melphalan and Thrombocytopenia

CAMT is a bone marrow failure syndrome that usually presents with isolated thrombocytopenia soon after birth. HSCT is curative, and MAC is associated with increased transplant-related morbidity and mortality, especially in the unrelated setting. We used a RIC regimen with alemtuzumab, fludarabine, and melphalan in a seven-month-old patient with CAMT who underwent a MUD HSCT. The transplant was well tolerated with few complications. Neutrophil and platelet engraftment occurred on day +12 and +29, respectively, and she had 100% donor chimerisms on days +19.

Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Blood Platelets; Congenital Bone Marrow Failure Syndromes; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Infant; Melphalan; Methylprednisolone; Mucositis; Neutrophils; Thrombocytopenia; Transplantation Conditioning; Vidarabine

The M-2 protocol (vincristine, cyclophosphamide, BCNU, melphalan, and prednisone) was administered monthly to 63 evaluable patients with advanced chronic lymphocytic leukemia. Complete remission (absence of all clinical and bone marrow evidence of leukemia) and partial response (greater than 50% decrease in organ enlargement and reduction of WBC count to below 15,000 x 10(6)/liter) were achieved in 17% and 44%, respectively, for a total response rate of 61%. The median survivals from therapy of patients achieving a CR, RR, or no response were 73+, 40, and 14 mo respectively. The median survival time from onset of treatment for stages II, III, and IV disease were 47, 20 and 19 mo, respectively, which was not statistically different from historical controls. However, when untreated patients are compared to this latter group, a significant survival advantage from diagnosis was found (p = 0.01), stressing the importance of prior therapy as the only unfavorable prognostic factor. Although complete remissions in CLL, as reflected in apparently normal bone marrow B-lymphocyte markers, can be induced wih acceptable morbidity, the majority of patients relapse after cessation of therapy. An alternative approach to the M-2 protocol will be needed to eradicate the disease.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Drug Therapy, Combination; Female; Femur Head Necrosis; Humans; Hypercalcemia; Leukemia, Lymphoid; Male; Melphalan; Neoplasms, Multiple Primary; Paresthesia; Prednisone; Prognosis; Thrombocytopenia; Vincristine

Genetically derived hematologic cytopenias are a rare heterogeneous group of disorders. Allogeneic hematopoietic cell transplantation (HCT) is curative but offset by organ toxicities from the preparative regimen, graft rejection, graft-versus-host disease (GVHD), or mortality. Because of these possibilities, consideration of HCT can be delayed, especially in the unrelated donor setting. We report a prospective multicenter trial of reduced-intensity conditioning (RIC) with alemtuzumab, fludarabine, and melphalan and HCT in 11 children with marrow failure of genetic origin (excluding Fanconi anemia) using the best available donor source (82% from unrelated donors). The median age at transplantation was 23 months (range, 2 months to 14 years). The median times to neutrophil (>500 × 10(6)/L) and platelet (>50 × 10(9)/L) engraftment were 13 (range, 12 to 24) and 30 (range, 7 to 55) days, respectively. The day +100 probability of grade II to IV acute GVHD and the 1-year probability of limited and extensive GVHD were 9% and 27%, respectively. The probability of 5-year overall and event-free survival was 82%; 9 patients were alive with normal blood counts at last follow-up and all were successfully off systemic immunosuppression. In patients with genetically derived severe hematologic cytopenias, allogeneic HCT with this RIC regimen was successful in achieving a cure. This experience supports consideration of HCT early in such patients even in the absence of suitable related donors.

Topics: Acute Disease; Adolescent; Alemtuzumab; Antibodies, Monoclonal, Humanized; Child; Child, Preschool; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Male; Melphalan; Myeloablative Agonists; Neutropenia; Prospective Studies; Risk; Siblings; Survival Analysis; Thrombocytopenia; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Unrelated Donors; Vidarabine

Bortezomib-melphalan-prednisone (VMP) has improved overall survival in multiple myeloma. This randomized trial compared VMP plus thalidomide (VMPT) induction followed by bortezomib-thalidomide maintenance (VMPT-VT) with VMP in patients with newly diagnosed multiple myeloma.. We randomly assigned 511 patients who were not eligible for transplantation to receive VMPT-VT (nine 5-week cycles of VMPT followed by 2 years of VT maintenance) or VMP (nine 5-week cycles without maintenance).. In the initial analysis with a median follow-up of 23 months, VMPT-VT improved complete response rate from 24% to 38% and 3-year progression-free-survival (PFS) from 41% to 56% compared with VMP. In this analysis, median follow-up was 54 months. The median PFS was significantly longer with VMPT-VT (35.3 months) than with VMP (24.8 months; hazard ratio [HR], 0.58; P < .001). The time to next therapy was 46.6 months in the VMPT-VT group and 27.8 months in the VMP group (HR, 0.52; P < .001). The 5-year overall survival (OS) was greater with VMPT-VT (61%) than with VMP (51%; HR, 0.70; P = .01). Survival from relapse was identical in both groups (HR, 0.92; P = .63). In the VMPT-VT group, the most frequent grade 3 to 4 adverse events included neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%). All of these, except for thrombocytopenia, were significantly more frequent in the VMPT-VT patients.. Bortezomib and thalidomide significantly improved OS in multiple myeloma patients not eligible for transplantation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Disease-Free Survival; Female; Follow-Up Studies; Humans; Induction Chemotherapy; Kaplan-Meier Estimate; Maintenance Chemotherapy; Male; Melphalan; Middle Aged; Multiple Myeloma; Neutropenia; Peripheral Nervous System Diseases; Prednisone; Pyrazines; Thalidomide; Thrombocytopenia; Treatment Outcome

Relapsed multiple myeloma has no standard treatment, and the role of autologous stem-cell transplantation (ASCT) has not been fully defined. We aimed to compare high-dose melphalan plus salvage ASCT with cyclophosphamide in patients with relapsed multiple myeloma who had previously undergone ASCT.. This multicentre, randomised, open-label, phase 3 study recruited patients aged at least 18 years with multiple myeloma who needed treatment for first progressive or relapsed disease at least 18 months after a previous ASCT from 51 centres across the UK. Before randomisation, eligible patients received bortezomib, doxorubicin, and dexamethasone (PAD) induction therapy and then underwent peripheral blood stem-cell mobilisation and harvesting if applicable. Eligible patients (with adequate stem-cell harvest) were randomly assigned (1:1), using an automated telephone randomisation line, to either high-dose melphalan 200 mg/m(2) plus salvage ASCT or oral cyclophosphamide (400mg/m(2) per week for 12 weeks). Randomisation was stratified by length of first remission or plateau and response to PAD re-induction therapy. The primary endpoint was time to disease progression, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747877, and EudraCT, number 2006-005890-24.. Between April 16, 2008, and Nov 19, 2012, 297 patients were registered, of whom 293 received PAD re-induction therapy. Between Aug 26, 2008, and Nov 16, 2012, 174 patients with sufficient PBSCs were randomised to salvage ASCT (n=89) or cyclophosphamide (n=85). After a median follow-up of 31 months (IQR 19-42), median time to progression was significantly longer in the salvage ASCT than in the cyclophosphamide group (19 months [95% CI 16-25] vs 11 months [9-12]; hazard ratio 0·36 [95% CI 0·25-0·53]; p<0·0001). Frequently reported (in >10% of patients) grade 3-4 adverse events with PAD induction, salvage ASCT, and cyclophosphamide were: neutropenia (125 [43%] of 293 patients after PAD, and 63 [76%] of 83 patients in the salvage ASCT group vs 11 [13%] of 84 patients in the cyclophosphamide group), thrombocytopenia (150 [51%] after PAD, and 60 [72%] vs four [5%], respectively), and peripheral neuropathy (35 [12%] after PAD, and none vs none, respectively).. This study provides evidence for the improved efficacy of high-dose melphalan plus salvage ASCT when compared with cyclophosphamide in patients with relapsed multiple myeloma eligible for intensive therapy, which might help to guide clinical decisions regarding the management of such patients.. Cancer Research UK.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Consolidation Chemotherapy; Cyclophosphamide; Dexamethasone; Disease Progression; Doxorubicin; Female; Humans; Induction Chemotherapy; Intention to Treat Analysis; Male; Melphalan; Middle Aged; Multiple Myeloma; Neutropenia; Peripheral Nervous System Diseases; Proportional Hazards Models; Pyrazines; Recurrence; Retreatment; Salvage Therapy; Stem Cell Transplantation; Thrombocytopenia; Time Factors; Transplantation, Autologous

The combination of melphalan, prednisone and thalidomide (MPT) has demonstrated efficacy and acceptable toxicity in newly diagnosed and relapsed/refractory patients with multiple myeloma (MM). Panobinostat is a potent oral pan-deacetylase inhibitor (pan-DACi). In preclinical and clinical studies, panobinostat showed good anti-myeloma activity in combination with several agents. This phase II study evaluated the combination of a fixed dose of MPT with escalating doses of panobinostat (three times weekly for 3 weeks, followed by a 9-day rest period) in relapsed/refractory MM. We used a two-stage design to determine whether the combination was safe and effective. At least a partial response was observed in 38.5% of patients. The maximum tolerated dose of panobinostat in combination with MPT could not be determined due to the high rate of dose-limiting toxicities experienced with panobinostat at doses of 10 and 15 mg. The most common grade 3/4 adverse events were neutropenia (71%) and thrombocytopenia (35.5%). In conclusion, MPT in combination with panobinostat three times weekly for 3 weeks followed by a 9-day rest period is not well tolerated in patients with relapsed/refractory MM. Future studies should evaluate alternative dose schedules of panobinostat.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Hydroxamic Acids; Indoles; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Neutropenia; Panobinostat; Prednisone; Recurrence; Thalidomide; Thrombocytopenia; Time Factors; Treatment Outcome

This multicenter phase I/II study investigated the maximum tolerated dose (MTD), safety, and efficacy of low dose intravenous (IV) melphalan in combination with bortezomib for patients with relapsed multiple myeloma (MM). Patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 and escalating doses of IV melphalan (2.5-10.0 mg/m(2)) on day 2 of a 28-day cycle for a maximum of eight cycles. Dexamethasone 20 mg was added for progressive or stable disease. Fifty-three patients were enrolled. The MTD was defined at melphalan 7.5 mg/m(2) and bortezomib 1.3 mg/m(2). The overall response rate (ORR) was 68% (23% complete or near-complete responses [CR/nCR]) whilst at the MTD (n = 33) the ORR was 76% (34% CR/nCR). After median follow-up of 17 months, the median progression free survival was 10 months, rising to 12 months at the MTD (P < 0.05 vs. non-MTD regimens). The median overall survival was 28 months, but was not yet reached at the MTD. Grade 3/4 adverse events included thrombocytopenia (62%), neutropenia (57%), infection (21%), and neuropathy (15%). Bortezomib and low-dose IV melphalan combination therapy is a safe and highly effective regimen for patients with relapsed MM. These data suggest further investigation of this combination is warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Disease-Free Survival; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Multiple Myeloma; Pyrazines; Recurrence; Statistics, Nonparametric; Thrombocytopenia

Initial analysis of the combination melphalan, prednisone, plus lenalidomide (MPR) showed significant antimyeloma activity in patients with untreated multiple myeloma, with neutropenia and thrombocytopenia as the most frequent side effects. This updated analysis reassessed the kinetics of neutropenia and thrombocytopenia as well as the safety and efficacy of MPR.. A total of 21 patients with newly diagnosed myeloma received melphalan 0.18 mg/kg on days 1-4, prednisone 2 mg/kg on days 1-4, and lenalidomide 10 mg daily on days 1-21 for nine 28-day cycles, followed by maintenance therapy with lenalidomide 10 mg daily on days 1-21.. Grade 3/4 neutropenia occurred in 52% of the patients, and granulocyte colonystimulating factor was administered in 43%. The mean neutrophil counts at the start of each MPR cycle, during nadir, and after 6 months of maintenance were 2.69 x 109/L, 1.43 x 109/L, and 2.11 x 109/L, respectively. Grade 3/4 thrombocytopenia occurred in 24% of the patients. Platelet transfusions were required by 1 patient (5%) with a platelet count of 16 x 109/L; however, no thrombocytopenia-associated bleeding was reported. The mean platelet counts at the start of each cycle, during nadir, and after 6 months of maintenance were 174 x 109/L, 121 x 109/L, and 158 x 109/L, respectively. Median follow-up was 29.6 months, median progression-free survival was 28.5 months, and 2-year overall survival was 91%.. MPR is a promising regimen with manageable hematologic toxicity.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Dose-Response Relationship, Drug; Granulocyte Colony-Stimulating Factor; Humans; Lenalidomide; Melphalan; Middle Aged; Multiple Myeloma; Neutropenia; Prednisone; Thalidomide; Thrombocytopenia

Bortezomib synergizes with melphalan in preclinical and early clinical studies. Updated data from our phase 1/2 study assessing the safety and efficacy of bortezomib plus melphalan in relapsed/refractory multiple myeloma (MM) are presented. Bortezomib (0.7, 1.0, or 1.3 mg/m(2)) on days 1, 4, 8, and 11 and oral melphalan (0.025-0.25 mg/kg) on days 1-4 of a 28-day cycle were administered. Hematologic toxicities defined the maximum tolerated dose as bortezomib 1.0 mg/m(2) and melphalan 0.10 mg/kg. Because dose-limiting toxicities were attributed to the more myelosuppressive melphalan, cohorts 9 and 10 with higher bortezomib (1.3 mg/m(2)) and lower melphalan (0.025 and 0.10 mg/kg) doses were added. Responses occurred in 32/46 (70%) evaluable patients: two complete (4%), five near-complete (11%), 16 partial (35%), and nine minimal (20%). Complete and near-complete responses were observed only with higher bortezomib doses. Response rates were similar in patients with prior melphalan or bortezomib. Median progression-free survival was 9 months (range, 1-24), and overall survival was 32 months (range, 1-54). The most common grade 3/4 hematologic adverse events (AEs) were neutropenia (31%/0%), thrombocytopenia (25%/2%), and anemia (13%/0%). Grade 4 tumor lysis syndrome was reported in one patient. Fewer grade 3/4 hematologic AEs were reported in cohorts 9 and 10 than in cohorts receiving lower bortezomib and higher melphalan doses. In conclusion, bortezomib plus melphalan is a steroid- and immunomodulatory drug-free regimen that may provide a treatment alternative for elderly patients and patients with significant comorbidity.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Neutropenia; Pyrazines; Thrombocytopenia

Standard treatment for patients with multiple myeloma is debulking chemotherapy with non-alkylating agents followed by a regimen to mobilize peripheral blood stem cells (PBSC) and the transplantation of the mobilized, autologous PBSC. The aim of this study was to evaluate the efficacy of a new regimen and compare it with that of a previous regimen.. In a large cohort of 106 patients (group I) we administered a new pre-transplant program which includes 2 courses of pulsed-VAD (vincristine, adriamycin, dexamethasone) followed by 2 courses of DCEP (dexamethasone, cyclophosphamide, etoposide and cis-platinum). We compared the efficacy of this new VAD-DCEP sequence, in terms of mobilizing capacity, toxicity and anti-myeloma activity in comparison with that of the previous VAD-high-dose cyclophosphamide program (group II, 40 patients).. In group I 81/106 (76.4%) patients yielded >or= 4x10(6)/kg CD34+ cells, as did 30/40 (75%) in group II but with a significantly higher toxicity in this latter group. In detail, 9 patients in group I (8.5%) had WHO grade III neutropenia versus 35 in group II (87.5%), 5 patients of group I (4.7%) had grade III thrombocytopenia versus 12 patients in group II (30%), and 8 patients in group I (7.5%) experienced an infections fever versus 9 patients in group II (22.5%). Therefore, nearly all patients in group II had to be admitted to hospital (39/40, 97.5%). There was a higher percentage of responses (CR+VGPR+PR) in group I than in group II: 73% versus 50% (p=0.02).. the VAD-DCEP sequence has an adequate mobilizing capacity, without significant toxicity, and a good anti-myeloma activity, and therefore represents a safe and effective therapeutic approach for multiple myeloma patients at the onset of their disease.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cohort Studies; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Hematopoietic Stem Cell Mobilization; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoadjuvant Therapy; Neutropenia; Thrombocytopenia; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Vincristine

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

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

The objectives of the present study were to determine the following: (a) the maximum tolerated dose (MTD) of melphalan using a 24-h continuous infusion; (b) the clinical toxicity; and (c) the pharmacokinetic characteristics of melphalan at each dose level. Twenty-one patients with refractory solid tumors were enrolled in the study. Melphalan, packaged in 3% sodium chloride, was administered i.v. over a 24-h period. Patients were assigned to one of three escalating dose levels of melphalan: (a) 20 mg/m2 (n = 5); (b) 30 mg/m2 (n = 7); and (c) 40 mg/m2 (n = 6). Each patient underwent pharmacokinetic evaluation during the first cycle of treatment. Melphalan concentrations in plasma were determined by high-performance liquid chromatography. Toxicity was evaluated after each course of chemotherapy. All of the patients were assessable for toxicity and pharmacokinetics, and 20 patients were assessable for response analysis. A total of 50 courses of melphalan was studied. The MTD was 30 mg/m2. The dose-limiting toxicity was neutropenia and thrombocytopenia. Hematotoxicity was reversible (nadir, 14-15 days; recovery, 3.5 and 12.5 days for 30 and 40 mg/m2, respectively), cumulative, and related to the administered dose and to the history of previous therapy. There were six episodes of neutropenic sepsis. Individual pharmacokinetic parameters were estimated using a Bayesian approach and linear elimination kinetics. Data were compatible with a one-compartment model. Relationships have been found between the area under the plasma concentration-time curve and doses and between Css and doses. Moreover, clearance, t1/2 elimination, and volume of distribution did not change statistically with dose, which suggests linear kinetics. Two partial responses were observed in patients with ovarian carcinoma or adenocarcinoma of unknown primary origin, and another patient had stabilization disease. In conclusion, melphalan MTD was determined to be 30 mg/m2 when administered as a 24-h infusion. Hematological toxicity was the dose-limiting toxicity. The most important nonhematological toxicity encountered was nausea and vomiting. The recommended dose for Phase II studies was 30 mg/m2.

Topics: Adolescent; Adult; Aged; Anemia; Antineoplastic Agents, Alkylating; Area Under Curve; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Melphalan; Middle Aged; Neoplasms; Neutropenia; Regression Analysis; Thrombocytopenia

Autologous stem cell transplantation after high-dose melphalan for the treatment with multiple myeloma has resulted in prolonged progression-free survival and overall survival in patients under 65 years. We have examined the role of autologous transplantation in 17 patients with multiple myeloma over 65 years at our centre using a matched pair analysis with younger patients. The median age of this cohort of patients over 65 years was 67 years (65-74) and their outcome and transplant-related morbidity was compared with 17 younger pair mates with a median age of 55 years (31-64). Sixteen patients received high-dose melphalan, and one received busulphan with autologous stem cell rescue. The high-dose therapy was well tolerated in both elderly patients and the matched pairs, with comparable time to recover neutrophils and platelets. Treatment-related mortality also did not differ significantly in both the groups. Median overall survival of the elderly patients was 3.59 years similar to 3.01 years of the pair mates (P = 0.92). Autologous stem cell transplantation after high-dose melphalan conditioning was equally well tolerated in groups of patients above and below 65 years. There was no difference in relapse rate, OS and myelotoxicity in both the groups. These findings suggest that advanced age should not be an exclusion criterion from autologous transplant programmes. Bone Marrow Transplantation (2000) 25, 533-539.

Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Carmustine; Chemical and Drug Induced Liver Injury; Cohort Studies; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Female; Graft Survival; Heart Diseases; Hematopoietic Stem Cell Mobilization; Hospitalization; Humans; Interferons; Kidney Diseases; Male; Matched-Pair Analysis; Melphalan; Methylprednisolone; Middle Aged; Multiple Myeloma; Neutropenia; Neutrophils; Platelet Count; Recurrence; Sepsis; Survival Rate; Thrombocytopenia; Transplantation, Autologous; Vincristine

With the aim of developing an effective therapy for heavily pretreated refractory MM outpatients, we evaluated the OPPEBVCAD regimen, a Hodgkin's disease-derived protocol that includes many drugs effective in MM administered in a sequential schedule. Twenty-two pts aged 42-72 years, with symptomatic highly-pretreated refractory (18 cases), or primary resistant MM (four cases. including two pts with plasma cell leukemia-PCL) received this therapy every 28 days (2-4 cycles, followed by a maintenance program). Therapeutic response (Chronic Leukemia-Myeloma Task Force criteria) and performance status (PS) and pain (W.H.O.) were evaluated. All of the pts were evaluable for response. There were 9 (40%) objective responses (OR: stabilization of blood counts and bone lesions, serum calcium normalization, 50% or more reduction in the concentration of serum monoclonal component (MC), 90% reduction in Bence-Jones proteinuria), 8 (36%) partial responses (PR: 25-50% reduction in serum MC), 1 no response or stable disease (NR), and 4 (18%) cases of progressive disease (PD). OR plus PR were 77%. Of the 4 primary resistant tumors (2 PCL and 2 MM), 2 achieved PR, 1 OR (a PCL case) and 1 progressed. Median survival was 15 months for responding pts (OR plus PR) and 4.5 months for non-responders (NR plus PD). PS and pain improved in 15 pts and did not change in 9. The most frequent side effects were cytopenias, with one drug related infective death. The OPPEBVCAD regimen proved to be an effective therapy for refractory relapsing or primary resistant MM: in responders (two-thirds of the pts), survival was prolonged by about 10 months. Its efficacy in anthracycline-treated pts, as well as the feasibility of using it on an outpatient basis without any continuous drug infusions, make this regimen a promising third line salvage therapy.

Topics: Adult; Aged; Agranulocytosis; Anemia; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cause of Death; Drug Administration Schedule; Drug Resistance, Neoplasm; Epirubicin; Humans; Lomustine; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Procarbazine; Salvage Therapy; Survival Rate; Thrombocytopenia; Treatment Outcome; Vinblastine; Vincristine; Vindesine

Severe systemic toxicity and hemodynamic changes after isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF-alpha) and melphalan, with or without interferon-gamma, have been reported in several series. We studied whether these side effects could be precluded by preventing leakage from the isolated circuit into the systemic circulation.. Clinical and pharmacokinetic data for 20 consecutive patients with recurrent melanoma of the limbs who were treated by ILP with TNF-alpha (3-4 mg) and melphalan, with or without interferon-gamma, were studied. Leakage rates and TNF-alpha levels were determined during and after ILP and were correlated with systemic toxicity and hemodynamic changes.. Only two patients experienced leaks (2% and 13%) during ILP. For 18 patients without leakage, the mean peak systemic TNF-alpha level was 2.8 ng/ml at 10 minutes after ILP. After leakage, the peak systemic TNF-alpha levels were 31.9 and 88.3 ng/ml at 5 minutes. Toxicity was mild and consisted mainly of fever (n = 17) and nausea/vomiting (n = 19) during the first day after ILP. Some patients developed tachycardia (n = 6), hypotension (n = 3; responding immediately to fluid challenge), a decrease in the WBC count (n = 3; grade I) or thrombocyte count (n = 11; grade I/II, no hemorrhage or therapeutic intervention), or hepatotoxicity [cytolysis (n = 15; 14 grade I/II and 1 grade IV) or hyperbilirubinemia (n = 7; grade I/II, all resolving spontaneously)]. Patients with tachycardia or hepatotoxicity exhibited significantly higher TNF-alpha levels after ILP, compared with other patients.. Systemic toxicity after ILP with TNF-alpha is minimal and does not differ from that after ILP with melphalan alone when leakage is adequately controlled.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Hypotension; Interferon-gamma; Leukopenia; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Tachycardia; Thrombocytopenia; Tumor Necrosis Factor-alpha

We analyzed the relationship between the reinfusion of large or very large amounts of peripheral blood progenitor cells (PBPC) and hematologic toxicity in twenty-one advanced breast cancer patients subjected to a myeloablative dose of melphalan at the end of a high-dose sequential chemotherapy (HDSC) program. We also evaluated the influence of the white blood cell (WBC) count to predict an optimal PBPC harvest after high-dose chemotherapy and growth factor priming. Twenty-one patients with high-risk or metastatic breast cancer sequentially received: high-dose cyclophosphamide (HD-Cy) and G-CSF followed by PBPC harvest, HD-methotrexate plus vincristine, HD-doxorubicin, cisplatin and finally HD-melphalan 200 mg/m2 (HD-L-PAM) followed by PBPC reinfusion. No growth factor was administered after HD-L-PAM. CD34+ cytofluorimetric analysis, WBC count and clonogenic assays were employed to monitor circulating cells and to analyze the PBPC harvest. Correlation between different PBPC doses and hematologic toxicity as well as leukocyte and platelet recovery time was attempted. Patients received a median number of 16 (4-25.1) x 10(6)/kg CD34+ cells, 81.3 (30.8-228) x 10(4)/kg CFU-GM and 4.2 (1.3-7.3) x 10(8)/kg nucleated cells (NC) after HD-L-PAM. The number of days with fewer than 1 x 10(9)/l leukocytes and 20 x 10(9)/l platelets were 6 (range 4-9) and 0 (range 0-3), respectively. The CD34+ cell dose significantly correlated with both platelet count nadir (r = 0.73) and time to 50 x 10(9)/l platelets (r = 0.7), but did not correlate with time to reach more than 1 x 10(9)/l WBC count (r = 0.2). In particular, we found that in 12 patients given very large amounts of CD34+ cells, ranging between 15.8 and 25. 1 x 10(6)/kg (V-LA-CD34+), the platelet nadir count never fell below 20 x 10(9)/l and platelet transfusions were not required. Conversely, nine patients who received only large amounts of CD34+ cells, ranging between 4 and 12 x 10(6)/kg (LA-CD34+), experienced a platelet nadir lower than 20 x 10(9)/l and required 2 days (range 1-4) to achieve independence from platelet transfusions (P = 0.001 and P = 0. 0005). The requirement for packed red blood cells (RBC) was 1.5 vs 3 units in the V-LA-CD34+ and LA-CD34+ groups respectively (P = 0.063). The analysis of 44 PBPC collections demonstrated that 29 aphereses performed with a WBC count <20 x 10(9)/l yielded a mean of 312 +/- 43 x 10(6) CD34+ cells and 1831 +/- 201 x 10(4) CFU-GM, whereas 15 collections performed with WB

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Leukocyte Count; Melphalan; Middle Aged; Platelet Count; Thrombocytopenia; Transplantation, Autologous

Thrombocytopoiesis of 21 multiple myeloma patients undergoing single or double transplant regimen was characterized by measuring the level of reticulated platelets and plasma glycocalicin. Since reticulated platelets are an index of thrombopoietic activity and glycocalicin plasma values are related to platelet damage and turnover, it may be possible to perform a novel type of analysis of the thrombopoietic compartment during the mobilizing regimen and during transplant-related chemotherapy. Patients underwent mobilizing therapy and first transplant. Some randomized patients also underwent a second transplant with mobilized peripheral blood stem cells. The results show that the percentage of reticulated platelets decreased after therapy and then gradually increased in the recovery phase either during first or second transplant. By contrast, the percentage of reticulated platelets increased until day +8 and then gradually decreased during the mobilizing regimen. The glycocalicin index (glycocalicin plasma value normalized for the individual platelet count) increased significantly both during the course of mobilization and after transplant-related chemotherapy when the platelet number was at its nadir. However, the glycocalicin index was more elevated after transplant-related chemotherapy than after the mobilizing regimen. Our findings suggest that chemotherapy-related thrombocytopenia may be due to a dual mechanism: thrombocytopenia results from decreased platelet production in addition to increased platelet damage and possible destruction.

Topics: Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Behavior Therapy; Biomarkers; Blood Platelets; Busulfan; Cyclophosphamide; Dexamethasone; Doxorubicin; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Melphalan; Multiple Myeloma; Platelet Aggregation Inhibitors; Platelet Count; Platelet Glycoprotein GPIb-IX Complex; Reticulocytes; RNA; Thrombocytopenia; Transplantation, Autologous; Vincristine

Cytopenia after high-dose chemotherapy and autologous stem cell reinfusion is a major cause of morbidity. Ex vivo cultured expansion and differentiation of CD34+ peripheral blood progenitor cells (PBPC) to neutrophil precursors may shorten the neutropenic period further. We explored the use of these ex vivo cultured PBPCs in nine patients with metastatic breast cancer. All underwent PBPC mobilization with cyclophosphamide, VP-16, and G-CSF. Subsequently, they underwent four to five apheresis procedures. One apheresis product from each patient was prepared using the Isolex 300 Magnetic Cell Separation System (Baxter Immunotherapy, Irvine, CA) to obtain CD34+ cells. These cells were then cultured in gas permeable bags containing serum-free X-VIVO 10 (BioWhittaker, Walkersville, MD) medium supplemented with 1% human serum albumin and 100 ng/mL PIXY321. At day 12 of culture the mean fold expansion was 26x with a range of 6 to 64x. One patient's cells did not expand because of a technical difficulty. The final cell product contained an average of 29.3% CD15+ neutrophil precursors with a range of 18.5% to 48.1%. The patients underwent high-dose chemotherapy with cyclophosphamide, carboplatin, and thiotepa. On day 0, the cryopreserved PBPCs were reinfused and on day +1 the 12-day cultured cells were washed, resuspended, and reinfused into eight of nine patients. One patient was not infused with cultured cells. The mean number of cultured cells reinfused was 44.6 x 10(6) cells/kg with a range of 0.8 to 156.6 x 10(6) cells/kg. No toxicity was observed after reinfusion. The eight patients have recovered absolute neutrophil counts > 500/microL on a median of 8 days (range 8 to 10 days); the median platelet transfusion independence occurred on day 10 (range 8 to 12 days) and platelet counts > 50,000/microL were achieved by day 12 (range 9 to 14) for the seven patients whose platelet counts could be determined. Expanded CD34+ selected PBPC can be obtained and safely reinfused into patients.

Topics: Adult; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Cell Culture Techniques; Cells, Cultured; Combined Modality Therapy; Culture Media; Cyclophosphamide; Doxorubicin; Etoposide; Feasibility Studies; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Immunomagnetic Separation; Leukapheresis; Lewis X Antigen; Melphalan; Middle Aged; Neutropenia; Tamoxifen; Thiotepa; Thrombocytopenia

The purpose of this study was to evaluate a new regimen for the treatment of multiple myeloma based on alternating 3-week cycles of chemotherapy and interferon (rIFN alpha 2). In this prospective phase II clinical trial the Eastern Cooperative Oncology Group evaluated a regimen consisting of 2 cycles of VBMCP (Vincristine 1.2 mg/M(2) IV d1, BCNU 20 mg/M(2) IV d1, Melphalan 8 mg/M(2) PO dl-4, Cyclophosphamide 400 mg/M2 IV d1, Prednisone 40 mg/M(2) PO d1-7) followed by alternating 3-week cycles of VBMCP and rIFN alpha2 5 Mu/M(2) SC 3x/week. Treatment was administered for 2 years. Fifty-eight patients with previously untreated multiple myeloma were entered. Objective response (OR) required 50% decrease in M-protein with correction of severe anemia and no progression of skeletal disease. Complete remission (CR) was defined by disappearance of M-protein and normalization of the bone marrow morphology. Life table analysis was utilized to express survival and response duration. Fifty-four patients were evaluable. Objective response was seen in 80% of patients including CR in 30% (16 patients). The median response duration is 35 months, 46 months for patients with CR. The median survival is 42 months for all patients. Five year survival is 42%. Although 78% of patients had neutrophil nadirs <1000 x 10(9)/L, the incidence of severe infection was only 9%. These data demonstrate that VBMCP + interferon is an effective new regimen combining chemotherapy with a biological response modifier for the treatment of multiple myeloma. The incidence of CR is high, and the response and survival durations appear to be 1 year longer than usually seen with standard chemotherapy. A current ECOG randomized trial compares VBMCP + interferon with VBMCP alone.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Immunologic Factors; Interferon alpha-2; Interferon-alpha; Life Tables; Male; Melphalan; Middle Aged; Multiple Myeloma; Myocardial Infarction; Neutropenia; Prednisone; Recombinant Proteins; Remission Induction; Survival Analysis; Thrombocytopenia; Treatment Outcome; Vincristine

Interferon (INF) has been incorporated as part of maintenance therapy after high dose treatment in order to make remissions more durable. In this study we have compared peripheral blood stem cell transplant (PBSCT) versus autologous bone marrow transplant (ABMT) with respect to INF tolerance. Thirty nine PBSCT patients have been compared to 37 ABMT patients for INF tolerance. This is followed by a comparison of 15 PBSCT patients versus 21 ABMT patients for engraftment details, response and survival. INF was started at a median of 61 days in the PBSCT and 58 days in the ABMT patients (P = NS). It was well tolerated in both groups without a significant difference in toxicity in the two arms. Engraftment was more rapid in the PBSCT patients with platelet recovery being significantly faster. Response and survival showed a favourable trend for ABMT patients though statistical significance was not reached and the cost of PBSCT was 12% cheaper. We were thus able to conclude that PBSCT grafts were as durable and could tolerate INF just as well as ABMT. Engraftment was more rapid and the procedure of PBSCT was also cheaper. Further studies with a larger group of patients will be required before comments on the efficacy of treatment can be made.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Disease-Free Survival; Fatigue; Female; Fever; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Interferon alpha-2; Interferon-alpha; Life Tables; Male; Melphalan; Middle Aged; Multiple Myeloma; Pain; Recombinant Proteins; Remission Induction; Survival Analysis; Thrombocytopenia; Transplantation, Autologous; Treatment Outcome

High-dose chemotherapy produces high complete remission (CR) rates and some survival advantage in patients with metastatic breast cancer (BC). A current issue is the possibility that these patients may have an even better prognosis with multiple high-dose treatments. In this study, we evaluated the feasibility of a four-step, high-dose sequential chemotherapy (HDSC) with double autologous hematopoietic progenitor-cell rescue. We also tested the hypothesis that peripheral-blood progenitor cells (PBPCs) harvested following a single recruitment with cyclophosphamide (CY) and granulocyte-macrophage colony-stimulating factor (GM-CSF) allow the safe administration of the whole HDSC with closely timed repeated courses of several non-cross-resistant agents.. The treatment plan included CY 7 g/m2, followed by GM-CSF 5 to 7 micrograms/kg/d administered by continuous intravenous (i.v.) infusion on days 2 to 14; PBPCs with or without bone marrow (BM) harvest; mitoxantrone (NOV) 60, 75, or 90 mg/m2 plus melphalan (L-PAM) 140 to 180 mg/m2 with hematopoietic rescue; methotrexate (MTX) 8 g/m2 plus vincristine (VCR) 1.4 mg/m2; and etoposide (VP-16) 1.5 g/m2 plus carboplatin (PP) 1.5 g/m2 with hematopoietic rescue.. All 15 patients enrolled completed the entire treatment and there were no toxic deaths. Hematologic reconstitution was good at each step. The median number of days with an absolute neutrophil count (ANC) less than 100/microL and platelet count less than 20,000/microL were 8 and 3, respectively, after NOV plus L-PAM, and 7 and 4, respectively, after VP-16 plus PP. The main non-hematologic toxicity was mucositis, while organ toxicity was mild and reversible.. This regimen is feasible, with acceptable toxicity. GM-CSF and PBPCs have a pivotal role, as they hasten hematologic reconstitution, abate toxicity, and allow rapid recycling.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Combined Modality Therapy; Cyclophosphamide; Etoposide; Feasibility Studies; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Methotrexate; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Neutropenia; Remission Induction; Thrombocytopenia; Vincristine

The Illinois Cancer Center entered 25 patients on a phase II trial of intravenous melphalan treating patients with recurrent, metastatic or locally advanced and inoperable squamous cell carcinoma of the head and neck. All patients had bi-dimensionally measurable disease, at least a sixty day life expectancy, and adequate performance status (ECOG scale < or = 2). All patients except one had received prior radiotherapy, chemotherapy or both. Melphalan dosage was 30 mg/m2 every three weeks. Twenty-four patients were evaluable for response. One patient with laryngeal carcinoma had a clinical complete response of a nodal metastasis. Four patients had stabilization of disease for one to three months. There was formidable toxicity, including neutropenia (ANC < 1000/microliters 36%), and thrombocytopenia (< 50,000/microliter 32%). There were no drug-related deaths. Melphalan administered intravenously does not appear to be efficacious therapy in patients with previously treated advanced head and neck squamous carcinomas.

Topics: Adult; Aged; Bone Marrow; Carcinoma, Squamous Cell; Drug Evaluation; Female; Head and Neck Neoplasms; Humans; Injections, Intravenous; Leukocyte Count; Male; Melphalan; Middle Aged; Neutropenia; Survival Rate; Thrombocytopenia

The use of intravenous melphalan at higher doses is limited by severe myelosuppression. It was postulated that GM-CSF would permit the use of higher dose melphalan with only moderate myelosuppression easily manageable in an outpatient setting. Therefore, a phase I study of intravenous melphalan utilizing GM-CSF (recombinant granulocyte-macrophage colony-stimulating factor) support was initiated. Intravenous melphalan at doses of 15-45 mg/m2 was administered every 28 days. GM-CSF was utilized at doses of 10-20 micrograms/kg/day subcutaneously Days 2-21 on a 28-day cycle. Twenty-five patients received 53 courses of therapy. The dose-limiting toxicities were severe or life-threatening granulocytopenia and thrombocytopenia. Utilizing 20 micrograms/kg/day GM-CSF, the maximum tolerated dose (MTD) of melphalan is 30 mg/m2 and, with 10 mg/kg/day GM-CSF, the maximum tolerated melphalan dose is only 20 mg/m2. One patient with ovarian cancer achieved a partial response. Because the reported MTD of intravenous melphalan without GM-CSF is 30 mg/m2, GM-CSF has not allowed sufficient escalation of the intravenous melphalan dose for routine outpatient use.

Topics: Adenocarcinoma; Adult; Agranulocytosis; Anemia; Drug Evaluation; Endometrial Neoplasms; Female; Genital Neoplasms, Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leiomyosarcoma; Melphalan; Ovarian Neoplasms; Recombinant Proteins; Thrombocytopenia

Fifty consecutive patients with recurrent and metastatic endometrial carcinoma were treated with melphalan, 5-fluorouracil, and medroxyprogesterone acetate with or without tamoxifen as first-line chemotherapy. The objective response rate was 48%, with 20% complete responses. The estimated median progression-free survival time was only five months (0.5 to 65 months) with estimated two- and five-year progression-free survival rates of 16 and 13%, respectively. The estimated median progression-free survival time was 24 months for complete responders; the progression-free survival times were significantly longer than the survival times (median = four months) for all other patients (P = .0002). Whether or not the addition of cytotoxic chemotherapy to progesterone hormonal therapy for metastatic endometrial carcinoma lengthens survival time is still open to question.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Female; Fluorouracil; Humans; Medroxyprogesterone; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prospective Studies; Random Allocation; Tamoxifen; Thrombocytopenia; Uterine Neoplasms

Between September 1976 and May 1980, 135 patients with operable breast cancer and positive axillary nodes received l-phenylalanine mustard, adjunct to surgery, 0.15 mg/kg for five days, six weekly, and were randomised prospectively to levamisole 150 mg for three days, two weekly, or a placebo. Treatment was continued for two years or until evidence of treatment failure, whichever was the sooner. At 4 1/2 years, for all patients, there was no significant difference between the two groups (P = 0.09), but in a subgroup of women less than or equal to 50 with 1-3 positive nodes, levamisole had a negative effect (P = 0.05). Although an analysis of the same age group, independent of the nodal status, did not reach significance, there was a trend in favor of placebo (P = 0.08) which was also apparent in premenopausal women (P = 0.15). In postmenopausal patients, however, and in those with more advanced disease with four or more positive nodes, although the results also failed to reach significance the trend in these subgroups favored levamisole. The results of this study suggest that levamisole has no place in the primary therapy of breast cancer in younger women and those with more favorable disease. The value of this agent in older patients and those with more advanced primary disease, remains unproven, but the favorable trends are in accord with a number of other studies with levamisole in metastatic breast and resectable lung cancer. Retrospective analysis confined to those women who received 75% or more of the total dose of l-phenylalanine mustard showed no evidence for a dose-responsive effect of adjuvant chemotherapy on the described pattern of results.

Topics: Age Factors; Breast Neoplasms; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Leukopenia; Levamisole; Lymphatic Metastasis; Melphalan; Menopause; Middle Aged; Placebos; Retrospective Studies; Thrombocytopenia

From May 1978 until November 1980, 169 previously untreated patients with advanced epithelial ovarian cancer were entered into a prospective randomized clinical trial comparing the combination of hexamethylmelamine, Adriamycin, and cyclophosphamide (HAC) to a combination of melphalan and cis-platinum. Eleven patients were excluded from analysis and another 5 patients were excluded from response analysis. Of 153 patients evaluable for response, there were 47, or 30.7%, complete responders (all determined surgically), 6 partial responders, and 100 nonresponders. The response rate for the HAC group was 31% and for the melphalan-platinum group was 37.8%. The overall response rate was 34.6%. Residual tumor diameter (less than or greater than 2 cm) exerted a statistically significant effect on response--47.8 vs 24.4%. Of the 47 complete responders, 7, or 14.9%, have relapsed, with the median duration of remission of 44+ months. Of the 158 patients evaluable for survival, 90 patients have died, with a median survival time of 27.9 months (HAC = 26.4 months, melphalan-platinum = 29.6 months). Age, FIGO stage, histologic grade, and residual disease all exerted a significant effect on survival time. Second-line therapy in the treatment failures was of no benefit. Hematologic toxicity was greater in the melphalan-platinum group. Gastrointestinal toxicity was severe in both groups. Other toxicities were minor and infrequent.

Topics: Adult; Altretamine; Anemia; Antineoplastic Agents; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leukopenia; Melphalan; Middle Aged; Ovarian Neoplasms; Prospective Studies; Random Allocation; Thrombocytopenia

Two hundred ninety-three patients were randomly assigned to three treatment regimens following mastectomy for operable but prognostically unfavorable breast cancer: L-PAM, CFP, or CFP with radiation therapy. For premenopausal patients an increased risk of recurrence was associated with the presence of unfavorable local signs, large number of lymph nodes involved, greater body weight, younger age, and L-PAM treatment. For the postmenopausal patients only three factors were associated with an increased risk of recurrent disease: large tumor size, large number of lymph nodes involved, and inner/central location of the primary lesion. Specifically, the treatment employed has shown no effect. Of particular importance is the fact that for neither group of patients does our experience presently demonstrate clear association of recurrent disease with the level of drug dose administered. Furthermore, evidence suggests that although patients who experience little or no myelosuppression have significantly worse disease-free intervals than patients who experience moderate or severe myelosuppression, here is no benefit for severe myelosuppression over moderate, myelosuppression.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leukocyte Count; Leukopenia; Mastectomy; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Prednisone; Prognosis; Random Allocation; Thrombocytopenia

Sixty-five patients with multiple myeloma resistant to melphalan were randomized to receive cyclophosphamide, doxorubicin (Adriamycin), and prednisone (CAP) (30 patients) or carmustine (BCNU), doxorubicin, and prednisone (BAP) (35 patients). Objective responses occurred in two patients in the CAP group and in seven in the BAP group. Indirect responses were noted in seven additional patients in the CAP group and in six additional patients in the BAP group. Toxic effects consisted mainly of leukopenia and thrombocytopenia. Median survival did not differ between the two treatment groups (CAP, 8.4 months; BAP, 7.7). Objective responders had a longer survival than nonresponders (14.5 vs 7.7 months).

Topics: Aged; Antineoplastic Agents; Carmustine; Cyclophosphamide; Doxorubicin; Drug Resistance; Drug Therapy, Combination; Female; Humans; Leukopenia; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Random Allocation; Thrombocytopenia

The influence of renal insufficiency on melphalan-induced myelosuppression was examined during the initial 10 weeks of treatment in 295 patients with multiple myeloma. Patients were randomized to receive either oral melphalan (0.15 mg/kg/day for 7 days, followed by 0.05 mg/kg/day after recovery from the wbc count nadir) or iv melphalan (16 mg/m2 every 2 weeks for four doses, followed by a single dose every 4 weeks). All patients received a 6-week tapering course of prednisone. Patients with renal insufficiency (BUN greater than or equal to 30 mg/100 ml) had a significantly higher frequency of severe leukopenia (less than or equal to 1000 cells/mm3) following iv melphalan than did patients with normal renal function (50% vs 15%, respectively; P = 0.007). The latter effect resulted in an increased frequency of drug-related deaths secondary to infection. The frequency of severe thrombocytopenia (less than or equal to 25,000 cells/mm3) was also greater in patients with renal failure following iv melphalan therapy. Reduction of iv melphalan dose to 50% in patients with elevated BUN reduced the frequency of these complications to levels that were not significantly different from those observed in patients with normal renal function. The frequency of severe myelosuppression was independent of renal function in patients receiving oral melphalan. Possible explanations for these findings are discussed.

Topics: Blood Urea Nitrogen; Bone Marrow; Humans; Kidney; Kidney Diseases; Leukopenia; Melphalan; Multiple Myeloma; Random Allocation; Thrombocytopenia

A total of 361 evaluable patients with previously untreated multiple myeloma were randomized to receive oral melphalan (0.15 mg/kg/day for seven days, followed by 0.05 mg/kg/day after recovery from the nadir of the leukocytes), BCNU (150 mg/m2 intravenously every six weeks) or CCNU (100 mg/m2 orally every six weeks). All patients received a tapering six-weeks) or CCNU (100 mg/m2 orally every six weeks). All patients received a tapering six-week course of prednisone starting at 0.8 mg/kg for the first two weeks. At week 22, one-half of the patients were randomized to receive vincristine (1 mg/m2) and prednisone (0.6 mg/kg for seven days) every two months in addition to previous therapy. The melphalan treated patients showed a significantly higher overall objective response frequency (59%), according to Myeloma Task Force criteria, when compared to those treated with BCNU (40%) or CCNU (42%). The survivals for all patients were not statistically different for the three treatment programs. However, the good-risk patients treated with melphalan had significantly longer survival (P = 0.02) than the equivalent patients who received BCNU or CCNU. The addition of vincristine and prednisone at week 2 did not significantly increase the percentage of subsequent objective responses or prolong the subsequent survival of any treatment group. It is concluded that oral melphalan is superior to BCNU and CCNU in producing objective responses and in prolonging survival in good risk patients.

Topics: Antineoplastic Agents; Carmustine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukopenia; Lomustine; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Random Allocation; Thrombocytopenia; Vincristine

Fifty-seven patients referred to Roswell Park Memorial Institute between 1971-1975 with Stage III or IV epithelial ovarian cancer treated with prior radiation therapy were randomly allocated to treatment with melphalan, 5-fluorouracil (5-Fu) plus melphalan (FUME), actinomycin-D plus 5-fluorouracil plus melphalan (ACFUME), actinomycin-D, or 5-fluorouracil plus cyclophosphamide (ACFUCY). These patients receiving 5-FU plus melphalan had longer median duration of survival with better quality of life. Combination chemotherapeutic agents effected significantly. better responses (P less than 0.05) than single agent chemotherapy. The ACFUME and ACFUCY combinations resulted in higher incidence of severe and life-threatening toxicity. Patients showing complete response had maximum median duration of survival.

Topics: Antineoplastic Agents; Cyclophosphamide; Dactinomycin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Middle Aged; Neoplasm Recurrence, Local; New York; Ovarian Neoplasms; Prospective Studies; Quality of Life; Thrombocytopenia

Topics: Adenocarcinoma, Mucinous; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leukopenia; Lymphatic Metastasis; Mastectomy; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prospective Studies; Thrombocytopenia

Topics: Cyclophosphamide; Drug Resistance; Female; Humans; Melphalan; Ovarian Neoplasms; Risk; Thrombocytopenia; Thrombophlebitis

Topics: Anemia, Aplastic; Clinical Trials as Topic; Cyclophosphamide; Drug Combinations; Evaluation Studies as Topic; Humans; Leukopenia; Melphalan; Middle Aged; Multiple Myeloma; Palliative Care; Prospective Studies; Radiography, Thoracic; Retrospective Studies; Thrombocytopenia

Topics: Adult; Aged; Bence Jones Protein; Blood Protein Electrophoresis; Blood Urea Nitrogen; Clinical Trials as Topic; Cyclophosphamide; gamma-Globulins; Hematocrit; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Placebos; Plasma Cells; Thrombocytopenia

Topics: Clinical Trials as Topic; Cyclophosphamide; Hematopoiesis; Humans; Leukopenia; Melphalan; Neoplasms; Thrombocytopenia

The DMAC protocol (dexamethasone, melphalan, actinomycin-D, cytarabine) has been evaluated in American studies for the treatment of relapsed canine lymphoma, comparing similarly to other rescue protocols. The aim of this study was to evaluate efficacy and toxicity of DMAC, in a larger UK cohort of resistant canine lymphomas. Medical records of dogs with resistant non-Hodgkin high-grade lymphomas that received DMAC as a rescue protocol were reviewed from 2007 to 2017. Response, time from initiation to discontinuation (TTD) and toxicity (Veterinary Cooperative Oncology Group criteria) were assessed. One hundred dogs were included; 86 received CEOP (modified CHOP including epirubicin) as first-line treatment. Thirty-five dogs (35%) responded: 21 complete responders (CRs) and 14 partial responders (PRs). Responders had significantly longer TTD (P < 0.001) compared with non-responders: 62 days (range 28-952) for CR vs 32 days (range 20-70) for PR. Six CR received more than six cycles of DMAC (range 7-36 cycles) and experienced a longer TTD (median 508, range 126-952 days). Thrombocytopenia occurred in 45% (24 grade 1-2, 21 grade 3-4) and neutropenia in 36% of cases (29 grade 1-2, 7 grade 3-4). Gastrointestinal toxicity occurred in 42% of dogs (40 grade 1-2, 2 grade 3-4). Owing to chemotherapy toxicity, treatment was discontinued in five, and hospitalization required in six cases. In this study, response to DMAC was lower and of generally shorter duration than previously reported. Toxicity was high, but infrequently led to hospitalization or discontinuation of treatment.

Topics: Animals; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Cytarabine; Dactinomycin; Databases, Factual; Dexamethasone; Dog Diseases; Dogs; Female; Kaplan-Meier Estimate; Lymphoma, Non-Hodgkin; Male; Melphalan; Neoplasm Recurrence, Local; Neutropenia; Remission Induction; Schools, Veterinary; Thrombocytopenia; Treatment Outcome; United Kingdom

Topics: Aged; Autografts; Female; Hematopoietic Stem Cell Transplantation; Heparin; Humans; Male; Melphalan; Middle Aged; Thrombocytopenia; Thrombosis

To evaluate the efficacy and adverse effects of low dose thalidomide (TD) combined with modified VCMP (vincristine+cyclophosphamide+melphalan+prednisone) (TD+mVCMP) and VAD (vincristine+doxorubicin+dexamethsone) (TD+VAD) regimens for treating aged patients with MM.. A total of 47 patients with newly diagnosed MM were enrolled in this study. Among them 27 cases were treated with TD+mVCMP regimen (TD+mVCMP group), 20 cases were treated with TD+VAD regimen (TD+VAD group). The dose of TD in 2 groups all was 100 mg/d. Each patient received 4 or more courses of treatment.. Out of 27 cases in TD+mVCMP group, 9 cases achieved complete remission (CR), 5 cases-very good partial remission (VGPR), 6 cases-partial remission (PR); among 20 cases in TD+VAD group, 3 cases achieved CR, 3 cases achieved VGPR, 4 cases achieved PR. The total effective rate in 2 group was 74.1% and 50% respectively, there was statistical difference between 2 groups (P<0.05). The differences of Hb level, plasmocytic ratio of bone marrow and M protein level in 2 groups before and after treatment were significant (P<0.05). The 5 years survival rate of patients in TD+mVCMP and TD+VAD group was 72.8% and 66.9% respectively, there was no statistical difference (P>0.05). The incidence of adverse reactions including caxdiac toxicity, severe leucopenia and thrombocytopenia in TD+mVCMP group was lower than that in TD+VAD group.. Low dose TD combined with modified VCMP regimen for treatment of newly diagnosed aged patients with MM is safe and effective, which may be used as the first line treatment regimen for population in aged MM patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Dexamethasone; Humans; Melphalan; Multiple Myeloma; Prednisone; Remission Induction; Survival Rate; Thalidomide; Thrombocytopenia; Vincristine

We report a 50-year-old female patient with diffuse and rapidly progressing splenic calcification. She had developed nephrotic syndrome and been diagnosed with renal amyloid light-chain amyloidosis in 2010. Although she had been given melphalan and dexamethasone therapy and high-dose melphalan followed by autologous blood stem-cell transplantation, her renal function worsened and hemodialysis was started in May 2011. Since November 2011, splenic calcification, probably associated with amyloidosis, had progressed, and diffuse calcification was observed throughout the splenic area in September 2012. During the same period, the patient was hospitalized for thrombocytopenia. Although splenic dysfunction due to calcification was suspected to be the cause of thrombocytopenia, the association between the two could not be established. The platelet count rose with an improvement in hepatic congestion due to reinforced fluid removal during dialysis.

Topics: Amyloidosis; Calcinosis; Dexamethasone; Disease Progression; Female; Humans; Melphalan; Middle Aged; Nephrotic Syndrome; Peripheral Blood Stem Cell Transplantation; Renal Insufficiency; Splenic Diseases; Thrombocytopenia; Transplantation, Autologous

To evaluate the impact of pegfilgrastim on engraftment, hospital stay and resources in patients with Hodgkin's and non-Hodgkin's lymphoma after conditioning with high-dose BEAM followed by autologous peripheral blood stem cell transplantation (APBSCT) compared with filgrastim.. We reviewed patient charts and our prospective transplantation database for clinical data from the post-transplant period. An integrated cost analysis, including the use of blood products and length of hospital stay, was also performed.. Fourteen (26%) patients with Hodgkin's lymphoma and 40 (74%) patients with non-Hodgkin's lymphoma were analyzed. Thirty-four (68%) patients received single-dose pegfilgrastim (6 mg), and 20 (32%) patients received daily filgrastim (5 μg/kg) after APBSCT. No differences were observed regarding duration of neutropenia grade 4 (pegfilgrastim median 7 days/filgrastim median 8 days; p = 0.13), thrombocytopenia grade 4 (7/9.5 days, respectively; p = 0.21), fever (4.5/2 days; p = 0.057), intravenous antibiotic treatment (11/10 days; p = 0.75) or length of hospital stay (16.5/16 days; p = 0.27) between the groups. The use of pegfilgrastim resulted in 12% higher treatment-related costs when compared to filgrastim, without reaching statistical significance (p = 0.38).. Pegfilgrastim appears to be equivalent to filgrastim after high-dose BEAM followed by APBSCT in the treatment of lymphoma patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Drug Administration Schedule; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hodgkin Disease; Humans; Length of Stay; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Neutropenia; Peripheral Blood Stem Cell Transplantation; Podophyllotoxin; Polyethylene Glycols; Recombinant Proteins; Severity of Illness Index; Thrombocytopenia; Time Factors; Transplantation, Autologous; Treatment Outcome; Young Adult

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Fatal Outcome; Gaucher Disease; Humans; Immunoglobulins; Leukemia, Myeloid, Acute; Male; Melphalan; Multiple Myeloma; Prednisone; Thrombocytopenia

To report thrombocytopenia in a patient prescribed thalidomide for multiple myeloma (MM).. A 70-year-old woman was diagnosed in 2003 with MM. At diagnosis, melphalan 0.25 mg/kg/day and prednisolone 2 mg/kg/day were started; however, the patient became refractory to therapy. Melphalan and prednisolone were discontinued, and monotherapy with dexamethasone 40 mg for 12 days per month was started. The patient's hematologic condition deteriorated again after about one year; dexamethasone was discontinued, and treatment with oral thalidomide 200 mg/day was initiated. About 2 weeks after thalidomide administration, the woman developed disabling adverse effects (flu-like symptoms, swollen fingers, rash and hematoma on her legs, shortness of breath, dry mouth, multiple petechiae). Laboratory testing showed neutropenia (neutrophils 0.4 x 10(9)/L) and thrombocytopenia (platelets 58 x 10(9)/L). Thalidomide was promptly discontinued; within 3 weeks, the laboratory values returned to pretreatment levels (1.3 x 10(9)/L and 267 x 10(9)/L, respectively) and her symptoms disappeared.. Thrombocytopenia is a rarely reported hematologic adverse consequence of thalidomide therapy. A recent report identified 5 patients who developed thrombocytopenia while undergoing monotherapy with thalidomide for MM. According to the Naranjo probability scale, thalidomide was classified as the probable cause of thrombocytopenia in our patient.. Unlike other antineoplastic drugs, thalidomide is rarely reported to cause severe hematologic toxicity. We present this case to increase clinicians' awareness for the potential of thalidomide to adversely affect platelet counts, particularly because its effectiveness in MM will likely result in expansion of its clinical use.

Topics: Administration, Oral; Aged; Dexamethasone; Female; Humans; Melphalan; Multiple Myeloma; Neutropenia; Prednisolone; Thalidomide; Thrombocytopenia; Treatment Outcome

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

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

Topics: Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Neutropenia; Thrombocytopenia; Transplantation, Autologous; Whole-Body Irradiation

Intermittent courses of melphalan and prednisone is still the standard chemotherapy for the initial treatment of multiple myeloma (MM) in patients who cannot undergo high-dose chemotherapy/radiotherapy with either allogeneic or autologous stem cell transplantation. However, the absorption of the drug from the gastrointestinal tract is highly variable from patient to patient and therefore, different plasma levels of the drug are reached in the blood of individual MM patients. In order to overcome this limitation we decided to use intermediate dose (15-30 mg/m2, day 1) intravenous melphalan in resistant or relapsing MM patients as well as in untreated patients not eligible for a more aggressive protocol. Moreover, considering the good results obtained by other investigators using dexamethasone alone or associated with interferon in the treatment of resistant or relapsing MM patients, dexamethasone (40 mg total dose, day 1) and the lymphoblastoid alpha interferon (3 MU, 3 times a week x 3 weeks, from day 8 to day 26 of each course) were added to intravenous melphalan. Courses were repeated every 5 weeks for a total of 6 cycles. We treated 62 MM patients obtaining a response (defined as reduction > 25% of the initial monoclonal component value associated with disappearance of the clinical symptoms) in 38 out 62 evaluable patients (61%) and stable disease (defined as a decrease of < 25% in the base-line serum monoclonal component level with disappearance of all symptoms present at diagnosis) in 9 (14.5%) more patients. The overall median response duration was 14 months and the overall median survival duration (from the time of inclusion in this protocol) for the 62 patients entered into the study was 34 months. No severe (Grade 3-4 of the WHO) hematological as well as non hematological toxicities were observed. This lack of severe toxicity allowed us to administer the drugs on an outpatient basis. In conclusion, the overall response and the low grade of toxicity in this category of patients are encouraging and suggest that this protocol is both effective and safe treatment for high risk MM patients.

Topics: Actuarial Analysis; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Dexamethasone; Disease-Free Survival; Drug Evaluation; Drug Resistance; Drug Therapy, Combination; Female; Humans; Interferon-alpha; Leukopenia; Male; Melphalan; Middle Aged; Multiple Myeloma; Recurrence; Risk Factors; Sepsis; Survival Rate; Thrombocytopenia; Treatment Outcome

Alkylating agents administered with predisone have been the standard therapy for myeloma over the lost three decades. Intensive treatment with autologous hematopoietic support has become the treatment of choice for multiple myeloma patients up to 60 years of age. From march 1999 to january 2000, seven patients with multiple myeloma (stage III) with a median age of 43 years (34-56) received an autologous stem cell transplantation. The myeloablative treatment regimen consisted of high-dose melphalan. All patients had sustained engraftment. The median duration of neutropenia (< 500/mm3) was 12 days (11-140) and the median duration of thrombocytopenia (< 20,000/mm3) was 13 days (11-110). One patient had a complete remission, one a very good partial remission, and 5 patients had a partial remission. With a median follow-up of 8 months (2-12), all patients are alive, without relapse.

Topics: Adult; Antineoplastic Agents, Alkylating; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neutropenia; Remission Induction; Thrombocytopenia; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Tunisia

Major dose-limiting factors of high-dose thiotepa (TEPA) and melphalan are life-threatening mucositis and neurotoxicity. To administer a maximum dose of these drugs safely and to obtain a maximum anti-cancer effect, a double-conditioning regimen with a single grafting, two cycles of administration of a combination of TEPA (300-600 mg/m2) plus melphalan (70-150 mg/m2) with a 1-week interval was attempted in 20 patients with pediatric advanced or chemotherapy-resistant solid tumors (seven rhabdomyosarcoma, four hepatoblastoma, three neuroblastoma and four other malignancy). Combinations of TEPA plus melphalan/busulfan (Bu) (8-10 mg/kg) and TEPA plus Bu were given to four and two patients with brain tumors, respectively. In an additional two patients, three cycles of drug administration were performed. According to the results of the dose-escalating study, the maximum tolerable doses of TEPA and melphalan for children aged 2 years old or older were 1000 mg/m2 and 280 mg/m2, respectively. Mucositis was dose-limiting. Renal toxicity was also dose-limiting in young children (<2 years old). There were two treatment-related deaths (7%) (fungal pneumonia and renal tubular acidosis). Among 13 patients who received high-dose chemotherapy during CR, 10 are alive with no evidence of disease (15-59 months, median: 35 months) and in 13 evaluable patients without CR, six are alive without regrowth of the disease (14-59 months, median: 39 months). Thus, these novel conditioning regimens allowed us to increase the dose intensity to nearly the maximum for each drug and seemed to reduce adverse effects compared to previously reported regimens with these drugs. With regard to the effect on outcome, the results of this study seem to be encouraging, but a further study on a larger number of patients is required.

Topics: Adolescent; Adult; Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Hematopoietic Stem Cell Transplantation; Humans; Infant; Melphalan; Neoplasms; Thiotepa; Thrombocytopenia; Transplantation Conditioning

The use of circulating progenitor cell support following high-dose chemotherapy for malignancies decreases but does not entirely abolish platelet transfusion requirement. We investigated the feasibility of supporting the posttransplant thrombocytopenic phase exclusively with autologous platelets collected by apheresis and cryopreserved.. 25 patients underwent plateletpheresis during the platelet rebound occurring after high-dose cyclophosphamide. Autologous platelets were cryopreserved in 5% dimethylsulfoxide, thawed and transfused during the aplastic phase after the myeloablative regimen whenever clinically required.. A single plateletpheresis was carried out in all patients, allowing the harvest of a platelet concentrate with a mean value of 7.7 x 10(11) platelets. No significant procedure- or transfusion-related side effects were recorded. Mean platelet recovery after freezing and thawing was 63% and the mean number of platelet reinfused was 4.8 x 10(11); 23 of 25 patients were fully supported with autologous platelets.. Plateletpheresis performed in our selected group of patients was found to be a safe and effective procedure to collect large amounts of autologous platelets; the numbers obtained proved to be sufficient for the transfusion demand of almost all patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Platelets; Blood Preservation; Blood Transfusion, Autologous; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Epirubicin; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Methotrexate; Platelet Transfusion; Thiotepa; Thrombocytopenia

Some new alkylating agents which bind to the minor groove of DNA and have sequence-specific patterns of alkylation have shown anti-neoplastic activity in pre-clinical systems. Two of them, carzelesin and tallimustine, are now in phase II. Considering the severe dose-limiting bone marrow toxicity of both these drugs in clinical use, it was of interest to investigate the mechanism of their myelotoxicity in a detailed pre-clinical study and compare it with a conventional alkylating agent, such as melphalan. The origin and progression of the myelotoxicity of carzelesin, tallimustine and melphalan were investigated comparatively in mice, combining data on bone marrow and peripheral blood cellularity with data on the proliferative activity of bone marrow cells, obtained by in vivo administration of bromodeoxyuridine. Significant differences were found between the hematopoietic response to the 3 drugs, though all caused severe leukopenia. Carzelesin induced a short-term increase in myeloid proliferative activity, which prevented the high leukocytopenia on day 3 observed with the other drugs. However, when this effect was exhausted, a second nadir was seen in peripheral blood, with a new wave of cell proliferation of all lineages in the bone marrow. Reconstruction of the lymphoid lineage was slow for all 3 drugs but particularly difficult with high-dose tallimustine. In general, the hematopoietic system response to tallimustine was dampened, with no overshoots, suggesting either lasting effects or extensive cytotoxicity from the early to late precursors of all lineages.

Topics: Animals; Antineoplastic Agents, Alkylating; Benzofurans; Body Weight; Bone Marrow Cells; Cell Cycle; Cell Division; Distamycins; Duocarmycins; Flow Cytometry; Indoles; Leukocyte Count; Male; Melphalan; Mice; Mice, Inbred Strains; Neutropenia; Nitrogen Mustard Compounds; Survival Rate; Thrombocytopenia

We treated 103 multiple myeloma (MM) patients with 7 g/m2 cyclophosphamide (Cy) followed by 300 micrograms G-CSF/d to harvest peripheral blood progenitor cells (PBPC). PBPC autografts containing > 2.0 x 10(6) CD34+ cells per kg body weight were obtained at the first attempt from 90/100 evaluable patients. The most significant factor predicting impairment of PBPC collection was the duration of previous melphalan treatment (P < 0.0001). In multivariate discriminate analysis, treatment with melphalan during the most recent chemotherapy cycles prior to mobilization (P = 0.0727) and previous radiotherapy (P = 0.0628) had a marginally significant negative influence on the efficacy of PBPC collection. We found no reduced functional capacity of CD34+ cells to restore haemopoiesis after myeloablative treatment related to the duration of melphalan exposure. At the time of best response to conventional treatment, a median paraprotein reduction of 21% was achieved following high-dose cyclophosphamide (HD-Cy). Two heavily pretreated patients died and one patient developed pulmonary toxicity W.H.O. grade IV following HD-Cy. Potential transplant candidates should undergo mobilization and harvesting of PBPC before melphalan-containing treatment. Combinations of haemopoietic growth factors and their dose-modifications should be investigated to improve PBPC collection, to allow a dosage reduction of the mobilization chemotherapy.

Topics: Adult; Antigens, CD19; Antigens, CD34; Antineoplastic Agents, Alkylating; Cyclophosphamide; Female; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neutropenia; Thrombocytopenia; Treatment Outcome

Glutathione (GSH) transferases (GST), a family of detoxification enzyme proteins, are suggested to play an important role in tumor cell resistance to melphalan. The GST-activity inhibitor ethacrynic acid has been shown to increase the antitumor activity of melphalan in vitro as well as in vivo. In this study we determined the activity and toxicity of melphalan in combination with another GST-activity inhibitor, sulfasalazine, an agent used to treat ulcerative colitis. We entered 37 previously treated patients with advanced cancer of different histologies on sulfasalazine given at the individually calculated maximum tolerated dose (MTD) and melphalan given at doses beginning at 20 mg/m2. The main toxicity arising from this combination was nausea and vomiting, whereas increased myelosuppression was not observed. A partial response was seen in 2/4 of the ovarian cancer patients only. Plasma sulfasalazine levels varied between 2.5 and 47.1 micrograms/ml. Although reductions in GSH/GST levels were observed in peripheral mononuclear cells of certain patients following sulfasalazine treatment, there was no correlation between the extent of reduction and the plasma sulfasalazine level. A larger patient population must be studied to determine the usefulness of this combination.

Topics: Drug Administration Schedule; Drug Therapy, Combination; Female; Glutathione Transferase; Humans; Male; Melphalan; Neoplasms; Neutropenia; Sulfasalazine; Thrombocytopenia

High dose melphalan is used widely in the treatment of multiple myeloma (MM) and in the conditioning regimen of autologous stem cell transplantation (ABST). Double courses of high dose melphalan and double autologous bone marrow transplantation (ABMT) programs also have been widely reported. However, there are no data about the feasibility and efficacy of three courses of high dose therapy, such as high dose melphalan or powerful therapies in the treatment of malignant disease.. In 1991, a retrospective study in France was initiated to evaluate how many patients with MM had received three courses of high dose therapy with or without hematopoietic stem cell rescue.. This small study of six patients with multiple myeloma showed that three courses of high dose therapy with or without stem cell rescue can be performed with relative safety. Stem cell rescue appears to shorten the duration of aplasia. In terms of antitumor response, long term response could be obtained in patients with MM that responded to the first course of high dose melphalan.. High dose therapy with or without ABMT can be an effective treatment for relapse in a subgroup of patients with MM who respond to high dose melphalan as initial treatment.

Topics: Adult; Bence Jones Protein; Bone Marrow Transplantation; Feasibility Studies; Female; France; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin kappa-Chains; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Neutropenia; Remission Induction; Retrospective Studies; Salvage Therapy; Thrombocytopenia; Transplantation, Autologous

Twenty-four patients with a variety of malignant diseases (13 lymphoma, 4 myeloma, 1 ALL, 6 solid tumours) were treated with the alkylating agents busulphan and melphalan as a preparative regimen for autologous BMT. Thirteen males and 11 females, aged 27-53 years (median 39.5 years) received oral busulphan 1 mg/kg q6 h on days -6 to -3, followed by i.v. melphalan 140 mg/m2 on day -2 and infusion of cryopreserved haemopoietic cells on day 0. The major toxicity seen was gastrointestinal with nausea, vomiting and diarrhoea in 17 patients and severe mucositis in 22. There was no evidence of cardiotoxicity, nephrotoxicity, haemorrhagic cystitis or clinical signs of hepatic veno-occlusive disease. Twenty-three patients engrafted with the median duration of neutropenia (< 0.05 x 10(9)/l) 10 days (range 5-63 days) and thrombocytopenia (< 50 x 10(9)/l) 43 days (range 5-350 days). Three patients died of transplant-related complications. Of 15 evaluable patients with active disease at BMT, 9 responded and 6 were refractory. Sixteen evaluable patients were in CR after BMT. Seven relapsed, 1 died in remission and 8 remain in CR 12-46 months (median 29 months) later. Of the group of 13 lymphomas, overall and relapse-free actuarial survival at 36 months was 64% and 58%, respectively, while for the entire group of 24 patients these values were 39% and 34%. Busulphan and melphalan is a safe and inexpensive conditioning regimen for autologous BMT with acceptable toxicity and substantial antitumour activity particularly against lymphomas.

Topics: Actuarial Analysis; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Busulfan; Combined Modality Therapy; Female; Gastrointestinal Diseases; Humans; Male; Melphalan; Middle Aged; Neoplasms; Neutropenia; Remission Induction; Stomatitis; Survival Analysis; Thrombocytopenia; Transplantation, Autologous; Treatment Outcome

A 29-year-old woman, with a slightly elevated temperature for 3 weeks, increasing dyspnoea at rest, markedly reduced general condition and in heart failure, was found to have a leucocytosis of 100,000/microliters, anaemia (haemoglobin 6.3 g/dl) and thrombocytopenia (41,000/microliters). There were 62% plasma cells in the blood smear. Immunoelectrophoresis of serum and urine revealed kappa-light chains and immunocytology demonstrated IgG-kappa. There was no radiological evidence of osteolysis, while ultrasound examination showed multiple abdominal lymphomas and marked hepatosplenomegaly. Bone marrow smear showed a 90% infiltration of plasma cells. High-dosage melphalan treatment (single intravenous injection of 140 mg/m2) resulted in complete remission after myelodepression over several weeks. Two extramedullary recurrences 5 and 12 months after the diagnosis had been made were successfully treated with high-dosage melphalan, but it was associated with severe and long-lasting myelodepression. Septicaemia with renal and hepatic failure developed and the patient died 6 weeks after the third course of high-dosage melphalan, 14 months after the diagnosis.

Topics: Acute Disease; Adult; Bone Marrow Examination; Cell Count; Female; Humans; Immunoglobulin Light Chains; Leukemia, Plasma Cell; Leukopenia; Melphalan; Plasma Cells; Thrombocytopenia

A high remission rate is achieved with high-dose melphalan (HDM) in multiple myeloma (MM), and autologous transplantation of hematopoietic stem cells allows a prompt hematologic recovery after high-dose therapy. We treated 97 patients with high-risk MM (group 1:44 advanced MM including 14 primary resistances and 30 relapses; group 2: 53 newly diagnosed MM) with a first course of HDM. For responding patients a second course of high-dose therapy with hematopoietic stem cell support was proposed. After the first HDM, the overall response and complete remission rates were 71% and 25% with no significant difference between the two groups. The median durations of neutropenia and thrombocytopenia were significantly longer in group 1 (29.5 days and 32 days, respectively) than in group 2 (23 days and 17 days, respectively). This severe myelosuppression led to eight toxic deaths and the fact that only 38 of the 69 responders could proceed to the second course (three allogenic and 35 autologous transplantations). Among the 35 patients undergoing autologous transplantation (10 in group 1, 25 in group 2), 31 received their marrow unpurged collected after the first HDM, and four received peripheral blood stem cells. The median durations of neutropenia and thrombocytopenia after autologous transplantation were 24 days and 49 days, respectively. Two toxic deaths and nine prolonged thrombocytopenias were observed. The median survival for the 97 patients was 24 months (17 months in group 1, 37 months in group 2) and the median duration of response was 20 months. The only parameters that have a significant impact on the survival are the age (+/- 50 years) and the response to HDM. The median survival of the 35 patients undergoing autologous transplantation is 41 months, but the median duration of remission is 28 months with no plateau of the remission duration curve. Patients responding to HDM may have prolonged survival, but even a second course of high-dose therapy probably cannot eradicate the malignant clone.

Topics: Adult; Aged; Bone Marrow Transplantation; Combined Modality Therapy; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neutropenia; Remission Induction; Survival Rate; Thrombocytopenia; Transplantation, Autologous

A 67-year-old woman, who presented polyneuropathy, pleural effusion, ascites and sclerosing changes in the ribs, was admitted to our hospital on June 17, 1987. On admission, cerebrospinal examination showed a marked protein-cell dissociation and a delay in nerve conduction velocity. Bence-Jones protein was detected in urine, and the immunohistochemical study of biopsied bone marrow of the rib revealed lambda-chain positive plasmacytoma. Serum immunoelectrophoresis, however, showed no monoclonal gamma-globulinemia. From the findings described above, she was diagnosed as having Crow-Fukase syndrome associated with lambda-type light chain disease. Even with a therapy by prednisolone, platelet counts progressively declined to 10,000/ml3. Bone marrow aspiration showed normal number of megakaryocytes. Since platelet-associated IgG was increased to 452 ng/1.0 x 10(8) plt, a diagnosis of autoimmune thrombocytopenia was considered. Melphalan and cyclophosphamide to plasmacytoma resulted in a marked improvement of platelets. In addition, the level of platelet-associated IgG returned to normal range. Polyneuropathy, however, didn't respond to those therapies. It was suggested that both Crow-Fukase syndrome and thrombocytopenia were closely concerned with plasmacytoma but developed in a different manner.

Topics: Aged; Cyclophosphamide; Female; Humans; Hypergammaglobulinemia; Immunoglobulin G; Immunoglobulin lambda-Chains; Immunoglobulin Light Chains; Melphalan; Paraproteinemias; POEMS Syndrome; Thrombocytopenia

A large dose of melphalan was given to 23 patients with advanced multiple myeloma that was refractory to multiple prior treatments. Sixteen patients received a dose of 80 to 100 mg/m2, and seven were given 140 mg/m2 followed by autologous bone marrow infusion. Tumor mass was reduced by more than 75% in 14 patients, including four who died of bone marrow aplasia. Serious infections were prevented in six of seven patients who received autologous bone marrow. The marked cytoreduction in patients with previously refractory disease indicated the apparent drug resistance could be overcome by dose escalation. However, short remission times in most responding patients were consistent with rapid regrowth of primordial tumor cells with high proliferative activity. Although high-dose melphalan was of limited benefit to patients with refractory myeloma, further studies are necessary to clarify its role during earlier phases of disease.

Topics: Adult; Aged; Agranulocytosis; Bone Marrow Transplantation; Combined Modality Therapy; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Thrombocytopenia

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

Cytogenetic studies were carried out on peripheral lymphocytes from cancer patients at different times after therapy with melphalan. The frequency of sister chromatid exchange (SCE) was increased markedly shortly after treatment, and then declined to near pretreatment levels over a four-week period. In-vitro studies showed that the SCE frequency induced by melphalan is reduced slowly in resting G0 lymphocytes and considerably faster in mitogen-stimulated G1 cells. The results demonstrate that measurement of SCE is useful for the study of newly-induced chromosome damage in melphalan-treated cells, but is less suitable for the detection of persistent, cytogenetic alterations long after therapy. The frequency of chromosomal aberrations in a cohort of 50 patients with ovarian carcinoma was increased for up to ten years after melphalan therapy. The predominant aberrations were chromosomal translocations, marker chromosomes and cells with multiple, complex rearrangements. The frequency distribution of chromosomes involved in aberrations was studied in cells from some of the patients. An overrepresentation of chromosomes 8 and 9 was found in these cells, whereas the X chromosome was overrepresented in cells from control subjects. An increased frequency of chromosomal rearrangements was found in long-term cultures of T-lymphocytes from three of the patients, indicating that these aberrations are compatible with cell survival and proliferation. Seven patients in the cohort developed a second, primary tumour during the observation time. The frequencies and types of aberrations in these patients were similar to those of the other patients in the cohort.

Topics: Carcinoma; Cell Division; Cell Survival; Chromosome Aberrations; Chromosomes; DNA Damage; Female; Humans; In Vitro Techniques; Karyotyping; Lymphocytes; Melanoma; Melphalan; Neoplasms; Ovarian Neoplasms; Sister Chromatid Exchange; Thrombocytopenia; Time Factors

During a 5 year period, 64 children with advanced stage malignant solid tumours have been treated with high dose melphalan (140-220 mg/m2) combined with non-cryopreserved autologous marrow transplantation. All children developed a profound neutropenia and thrombocytopenia following high dose melphalan. Both the duration of neutropenia (median 11 d) and the duration of thrombocytopenia (median 18 d) were related to the nucleated cell count of the reinfused marrow but neither appeared to be affected by the dose of melphalan. This suggests that the initial recovery of the peripheral blood count results from the engrafted autologous marrow. We conclude that autologous marrow transplantation accelerates haemopoietic recovery in children with solid tumours treated with high dose melphalan.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Humans; Infant; Leukocyte Count; Melphalan; Neoplasms; Neutropenia; Neutrophils; Platelet Count; Thrombocytopenia; Time Factors; Transplantation, Autologous

Peptichemio (PTC), a multipeptidic complex of m-L-phenyl-alanine mustard, was administered to 39 children with neuroblastoma at relapse. The compound was given in two 5-day cycles at dosages varying from 1.0-1.5 mg/kg/day. We were able to evaluate 29 of the initial 39 children for PTC effect; 21 of them had received PTC as first therapy following diagnosis. Ten patients underwent other chemotherapy for relapse before PTC. Three patients were off therapy when relapse occurred. Subjective improvement was observed in 18 cases (62%). Eleven patients (38%) experienced an objective regression, which was scored as complete response in three cases, partial response in two, mixed response in six. In ten children no significant disease change was observed; the remaining eight had a progression of their disease while receiving PTC. The incidence of responses has been higher in patients off therapy at moment of relapse, and lower in those pretreated for their relapse. Previous administration of PTC did not reduce the chance of response at relapse. Major toxic effects were transient, mostly moderate myelodepression and phlebosclerosis. Allergic reactions, nausea, and vomiting, occurred in a few patients. These data indicate that PTC may exert objective antitumor activity in approximately one-third of neuroblastoma patients at relapse.

Topics: Child; Child, Preschool; Drug Evaluation; Female; Humans; Infant; Leukopenia; Male; Melphalan; Neuroblastoma; Peptichemio; Recurrence; Thrombocytopenia; Veins

Mitotic reactivity following 48/80-induced mast-cell secretion was studied in the mesentery of rats made thrombocytopenic, 7 days following a single injection of melphalan. In spite of a low platelet count (7% of normal), the mitogenic reaction of the mesenteric fibroblasts and mesothelial cells was normal as judged by DNA-synthesis and mitotic index. The findings suggest that platelets and platelet-growth factors are not essential for the mast-cell-mediated mitogenic reaction of these two types of connective-tissue cells studied in vivo.

Topics: Animals; DNA; Fibroblasts; Histamine Release; Male; Melphalan; Mesentery; Mitosis; Mitotic Index; Rats; Thrombocytopenia

Thirty-three adult and pediatric patients with refractory malignancies were treated with escalating doses of melphalan (120-225 mg/m2 IV over 3 days) followed by reinfusion of previously harvested and cryopreserved autologous marrow. The hematological and nonhematological toxicities and the therapeutic effects of this regimen were evaluated. Increasing doses of melphalan did not alter the rate of decline nor the recovery of peripheral blood counts. Granulocyte (greater than 500/microL) and platelet count (greater than 20,000/microL) recovery occurred in a median of 19 (range 12-54) and 24 (range: 12-54) days after bone marrow transplantation, respectively. Five patients experienced severe infection, three of which were fatal, and one patient died due to thrombocytopenic hemorrhage. Toxicity to the gastrointestinal system was dose limiting. The maximum tolerated dose of melphalan was 180 mg/m2; only three of 24 patients experienced severe stomatitis, esophagitis, and diarrhea at this level or less, while eight of nine patients at 225 mg/m2 were affected (p less than 0.005). Administration of cyclophosphamide (300 mg/m2 IV) 1 week before melphalan therapy did not reduce the incidence of severe gastrointestinal toxicity. Plasma melphalan concentration peaked 30-60 min after infusion (4.8-11.5 micrograms/mL) but declined rapidly. Cerebrospinal fluid concentration was 10% of the corresponding plasma concentration and was undetectable at 3 hours. Antitumor responses occurred in nine of 13 patients with malignant melanoma (five complete and four partial remissions), and ranged 2-12+ months with a median of 5 months. Four of six neuroblastomas demonstrated responses (three complete and one partial remission( lasting a median of 7.5 (range: 5-10) months. Other tumors in which this regimen had activity included breast cancer and Ewing's sarcoma. The overall response rate for the 33 patients was 30% complete remissions (10 patients) and 21% partial remissions (seven patients). High dose melphalan and autologous bone marrow transplantation is a promising therapy for patients with malignancies for which no effective treatment is known or for patients whose cancer is refractory to conventional therapeutic agents.

Topics: Adolescent; Adult; Aged; Bone Marrow Transplantation; Breast Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Evaluation Studies as Topic; Female; Gastrointestinal Diseases; Humans; Male; Melanoma; Melphalan; Middle Aged; Neuroblastoma; Neutropenia; Sarcoma, Ewing; Thrombocytopenia; Time Factors

The results achieved with different approaches of chemotherapy protocols applied to 81 patients affected by multiple mieloma and followed up for a duration of 16 years in the geographical area pertaining to the Saronno County Hospital are presented. All the patients are divided into sub-groups, according to the type of treatment they required while being monitored over the years. Each single sub-group is evaluated according to the following criteria: objective response to therapy; median survival rates; toxic effects due to drug exposure. The results are analyzed with reference to the most relevant literature on the matter. A comprehensive retrospective review of emerging data suggests an overlapping median survival--30 and 31 months--in patients given monochemotherapy as such as in those given polychemotherapy. Evidence is also made for a clearly meaningful increase of survival in treated patients compared with that of untreated ones. Median survival depends significantly on the initial stage of the disease. Both therapeutical effectiveness and toxicity are shown to be higher, in accordance with the current literature, in polychemotherapy which include vincristine--especially when a large tumor cell mass is pointed out--compared with therapy based on alkilating agents and prednisone.

Topics: Adult; Aged; Antineoplastic Agents; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Leukopenia; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Thrombocytopenia; Vincristine

A combination of AMSA and peptichemio was evaluated in patients with advanced breast cancer refractory to conventional chemotherapy. Of 33 evaluable patients, five patients (15%) achieved partial remission, two patients (6%) had less-than-partial remission, nine patients (27%) had stable disease, and seventeen patients (52%) had progressive disease. The median duration of response was 6 months (range: 3-8 months). The median duration of stable disease was 5 months (range: 2-7 months). Myelosuppression was the dose-limiting toxicity. This combination of AMSA and peptichemio did not result in an improved response rate or duration of remission compared to the previous experience with single-agent therapy with either of these agents.

Topics: Adult; Aged; Aminoacridines; Amsacrine; Antineoplastic Agents; Breast Neoplasms; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Leukopenia; Melphalan; Middle Aged; Neoplasm Metastasis; Peptichemio; Thrombocytopenia

From January 1975 to May 1981, 25 consecutive patients with multiple myeloma (MM) were entered in a prospective study and treated with the M-2 protocol (melphalan, prednisone, cyclophosphamide, vincristine, and carmustine [BCNU]). The Karnofsky performance status was less than 70 in 62% of the patients. Nineteen patients were classified as being in stage III, three were in stage II, and three were in stage I. All patients had symptomatic and previously untreated MM. In 17 of 21 (80.9%) evaluable patients, an objective response according to Myeloma Task Force criteria was obtained. There was no difference in response rate among patients in the various stages of the disease or according to types of proteins secreted. The median time to obtain an objective response was 2 months and the median duration of the remission is 18+ months. The actuarial median survival was 42 months. In the first 15 months of follow-up, 20% of the patients died. Toxicity was not negligible and was mainly hematologic. One treatment-related death occurred. Our study confirms the efficacy of the M-2 protocol in MM and supports the data reported by the Memorial Hospital group.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Leukopenia; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prospective Studies; Thrombocytopenia; Vincristine

A woman with multiple myeloma relapsed after 6 years of satisfactory tumor control with melphalan therapy. When progression then occurred, she was given exogenous human leukocyte interferon, 3 x 10(6) reference units twice daily i.m., as the sole therapy. Side-effects of the interferon therapy consisted of fever reactions and thrombocytopenia. One month after the initiation of interferon therapy there was 1) improvement of general health with less pain and tiredness, 2) reduction of the M-component, IgG-lambda, in the serum, and 3) a reduced plasma cell concentration in the bone marrow. After 5 months of interferon therapy tumor progression occurred despite continuous interferon treatment. At the same time, the tumor cells were less sensitive to interferon in in vitro tests than prior to interferon therapy. It is suggested that interferon therapy should be given as initial treatment to a few patients with multiple myeloma in a phase I trial.

Topics: Aged; Bone Marrow; Bone Marrow Examination; Cell Count; Cells, Cultured; Drug Evaluation; Drug Resistance; Female; Fever; Hemoglobins; Humans; Immunoglobulin G; Immunoglobulin lambda-Chains; Interferons; Melphalan; Multiple Myeloma; Neoplasm Recurrence, Local; Thrombocytopenia

Topics: Humans; Injections, Intravenous; Leukopenia; Melphalan; Metabolic Clearance Rate; Multiple Myeloma; Thrombocytopenia

Leukopenia and thrombocytopenia were studied after loading doses of melphalan (5 mg/daily for 18-25 days) in 71 myeloma patients. Seventy per cent of the patients developed pronounced leukopenia (white cells less than 2.0 X 10(9)/l) and/or thrombocytopenia (platelets less than 100 X 10(9)/l). The patients with pronounced and moderate hematological side-effects, respectively, were compared for weight and age. The body weight was the same in the two groups, indicating that the patient's weight is of minor importance for the dosage of melphalan. There was a numerical difference in age, on the borderline for statistical significance, indicating that the age of the myeloma patient may be of minor importance for the dosage of melphalan. It is possible that more pronounced age differences may be of greater importance in this respect. Fifteen patients with myeloma were treated with cyclophosphamide. Compared with melphalan, the effect on white cells was the smae, while the incidence of thrombocytopenia was statistically significantly lower with cyclophosphamide.

Topics: Aged; Bone Marrow; Cyclophosphamide; Humans; Leukopenia; Melphalan; Middle Aged; Multiple Myeloma; Thrombocytopenia

A four-drug adjuvant chemotherapy regimen (CONPADRI-I) was utilized in the primary treatment of 18 children with osteogenic sarcoma. All patients had surgical amputation for the primary lesion. The children then received cyclophosphamide, vincristine, melphalan, and adriamycin in defined combinations intermittently over a 72-week period. Of the 18 patients, 10 (55%) remain free of disease 24 months or longer from time of amputation.

Topics: Adolescent; Adult; Amputation, Surgical; Antineoplastic Agents; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Heart; Humans; Leukopenia; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Osteosarcoma; Thrombocytopenia; Vincristine

Topics: Afibrinogenemia; Animals; Antifibrinolytic Agents; Blood Cell Count; Blood Platelets; Chromium Radioisotopes; Coagulase; Cyclohexanecarboxylic Acids; Dogs; Female; Fibrinogen; Hematocrit; Immune Sera; Iodine Radioisotopes; Leukocyte Count; Leukopenia; Male; Melphalan; Oxygen; Partial Pressure; Pulmonary Embolism; Rabbits; Respiratory Insufficiency; Thrombin; Thrombocytopenia

Topics: Blood Cell Count; Blood Platelets; Drug Combinations; Humans; Leukocyte Count; Leukopenia; Melphalan; Plasmacytoma; Prednisolone; Prednisone; Thrombocytopenia

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; Adult; Bone Marrow; Child; Child, Preschool; Dosage Forms; Female; Humans; Injections, Intravenous; Leukopenia; Male; Melphalan; Neoplasm Metastasis; Osteosarcoma; Thrombocytopenia; Time Factors

Topics: Humans; Leukopenia; Melphalan; Multiple Myeloma; Thrombocytopenia

Topics: Anemia; Fluorouracil; Humans; Leukopenia; Melphalan; Nitrogen Mustard Compounds; Stomach Neoplasms; Thiotepa; Thrombocytopenia

Topics: Bence Jones Protein; Blood Protein Electrophoresis; Bone Marrow Examination; Diagnosis, Differential; Female; gamma-Globulins; Humans; Infarction; Leukemia, Plasma Cell; Leukocytosis; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Metastasis; Plasma Cells; Prednisone; Spleen; Splenic Neoplasms; Splenic Rupture; Subarachnoid Hemorrhage; Thrombocytopenia

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: Blood Cell Count; Humans; Leukopenia; Melphalan; Multiple Myeloma; Thrombocytopenia

Topics: Humans; Leukopenia; Melphalan; Polycythemia Vera; Splenomegaly; Thrombocytopenia

Topics: Bence Jones Protein; Blood Cell Count; Bone Marrow; Electrophoresis; Humans; Leukocyte Count; Leukopenia; Melphalan; Multiple Myeloma; Thrombocytopenia

Topics: Anemia; Blood Protein Disorders; Chlorambucil; Humans; Hypercalcemia; Leukopenia; Melphalan; Plasmacytoma; Thrombocytopenia

Topics: Albuminuria; Blood Protein Electrophoresis; Humans; Leukocyte Disorders; Leukopenia; Mechlorethamine; Melphalan; Multiple Myeloma; Neoplasms; Thrombocytopenia

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