melphalan and Bone-Marrow-Diseases

Intensive therapy and autologous marrow or peripheral blood stem cell transplantation is often utilized in Hodgkin's disease patients whose disease has progressed after primary conventional chemotherapy. A number of studies have described long-term disease-free survival in up to 50% of transplanted patients. High-dose chemotherapy conditioning regimens such as "CBV" or "BEAM" have been used more often than regimens containing total body irradiation. Usually unpurged autologous bone marrow has been utilized as the source of hematopoietic stem cell reconstitution, although recently the use of "primed" peripheral blood stem cells has increased markedly. The challenges of transplant-related toxicity and recurrence of disease post-transplant are discussed, as well as possible strategies to reduce these problems. The use of autologous transplantation is discussed in three clinical settings: patients who have failed to enter a complete remission (CR) after primary chemotherapy, those who have relapsed within 12 months of attaining a CR and those who have relapsed after a longer (i.e., > or = 12 months) first CR. When compared with conventional salvage chemotherapy, transplantation appears to produce a higher long-term disease-free survival rate in all of these patient groups. However, assessment of an advantage for autotransplantation, particularly in patients with long first remissions, is difficult without a Phase III trial. On the other hand, recently updated results from our center indicate that 72% of patients relapsing after long initial remissions benefit from autotransplantation at this point in their disease course, and that transplant-related mortality is low in this setting. Other issues addressed include the potential role of autologous transplantation as consolidation therapy in selected high-risk patients in an initial CR, as well as the utility of conventional chemotherapy and involved-field radiotherapy in conjunction with autotransplantation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bone Marrow Transplantation; Carmustine; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Digestive System Diseases; Etoposide; Heart Diseases; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Lung Diseases; Melphalan; Multicenter Studies as Topic; Podophyllotoxin; Recurrence; Remission Induction; Salvage Therapy; Survival Rate; Treatment Outcome; Whole-Body Irradiation

The majority of cytotoxic drugs exert a dose-dependent injury to the hemopoietic bone marrow. In experimental systems, two different types of damage to the hemopoietic stem cell compartments have been demonstrated to occur following cytotoxic drug exposure. First, a reversible reduction of the size of these stem cell compartments; recovery of compartment size results from a transiently increased proliferative activity of those stem cells surviving the cytotoxic drug exposure. Second, irreversibly decreased proliferative potential of pluripotent stem cells has been observed after some cytotoxic agents. Experimental evidence indicates that such permanent stem cell damage may lead to the failure of the hemopoietic bone marrow to produce sufficient numbers of blood cells. There are indications that a similar permanent damage to the hemopoietic system may occur in man following repeated exposure to at least some cytotoxic agents.

Topics: Animals; Antineoplastic Agents; Bone Marrow Diseases; Busulfan; Carmustine; Cell Division; Cell Survival; Cyclophosphamide; Dose-Response Relationship, Drug; Doxorubicin; Hematopoiesis; Hematopoietic Stem Cells; Humans; Melphalan; Semustine; Time Factors

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only definitive treatment for severe bone marrow dysfunction and clonal disorders in patients diagnosed with Shwachman-Diamond syndrome (SDS). In an attempt to minimize regimen-related toxicity (RRT), we have initiated a fludarabine/treosulfan/melphalan-based pilot protocol avoiding the combination of busulfan and cyclophosphamide. Median age at transplantation was 9.6 years (range 1.5-17 years). All three patients received conditioning with fludarabine (30 mg/m2/day x 6), treosulfan (12 g/m2/day x 3) and melphalan (140 mg/m2/day x 1). CAMPATH-1H (0.1 mg/kg x 2) was added in two cases, while rabbit ATG (Genzyme; 3 x 2.5 mg/kg) was given to the cord blood recipient. One patient was transplanted with a non-manipulated marrow graft from an HLA-identical sibling, one with a marrow graft from a 10/10 matched unrelated donor, and one with a 9/10 matched unrelated umbilical cord blood (UCB) unit. Mean cell doses given were 3.6 x 10(8) nucleated cells/kg BW for the bone marrow recipients and 4.2 x 10(7) nucleated cells/kg BW for UCB recipient. Overall, two of three patients are alive and display 100% donor chimerism. Acute graft-versus-host disease grade II was seen in one patient, while no GVHD exceeding grade I occurred in the remaining two.

Topics: Abnormalities, Multiple; Adolescent; Bone Marrow Diseases; Busulfan; Child; Child, Preschool; Cyclophosphamide; Drug Therapy, Combination; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Melphalan; Pilot Projects; Syndrome; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

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

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

This study was designed to estimate the partial and complete response rates (CR and PR) of two novel drug pairs (vincristine and melphalan vs. ifosfamide and etoposide) and to improve overall survival of previously untreated patients with metastatic rhabdomyosarcoma.. One hundred twenty-eight patients were randomly assigned to phase II window therapy consisting of vincristine and melphalan (VM-containing regimen) or ifosfamide and etoposide (IE-containing regimen). Brief window therapy (12 wks) was immediately followed-up by vincristine, dactinomycin, and cyclophosphamide (VAC), chemotherapy, surgery, and irradiation, with continuation of either VM or IE in patients with initial response. Major endpoints were initial CR and PR rates after the phase II window phase of therapy, failure-free survival (FFS), and survival.. Patients who received the VM-containing regimen experienced significantly more anemia, neutropenia, thrombocytopenia, and had more cyclophosphamide dose reductions. The initial PR and CR rates were not significantly different for patients treated with either regimen (VM, 74%; IE, 79%; P = 0.428). However, FFS and overall survival (OS) at 3 years were significantly better with the IE-containing regimen (FFS: 33% vs. 19%; P = 0.043; OS: 55% vs. 27%; P = 0.012).. Although the VM-containing regimen produced a high response rate, inclusion of melphalan appeared to limit the cyclophosphamide dose that could be administered, and ultimately, this regimen was associated with a significantly worse outcome than was the IE-containing regimen. Also, the IE-containing regimen was associated with a gratifyingly high survival rate at 3 years (55%), which is significantly higher than has been observed on any previous Intergroup Rhabdomyosarcoma Study Group regimen for similar patients. We believe that this promising outcome indicates that this drug pair merits further randomized testing in metastatic rhabdomyosarcoma.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bronchiolitis Obliterans; Chemotherapy, Adjuvant; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Dactinomycin; Disease-Free Survival; Etoposide; Female; Follow-Up Studies; Humans; Ifosfamide; Infant; Kidney Diseases; Life Tables; Male; Melphalan; Neoplasm Metastasis; Radiotherapy, Adjuvant; Remission Induction; Rhabdomyosarcoma; Sepsis; Soft Tissue Neoplasms; Survival Analysis; Treatment Outcome; Vincristine

High-dose chemotherapy and autologous bone marrow transplantation (ABMT) has become the standard approach for most patients with relapsed or refractory Hodgkin's disease. Disease status at transplant has been correlated with outcome following ABMT. In light of this, we employ mini-BEAM (BCNU, etoposide, cytarabine and melphalan) salvage therapy in order to achieve a state of minimal residual disease prior to transplantation.. From February 1992 to June 1998 twenty-four patients receiving mini-BEAM therapy for resistance or relapse of their Hodgkin's disease were included. Four patients had obtained no response with initial chemotherapy (refractory), eight had obtained an incomplete response, seven were in first relapse and five in second or subsequent relapse. Fifteen patients received mini-BEAM as first salvage chemotherapy regimen. The remaining nine patients had previously been exposed to a median of one salvage regimen. Patients received a median of three cycles of mini-BEAM.. Sixteen patients achieved complete remission and four partial remission, yielding an overall response rate of 83%. No significant differences in response were observed between patients who received mini-BEAM as initial salvage therapy and those who had received a prior salvage regimen. Eighteen out of the twenty responding patients went on to intensive therapy and peripheral blood stem cell transplantation. With a median follow-up of 52 months, the cumulative probability of 7-year overall survival is 71% for the responders and that of the 6-year disease-free survival is 42%. No treatment-related deaths were observed.. Mini-BEAM is an effective salvage regimen with moderate toxicity that may be useful for cytoreduction prior to stem cell procedures.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Carmustine; Cytarabine; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Male; Melphalan; Middle Aged; Podophyllotoxin; Recurrence; Salvage Therapy; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

The purpose of this study was to develop a high-dose chemotherapy (HDC) and peripheral blood stem cell (PBSC) regimen for treatment of patients with ovarian carcinoma that could be administered in an outpatient setting. Fourteen patients with advanced ovarian (n = 9) or breast (n = 5) carcinoma, who had failed conventional chemotherapy, were entered into a dose-escalation trial to determine the maximum tolerated dose (MTD) of carboplatin that could be administered with fixed doses of melphalan (160 mg/m2) and mitoxantrone (50 mg/m2). Twenty-five additional patients were included in a phase II trial at the MTD. Two of two patients had grade 4 severe regimen-related toxicities (RRT), one fatal, at a dose level of 1600 mg/m2. Two of 29 patients (6.9%) treated at the MTD (carboplatin, 1400 mg/m2) died of RRT. All three patients who died of toxicity had a calculated AUC for carboplatin >30 mg/ml/min. Thirty-one patients with ovarian cancer who had failed chemotherapy were treated, 24 at the MTD. Fourteen of 20 patients (70%) with ovarian carcinoma with evaluable disease achieved a CR and seven (35%) are alive disease-free a median of 20 months (range, 7-26). Five of seven patients with ovarian cancer who had failed chemotherapy but were rendered clinically disease-free following surgery survive without progression a median of 13 months (range, 9-19). Eight of 16 (50%) platinum-resistant and 4/12 (33%) platinum-sensitive patients with ovarian cancer survive disease-free.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Breast Neoplasms; Carboplatin; Carcinoma; Cerebral Hemorrhage; Combined Modality Therapy; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Life Tables; Lung Diseases, Interstitial; Melphalan; Middle Aged; Mitoxantrone; Ovarian Neoplasms; Renal Insufficiency; Salvage Therapy; Treatment Outcome

It was the objective of our study to evaluate the efficacy of a sequential high-dose therapy with peripheral blood progenitor cell (PBPC) support in patients with low-grade non-Hodgkin's lymphoma (NHL). Since July 1991, 48 patients (23 male/25 female) with a median age of 43 years (range 26-55) were included in the study. At the time of entry, 28 patients were in first and seven in second or higher remission. Twelve patients had relapse of disease and one patient had tumor progression. PBPC were collected during granulocyte colony-stimulating factor (G-CSF)-enhanced leukocyte recovery following treatment with high-dose cytarabine and mitoxantrone (HAM). A median of two leukaphereses (range 2-7) resulted in 6.9 x 10(6) CD34+ cells/kg (median, range 2.1 x 10(6)-38.8 x 10(6)). A comparison was made between the harvests obtained from patients in first remission and those from patients in second remission, in relapse or progressive disease. Patients mobilized in first remission tended to have a greater collection efficiency for CD34+ cells comprising a significantly greater proportion of more primitive CD34+/Thy-1+ progenitor cells. Conversely, leukapheresis (LP) products collected during first remission contained a significantly smaller proportion of CD34+/CD45RA+ cells and CD34+/c-kit+ cells, subsets which reflect a more differentiated progenitor cell stage. Following high-dose therapy and PBPC autografting, the median time to reach platelets > or = 20 x 10(9)/l and neutrophils > or = 0.5 x 10(9)/l and 12 and 13 days, respectively. Two patients died of treatment-related toxic organ failure. Thirty-nine patients are alive in remission after a median follow-up time of 15 months (range 1-31), while seven patients relapsed between 5 and 29 months post-transplantation. Except for one patient autografted in first remission, the patients with relapse had a history of previous relapse or progressive disease. Since the probability of disease-free survival appears to be related to the disease status at the time of autografting, PBPC-supported high-dose therapy including total body irradiation should be investigated further for patients with low-grade NHL while they are in first remission.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Bone Marrow Diseases; Carmustine; Cyclophosphamide; Cytarabine; Disease-Free Survival; Etoposide; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Leukapheresis; Life Tables; Lymphoma, Follicular; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Mitoxantrone; Neoplasm Recurrence, Local; Polymerase Chain Reaction; Recombinant Proteins; Remission Induction; Salvage Therapy; Survival Analysis; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

The analysis was undertaken to determine if the time to progression and survival for women with breast cancer treated with high-dose chemotherapy after a conventional-dose induction therapy differs significantly for women younger and older than 40 years of age. All patients treated in phase II or III protocols of high-dose chemotherapy for breast cancer are included in this analysis. Women were treated on one of six protocols: four sequential phase II protocols for metastatic breast cancer involving cyclophosphamide at a dose of 6000 mg/m2, thiotepa at 500 mg/m2, and carboplatin at 800 mg/m2 (CTCb) chemotherapy; one phase II study of CTCb chemotherapy for stage III or inflammatory breast cancer; and a Cancer and Leukemia Group B phase III study of cyclophosphamide, carmustine, and cisplatin for women with more than 10 involved lymph nodes after primary therapy. Eligibility criteria for the patients with metastatic disease included histologically documented breast cancer, at least a partial response to conventional dose therapy, no prior pelvic radiotherapy, cumulative doxorubicin of less than 500 mg/m2, and physiologic age of 18-55 years. Patients with inadequate renal, hepatic, pulmonary, and cardiac function or tumor involvement of marrow or central nervous system were excluded. Of 99 registered patients, three (3%) died of toxicity. There were no toxic deaths in protocols for stage II and III disease, and to date none of these patients have relapsed. Thus, there are no differences by age for these studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bone Marrow Transplantation; Breast Neoplasms; Carboplatin; Carmustine; Cyclophosphamide; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Salvage Therapy; Survival Analysis; Thiotepa; Treatment Outcome

Two consecutive studies were undertaken in patients with advanced adenocarcinoma of the ovary to compare melphalan, adriamycin and 5-fluorouracil (MAF) with cyclophosphamide, adriamycin and 5-fluorouracil (CAF). Twenty-one patients received MAF and 19 received CAF. The objective response rate was 35% for MAF and 62% for CAF patients, and complete remission occurred in 23% of MAF, and in 56% of CAF, patients. These differences were not statistically significant. In both groups, complete remission had a statistically significant and favourable influence on survival. Toxic effects were predominantly haemopoietic and gastrointestinal, MAF having a significantly greater thrombocytopenic potential than CAF, but over-all tolerance was good on both protocols. MAF and CAF are comparable and effective combinations for the treatment of advanced ovarian cancer, but do not demonstrate superiority to single alkylating agent therapy or to other combinations. This emphasizes the continuing need for well designed randomized trials comparing single alkylating agents with combinations of known active agents.

Topics: Antineoplastic Agents; Bone Marrow Diseases; Carcinoma; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leukemia; Melphalan; Ovarian Neoplasms

One hundred and forty-nine patients with early cancer of the ovary who were suitable for postoperative radiotherapy were treated in a random study in which whole abdominal irradiation with additional treatment to the pelvis was compared to chemotherapy with Melphalan. The number of patients without evidence of disease at 2 yr seems to show that the results of treatment are similar. When the Berkson-Gage method of projection is used, however, the survival rate in stage I is apparently improved with irradiation; there is only a minor difference in the results of the two methods in stage II, and survival rates are improved for patients with stage III disease who were treated with chemotherapy. The complications of treatment in this study were quite different. Melphalan was well tolerated, and only one patient had serious bone marrow depression as a result of this treatment. All had prompt recovery of blood counts to normal after completing the prescribed chemotherapy. Seven patients treated by radiotherapy developed a small bowel injury which required surgery. Six of these were treated with irradiation to the pelvis followed by strip irradiation to the entire abdomen. This treatment plan probably gives excessive doses of irradiation to the pelvis and has been discontinued. This type of complication is much less frequent with the other sequence of treatment--strip irradiation to the whole abdomen and subsequent treatment to the pelvis. The cost to the patient of the two treatment programs varied considerably. Patients who received irradiation had the added expense of living in Houston for the duration of treatment. Patients treated with chemotherapy were often seen a 2- or 3-mo intervals and had their chemotherapy supervised by their personal physician.

Topics: Antineoplastic Agents; Bone Marrow Diseases; Female; Humans; Melphalan; Ovarian Neoplasms; Postoperative Care; Radiotherapy

Autologous peripheral stem cell transplantation (APSCT) is increasingly used for various hematologic malignancies and solid tumors. The objective of this study was to analyze the immune reconstitution after APSCT and see if there was any correlation with diagnosis, age, type of high-dose therapy, CD34(+) selection of the autograft and double vs single APSCT.. Lymphocyte subset recovery was studied in 46 consecutive patients with hematologic malignancies and breast cancer, who underwent APSCT. Eleven patients with multiple myeloma received tandem autografts. Thirty-one patients were given total body irradiation (TBI) as part of the high-dose treatment. Eighteen patients received a CD34(+) selected graft. The percentage and absolute numbers of lymphocyte populations, T-cells (CD2(+), CD3(+)), B-cells (CD19(+)), NK cells (CD56(+ )CD3(-) and CD16(+)CD3(-)) and T-cell subpopulations (CD4(+), CD8(+), CD4(+)CD45RA(+), CD4(+ )CD45RO(+), CD4(+)DR(+), CD8(+ )CD45RO(+), CD8(+)DR(+)), were monitored with flow cytometry during the first year after APSCT.. The total B-cell (CD19(+)) and T-cell (CD3(+)) counts were reconstituted to normal levels 2-4 months after APSCT. All patients had a low CD4/CD8 ratio during the observation period, related to both a low number of CD4(+) cells and elevated numbers of CD8(+) cells. The low number of CD4(+) cells was due to a persistently low level of naive CD4(+)CD45RA(+) cells. A high proportion of the CD8+ cells displayed a phenotype compatible with activated T-cells (CD8(+)DR(+)) up to 10 months after autografting. The number of NK cells (CD56(+)3(-) or CD16(+)3(-)) reached normal values within one month post-transplant. No single variable, such as diagnoses, age, TBI as part of the high-dose treatment, tandem autografting or CD34(+) selection of the graft, influenced the immune or hematopoietic reconstitution and no correlation with documented infectious complications was found.. Despite heterogeneity of diseases, age, initial treatment and high-dose regimens, lymphocyte subset analysis did not reveal any differences in hematopoietic or immune reconstitution. All patients had a low CD4(+)/CD8(+) ratio during at least the first year post-transplant, caused by a persistent increase of CD8(+) lymphocytes and a constant reduction of CD4(+) lymphocytes, making the patients susceptible to infections for a prolonged period of time post-transplant.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Breast Neoplasms; Carmustine; Cell Lineage; Combined Modality Therapy; Cytarabine; Disease Susceptibility; Female; Graft Survival; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Infections; Lymphocyte Count; Lymphocyte Subsets; Lymphopenia; Male; Melphalan; Middle Aged; Podophyllotoxin; Sweden; Transplantation Conditioning; Transplantation, Autologous

We conducted a pilot study in 20 patients with high-risk or recurrent/refractory non-Hodgkin's lymphoma (NHL) using high-dose sequential chemotherapy (HDSC) and autologous hematopoietic cell transplantation (AHCT). After cytoreduction with standard salvage therapy, HDSC/AHCT was administered in 4 phases at 2- to 4-week intervals. Phase 1 consisted of cyclophosphamide 7 g/m2 followed by granulocyte colony-stimulating factor (G-CSF) at 10 microg/kg per day and leukapheresis upon recovery from white blood cell nadir. The hematopoietic cell product was enriched by Percoll gradient separation and purged with a B-cell or T-cell monoclonal antibody panel and complement. Phase 2 consisted of methotrexate 8 g/m2 with leucovorin rescue and vincristine 1.4 mg/m2. Phase 3 was etoposide 2 g/m2 with G-CSF 5 microg/kg per day. In phase 4, the preparative regimen of mitoxantrone 60 mg/m2 and melphalan 180 mg/m2 was administered followed by AHCT. The NHL histologies were diffuse large cell, follicular/diffuse mixed, small noncleaved cell, T-cell-rich B-cell, lymphoblastic, and peripheral T cell. The remission status was first partial remission (PR1; n = 1) or beyond first complete remission (post-CR1; n = 19). Of the 20 patients enrolled, 11 proceeded through all 4 phases. Nine were removed from the study after the first or second phase because of progressive disease (n = 5), poor hematopoietic cell mobilization (n = 1), excessive toxicity (n = 2), and chronic active hepatitis C (n = 1). Treatment-related toxicities in the remaining 11 transplant recipients were cardiomyopathy, hemorrhagic cystitis, persistent cytopenias, acute renal failure, abnormal liver function test results, and infectious complications. There were no treatment-related deaths. Eight of the 11 transplant recipients were alive, 6 without disease, at a median follow-up of 2.7 years. The estimated median 2-year event-free survival was 55%, and overall survival was 70%. We conclude that HDSC/AHCT in refractory/recurrent NHL is associated with considerable acute and chronic toxicities. Given the toxicity profile, efficacy data were not sufficiently promising to warrant further study.

Topics: Acute Kidney Injury; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bone Marrow Purging; Cardiomyopathies; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Cyclophosphamide; Cystitis; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Etoposide; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hemorrhage; Humans; Infections; Leucovorin; Life Tables; Lymphoma, Non-Hodgkin; Male; Melphalan; Methotrexate; Middle Aged; Mitoxantrone; Pilot Projects; Salvage Therapy; Survival Analysis; Survival Rate; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Vincristine

Of 496 consecutive patients with multiple myeloma (MM) enrolled in clinical trials of tandem transplants with peripheral blood stem cells support, 470 (95%) completed the first autotransplant with melphalan 200 mg/m2 (MEL 200) and 363 (73%) completed the second transplant with either MEL 200 (40%), MEL 140 mg/m2 (MEL 140) with total-body irradiation (17%), or a combination of alkylating agents (16%), depending on the response status prior to the second transplant; 31 patients up to age 60 years received an allograft as the second transplant. The median interval from first to second transplant was 5 months. Treatment-related mortality during the first year after transplantation was 7%, and complete remission (CR) was obtained in 36%; the median durations of event-free survival (EFS) and overall survival (OS) after transplant were 26 and 41 months, respectively. Low beta 2-microglobulin ([B2M] < or = 2.5 mg/L) and C-reactive protein ([CRP] < or = 0.4 mg/dL) were the most significant standard parameters associated with both prolonged EFS and OS. Median OS exceeded 5.5 years in the one third of patients with both low B2M and CRP. When cytogenetics were included in the analysis, the presence of 11q abnormalities and/or complete or partial deletion of chromosome 13 ("unfavorable karyotype") became a dominant negative feature for both EFS and OS. In addition to these pretransplant parameters, attainment of CR and application of two transplants within 6 months both significantly extended EFS and OS. The group of patients (7%) with high B2M and CRP with either IgA isotype or unfavorable karyotype had the worst prognosis (EFS, < or = 10 months; median OS, < or = 12 months) and will require novel therapy. We conclude that tandem transplants are feasible in the majority of patients up to age 70 years, effecting CR in one third of all patients. Median OS was greater than 5.5 years, regardless of pretransplant features, if the first transplant was applied within 12 months of initial treatment and the second transplant no more than 6 months later.

Topics: Adult; Antineoplastic Agents, Alkylating; Bone Marrow Diseases; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Life Tables; Melphalan; Middle Aged; Multiple Myeloma; Radiation Injuries; Remission Induction; Retrospective Studies; Survival Analysis; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

Carboplatin and melphalan are two drugs whose toxicity profile makes them suitable for use in high doses followed by stem cell rescue. We report the use of high-dose carboplatin, with the dose based on glomerular filtration rate (GFR), combined with melphalan followed by autologous stem cell rescue in children with advanced stage or chemoresistant solid tumours. Thirty children were treated. After multiagent induction chemotherapy before BMT, 13 were in CR, five in VGPR, 11 in PR and one had progressive disease. They received melphalan, 180 mg/m2 and carboplatin, followed by autologous stem cell rescue. The dose of carboplatin was varied by GFR rather than fixed by surface area. The dose given ranged from 0.7 to 2.6 g/m2. Haematological and gastrointestinal toxicities were severe. Life-threatening or fatal toxicity was attributable to opportunistic infection in two cases and regimen-related in two cases. Of the 30 patients, 15 are alive and 13 disease-free at 4-36 months post-BMT. This simple two-drug combination has been used as consolidation of initial remission for patients with high-risk tumours. The toxicity is severe but tolerable. Use of a carboplatin dose based on GFR should optimise effectiveness in patients with good renal function and avoid excessive toxicity where renal function is impaired.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Carboplatin; Child; Child, Preschool; Disease-Free Survival; Female; Glomerular Filtration Rate; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infections; Kidney Diseases; Male; Melphalan; Neoplasms; Neuroblastoma; Treatment Outcome

We evaluated the efficacy, toxicity and feasibility of two cycles of high-dose chemotherapy (HDC), each supported with mobilized peripheral blood progenitor cells (PBPC). Ninety-six patients with metastatic or high-risk cancers received disease-specific HDC regimens. The first cycle consisted of cyclophosphamide 6000 mg/m2, thiotepa 500 mg/m2 and carboplatin 1200 mg/m2. Alternatively, some patients received etoposide 1800 mg/m2 substituted for thiotepa. A second cycle was planned 6-8 weeks later and consisted of mitoxantrone 60 mg/m2 with either melphalan 140 mg/m2 or thiotepa 600 mg/m2. PBPC were mobilized with either growth factor alone or cyclophosphamide followed by growth factor(s). Thirty-four of 96 enrolled patients (35%) did not receive the second cycle. The reasons were: patient refusal (15); insurance refusal (three); toxicities of cycle 1 (seven); no response to cycle 1 (four); and inadequate mobilization or poor engraftment, (five). Of the 33 patients who entered cycle 2 with measurable disease, 28 demonstrated further response after cycle 2 (including 10 who entered CR). One patient died of toxicity after each cycle. Hematologic recovery was rapid and complete in most patients. Tandem cycles of high-dose chemotherapy supported by PBPC are feasible and safe, although many patients fail to receive the second treatment. Preliminary evaluation shows evidence of further antitumor efficacy following cycle 2.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bone Marrow Transplantation; Carboplatin; Cyclophosphamide; Drug Administration Schedule; Etoposide; Feasibility Studies; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Leukapheresis; Male; Melphalan; Middle Aged; Mitoxantrone; Neoplasms; Patient Acceptance of Health Care; Remission Induction; Salvage Therapy; Thiotepa; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Chemotherapy induces high remission rates in high-grade lymphoma. However relapse remains a major problem. One approach to this is myeloablative chemotherapy with transplantation of autologous bone marrow or peripheral blood progenitor cells (PBPC). Immunological mechanisms have been suggested to play a role in the prevention of relapse after transplantation. We investigated the recovery of cellular immune functions after high-dose chemotherapy and PBPC transplantation in 5 patients with high grade non-Hodgkin's lymphoma. All patients showed rapid reconstitution of natural killer (NK) and inducible lymphokine-activated killer (LAK)-activity 10-14 days after transplantation. Four of 5 patients showed higher levels of LAK-generation in the post-transplant period compared with levels prior to myeloablative treatment. Absolute lymphocyte counts in peripheral blood reached 1.0 x 10(9)/l between days 10 and 13 with a predominance of CD8+ cells and an inversion of the CD4/CD8 ratio. Four of 5 patients had a transient increase in CD56+ and CD16+ cell counts post-transplant. No change in the proportion of CD25+ cells was noted. These results show that PBPC transplantation leads to a rapid recovery of cellular immune functions after myeloablative chemotherapy and provides evidence for an increased presence of LAK precursor cells early in the post-transplant period which can be activated by IL-2 to exert high levels of cytotoxicity.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Marrow Diseases; Busulfan; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Doxorubicin; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Leukapheresis; Lymphocyte Count; Lymphocyte Subsets; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Male; Melphalan; Mesna; Middle Aged; Podophyllotoxin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Time Factors; Treatment Outcome; Vincristine

The value of early myeloablative therapy supported by autologous bone marrow or blood progenitor cells was assessed in 72 patients with multiple myeloma who were treated within 1 year of initial therapy. Forty-five patients were consolidated during remission, and 27 patients were treated for primary refractory disease. Outcomes were compared with those of similar patients who did not receive intensive treatment primarily for socioeconomic reasons. Among patients who had responded previously, myeloablative therapy increased the rate of complete remission from 5% to 45% (P < .01) but did not prolong progression-free intervals or survival times. The same treatment controlled the myeloma in 70% of patients with primary resistant disease and prolonged the median survival from 37 to 83 months (P = .03). Intensive treatment for primary resistant myeloma administered later in the disease course resulted in significantly lower response rates and shorter progression-free intervals. Current myeloablative regimens supported by autologous stem cells appeared useful primarily in patients with primary resistant disease during the first year of therapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Doxorubicin; Drug Resistance; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Life Tables; Melphalan; Middle Aged; Multiple Myeloma; Radiation Injuries; Remission Induction; Retrospective Studies; Salvage Therapy; Survival Analysis; Thiotepa; Treatment Outcome; Vincristine; Whole-Body Irradiation

We initiated in February 1982 a pilot study of high dose melphalan (HDM) and ABMT as consolidation treatment for ovarian carcinoma. Eleven patients entered into this study; 6 patients received HDM and ABMT (group 1), 5 patients received HDM in combination with flash abdominal radiotherapy followed by ABMT (group 2). Two of 6 group 1 patients and 3 of 5 group 2 patients are still alive with NED more than 3 years after ABMT (58+, 72+, 37+, 39+, 43+) and are hopefully cured. Main toxicity was haematological, we have not observed any death related to therapy. HDM and ABMT compared favorably with other consolidation treatments (abdominopelvic radiotherapy or IP chemotherapy) and merits a larger evaluation.

Topics: Abdominal Neoplasms; Adult; Bone Marrow Diseases; Bone Marrow Transplantation; Combined Modality Therapy; Cystadenocarcinoma; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Ovariectomy; Prognosis; Remission Induction; Transplantation, Autologous

A 63-year-old male with refractory anemia with excess of blasts (RAEB) and hypoplastic marrow was treated with K-18 (240 mg/day P.O.). On admission, peripheral blood revealed pancytopenia. Bone marrow specimen revealed severe hypocellularity with 18.9% of the blast cells. Ten months later, the blast cells in the bone marrow decreased to 3.8%, and complete remission (CR) was obtained. CR was eight weeks. Duration of response (CR + PR) continued for about eight months. K-18 is an antitumor agent with minimal side effects, and seems to be effective for RAEB with hypoplastic marrow.

Topics: Anemia, Refractory, with Excess of Blasts; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Humans; Immunoglobulin G; Male; Melphalan; Middle Aged; Remission Induction

Among 62 children over 1 year of age at diagnosis, who were treated for stage IV neuroblastoma, 33 entered complete remission (CR) or good partial remission (GPR) after conventional therapy and received high-dose chemotherapy (HDC) with in vitro purged autologous bone marrow transplantation (ABMT) as consolidation therapy. The HDC was a combination of carmustine (BCNU), teniposide (VM-26), and melphalan. Thirty-three patients received one course of this regimen, and 18 received two courses. At present, 16 of the 33 grafted patients are alive in continuous CR, with a median follow-up of 28 months. Toxicity of this regimen was tolerable, principally marked by bone marrow depression and gastrointestinal (GI) tract complications. Four complication-related deaths were observed. Relapse post-ABMT occurred most often in the bone marrow. Under this treatment, actuarial disease-free survival is improved compared with that observed under conventional therapy.

Topics: Abdominal Neoplasms; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bone Marrow Transplantation; Carmustine; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Etoposide; Gastrointestinal Diseases; Humans; Infant; Infections; Melphalan; Neuroblastoma; Teniposide; Thoracic Neoplasms; Transplantation, Autologous; Vincristine

High-dose chemotherapy with BCNU, melphalan, or both, followed by autologous bone marrow transplantation (ABMT) has been reported to produce response rates in excess of 60% in patients with advanced melanoma. We tested doses of BCNU associated with reversible bone marrow toxicity and acceptable extramedullary toxicity without the use of ABMT in 19 patients with a diagnosis of advanced malignant melanoma. All patients were evaluable for toxicity and 18 were evaluable for response; one patient had a new primary tumor. The patient population had a median age of 44 years (range, 16 to 71) and a median Karnofsky performance status of 80 (range, 50 to 100). Ten were women and nine were men, all had visceral dominant disease, and none had received previous chemotherapy. Our purpose was to test the feasibility of treatment without ABMT, its toxicity and efficacy, and the possibility of administering sequential repeated courses of therapy. Vincristine was added to the regimen to potentially increase efficacy. Treatment consisted of BCNU (750 mg/m2) and vincristine (2 mg days 1 and 8). Six patients who recovered bone marrow function received melphalan (60 mg/m2) and vincristine (2 mg days 1 and 8). Twenty-two percent (95% confidence limits, 3% to 39%) of patients had remissions (all partial) and these were of short duration. Toxicity was substantial with 16% early lethality and 29% incidence of lethal drug-related complications. Two patients (11%) died toxic after a second course of BCNU. Our results suggest that there is no practical role for high-dose BCNU in the treatment of melanoma.

Topics: Adolescent; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bone Marrow Transplantation; Carmustine; Central Nervous System Diseases; Drug Administration Schedule; Female; Humans; Lung Diseases; Male; Melanoma; Melphalan; Middle Aged; Thrombocytopenia; Vincristine

We administered melphalan by the intraperitoneal route to investigate its toxicity and pharmacokinetics. The drug was instilled with 2 litres of fluid and allowed to dwell in the peritoneal cavity for 4 hours. No local toxicity was detected by clinical examination, laboratory tests, or histologic examination. The intraperitoneal route allowed the dose to be increased to approximately three times the maximum dose tolerated intravenously before drug leaking into the systemic circulation produced dose-limiting myelosuppression. The peak peritoneal concentration averaged 93-fold greater than the plasma concentration, and total drug exposure for the peritoneal cavity averaged 63-fold greater than that for plasma. Tumor regressions were observed in patients with ovarian carcinoma and gastrointestinal adenocarcinomas. This study shows that from the pharmacologic point of view, if any portion of the tumor can be reached by intraperitoneal instillation, then there is a very strong rationale for the administration of melphalan by the intraperitoneal route, rather than the oral or intravenous route, for the treatment of tumors confined to the peritoneal cavity.

Topics: Adult; Aged; Ascites; Ascitic Fluid; Bone Marrow Diseases; Colonic Neoplasms; Female; Humans; Infusions, Parenteral; Kinetics; Laparotomy; Male; Melphalan; Middle Aged; Models, Biological; Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Peritoneal Cavity; Stomach Neoplasms

The case histories of 4 patients who developed bone marrow damage after therapy with melphalan are described. In 3 patients bone marrow damage manifested initially as a sideroblastic anaemia which was later followed by acute myeloid leukaemia. The last patient developed a dyserythropoietic anaemia with leucopenia, but thus far there has been no further progression. None of the 4 patients had any haematological abnormality prior to the melphalan therapy. Two were suffering from carcinoma of the breast and 2 had ovarian neoplasms. The fact that melphalan was given as adjuvant therapy in all 4 patients prior to the development of the haematological abnormalities supports the concept that it was of aetiological importance. These findings are in line with a number of reports in the literature in which acute leukaemia has developed in subjects treated for malignant tumours (especially multiple myeloma and ovarian cancer) with melphalan.

Topics: Acute Disease; Aged; Antineoplastic Agents; Bone Marrow Diseases; Female; Humans; Leukemia; Leukemia, Myeloid; Melphalan; Middle Aged

Topics: Antineoplastic Agents; Benzene; Bone Marrow Diseases; Chloramphenicol; Cyclophosphamide; Dose-Response Relationship, Radiation; Humans; Immunosuppressive Agents; Leukemia; Leukemia, Monocytic, Acute; Leukemia, Myeloid; Leukemia, Radiation-Induced; Melphalan; Multiple Myeloma; Phenylbutazone; Phenytoin; Polycythemia Vera

Topics: Autopsy; Bone Marrow Diseases; Female; Humans; Leukemia, Myeloid; Melphalan; Middle Aged; Radiography

Topics: Amputation, Surgical; Bone Marrow Diseases; Chemotherapy, Cancer, Regional Perfusion; Extracorporeal Circulation; Extremities; Fascia; Female; Hepatitis B; Humans; Lymph Node Excision; Lymphatic Metastasis; Male; Melanoma; Melphalan; Methods; Necrosis; Neoplasm Recurrence, Local; Neuritis; Prognosis; Thrombophlebitis

Topics: Adolescent; Adult; Alopecia; Bone Marrow Diseases; Bone Neoplasms; Cyclophosphamide; Female; Humans; Male; Melphalan; Sarcoma, Ewing; Vomiting