melphalan and Hematologic-Diseases

Hematopoietic stem cell transplantation (HCT) is a potentially life-saving therapy for patients with malignant and nonmalignant disease states. This article reviews the current published literature on the dosing of pharmacologic agents used for HCT preparative regimens with specific focus on the obese patient population. The review found that dose adjustments for obesity have, to date, been based empirically or extrapolated from published data in the nontransplantation patient population. As a result, the Committee determined that clear standards or dosing guidelines are unable to be made for the obese population because Level I and II evidence are unavailable at this time. Instead, the Committee provides a current published literature review to serve as a platform for conditioning agent dose selection in the setting of obesity. A necessary goal should be to encourage future prospective trials in this patient population because further information is needed to enhance our knowledge of the pharmacokinetics and pharmacodynamics of conditioning agents in the setting of obesity.

Topics: Antilymphocyte Serum; Bone Marrow Transplantation; Busulfan; Cyclophosphamide; Cytarabine; Drug Administration Schedule; Drug Dosage Calculations; Etoposide; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Myeloablative Agonists; Obesity; Transplantation Conditioning

Following recent data on multiple myeloma (MM) in the literature, a possible model of myeloma development, involving different cytokine signals, is advanced, and the prognostic significance of two principle staging systems is evaluated. Different therapeutic approaches to MM have been employed, consisting of either treatment with only melphalan and prednisone, or combination chemotherapy, especially in patients with a poor prognosis. However, for the initial therapy, melphalan plus prednisone in doses that compensate for individual variation in drug absorption still appears the best choice in the vast majority of MM patients. The main clinical and hematological features which distinguish Waldenström's macroglobulinemia from MM are described, as are the criteria which should be used in choosing the most appropriate treatment based, when necessary, on chemotherapy with standard alkylating agents, as well as on the new nucleoside analogues, and repeated courses of plasmapheresis.

Topics: Aging; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Diagnosis, Differential; Drug Therapy, Combination; Hematologic Diseases; Humans; Melphalan; Multiple Myeloma; Prednisone; Waldenstrom Macroglobulinemia

Patients with transplant-ineligible relapsed and refractory multiple myeloma (RRMM) have a short life expectancy, especially when they have failed both the proteasome inhibitor and immunomodulator therapies. This study aimed to assess the efficacy and safety of pomalidomide, cyclophosphamide, and dexamethasone (PCd) in elderly patients with RRMM. This phase 2 clinical trial recruited 55 elderly patients with RRMM. The patients underwent a 28-day treatment cycle: pomalidomide (4 mg/day on days 1-21, administered orally) and cyclophosphamide (400 mg/day on days 1, 8, and 15; administered orally) plus dexamethasone. The median (range) age of the patients was 73.3 (64-86) years, and 8 (14.5%) patients who were ≥ 80 years old. Eight (14.5%) and 31 (56.4%) patients exhibited stage III (revised international staging system) and frail status (simplified frailty scale), respectively. The overall response rate (ORR) and clinical benefit rate (CBR) of PCd therapy were 58.2% and 72.7%, respectively. The median PFS and median overall survival (OS) were 6.90 months (95% CI, 4.7-9.0) and 18.48 months (95% CI, 9.4-27.6), respectively. The incidence rate of grade ≥ 3 non-hematological toxicities was 70.8%. In particular, the incidence rate of primary infection was 45.4%, including 21.8% for pneumonia, 9.0% for sepsis, and 14.6% for febrile neutropenia. In conclusion, PCd is an effective regimen for elderly patients with RRMM who had failed both bortezomib and lenalidomide treatments, but in whom the treatment-associated infection is the main cause of morbidity and mortality.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cyclophosphamide; Dexamethasone; Drug Resistance, Neoplasm; Febrile Neutropenia; Female; Frail Elderly; Frailty; Hematologic Diseases; Humans; Incidence; Infections; Kaplan-Meier Estimate; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloma Proteins; Prednisone; Progression-Free Survival; Recurrence; Republic of Korea; Thalidomide

Melflufen (melphalan flufenamide, previously designated J1) is an optimized and targeted derivative of melphalan, hydrolyzed by aminopeptidases overexpressed in tumor cells resulting in selective release and trapping of melphalan, and enhanced activity in preclinical models.. This was a prospective, single-armed, open-label, first-in-human, dose-finding phase I/IIa study in 45 adult patients with advanced and progressive solid tumors without standard treatment options. Most common tumor types were ovarian carcinoma (n = 20) and non-small-cell lung cancer (NSCLC, n = 11).. In the dose-escalating phase I part of the study, seven patients were treated with increasing fixed doses of melflufen (25-130 mg) Q3W. In the subsequent phase IIa part, 38 patients received in total 115 cycles of therapy at doses of 30-75 mg. No dose-limiting toxicities (DLTs) were observed at 25 and 50 mg; at higher doses DLTs were reversible neutropenias and thrombocytopenias, particularly evident in heavily pretreated patients, and the recommended phase II dose (RPTD) was set to 50 mg. Response Evaluation Criteria In Solid Tumors (RECIST) evaluation after 3 cycles of therapy (27 patients) showed partial response in one (ovarian cancer), and stable disease in 18 patients. One NSCLC patient received nine cycles of melflufen and progressed after 7 months of therapy.. In conclusion, melflufen can safely be given to cancer patients, and the toxicity profile was as expected for alkylating agents; RPTD is 50 mg Q3W. Reversible and manageable bone marrow suppression was identified as a DLT. Clinical activity is suggested in ovarian cancer, but modest activity in treatment of refractory NSCLC.

Topics: Adult; Aged; Aged, 80 and over; Alkylation; Antineoplastic Agents, Alkylating; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hematologic Diseases; Humans; Male; Melphalan; Middle Aged; Neoplasms; Peptide Hydrolases; Phenylalanine; Prospective Studies

Influence of age and sex on chemotherapy-related toxicity was evaluated in children (3-9 years), adolescents (10-17 years), and adults (up to 40 years) with localized Ewing sarcoma (ES) enrolled in the ISG/SSG III protocol. Treatment was based on vincristine, doxorubicin, cyclophosphamide, ifosfamide, dactinomycin, and etoposide. High-dose chemotherapy with busulfan and melphalan was given in poor responder patients. The analysis was based on 2191 courses of standard chemotherapy and 230 patients. A lower risk of G4 leukopenia and thrombocytopenia, hospitalization, febrile neutropenia, and red blood cell (RBC) transfusions was observed in males. Use of granulocyte colony-stimulating factor (G-CSF) was more frequent in adults, while children more often received RBC transfusions. A significant correlation between sex and chemotherapy-related toxicity was observed in the study, whereas no significant differences in terms of bone marrow toxicity can be expected according to patient age. Further studies should analyse the role of pharmacokinetics, pharmacogenomics, and clinical characteristics.

Topics: Adolescent; Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Child, Preschool; Cyclophosphamide; Doxorubicin; Etoposide; Female; Follow-Up Studies; Hematologic Diseases; Humans; Ifosfamide; Male; Melphalan; Mesna; Neoplasm Staging; Prognosis; Prospective Studies; Sarcoma, Ewing; Sex Factors; Survival Rate; Vincristine; Young Adult

Panobinostat is a histone deacetylase inhibitor that has shown synergistic preclinical anti-myeloma activity when combined with other agents, recently exhibiting synergy with the alkylating agent melphalan (Sanchez et al., Leuk Res 35(3):373-379, 2011). This phase 1/2 trial investigated the safety and efficacy of panobinostat in combination with melphalan for relapsed/refractory multiple myeloma patients. There were four different trial treatment schedules due to tolerability issues, with the final treatment schedule (treatment schedule D) consisting of panobinostat (15 or 20 mg) and melphalan (0.05 or 0.10 mg/kg), both administered on days 1, 3, and 5 of a 28-day cycle. A total of 40 patients were enrolled; 3 in treatment schedule A, 9 in schedule B, 7 in schedule C, and finally 21 schedule D. Patients had been treated with a median of four regimens (range, 1-16) and two prior bortezomib-containing regimens (range, 0-9). Maximum-tolerated dose was established at 20 mg panobinostat and 0.05 mg/kg melphalan in treatment schedule D. Overall, 3 patients (7.5 %) achieved ≥partial response (two very good PRs and one PR) while 23 exhibited stable disease and 14 showed progressive disease. All three responders were enrolled in cohort 2 of treatment schedule B (panobinostat 20 mg thrice weekly continuously with melphalan 0.05 mg/kg on days 1, 3, and 5). Neutropenia and thrombocytopenia were common, with 30.8 and 23.1 % of patients exhibiting ≥grade 3, respectively. Panobinostat + melphalan appears to have tolerability issues in a dosing regimen capable of producing a response. Care must be taken to balance tolerability and efficacy with this combination.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hydroxamic Acids; Indoles; Infections; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Multiple Myeloma; Panobinostat; Recurrence; Salvage Therapy

The current study was designed to assess the safety and efficacy of bortezomib in combination with fludarabine and melphalan as reduced intensity conditioning before allogeneic stem cell transplantation in patients with high risk multiple myeloma. Sixteen patients were evaluable. The median number of previous line of treatment was 3; all patients had relapsed following a prior autograft and 13 had previously received bortezomib. Fifteen of them either remained stable or improved disease status at day +100 post-transplant, including 11 patients with active disease. More specifically, nine patients (56%) and five patients (31%) reached complete remission and partial response, respectively. 25% developed grade III acute graft-versus-host disease. The cumulative incidence of non-relapse mortality, relapse and overall survival were 25%, 54% and 41%, respectively, at 3 years. Regarding the non-haematological toxicity (grade>2), two patients developed peripheral neuropathy, two patients liver toxicity and 1 pulmonary toxicity early post-transplant. The haematological toxicity was only observed during the first three cycles mostly related to low haemoglobin and platelet levels. The current trial is the first one evaluating the safety and efficacy of bortezomib as part of a reduced intensity conditioning regimen among patients with high risk multiple myeloma.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Boronic Acids; Bortezomib; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Cyclosporine; Drug Synergism; Female; Graft vs Host Disease; Hematologic Diseases; Humans; Immunosuppressive Agents; Maintenance Chemotherapy; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Peripheral Nervous System Diseases; Protease Inhibitors; Pyrazines; Remission Induction; Reoperation; Salvage Therapy; T-Lymphocyte Subsets; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Vidarabine

Treatment of mantle cell lymphoma (MCL) in younger patients remains a challenge. We report results of a phase 2 trial using cytarabine and rituximab as induction regimen before autologous stem cell transplantation. Patients younger than 66 years with stage 3 or 4 MCL were included. Treatment consisted of 3 courses of CHOP(21) with rituximab at the third one and 3 of R-DHAP. Responding patients were eligible for autologous stem cell transplantation with TAM6 or BEAM. Sixty patients were included. Median age was 57 years. Characteristics of patients were: BM involvement 85%, leukemic disease 48%, gastrointestinal involvement 52%, Performance Status > 16%, lactate dehydrogenase > 1N 38%, Mantle Cell Lymphoma International Prognostic Index (low 55%, intermediate 38%, high 13%). The overall response rate was 93% after (R)-CHOP and 95% after R-DHAP. Although uncommon after (R)-CHOP (12%), 57% of patients were in complete response after R-DHAP. With median follow-up of 67 months, median event-free survival is 83 months, and median overall survival is not reached. Five-year overall survival is 75%. Comparison with a previous study without rituximab shows improvement of outcome (median event-free survival, 51 vs 83 months). No toxic death or unexpected toxicities were observed. This study confirms that induction with rituximab and cytarabine-based regimens is safe and effective in MCL patients. This regimen is currently compared with R-CHOP(21) induction in a multicentric European protocol.

Topics: Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Cytarabine; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; Hematologic Diseases; Humans; Kaplan-Meier Estimate; Kidney Diseases; Lymphoma, Mantle-Cell; Male; Melphalan; Middle Aged; Neoplasms, Second Primary; Peripheral Blood Stem Cell Transplantation; Prednisone; Rituximab; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Vincristine; Whole-Body Irradiation

To improve the outcome of allogeneic stem cell transplantation (allo-SCT) in multiple myeloma as part of first-line treatment, we prospectively investigated the feasibility and efficacy of lenalidomide maintenance. Patients started maintenance 1 to 6 months after nonmyeloablative allo-SCT. Lenalidomide was dosed 10 mg on days 1 to 21 of a 28-day schedule for a total of 24 cycles. Peripheral blood samples were taken to evaluate immune modulating effects. Thirty-five eligible patients were enrolled, and 30 started with lenalidomide. After 2 cycles, 14 patients (47%) had to stop treatment, mainly because of the development of acute graft versus host disease (GVHD). In total, 13 patients (43%) stopped treatment because of development of GVHD, 5 patients (17%) because of other adverse events, and 5 patients (17%) because of progression. Responses improved in 37% of patients, and the estimated 1-year progression-free survival from start of maintenance was 69% (90% confidence interval, 53%-81%). Lenalidomide increased the frequency of human leukocyte antigen-DR(+) T cells and regulatory T cells, without correlation with clinical parameters. In conclusion, lenalidomide maintenance 10 mg daily after nonmyeloablative allo-SCT with unmanipulated graft in multiple myeloma patients is not feasible, mainly because of the induction of acute GVHD. This trial was registered at www.trialregister.nl as #NTR1645.

Topics: Acute Disease; Adult; Aged; Antineoplastic Agents; Combined Modality Therapy; Cyclophosphamide; Cyclosporine; Disease-Free Survival; Drug Eruptions; Feasibility Studies; Female; Graft vs Host Disease; Hematologic Diseases; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Immunosuppressive Agents; Lenalidomide; Lymphocyte Count; Male; Melphalan; Middle Aged; Multiple Myeloma; Mycophenolic Acid; Prospective Studies; Remission Induction; Thalidomide; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Whole-Body Irradiation

Oral busulfan clearance is age-dependent and children experience a wide variability in plasma exposure. BSA- or age-based dosing is used with therapeutic drug monitoring (TDM) to reduce this variability.. A new intravenous (IV) dosing of busulfan (Bu) based on body weight, designed to improve AUC targeting without TDM and dose-adjustment, was prospectively evaluated.. Bu was administered as a 2 h IV infusion every 6 h over 4 days (16 administrations). Five dose levels were defined on body weight as follows: 1.0 mg/kg for <9 kg; 1.2 mg/kg for 9 to <16 kg; 1.1 mg/kg for 16-23 kg; 0.95 mg/kg for >23-34 kg; 0.80 mg/kg for >34 kg. Bu treatment was followed by Cyclophosphamide or Melphalan prior to allogeneic or autologous transplantation in 55 children aged 0.3-17.2 years (median 5.6 years).. No difference in AUC values was observed between weight strata (mean +/- SD 1248 +/- 205 micromol.min), whereas a significant difference in Bu clearance was demonstrated. This new dosing enabled to achieve a mean exposure comparable to that in adults. At dose 1, 91% of patients achieved the targeted AUC range (900-1500 micromol.min) while no patients were underexposed. At doses 9 and 13, over 75% of patients remained within that target whilst most of the others were slightly above. Successful engraftment was achieved in all patients. In conclusion, from infants to adults this new dosing enabled, without TDM and dose adjustment, to successfully target a therapeutic AUC window.

Topics: Adolescent; Age Factors; Antineoplastic Agents, Alkylating; Area Under Curve; Body Weight; Busulfan; Child; Child, Preschool; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Monitoring; Female; Hematologic Diseases; Humans; Infant; Infusions, Intravenous; Male; Melphalan; Models, Biological; Neoplasms; Prospective Studies; Stem Cell Transplantation

New treatment options offering enhanced activity in elderly, newly diagnosed patients with multiple myeloma are required. One strategy is to combine melphalan and prednisone with novel agents. We previously reported an 89% response rate, including 32% complete responses and 11% near complete responses, in our phase 1/2 study of bortezomib plus melphalan and prednisone (VMP) in 60 newly diagnosed multiple myeloma patients with a median age of 75 years. Here, we report updated time-to-events data and the impact of poor prognosis factors on outcome.. Updated analyses of time to biochemical progression and overall survival with VMP were conducted, and compared with those of historical controls treated with melphalan and prednisone. A univariate analysis was performed to evaluate the influence of known prognostic factors on the time to progression.. After a median follow-up of 26 months, the median time to progression with VMP was 27.2 months, compared with 20.0 months with melphalan plus prednisone. The median overall survival with VMP was not reached versus 26 months with melphalan and prednisone; the survival rate at 38 months was 85% versus 38%, respectively. Time to progression was not significantly affected by elevated beta(2)-microglobulin or lactate dehydrogenase levels, advanced age, or cytogenetic abnormalities, but was shorter in patients with albumin < 3 g/dL, Karnofsky performance status < or =70%, bone marrow plasma cell infiltration > or =40%, and, particularly, high plasma cell proliferative activity (> or = 2.5% S-phase cells).. VMP is highly active and well tolerated in elderly patients with newly diagnosed multiple myeloma, with 85% of patients alive at 3 years. Moreover, VMP may overcome the poor prognostic impact of various factors, particularly cytogenetic abnormalities.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Boronic Acids; Bortezomib; Disease Progression; Disease-Free Survival; Female; Follow-Up Studies; Gastrointestinal Diseases; Hematologic Diseases; Humans; Karnofsky Performance Status; Male; Melphalan; Multiple Myeloma; Prednisone; Prognosis; Pyrazines; Survival Analysis

In a phase I-II study for patients aged 55-65 years, we employed radioimmunotherapy using an anti-CD-66 antibody as part of a dose-reduced conditioning regimen, which was followed by a T-cell-depleted graft. 20 patients with a median age of 63 years suffering from acute leukaemia (n=17) or myelodysplastic syndrome (n=3) received the antibody labelled either with 188Rhenium (n=8) or with 90Yttrium (n=12) during conditioning. Radioimmunotherapy provided a mean dose of 21.9 (+/-8.4) Gy to the bone marrow with a significantly higher dose when 90Yttrium was used. Additional conditioning was fludarabine-based plus anti-thymocyte globulin in matched related donor transplants (n=11), or plus melphalan in matched unrelated donor transplants (n=9). Regimen-related toxicity was low, with two patients developing three episodes of grade III organ toxicity. All patients engrafted, grade II-IV acute graft-versus-host disease (GvHD) was observed in one patient (5%) and chronic GvHD in three patients (15%). The cumulative incidence of non-relapse mortality was 25%, the cumulative incidence of relapse 55%. The probability of survival was estimated to be 70% at 1 year and 52% at 2 years post-transplant, although no plateau was reached afterwards. In conclusion, radioimmunotherapy using the anti-CD66 antibody was feasible and safe in our elderly patient group and provided a high marrow dose.

Topics: Aged; Antibodies, Monoclonal; Antigens, CD; Antigens, Differentiation; Antilymphocyte Serum; Antineoplastic Agents; Cell Adhesion Molecules; Female; Follow-Up Studies; Hematologic Diseases; Humans; Immunosuppressive Agents; Leukemia; Lymphocyte Depletion; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Radioimmunotherapy; Radioisotopes; Radiometry; Rhenium; Stem Cell Transplantation; Survival Rate; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine; Yttrium Radioisotopes

Despite reports that i.v. melphalan is active in the settings of conditioning regimens utilizing high-dose chemotherapy for autologous bone marrow transplantation and in isolated limb perfusion for the treatment of malignant melanoma, its activity at conventional doses has never been defined in this disease. We conducted a phase II study of conventional-dose i.v. melphalan (30 mg/m2) in 17 patients with metastatic melanoma. All patients were previously untreated with chemotherapy with performance status 0, 1 or 2. Forty-seven cycles were given with a median of two cycles. One patient was not evaluable due to early death. There were no responses in the 16 patients, resulting in a 0% response rate (95% confidence interval = 0-17%). We conclude that conventional-dose melphalan by i.v. administration has no appreciable activity in patients with metastatic malignant melanoma.

Topics: Adrenal Gland Neoplasms; Adult; Aged; Antineoplastic Agents, Alkylating; Brain Neoplasms; Dose-Response Relationship, Drug; Female; Gastrointestinal Neoplasms; Hematologic Diseases; Humans; Liver Neoplasms; Lung Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms; Soft Tissue Neoplasms; Treatment Outcome

Interferon (IFN) has demonstrated activity in the treatment of patients with multiple myeloma. A previous Eastern Cooperative Oncology Group (ECOG) study suggested that the rates of complete response (CR) and survival were increased with a regimen that alternated IFN with chemotherapy. The current study was designed to evaluate the effect of adding alternating cycles of IFN or early intensification with high dose cyclophosphamide (HiCy) to the VBMCP regimen for the treatment of multiple myeloma patients.. From February 1988 to May 1992, the ECOG entered previously untreated patients with active multiple myeloma on a study in which they were randomized to VBMCP (vincristine 1.2 mg/m(2) administered intravenously [i.v.] on Day 1, BCNU 20 mg/m(2) i.v. on Day 1, melphalan 8 mg/m(2) administered orally [p.o.] on Days 1-4, cyclophosphamide 400 mg/m(2) i.v. on Day 1, and prednisone 40 mg/m(2) p.o. on Days 1-7; 5-week cycles) or VBMCP + rIFN(alpha2), the latter given at 5 Mu/m(2) 3 times a week starting on Day 22 of each 6-week cycle after 2 initial cycles of VBMCP. Patients younger than 70 years were also randomized to a third treatment that substituted cyclophosphamide 600 mg/m(2) i.v. on Days 1-4 and prednisone 100 mg/m(2) p.o. on Days 1-4 for cycles 3 and 5 of VBMCP (VBMCP + HiCy). Treatment was continued for 2 years.. Of the 653 patients entered, 628 were eligible for the study. All were evaluated for response. With median follow-up for surviving patients of 54 months, the median survival duration was 42 months-1 year longer than usually reported for melphalan combined with prednisone. A comparison of the three regimens revealed no significant difference in the rates of survival or objective response (OR). However, CRs were increased among patients treated with VBMCP + rIFN(alpha2) compared with VBMCP alone (18% vs. 10%, P = 0.03). Patients treated with VBMCP + rIFN(alpha2) had a longer response duration than patients treated with VBMCP alone (30 vs. 25 months, P = 0.035). There was a greater response rate with the IFN regimen among elderly patients (OR and CR = 67% and 31%, respectively) and patients with immunoglobulin A (IgA) myeloma (OR and CR = 83% and 29%, respectively). Severe infections were seen as often with VBMCP as with VBMCP + rIFN(alpha2) (13% vs. 15%), but they were more frequent with VBMCP + HiCy (25%).. VBMCP + rIFN(alpha2) yields a higher rate of CR and a longer response duration than VBMCP alone but appears to make no difference in the rates of overall response or survival compared with VBMCP or VBMCP + HiCy. The superior ability of VBMCP + rIFN(alpha2) induction therapy to produce CR and more durable responses, as well as its activity in older patients and in those with IgA myeloma, suggest that this therapy has important biologic activity in myeloma and merits further clinical investigation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cardiovascular Diseases; Carmustine; Cyclophosphamide; Hematologic Diseases; Humans; Infections; Interferon Type I; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recombinant Proteins; Survival Analysis; Vincristine

The present report describes the non-haematological toxicity and the influence of growth factor administration on haematological toxicity and haematopoietic recovery observed after high-dose carboplatin (1200 mg m(-2)), etoposide (900 mg m(-2)) and melphalan (100 mg m(-2)) (CEM) followed by peripheral blood progenitor cell transplantation (PBPCT) in 40 patients with high-risk cancer during their first-line treatment. PBPCs were collected during the previous outpatient induction chemotherapy programme by leukaphereses. CEM administration with PBPCT was associated with low non-haematological toxicity and the only significant toxicity consisted of a reversible grade III/IV increase in liver enzymes in 32% of the patients. Haematopoietic recovery was very fast in all patients and the administration of granulocyte colony-stimulating factor (G-CSF) plus erythropoietin (EPO) or granulocyte-macrophage colony-stimulating factor (GM-CSF) plus EPO after PBPCT significantly reduced haematological toxicity, abrogated antibiotic administration during neutropenia and significantly reduced hospital stay and patient's hospital charge compared with patients treated with PBPCT only. None of the patients died early of CEM plus PBPCT-related complications. Low non-haematological toxicity and accelerated haematopoietic recovery renders CEM with PBPC/growth factor support an acceptable therapeutic approach in an adjuvant or neoadjuvant setting.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Chemotherapy, Adjuvant; Erythropoietin; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Humans; Length of Stay; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Recombinant Proteins; Survival Rate

Current treatments for metastatic breast cancer are not associated with significant survival benefits despite response rates of over 50%. High-dose therapy with autologous bone marrow transplantation (ABMT) has been investigated, particularly in North America, and prolonged survival in up to 25% of women has been reported, but with a significant treatment-related mortality. However, in patients with haematological malignancies undergoing autologous transplantation, haematopoietic reconstruction is significantly quicker and mortality lower than with ABMT, when peripheral blood progenitor cells (PBPCs) are used. In 32 women with metastatic breast cancer, we investigated the feasibility of PBPC mobilisation with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) after 12 weeks' infusional induction chemotherapy and the subsequent efficacy of the haematopoietic reconstitution after conditioning with melphalan and either etoposide or thiotepa. PBPC mobilisation was successful in 28/32 (88%) patients, and there was a rapid post-transplantation haematopoietic recovery: median time to neutrophils > 0.5 x 10(9) l-1 was 14 days and to platelets > 20 x 10(9) l-1 was 10 days. There was no procedure-related mortality, and the major morbidity was mucositis (WHO grade 3-4) in 18/32 patients (56%). In a patient group of which the majority had very poor prognostic features, the median survival from start of induction chemotherapy was 15 months. Thus, PBPC mobilisation and support of high-dose chemotherapy is feasible after infusional induction chemotherapy for patients with metastatic breast cancer, although the optimum drug combination has not yet been determined.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Central Nervous System Neoplasms; Chi-Square Distribution; Confidence Intervals; Diarrhea; Disease-Free Survival; Etoposide; Female; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Herpes Zoster; Humans; Liver Neoplasms; Lung Neoplasms; Melphalan; Middle Aged; Neoplasm Staging; Survival Rate; Thiotepa; Treatment Outcome

This prospective multicenter randomized trial was performed to compare the effectiveness and safety of intravenous (i.v.) vinorelbine tartrate (Navelbine [NVB]; Burroughs Wellcome Co, Research Triangle Park, NC) with i.v. melphalan (Alkeran [ALK]; Burroughs Wellcome Co) in a heavily pretreated population of patients with anthracycline-refractory advanced breast cancer (ABC). Efficacy end points included time to disease progression (TDP), time to treatment failure (TTF), survival, tumor response rates, and quality of life (QL) and relief of cancer-related symptoms.. Between August 24, 1990, and December 1, 1992, 183 patients were randomized (2:1) to treatment with NVB (30 mg/m2 weekly) or ALK (25 mg/m2 every 4 weeks) i.v. Patients were stratified by measurable or nonmeasurable-assessable disease and by treatment center.. Time to disease progression was significantly longer with NVB than with ALK, with a median 12 weeks versus 8 weeks, respectively (P < .001). NVB patients also had significantly longer time to treatment failure than ALK patients, with a median 12 weeks versus 8 weeks, respectively (P < .001). The effect of NVB on survival was also statistically significant (P = .034): 1-year survival rates were 35.7% with NVB and 21.7% with ALK and the median survival rate was 35 weeks and 31 weeks, respectively. In total, 46.5% of NVB patients and 28.2% of ALK patients achieved an objective response or stabilization of disease (P = .06). No intergroup differences were noted in patient-assessed QL and cancer-related symptoms. The most common toxicities were hematologic, including granulocytopenia with NVB and thrombocytopenia and granulocytopenia with ALK. Both drugs were generally well tolerated, and no septic deaths were reported.. This randomized trial demonstrates a survival benefit in anthracycline-refractory ABC. NVB was well tolerated and demonstrated activity superior to ALK in anthracycline-refractory ABC, without compromising QL. Based on activity of single-agent NVB in this difficult-to-treat patient population, investigations of NVB in combination with other anticancer drugs are warranted.

Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Disease Progression; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Hematologic Diseases; Humans; Injections, Intravenous; Melphalan; Middle Aged; Proportional Hazards Models; Prospective Studies; Quality of Life; Survival Rate; Vinblastine; Vinorelbine

Four hundred forty previously untreated patients with active multiple myeloma were entered into a randomized trial (Southwest Oncology Group [SWOG] study 7927/28) comparing vincristine, melphalan, Cytoxan (Mead Johnson & Company, Evansville, Ind), and prednisone (VMCP) alternating with vincristine, BCNU, Adriamycin (Adria Laboratories, Columbus, Ohio) and prednisone (VBAP) with or without levamisole with vincristine, Cytoxan, and prednisone (VCP) with or without levamisole for induction therapy. The treatment groups were well balanced for all of the known major prognostic factors. Patients receiving VMCP-VBAP responded (greater than or equal to 75% regression) more frequently to induction therapy, both without (54%) and with (44%) levamisole v VCP without (28%) or with (28%) levamisole (P less than .001). In addition, patients receiving VMCP-VBAP (+/- levamisole) had a survival duration determined to be significantly increased by all forms of analysis: 48 and 33 months for VMCP-VBAP without and with levamisole v 29 and 26 months for VCP without and with levamisole (P = .011 overall). Levamisole did not improve response rates or survival duration (P greater than or equal to .1), nor did it prolong remission in the maintenance phase (P = .85). Analysis of SWOG study 7704/05 (updated April 1985) confirmed improved survival for combination therapy v MP, but no benefit for levamisole. The overall findings support the use of VMCP-VBAP as an excellent treatment option for remission induction in patients with active myeloma of all stages and prognostic categories.

Topics: Actuarial Analysis; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Hematologic Diseases; Humans; Levamisole; Melphalan; Multiple Myeloma; Neoplasm Staging; Prednisone; Prognosis; Random Allocation; Vincristine

Daratumumab is a CD38-targeting monoclonal antibody approved for intravenous (IV) infusion for multiple myeloma (MM). We describe the Phase II PLEIADES study of a subcutaneous formulation of daratumumab (DARA SC) in combination with standard-of-care regimens: DARA SC plus bortezomib/lenalidomide/dexamethasone (D-VRd) for transplant-eligible newly diagnosed MM (NDMM); DARA SC plus bortezomib/melphalan/prednisone (D-VMP) for transplant-ineligible NDMM; and DARA SC plus lenalidomide/dexamethasone (D-Rd) for relapsed/refractory MM. In total, 199 patients were treated (D-VRd, n = 67; D-VMP, n = 67; D-Rd, n = 65). The primary endpoints were met for all cohorts: the ≥very good partial response (VGPR) rate after four 21-day induction cycles for D-VRd was 71·6% [90% confidence interval (CI) 61·2-80·6%], and the overall response rates (ORRs) for D-VMP and D-Rd were 88·1% (90% CI 79·5-93·9%) and 90·8% (90% CI 82·6-95·9%). With longer median follow-up for D-VMP and D-Rd (14·3 and 14·7 months respectively), responses deepened (ORR: 89·6%, 93·8%; ≥VGPR: 77·6%, 78·5%), and minimal residual disease-negativity (10

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Combined Modality Therapy; Dexamethasone; Female; Follow-Up Studies; Hematologic Diseases; Humans; Immunotherapy; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Standard of Care; Treatment Outcome

Hematopoietic stem cell allograft is a treatment for patients with severe constitutional or acquired hematopoietic system diseases. This act is always linked to complications requiring multidisciplinary care. Our study describes the post-allograft cutaneous complications.. A prospective study was conducted at the Hematology department of "20 Août Hospital" in Casablanca during a period going from January 2018 to December 2020; including all patients who presented acute or chronic cutaneous complications post-allograft.. Twenty-five patients were included. All patients received induction chemotherapy (Busulfan/Fludarabine or Busulfan/Melphalan). A skin infection was found in 8 patients : four cases of Malassezia folliculitis, one case of perineal zona, one case of genital herpes, one case of varicella and one case of Candida sepsis. The acute graft versus host reaction was found in 3 patients, revealed by an erythematous rash all over the body. The chronic graft versus host reaction was found in five patients on a lichenoid form. Nine patients had a hyperpigmentation of the folds followed by detachment in the same areas, concluding to a Busulfan toxidermy.. Hematopoietic stem cell allograft has many complications. The literature mainly specifies hematological and digestive complications, while skin complications are little described. Our series is special by reporting different types and mechanisms of skin complications that can occur; with a predominance of skin graft-on-host reactions and infections. It also reports an unusual Busulfan toxidermy.

Topics: Acute Disease; Adolescent; Adult; Allografts; Busulfan; Candidiasis; Chickenpox; Child; Chronic Disease; Dermatomycoses; Female; Graft vs Host Disease; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Herpes Genitalis; Humans; Induction Chemotherapy; Malassezia; Male; Melphalan; Middle Aged; Morocco; Prospective Studies; Skin Diseases; Skin Diseases, Infectious; Vidarabine; Young Adult

Topics: Adult; Aged; Busulfan; Cord Blood Stem Cell Transplantation; Disease-Free Survival; Female; Hematologic Diseases; Humans; Male; Melphalan; Middle Aged; Risk Factors; Survival Rate; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation

Novel agents in combination with melphalan and prednisone (MP) significantly improved progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM). Randomized trials comparing MP plus bortezomib (VMP) versus MP plus thalidomide (MPT) are lacking. Nine hundred and fifty-six elderly (>65 years) newly diagnosed MM patients from six European randomized trials were retrospectively analyzed and matched for age, albumin, and beta2-microglobulin at diagnosis, 296 patients were selected from the VMP groups, and 294 from MPT. Complete response rate was 21% in the VMP patients and 13% in the MPT patients (P = 0.007). After a median follow-up of 34 months (range, 1-92), VMP significantly prolonged both PFS (median 32.5 vs. 22.9 months, HR 0.65; 95% CI 0.52-0.82; P < 0.001) and OS (median 79.7 vs. 45.1 months, HR 0.44; 95% CI 0.32-0.59; P < 0.001) in comparison with MPT. The benefit in terms of OS of the VMP group was quite similar among patients with different risk factors defined by sex, ISS, ECOG performance status, or serum creatinine but not among patients ≥ 75 years. Multivariate analysis confirmed that VMP was an independent predictor of longer PFS and OS. In a control-case matched analysis, PFS and OS were prolonged in patients who received VMP in comparison with those treated with MPT.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Case-Control Studies; Disease-Free Survival; Drug Evaluation; Female; Hematologic Diseases; Humans; Kaplan-Meier Estimate; Male; Melphalan; Multiple Myeloma; Nervous System Diseases; Prednisone; Prognosis; Proportional Hazards Models; Pyrazines; Randomized Controlled Trials as Topic; Retrospective Studies; Thalidomide; Treatment Outcome

High-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) is considered standard in the treatment of patients with relapsed or refractory aggressive peripheral T cell lymphoma (PTCL). However, the optimal salvage regimen before ASCT has not yet been established. We retrospectively analyzed 31 patients with relapsed or refractory aggressive PTCL after anthracycline-based first-line chemotherapy who received either DexaBEAM (dexamethasone, carmustine, etoposide, cytarabine, and melphalan; n = 16) or ICE (ifosfamide, carboplatin, and etoposide; n = 15) regimen as first salvage chemotherapy followed by HDT/ASCT. The overall response rate (OR) was significantly higher for patients treated with DexaBEAM (69 %; 95 % confidence interval 46.0-91.5 %) as compared to the ICE group (20 %; 95 % confidence interval -0.2-40.2 %; P = 0.01), with higher complete response (CR; 38 %; 95 % confidence interval 13.8-61.2 %; vs. 7 %; 95 % confidence interval -6.0-19.6 %) as well as partial response (PR; 31 vs. 13 %) rate. Changing regimen due to failure of first salvage therapy, 12 patients initially receiving ICE still achieved an OR of 58 % (33 % CR, 25 % PR) with DexaBEAM as second salvage therapy, whereas in three patients receiving ICE after DexaBEAM failure, only one achieved an OR (1 PR). Median progression-free survival was significantly higher in the DexaBEAM group (6.4 vs. 2 months; P = 0.01). Major adverse event in both groups was myelosuppression with higher but tolerable treatment-related toxicity for patients in the DexaBEAM group. For all patients proceeding to HDT/ASCT, a 3-year overall survival was 50 %. Together, considering the limitations of the retrospective design of the evaluation and the small sample size, our data suggest that DexaBEAM salvage chemotherapy is superior to ICE for patients with relapsed or refractory aggressive PTCL for remission induction prior to autologous transplantation, with higher but manageable treatment-related toxicity.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carmustine; Combined Modality Therapy; Cytarabine; Dexamethasone; Disease-Free Survival; Drug Evaluation; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Hematologic Diseases; Hematopoietic Stem Cell Mobilization; Humans; Ifosfamide; Kaplan-Meier Estimate; Lymphoma, T-Cell, Peripheral; Male; Melphalan; Middle Aged; Mucositis; Peripheral Blood Stem Cell Transplantation; Preoperative Care; Retrospective Studies; Salvage Therapy; Transplantation, Autologous; Treatment Outcome; Young Adult

We retrospectively investigated the efficacy and predictive factors for the treatment outcomes of bortezomib plus dexamethasone (BD) as second-line induction therapy prior to high-dose chemotherapy supported by autologous stem cell transplantation (HDT/ASCT) in multiple myeloma (MM) patients.. Sixty-six transplant eligible MM patients treated by the Kyoto Clinical Hematology Study Group between 2006 and 2011 were investigated. Conventional induction chemotherapy, including vincristine, doxorubicin and dexamethasone (VAD) and high-dose dexamethasone (HDD), was used as first-line induction therapy in all patients, seven (10.6%) of whom attained a very good partial response (VGPR). Of the 59 patients who did not attain VGPR with VAD or HDD, 33 were given BD as second-line induction therapy prior to HDT/ASCT.. Patients not treated with BD induction showed an overall response rate (ORR, i.e., better than partial response) of 85.3% after induction therapy, while the ORR of patients treated with BD induction improved from 42.4% after conventional induction therapy to 84.8% after BD. The overall survival (OS) and progression-free survival (PFS) of patients not treated with BD induction were not significantly influenced by the response to induction therapy. Among the patients treated with BD, failure in attaining VGPR prior to ASCT was associated with a significantly shorter PFS and it also tended to show a shorter OS, while the disease stage and achievement of a complete response after HDT/ASCT had no impact on OS or PFS.. The achievement of at least VGPR with second-line BD induction therapy is a prerequisite for attaining longer OS and PFS after HDT/ASCT.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Chromosome Aberrations; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Female; Forecasting; Hematologic Diseases; Humans; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Peripheral Nervous System Diseases; Prednisone; Pyrazines; Remission Induction; Retrospective Studies; Transplantation, Autologous; Treatment Outcome; Vincristine

Renal impairment (RI) is a severe complication throughout the course of multiple myeloma (MM). Bortezomib has been shown to be highly active in MM patients with RI. We designed this retrospective analysis to investigate the safety and efficacy of bortezomib-based therapy in 117 MM patients with RI, 14 cases required dialysis. A total of 603 cycles of bortezomib were administered (median number, five cycles/patient). Ten patients required early discontinuation of bortezomib because of WHO grade IV toxicity. The rate of bortezomib discontinuation in cases with severe, moderate and mild RI was 11%, 5% and 0%, respectively (P = NS). Overall, 91 episodes of WHO grade III/IV toxicity were observed. At least a partial response was documented in 83/113 evaluable patients (73%), including complete response (19%) and near complete response (8%). The overall response rate was similar across RI subgroups. Reversal of RI was documented in 41% of patients after a median of 2.3 months (range 0.4-7.9). In three of 14 patients on dialysis, renal replacement therapy was discontinued after 1, 1 and 4 months. The 2-yr estimate of response duration and overall survival was 70% and 51%, respectively. In conclusion, bortezomib-based regimens are safe and effective and should be considered as appropriate treatment options for MM patients with any degree of RI.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cardiovascular Diseases; Clinical Trials as Topic; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Follow-Up Studies; Gastrointestinal Diseases; Glomerular Filtration Rate; Hematologic Diseases; Humans; Italy; Kidney Diseases; Male; Melphalan; Middle Aged; Multicenter Studies as Topic; Multiple Myeloma; Neoplasm Proteins; Peripheral Nervous System Diseases; Protease Inhibitors; Proteasome Inhibitors; Pyrazines; Retrospective Studies; Survival Analysis; Thalidomide

Between April 2006 and June 2009, 34 newly diagnosed patients with multiple myeloma received one to three courses of bortezomib 1.3 mg/m(2) i.v. four times, lenalidomide 25 mg p.o. daily for 21 days and dexamethasone 20 mg/m(2) p.o. for 4 days beginning on days 1, 9 and 17 (BLD). There was rapid onset of remission in 30 patients (88%) similar to the frequency of 87% induced by a previous combination of bortezomib-thalidomide-dexamethasone (BTD). After a median of 3.6 months, 28 patients received intensive therapy with high-dose melphalan supported by autologous blood stem cells, so that the overall frequency of complete remission (CR) was 44%, similar to the frequency of 37% observed previously. Side effects due to thalidomide with previous BTD were less frequent and severe with BLD. The combination of BLD given for one or two courses was an effective primary treatment for newly diagnosed patients with multiple myeloma.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Combined Modality Therapy; Dexamethasone; Drug Evaluation; Female; Hematologic Diseases; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Nervous System Diseases; Peripheral Blood Stem Cell Transplantation; Pyrazines; Remission Induction; Retrospective Studies; Thalidomide; Time Factors; Transplantation, Autologous

The purpose of this study was to analyse our experience of early discharge 2 days after high-dose melphalan (HDM) (Day-1) followed by peripheral blood stem cell re-infusion (Day-0) and re-admission on Day +5 in patients with hematological diseases or solid tumors. From 2000 to November 2005, seven patients received tandem Melphalan 200 mg/m(2) HDM with peripheral blood stem cells transplantation (PBSC-T), 130 a single HDM, for a total of 144 procedures. In 123 of them, patients were discharged on Day +1 for re-admission on Day +5 or earlier in the event of complications. Antibiotic prophylaxis was not used. Patients were hospitalised in positive-pressure reverse isolation room during the neutropenic period. Of the 123 procedures eligible for our mixed inpatient-outpatient management regimen, six (5%) required early re-admission for complications. Full engraftment was achieved in all cases. Median time to neutrophil count >0.5 x 10(9)/microL and >1 x 10(9)/microL were 12 and 14 days, respectively. Median time to platelet recovery (>20 x 10(9)/microL) was 13 days. Severe extra-hematological toxicities occurred in 78 (63%) patients: all had oral mucositis and five had associated diarrhoea. During hospitalisation, 94/123 (76%) experienced febrile neutropenia, 20/94 (21%) had documented infection and 74/94 (79%) were considered fever of unknown origin. Median fever duration was 1 day (range 0-11). Median duration of antibiotic treatment was 6 days (range 3-26). Median time to discharge (from Day 0) was 16 days (range 11-57). There was no mortality by on Day +100. Our experience of early discharge after HDM and PBSC-T with re-admission on Day +5 is safe and feasible with acceptable frequency of hematological and extra-hematological toxicities. The regimen allows reduced hospital stay and hence cost savings.

Topics: Adolescent; Adult; Aged; Female; Hematologic Diseases; Humans; Infusions, Parenteral; Male; Melphalan; Middle Aged; Neoplasms; Patient Discharge; Peripheral Blood Stem Cell Transplantation; Time Factors

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

We retrospectively evaluated the outcome of reduced-intensity conditioning (RIC) followed by allogeneic hematopoietic stem cell transplantation (HCT) in 43 patients with myelodysplastic syndrome (MDS) or AML arising from MDS. All patients received fludarabine plus melphalan followed by an allogeneic HCT from an HLA-identical sibling (SIB: n=19) or unrelated donor (MUD: n=24). Median age was 58 years (range: 30-71). Diagnoses at transplantation were RA (n=8), RARS (n=1), RAEB (n=13), RAEB-T (n=6), or AML arising from MDS (n=15). Of 28 patients with MDS, two patients had low, 10 had intermediate-1, nine had intermediate-2 and seven had high-risk MDS by IPSS criteria. All patients initially engrafted with the median neutrophil recovery of 15 days (range: 9-27). The 2-year overall survival, disease-free survival, relapse and transplant-related mortality were 53.5% (CI 45.2-61.1), 51.2% (CI 43.3-58.5), 16.3% (CI 7.9-30.7) and 35.2% (26.4-45.7), respectively. Grade II-IV acute graft-versus-host disease occurred in 27 (63%) patients. There was no significant survival difference between SIB and MUD-HCT, but the relapse rate was higher among SIB donor recipients when compared to MUD (38.5 versus 7%, P=0.02). RIC with fludarabine plus melphalan was associated with durable disease control and acceptable toxicity in this high-risk cohort.

Topics: Adult; Aged; Graft Survival; Graft vs Host Disease; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Myelodysplastic Syndromes; Retrospective Studies; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

Liver injury is a common complication in allogeneic hematopoietic stem cell transplantation. Its major causes comprise graft-versus-host disease (GVHD), infection, and toxicities of preparative regimens and immunosuppressants; however, we have little information on liver injuries after reduced intensity cord blood transplantation (RICBT). We reviewed medical records of 104 recipients who underwent RICBT between March 2002 and May 2004 at Toranomon Hospital. Preparative regimen and GVHD prophylaxis comprised fludarabine/melphalan/total body irradiation and cyclosporine or tacrolimus. We assessed the etiology of liver injuries based on the clinical presentation, laboratory results, comorbid events, and imaging studies in 85 patients who achieved primary engraftment. The severity of liver dysfunction was assessed according to the National Cancer Institute Common Toxicity Criteria version 2.0. Hyperbilirubinemia was graded according to a report by Hogan et al (Blood. 2004;103:78-84). Moderate to very severe liver injuries were observed in 36 patients. Their causes included cholestatic liver disease (CLD) related to GVHD or sepsis (n = 15), GVHD (n = 7), cholangitis lenta (n = 5), and others (n = 9). Median onsets of CLD, GVHD, and cholangitis lenta were days 37, 40, and 22, respectively. Frequencies of grade 3-4 alanine aminotransferase elevation were comparable across the 3 types of hepatic injuries. Serum gamma-glutamil transpeptidase was not elevated in any patients with cholangitis lenta, whereas 27% and 40% of patients with CLD and GVHD, respectively, developed grade 3-4 gamma-glutamil transpeptidase elevation. Multivariate analysis identified 2 risk factors for hyperbilirubinemia; grade II-IV acute GVHD (relative risk, 2.23; 95% confidential interval, 1.11-4.47; P = .024) and blood stream infection (relative risk, 3.77; 95% confidential interval, 1.91-7.44; P = .00013). In conclusion, the present study has demonstrated that the hepatic injuries are significant problems after RICBT, and that GVHD and blood stream infection contribute to their pathogenesis.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacterial Infections; Busulfan; Chemical and Drug Induced Liver Injury; Cholangitis; Cord Blood Stem Cell Transplantation; Cyclosporine; Female; Hematologic Diseases; Hematologic Neoplasms; Hepatic Veno-Occlusive Disease; Humans; Hyperbilirubinemia; Immunosuppressive Agents; Incidence; Infant, Newborn; Liver Diseases; Liver Function Tests; Male; Melphalan; Middle Aged; Postoperative Complications; Risk Factors; Tacrolimus; Tissue Donors; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation

Topics: Antineoplastic Agents, Alkylating; Graft Rejection; Granulocyte Precursor Cells; Hematologic Diseases; Humans; Immunosuppressive Agents; Melphalan; Stem Cell Transplantation; Transplantation Conditioning; Vidarabine

Children with Wilms tumor who have a particular risk of failure at relapse or at primary diagnosis were treated with high-dose chemotherapy (HDC) and autologous peripheral blood stem cell rescue in order to improve their probability of survival. From April 1992 to December 1998, 23 evaluable patients received HDC within the German Cooperative Wilms Tumor Studies. Nineteen were given melphalan, etoposide and carboplatin (MEC); the others received different regimens. The dose of carboplatin was adjusted according to renal function. Indications for HDC were high-risk relapse in 20 patients, bone metastases in two patients and no response in one patient. Fourteen of 23 patients are alive after a median observation time of 41 months, 11 of 14 in continuous complete remission, three in CR after relapse post HDC. The estimated survival and event-free survival for these patients are 60.9% and 48.2%. Twelve children relapsed after HDC; nine of them died within 12 months and three are surviving from 20 to 33 months after relapse. The main toxicities were hematologic, mucositis and renal (tubular dysfunction; intermittent hemodialysis in one patient). There were no toxic deaths. About half of the children suffering from Wilms tumor with very unfavorable prognostic factors survive disease-free after HDC for over 3 years. Besides hematological toxicity, mucositis and infections, renal function is at risk during HDC. With dose adjustment on glomerular filtration rate, however, no permanent renal failure was observed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Etoposide; Female; Germany; Hematologic Diseases; Humans; Ifosfamide; Infant; Kidney Diseases; Kidney Neoplasms; Life Tables; Lung Neoplasms; Male; Melphalan; Peripheral Blood Stem Cell Transplantation; Prognosis; Stomatitis; Survival Analysis; Thiotepa; Transplantation, Autologous; Wilms Tumor

To evaluate the use of high-dose busulfan (HDB) with autologous bone marrow transplantation (ABMT) in patients with myeloma.. Fifteen patients received HDB (16 mg/kg), eight of whom received high-dose melphalan (HDM) but had experienced a short remission or progression-free interval. Two patients had received HDM on two previous occasions, one had no response to low-dose melphalan, and four had impaired renal function (edathamil clearance < 40 mL/min). All patients received induction chemotherapy before HDB.. Two patients were in complete remission (CR) after induction chemotherapy before HDB. Of the remaining 13 patients, four (31%) achieved CR and two (15%) achieved a partial remission for an overall response rate of 46%. There were three treatment-related deaths, but the toxicity was otherwise predictable and manageable.. In heavily pretreated patients, HDB results in a relatively high response rate. It can also be used safely in patients with renal impairment who are not suitable for HDM.

Topics: Adult; Bone Marrow Transplantation; Busulfan; Combined Modality Therapy; Creatinine; Female; Hematologic Diseases; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Pilot Projects; Remission Induction; Transplantation, Autologous

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

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

Fifty-nine patients received 61 courses of cyclophosphamide, cisplatin, and carmustine combined. The phase I study consisted of seven dose escalations. Dose levels 5 and 6 also included the attempted addition of melphalan at 40 and 80 mg/m2. The maximum tolerated dose for the three-drug combination was 5620 mg/m2 of cyclophosphamide, 165 mg/m2 of cisplatin, and 600 mg/m2 of carmustine. The dose-limiting toxic effect was fatal veno-occlusive disease of the liver in two of five patients treated at the highest dose level. Veno-occlusive disease of the liver was fatal in two of 40 patients treated at Dose level 4, the maximum tolerated dose. The median time to recovery of polymorphonuclear leukocyte counts to greater than 500/microliters and platelet counts to transfusion independence greater than 20,000/microliters was 19 and 22 days, respectively, after marrow reinfusion. Other toxic effects observed included postdischarge pulmonary toxicity, which appeared to respond to prednisone therapy. Thus, this combination of alkylating agents can be combined at close to the transplant dose of each individual agent. The response rate was high despite considerable prior treatment in most patients. Of 16 evaluable patients with breast cancer, 15 responded (six complete responses). Of six evaluable patients with sarcoma, six responded (one complete response). While patients with melanoma had had no prior treatment, 11 of 17 patients responded (65%). There are currently three patients who are disease-free. Two patients with melanoma were rendered disease-free by excisional biopsy of the only remaining nodule after good partial response, and a patient with metastatic breast cancer remains disease-free after a complete response at 36+ months.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Carmustine; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Drug Evaluation; Female; Hematologic Diseases; Humans; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasms; Statistics as Topic

Dose-effect relationships of high-dose melphalan were evaluated in 37 patients with measurable relapsed or refractory acute leukemias. Thirteen patients (Group 1) received 70-100 mg/m2 of melphalan without marrow rescue and 24 patients (Group 2) received 140-180 mg/m2 of melphalan followed by marrow transplantation. Patients in both groups were comparable with respect to age, sex, diagnosis, and status of the leukemia. The complete remission rate was 23% in Group 1 versus 75% in Group 2 (P less than 0.01). Hematological recovery of remission patients was not statistically different in either group. Nonhematological toxicity was comparable in the two dose ranges examined. These results demonstrate the existence of a dose-response effect of high-dose melphalan regimens in relapsed acute leukemias, without marked increases in nonhematological toxicity with these doses.

Topics: Acute Disease; Adolescent; Adult; Aged; Bone Marrow; Bone Marrow Transplantation; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Hematologic Diseases; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Retrospective Studies

Colon carcinoma, the second leading cause of cancer-related deaths in the United States, is resistant to chemotherapy in a large majority of cases. Single-agent and combination chemotherapy have failed to prolong survival. New approaches are clearly needed. In experimental models, a steep dose-response curve for colorectal cancer has been demonstrated using various agents. The hematopoietic toxicity of high-dose therapy with these drugs can be circumvented by autologous bone marrow transplantation. We investigated the use of high-dose melphalan with autologous bone marrow rescue in 20 patients with metastatic colon carcinoma. Each patient received melphalan, 180 mg/m2 intravenously (IV), followed eight hours later by bone marrow infusion. Median duration of granulocytopenia (less than 500 neutrophils/microL) was twelve days (range, 5 to 35 days), while transfusion-dependent thrombocytopenia (less than 20,000 platelets/microL) had a median duration of eight days (range, 3 to 23 days). Time to bone marrow engraftment was not affected by prior 5-fluorouracil therapy. Nausea and vomiting occurred in 14 patients but was generally short lived. Mild stomatitis, esophagitis, and diarrhea were common. Severe gastrointestinal (GI) side effects did not occur. One treatment-related death occurred secondary to intramural tumor necrosis, which resulted in massive lower GI bleeding. Complete responses were observed in three patients (15%) and partial responses in six patients (30%), for an overall response rate of 45%. Median survival was 198 days in this group of patients with extensive disease. High-dose melphalan therapy for metastatic colon carcinoma, when used with autologous bone marrow transplantation, appears to achieve a high response rate with tolerable toxicity. Further investigation is needed to define the role of this therapy in the care of advanced colon carcinoma.

Topics: Adult; Aged; Bone Marrow Transplantation; Colonic Neoplasms; Combined Modality Therapy; Drug Evaluation; Gastrointestinal Diseases; Hematologic Diseases; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Tomography, X-Ray Computed

Thirty-six patients with lung cancer, 24 with prior chemotherapy and 12 without prior chemotherapy, received iv melphalan at doses ranging from 20 to 40 mg/m2 of body surface area. Patients who showed moderate myelosuppression and remained in the study were also investigated to determine if cyclophosphamide (300 mg/m2) administered 1 week before the identical dose of i.v. melphalan modified the hematopoietic toxicity of melphalan (cyclophosphamide priming). In this study, the activity of melphalan was minimal, four minor responses with no partial or complete responses. Three of these minor responses were in previously untreated patients. The major toxicity was hematopoietic and the maximum tolerated i.v. dose was 20 mg/m2 in the patients previously treated with chemotherapy and 30 mg/m2 in those without prior chemotherapy. Cyclophosphamide priming did not reduce the myeloid toxicity. Myelosuppression was more severe in the course that included cyclophosphamide. Recovery, however, appeared to be similar in both courses. I.v. melphalan at these doses has minimal activity in lung cancer. Cyclophosphamide administered 1 week before i.v. melphalan does not decrease the myelosuppression but should be investigated further for its effect on the rate of wbc and neutrophil count recovery.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Bronchogenic; Cyclophosphamide; Female; Hematologic Diseases; Humans; Leukocyte Count; Lung Neoplasms; Male; Melphalan; Middle Aged; Nausea; Neutrophils; Platelet Count

A clinical evaluation of peptichemio (40-45 mg/m2/day for 3 days every 3-4 weeks) was conducted in 32 patients with advanced breast cancer, 28 of whom were evaluable for both toxicity and response. The overall response rate was 18% (one complete remission and four partial remissions), with a median duration of 4 months (range, 2-6). The major side effects were cumulative myelotoxicity, phlebitis, mild nausea, and vomiting. A posttreatment heparin infusion was used to prevent phlebitis.

Topics: Breast Neoplasms; Drug Administration Schedule; Drug Evaluation; Female; Hematologic Diseases; Heparin; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Peptichemio; Thrombophlebitis

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Child; Child, Preschool; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Hematologic Diseases; Humans; Infant; Male; Melphalan; Neuroblastoma; Teniposide

Fifty-seven patients with metastatic breast carcinoma have been treated with mitomycin C (10 mg/m2 IV 6-weekly), melphalan (6 mg/m2 PO X 3 days, 3-weekly), and methotrexate (35 mg/m2 IV 3-weekly) to assess the efficacy and toxicity of this regimen. Of 48 evaluable patients 19 (40%) responded for a median period of 5 months and 12 (25%) had stabilisation of disease. Of the 12 patients previously treated with adriamycin only one responded, whereas 18 of the 36 patients without previous chemotherapy responded. Although healing of bone metastases was infrequent control of hypercalcaemia was commonly seen. Generally the treatment was well tolerated and treatment was stopped in only five patients because of toxicity. Cumulative marrow toxicity was observed but was not a significant problem in the first 6 months of treatment. Mitomycin C, melphalan, and methotrexate (MMM) appears to provide an effective, well tolerated chemotherapy combination for metastatic breast carcinoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Evaluation; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Melphalan; Methotrexate; Middle Aged; Mitomycin; Mitomycins; Neoplasm Metastasis; Palliative Care

A 40-year-old woman had cryocrystalglobulinemia with IgG2(K1). To date, 27 other cases of spontaneous crystallization of a plasma protein have been reported. In all, the protein, a cryoglobulin, has been found to be an IgG molecule. The disease most commonly associated with this phenomenon has been multiple myeloma. None of the patients have had Raynaud's phenomenon, but many have had purpuric skin lesions made worse by exposure to cold. In the two cases of essential cryocrystalglobulinemia, crystals were found in the peripheral blood film. Immunologic, biochemical and ultrastructural studies have so far not demonstrated any property common to all cryocrystalglobulins.

Topics: Adult; Cryoglobulins; Crystallization; Cyclophosphamide; Female; Hematologic Diseases; Humans; Melphalan; Prednisone

Topics: Extracorporeal Circulation; Extremities; Hematologic Diseases; Humans; Melphalan; Neoplasms; Perfusion; Regional Blood Flow; Thiotepa

Topics: Chemotherapy, Cancer, Regional Perfusion; Coccidioidomycosis; Dactinomycin; Drug Hypersensitivity; Drug Therapy; Hematologic Diseases; Humans; Melanoma; Melphalan; Mycetoma; Neoplasms; Sarcoma; Sepsis; Toxicology