10 centers associated with Gruppo Italiano Terapie Innnovative nei Linfomi for 522 patients with DLB-CL and 223 patients with FL (median age, 47 years) who received the original or a modified high-dose sequential (HDS) chemotherapy regimen. HDS was delivered to 396 patients without (R-) and to 349 patients with (R+) rituximab; 154 (39%) and 178 patients (51%) in the R- and R+ subsets, respectively, underwent HDS for relapsed/refractory disease.. A total of 355 R- (90%) and 309 R+ patients (88%) completed the final PBPC autograft. Early treatment-related mortality was 3.3% for R- and 2.8% for R+ (P = not significant). Two parameters significantly influenced the outcome: disease status at HDS, with 5-year overall survival (OS) projections of 69% versus 57% for diagnosis versus refractory/relapsed status, respectively, and rituximab addition, with 5-year OS of 69% versus 60% in the R+ versus R- groups, respectively. In the multivariate analysis, these two variables maintained an independent prognostic value. The marked benefit of rituximab was evident in patients receiving HDS as salvage treatment: the 5-year OS projections for R+ versus R- were, respectively, 64% versus 38%, for patients with refractory disease or early relapse and 71% versus 57%, for patients with late relapse, partial response, or second/third relapse.. The results of this large series indicate that rituximab should be included in the current practice of PBPC autograft for DLB-CL and FL.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Cytarabine; Disease Progression; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Humans; Italy; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Methotrexate; Middle Aged; Prognosis; Proportional Hazards Models; Retrospective Studies; Risk Factors; Rituximab; Survival Rate; Thiotepa; Transplantation, Autologous; Treatment Outcome

Topics: Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Disease Progression; Drug Therapy, Combination; Hematologic Diseases; Hematology; Humans; Lenalidomide; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Melphalan; Multiple Myeloma; Prednisone; Pyrazines; Quinolones; Recurrence; Stem Cell Transplantation; Thalidomide; Transplantation Conditioning; Transplantation, Autologous

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

A prospective multicenter program was performed to evaluate the combination of rituximab and high-dose (hd) sequential chemotherapy delivered with multiple autologous peripheral blood progenitor cell (PBPC) support (R-HDS-maps regimen) in previously untreated patients with diffuse large B-cell lymphoma (DLB-CL) and age-adjusted International Prognostic Score (aaIPI) score 2-3. R-HDS-maps includes: (i) three APO courses; (ii) sequential administration of hd-cyclophosphamide (CY), hd-Ara-C, both supplemented with rituximab, hd-etoposide/cisplatin, PBPC harvests, following hd-CY and hd-Ara-C; (iii) hd-mitoxantrone (hd-Mito)/L-Pam + 2 further rituximab doses; (iv) involved-field radiotherapy. PBPC rescue was scheduled following Ara-C, etoposide/cisplatin and Mito/L-Pam. Between 1999 and 2004, 112 consecutive patients aged <65 years (74 score 2, 38 score 3) entered the study protocol. There were five early and two late toxic deaths. Overall 90 patients (80%) reached clinical remission (CR); at a median 48 months follow-up, 87 (78%) patients are alive, 82 (73%) in continuous CR, with 4 year overall survival (OS) and event-free survival (EFS) projections of 76% (CI 68-85%) and 73% (CI 64-81%), respectively. There were no significant differences in OS and EFS between subgroups with Germinal-Center and Activated B-cell phenotype. Thus, life expectancy of younger patients with aaIPI 2-3 DLB-CL is improved with the early administration of rituximab-supplemented intensive chemotherapy compared with the poor outcome following conventional chemotherapy.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Disease-Free Survival; Etoposide; Feasibility Studies; Female; Humans; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Mitoxantrone; Peripheral Blood Stem Cell Transplantation; Prospective Studies; Rituximab; Transplantation, Autologous; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cryoglobulins; Cytarabine; Humans; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Podophyllotoxin; Transplantation, Autologous

Cell adhesion to fibronectin is known to confer a temporally related cell adhesion-mediated drug resistance (CAM-DR). However, it is unknown whether cell adhesion during drug selection influences the more permanent form of acquired drug resistance. To examine this question, we compared the acquisition of mitoxantrone resistance in U937 cells adhered to fibronectin versus cells selected in a traditional suspension culture. Our data show that acquired drug resistance levels of resistance to mitoxantrone are 2- to 3-fold greater for cells adhered to fibronectin compared with cells in suspension culture. We also compared mechanism(s) of resistance associated with drug selection in suspension versus fibronectin-adherent cultures. Drug resistance in both suspension and fibronectin-adhered cultures correlated with reduced drug-induced DNA damage and diminished topoisomerase II levels and activity; however, mechanisms regulating topoisomerase II levels differed depending on culture conditions. In suspension cultures, a reduction in topoisomerase IIbeta levels was detected at both RNA and protein levels. Furthermore, the decreased expression of topoisomerase IIbeta mRNA levels correlated with decreased expression of NF-YA. In contrast, in spite of no changes in NF-YA or topoisomerase IIbeta RNA expression, topoisomerase IIbeta protein levels were decreased in fibronectin-adherent, drug-resistant cells. In addition, topoisomerase IIalpha protein levels (but not RNA levels) were reduced in drug resistance cells selected on fibronectin; however, no change in topoisomerase IIalpha was observed in cells selected with mitoxantrone in suspension culture. Taken together, our results suggest that the development of drug resistance models must consider interactions with the microenvironment to identify clinically relevant targets and mechanisms associated with acquired drug resistance.

Topics: Cell Adhesion; DNA Damage; DNA Topoisomerases, Type II; Drug Resistance, Neoplasm; Fanconi Anemia Complementation Group E Protein; Fibronectins; Gene Expression Profiling; Humans; Lymphoma, Large B-Cell, Diffuse; Melphalan; Mitoxantrone; Oligonucleotide Array Sequence Analysis; U937 Cells

Reduced-intensity regimens (RIRs) are being used with increasing frequency in patients with non-Hodgkin's lymphoma (NHL) undergoing allogeneic transplantation. The impact of dose reduction on relapse and survival has not been extensively studied. We performed a retrospective analysis of 88 patients conditioned with conventional myeloablative regimens (CMRs) (n = 48) and an RIR (n = 40) of fludarabine 125 mg/m(2) and melphalan 140 mg/m(2). Compared with the patients receiving CMR, those receiving RIR were older, had more often failed autologous transplantation, and had more frequently received peripheral blood and unrelated donor transplants. Graft-versus-host disease prophylaxis was provided with cyclosporine + methotrexate +/- prednisone for the CMR and with cyclosporine + mycophenolate +/- methotrexate for the RIR. The relapse rate was significantly lower in the patients receiving CMR than in those receiving RIR (13% vs 28%; P = .05). The 1-year transplantation-related mortality rate was 33% for CMR and 28% for RIR (P = .40). Kaplan-Meier 2-year overall survival and progression-free survival were 52% and 46% for CMR versus 53% and 40% for RIR (P = not significant). Using cumulative incidence functions based on competing risks, univariate analysis, and treatment-related prognostic factors, we found that higher treatment intensity (P = .03; relative risk [RR] = 35%) and absence of previous autologous transplantation (P = .0007; RR = 20%) were associated with a lower relapse rate. Using a Cox univariate proportional hazards model, we found that chemosensitive disease at transplantation (P = .05; RR = 57%) and absence of previous autologous transplantation (P = .002; RR = 37%) were associated with improved survival. Our observation of similar survival in the patients receiving CMR and those receiving RIR confirms that RIRs are feasible alternatives for high-risk patients with NHL; however, the data suggest that reduced treatment intensity and previous autologous transplantation are associated with increased relapse.

Topics: Adolescent; Adult; Aged; Busulfan; Cause of Death; Cohort Studies; Cyclophosphamide; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Graft vs Host Disease; Hepatic Veno-Occlusive Disease; Humans; Infections; Kaplan-Meier Estimate; Lung Diseases, Interstitial; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Lymphoma, T-Cell; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Proportional Hazards Models; Reoperation; Retrospective Studies; Risk Factors; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine; Whole-Body Irradiation

Previously, we have shown that patients with diffuse large B-cell lymphoma (DLBCL) transplanted with contaminated bone marrow (BM) generally have a poor outcome. Whether this is also the case when peripheral blood progenitor cell (PBPC) grafts are used is not known. Forty-three patients with chemosensitive DLBCL or follicular lymphoma grade 3 (FLgr3) were treated with high-dose therapy (HDT) and autologous stem cell support. Nine patients received purged grafts. Quantitative real-time polymerase chain reaction (QRT-PCR) for either the BCL2/IgH translocation or allele specific oligonucleotide (ASO) QRT-PCR for the immunoglobulin heavy chain (IgH) complementarity-determining region 3 were used. Nine of 25 (36%) PBPC grafts contained tumour cells as tested by QRT-PCR, including two grafts purged by CD34(+) cell enrichment combined with B-cell depletion. The level of contamination of the PBPC/CD34(+) cells ranged from 0 to 8.28%. No relationship could be shown between the total number of tumour cells infused and relapse. Patients receiving PCR-positive or PCR-negative PBPC grafts had similar progression-free survival (PFS) (P = 0.49). However, a significant difference was seen in PFS and overall survival (OS) for the patients given >/=6.1 x 10(6) CD34(+) cells/kg compared with those given <6.1 x 10(6) CD34(+) cells/kg (P = 0.01 and P < 0.05 respectively).

Topics: Adult; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cytarabine; Disease-Free Survival; Etoposide; Female; Graft Survival; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, B-Cell; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Salvage Therapy; Treatment Outcome

From January 1st 1995 to March 31st 2003 a total of 51 autologous stem-cell transplantations (auto-HSCT) in 49 children with non Hodgkin lymphomas (NHL) were carried out in the transplantation centres of the Polish Pediatric Group for Treating Leukemias and Lymphomas (PPGLBC). In 2 patients the transplantations were carried out twice. The age of children at the moment of the transplantation ranged from 2.8 to 17.3 years (median 10.0), with higher representation of boys than girls. Twenty eight of the procedures were carried out in children with the diagnosis of B-cell non Hodgkins lymphoma (B-NHL), eight--in children with non B-cell non Hodgkins lymphoma (NB-NHL) and thirteen--in patients with anaplastic large cell lymphoma (LCAL). 16 procedures were performed in children who at the moment of transplantation were in their first complete remission (CR), another 16 were carried out while in their 2nd and 3rd CRs, and 17 transplants were performed at partial remission (PR). In addition, two children received transplants in the phase of the disease relapse. In most cases (44) the BEAM protocol was applied as megachemotherapy. In 49 procedures peripheral blood was the source of stem-cells, in one--bone marrow, in one--bone marrow + peripheral blood. The number of CD34/kg cells transplanted ranged from 1.2 x 10(6) to 8.0 x 10(6) (median 4.2 x 10(6)). Hematologic reconstitution occurred in all but one patient who died on the 10th day from HSCT. 42 out of the 49 children (87%) survived with the observation time ranging from 1 to 94 months (median 47 months). During the observation time, 34 of children were in CR. In 15, disease relapses or progression were noted within the time ranging from 3 to 22 months from HSCT (median 6 months). Seven children died (14%) including 5 due to relapse. Expected overall survival (OS) at 5 years from transplantation for the whole group of patients was 0.85 and varied only slightly for individual categories of NHL. The probability of 5-year disease-free survival (DFS) for the whole group was 0.67 and was the highest in B-NHL (0.84) and was much lower in LCAL and in NB-NHL, 0.5 and 0.47 respectively. Our results suggest that BEAM megachemotherapy with autologous transplantation in children with NHL is a safe procedure, which at the same time improves the results of standard treatment, especially in children with NHL primary resistant to chemotherapy.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Child; Child, Preschool; Cytarabine; Disease-Free Survival; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Infant; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Melphalan; Podophyllotoxin; Poland; Retrospective Studies; Survival Analysis; Time Factors; Transplantation, Autologous; Treatment Outcome

The purpose of this study was to analyse the results and prognostic factors influencing overall survival (OS) and disease-free survival (DFS) in 452 patients diagnosed with diffuse large cell lymphomas (DLCL) treated with high-dose therapy (HDT) included in the Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL-TAMO) Spanish registry.. At transplantation, median age was 42 years (range 15-73), 146 patients (32%) were transplanted in first complete remission (1st CR), 19% in second CR (2nd CR) and 47% had active disease: sensitive disease in 157 (35%) patients [95 were in first partial remission (1st PR) and 62 in second PR (2nd PR)] and refractory disease in 55 (12%) patients. Age-adjusted International Prognostic Index (IPI) was 2 or 3 in 51 patients (12%). Conditioning regimen consisted of BEAM (carmustine, etoposide, cytarabine and melphalan) in 39% of patients, BEAC (carmustine, etoposide, cytarabine and cyclophosphamide) in 33%, CBV (carmustine, etoposide and cyclophosphamide) in 10% and cyclophosphamide plus total body irradiation (TBI) in 12%.. Estimated overall survival (OS) and disease-free survival (DFS) at 5 years were 53% and 43%, respectively. The transplant-related mortality was 11% (53 cases). By multivariate analysis three variables significantly influenced OS and DFS: number of protocols to reach 1st CR, disease status at transplant and TBI in the conditioning regimen. Age-adjusted IPI at transplantation also influenced OS.. Prolonged OS and DFS can be achieved in patients with DLCL after HDT and our results suggest that the best line of chemotherapy should be used up-front in patients considered as candidates for HDT in order to obtain an early CR. Resistant patients are not good candidates for HDT and they should be offered newer strategies. Finally, polichemotherapy conditioning regimens offer better results compared with TBI.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Cytokines; Doxorubicin; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; L-Lactate Dehydrogenase; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Podophyllotoxin; Prednisone; Prognosis; Radiotherapy, Adjuvant; Remission Induction; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Vincristine

Topics: 4-Quinolones; Aged; Anti-Infective Agents; Antineoplastic Combined Chemotherapy Protocols; Bacteremia; Capnocytophaga; Carmustine; Combined Modality Therapy; Cytarabine; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Multiple Myeloma; Podophyllotoxin; Transplantation Conditioning

The purpose of this study was to evaluate the outcome of high-dose chemotherapy (HDCT) followed by autologous haematopoietic stem cell transplant (ASCT) for patients with relapsed T-cell non-Hodgkin's lymphoma. We reviewed 36 patients with peripheral T-cell lymphoma (PTL) who underwent ASCT between January 1987 and June 2001. Patients had chemosensitive disease, and received high-dose melphalan and etoposide with or without total body irradiation supported by unpurged autologous stem cells. Comparisons were made with 97 diffuse large B-cell lymphoma (DLBL) patients. PTL patients had a median age of 46 years (19-62 years). Twenty-nine had relapsed and seven had primary refractory disease. DLBL patients were statistically similar in baseline characteristics. Of patients with PTL, six (17%) died of treatment-related complications and 14 (39%) were in remission with a median follow-up of 42 months (range 6-116 months). Three-year overall survival and event-free survival (EFS) were 48% and 37%, respectively, for PTL, compared with 53% and 42% for DLBL (P = 0.41 and 0.29 respectively). There was no significant prognostic variable found by univariate analysis for the PTL cohort. Major PTL subtypes were analysed for outcomes. The 20 patients with PTL, not otherwise specified (PTL-NOS), had an inferior EFS compared with DLBL patients (23%, P = 0.028). In contrast, the nine patients with anaplastic large T/null cell lymphoma had a non-significant trend for improved EFS (67%, P = 0.41). While ASCT in patients with relapsed or primary refractory PTL results in long-term remission rates comparable to DLBL patients, those with PTL-NOS do significantly worse.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chi-Square Distribution; Disease-Free Survival; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, T-Cell, Peripheral; Male; Melphalan; Middle Aged; Recurrence; Retrospective Studies; Salvage Therapy; Survival Rate; Transplantation Conditioning; Transplantation, Autologous

Although point mutations of the 5' noncoding regions of the BCL-6 proto-oncogene are frequently detected in B-diffuse large cell lymphoma (B-DLCL), a thorough analysis of the clinical correlation of these mutations has not been performed to date. In this study, BCL-6 mutations were examined by DNA direct sequencing in 103 patients with B-DLCL. BCL-6 mutations were found in 53/103 patients, including 38/76 treated with standard chemotherapy and 15/27 treated with autologous stem cell transplantation (ASCT) up front. The presence of BCL-6 mutations was correlated with clinical features at diagnosis and outcome. Mutated patients had a significantly higher LDH level (66% vs 38%, P < 0.05), and bulky disease (51% vs 32%, P = 0.05). In the whole series of patients BCL-6 mutations did not affect CR and OS. Patients with BCL-6 mutations tended to have a prolonged 5-years DFS and FFS compared to those without mutations (DFS 82% vs 63%, FFS 63% vs 49%). Among B-DLCL treated with standard chemotherapy, mutated patients showed a significantly improved 5-year DFS (85% vs 61%, P < 0.05) and, notably, the only four relapses observed among mutated patients occurred in less than 8 months. The multivariate regression analysis (P < 0.01) with DFS as endpoint confirmed the independent prognostic value of BCL-6 mutations. There was a trend for 5-year failure-free survival to be better for patients with BCL-6 mutations (63% vs 43%, P = 0.09). In the 27 patients treated with ASCT, BCL-6 mutations did not correlate with outcome. These results suggest that BCL-6 mutations may predict a higher chance of being free of disease in B-DLCL treated with standard chemotherapy. Larger series of patients need to be analyzed to evaluate the clinical relevance of BCL-6 mutations properly.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carmustine; Chromosomes, Human, Pair 3; Cyclophosphamide; Cytarabine; Disease-Free Survival; DNA Mutational Analysis; DNA-Binding Proteins; DNA, Neoplasm; Doxorubicin; Etoposide; Female; Genes, bcl-2; Humans; Life Tables; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Methotrexate; Middle Aged; Neoplasm Proteins; Neoplasm Staging; Point Mutation; Prednisolone; Prednisone; Prognosis; Proto-Oncogene Mas; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-6; Proto-Oncogenes; Transcription Factors; Treatment Outcome; Vincristine

In our previous study with MACOPB, we identified a high-risk group of patients with a poor 3-year survival rate of 29%. These patients were defined as having at diagnosis advanced-stage disease with high tumor burden (TB) and elevated lactate dehydrogenase (LDH) level or bone marrow (BM) involvement. A novel therapeutic scheme was investigated to improve the outcome of these patients.. Fifty patients with high-risk diffuse large-cell lymphoma (DLCL) were enrolled. The therapeutic scheme includes three phases: induction with 8 weeks of MACOPB; intensification with a 3-day course of mitoxantrone 8 mg/m2 plus high-dose cytarabine (HDARA-C) 2 g/m2 every 12 hours plus dexamethasone 4 mg/m2 every 12 hours (MAD protocol) and granulocyte colony-stimulating factor (G-CSF) 5 microg/kg on days 4 to 17 to harvest peripheral-blood progenitor cells (PBPC); consolidation with carmustine (BCNU), etoposide, ARA-C, and melphalan (BEAM) regimen; plus autologous stem-cell transplantation (ASCT) with PBPC, marrow, or both.. Thirty-six patients (72%) achieved a complete response (CR), 11 (22%) showed no response (NR), and three (6%) died of toxicity. Among the 22 PRs or NRs after the induction phase, 56% of patients achieved a CR with subsequent intensified therapy. With a median follow-up duration of 32 months, the overall survival and failure-free survival rates were 56% and 50%, respectively. The disease-free survival rate is 69% at 32 months. Leukapheresis after MAD and G-CSF yielded a median of 32 x 10(6)/kg CD34+ cells and 80 x 10(4)/kg granulocyte-macrophage colony-forming units (CFU-GM). Thirty-nine patients were autografted and 11 did not undergo ASCT: six because of disease progression, four due to toxicity, and one because of patient refusal. The median times to achieve engrafment were 11 days (range, 7 to 19) to a neutrophil count greater than 0.5 x 10(9)/L and 12 days (range, 8 to 60) to a platelet count greater than 50 x 10(9)/L.. This sequential scheme with intensified and high-dose chemotherapy with ASCT is feasible with moderate toxicity and may improve the outcome in high-risk DLCL.

Topics: Adult; Antimetabolites, Antineoplastic; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Marrow Transplantation; Carmustine; Cyclophosphamide; Cytarabine; Dexamethasone; Disease-Free Survival; Doxorubicin; Etoposide; Feasibility Studies; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Leucovorin; Leukapheresis; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Methotrexate; Middle Aged; Mitoxantrone; Pilot Projects; Prednisone; Risk; Survival Analysis; Transplantation, Autologous; Treatment Outcome; Vincristine

The benzoyl nitrogen mustard derivative of distamycin A, tallimustine, belongs to a new class of alkylating agents, known as DNA minor groove alkylating agents. It alkylates adenine N3 with high sequence specificity, causing no alkylation of guanine N7, the main site of alkylation of clinically used nitrogen mustards such as L-PAM. The present study investigated the in vivo antitumour activity of a combination of tallimustine and melphalan (L-PAM). Two murine tumours were used: i.p. (intraperitoneally) transplanted L1210 leukaemia and i.m. (intramuscularly) transplanted M5076 ovarian reticulum cell sarcoma (M5). In L1210, which is only marginally sensitive to tallimustine, the combination of tallimustine 3 mg/kg i.p. with L-PAM 10 mg/kg i.p. was as effective as 20 mg/kg L-PAM, which is the maximum tolerated dose. In M5, which is sensitive to both drugs, the combination was superior to either drug alone. The results suggest that the combination of tallimustine and L-PAM--or possibly in general, minor groove alkylators and major groove alkylators--may be therapeutically advantageous and therefore should be investigated clinically.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Distamycins; Female; Leukemia L1210; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Neoplasm Transplantation; Nitrogen Mustard Compounds; Ovarian Neoplasms; Survival Rate

In two consecutive and unselected cohorts of diffuse large cell lymphoma (DLCL) patients with advanced stage disease (IIB or bulk or more) and aged < 60 years, we compared a standard (MACOP-B for 12 weeks, 60 patients) versus a high-dose chemotherapy programme (8 weeks of MACOP-B plus one or two cycles of intensification with mitoxanthrone, dexamethasone, high-dose Ara-C, and finally BEAM chemotherapy with autologous haemopoietic progenitor cell transplantation, 61 patients). 41 patients (68%) in the standard group and 51 (84%) in the high-dose chemotherapy group, achieved a complete remission (CR) or an uncertain complete remission (CRu) (P = 0.0491). With a median follow-up time of 28 months for the high-dose group and 63.5 months for the standard group, the actuarial estimate of event-free survival (EFS) at 2 years demonstrates a significant benefit (70% v 50%, P = 0.03) for patients treated with the intensive regimen. The analysis of subgroups of patients showed that only high-risk patients (two or three risk factors) benefitted from the high-dose chemotherapy programme. Nevertheless, the overall survival does not show a significant difference between the two treatment modalities. The treatment-related morbidity was similar and the mortality rate was 8% in the standard (MACOP-B) group and 3% in the high-dose chemotherapy programme. In conclusion, our results show that high-dose chemotherapy and autologous stem cell transplantation is a safe procedure which should be considered for the front-line treatment of non-Hodgkin lymphoma patients with poor prognostic features.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carmustine; Cyclophosphamide; Cytarabine; Disease-Free Survival; Doxorubicin; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Leucovorin; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Methotrexate; Middle Aged; Prednisone; Survival Rate; Treatment Outcome; Vincristine

Adriamycin containing combination chemotherapy (ACCC) is usually delivered to patients with stages III, IV diffuse large cell (DLCL) non-Hodgkin's lymphoma (NHL). Although this mode of therapy is also commonly used in other intermediate grade lymphomas, it's role in the latter subset of patients is not well defined. In a retrospective analysis we evaluated and compared the outcome of previously untreated DLCL and non-DLCL intermediate grade lymphoma patients who received as initial therapy, "first generation" ACCC. No differences in response and relapse rates between these subgroups were observed. The trend towards the survival advantage observed for the non-DLCL patients, is probably due to a lower mortality over 5-8 years, for complete responders.

Topics: Actuarial Analysis; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cisplatin; Cyclophosphamide; Dexamethasone; Doxorubicin; Etoposide; Follow-Up Studies; Humans; Leucovorin; Lomustine; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Methotrexate; Middle Aged; Phosphoramide Mustards; Prednisolone; Prednisone; Prognosis; Retrospective Studies; Survival Analysis; Time Factors; Treatment Outcome; Vincristine

In the present paper, we report two cases of normal pregnancy after high dose chemotherapy and autologous stem cell transplantation (ASCT) in two of the 72 women belonging to a group of 188 patients transplanted in our unit for advanced malignant lymphoma. These pregnancies occurred 19 and 33 months after high dose therapy in two women aged 27 and 28, neither of whom had received previous total body irradiation or pelvic radiotherapy. There are several reasons for the relatively low frequency of pregnancies after ASCT. In particular, the median age of the patients is 35 years, most of these women are transplanted in relapse and have received previous pretreatment with alkylating agents and the disease free survival rate does not exceed 40%. The preservation of long term fertility should be taken into account when deciding therapeutic options for young women with curable disease.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Infant, Newborn; Lymphoma, Large B-Cell, Diffuse; Mechlorethamine; Melphalan; Podophyllotoxin; Prednisone; Pregnancy; Pregnancy Outcome; Procarbazine; Remission Induction; Salvage Therapy; Vincristine

Resistance of mouse M5076 (M5) ovarian reticular cell sarcoma to cyclophosphamide (CTX) was obtained in vivo by repeated drug treatment followed by transplantation of the regrowing tumor. After 16 passages, we obtained an M5 subline resistant to CTX (M5-CTX-16R). Median survival times were approximately 29 and 39 days for M5 and M5-CTX-16R, respectively. Survival of M5-bearing mice given a single i.p. dose of 200 or 300 mg/kg was 160 and 168% of controls, respectively, whereas in M5-CTX-16R it ws 103 and 123%, respectively. The resistance was not reversible after 14 additional passages with no further CTX treatment. M5 and M5-CTX-16R appear similar in histological features, pattern of metastasis formation, and DNA content, as assessed by flow cytometry (hypotetraploid). Metastases of M5-CTX-16R were also resistant to CTX. Flow cytometry studies 12 and 24 hr after CTX treatment revealed a block in S and G2-M phases in both tumors. After 48 hr and at subsequent times, no cytokinetic pertubation was evident in M5-CTX-16R, whereas in M5 marked accumulation of cells in G2-M was observed at 48, 72, 96, and 120 hr. Cross-resistance was found between CTX, L-phenylalanine mustard, chlorambucil, and hexamethylmelamine. M5-CTX-16R was sensitive, but less so than M5, to cis-platinum, 1,3-bis(2-chloroethyl)-1-nitrosourea, and imidazole-4-carboxamide,5-(3,3-dimethyl-1-triazene). Adriamycin was equally active on M5 and M5-CTX-16R, while 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidine-beta-D-glucopyranoside) was inactive. This model appears to be suitable for studies on the mechanism of resistance to CTX and alkylating agents and for screening new, non-cross-resistant drugs.

Topics: Animals; Antineoplastic Agents; Carmustine; Cell Cycle; Cell Line; Cyclophosphamide; Dacarbazine; Drug Resistance; Female; Lymphoma, Large B-Cell, Diffuse; Melphalan; Mice; Mice, Inbred C57BL; Ovarian Neoplasms

Topics: Adolescent; Bone Neoplasms; Child; Child, Preschool; Chondrosarcoma; Cyclophosphamide; Humans; Infant; Lymphoma, Large B-Cell, Diffuse; Melphalan; Methotrexate; Sarcoma, Ewing

Chromosomal findings are reported in three patients with acute myelomonocytic leukemia and in one with reticulosarcoma leukemia who had been treated for multiple myeloma with melphalan and X-ray. All four patients had striking chromosomal anomalies. An iatrogenic causation of aneuploidy is suggested. This is supported by chromosomal findings in patients with acute leukemia following polycythemia vera and Hodgkin's disease; practically all of the leukemias have been aneuploid. A comparison is made of such "secondary" acute leukemias with "primary" acute leukemias that are aneuploid in only 40% of the cases. Chromosomal changes are not considered to be the initial event in leukemogenesis.

Topics: Aneuploidy; Chromosome Aberrations; Female; Humans; Leukemia, Myeloid, Acute; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Multiple Myeloma; X-Rays

Topics: Adolescent; Adult; Amputation, Surgical; Bone Neoplasms; Child; Chondrosarcoma; Female; Humans; Hypothermia, Induced; Hypoxia; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Methods; Osteosarcoma; Radiation Injuries; Tourniquets

Three patients with multiple myeloma who developed a plasma cell sarcoma during apparently successful chemothapy are described. It is postulated that the chemotherapy induced the sarcomatous change.

Topics: Aged; Bence Jones Protein; Bone Marrow; Cyclophosphamide; Female; Humans; Immunoelectrophoresis; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Lung Neoplasms; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Multiple Myeloma; Nitrogen Mustard Compounds; Pleural Neoplasms; Time Factors

Topics: Adolescent; Aged; Bone Neoplasms; Female; Hemangiosarcoma; Hodgkin Disease; Humans; Leukopenia; Lymphoma, Large B-Cell, Diffuse; Male; Melanoma; Melphalan; Neoplasms; Ovarian Neoplasms; Sarcoma, Ewing; Testicular Neoplasms; Thrombocytopenia; Tonsillar Neoplasms; Uterine Neoplasms

Topics: Adolescent; Amputation, Surgical; Anti-Bacterial Agents; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Child; Chondrosarcoma; Giant Cell Tumors; Hip; Humans; Lymphoma, Large B-Cell, Diffuse; Melphalan; Neoplasm Metastasis; Osteosarcoma; Radioisotopes; Sarcoma, Ewing; Shoulder; Vitamins

Topics: Adolescent; Adult; Aged; Bone Neoplasms; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Child; Extremities; Female; Hemorrhage; Humans; Hypotension; Leukopenia; Lymph Node Excision; Lymphoma, Large B-Cell, Diffuse; Male; Melanoma; Melphalan; Methods; Middle Aged; Postoperative Complications; Sarcoma; Skin Neoplasms

Topics: Administration, Oral; Adolescent; Aged; Chemotherapy, Cancer, Regional Perfusion; Cyclophosphamide; Female; Fibrosarcoma; Humans; Knee; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Retroperitoneal Neoplasms; Sarcoma; Stomach Neoplasms

Topics: Adolescent; Adult; Aged; Child; Fibrosarcoma; Giant Cell Tumors; Hemangiosarcoma; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Maxillary Neoplasms; Melphalan; Middle Aged; Myxosarcoma; Osteosarcoma; Radioisotope Teletherapy; Sarcoma; Thiotepa

Topics: Adolescent; Adult; Antibiotics, Antineoplastic; Carcinoma, Squamous Cell; Chlorpromazine; Cyclophosphamide; Female; Fever; Humans; Liver Neoplasms; Lymphatic Metastasis; Lymphoma, Large B-Cell, Diffuse; Male; Mechlorethamine; Melphalan; Middle Aged; Nasopharyngeal Neoplasms; Nausea; Neoplasm Recurrence, Local; Olivomycins; Thiotepa; Thrombocytopenia; Tonsillar Neoplasms; Vomiting

Topics: Carcinoma; Cecal Neoplasms; Cobalt Isotopes; Female; Fibrosarcoma; Humans; Kidney Neoplasms; Lymphoma, Large B-Cell, Diffuse; Male; Maxillary Neoplasms; Melanoma; Melphalan; Multiple Myeloma; Myxosarcoma; Palliative Care; Radioisotope Teletherapy; Testicular Neoplasms

Topics: Alkylating Agents; Bone Neoplasms; Cyclophosphamide; Dysgerminoma; Lymphatic Metastasis; Lymphoma, Large B-Cell, Diffuse; Male; Mechlorethamine; Melphalan; Neoplasm Metastasis; Testicular Neoplasms

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Stomach Neoplasms

Topics: Adrenal Cortex Hormones; Adult; Blood Transfusion; Female; Humans; Leukemia; Lymphatic Diseases; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Uracil; Vitamins

Topics: Female; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Melphalan; Multiple Myeloma; Neoplasms; Osteosarcoma; Ovarian Neoplasms; Research; Sarcoma; Sarcoma, Ewing; Testicular Neoplasms; Thymoma

Topics: Animals; Carcinoma 256, Walker; DNA; DNA, Neoplasm; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Phosphorus Isotopes; Rats; Research; RNA; RNA, Neoplasm; Sarcoma; Sarcoma, Yoshida; Tissue Culture Techniques

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: Adenine; Bone Marrow Transplantation; Breast Neoplasms; DNA; Female; Folic Acid; Humans; Lung Neoplasms; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Neoplasms; Ovarian Neoplasms; Perfusion; Sarcoma; Thiotepa; Triethylenemelamine

Topics: Geriatrics; Hodgkin Disease; Iatrogenic Disease; Leukopenia; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Multiple Myeloma; Neoplasms; Radiography, Thoracic; Sarcoma; Thrombocytopenia; Toxicology

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: 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: Hodgkin Disease; Humans; Leukemia; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mechlorethamine; Melphalan; Multiple Myeloma; Nitrogen Mustard Compounds; Phenylalanine; Plasma Cells; Sarcoma