melphalan and Acute-Disease

Drug-induced liver injury (DILI) is a leading cause of liver failure and an important safety issue in drug development. Thalidomide is nowadays used for the treatment of several conditions including multiple myeloma (MM). Several adverse effects have been described but liver toxicity was seldom reported. We describe a case of thalidomide-induced hepatitis in a man treated for MM. The clinical setting and temporal association between the start of the drug and liver injury allowed the assumption of the causative role of thalidomide. As its clinical indications expand we wish to increase awareness of a new potential side effect of thalidomide. A short review on thalidomide-induced liver injury is also presented.

Topics: Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Chemical and Drug Induced Liver Injury; Darbepoetin alfa; Diazepam; Erythropoietin; Fatal Outcome; Humans; Jaundice, Obstructive; Liver Function Tests; Male; Melphalan; Multiple Myeloma; Omeprazole; Pneumonia; Polypharmacy; Prednisolone; Thalidomide

Topics: Acute Disease; Cyclophosphamide; Cytarabine; Etoposide; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Melphalan; Recurrence; Risk; Transplantation Conditioning; Transplantation, Homologous; Whole-Body Irradiation

The incidence of secondary myelodysplasia/acute myeloid leukemia (AML) was retrospectively assessed in an international joint study in 305 node-positive breast cancer patients, who received mitoxantrone-based high-dose chemotherapy (HDCT) followed by autologous stem cell support as adjuvant therapy. The median age of the patients was 57 years (range 22-67). In all, 268 patients received peripheral blood stem cells, and 47 patients received autologous bone marrow. After a median follow-up of 57 months (range 10-125), three cases of secondary AML (sAML) were observed, resulting in a cumulative incidence of 0.94%. One case of sAML developed 18 months after HDCT (FAB M3) The karyotype was translocation 15;17 and, after induction therapy, the patient underwent autologous stem cell transplantation, and is in complete remission (CR) of both breast cancer and AML. The second patient developed AML (FAB M4eo with inversion 16) 5 months after HDCT. This patient achieved CR after induction therapy, but died of infectious complication. A third patient developed AML (FAB M4) 6 months after HDCT. She achieved CR after induction therapy, but relapsed and expired 28 months after diagnosis of AML. sAML after mitoxantrone-based HDCT is a possible, but rare complication in breast cancer patients.

Topics: Acute Disease; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Epirubicin; Female; Humans; Incidence; Leukemia, Myeloid; Leukemia, Myelomonocytic, Acute; Leukemia, Promyelocytic, Acute; Leukemia, Radiation-Induced; Lymphatic Metastasis; Melphalan; Middle Aged; Mitoxantrone; Neoplasms, Second Primary; Paclitaxel; Peripheral Blood Stem Cell Transplantation; Radiotherapy, Adjuvant; Thiotepa; Transplantation Conditioning; Transplantation, Autologous

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

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

A case of acute interstitial pneumonia with hypoxaemia is described; this occurred after the cessation of cortico steroids in a patient suffering from myeloma treated with melphalan. The absence of any microbes and the lymphocytosis in the bronchoalveolar lavage and the rapid and favourable improvement on cortico steroids led to a diagnosis of melphalan induced pneumonia. This acute form is probably due to a hypersensitivity mechanism and should be distinguished from the majority of cases of sub-acute fibrosing pneumonitis due to melphalan which have been published before. Urgent treatment with glucocorticoids is justified as well as the immediate and final cessation of the medication responsible, because it is this which will affect prognosis.

Topics: Acute Disease; Aged; Aged, 80 and over; Drug Hypersensitivity; Female; Humans; Melphalan; Pulmonary Fibrosis; Radiography

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

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

The results of a follow-up study of 112 patients with multiple myeloma are presented. Three of these patients developed acute leukaemia during the respective period of clinical observation (maximum: 11 years)--one case of acute myeloblastic leukaemia, myelomonocytic leukaemia and erythroleukaemia, respectively. For estimating the incidence of acute leukaemia in the presence of multiple myeloma an extended life table method was applied. On the basis of our data this method gave a probability of 5.9% for a patient to develop acute leukaemia at any time after the diagnosis of multiple myeloma. In a statistical discussion this result is considered to confirm the assumption of a highly increased AL-risk in patients with multiple myeloma. In a survey of the literature some important data of 100 cases with the association acute leukaemia--multiple myeloma are reported.

Topics: Acute Disease; Aged; Female; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Probability; Time Factors

Topics: Acute Disease; Adenofibroma; Animals; Carcinogens; Drug Evaluation, Preclinical; Female; Humans; Lethal Dose 50; Leukemia; Male; Mammary Neoplasms, Experimental; Melphalan; Mice; Neoplasms; Rats; Stereoisomerism

Topics: Acute Disease; Animals; Asparaginase; Burkitt Lymphoma; Child; Cyclophosphamide; Cytarabine; Dactinomycin; Daunorubicin; Fluorouracil; Humans; Leukemia; Melphalan; Mercaptopurine; Methotrexate; Mice; Oncogenic Viruses; Prednisolone; Prednisone; Vincristine

The usage of a T-cell depleted, reduced intensity conditioning (RIC) approach to haematopoietic cell transplantation (HCT) in adult patients with acute lymphoblastic leukaemia (ALL) over 40 years of age and in first complete remission (CR) has resulted in encouraging rates of event-free and overall survival in a population of adults with high risk disease. However, relapse rates remain high-with disease progression being the major cause of treatment failure. Using different, more powerful conditioning approaches is the logical next step in examining the role of RIC allogeneic HCT in adult ALL.. The ALL-RIC trial is a two-arm, phase II, multicentre, randomised clinical trial in adult patients with ALL in first or second CR, who are undergoing allogeneic HCT. Comparison of a novel RIC transplant conditioning regimen using reduced-dose total body irradiation (TBI), cyclophosphamide and alemtuzumab, is made against a standardised RIC approach using fludarabine, melphalan and alemtuzumab. The primary outcome of the study is disease-free survival at 3 years, defined as time from randomisation to the first of either relapse or death from any cause. Patients who are still alive and progression-free at the end of the trial will be censored at their last date known to be alive. Secondary outcomes include overall survival and non-relapse mortality.. The protocol was approved by the East Midlands-Leicester Central Research Ethics committee (18/EM/0112). Initial approval was received on 12 June 2018. Current protocol version (V.6.0) approval obtained on 18 November 2019. The Medicines and Healthcare products Regulatory Agency (MHRA) also approved all protocol versions. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications.. EudraCT Number: 2017-004800-23.ISRCTN99927695.

Topics: Acute Disease; Adult; Alemtuzumab; Clinical Trials, Phase II as Topic; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Multicenter Studies as Topic; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Randomized Controlled Trials as Topic; Whole-Body Irradiation

Post-transplantation cyclophosphamide (PTCY) therapy has made haploidentical transplantation a global reality in adults, but the literature is largely silent on the feasibility of this approach in children. We conducted a prospective study of 20 patients (median age, 12 years; range, 2-20 years) with advanced acute leukemia to evaluate the feasibility of PTCY-based haploidentical peripheral blood stem cell (PBSC) transplantation in children. The conditioning regimen comprised fludarabine, i.v. busulfan, and melphalan (Flu-Bu-Mel). PTCY on days +3 and +4 was followed by mycophenolate mofetil for 14-21 days and cyclosporine for 60 days. Thirteen patients (65%) had refractory or relapsed myelogenous leukemia, and the remainder had high-risk lymphoblastic leukemia. Prompt engraftment was noted at a median of 14 days, with full donor chimerism by day +28. The cumulative incidence of acute and chronic graft-versus-host disease was 35% and 5%, respectively. Nonrelapse mortality at 1 year was 20%. The incidence of disease progression was 25.7%. The actuarial overall survival at 2 years was 64.3% (95% confidence interval, 53.4%-75.2%). Our data suggest that Flu-Bu-Mel-based conditioning followed by PTCY-based haploidentical PBSC transplantation with reduced duration of immunosuppression is feasible in pediatric patients with advanced leukemia.

Topics: Acute Disease; Adolescent; Adult; Allografts; Busulfan; Child; Child, Preschool; Chronic Disease; Cyclophosphamide; Disease-Free Survival; Female; Graft vs Host Disease; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Peripheral Blood Stem Cell Transplantation; Survival Rate; Transplantation Conditioning; Vidarabine

Relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains one of the leading causes of mortality in patients with leukemia. Treatment options in this population remain limited, with concern for both increased toxicity and further relapse. We treated 18 patients with acute leukemia for marrow ± extramedullary relapse after a previous alloHSCT with a myeloablative cytoreductive regimen including clofarabine, melphalan, and thiotepa followed by a second or third transplantation from the same or a different donor. All patients were in remission at the time of the second or third transplantation. All evaluable patients engrafted. The most common toxicity was reversible transaminitis associated with clofarabine. Two patients died from transplantation-related causes. Seven patients relapsed after their second or third transplanation and died of disease. Nine of 18 patients are alive and disease free, with a 3-year 49% probability of overall survival (OS). Patients whose remission duration after initial alloHSCT was >6 months achieved superior outcomes (3-year OS, 74%, 95% confidence interval, 53% to 100%), compared with those relapsing within 6 months (0%) (P < .001). This new cytoreductive regimen has yielded promising results with acceptable toxicity for second or third transplantations in patients with high-risk acute leukemia who relapsed after a prior transplantation, using various graft and donor options. This approach merits further evaluation in collaborative group studies.

Topics: Acute Disease; Adenine Nucleotides; Adolescent; Adult; Arabinonucleosides; Child; Child, Preschool; Clofarabine; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Melphalan; Myeloablative Agonists; Remission Induction; Salvage Therapy; Survival Analysis; Thiotepa; Transplantation, Homologous; Young Adult

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

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

The aim of this prospective study was to investigate the feasibility of reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (SCT) in 37 adults with high-risk acute lymphoblastic leukemia (ALL) in first (n=30) or second (n=7) complete remission (CR). All patients were treated with fludarabine (150 mg/m(2)) and melphalan (140 mg/m(2)) followed by transplantation from matched sibling (n=27) or unrelated (n=10) donors. The indications for reduced-intensity conditioning allogeneic SCT (RIC-SCT) were as follows: (1) > or = 50 years, 16 (43.2%) and (2) decreased organ function or active infections, 21 (56.8%). Graft-versus-host disease (GVHD) prophylaxis consisted of calcineurin inhibitor (cyclosporine for sibling and tacrolimus for unrelated transplants) and methotrexate. The cumulative incidence of acute (grades II-IV) and chronic GVHD was 43.2 and 65.6%, respectively. After a median follow-up of 36 months for surviving transplants, the 3-year relapse, non-relapse mortality, disease-free survival and overall survival rates were 19.7, 17.7, 62.6 and 64.1%, respectively. Transplants in first CR showed better transplantation outcomes than those in second CR. The potential of antileukemic activity of chronic GVHD was also found. This study suggests that RIC-SCT is a potential therapeutic approach for adults with high-risk ALL in remission who are ineligible for myeloablative transplantation.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Feasibility Studies; Female; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Remission Induction; Risk Factors; Survival Rate; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine; Young Adult

This prospective phase II study evaluated toxicity, relapse rate, progression-free survival, and overall survival after allogeneic transplantation and conditioning with fludarabine, melphalan, and alemtuzumab in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).. Fifty-two consecutive adults with AML and MDS were enrolled onto the study. Median age was 52 years (range, 17 to 71 years) and the majority of patients had high-risk disease, comorbidities, and/or modest reduction in performance status. Fifty-six percent of patients had unrelated or mismatched related donors.. After a median follow-up of 18 months (range, 2 to 34 months), 1-year survival was 48% (95% CI, 34% to 61%), progression-free survival was 38% (95% CI, 25% to 52%), relapse rate was 27% (95% CI, 15% to 40%), and treatment-related mortality was 33% (95% CI, 20% to 46%). The cumulative probability of extensive chronic graft-versus-host disease (GVHD) was only 18% (95% CI, 8% to 40%); extensive chronic GVHD was only observed in recipients of unrelated donor transplants. Performance score and disease status were the major predictors of outcome. High-risk disease (ie, active AML or MDS with > 5% blasts) or even modest decreases in performance status were associated with poor outcomes. Patients with standard-risk leukemia (first or second complete remission) or MDS (< 5% blasts) had excellent outcomes despite unfavorable disease characteristics.. Fludarabine and melphalan combined with in vivo alemtuzumab is a promising transplantation regimen for patients with AML or MDS and low tumor burden. For patients with active disease, this regimen provides at best modest palliation. Despite a low incidence of GVHD, transplantation is still associated with considerable nonrelapse mortality in patients with decreased performance status.

Topics: Acute Disease; Adolescent; Adult; Aged; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Graft vs Host Disease; Humans; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Proportional Hazards Models; Prospective Studies; Remission Induction; Stem Cell Transplantation; Transplantation Conditioning; Vidarabine

The toxicity of allogeneic stem-cell transplantation can be substantially reduced using a reduced-intensity conditioning (RIC) regimen. This has increased the proportion of patients with myeloid malignancies eligible for allogeneic transplantation. However, the capacity of RIC allografts to produce durable remissions in patients with acute myeloid leukemia (AML) and myelodysplasia (MDS) has not yet been defined, and consequently, the role of RIC allografts in the management of these diseases remains conjectural.. Seventy-six patients with high-risk AML or MDS received an allograft using a fludarabine/melphalan RIC regimen incorporating alemtuzumab. The median age of the cohort was 52 years (range, 18 to 71 years).. The 100-day transplantation-related mortality rate was 9%, and no patient developed greater than grade 2 graft-versus-host disease. With a median follow-up of 36 months (range, 13 to 70 months), 27 patients were alive and in remission, with 3-year actuarial overall survival (OS) and disease-free survival (DFS) rates of 41% and 37%, respectively. The 3-year OS and DFS rates of patients with AML in complete remission at the time of transplantation were 48% and 42%, respectively. Disease relapse was the most common cause of treatment failure and occurred at a median time of 6 months after transplantation. All but one patient destined to relapse did so within 24 months of transplantation.. The extended follow-up in this series identifies a high risk of early disease relapse but provides evidence that RIC allografts can produce sustained DFS in a significant number of patients with AML who would be ineligible for allogeneic transplantation with myeloablative conditioning.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Graft vs Host Disease; Humans; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Recurrence; Risk Factors; Stem Cell Transplantation; Survival Analysis; Transplantation, Homologous; Treatment Outcome; Vidarabine

Intensive therapy and autologous blood and marrow transplantation (ABMT) is an established post-remission treatment for acute myeloid leukemia (AML), although its exact role remains controversial and few data are available regarding longer-term outcomes. We examined the long-term outcome of patients with AML transplanted at a single center using uniform intensive therapy consisting of etoposide, melphalan and TBI. In all, 145 patients with AML underwent ABMT: 117 in first remission, 21 in second remission and seven beyond second remission. EFS and OS were significantly predicted by remission status (P<0.0001). For transplantation in first remission, 8 year EFS and OS were 55% (95% CI, 44-64%) and 62% (95% CI, 50-72%), respectively. By multivariate analysis, only age (P=0.04) and cytogenetic risk group (P=0.006) influenced OS. For patients transplanted in second remission, 8 year EFS and OS were 30% (95% CI, 9-55%) and 36% (95% CI, 13-60%), respectively. No pre-transplant variables significantly predicted outcome. None of the seven patients who underwent ABMT beyond second remission or in early relapse were long-term survivors. ABMT can provide long-term antileukemic control for patients with AML in first remission. For patients in second remission approximately 30% can achieve cure with ABMT, and this option may be preferable to alternate donor allogeneic stem cell transplantation.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Data Collection; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid; Longitudinal Studies; Melphalan; Middle Aged; Remission Induction; Risk Factors; Survival Analysis; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

We report the use of reduced-intensity conditioning (RIC)-matched sibling allogeneic bone marrow stem cell transplantation as a method of establishing a graft-vs.-leukaemia (GvL) effect against myeloid disorders using a fludarabine-melphalan protocol without the use of T-lymphocyte-depleting antibodies. The 16 patients in this group had predominantly poor-risk acute myeloid leukaemia (AML) (n=10), AML/myelodysplasia (MDS) (n=2) and MDS (n=4). All but one patient achieved full haematopoietic engraftment. Thirteen of 16 patients are alive and in continued complete remission on completion of this study with a median follow-up of 426 d (range 83-1524). The actuarial 4 yr disease-free and overall survival is 79% for both. Only one patient relapsed following transplant, giving a relapse rate of 6% during the study period. The treatment-related mortality was 13% (n= 2). Overall, acute graft-vs.-host disease (GvHD) occurred in 53% (8/15), with acute GvHD grade II or above occurring in 47% (7/15). In the 13 evaluable patients, chronic GvHD occurred in 46% (6/13), with this being extensive in three patients. These results suggest that a GvL effect can be delivered against poor-risk myeloid disorders with a low non-relapse mortality using this fludarabine-melphalan RIC protocol.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Disease-Free Survival; Female; Graft Survival; Graft vs Host Disease; Graft vs Leukemia Effect; Humans; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Siblings; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

A reduced-intensity preparative regimen consisting of melphalan and a purine analog was evaluated for allogeneic transplantation in 86 patients who had a variety of hematologic malignancies and were considered poor candidates for conventional myeloablative therapies because of age or comorbidity. Seventy-eight patients received fludarabine 25 mg/m(2) daily for 5 days in combination with melphalan 180 mg/m(2) (n = 66) or 140 mg/m(2) (n = 12). Eight patients received cladribine 12 mg/m(2) continuous infusion for 5 days with melphalan 180 mg/m(2). The median age was 52 years (range, 22-70 years). Disease status at transplantation was either first remission or first chronic phase in 7 patients, untreated first relapse or subsequent remission in 16 patients, and refractory leukemia or transformed chronic myelogenous leukemia in 63 patients. Nonrelapse mortality rates on day 100 were 37.4% for the fludarabine/melphalan combination and 87.5% for the cladribine/melphalan combination. The median percentage of donor cells at 1 month in 75 patients was 100% (range, 0%-100%). The probability of grade 2-4 and 3-4 acute graft-versus-host disease was 0.49 (95% CI, 0.38-0.60) and 0.29 (95% CI, 0.18-0.41), respectively. Disease-free survival at 1 year was 57% for patients in first remission or chronic phase and 49% for patients with untreated first relapse or in a second or later remission. On multivariate analysis the strongest predictor for disease-free survival was a good or intermediate risk category. In summary, fludarabine/melphalan combinations are feasible in older patients with associated comorbidities, and long-term disease control can be achieved with reduced-intensity conditioning in this population.

Topics: Acute Disease; Adenosine; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chronic Disease; Cladribine; Disease-Free Survival; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Survival Rate; Transplantation Chimera; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

Patients with acute leukemias relapsing within 1 year of an allogeneic BMT have a poor prognosis. We studied the use of melphalan 180 mg/m2 followed by allogeneic peripheral blood stem cells (PBSC) as salvage treatment for patients relapsing after related (n = 7) or matched unrelated transplants (n = 3). Diagnoses were AML (n = 4), ALL (n = 3), biphenotypic acute leukemia (n = 2) and CML in blast crisis (n = 1). Eight patients were beyond first relapse and none were in remission. The median time from previous transplant to relapse was 146 days (range 66-206). The melphalan dose was 90 mg/m2 intravenously on days -4 and -3 with PBSC infusion on day 0. GVHD prophylaxis consisted of cyclosporine and methylprednisolone. The median time to an absolute neutrophil count >0.5 x 10(9)/l and to a platelet count >20 x 10(9)/l was 11 and 13 days, respectively. All engrafting patients (n = 8) had 100% donor cells. Two patients died before day 30, but no other grade 3 or 4 toxicity occurred. Acute GVHD grades II-III occurred in two subjects, and chronic GVHD in four. Seven patients achieved CR, but relapsed at a median of 116 days (range 56-614). Leukemia was the cause of death in eight patients. Median survival was 149 days (range 6-614). This treatment produced responses in the majority of this poor prognosis group. However, durable remissions were not observed, and new treatments to consolidate the responses achieved in this setting are needed. This regimen could be considered for short-term disease control to facilitate donor lymphocyte infusion-based immunotherapy or other measures to prevent disease recurrence.

Topics: Acute Disease; Adult; Antineoplastic Agents, Alkylating; Bone Marrow Transplantation; Child; Chronic Disease; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Transplantation Chimera

A cohort of 76 patients with previous chemotherapy for Hodgkin's disease and non-Hodgkin lymphomas received high-dose carmustine, etoposide, cytosine-arabinoside and melphalan (BEAM) followed by autologous stem cell transplantation (ASCT) and was followed for relapse and development of leukemic complications. Six patients, four with Hodgkin's disease and two with non-Hodgkin lymphomas, developed leukemic complications, myelodysplasia (MDS) in four cases and overt acute myeloid leukemia (AML) in two. All six showed an abnormal karyotype, in four of them highly characteristic of therapy-related MDS (t-MDS) and therapy-related AML (t-AML). The cumulative risk of t-MDS and t-AML increased from 16 months after start of the primary chemotherapy for lymphoma and reached 17.3% (s.e. 8.5%) after 74 months. If calculated from start of BEAM and ASCT, the cumulative risk increased as early as 4 months and reached 24.3% (s.e. 12.9%) after 43 months. For the whole course of the disease, the relative risk (RR) of AML was 357 (95% CI: 43-1290), as two overt leukemias were observed vs 0.0056 expected cases of de novo AML. In the present cohort the risk of t-MDS and t-AML although high, did not differ from our previous experience in patients treated conventionally for Hodgkin's disease and non-Hodgkin lymphomas, and did not differ for patients receiving stem cells isolated from the bone marrow as compared to patients receiving stem cells isolated from peripheral blood. Antecedent chemotherapy seems to be the critical factor for the development of t-MDS and t-AML rather than the BEAM and ASCT regimen, which however may accelerate the evolution of the disease.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cytarabine; Dose-Response Relationship, Drug; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Leukemia, Myeloid; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Neoplasms, Second Primary; Podophyllotoxin; Risk Factors

Leukemic relapse remains a major problem after both autologous and allogeneic transplantation. In the single-arm ALL autograft study our results were very encouraging and suggest that Melph/TBI can produce disease-free survival results at least as good as with other conditioning regimens. The role of postautograft maintenance remains unclear, but we feel our results are sufficiently encouraging to justify a randomized study, particularly as we studied a group of patients with relatively poor prognoses. In our study comparing Cy and TBI with Melph and TBI in AML, we have shown a significant increase in antileukemic activity after transplantation following the latter conditioning regimen. The retrospective study of Melph/TBI in autologous versus allogenic transplantation suggested that in AML this antileukemic effect may derive from increased GvHD and is not present in the autologous setting. We hope that by increasing the intensity of our GvHD prophylaxis we can reduce the toxicity of Melph/TBI and preserve its antileukemia effect. Our experience with GM-CSF has been a little disappointing: despite facilitating neutrophil recovery, we were unable to demonstrate a clinical benefit in the treatment arm. We hope to further investigate the use of cytokine combinations in the transplant setting.

Topics: Acute Disease; Adolescent; Adult; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; England; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukemia, Myeloid; Male; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Transplantation, Autologous; Whole-Body Irradiation

We have evaluated the relation between alkylating agents and leukemic disorders in 3363 1-year survivors of ovarian cancer who were treated in five randomized clinical trials and at two large medical centers. Overall, 28 patients developed acute nonlymphocytic leukemia (expected, 1.2) and 7 developed preleukemia. A 93-fold increased risk for acute nonlymphocytic leukemia was seen in 1794 women treated with chemotherapy; the incidence of leukemic disorders was 7.7/1000 women per year. Risk was highest 5 to 6 years after the first treatment and appeared to decrease thereafter. The use of radiation therapy did not affect risk. The 10-year cumulative risk (mean +/- SE) of acquiring a leukemic disorder was 8.5% +/- 1.6% after treatment with any alkylating agent, 11.2% +/- 2.6% after treatment with melphalan, and 5.4% +/- 3.2% after cyclophosphamide treatment. A dose-response relationship was apparent in 605 women receiving melphalan and suggested in 333 women receiving cyclophosphamide. Women receiving melphalan were two to three times as likely to develop leukemic disorders than were women receiving cyclophosphamide. These data indicate that choice of chemotherapeutic agent and drug dosage may influence significantly the risk for long-term adverse effects of cancer therapy.

Topics: Acute Disease; Adult; Aged; Cyclophosphamide; Dose-Response Relationship, Drug; Epidemiologic Methods; Female; Humans; Leukemia; Melphalan; Middle Aged; Ovarian Neoplasms; Preleukemia; Probability; Time Factors

We evaluated the occurrence of acute nonlymphocytic leukemia (ANL) among 1399 women with ovarian cancer who were treated in five randomized clinical trials. Of the 1399 women, 998 had been treated with alkylating agents, and among these, 12 cases of ANL were observed; the expected number was 0.11. Ten patients with ANL had received melphalan, and two chlorambucil. ANL was not observed in 401 women who had been treated with surgery or radiation or both, without alkylating agents. The excess risk of ANL that was associated with alkylating-agent therapy was 5.8 cases per 1000 women per year, and the cumulative seven-year risk of ANL among patients who were treated with chemotherapy alone was indistinguishable from that observed in patients receiving both radiation and chemotherapy. A positive correlation between initial drug dose and the risk of ANL was suggested. These data underscore the need to assess other cytotoxic agents and regimens of drug administration to identify those that do not have harmful late effects.

Topics: Acute Disease; Adult; Aged; Alkylating Agents; Animals; Chlorambucil; Clinical Trials as Topic; Female; Humans; Leukemia; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Ovarian Neoplasms; Random Allocation; Risk

Previously untreated patients with myeloma were randomized to initial treatment with melphalan and prednisone (and to cyclophosphamide or carmustine if relapse or progression occurred)(Group A, 125 patients), melphalan, cyclophosphamide, carmustine and prednisone in alternating (Group B, 123 patients) or concurrent (Group C, 116 patients) schedules. The groups were similar with respect to known prognostic factors. Response rates and survival were also similar. We were unable to identify a subgroup of patients who responded or survived better on melphalan-cyclophosphamide-carmustine and prednisone than on melphalan and prednisone. We conclude that the combination of the four drugs is not better than melphalen and prednisone for inducing responses or prolonging the survival of patients with myeloma. Myelomas producing only gamma chains have a poorer prognosis (P greater than 0.001) than IgG, IgA, or kappa myeloma. Acute leukemia has developed in 14 patients. The actuarial risk of developing acute leukemia, has increased rapidly to 17.4 per cent at 50 months.

Topics: Acute Disease; Adult; Aged; Alkylating Agents; Carmustine; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Immunoglobulins; Leukemia; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Prospective Studies; Risk

We retrospectively compared the impact of the conditioning regimen in adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) that received high-dose myeloablative chemotherapy followed by autologous stem cell transplantation (ASCT) from 2010 to 2021 with either high-dose cytarabine, etoposide and busulfan (BEA), busulfan with cyclophosphamide (BUCY) or busulfan and high-dose melphalan (BUMEL) registered in the EBMT database. Overall 1560 patients underwent ASCT, of which 156, 1143 and 261 received BEA, BUCY and BUMEL, respectively. Compared to BUCY and BUMEL, BEA patients were younger (p < 0.001) and less frequently had NPM1 mutations (p = 0.03). Transplant outcomes at 5 years with BEA, BUCY and BUMEL were: cumulative incidence of relapse 41.8%, 46.6% and 51.6%; non-relapse mortality (NRM) 1.5%, 5.2% and 7.3%; probability of leukemia-free survival (LFS) 56.7%, 48.2% and 41.1%; and overall survival (OS) 71.3%, 62.3% and 56%, respectively. In multivariable analysis the BEA regimen showed significant improvement in OS compared to BUCY (hazard ratio [HR] 0.65; 95% CI, 0.42-0.83; p = 0.048) and BUMEL (HR 0.59; 95% CI, 0.37-0.94; p = 0.029). In conclusion, high-dose myeloablative combination chemotherapy with BEA offered improved outcomes compared to classical BUCY or BUMEL in patients with AML in CR1 undergoing ASCT.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Cyclophosphamide; Cytarabine; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Melphalan; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous

To identify risk factors for acute choroidal ischemia (ACI) after intra-arterial chemotherapy (IAC) for retinoblastoma.. Retrospective cohort study.. Two hundred twenty patients (248 eyes) treated with IAC in Lausanne between November 2008 and September 2019 (665 procedures). All patients were evaluated on a monthly basis with fundus photography and fluorescein angiography before and after each IAC injection.. Acute choroidal ischemia, defined as any new choroidal ischemia clinically diagnosed within 35 days after an IAC injection, were noted. Eyes with choroidal complications diagnosed later than 35 days after the last IAC injection (n = 7) or those for which the status of the choroid was not assessable (n = 35) were excluded. Specific procedure parameters and treatment regimens were compared between the group of eyes with and without ACI.. Procedure-related risk factors for ACI after IAC injection and visual acuity assessment in the group of eyes with ACI.. Acute choroidal ischemia developed in 35 of 206 included eyes after a mean of 2 injections. No differences were found between the two study groups regarding age at first IAC injection, disease grouping at diagnosis, previously administered treatments, number of IAC injections, drug dose, mean injection time, injection method (pulsatile vs. continuous), or concomitant intravitreal melphalan use. Treatment regimen (melphalan vs. combined melphalan plus topotecan; P < 0.05), catheterization route (internal carotid artery vs. external carotid or posterior communicating artery; P < 0.001), and catheterization type (occlusive into the ophthalmic artery [OA] vs. nonocclusive; P < 0.001) were included in multivariate analysis, and occlusive catheterization was identified as an independent risk factor for ACI (P < 0.001). In the subgroup undergoing an occlusive procedure, placement of the catheter tip into the OA distal third versus medial and proximal thirds (P = 0.04) and a mean catheter diameter-to-OA lumen ratio of 0.6 or more (P < 0.001) were correlated significantly with ACI. Complete vision loss was noted in 27% of the eyes with ACI that were old enough for visual assessment (n = 9/33), whereas 33% maintained a useful vision ranging between 0.1 and 0.8 (n = 11/33).. Catheterization of the OA should be attempted from an ostial position or an external carotid approach to minimize the risk of potentially vision-threatening choroidal complications.

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Agents, Alkylating; Catheterization; Child; Choroid; Female; Fluorescein Angiography; Humans; Incidence; Infusions, Intra-Arterial; Ischemia; Male; Melphalan; Middle Aged; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Risk Factors; Visual Acuity

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

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

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

Increasing numbers of patients are receiving haplo-identical stem cell transplantation (haplo-SCT) for treatment of acute leukemia with reduced intensity (RIC) or myeloablative (MAC) conditioning regimens. The impact of conditioning intensity in haplo-SCT is unknown.. We performed a retrospective registry-based study comparing outcomes after T-replete haplo-SCT for patients with acute myeloid (AML) or lymphoid leukemia (ALL) after RIC (n = 271) and MAC (n = 425). Regimens were classified as MAC or RIC based on published criteria.. A combination of post-transplant cyclophosphamide (PT-Cy) with one calcineurin inhibitor and mycophenolate mofetil (PT-Cy-based regimen) for graft-versus-host disease (GVHD) prophylaxis was used in 66 (25%) patients in RIC and 125 (32%) in MAC groups. Patients of RIC group were older and had been transplanted more recently and more frequently for AML with active disease at transplant. Percentage of engraftment (90 vs. 92%; p = 0.58) and day 100 grade II to IV acute GVHD (24 vs. 29%, p = 0.23) were not different between RIC and MAC groups. Multivariable analyses, run separately in AML and ALL, showed a trend toward higher relapse incidence with RIC in comparison to MAC in AML (hazard ratio (HR) 1.34, p = 0.09), and no difference in both AML and ALL in terms of non-relapse mortality (NRM) chronic GVHD and leukemia-free survival. There was no impact of conditioning regimen intensity in overall survival (OS) in AML (HR = 0.97, p = 0.79) but a trend for worse OS with RIC in ALL (HR = 1.44, p = 0.10). The main factor impacting outcomes was disease status at transplantation (HR ≥ 1.4, p ≤ 0.01). GVHD prophylaxis with PT-Cy-based regimen was independently associated with reduced NRM (HR 0.63, p = 0.02) without impact on relapse incidence (HR 0.99, p = 0.94).. These data suggest that T-replete haplo-SCT with both RIC and MAC, in particular associated with PT-Cy, are valid options in first line treatment of high risk AML or ALL.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Disease-Free Survival; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Transplantation Conditioning; Treatment Outcome

The acute pulmonary responses after exposure to sulfur and nitrogen mustards are well documented whereas the late pulmonary effects are not. With a novel focus on the immune system this paper investigate whether late phase pulmonary effects developed in rats exposed to the nitrogen mustard melphalan are linked to the acute responses and whether the reactions are genetically regulated. The DA rat strain was used to establish a lung exposure model. Five other inbred rat strains (PVG, PVG.1AV1, LEW, WF and F344) were compared within the model at selected time points. All rat strains displayed a biphasic pattern of leukocyte infiltration in the lungs, dominated by neutrophils 2 days after exposure and a second peak dominated by macrophages 29 days after exposure. The number of macrophages was higher in the DA rat compared with the other strains. The infiltration of lymphocytes in the lungs varied in both time of appearance and magnitude between strains. The quantity of collagen deposition in the lungs varied between strains at day 90; LEW and WF displayed high collagen content which coincided with an increased level of cytotoxic T cells. LEW further displayed an increased number of T helper cells and natural killer (NK) T cells in the lungs. The results in this study suggest there is a link between the development of lung fibrosis and high cytotoxic cell responses and that there is a genetic influence, as there are variations in acute and late adverse reactions between rat strains in both timing and magnitude.

Topics: Acute Disease; Animals; Chemical Warfare Agents; Disease Models, Animal; Female; Genetic Predisposition to Disease; Instillation, Drug; Intubation, Intratracheal; Killer Cells, Natural; Lymphocyte Count; Melphalan; Neutrophil Infiltration; Pneumonia; Pulmonary Fibrosis; Rats; Rats, Inbred Strains; Severity of Illness Index; Species Specificity; T-Lymphocytes, Helper-Inducer; Time Factors

MTX is a standard component of acute GVHD prophylaxis. However, its use can be limited by toxicity. On the basis of disease risk, we prospectively assigned 132 consecutive patients from January 2005 to February 2011 undergoing first allogeneic hematopoietic cell transplant after conditioning with fludarabine and melphalan to acute GVHD prophylaxis with tacrolimus/MTX (TAC/MTX, N=22), TAC/micro-dose MTX/mycophenolate mofetil (TAC/μMTX/MMF, N=78) or TAC/MMF (TAC/MMF, N=32), to optimize acute GVHD prevention and decrease mortality. The median (range) follow-up was 24 (0.8-60) months. The median patient ages (range) were 37 (23-63), 56 (20-68) and 54 (22-68) years (P<0.0001) for TAC/MTX, TAC/μMTX/MMF and TAC/MMF, respectively. The 100-day cumulative incidences of grade III-IV acute GVHD were 19, 23 and 49% (P=0.015), respectively. The cumulative incidences of severe chronic GVHD at 1 year were 38, 29 and 79% (P<0.001), respectively. Regimen-related toxicities were not significantly different among the three prophylaxis regimens. PFS and OS were equivalent between the TAC/MTX and TAC/μMTX/MMF arms despite significantly older patients in the latter arm, and both had superior PFS and OS than the TAC/MMF arm. Acute GVHD prophylaxis with TAC/μMTX/MMF is as effective as TAC/MTX and superior to TAC/MMF.

Topics: Acute Disease; Adult; Antimetabolites, Antineoplastic; Female; Graft vs Host Disease; Humans; Male; Melphalan; Methotrexate; Middle Aged; Vidarabine; Young Adult

To assess factors associated with severe pulmonary toxicity after myeloablative conditioning using total body irradiation (TBI) followed by allogeneic stem cell transplantation.. A total of 101 adult patients who underwent TBI-based myeloablative conditioning for hematologic malignancies at Duke University between 1998 and 2008 were reviewed. TBI was combined with high-dose cyclophosphamide, melphalan, fludarabine, or etoposide, depending on the underlying disease. Acute pulmonary toxicity, occurring within 90 days of transplantation, was scored using Common Terminology Criteria for Adverse Events version 3.0. Actuarial overall survival and the cumulative incidence of acute pulmonary toxicity were calculated via the Kaplan-Meier method and compared using a log-rank test. A binary logistic regression analysis was performed to assess factors independently associated with acute severe pulmonary toxicity.. The 90-day actuarial risk of developing severe (Grade 3-5) pulmonary toxicity was 33%. Actuarial survival at 90 days was 49% in patients with severe pulmonary toxicity vs. 94% in patients without (p < 0.001). On multivariate analysis, the number of prior chemotherapy regimens was the only factor independently associated with development of severe pulmonary toxicity (odds ratio, 2.7 per regimen).. Severe acute pulmonary toxicity is prevalent after TBI-based myeloablative conditioning regimens, occurring in approximately 33% of patients. The number of prior chemotherapy regimens appears to be an important risk factor.

Topics: Acute Disease; Adult; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Etoposide; Female; Graft vs Host Disease; Hematologic Neoplasms; Humans; Lung; Male; Melphalan; Middle Aged; Pneumonia; Retrospective Studies; Risk Factors; Stem Cell Transplantation; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation; Young Adult

Nine plasma cell myeloma patients spontaneously developed histologically proven autologous graft-versus-host disease (GVHD) limited predominantly to the gastrointestinal tract within 1 month of initial autologous hematopoietic cell transplantation (AHCT) using high-dose melphalan conditioning. All recipients responded promptly to systemic and nonabsorbable oral corticosteroid therapy. All patients previously received systemic therapy with thalidomide, lenalidomide, or bortezomib before AHCT. Using enzymatic amplification staining-enhanced flow cytometry, we evaluated expression of selected transcription regulators, pathway molecules, and surface receptors on samples of the infused hematopoietic cell grafts. We demonstrated significantly enhanced expression of GATA-2, CD130, and CXCR4 on CD34(+) hematopoietic progenitor cells of affected patients compared with 42 unaffected AHCT controls. These 3 overexpressed markers have not been previously implicated in autologous GVHD. Although we did not specifically evaluate T cells, we postulate that exposure over time to the various immunomodulating therapies used for induction treatment affected not only the CD34(+) cells but also T cells or relevant T cell subpopulations capable of mediating GVHD. After infusion, the affected hematopoietic progenitor cells then encounter a host that has been further altered by the high-dose melphalan preparative regimen; such a situation leads to the syndrome. These surface markers could be used to develop a model to predict development of this syndrome. Autologous GVHD potentially is a serious complication of AHCT and should be considered in plasma cell myeloma patients with otherwise unexplained gastrointestinal symptoms in the immediate post-AHCT period. Prompt recognition of this condition and protracted treatment with nonabsorbable or systemic corticosteroids or the combination may lead to resolution.

Topics: Acute Disease; Adrenal Cortex Hormones; Adult; Aged; Biomarkers; Boronic Acids; Bortezomib; Case-Control Studies; Cytokine Receptor gp130; Female; GATA2 Transcription Factor; Graft vs Host Disease; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Pyrazines; Receptors, CXCR4; T-Lymphocyte Subsets; Thalidomide; Transplantation, Autologous

Oral graft-versus-host disease (GVHD) is a significant complication after allogeneic stem cell transplantation (SCT) and there is no consistent information about its characteristics in patients after reduced-intensity conditioning regimen FLU/MEL (fludarabine 120 mg/m² and melphalan 140 mg/m²).. This was a single-centre prospective observational study of patients after allogeneic SCT with FLU/MEL conditioning performed during the period 1/2005-12/2007. Characteristics of oral GVHD were observed in 71 patients. The observation was discontinued due to death, donor lymphocyte infusion (DLI) or new chemotherapy administration.. In 10/2010, the median duration of the observation of the cohort of the patients was 13 (0.2-69) months, and 42 (35-69) months in the still-ongoing 20/71 (28%) patients. Oral acute GVHD had sporadic 7% incidence, whereas oral chronic GVHD was observed in 33% of patients and persisted with median duration of 188 (11-665) days. Clinical and histopathological features were similar in both acute and chronic oral GVHD and included mucosal lichenoid changes, erythema, ulcerations and pseudomembranes, satellite necrosis, apoptotic bodies and lichenoid interface inflammation.. It is necessary to consider complex clinical symptomatology and pathological correlations when classifying the oral GVHD, because local oral symptoms and histopathological features in both acute and chronic oral GVHD forms can be similar. Even though the oral chronic GVHD was mild in the majority of patients, it can be considered as clinically significant due to its incidence, duration and symptomatology. The FLU/MEL conditioning regimen should not be considered as low-risk protocol in this context.

Topics: Acute Disease; Adult; Aged; Chronic Disease; Female; Graft vs Host Disease; Humans; Male; Melphalan; Middle Aged; Mouth Diseases; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Young Adult

The impact of human leukocyte antigen (HLA) mismatch after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIT) using unrelated donors (UD) is unclear, and may be modulated by T-cell depletion. We therefore examined outcomes of 157 consecutive patients undergoing RIT after uniform conditioning with fludarabine, melphalan, and alemtuzumab (FMC). Donors were 10/10 HLA-matched (MUDs, n = 107) and 6 to 9/10 HLA-matched (MMUDs, n = 50), with no significant differences in baseline characteristics other than increased cytomegalovirus seropositivity in MMUDs. Rates of durable engraftment were high. Graft failure rates (persistent cytopenias with donor chimerism) were similar (8% vs 3%, P = .21), though rejection (recipient chimerism) was more frequent in MMUDs (8% vs 0%, P < .01). There were no significant differences between donors in the incidences of acute graft-versus-host disease (GVHD; 20% vs 22% grade 2-4, respectively, P = .83), chronic extensive GVHD (3-year cumulative incidence [CI] 23% vs 24%, P = .56), or treatment-related mortality (1-year CI 27% vs 27%, P = .96). Furthermore, there was no difference in 3-year overall survival (OS; 53% vs 49%, P = .44). Mismatch occurred at the antigenic level in 40 cases. The outcome in these cases did not differ significantly from the rest of the cohort. We conclude that RIT using HLA-mismatched grafts is a viable option using FMC conditioning.

Topics: Acute Disease; Adolescent; Adult; Aged; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Agents; Chronic Disease; Disease-Free Survival; Female; Graft Rejection; Graft Survival; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; HLA Antigens; Humans; Incidence; Living Donors; Lymphocyte Depletion; Male; Melphalan; Middle Aged; Myeloablative Agonists; Retrospective Studies; Survival Rate; Time Factors; Transplantation Chimera; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

A 60-year-old woman was admitted with acute heart failure and was diagnosed as having primary systemic AL amyloidosis with cardiac involvement by endomyocardial biopsy. Electrophoresis revealed an IgG-lambda monoclonal component and amyloidosis was evident in the gastric and rectal mucosa. Her cardiac function at diagnosis was poor, including an ejection fraction of 59% and IVS of 19 mm, and serum cardiac troponin T (cTnT) was elevated (0.12 ng/ml). She was treated with melphalan-dexamethasone (Mel-Dex) therapy once a month. After more than a year, cardiac function and performance status were maintained, with decreasing levels of cTnT, indicating that Mel-Dex represents a feasible and effective therapeutic option for patients with AL amyloidosis with cardiac dysfunction.

Topics: Acute Disease; Amyloidosis; Biomarkers; Dexamethasone; Female; Heart Failure; Humans; Melphalan; Middle Aged; Treatment Outcome; Troponin T

The role of haematopoietic stem cell transplantation (HSCT) in relapsed follicular lymphoma remains controversial. This study analysed 126 patients with relapsed, advanced stage follicular lymphoma who received BEAM (BCNU [carmustine], cytarabine, etoposide, melphalan)-alemtuzumab allogeneic HSCT (BEAM-allo) (n = 44) or BEAM-autologous HSCT (BEAM-auto) (n = 82). The BEAM-allo group had a younger median age (48 years vs. 56 years, P < 0.001) but received a higher median number of therapies pretransplant (P = 0.015) compared with the BEAM-auto group. There was a higher non-relapse mortality (NRM) in the BEAM-allo group compared with the BEAM-auto group at 1 year (20% vs. 2%, P = 0.001). Older age and heavily pretreated patients were associated with a higher NRM and poorer survival in the BEAM-allo group. There was, however, a significantly lower relapse rate (20% vs. 43%, P = 0.01) at 3 years with BEAM-alemtuzumab, with no relapses after 2 years, compared with a continued pattern of relapse in the autologous group. No difference in overall survival (OS) (P = 0.99) or disease-free survival (DFS) (P = 0.90) was identified at 3 years, whereas a plateau in OS and DFS with crossing of the survival curves in favour of BEAM-allo group was observed. Furthermore, the ability to re-induce remissions with donor leucocytes provides additional benefit in favour of allogeneic HSCT.

Topics: Acute Disease; Adult; Aged; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Etoposide; Female; Follow-Up Studies; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Histocompatibility Testing; Humans; Lymphoma, Follicular; Male; Melphalan; Middle Aged; Retrospective Studies; Transplantation Chimera; Transplantation Conditioning; Treatment Outcome

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

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

The results of allogeneic stem cell transplantation for patients with chemotherapy-resistant non-remission acute leukemia have been very poor. We have used a melphalan-preceding intensified preparative regimen in which a six-day interval is set between melphalan 70 mg/m2 and the main part of the preparative regimen to avoid toxicity in 15 consecutive pediatric patients with refractory acute leukemia. Only one patient died of transplant-related toxicity within 100 days of transplant. One patient had refractory anemia originating from donor cells at three months after transplant. Eight patients relapsed at a median of six months after transplant; therefore, five of 15 patients have been in complete remission (CR) for a median of 61 months. Four of six patients who did not have blasts in their peripheral blood before melphalan are in CR This method seems to be safe and effective for refractory acute leukemia.

Topics: Acute Disease; Adolescent; Antineoplastic Agents, Alkylating; Child; Child, Preschool; Humans; Leukemia; Melphalan; Myeloablative Agonists; Remission Induction; Stem Cell Transplantation; Transplantation Conditioning; Treatment Outcome

Therapy-related acute myeloid leukemias arise as a result of cytotoxic chemotherapy and/or radiation therapy. The most common types of acute myeloid leukemia arising in this setting are acute myeloid leukemia with maturation, and lesser numbers of acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, or acute megakaryocytic leukemia. We present a patient with multiple myeloma who was treated with melphalan and 4 years later developed acute erythroid leukemia. The morphologic diagnosis of pure erythroid leukemia developing in the setting of multiple myeloma may be challenging.

Topics: Acute Disease; Aged, 80 and over; Antineoplastic Agents, Alkylating; Epistaxis; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid; Male; Melphalan; Multiple Myeloma; Muscle Weakness

Relapsed acute myeloid leukemia (AML) in adults has a poor prognosis if treated with chemotherapy alone. Case series have previously supported the role of myeloablation and autologous transplantation as a potentially curative treatment. This study aimed to use the large numbers and extended follow-up data in the British Society of Blood and Marrow Transplantation (BSBMT) registry database to establish long-term outcomes and relate these to biological and procedural factors. The BSBMT registry database was used to retrospectively identify 152 adult patients (age, 16-69 years) with AML in second remission treated with autologous transplantation in 1982-2003. Cytogenetic data were available for 68% of the patients; of these, at diagnosis, 42% had good risk features, 57% had standard risk features, and 1% had poor risk features. Conditioning regimens varied; autologous rescue was provided with bone marrow (BM) (71%), peripheral blood stem cells (PBSCs) (18%), or both (11%), which were harvested during first complete remission (CR1) and/or second CR (CR2). Median follow-up was 84 months (range, 2-200 months). At 10 years, actuarial overall survival (OS) was 32%, progression-free survival (PFS) was 28%, and relapse rate (RR) was 57%. The 100-day nonrelapse mortality (NRM) was 7%, rising to 11% at 1 year and to 14% at 10 years. OS was significantly related to M3 subtype (5-year OS, 66%; P = .005), patient age at diagnosis (P = .005) and transplantation (P = .026), and length of CR1, with greatest significance if the patient was dichotomized at CR1 duration of < 8 months or > or = 8 months (P = .0001). There was no difference in OS between regimens containing total body irradiation (TBI) and chemotherapy alone (P = .7). In relation to the nature of autologous graft material, there was improved OS (P = .025) and PFS (P = .009) with the use of cells harvested entirely in CR1 compared with cells harvested in CR2 or in both CR1 and CR2. Engraftment times were significantly shortened with the use of PBSCs alone or in combination with BM compared with BM alone (P = .0001), but there was no significant long-term impact on OS, PFS, RR, or NRM. This study provides long-term follow-up data in one of the largest series of patients with standard-risk and good-risk AML in CR2 treated with autologous transplantation and supports earlier observations that long-term survival is achievable in about 1/3 of patients overall and in about 2/3 of patients with M3 with a relatively low

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Bone Marrow Transplantation; Busulfan; Cyclophosphamide; Etoposide; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Registries; Remission Induction; Retrospective Studies; Risk Factors; Salvage Therapy; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; United Kingdom; Whole-Body Irradiation

Natural killer (NK)-cell leukemia/lymphoma is a rare entity that has been defined only in recent years. In the Revised European-American Lymphoma and World Health Organization classifications, only the mature NK-cell malignancies are included. However, at least 3 types of precursor NK-cell neoplasms have been reported in the literature. These include myeloid/NK-cell acute leukemia, myeloid/NK-cell precursor acute leukemia, and blastic NK-cell lymphoma/leukemia. These leukemias are characterized by the presence of blasts, which express CD56, in the peripheral blood, bone marrow, lymph nodes, and/or extranodal tissues. We report a case that is morphologically consistent with myeloid/NK-cell acute leukemia but immunologically is myeloid/NK-cell precursor acute leukemia. This case is unique in its cutaneous presentation without involvement of the peripheral blood. Extensive flow cytometric studies were performed on the skin biopsy and bone marrow aspirate specimens, which included many markers that had not been tested before in these entities. The clinical implications of these findings are discussed.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Carmustine; CD2 Antigens; Cytarabine; Flow Cytometry; Humans; Immunophenotyping; Killer Cells, Natural; Leukemia, Lymphoid; Male; Melphalan; Podophyllotoxin

Effective therapy of myelodysplatic syndromes and acute myeloid leukemia originating from myelodysplastic syndrome has remained an unresolved problem. Advanced age of the patients and persistent pancytopenia make the treatment difficult. Despite large number of therapeutic options none of them is satisfactory. Recently palliative treatment with low-dose melphalan has been reported to have certain activity. The aim of the study was to evaluate the efficacy of low-dose melphalan in high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia with multilineage dysplasia (AML). Twenty three patients were eligible for the study: 8 with MDS and 15 with AML with multilineage dysplasia. All of them received oral melphalan in a daily dose of 2 mg. Median total dose of the drug was 120 mg (40-840 mg). Ten patients responded to the therapy. We observed complete remission (CR) in 4, partial remission (PR) in 3 and stabilization of the disease in 3 patients. Thirteen patients did not respond to the therapy. The survival time of the patients from the day of diagnosis and from the beginning of the treatment with melphalan was longer in patients responding to the therapy (median 15 and 10 months, respectively) than in non-responders (4.5 and 4 months, p=0.003 and p=0.008, respectively). Low-dose melphalan shows significant activity in high-risk MDS and AML with multilineage dysplasia with acceptable toxicity.

Topics: Acute Disease; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Cell Lineage; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Remission Induction; Risk Factors; Safety

The apparent contradiction between clonal expansion and marrow failure encountered in myelodysplastic syndromes (MDS) is more evident in hypocellular forms at presentation. Hypoplastic MDS (hMDS) appears to be a distinct clinicopathologic entity, accounting for about 15% from all MDS. The pathogeny is supposed to result from immunosupressive mechanisms and some observations on successful treatment with Cyclosporine A (CsA) are reported. The case of a young female patient diagnosed by bone marrow core biopsy with hMDS - refractory anemia (FAB and WHO classification) with normal karyotype and scarce CD34(+) cells by immunohistophenotyping is presented. She was treated with androgens followed by CsA for a few months and shortly after she developed an acute myeloid leukemia (M4) which responded to low-doses of daily oral melphalan. This is one of the first few reports on such an event during the immunosuppressive therapy in MDS and the possible explanations for this unusual evolution are discussed.

Topics: Acute Disease; Adult; Antineoplastic Agents, Alkylating; Cyclosporine; Female; Humans; Immunosuppressive Agents; Leukemia, Myeloid; Melphalan; Myelodysplastic Syndromes; Treatment Failure

Topics: Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; Clone Cells; Combined Modality Therapy; Dexamethasone; Disease Progression; Doxorubicin; Fatal Outcome; Female; Gene Rearrangement, B-Lymphocyte, Heavy Chain; Humans; Leukemia, Plasma Cell; Leukemia, Radiation-Induced; Melphalan; Multiple Myeloma; Neoplasms, Second Primary; Neoplastic Stem Cells; Polymerase Chain Reaction; Prednisone; Radiotherapy; Vincristine

Eight children developed osteochondroma (OS) at a mean of 88 months after hematopoietic stem cell transplantation (HSCT). The mean age at HSCT was 56 months (12-84). This represents a cumulative incidence of 20% among patients less than 18 years of age transplanted from 1981 to 1997. These eight patients underwent allogeneic (n = 2) or autologous (n = 6) transplantation for either acute leukemia (n = 6) or neuroblastoma (n = 2) after a conditioning regimen including TBI (n = 7) or a combination of Bu and CY. OS was multiple in seven patients and solitary in one. Eight lesions were resected and all were benign. Four children received growth hormone before diagnosis of OS, but there was no clinical, radiological or histological difference between those who did not. Univariate analysis showed an increased rate associated only with autologous HSCT, with a 31.7% probability of a new OS at 12 years after HSCT. Osteochondroma should be added to the other adverse effects of HSCT in children.

Topics: Actuarial Analysis; Acute Disease; Bone Neoplasms; Busulfan; Child; Child, Preschool; Cranial Irradiation; Cyclophosphamide; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Leukemia, Myeloid; Male; Melphalan; Neoplasms, Radiation-Induced; Neoplasms, Second Primary; Neuroblastoma; Osteochondroma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation Conditioning; Whole-Body Irradiation

Cardiotoxicity has rarely been reported as a complication of melphalan or fludarabine administration as single agents. Recently, melphalan and fludarabine have been used in combination as non-myeloablative conditioning chemotherapy prior to allogeneic stem cell transplantation. We have observed the development of severe left ventricular failure in three of 21 patients treated with this combination. Cardiotoxicity in this context has not previously been reported and has implications for the assessment, monitoring and treatment of patients undergoing pre-transplant conditioning with melphalan and fludarabine.

Topics: Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Transplantation Conditioning; Transplantation, Homologous; Ventricular Dysfunction, Left; Vidarabine

We treated 21 elderly patients with high-risk myelodysplasia (n = 14) or secondary acute myeloid leukaemia (n = 7) with 2 mg of melphalan orally once a day until a complete peripheral response was obtained or until there was evidence of treatment failure. We observed seven (30%) complete and two (10%) partial peripheral responses occurring within 4-16 weeks and lasting for 12 + to 55 weeks. In relapse, retreatment was successful in most of the patients. Responses were associated with the absence of complex cytogenetic abnormalities and with a normal or reduced bone marrow cellularity.

Topics: Acute Disease; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Female; Humans; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Risk Factors

Topics: Acute Disease; Aged; Antineoplastic Agents, Alkylating; Bone Marrow; Chromosome Painting; Chromosomes, Human, Pair 17; Chromosomes, Human, Pair 20; Dose-Response Relationship, Drug; Female; Humans; In Situ Hybridization, Fluorescence; Karyotyping; Leukemia, Myeloid; Male; Melphalan; Recurrence; Translocation, Genetic; Treatment Outcome

Quantitative expression of neutrophil CD11b/CD18 following chemotherapy (either conventional dose consolidation chemotherapy or high dose chemotherapy with autologous stem cell transplantation) was investigated during the early recovery phase (neutrophil count 0. 5-1.0x109/l) and at full recovery (neutrophil count 1.0-2.5x109/l) following treatment. CD11b/18 expression was normal in stem cell transplantation supported patients during both early and full neutrophil recovery. By contrast CD11b/CD18 expression was markedly decreased in patients who received chemotherapy without stem cell support. These results suggest that recovery of neutrophil count may not always coincide with recovery of neutrophil function and that G-CSF stimulated peripheral stem cell transplantation enhances neutrophil function post chemotherapy.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Breast Neoplasms; CD18 Antigens; Combined Modality Therapy; Cytarabine; Etoposide; Female; Filgrastim; Gene Expression Regulation, Leukemic; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid; Macrophage-1 Antigen; Male; Melphalan; Middle Aged; Neoplasm Proteins; Neutropenia; Recombinant Proteins; Remission Induction

The occurrence of acute leukaemia and other secondary neoplasms in 432 patients treated with conventional chemotherapy for multiple myeloma was analysed after a follow-up period of 11-19 yr (mean 16 yr). The number and organ-specific distribution of observed solid neoplasms was close to that expected in the general population. Non-Hodgkin's lymphoma developed in three patients (expected 0.7, p = 0.19). Acute leukaemia was diagnosed in 14 patients with an actuarial risk of 9.8% at 9 yr. No further cases were diagnosed thereafter. The average numbers of courses (26.2 vs. 25.5) and cumulative doses of melphalan (1440 and 1400 mg) were similar in patients with or without acute leukaemia. It seems possible that the advanced stage of multiple myeloma is more vulnerable to the leukaemogenic effect of melphalan compared with the earlier stages.

Topics: Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Finland; Follow-Up Studies; Humans; Leukemia; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Neoplasms, Second Primary; Organ Specificity

Hodgkin's disease is curable in the majority of patients, although a proportion of patients are resistant to or relapse after initial therapy. High-dose therapy with autologous stem cell support has become the standard salvage therapy for patients failing chemotherapy, but there have been reports of a high incidence of myelodysplasia/acute myeloid leukaemia (MDS/AML) following such treatment. Patients who receive such therapy form a selected group, however, who have already been subjected to other leukaemogenic factors, such as treatment with alkylating agents. In order to ascertain the true risk of MDS/AML, comparison must be made with other patients subjected to the same risks but not undergoing transplantation. We report a retrospective comparative study of 4576 patients with Hodgkin's disease from the BNLI and UCLH Hodgkin's databases, which includes 595 patients who have received a transplant. Statistical analysis including Cox's proportional hazards multivariate regression model with time-dependent covariates was employed. This analysis reveals that the risk of developing MDS/AML was dominated by three factors, namely quantity of prior therapy (relative risk [RR] 2.01, 95% confidence intervals [CI] 1.49-2.71, for each treatment block, P < 0.0001) and whether the patient had been exposed to MOPP (RR 3.61, 95% CI 1.64-7.95, P = 0.0009) or lomustine chemotherapy (RR 4.53, 95% CI 1.96-10.44, P = 0.001). Following adjustment for these factors in the multivariate model the relative risk associated with transplantation was 1.83 (95% CI 0.66-5.11, P = 0.25). This study provides no evidence of a significantly increased risk of MDS/AML associated with BEAM therapy and autologous transplantation in Hodgkin's disease. Concern over MDS/AML should not mitigate against the timely use of this treatment modality.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Child; Child, Preschool; Chlorambucil; Cohort Studies; Combined Modality Therapy; Cytarabine; Doxorubicin; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Incidence; Infant; Leukemia, Myeloid; Life Tables; Lomustine; Male; Mechlorethamine; Melphalan; Middle Aged; Myelodysplastic Syndromes; Neoplasms, Second Primary; Podophyllotoxin; Prednisolone; Prednisone; Procarbazine; Retrospective Studies; Risk; Salvage Therapy; Vinblastine; Vincristine

Tumour lysis syndrome (TLS) in plasma cell dyscrasias is extremely rare. TLS has been described in eight cases of multiple myeloma undergoing high-dose therapy with autologous stem cell transplant (ASCT). Recently, clinical trials of intensive chemotherapy followed by autologous or allogeneic stem cell support has been shown to offer potential benefit in AL (amyloid light-chain) amyloidosis. TLS in primary AL amyloidosis in this setting has not been previously reported. We report a case of TLS in a patient with AL amyloidosis which developed after high-dose melphalan chemotherapy supported by ASCT.

Topics: Acute Disease; Aged; Amyloidosis; Antineoplastic Agents, Alkylating; Fatal Outcome; Female; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Tumor Lysis Syndrome

Causes of treatment-related death were studied amongst 138 patients with acute myeloid (n = 90) or lymphoblastic (n = 48) leukemia allografted from HLA-identical siblings in first (n = 107) or second (n = 31) remission after a conditioning regimen comprising 110 mg/m2 melphalan and 1050 cGy single-fraction total-body irradiation (TBI) prescribed as maximum lung dose. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (n = 78) or cyclosporine-methotrexate (n = 60). Eighty-one patients died of causes other than relapse 16-2917 days (median 77) after transplantation. The actuarial probability of non-relapse mortality was 62% at 5 years. The major primary causes of death were pneumonitis (n = 38, 47%), GVHD (n = 18, 22%), and sepsis (n = 11, 14%). Pneumonitis contributed to 42 of the deaths (52%), and its etiology was infective (n = 27), idiopathic (n = 14), or a combination of the two (n = 1). On multivariate analysis, GVHD prophylaxis with cyclosporine alone was associated with a higher overall toxic death rate. The use of cyclosporine alone and a low infused cell dose (<2.5 x 10(8) total nucleated cells/kg or <0.6 x 10(8) mononuclear cells/kg) were associated with a higher risk of death from pneumonitis. We conclude that the use of cyclosporine alone as GVHD prophylaxis is associated with increased transplant-related toxicity, and the addition of methotrexate and infusion of a higher number of cells decrease the incidence of fatal pneumonitis.

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Agents, Alkylating; Bone Marrow Transplantation; Child; Child, Preschool; Female; Graft vs Host Disease; Humans; Leukemia, Myeloid; Lung Diseases, Interstitial; Male; Melphalan; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sepsis; Transplantation Conditioning; Whole-Body Irradiation

Topics: Acute Disease; Adult; Anti-Bacterial Agents; Antineoplastic Combined Chemotherapy Protocols; Daunorubicin; Diuretics; Drug Therapy, Combination; Female; Humans; Leukemia, Plasma Cell; Melphalan; Prednisolone; Time Factors; Vasodilator Agents; Vincristine

In polycythemia vera (PV), treatment with chlorambucil and radioactive phosphorus (p32) increases the risk of leukemic transformation from 1% to 13-14%. This risk has been estimated to be 1-5.9% with hydroxyurea (HU) therapy. When compared with historical controls, the risk with use of HU does not appear to be statistically significant. The leukemogenic risk of HU therapy in essential thrombocytosis (ET) and in myelofibrosis with myeloid metaplasia (MMM) is unknown. HU remains the main myelotoxic agent in the treatment of PV, ET, and MMM. We studied 64 patients with these three disorders, seen at our institution during 1993-1995. The patients were studied for their clinical characteristics at diagnosis, therapies received, and development of myelodysplasia or acute leukemia (MDS/AL). Forty-two had PV, 15 ET, and 6 MMM, and 1 had an unclassified myeloproliferative disorder. Of the 42 patients with PV, 18 were treated with phlebotomy alone, 16 with HU alone, 2 with p32, 2 with multiple myelotoxic agents, and 2 with interferon-alpha (IFN-alpha). Two patients from the phlebotomy-treated group, one from the HU-treated group, and 1 from the multiple myelotoxic agent-treated group developed MDS/AL. In the larger group, 11 received no treatment or aspirin alone, 18 were treated with phlebotomy alone, 25 with HU, 5 with multiple myelotoxic agents, 2 with p32, 2 with IFN-alpha, and 1 with melphalan. Study of the entire group of 64 patients showed that only one additional patient (total of 5 out of 64) developed MDS/AL. This patient had been treated with HU alone. Statistical analysis did not show any association between clinical characteristics at diagnosis, or HU therapy, and development of MDS/AL (P=0.5). Thus, our data provide no evidence suggestive of increased risk of transformation to MDS/AL with HU therapy in PV, ET, and MMM. Larger, prospective studies are needed to study this issue further.

Topics: Acute Disease; Anemia, Refractory, with Excess of Blasts; Busulfan; Cell Transformation, Neoplastic; Chlorambucil; Cohort Studies; Disease Progression; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Hydroxyurea; Incidence; Interferon-alpha; Leukemia; Leukemia, Radiation-Induced; Male; Melphalan; Middle Aged; Phlebotomy; Phosphorus Radioisotopes; Polycythemia Vera; Preleukemia; Primary Myelofibrosis; Retrospective Studies; Ribonucleotide Reductases; Risk; Thrombocythemia, Essential

Forty-four adults with AML (n = 18) or ALL (n = 26) beyond first remission underwent unpurged (n = 39) or purged (n = 5) autografting after 110-140 mg/m2 melphalan and 1050 cGy TBI. ALL patients were eligible to receive maintenance chemotherapy with 6-mercaptopurine and methotrexate for 2 years after hematologic recovery. The duration of first remission was 1-167 months (median 11). The median time to 50 x 10(9)/I platelets was 76 days, and that to 0.5 x 10(9)/I neutrophils 31 days. Eight patients died of transplant-related toxicity; seven within 1 year. Twenty-two patients relapsed at 1-20 months (median 2.5 months). The 3-year probabilities (95% CI) of relapse and disease-free survival are 58% (43-75%) and 31% (17-45%), respectively. The duration of the first remission (< 1 year vs > or = 1 year) and the stage of transplant (second remission vs other) had no effect on relapse or disease-free survival. There was a trend towards higher relapse rates (76 vs 34%) and poorer disease-free survival (19 vs 49%) among ALL patients compared with AML which did not reach significant levels due to small patient numbers. We conclude that melphalan-TBI is a suitable conditioning regimen for autografting in advanced leukemia. The outcome of AML patients is comparable to standard regimens, but the outcome of ALL patients is poor and measures to enhance the anti-leukemic efficacy are necessary.

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Leukemia; Leukemia, Myeloid; Male; Melphalan; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Salvage Therapy; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

A 42-year-old male patient with a history of occupational exposure to benzene presented with pancytopenia. His bone marrow showed evidence of trilineage dysplasia and cytogenetic analysis revealed a unique t(9;13)(q34;q12) translocation. Five months after diagnosis he developed secondary AML. He was treated with four courses of chemotherapy and an autologous bone marrow transplantation (BMT). Four years post-transplantation he remains in haematological and morphological remission though the cytogenetic abnormality is still present in all metaphases examined.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Benzene; Bone Marrow; Bone Marrow Transplantation; Carmustine; Chromosomes, Human, Pair 13; Chromosomes, Human, Pair 9; Combined Modality Therapy; Etoposide; Follow-Up Studies; Humans; Leukemia, Myeloid; Male; Melphalan; Myelodysplastic Syndromes; Neoplastic Stem Cells; Occupational Diseases; Occupational Exposure; Pancytopenia; Remission Induction; Solvents; Translocation, Genetic; Transplantation, Homologous

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Cyclophosphamide; Esophageal Stenosis; Esophagitis; Etoposide; Fatal Outcome; Female; Humans; Immunocompromised Host; Leukemia, Myeloid; Melphalan; Middle Aged

Peripheral blood stem cells (PBSC) were used to augment autologous bone marrow transplantation (ABMT), aiming to hasten engraftment after high dose treatment in a group of heavily pretreated patients. PBSC were obtained by leukapheresis during the rebound after standard chemotherapy. In 11 patients aged 7-17 years, high dose chemotherapy consisted of busulphan 16 mg/kg orally with melphalan 160 mg/m2 intravenously for seven patients, and melphalan 200 mg/m2 intravenously alone for four. The median number of granulocyte-macrophage colony forming units in the reinfused PBSC was 3.42 x 10(4)/kg (3.03-18.01) and bone marrow 12.4 x 10(4)/kg (4.16-28.6). Neutrophil recovery to > or = 0.5 x 10(9)/l and platelet transfusion independence occurred at a median of 14 days (11-18) and 22 days (9-84) respectively. In five patients the early engraftment was transient with neutrophils again dropping below 0.5 x 10(9)/l then slowly recovering. There was one toxic death due to sepsis. PBSC harvesting in these children was undertaken without interrupting routine chemotherapy and without the use of bone marrow growth factors. In some patients PBSC failed to influence engraftment and the use of combined chemotherapy and growth factor priming for PBSC collection may give improved results.

Topics: Acute Disease; Adolescent; Bone Marrow Transplantation; Busulfan; Child; Combined Modality Therapy; Cryopreservation; Female; Hemangiosarcoma; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Leukapheresis; Leukemia, Myeloid; Male; Melphalan; Rhabdomyosarcoma; Sarcoma, Ewing

Topics: Acute Disease; Amyloidosis; Cardiomyopathies; Cholangitis; Cholestasis; Female; Humans; Liver Diseases; Melphalan; Middle Aged

Childhood acute myeloid leukemia (AML) has a poor prognosis with standard chemotherapy. Allogeneic bone marrow transplantation (BMT) in remission improves the outlook only for the one third of patients with sibling donors. Autologous BMT with a lower morbidity and mortality is available to all. In this study, maximum cytoreduction was achieved by intensive early chemotherapy. Final intensification, with autologous BMT was offered to all those remaining in first complete remission (CR). Patients received two induction and two consolidation courses of intensively scheduled chemotherapy. Cytoreduction was assessed on day 14 and remission was assessed after courses 2 and 4. Bone marrow was harvested after recovery from the second consolidation course or after the first maintenance course and separated on a discontinuous percoll gradient before cryopreservation. Twenty-eight of 31 consecutively enrolled patients achieved CR. Three relapsed early and, of the 25 eligible, 24 underwent autologous BMT. Twenty-three patients received high-dose melphalan and 1 received busulphan and cyclophosphamide before autologous BMT at a median of 113 days (range, 86 to 301) after initial CR. Trilineage engraftment occurred in all. Neutrophil recovery to greater than 0.5 x 10(9)/L occurred at a median of 46 days (range, 13 to 92) after autologous BMT. Platelet recovery was delayed, with a median time to achieve greater than 20 x 10(9)/L of 42 days (range, 18 to 215). With a minimum follow up of 25 months following autologous BMT only 3 children have relapsed. The 5-year event-free survival rate (EFS) from diagnosis is 68% (95% confidence interval, 46% to 90%). Five-year EFS following autologous BMT is 87% (95% confidence interval, 67% to 100%). Autologous BMT with high-dose melphalan administration after intensive chemotherapy has produced EFS equivalent to allogeneic BMT and is associated with a strikingly low relapse rate. High-dose melphalan appears to be a valuable agent for conditioning therapy in AML.

Topics: Acute Disease; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Female; Humans; Infant; Leukemia, Myeloid; Male; Melphalan; Probability; Remission Induction; Survival Analysis; Time Factors; Transplantation, Autologous

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

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biomarkers, Tumor; Colonic Neoplasms; Cytarabine; Daunorubicin; Drug Resistance; Female; Gene Expression Regulation, Neoplastic; Humans; Leukemia; Male; Melphalan; Membrane Glycoproteins; Middle Aged; Multiple Myeloma; Neoplasm Proteins; Neoplastic Stem Cells; Peptichemio; Plasma Cells; Prednisone; Remission Induction; Survival Rate; Tumor Cells, Cultured; Vincristine

Etoposide is an important component of several intensive therapy regimens in allogeneic and autologous bone marrow transplantation for advanced hematologic malignancies. We observed the occurrence of transient acute parotid and submandibular sialoadenitis in nine of 19 patients receiving high dose etoposide and melphalan followed by autologous bone marrow rescue. Manifestations included pain, tenderness and swelling of the parotid and submandibular glands. Symptoms arose 4-16 h after completion of etoposide infusion and resolved within 72 h. Elevation of serum amylase accompanied the symptoms, and was also observed in some patients who were asymptomatic. Discomfort was controlled with analgesics and the clinical course was uncomplicated in all cases. Transient parotitis is a relatively frequent and benign complication of high dose etoposide therapy.

Topics: Acute Disease; Adult; Amylases; Bone Marrow Transplantation; Dose-Response Relationship, Drug; Etoposide; Female; Humans; Male; Melphalan; Parotitis

This report describes the development of acute myeloblastic leukemia in a patient after long-term alkylator therapy for multiple myeloma. Despite chromosome deletions -5, -7, the patient lacked the histochemistry and clinical findings characteristic of therapy-induced leukemia. In double-labeled surface marker studies by flow cytometry, the leukemic blast cells co-expressed myeloid and plasma cell surface markers. The findings may support the hypothesis of a single stem cell abnormality's being responsible for both the malignant plasma cells and the myeloid leukemic cells.

Topics: Acute Disease; Antigens, Neoplasm; Antigens, Surface; Bone Marrow; Chromosome Aberrations; Chromosome Disorders; Female; Flow Cytometry; Humans; Leukemia, Myeloid; Melphalan; Middle Aged; Multiple Myeloma; Plasma Cells; Prednisone; Time Factors

Topics: Acute Disease; Female; Humans; Leukemia; Melphalan; Middle Aged; Myelodysplastic Syndromes; Thrombocythemia, Essential

A cytogenetic study is reported on the lesions induced in vitro by melphalan, a currently used anticancer drug. The distribution of 2166 breakpoints shows that they do not occur at random. There is a large excess of breaks in region q1 of chromosome 9 and R bands are significantly more affected than G-band-rich segments. Furthermore, some regions of chromosomes 5, 7, 11, and 17, which are the chromosomes usually rearranged and deleted in secondary leukemias, presumably induced by such treatments, are frequently affected. It is presumed that the frequent involvement of 9q1 largely reflects preexisting monostrand breaks. The frequent breakage of chromosomes 5, 7, 11, and 17 and of R bands in general, which are known to be G-C rich, may result from the preferential methylation of the O6 of guanine by melphalan.

Topics: Acute Disease; Cells, Cultured; Chromosome Aberrations; Chromosome Banding; Genetic Markers; Humans; Karyotyping; Leukemia; Melphalan

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

Twenty-six children with acute leukemia were treated with allogeneic marrow transplantation from HLA identical siblings after a conditioning regimen with Cyclophosphamide-total body irradiation (19 patients), Melphalan-total body irradiation (6 patients) or Busulfan-cyclophosphamide (1 patient). Eighteen were transplanted in complete remission (4 with acute non lymphoblastic leukemia in first remission, 14 with acute lymphoblastic leukemia: 6 in first, 6 in second and 2 in subsequent remission): 2 died of cytomegalovirus pneumoniae, 1 relapsed and 15 survive in continuous complete remission from 5 to 42 months after transplantation (median = 22 months). Eight were transplanted in relapse, 7 achieve complete remission, 5 of them relapsed, 1 died of G.V.H. and 1 survives in continuous complete remission 46 months after transplantation. Actuarial analysis shows a disease free survival rate at 3 years of 82% for patients transplanted in remission and 12% for patients transplanted in relapse (p less than 0.01).

Topics: Acute Disease; Adolescent; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Leukemia; Male; Melphalan; Whole-Body Irradiation

Haemopoietic reconstitution (HR) using autologous peripheral blood stem cells (PBSC) was attempted after intensive chemotherapy or chemoradiotherapy in two patients with relapsed acute non-lymphoblastic leukaemia (ANLL). The PBSC were collected by leukapheresis very early in first remission and cryopreserved in liquid nitrogen. Both patients demonstrated early evidence of trilineage engraftment. The first patient received melphalan 200 mg/m2 followed by rescue with 1.3 X 10(8) mononuclear cells/kg body weight containing 29 X 10(4) granulocyte-macrophage progenitor cells (CFU-GM)/kg, and HR was evident by Day 14. The second patient was treated with supralethal chemoradiotherapy followed by rescue with 3.0 X 10(8) mononuclear cells/kg containing 23 X 10(4) CFU-GM/kg. He demonstrated early engraftment with near normal peripheral blood counts by Day 16. There was a subsequent fall in both bone marrow cellularity and peripheral blood counts to a level of low but persistent activity. There was a further phase of haematological recovery from 8 weeks following transplantation with an increase in peripheral blood counts and bone marrow cellularity until final relapse at 13 weeks. This study demonstrates that circulating stem cells have haemopoietic reconstitutive capacity, previously only shown with buffy coat cells from chronic granulocytic leukaemia. The minimum number of PBSC required for satisfactory engraftment remains unknown, although it seems probable that the ratio of pluripotent stem cells to committed progenitor cells is lower in very early remission peripheral blood than in either allogeneic normal bone marrow or autologous bone marrow collected later in stable remission. The question of leukaemic contamination of the PBSC remains to be answered.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Blood Preservation; Blood Transfusion; Combined Modality Therapy; Freezing; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Male; Melphalan; Middle Aged

Topics: Acute Disease; Adolescent; Adult; Aged; Bone Marrow; Bone Marrow Transplantation; Cell Survival; Child; Colony-Forming Units Assay; Combined Modality Therapy; Drug Administration Schedule; Female; Humans; Leukemia; Male; Melphalan; Middle Aged; Transplantation, Autologous

A 71-year-old woman with multiple myeloma was successfully managed for 8 years with melphalan (total dose 2056 mg). She developed a refractory anemia (myelodysplastic state), which terminated in acute eosinophilic leukemia. This form of acute leukemia, induced by chemotherapy, appears to be very rare. The cytogenetic changes, including 5q- and monosomy 7, were similar to those observed in other patients with acute nonlymphocytic leukemia as a secondary malignancy following treatments of other primary tumors.

Topics: Acute Disease; Aged; Bone Marrow; Chromosome Aberrations; Eosinophils; Female; Humans; Leukemia; Melphalan; Multiple Myeloma

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Bone Diseases; Drug Resistance; Humans; Leukemia; Melphalan; Multiple Myeloma; Pain Management; Prednisone

Four cases of acute myelodysplastic-non-lymphocytic leukemia secondary to cytotoxic agents were reported. Primary diseases were breast cancer (1 patient), ovarian cancer (2 patients) and multiple myeloma (1 patient). All except one (with multiple myeloma) were in clinical remission of their primary diseases. Common cytotoxic agent used was melphalan. Median total drug dose and median latent period from diagnosis of primary diseases were 1299 mg and 63 months respectively. None with the exception of one received specific treatment. All died except one who is in a very poor condition. Survival from the diagnosis of hematologic diseases ranged from 3-9 months. Clinical features, cytogenetic findings, pathogenetic mechanism and risk of the disease were briefly discussed.

Topics: Acute Disease; Adult; Breast Neoplasms; Chromosome Aberrations; Female; Humans; Leukemia; Leukemia, Radiation-Induced; Melphalan; Middle Aged; Multiple Myeloma; Ovarian Neoplasms; Radiotherapy

Acute nonlymphocytic leukemia developed in a 57-year-old woman following adjuvant therapy with melphalan for ovarian carcinoma. Maturation of differentiating marrow myeloid and erythroid precursors was megaloblastic. The serum vitamin B12 level was low, and Schilling test revealed vitamin B12 malabsorption correctable with intrinsic factor. Megaloblastic maturation of the marrow cells was converted to normoblastic following treatment with vitamin B12 and folic acid. However, blast cells persisted in the marrow, and cytogenetic analysis revealed aneuploidy and trisomy 18. In contrast to the marrow blast cells, there was a decline in circulating blast cells following vitamin replacement, suggesting that these cells were capable of maturation but required vitamin B12 for this purpose.

Topics: Acute Disease; Anemia, Pernicious; Bone Marrow; Cell Division; Cystadenocarcinoma; Female; Folic Acid; Hemoglobins; Humans; Leukemia; Melphalan; Middle Aged; Ovarian Neoplasms; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Acute Disease; Alkylating Agents; Female; Humans; Leukemia; Melphalan; Ovarian Neoplasms

Late side effects of chemotherapy were studied in 51 women who had received at least 300 mg of melphalan for ovarian cancer and had survived for at least three years. Hematologic, statistical, and cytogenetic methods were employed. Six cases of iatrogenic leukemia were found. They appeared to represent a hematologic entity that is fairly difficult to recognize. The risk of iatrogenic leukemia in women who survived for three years or more after melphalan treatment was calculated to be 950 times greater than the leukemia risk in the total female population. The cytogenetic changes were studied with three methods focused on sister chromatid exchange, chromosome aberrations, and DNA damage. The sister chromatid exchange frequency showed a marked increase, but it was corrected within a few months. Chromosome aberrations expressed by chromosome rearrangements were increased in the peripheral lymphocytes and may persist for several years. The frequency of DNA stand breaks was decreased indicating the presence of DNA cross-links. Any of these types of genetic alteration could be the initiating event in carcinogenesis.

Topics: Acute Disease; Adult; Aged; Bone Marrow; Female; Follow-Up Studies; Humans; Iatrogenic Disease; Leukemia; Melphalan; Middle Aged; Ovarian Neoplasms; Risk; Sister Chromatid Exchange; Smoking

Five patients with multiple myeloma ending in acute leukemia are described. The preleukemic phase was characterized by anemia, leukopenia and/or thrombocytopenia. The incidence of acute leukemia in myeloma was calculated to be 6%. Melphalan therapy for more than two years increased the incidence to 14%. All patients who developed leukemia had received a total melphalan dose of at least 1 100 mg.

Topics: Acute Disease; Aged; Blood Cell Count; Female; Humans; Leukemia; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasms, Multiple Primary

Topics: Acute Disease; Aged; Alkylating Agents; Female; Humans; Leukemia; Melphalan; Ovarian Neoplasms; Prognosis

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

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

During the years 1966-1973 474 patients with ovarian carcinoma were treated with melphalan. Of these, 48 patients received at least 300 mg melphalan and survived at least 3 years; four cases of acute leukemia were found among these 48 patients. All cases belonged to a group of 12 cases receiving 800 mg melphalan or more.

Topics: Acute Disease; Aged; Female; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Neoplasms, Multiple Primary; Ovarian Neoplasms; Time Factors

Topics: Acute Disease; Female; Humans; Leukemia; Melphalan; Middle Aged; Multiple Myeloma

To estimate the leukemogenic potential of alkylating agents, we surveyed 70 institutions using these drugs for the frequency of second cancers in patients with advanced ovarian cancer. Thirteen cases of acute nonlymphocytic leukemia occurred among 5455 patients, as compared to 0.62 cases expected (relative risk = 21.0). All 13 had received alkylating agents. Nine also received radiotherapy. The relative risk for patients given chemotherapy was 36.1 and rose to 171.4 for those surviving for two years (rate = 13.75 per 1000 patients per year). To evaluate the role of therapy versus underlying disease, a historical control of 13,309 patients with ovarian cancer in the National Cancer Institute's End Results Program was analyzed. No excess of leukemia was noted in this group, even among 6596 women receiving radiation. The excess of acute nonlymphocytic leukemia, therefore, appears attribute to alkylating agents, although the effect may be enhanced by exposure to radiation, as previously suggested for Hodgkin's disease.

Topics: Acute Disease; Alkylating Agents; Altretamine; Chlorambucil; Cyclophosphamide; Female; Fluorouracil; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Neoplasm Metastasis; Ovarian Neoplasms; Risk; Thiotepa; Time Factors; Uracil Mustard

The peripheral blood cells of a patient with acute plasma cell leukemia were examined with transmission (TEM) and scanning (SEM) electron microscopes. The TEM features of the immature plasma cells comprised lobulated and irregulary shaped nuclei, with scanty heterochromating and bizarre nucleoli, parallel arrays of endoplasmic reticulum, cytoplasmic fibrils and numerous polymorphic mitochondria. SEM examination of the cells showed long, thin irregular ruffles, or round blebs on the cell surface, with appearance different from this observed on other types of leukemia. A remarkable clinical and hematological remission was achieved with administration of melphalan and steroids.

Topics: Acute Disease; Cell Nucleolus; Cell Nucleus; Endoplasmic Reticulum; Humans; Leukemia, Plasma Cell; Male; Melphalan; Microscopy, Electron; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Plasma Cells; Prednisone; Remission, Spontaneous

Topics: Acute Disease; Female; Humans; Leukemia; Melphalan; Middle Aged; Ovarian Neoplasms

A patient with multiple myeloma in whom acute erythroleukaemia developed 5 years following treatment with irradiation and melphalan is reported. Immunoglobulin synthesis and immunofluorescence investigations provided evidence that the blast cells in the peripheral blood did not belong to the plasma cell series; ultrastructure examination demonstrated their myeloid origin. Chromosomally abnormal cells were observed in both the bone marrow and peripheral blood. Light-and electron microscopy of erythropoiesis in this case showed distinct features of dyserythropoiesis, similar to those described in other entities. The erythroid cell abnormalities are discussed in the light of their being either indications of malignancy or of a reactive process.

Topics: Acute Disease; Bone Marrow; Bone Marrow Cells; Chromosome Aberrations; Erythroblasts; Erythrocytes; Erythropoiesis; Humans; Immunoglobulins; Leukemia, Erythroblastic, Acute; Male; Megakaryocytes; Melphalan; Middle Aged; Multiple Myeloma

Because cross-resistance between alkylating agents has not been observed, we attempt in a prospective trial to determine the advantages, if any, in administering three alkylating agents sequentially, alternately, or concurrently. A patient with myeloma, showing progressive shortening of M-protein doubling time from 98 to 15 days, developed an acute terminal phase, characterized by fever and pancytopenia. A similar acute terminal phase was observed in 17 of 50 deaths from myeloma. Since alkylating agents are only effective in controlling the chronic phase of myeloma, future improvements will require the discovery of agents that delay, prevent, or are effective in the treatment of the acute phase. Forty-five patients with kappa- and 36 with lambda-light-chain disease showed no differences in frequency of amyloidosis, renal failure, response to treatment, or survival after treatment with alkylating agents.

Topics: Acute Disease; Alkylating Agents; Bence Jones Protein; Bone Neoplasms; Carmustine; Cell Count; Cyclophosphamide; Drug Therapy, Combination; Humans; Immunoglobulin kappa-Chains; Immunoglobulin lambda-Chains; Mechlorethamine; Melphalan; Multiple Myeloma; Myeloma Proteins; Prednisone; Remission, Spontaneous; Time Factors

Rapidly fatal acute myelomonocytic leukemia developed in five patients with multiple myeloma who were treated with melphalan for 28 to 54 months. In each patient, multiple myeloma responded to therapy and progress was satisfactory until the development of acute leukemia. At postmortem examination, leukemic infiltration of organs was seen, and there was little or no evidence of myeloma. Consideration of these cases and a review of the literature suggest that these circumstances represent the development of acute myelomonocytic leukemia rather than plasma cell leukemia; there also appears to be an increased incidence of acute leukemia in multiple myeloma, probably related to the alkylating agent.

Topics: Acute Disease; Aged; Bone Marrow; Bone Marrow Cells; Bone Marrow Examination; Bone Neoplasms; Hemoglobins; Humans; Leukemia, Myeloid; Leukemia, Plasma Cell; Leukocyte Count; Male; Melphalan; Microscopy, Electron; Middle Aged; Multiple Myeloma; Plasma Cells; Prednisone; Testosterone; Time Factors

Topics: Acute Disease; Aged; Female; Humans; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Multiple Myeloma

Topics: Acute Disease; Antineoplastic Agents; Leukemia; Melphalan