melphalan and Leukemia

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

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

Conditioning regimens for transplantation are important in determining transplant outcome. This review focuses on transplantation in aplastic anemia and leukemia using marrow from HLA-identical siblings. Results of conditioning with newer regimens such as busulfan plus cyclophosphamide and etoposide plus total body irradiation are reviewed and compared to results achieved with cyclophosphamide and total body irradiation. The potential for improved results using recent innovations such as dose adjustment of busulfan, agents which may decrease transplant-related toxicity, and directed radiation are discussed.

Topics: Anemia, Aplastic; Antilymphocyte Serum; Bone Marrow Purging; Bone Marrow Transplantation; Busulfan; Cyclophosphamide; Cytarabine; Etoposide; Humans; Leukemia; Lymphocyte Depletion; Melphalan; T-Lymphocytes; Transplantation, Homologous; Whole-Body Irradiation

The incidence of second malignancies was assessed by retrospectively analyzing data from previous studies in well-defined and closely followed patient cohorts. After a median follow-up of more than 6 years following MOPP (mechlorethamine/vincristine/procarbazine/prednisone) chemotherapy with or without radiotherapy, 5% of patients with Hodgkin's disease developed second primaries, 60% of which were leukemias. Melphalan caused a 3% leukemia rate among 1129 patients with ovarian cancer who were followed for a median period of 4 years. No leukemia was observed among 1132 breast cancer patients treated with adjuvant CMF (cyclophosphamide/methotrexate/5-fluorouracil) after a median follow-up of 7.5 years. Long-term, comprehensive studies are needed to improve the current knowledge and the prognosis of patients with second primary neoplasms.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Hodgkin Disease; Humans; Leukemia; Mechlorethamine; Melphalan; Neoplasms, Multiple Primary; Ovarian Neoplasms; Prednisone; Procarbazine; Randomized Controlled Trials as Topic; Retrospective Studies; Vincristine

MOPP chemotherapy was the significant breakthrough that improved the outlook for patients with advanced Hodgkin's disease. Results with alternating potentially non-cross-resistant drug combinations, including MOPP/ABVD, CAD/MOPP/ABV, and MOPP/ABV, are similar and seem to be slightly superior to those with MOPP alone. Limited adjuvant RT does not seem to add appreciably to the morbidity of chemotherapy, although its role in improving on results with chemotherapy alone has not been well studied in prospective, randomized, controlled clinical trials. There are two major challenges for the future. The first is to improve the outcome for advanced Hodgkin's disease patients, perhaps with more intensive chemotherapy and RT with use of cytokines such as the colony-stimulating factors or interleukin-1 or with rescue employing autologous bone marrow transplantation or both. The second challenge is to reduce the morbidity but not the effectiveness of treatment for advanced Hodgkin's disease patients without adverse prognostic factors.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Clinical Trials as Topic; Combined Modality Therapy; Dacarbazine; Doxorubicin; Female; Hodgkin Disease; Humans; Leukemia; Lomustine; Lymphoma; Male; Mechlorethamine; Melphalan; Middle Aged; Neoplasms, Multiple Primary; Prednisone; Procarbazine; Remission Induction; Vinblastine; Vincristine; Vindesine

Topics: Anemia, Aplastic; Antineoplastic Agents; Colony-Stimulating Factors; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Drug Evaluation; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Melphalan; Neoplasms; Radiotherapy

Topics: Bone Marrow Transplantation; Combined Modality Therapy; Graft vs Host Disease; Humans; Leukemia; Melphalan; Whole-Body Irradiation

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Drug Evaluation; Etoposide; Hodgkin Disease; Humans; Leukemia; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Lomustine; Melphalan; Mitoxantrone

Topics: Adrenal Cortex Hormones; Animals; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Breast Neoplasms; Cyclophosphamide; Dacarbazine; Doxorubicin; Drug Therapy, Combination; Dyspnea; Fluorouracil; Hodgkin Disease; Humans; Hypercalcemia; Leukemia; Leukemia, Lymphoid; Lymphoma; Mechlorethamine; Melphalan; Methotrexate; Multiple Myeloma; Palliative Care; Prednisone; Procarbazine; Receptors, Glucocorticoid; Vinblastine; Vincristine; Vomiting

Topics: Alkylating Agents; Amyloidosis; Anemia; Anemia, Refractory; Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bacterial Infections; Blood Transfusion; Bone and Bones; Bone Marrow Examination; Bone Marrow Transplantation; Bone Neoplasms; Calcium; Combined Modality Therapy; Diagnosis, Differential; Heavy Chain Disease; Humans; Immunoglobulin D; Immunotherapy; Interferons; Kidney Failure, Chronic; Leukemia; Melphalan; Mice; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Myeloma Proteins; Osteolysis; Osteosclerosis; Paraproteinemias; Plasma Cells; Plasmacytoma; Prednisone; Radionuclide Imaging; Waldenstrom Macroglobulinemia

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Drug Evaluation; Drug Resistance; Etoposide; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Melphalan; Neoplasm Recurrence, Local; Neoplasms; Thioguanine; Transplantation, Autologous

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

Topics: Altretamine; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Leukemia; Melphalan; Ovarian Neoplasms

The human population may be exposed to potentially leukemogenic agents, either in the form of drugs and food additives or as environmental contaminants and pollutants. However, in spite of the large number and diversity of these chemicals, only a few have been implicated as human leukemogens. One such agent is benzene, a known bone marrow depressant. A number of case reports have associated chronic exposure to this agent with the development of acute leukemia, as have several epidemiologic surveys. Treatment with various antitumor agents, including procarbazine, melphalan, thio-TEPA, chlorambucil, and cyclophosphamide, has also been associated with the development of acute leukemia. In addition, chloramphenicol and phenylbutazone have been implicated as human leukemogens, but the association between exposure to these two agents and acute leukemia appears at present to be weaker than it is for benzene and antitumor agent exposure. Despite such associations between exposure to chemicals and acute leukemia, several important problems exist with regard to implicating specific agents in the development of this neoplasm in man, including the paucity of animal models for chemically induced leukemia, and the frequent necessity to rely on single case reports or clusters of cases in which chemical exposures are associated with acute leukemia. Future efforts should be directed at performing properly designed and well executed epidemiologic studies, and at developing new in vitro and in vivo models for the study of this neoplasm.

Topics: Benzene; Chlorambucil; Chloramphenicol; Cyclophosphamide; Humans; Leukemia; Melphalan; Phenylbutazone; Procarbazine; Thiotepa

Topics: Adrenal Cortex Hormones; Antineoplastic Agents; Blood Viscosity; Cyclophosphamide; Drug Therapy, Combination; Humans; Leukemia; Melphalan; Multiple Myeloma; Neoplasm Staging; Prognosis

Topics: Adult; Aged; Arsenic; Benzene; Bone Marrow; Breast Neoplasms; Female; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Mycosis Fungoides; Ovarian Neoplasms; Paraproteinemias; Waldenstrom Macroglobulinemia

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: 2-Naphthylamine; Alkylating Agents; Antineoplastic Agents; Busulfan; Carcinogens; Cocarcinogenesis; Cyclophosphamide; Female; Hodgkin Disease; Humans; Leukemia; Male; Melphalan; Neoplasms; Nitrogen Mustard Compounds; Radiotherapy; Time Factors

Topics: Anemia, Aplastic; Benzene; Benzene Derivatives; Bone Marrow; Bone Marrow Cells; Chloramphenicol; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Lymphoid; Leukemia, Myeloid; Melphalan; Mutation; Occupational Diseases; Oxymetholone; Phenylbutazone

Topics: Adult; Aged; Antineoplastic Agents; Bone Marrow; Bone Marrow Cells; Drug Therapy, Combination; Female; Hematocrit; Hemoglobins; Humans; Immunoglobulins; Leukemia; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Remission, Spontaneous; Syndrome

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Anemia; Anemia, Hemolytic, Autoimmune; Blood Urea Nitrogen; Glucocorticoids; Humans; Hypercalcemia; Immunoglobulins; Leukemia; Lymphoma; Melphalan; Multiple Myeloma; Myeloma Proteins; Prednisone; Waldenstrom Macroglobulinemia

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

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

Microsatellite instability (MSI) induction by alkylating agent-based chemotherapy (ACHT) may underlie both tumor resistance to chemotherapy and secondary leukaemias in cancer patients. We investigated if ACHT could induce MSI in tumor-derived plasma-circulating DNA (pfDNA) and in normal peripheral blood mononuclear (PBMN) cells. We also evaluated if amifostine could interfere with this process in an in-vitro model.. MSI was determined in pfDNA, PBMN cells and urine cell-free DNA (ufDNA) of 33 breast cancer patients before and after ACHT. MCF-7 cells and PBMN from normal donors were exposed in vitro to melphalan, with or without amifostine.. We observed at least one MSI event in PBMN cells, pfDNA or ufDNA of 87, 80 and 80% of patients, respectively. In vitro, melphalan induced MSI in both MCF-7 and normal PBMN cells. In PBMN cells, ACHT-induced MSI occurred together with a significant decrease in the expression of the DNA mismatch repair gene hMSH2. Amifostine decreased hMSH2 expression and also prevented MSI induction only in normal PBMN cells.. ACHT induced MSI in PBMN cells and in tumour-derived pfDNA. Because of its protective effect against ACHT induction of MSI in normal PBMN cells in vitro, amifostine may be a potential agent for preventing secondary leukaemias in patients exposed to ACHT.

Topics: Amifostine; Antimutagenic Agents; Antineoplastic Agents, Alkylating; Breast Neoplasms; Cell Line, Tumor; DNA Mismatch Repair; Female; Humans; Leukemia; Leukocytes, Mononuclear; Melphalan; Microsatellite Instability; Microsatellite Repeats; Middle Aged; MutS Homolog 2 Protein; Reference Values

A non-total body irradiation-containing preparative regimen was studied in young children (<4 years old) undergoing unrelated donor cord blood transplantation as part of the Cord Blood Transplantation trial for the treatment of acute lymphoblastic leukemia (n = 14), acute myeloid leukemia (n = 13), undifferentiated leukemia (n = 1), juvenile myelomonocytic leukemia (n = 2), and myelodysplastic syndromes (n = 2). Donor/recipient HLA matching based on low-/intermediate-resolution molecular typing for HLA-A and -B and high-resolution HLA-DRB1 typing was 5/6 or 6/6 (n = 21) or 4/6 (n = 11). The preparative therapy consisted of busulfan, melphalan, and antithymocyte globulin, with cyclosporine and corticosteroids for graft-versus-host disease (GVHD) prophylaxis. The median age was 1.6 years (range, 0.5-3.9 years), and the median weight was 10.5 kg (range, 5.8-19.5 kg). Cord blood grafts contained a median of 10.7 x 10 7 nucleated cells per kilogram (range, 4.6-29.2) and 2.6 x 10(5) CD34+ cells per kilogram (range, 0.7-8.3). The cumulative incidence (CINC) of neutrophil recovery (absolute neutrophil count >500/microL) at day 42 was 0.59 (95% confidence interval [CI], 0.44-0.78) at a median of 31 days (range, 23-55 days). The CINC and Kaplan-Meier estimates of platelet engraftment at day 180 were 0.53 (95% CI, 0.34-0.69) and 0.82 (95% CI, 0.61-1.00), respectively. CINC estimates of grade III/IV acute GVHD at day 100 and chronic GVHD at 1 year were 0.25 (95% CI, 0.09-0.41) and 0.26 (95% CI, 0.09-0.44), respectively. The CINC estimate of relapse was 0.31 (95% CI, 0.16-0.47) at 2 years. With a median follow-up of 27.8 months (range, 23.4-46.7 months), the probability of survival at 1 year was 0.47 (95% CI, 0.30-0.64). A preparative regimen containing a busulfan/melphalan/antithymocyte globulin preparative regimen is well tolerated in the setting of unrelated donor cord blood transplantation for childhood leukemia and can serve as a platform preparative regimen for intensifying host immunosuppression and antileukemic therapy to allow for improved engraftment and improved relapse-free survival.

Topics: Antilymphocyte Serum; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child, Preschool; Cord Blood Stem Cell Transplantation; Disease-Free Survival; Female; Graft Survival; Graft vs Host Disease; Histocompatibility Testing; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Leukemia; Male; Melphalan; Retrospective Studies; Transplantation Conditioning; Whole-Body Irradiation

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

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

The anti-emetic efficacy of a combination of tropisetron and dexamethasone was studied in 33 patients who underwent bone marrow transplantation. Another 50 patients receiving conventional anti-emetic therapies in bone marrow transplantation served as control. On the first and second days of preconditioning chemotherapy, 51% and 36% respectively of patients in the tropisetron and dexamethasone group did not experience vomiting, compared with only 12% and 10% of control group patients (P < 0.001). The mean number of episodes of vomiting in the tropisetron and dexamethasone group was also significantly lower than in the control group (0.97+/-1.65 vs 3.50+/-2.45 and 1.30+/-1.40 vs 4.44+/-2.91 respectively, both P < 0.001). Control of vomiting in the two groups was not significantly different during days 3-6. Analysis of patients receiving busulfan and cyclophosphamide as the preconditioning regimen still showed better anti-emetic control in the tropisetron and dexamethasone group than in the control group on the first two days of treatment (total control rate 33.3% vs 6.5% and 44.4% vs 12.9% respectively, P < 0.001). Patients given tropisetron and dexamethasone combination more frequently suffered from dizziness and burning sensation of the chest. However, diarrhea and extrapyramidal symptoms were the most frequent adverse effects seen after using conventional anti-emetic combination. The combination of tropisetron and dexamethasone was thus superior to conventional anti-emetic combinations in preventing vomiting during preconditioning period of bone marrow transplantation. The adverse effects of this combination were minimal and well tolerated by patients.

Topics: Adolescent; Adult; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Carmustine; Child; Cyclophosphamide; Cytarabine; Dexamethasone; Dizziness; Drug Therapy, Combination; Female; Headache; Heartburn; Humans; Indoles; Leukemia; Male; Melphalan; Middle Aged; Multiple Myeloma; Podophyllotoxin; Transplantation Conditioning; Tropisetron; Vomiting; Whole-Body Irradiation

Sixteen patients with poor-prognosis acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and non-Hodgkin's lymphoma (NHL) underwent conditioning with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) (BUCY-2) plus melphalan (90 or 135 mg/m2) and autologous bone marrow transplantation (AuBMT) in a phase I study. At the melphalan dose of 90 mg/m2, grade greater than or equal to 3 regimen-related toxicity (RRT) was observed in five patients (31%; 95% confidence interval [CI], 11% to 59%), with hepatic (venoocclusive disease [VOD]) and urinary (hemorrhagic cystitis) RRT being the most frequent complications. Further escalation of the melphalan dose to 135 mg/m2 was deemed excessively toxic, as three of five patients had grade greater than or equal to 3 RRT. Following this experience, 21 patients with multiple myeloma (MM) and chronic myelogenous leukemia (CML) were treated with BUCY-2 plus melphalan 90 mg/m2 and AuBMT in separate studies. Three of these patients--all with extensively pretreated MM--had grade greater than or equal to 3 RRT (14%; 95% CI, 3% to 36%); no others had grade greater than or equal to 3 RRT. Therefore, a total of eight of the 37 patients (22%; 95% CI, 10% to 38%) who received BUCY-2 plus melphalan 90 mg/m2 conditioning developed grade greater than or equal to 3 RRT; three of these patients (8%; 95% CI, 3% to 25%) died of RRT. Although limited by the relatively small number of patients, our analysis of the patients receiving this regimen showed that the presence of parameters denoting the lymphoid diagnostic group (ie, ALL, NHL, and MM), more extensive pretreatment, and/or more advanced disease status were associated with a higher incidence of grade greater than or equal to 3 RRT. Response data on the AML, ALL, and NHL patients who received BUCY-2 plus melphalan 90 mg/m2 were analyzed: three patients (all with AML in first or second remission) are leukemia-free at 3.0, 2.8, and 1.4 years after AuBMT. The actuarial 2-year event-free survival in this group is 17% (95% CI, 5% to 54%). Response data on the MM and CML patients will be reported subsequently. BUCY-2 plus melphalan at a dose of 90 mg/m2 before AuBMT produces acceptable toxicity in patients who are not heavily pretreated. A full evaluation of the antineoplastic effects of this regimen requires further study.

Topics: Actuarial Analysis; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Combined Modality Therapy; Cyclophosphamide; Drug Evaluation; Female; Humans; Leukemia; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survival Analysis; Transplantation, Autologous

An international collaborative group of cancer registries and hospitals identified 114 cases of leukemia following ovarian cancer. We investigated the possible etiologic role of chemotherapy, radiotherapy, and other factors, using a case-control study design, with three controls matched to each case of leukemia. Chemotherapy alone was associated with a relative risk of 12 (95 percent confidence interval, 4.4 to 32), as compared with surgery alone, and patients treated with both chemotherapy and radiotherapy had a relative risk of 10 (95 percent confidence interval, 3.4 to 28). Radiotherapy alone did not produce a significant increase in risk as compared with surgery alone. The risk of leukemia was greatest four or five years after chemotherapy began, and the risk was elevated for at least eight years after the cessation of chemotherapy. The drugs cyclophosphamide, chlorambucil, melphalan, thiotepa, and treosulfan were independently associated with significantly increased risks of leukemia, as was the combination of doxorubicin hydrochloride and cisplatin. Chlorambucil and melphalan were the most leukemogenic drugs, followed by thiotepa; cyclophosphamide and treosulfan were the weakest leukemogens, and the effect per gram was substantially lower at high doses than at lower doses. The extent to which the relative risks of leukemia are offset by differences in chemotherapeutic effectiveness is not known.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Case-Control Studies; Chlorambucil; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Leukemia; Melphalan; Multicenter Studies as Topic; Neoplasms, Multiple Primary; Ovarian Neoplasms; Registries; Risk Factors; Thiotepa

MOPP chemotherapy was the significant breakthrough that improved the outlook for patients with advanced Hodgkin's disease. Results with alternating potentially non-cross-resistant drug combinations, including MOPP/ABVD, CAD/MOPP/ABV, and MOPP/ABV, are similar and seem to be slightly superior to those with MOPP alone. Limited adjuvant RT does not seem to add appreciably to the morbidity of chemotherapy, although its role in improving on results with chemotherapy alone has not been well studied in prospective, randomized, controlled clinical trials. There are two major challenges for the future. The first is to improve the outcome for advanced Hodgkin's disease patients, perhaps with more intensive chemotherapy and RT with use of cytokines such as the colony-stimulating factors or interleukin-1 or with rescue employing autologous bone marrow transplantation or both. The second challenge is to reduce the morbidity but not the effectiveness of treatment for advanced Hodgkin's disease patients without adverse prognostic factors.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Clinical Trials as Topic; Combined Modality Therapy; Dacarbazine; Doxorubicin; Female; Hodgkin Disease; Humans; Leukemia; Lomustine; Lymphoma; Male; Mechlorethamine; Melphalan; Middle Aged; Neoplasms, Multiple Primary; Prednisone; Procarbazine; Remission Induction; Vinblastine; Vincristine; Vindesine

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Drug Evaluation; Drug Resistance; Etoposide; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Melphalan; Neoplasm Recurrence, Local; Neoplasms; Thioguanine; Transplantation, Autologous

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

Topics: Altretamine; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Leukemia; Melphalan; Ovarian Neoplasms

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

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

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

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

Despite the continuous developments in pharmacology and the high therapeutic effect of new treatment options for patients with hematological malignancies, these diseases remain a major health issue. Our study aimed to synthesize, analyze in silico, and determine the biological properties of new melphalan derivatives. We obtained three methyl esters of melphalan having in their structures amidine moieties substituted with thiomorpholine (EM-T-MEL), indoline (EM-I-MEL), or 4-(4-morpholinyl) piperidine (EM-MORPIP-MEL). These have not yet been described in the literature. The in vitro anticancer properties of the analogs were determined against THP1, HL60, and RPMI8226 cells. Melphalan derivatives were evaluated for cytotoxicity (resazurin viability assay), genotoxicity (alkaline comet assay), and their ability to induce apoptosis (Hoechst33342/propidium iodide double staining method; phosphatidylserine translocation; and caspase 3/7, 8, and 9 activity measurements). Changes in mitochondrial membrane potential were examined using the specific fluorescence probe JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazol carbocyanine). The EM-T-MEL derivative had the highest biological activity, showing higher cytotoxic and genotoxic properties than the parent drug. Moreover, it showed a high ability to induce apoptosis in the tested cancer cells. This compound also had a beneficial effect in peripheral blood mononuclear cells (PBMC). In conclusion, we verified and confirmed the hypothesis that chemical modifications of the melphalan structure improved its anticancer properties. The conducted study allowed the selection of the compound with the highest biological activity and provided a basis for chemical structure-biological activity analyses.

Topics: Apoptosis; Caspases; Cell Line, Tumor; DNA Fragmentation; Hematologic Neoplasms; Humans; Leukemia; Melphalan; Membrane Potential, Mitochondrial; Models, Biological; Staining and Labeling

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

We report a pilot series of five patients who received stem cell transplantation (SCT) from a spouse for post-transplant relapse or rejection. The inclusion criterion regarding HLA disparities was three or fewer antigen mismatches in the graft-versus-host direction at the HLA-A, B, and DR loci. Four patients received spousal SCT as a third transplant attempt after post-transplant relapse and one as rescue for graft rejection. The reduced intensity conditioning (RIC) regimen consisted of fludarabine, melphalan, and anti-thymocyte globulin (ATG) with 3 Gy of total body irradiation (TBI) for relapse cases and ATG plus 4 Gy of TBI for the rejection case. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus, methylprednisolone, and mycophenolate mofetil. Peripheral blood stem cells were transplanted. Granulocyte engraftment was achieved in all cases between days 9 and 11 (median, 10) with complete spousal chimerism. In three of the five patients, no acute GVHD was observed, while one case developed grade III GVHD and one case grade IV. All four patients evaluable for the anti-leukemic effect achieved complete remission; however, all relapsed between 106 and 334 day post-transplant, and died between days 152 and 548. We suggest that spousal SCT can be performed as a repetitive SCT using a RIC regimen with low-dose ATG and steroid-containing GVHD prophylaxis.

Topics: Adult; Allografts; Antilymphocyte Serum; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Fatal Outcome; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Histocompatibility; HLA Antigens; Humans; Leukemia; Male; Melphalan; Middle Aged; Radiotherapy Dosage; Recurrence; Spouses; Transplantation Conditioning; Treatment Outcome; Vidarabine

Novel clusters of 3,5-bis(benzylidene)-4-oxo-1-piperidinyl dimers 3-5 were evaluated against human Molt4/C8 and CEM T-lymphocytes and human HeLa cervix adenocarcinoma cells as well as murine L1210 leukemia neoplasms. Several of these compounds demonstrated IC50 values in the submicromolar and low micromolar range and compounds possessing 4-fluoro, 4-chloro and 3,4,5-trimethoxy substituents in the series 3 and 4 were identified as potent molecules. A heat map revealed the very high cytotoxic potencies of representative compounds against a number of additional leukemic and lymphoma cell lines and displayed greater toxicity to these cells than nonmalignant MCF10A and Hs-27 neoplasms. These dienones are more refractory to breast and prostate cancers. The evaluation of representative compounds in series 3-5 against a panel of human cancer cell lines revealed them to be potent cytotoxins with average IC50 values ranging from 0.05 to 8.51 μM. In particular, the most potent compound 4g demonstrated over 382-fold and 590-fold greater average cytotoxic potencies in this screen than the reference drugs, melphalan and 5-fluorouracil, respectively. A mode of action investigation of two representative compounds 3f and 4f indicated that they induce apoptosis which is due, at least in part, to the activation of caspase-3 and depolarization of the mitochondrial membrane potential.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Dimerization; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HeLa Cells; HL-60 Cells; Humans; Leukemia; Lymphoma; Molecular Structure; Piperidines; Structure-Activity Relationship

Apoptosis is the principal molecular goal of chemotherapeutics for effective anticancer action. We studied the effect of 50% ethanolic-water extracts of Pinus kesiya, Cratoxylum formosum ssp. pruniflorum and melphalan on cytotoxicity and apoptosis induction for human leukemic U937 cells, and explored the mode of action using FTIR microspectroscopy. The number of viable U937 cells in vitro was decreased in a concentration-dependent manner by all tested compounds, although potency differed between the U937 and Vero cells. Melphalan and the extract of C. formosum exhibited relatively lower IC(50) values (15.0 ± 1.0 and 82.7 ± 3.2 μg/mL respectively) and higher selectivity (selective index>3) than the extract of P. kesiya (299.0 ± 5.2 μg/mL; selective index<3) on the U937 cells. All three compounds significantly induced apoptosis through the late stage - seen by the indicative DNA ladder - with the most effective being melphalan, then the P. kesiya and C. formosum extracts. FTIR microspectroscopy revealed that all three compounds raised the intensity of the β-pleated sheet - higher than that of the untreated U937 cells - corresponding to a shift in the α-helix band associated with an alteration in the secondary structure of the protein band, confirming induction of apoptosis via pro-apoptotic proteins. The differences in intensity of the FTIR bands associated with lipids, proteins and nucleic acids were responsible for discrimination of the anticancer mode of action of each of the three compounds. The FTIR data suggest that the two plant extracts possessed anticancer activity with a different mode of action than melphalan.

Topics: Antineoplastic Agents; Apoptosis; Carbohydrates; Cell Line, Tumor; Clusiaceae; Cluster Analysis; DNA; Ethanol; Humans; Leukemia; Lipids; Melphalan; Pinus; Plant Extracts; Principal Component Analysis; Proteins; RNA; Spectroscopy, Fourier Transform Infrared; Water

Microtubules are dynamic structures that play a crucial role in cellular division and are recognized as an important target for cancer therapy. In search of new compounds with strong antiproliferative activity and simple molecular structure, a new series of 2-amino-3-(3',4',5'-trimethoxybenzoyl)-5-(hetero)aryl ethynyl thiophene derivatives was prepared by the Sonogashira coupling reaction of the corresponding 5-bromothiophenes with several (hetero)aryl acetylenes. When these compounds were analyzed in vitro for their inhibition of cell proliferation, the 2- and 3-thiophenyl acetylene derivatives were the most powerful compounds, both of which exerted cytostatic effects at submicromolar concentrations. In contrast, the presence of a more flexible ethyl chain between the (hetero)aryl and the 5-position of the thiophene ring resulted in significant reduction in activity relative to the 5-(hetero)aryl acetylene substituted derivatives. The effects of a selected series of compounds on cell cycle progression correlated well with their strong antiproliferative activity and inhibition of tubulin polymerization. We found that the antiproliferative effects of the most active compounds were associated with increase of the proportion of cells in the G(2)/M and sub-G(1) phases of the cell cycle.

Topics: Animals; Antimitotic Agents; Cell Line, Tumor; Cell Proliferation; Female; Humans; Leukemia; Mice; Molecular Structure; Structure-Activity Relationship; Thiophenes; Uterine Cervical Neoplasms

The main limitations to umbilical cord blood (UCB) transplantation (UCBT) in adults are delayed engraftment, poor immunological reconstitution and high rates of non-relapse mortality (NRM). Double UCBT (DUCBT) has been used to circumvent the issue of low cell dose, but acute GVHD remains a significant problem. We describe our experience in 32 subjects, who underwent DUCBT after reduced-intensity conditioning with fludarabine/melphalan/antithymocyte globulin and who received sirolimus and tacrolimus to prevent acute GVHD. Engraftment of neutrophils occurred in all patients at a median of 21 days, and platelet engraftment occurred at a median of 42 days. Three subjects had grade II-IV acute GVHD (9.4%) and chronic GVHD occurred in four subjects (cumulative incidence 12.5%). No deaths were caused by GVHD and NRM at 100 days was 12.5%. At 2 years, NRM, PFS and OS were 34.4, 31.2 and 53.1%, respectively. As expected, immunologic reconstitution was slow, but PFS and OS were associated with reconstitution of CD4(+) and CD8(+) lymphocyte subsets, suggesting that recovery of adaptive immunity is required for the prevention of infection and relapse after transplantation. In summary, sirolimus and tacrolimus provide excellent GVHD prophylaxis in DUCBT, and this regimen is associated with low NRM after DUCBT.

Topics: Adult; Aged; Antilymphocyte Serum; Cord Blood Stem Cell Transplantation; Fetal Blood; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Melphalan; Middle Aged; Sirolimus; Tacrolimus; Transplantation Conditioning; Vidarabine

Topics: Animals; Antineoplastic Agents, Alkylating; Carcinogenicity Tests; Carcinogens, Environmental; Drug Labeling; Government Regulation; Guidelines as Topic; Humans; Leukemia; Melphalan; Mice; Molecular Structure; Neoplasms; Rats

Leukemic transformation (LT) from myelofibrosis has a very poor prognosis with the current treatment strategies. We hypothesized that allogeneic stem cell transplantation (ASCT) can improve outcomes for patients with LT, and reviewed 55 consecutive patients that were treated for myelofibrosis with ASCT at our institution. Fourteen patients (25%) were identified to have LT. Thirteen of these patients received induction chemotherapy and 6 achieved remission at the time of transplant. Conditioning regimen was melphalan (Mel)-based in 9 patients. All patients engrafted and achieved remission after transplant, whereas 4 subsequently relapsed. After a median follow-up of 31 months, 6 patients (49%) survived long term. Although limited by a small number of patients, this study suggests that patients with myelofibrosis and LT may achieve long-term remission after induction chemotherapy and ASCT.

Topics: Aged; Cell Transformation, Neoplastic; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Male; Melphalan; Middle Aged; Primary Myelofibrosis; Prognosis; Transplantation Conditioning; Treatment Outcome

Cytotoxicity assays in 96-well tissue culture plates allow rapid sample handling for multicondition experiments but have a limited dynamic range. Using DIMSCAN, a fluorescence digital image system for quantifying relative cell numbers in tissue culture plates, we have developed a 96-well cytotoxicity assay with a >4-log dynamic range.. To overcome background fluorescence that limits detection of viable cells with fluorescein diacetate, we used 2'4'5'6'-tetrabromofluorescein (eosin Y) to quench background fluorescence in the medium and in nonviable cells to enhance the reduction of background fluorescence achieved with digital image thresholding. The sensitivity and linearity of the new assay were tested with serial dilutions of neuroblastoma and leukemia cell lines. DIMSCAN was compared with other in vitro cytotoxicity assays: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony formation, and trypan blue dye exclusion.. Without background fluorescence reduction, scans produced a nearly flat curve across various cell concentrations from 100 to 10(6) cells per well. Either digital image thresholding or eosin Y dramatically reduced background fluorescence, and combining them achieved a linear correlation (r > 0.9) of relative fluorescence to viable cell number over >4 logs of dynamic range, even in the presence of 4 x 10(4) nonviable cells per well. Cytotoxicity of deferoxamine for neuroblastoma cell lines measured by the DIMSCAN assay achieved dose-response curves similar to data obtained by manual trypan blue counts or colony formation in soft agar but with a wider dynamic range. Long-term cultures documented the clonogenic ability of viable cells detected by DIMSCAN over the entire dynamic range. The cytotoxicity of two drug combinations (buthionine sulfoximine + melphalan or fenretinide + safingol) was tested using both DIMSCAN and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, and the wider dynamic range of DIMSCAN facilitated detection of synergistic interactions.. DIMSCAN offers the ability to rapidly and efficiently conduct cytotoxicity assays in 96-well plates with a dynamic range of >4 logs. This assay enables rapid testing of anticancer drug combinations in microplates.

Topics: Antineoplastic Combined Chemotherapy Protocols; Buthionine Sulfoximine; Cell Proliferation; Drug Screening Assays, Antitumor; Drug Synergism; Enzyme Inhibitors; Eosine Yellowish-(YS); Fenretinide; Fluorescent Dyes; Humans; Leukemia; Melphalan; Microscopy, Fluorescence; Neuroblastoma; Protein Kinase C; Sphingosine; Tumor Cells, Cultured; Tumor Stem Cell Assay

Reduced-intensity conditioning (RIC) regimens are increasingly used in allogeneic stem-cell transplantation (SCT). There are no data whether any of these regimens has advantage and in what setting. We retrospectively analyzed SCT outcomes in 151 patients given fludarabine-based RIC for various hematological malignancies; 72 conditioned with fludarabine and intravenous-busulfan (FB) and 79 with fludarabine and melphalan (FM). FM was more myelosuppressive. Grade III-IV organ toxicity occurred in 31 and 53% of FB and FM recipients (P=0.005) and acute graft-versus-host disease grade II-IV in 33 and 53%, respectively (P=0.01). Non-relapse mortality rate (NRM) was 16 and 40%, respectively (P=0.003). Active disease (HR 2.2, P=0.003) and prior autologous SCT (HR 1.7, P=0.04) predicted inferior overall survival (OS). Among patients transplanted in remission, OS was 72 and 36% after FB and FM, respectively (P=0.03) due to increased NRM with FM. Similarly, patients transplanted in active disease experienced higher NRM with FM, however lower relapse rates resulted in equivalent OS. In conclusion, there are marked differences in outcome between RIC regimens that are theoretically dose-equivalent. The FM regimen is more myelosuppressive and toxic but controls disease better. FB was associated with improved survival in patients transplanted in remission. These observations merit further study in prospective studies.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Male; Melphalan; Middle Aged; Recurrence; Retrospective Studies; Time Factors; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

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

The use of low density lipoprotein (LDL) as drug carrier in acute myeloblastic leukemia chemotherapy is attractive due to high LDL uptake by leukemic cells. Lipid-based formulations, such as liposomes or microemulsions are promising alternatives. In the current study, we incorporated N-trifluoroacetyl-adriamycin-14-valerate (AD32), a lipophilic derivative of daunorubicin (DNR), and WB4291, a lipophilic alkylating agent, into LDL or lipid microemulsions and evaluated their cytotoxic activities towards leukemic cell lines using as references DNR and melphalan. The incorporation of AD32 into LDL or emulsion resulted in complexes with poor cytotoxicity. WB4291-LDL and WB4291-emulsion exerted, on the other hand, promising cytotoxic effects towards parental and resistant K562 and HL60 cell lines.

Topics: Antineoplastic Agents, Alkylating; Drug Carriers; Drug Stability; Emulsions; HL-60 Cells; Humans; K562 Cells; Leukemia; Lipoproteins, LDL; Melphalan; Nitrogen Mustard Compounds; Oleic Acid

We prospectively assessed the effectiveness of cryotherapy after high-dose L-PAM to prevent oral mucositis. Cryotherapy with ice tips was commenced 15 minutes before L-PAM administration, and continued until the end of administration. Twenty-six patients were enrolled in this study. Thirteen patients with myeloma were treated with 200 mg/m2 L-PAM followed by autologous peripheral blood stem cell transplantation, and 13 patients (4 AML, 4 MDS, 2 ALL, 2 lymphoma and 1 CML) were treated with 140 mg/m2 L-PAM followed by allogeneic stem cell transplantation. Grade 1 mucositis occurred in four of 13 patients (31%) with 200 mg/m2 L-PAM, and 2 of 13 patients (16%) with 140 mg/m2 L-PAM. Only one patient had grade 2 mucositis, and no grade 3 mucositis were observed. The procedure was well tolerated in all patients. These data suggest that cryotherapy is effective to minimize L-PAM-induced oral mucositis.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Cryotherapy; Female; Humans; Leukemia; Lymphoma; Male; Melphalan; Middle Aged; Stem Cell Transplantation; Stomatitis

Polyadenosylation of nuclear enzymes is well known to regulate the cellular repair capacity after DNA damage. PARP mediates the transfer of poly-ADP-ribose moieties on itself and other nuclear proteins by the breakdown of NAD+. The present study investigated how modulation of PARP activity interferes with cell death induced by two different alkylating agents used in cancer chemotherapy. 1-methyl-3-nitro-1-nitrosoguanidinium (MNNG) decreased cellular reduction capacity (WST-1 assay) in HL60 and CCRF-CEM cells, accompanied by increased activity of PARP and depletion of intracellular NAD+ and ATP. Pretreatment with the PARP inhibitors 3-AB or 4-AN resulted in transient cell protection, which was associated with a switch from necrosis to apoptosis in CCRF-CEM cells and enhanced apoptosis in HL60 cells. Both PARP inhibitors delayed the drop in WST-1 reduction and retained NAD+ and ATP levels required for apoptosis. Furthermore, 3-AB or 4-AN prevented progressive DNA degradation in MNNG-treated CCRF-CEM cells. In contrast to MNNG, we did not observe early activation of PARP, decrease in WST-1 reduction, or wasteful consumption of NAD+ and ATP after treatment with melphalan. However, preincubation with 3-AB or 4-AN resulted in decreased HL60 cell membrane blebbing and reduced formation of apoptotic bodies. In conclusion, the cell death preventing effects of PARP inhibitors are mediated by their ability to maintain cellular energy metabolism, to inhibit the activation of endonucleolytic DNA degradation and to prevent cell blebbing. Surprisingly, these protective effects of PARP inhibitors on different cell functions seem to be independent of each other and are rather determined by the respective cytotoxic mechanisms implicated by different drugs. Our results support the hypothesis, that PARP activation and/or cleavage plays a regulatory role in the induction of apoptosis.

Topics: 1-Naphthylamine; Adenosine Triphosphate; Alkylating Agents; Apoptosis; Benzamides; Cell Death; Cell Line, Tumor; Cell Size; Enzyme Inhibitors; HL-60 Cells; Humans; Leukemia; Melphalan; Methylnitronitrosoguanidine; NAD; Naphthalimides; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Quinolones

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

Platinum-based chemotherapy is the cornerstone of modern treatment for ovarian, testicular, and other cancers, but few investigations have quantified the late sequelae of such treatment.. We conducted a case-control study of secondary leukemia in a population-based cohort of 28,971 women in North America and Europe who had received a diagnosis of invasive ovarian cancer between 1980 and 1993. Leukemia developed after the administration of platinum-based therapy in 96 women. These women were matched to 272 control patients. The type, cumulative dose, and duration of chemotherapy and the dose of radiation delivered to active bone marrow were compared in the two groups.. Among the women who received platinum-based combination chemotherapy for ovarian cancer, the relative risk of leukemia was 4.0 (95 percent confidence interval, 1.4 to 11.4). The relative risks for treatment with carboplatin and for treatment with cisplatin were 6.5 (95 percent confidence interval, 1.2 to 36.6) and 3.3 (95 percent confidence interval, 1.1 to 9.4), respectively. We found evidence of a dose-response relation, with relative risks reaching 7.6 at doses of 1000 mg or more of platinum (P for trend <0.001). Radiotherapy without chemotherapy (median dose, 18.4 Gy) did not increase the risk of leukemia.. Platinum-based treatment of ovarian cancer increases the risk of secondary leukemia. Nevertheless, the substantial benefit that platinum-based treatment offers patients with advanced disease outweighs the relatively small excess risk of leukemia.

Topics: Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Carboplatin; Case-Control Studies; Cisplatin; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Humans; Leukemia; Logistic Models; Melphalan; Middle Aged; Ovarian Neoplasms; Risk Factors

DNA repair has been proposed to be an important determinant of cancer cell sensitivity to alkylating agents and cisplatin (DDP). Nucleotide excision repair (NER), which represents one of the most important cellular DNA repair processes able to remove a broad spectrum of DNA lesions, is involved in the recognition and repair of the crosslinks caused by DDP and melphalan (L-PAM). In this study, the mRNA levels of the different genes involved in NER (ERCC1, XPA, XPB, XPC, XPD, XPF) were examined in a panel of eight different human cancer cell lines, together with the overall DNA repair capacity using a host cell reactivation assay of a damaged plasmid. A statistically significant correlation was observed between the relative expression of XPA/XPC (P < 0.05) and ERCC1/XPC (P < 0.05) mRNAs. No correlation was found between the DDP and L-PAM IC50S and the relative mRNA expression of the tested NER genes. When the overall cellular DNA repair capacity was studied, carcinomas seemed to have a higher repair activity than leukaemias; but this repair DNA activity correlated neither with the mRNA expression of the different NER genes nor with DDP and L-PAM IC50S. These data seem to suggest that even if the NER pathway is an important determinant for the cytotoxicity of alkylating agents, as demonstrated by the extremely high sensitivity to alkylating agents in cells lacking this repair system, other factors have to play a role in regulating the cellular sensitivity/resistance to these antitumour drugs.

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Blotting, Northern; Cisplatin; Colonic Neoplasms; DNA Repair; Female; Gene Expression; Humans; Leukemia; Melphalan; Neoplasms; Ovarian Neoplasms; Tumor Cells, Cultured

Between February 1993 and November 1997, 62 patients with severe aplastic anaemia (SAA), acute myeloid (AML), acute lymphoid (ALL), or chronic myeloid leukaemia (CML) as well as two patients with NHL underwent allogeneic marrow transplantation (BMT) from HLA-identical or one-antigen mismatched sibling or unrelated donors. Patients received preparative regimens according to the baseline disease. Patients with SAA were conditioned with ATG/Cy (2 cases) and TAI/Cy (3 cases), AML, ALL and NHL with TBI/Cy (21 cases including two retransplantations) and CML with Mitobronitol/Ara-C/Cy except two patients conditioned traditionally with Bu/Cy. For GVHD prevention, patients received cyclosporin-A (CsA) with short course methotheraxe according to the Seattle protocol. Significantly better overall survival rates were associated with the Mitobronitol (DBM)/Ara-C/Cy conditioning regarded the patients as a whole. Autologous stem cell transplantation (bone marrow and/or peripheral blood) were performed in ten cases including 2 AML, 4 non-Hodgkin's lymphoma (NHL), 3 Hodgkin's disease (HD) and 1 patient with multiple myeloma (MM). Patients with AML and two patients with NHL were conditioned with TBI/Cy and the others with BEAM combined chemotherapy. Eight out of ten patients are leukaemia- or lymphoma-free survivors. One patient relapsed having conventional chemotherapy and interferon maintenance therapy. One patient died in a rapid relapse five months post-BMT.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Histocompatibility Testing; Humans; Hungary; Leukemia; Melphalan; Podophyllotoxin; Recurrence; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

ID50 and ID90 values for L-prolyl-L-m-[bis(chloroethyl)amino]-phenylalanyl-L-norvaline ethyl ester HCl (MF13), were determined in four murine (leukemia, lymphoma, melanoma, and lung) and eight human cancer cell lines (two leukemia, prostate, kidney, colon, two melanoma, and breast). Cytotoxic activity was 2-5 times higher than that of sarcolysin [(L-3-[bis(2-chloroethyl)amino]-L-phenylalanine] against all leukemias and lymphomas, ID50 0.5-0.9 microM, and against human solid tumors, ID50 0.4-2.1 microM. Sensitivities of L-phenylalanine mustard-resistant and methotrexate-resistant L1210 cells were the same as the naive lines, ID50 0.5 microM. Apoptosis was confirmed by: (a) morphology, revealing chromatin condensation and nuclear fragmentation; (b) flow cytometry, showing changes in cell size and DNA integrity; and (c) DNA electrophoresis, demonstrating multiples of 180-200-bp DNA units. MF13 had no cytotoxicity against human peripheral blood lymphocytes at concentrations lethal to tumor cells (ID50, 13.3 microM without and 11 microM with phytohemagglutinin stimulation) and failed to induce apoptosis. s.c. MF13 treatment of mice with advanced EL4 leukemic ascites yielded extensive apoptosis, with DNA degradation identical to that seen in vitro, and resulted in complete tumor regression in all treated mice. These results suggest MF13 as a potential chemotherapeutic agent.

Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Cell Survival; DNA Fragmentation; DNA, Neoplasm; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Flow Cytometry; Humans; Lethal Dose 50; Leukemia; Leukemia L1210; Lymphoma; Melphalan; Methotrexate; Mice; Neoplasms; Oligopeptides; Tumor Cells, Cultured

Multidrug resistance (MDR) in human cancer cells is multifactorial. Previously, we reported on the association between expression of P-glycoprotein (Pgp), the multidrug resistance-associated protein (MRP), and the lung resistance protein (LRP) with the MDR phenotype in the NCI panel of 60 human cancer cell lines used for in vitro anticancer drug screening. Eight cell lines from this panel, manifesting widely divergent levels of in vitro drug resistance were chosen to investigate the role of MRP and LRP expression at the molecular level. LRP mRNA levels, as determined by ribonuclease protection assay, varied significantly among the 8 cell lines, and correlated closely with in vitro drug resistance to both MDR and non-MDR related drugs. LRP mRNA expression was determined to be a stronger correlate of drug sensitivity than protein expression. In contrast, MRP mRNA levels were not significantly correlated with drug sensitivity. The rates of newly transcribed LRP or MRP mRNA did not correlate with mRNA levels, indicating that mRNA stability or other features of processing may be important in regulation of LRP and MRP mRNA levels. Using Southern blot analysis, LRP gene amplification was shown not to be associated with LRP overexpression. These data suggest that LRP expression may be an important determinant of the MDR phenotype in cell lines intrinsically resistant to cancer chemotherapeutic agents.

Topics: Amsacrine; Antineoplastic Agents; ATP-Binding Cassette Transporters; Cell Nucleus; Cisplatin; Colonic Neoplasms; Doxorubicin; Drug Resistance, Multiple; Female; Glycoproteins; Humans; Kidney Neoplasms; Leukemia; Lung Neoplasms; Melphalan; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Ovarian Neoplasms; Phenotype; RNA, Messenger; Transcription, Genetic; Tumor Cells, Cultured; Vault Ribonucleoprotein Particles

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

We have investigated the toxicity of dose-escalation of BCNU, etoposide and melphalan ('BEM') chemotherapy with autologous stem cell transplantation in patients with haematological malignancies. Seventy-two patients with haematological malignancies were treated with BCNU (600 mg/m2, 450 mg/m2 or 300 mg/m2), etoposide 2 g/m2 and melphalan 140 mg/m2 followed by autologous bone marrow transplantation (ABMT), n = 51, or autologous peripheral blood progenitor cell transplantation (APBPCT), n = 21. Liver and pulmonary function was monitored pretransplant and at regular intervals post-transplant. Mucositis was graded daily during in-patient stay. There was a significantly higher incidence of symptomatic pulmonary toxicity in the patients who received BCNU at 600 mg/m2 than in the other two groups, and there was a significant increase in the incidence of asymptomatic decrease in carbon monoxide (KCO) in the patients who received BCNU 450 mg/m2. There was no significant difference between the three groups in the incidence and severity of mucositis or in the incidence of transiently abnormal liver function. We conclude that etoposide at 2 g/m2 can be used without unacceptable mucositis. BCNU at 600 mg/m2 is associated with an unacceptably high incidence of lung toxicity, but at 450 mg/m2 there is minimal symptomatic lung toxicity.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Dose-Response Relationship, Drug; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Liver Function Tests; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Respiratory Function Tests; Retrospective Studies; Transplantation, Autologous

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

To study the mechanisms of resistance to alkylating agent melphalan (Mel) in leukemia cell and to investigate effect of modulation of resistance to Mel by IFN alpha.. A Mel-resistant variant of the leukemic cell line (K562/Mel) was developed in vitro by continuous exposure to Mel. The level of expression of several resistance-related gene in K562/Mel and the effect of reversal of resistance to Mel by IFN alpha were observed.. K562/Mel was 8.0-fold resistant to Mel and also cross-resistant to nitrogen mustand and thiophosphoramide, but not to carmustine and doxorubicin. This enhanced Mel resistance was associated with increased level of GST alpha gene and total GST, but not with increased level of expression of GST pi, GST mu, MDR-1 and Top-II gene. IFN alpha, at 500 IU/ml, a noncytotoxic dosage significantly increased the cytotoxicity of Mel to K562/Mel. The reversal of Mel resistance is related to the decrease of the level of expression of GST alpha gene.. Resistance to Mel is associated with increased level of GST alpha gene and total GST in leukemic cell. IFN alpha can reverse Mel resistance.

Topics: Antineoplastic Agents, Alkylating; Drug Resistance, Neoplasm; Genes, MDR; Glutathione Transferase; Humans; Interferon-alpha; Leukemia; Melphalan; Tumor Cells, Cultured

Bone marrow transplant (BMT) complications such as graft-versus-host disease (GVHD), veno-occlusive disease (VOD) and cytomegalovirus (CMV) infection are associated with high levels of circulating tumour necrosis factor-alpha (TNF), much of which may be monocyte derived. We therefore studied monocyte activation after BMT in 36 patients (18 allografts and 18 autografts); plasma neopterin and in vitro secretion of superoxide, neopterin and TNF by peripheral blood monocytes were assessed. Monocyte respiratory burst was raised at regeneration but returned to near-normal within 7 days. Plasma neopterin, and in vitro secretion of neopterin and TNF, were greater than twice normal at regeneration and remained raised for up to 6 weeks after BMT. Plasma neopterin was higher following allogeneic BMT than autologous BMT and was independent of GVHD or VOD. Low levels were seen in one patient who failed to engraft. There is evidence of increased activation of monocytes at the time of and for several weeks after engraftment post-BMT. Abnormal monocyte activation may predispose to, rather than result from, the development of complications in the early post-transplant period.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Biopterins; Bone Marrow Transplantation; Busulfan; Carmustine; Cells, Cultured; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Disease Susceptibility; Female; Graft vs Host Disease; Hepatic Veno-Occlusive Disease; Humans; Leukemia; Lymphoma; Male; Melphalan; Middle Aged; Monocytes; Neopterin; Podophyllotoxin; Respiratory Burst; Superoxides; Tumor Necrosis Factor-alpha; Whole-Body Irradiation

Apoptosis, originally defined by specific morphological changes, is characterised biochemically by non-random cleavage of DNA. Depending on cell type, this DNA cleavage proceeds from 300 and 50kbp fragments prior to, concomitantly with, or in the absence of 180bp integer fragmentation. Incorporation into fragmented DNA of biotin-labelled nucleotides by terminal deoxynucleotidyl transferase (TdT) has recently become a standard flow cytometric assay for the identification and quantitation of apoptosis. Nucleotide incorporation is visualized using avidin-tagged fluorescein isothiocyanate (FITC) (Gorczyca et al.: Cancer Res 53:1945-1951, 1993; Jonker et al.: Cytometry (Suppl 13):Abstr 99A, 1993). Here, we characterise this assay further in three different haemopoietic cell lines. Drug-induced DNA damage is not identified by the TdT assay unless it is coupled to the apoptotic response. This was demonstrated using cells in which activation of the oncogenic Abelson-encoded protein tyrosine kinase suppressed drug-induced apoptosis, but did not inhibit drug-induced DNA damage (by melphalan, hydroxyurea, or etoposide). Furthermore, the TdT assay identifies DNA fragments formed during apoptosis induced by etoposide and N-methylformamide in HL60 and MOLT-4 cells, including those high molecular weight DNA fragments formed in MOLT-4 cells which were not further cleaved to 180-200bp integer fragments. Our results support the use of flow cytometry and the TdT assay to reliably measure apoptotic cells in heterogeneous cell samples.

Topics: Abelson murine leukemia virus; Antineoplastic Agents; Apoptosis; Cell Nucleus; DNA Damage; DNA Nucleotidylexotransferase; DNA, Neoplasm; Drug Resistance, Neoplasm; Etoposide; Flow Cytometry; HL-60 Cells; Humans; Hydroxyurea; Leukemia; Melphalan; Oncogene Proteins v-abl; Protein-Tyrosine Kinases; Recombinant Proteins; Tumor Cells, Cultured

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Combined Modality Therapy; Cyclophosphamide; Female; Fluorouracil; Humans; Leukemia; Leukemia, Radiation-Induced; Manitoba; Melphalan; Methotrexate; Middle Aged; Multivariate Analysis; Neoplasms, Second Primary; Postoperative Care; Radiotherapy, Adjuvant; Time Factors

Permanent alopecia after BMT has been reported as a side-effect associated with GVHD or after busulphan conditioning therapy, primarily in adults. We have reviewed children undergoing BMT to document the frequency of incomplete hair regrowth and to evaluate factors associated with this problem. Hair regrowth was studied in 74 children who survived > 6 months following BMT undertaken for malignant and non-malignant diseases. Alopecia was categorised as severe (< 50% of pre-transplant status), moderate (50-75%) or mild (> 75% but less than normal). Overall, 18 (24.3%) of 74 patients had mild (n = 5), moderate (n = 4) or severe (n = 9) alopecia. Risk factors for alopecia were presence of chronic GVHD (67%; p < 0.001), older age (p < 0.001) and prior cranial irradiation (42%; p = 0.03). Alopecia occurred in children receiving either busulphan (31%) or total body irradiation (16%; p = 0.15) as conditioning therapy. The highest frequency was seen in patients conditioned with busulphan with or without melphalan and who received prior cranial irradiation and/or developed chronic GVHD (75%). These data indicate that alopecia after BMT in children is a significant problem and confirm, in children, the previously noted association between alopecia and chronic GVHD and busulphan. Further risk factors of older age and prior cranial irradiation are identified. Consideration needs to be given to the use of an alternative to busulphan in children who are of older age, have received prior cranial irradiation and/or are at increased risk of GVHD.

Topics: Adolescent; Adult; Age Factors; Alopecia; Bone Marrow Purging; Bone Marrow Transplantation; Busulfan; Child, Preschool; Chronic Disease; Cranial Irradiation; Female; Graft vs Host Disease; Hair; Humans; Infant; Leukemia; Male; Melphalan; Radiation Injuries; Risk Factors; Whole-Body Irradiation

This study analyses the growth and the growth hormone secretion of children given various conditioning protocols before bone marrow transplantation (BMT). Twenty nine children (14 boys, 15 girls) given BMT were classified according to their conditioning protocol: total body irradiation (TBI) given as a single exposure of 10 Grays (Gy, group I, 11 cases), or 8 Gy (group II, four cases), 12 Gy given as six fractionated doses (Group III, seven cases), or chemotherapy alone (group IV, seven cases). The arginine-insulin stimulated growth hormone peak, 2-7.5 years after BMT, was > 10 micrograms/l in all patients except four from group I (6.9-8.9 micrograms/l). A second growth hormone secretion evaluation was performed in 10 group I patients because of persistent low growth velocity despite a normal growth hormone peak. There were no significant changes in the mean (SEM) stimulated growth hormone peak (18.4 (2.2) v 20.1 (3.6) micrograms/l) at 3 (0.3) to 5.2 (0.6) years after BMT. The sleep growth hormone peaks and concentrations (n = 6) were normal. The mean cumulative height changes (SD) during the three years after BMT were: -1.4 (0.2) in group I, -0.1 (0.4) in group II, -0.4 (0.2) in group III, and 1.5 (0.5) in group IV; this was significant in groups I and IV. The final heights of two monozygotic twins (BMT donor and recipient) had differed by 17.5 cm, despite them both having normal growth hormone peaks and puberty. Eight patients, treated for congenital immune deficiency syndrome, were growth retarded at the time of BMT. Of these, only those conditioned by chemotherapy alone had significant catch up growth (2(0.6)SD) while those conditioned by a single Gy exposure did not (0(0.4)SD). It is concluded that the total radiation dose is critical for growth evolution, as is the fractionation schedule. For the TBI doses and the interval since BMT studied, there was no correlation between growth hormone peak and the height loss. The rapidity of decreased growth velocity after TBI and the comparison between the monozygotic twins suggest that radiation induced skeletal lesions are partly responsible for the decreased growth.

Topics: Bone Marrow Transplantation; Child; Child, Preschool; Clinical Protocols; Cyclophosphamide; Etoposide; Female; Growth; Growth Disorders; Growth Hormone; Humans; Infant; Insulin-Like Growth Factor I; Leukemia; Male; Melphalan; Radiotherapy Dosage; Whole-Body Irradiation

Few studies have evaluated the late effects of adjuvant chemotherapy for breast cancer. Moreover, the relation between the risk of leukemia and the amount of drug given and the interaction of chemotherapy with radiotherapy have not been described in detail.. We conducted a case-control study in a cohort of 82,700 women given a diagnosis of breast cancer from 1973 to 1985 in five areas of the United States. Detailed information about therapy was obtained for 90 patients with leukemia and 264 matched controls. The dose of radiation to the active marrow was estimated from individual radiotherapy records (mean dose, 7.5 Gy).. The risk of acute nonlymphocytic leukemia was significantly increased after regional radiotherapy alone (relative risk, 2.4), alkylating agents alone (relative risk, 10.0), and combined radiation and drug therapy (relative risk, 17.4). Dose-dependent risks were observed after radiotherapy and treatment with melphalan and cyclophosphamide. Melphalan was 10 times more leukemogenic than cyclophosphamide (relative risk, 31.4 vs. 3.1). There was little increase in the risk associated with total cyclophosphamide doses of less than 20,000 mg.. Although leukemia occurs in few patients with breast cancer, significantly elevated risks were linked to treatments with regional radiation and alkylating agents. Melphalan is a more potent leukemogen than cyclophosphamide or radiotherapy. Low risks were associated with the levels of cyclophosphamide in common use today. Systemic drug therapy combined with radiotherapy that delivers high doses to the marrow appears to enhance the risk of leukemia.

Topics: Aged; Alkylating Agents; Breast Neoplasms; Case-Control Studies; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Female; Humans; Leukemia; Leukemia, Myeloid, Acute; Leukemia, Radiation-Induced; Melphalan; Middle Aged; Myelodysplastic Syndromes; Radiotherapy; Radiotherapy Dosage; Risk

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

Two murine tumour models, the L1210 leukaemia and the ADJ/PC6 plasmacytoma, have featured prominently in the preclinical development of platinum drugs. Mindful of the unequivocal need to discover new platinum-based drugs exhibiting activity in cisplatin/carboplatin refractory and relapsed cancers, and to devise clinically-predictive screening models, we have generated resistance in vivo in the ADJ/PC6 plasmacytoma to cisplatin (19- to 21-fold), to carboplatin (25-fold), iproplatin (greater than 14-fold) and tetraplatin (10-fold). The chemo-sensitivity profiles of these tumours have been compared with L1210 leukaemia lines resistant to either cisplatin (10-fold) or tetraplatin (34-fold). In cross-resistance studies, the L1210 and ADJ/PC6 resistant variants provided conflicting predictions of structures likely to circumvent cisplatin-acquired resistance. In particular, the L1210/cisplatin resistant model exhibited cross-resistance to carboplatin and iproplatin, whereas the diaminocyclohexane (DACH)-containing complex, tetraplatin, was even more active in the cisplatin resistant tumour than in the 'wild-type' tumour. The ADJ/PC6/cisplatin resistant tumour, however, was cross-resistant, not only to carboplatin and iproplatin, but also to tetraplatin. These data provide an important caveat on the adoption of single acquired resistant animal tumour models for platinum drug development.

Topics: Animals; Carboplatin; Cell Line, Transformed; Cisplatin; Drug Resistance; Drug Screening Assays, Antitumor; Female; Leukemia; Melphalan; Mice; Mice, Inbred Strains; Neoplasms, Experimental; Organoplatinum Compounds; Plasmacytoma

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

Topics: Antineoplastic Agents; Chlorambucil; Hodgkin Disease; Humans; Leukemia; Melphalan; Neoplasms; Risk Factors

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

Three cases of secondary leukemia developing after chemotherapy and/or radiotherapy for myeloma, mycosis fungoides, and non-Hodgkin's lymphoma are reported. The first case was a 51-year-old man with IgG-lambda myeloma, treated with melphalan and prednisolone, who developed acute myelomonocytic leukemia 54 months after the diagnosis of myeloma. The second case was a 54-year-old woman with mycosis fungoides treated with radiation, predonine, and cyclophosphamide, who developed acute megakaryoblastic leukemia 298 months after the diagnosis of mycosis fungoides. The third case was a 35-year-old woman with stage IV non-Hodgkin's lymphoma treated with VEMP who developed acute myelogenous leukemia 26 months after the diagnosis of malignant lymphoma. All cases showed pancytopenia and two of three cases had morphologic abnormality in several hemopoietic cell lineages in the leukemic stage. There is a possibility that second malignancies are an increasingly recognized complication in the patients treated with a large amount of chemo-radiotherapy.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Humans; Leukemia; Leukemia, Megakaryoblastic, Acute; Leukemia, Myeloid, Acute; Leukemia, Radiation-Induced; Lymphoma, Non-Hodgkin; Male; Melphalan; Mercaptopurine; Middle Aged; Multiple Myeloma; Mycosis Fungoides; Pancytopenia; Prednisolone; Vincristine

K 18, an IgG-Melphalan conjugate was administered to 30 patients, who had recurrent hematopoietic malignancy. Ten out of the 30 patients received single doses of 1 to 20 enteric tablets containing 10 mg of K 18, as a phase I study. No side effects were observed. K 18 was administered every day to the remaining 20 patients in order to evaluate the side effects and therapeutic effects, as a phase II study. One patient attained partial remission. Although no remission effect was obtained in 14 of the 20 patients, antitumor effects such as a decrease in leukemia cells, were observed in 4 of 20 patients. As to side effects, neither recurrence of tumor nor cumulative toxicity were shown in one patient with NHL who received only K 18 for 14 months as maintenance therapy. Evaluation of antitumor effect was difficult in the case of the remaining 4 patients. In the 20 cases who entered the phase II study, a decrease in neutrophils was observed in 2 patients, a slight decrease in platelets in 3 patients and increased transaminase activity in one patient as side effects of K 18. In brief, compared with Melphalan, K 18 has between 1.3 and 2 times a more potent therapeutic effect, with extremely low side effects.

Topics: Administration, Oral; Adolescent; Adult; Drug Administration Schedule; Drug Evaluation; Female; Humans; Immunoglobulin G; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Multiple Myeloma

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

Experience with 19 autologous bone marrow transplantations shows that this approach may produce a high proportion of complete remissions in otherwise resistant tumours. Although most responses are of short duration, they suggest that longterm disease-free survival may be achieved in patients with poor prognosis if treated earlier in the course of disease.

Topics: Adult; Bone Marrow Transplantation; Child; Cyclophosphamide; Female; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphoma; Male; Melphalan; Middle Aged; Postoperative Complications; Remission Induction

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: Adolescent; Adult; Bone Marrow Transplantation; Cyclophosphamide; Female; Humans; Leukemia; Lymphoma; Male; Melphalan

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

Among 20 patients with acute nonlymphocytic leukemia or dysmyelopoietic preleukemia secondary to Alkeran therapy for another tumor, four had a del(12)(p11-p12) and four had a translocation to 19q13 among multiple karyotypic alterations in their neoplastic hematopoetic clones. It is suggested that these two cytogenetic abnormalities may occur nonrandomly in such hemic disorders and may play a limited role in their pathogenesis.

Topics: Chromosome Deletion; Chromosomes, Human, 19-20; Chromosomes, Human, 6-12 and X; Humans; Leukemia; Melphalan; Preleukemia; Translocation, Genetic

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

A register of 746 cases of secondary acute leukemias has been established by reviewing the literature from 1930-1980. Out of these 680 belong to acute nonlymphocytic leukemias, FAB M1-M6. Data have been subjected to a multiparameter analysis in term of previous therapy and subtype characteristics of acute nonlymphocytic leukemia (ANLL). There are indications that secondary ANLL are characterized by the preponderance of early acute myeloblastic leukemias if compared to de novo ones. Furthermore it has been shown that alkylating agents induced decidedly more acute myelomonocytic leukemias whereas irradiation tended to induce more acute myeloblastic leukemia. Since secondary acute leukemias represent a serious late consequence of alkylating agent and irradiation therapy it is high time to find new therapeutical modalities for lymphomas and to consider the withdrawal of alkylating agents from the therapy of autoimmune disorders.

Topics: Alkylating Agents; Cell Differentiation; Chlorambucil; Combined Modality Therapy; Cyclophosphamide; Esterases; Humans; Leukemia; Leukemia, Radiation-Induced; Melphalan; Peroxidases

Topics: Adult; Bone Marrow Transplantation; Combined Modality Therapy; Humans; Infant; Leukemia; Male; Melphalan; Neoplasms

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

Seven patients with relapsed acute leukaemia were treated with high-dose melphalan (HDM) followed by the infusion of autologous cryopreserved remission marrow. Toxicity was minimal and all seven patients had a complete response. Four patients are still in unmaintained remission at 14, 13, 10, and 3 months, the first two having received a second course of HDM to consolidate the result. The role of HDM as a form of intensification therapy for patients with acute myeloid leukaemia in first remission should be investigated.

Topics: Adult; Aged; Bone Marrow; Bone Marrow Transplantation; Child, Preschool; Female; Humans; Leukemia; Male; Melphalan; Middle Aged; Nausea; Prognosis; Recurrence

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

Two patients with IgA myeloma and one patient with kappa light chain disease developed sideroblastic anaemia from two to four years after the initial diagnosis. All had previously received radiotherapy and chemotherapy (melphalan and prednisone). In two patients the myeloma was quiescent when the sideroblastic change occurred. Leukaemia occurred in two patients two and seven months respectively after the diagnosis of sideroblastic anaemia was made. In one of them, the myeloma became active again at the same time. The development of sideroblastic anaemia may be a pre-leukaemic event and may be recognised by the appearance of a dimorphic blood film.

Topics: Anemia, Sideroblastic; Female; Humans; Immunoglobulin A; Immunoglobulin kappa-Chains; Leukemia; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Preleukemia

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

Topics: Female; Humans; Leukemia; Lichen Planus; Melphalan; Middle Aged

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

Topics: Cell Transformation, Neoplastic; Humans; Leukemia; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Time Factors

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

An antitoxic polytissular principle extracted from various tissues, improves the survival time of the AKR genetically leukemic mouse and protects it against the toxicity of an antimitotic, the para-di-(2-chlorethyl)-1-phenylalanine, used in leukemia and myelomae.

Topics: Animals; Leukemia; Melphalan; Mice; Mice, Inbred AKR; Tissue Extracts

DNA/cell distributions were recorded by automated cytofluorometry (=pulse cytophotometry) in bone-marrow aspirates of leukaemia and lymphosarcoma patients subjected to chemotherapy. In most cases, early perturbations in DNA/cell histographs were observed, characteristically reflecting the known mode of action of the drugs. These changes in general preceded the clinical observation of drug response. In a series of 23 measurements in 19 patients, a positive correlation between early cytophotometric changes and clinical effects of chemotherapy was observed in 17 patients. Five patients were negative for both cytophotometric and clinical reactions and one patient was probably false-positive. The validity of the assay for early detection of drug resistance in acute leukaemia and related diseases is discussed.

Topics: Adult; Antineoplastic Agents; Asparaginase; Bone Marrow; Bone Marrow Cells; Cell Division; Child; Cytarabine; DNA, Neoplasm; Doxorubicin; Fluorometry; Humans; Leukemia; Lymphoma, Non-Hodgkin; Melphalan; Prednisone; Vincristine

Two patients with multiple myeloma and one patient with a plasma-cytoma are reported in whom acute leukaemia developed following long-term treatment with melphalan. Each patient had a complete remission of the plasma cell disorder during which time the bone marrow was moderately to severely hypoplastic. The end of the clinical remission was heralded by a dyserythropoietic anaemia which persisted several months before the emergence of the terminal acute leukaemia. Marked chromosomal abnormalities were observed in marrow cells during the dyserythropoietic phase.

Topics: Bone Marrow; Bone Marrow Cells; Chromosome Aberrations; Chromosomes; Erythropoiesis; Female; Humans; Leukemia; Male; Melphalan; Middle Aged; Multiple Myeloma; Plasmacytoma

Topics: Adenine Nucleotides; Adenosine Diphosphate; Amidines; Antibiotics, Antineoplastic; Bleomycin; Blood Platelets; Breast Neoplasms; Bronchial Neoplasms; Cyclophosphamide; Doxorubicin; Firefly Luciferin; Fluorouracil; Glyoxal; Hodgkin Disease; Humans; Hydrazones; Leukemia; Luciferases; Lymphocytes; Melphalan; Methotrexate; Neoplasms; Nephelometry and Turbidimetry; Plasmacytoma; Platelet Aggregation; Vinca Alkaloids

Topics: Animals; Antineoplastic Agents; Biological Assay; Carmustine; Cyclohexanes; Cyclophosphamide; Cytarabine; Daunorubicin; Disease Models, Animal; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Fluorouracil; Hodgkin Disease; Humans; Leukemia; Leukemia L1210; Leukemia, Experimental; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphoma; Male; Mechlorethamine; Melphalan; Mice; Mice, Inbred AKR; Multiple Myeloma; Nitrosourea Compounds; Prednisone; Remission, Spontaneous; Vinblastine; Vincristine

Topics: Adult; Aged; Alkylating Agents; Cyclophosphamide; Female; Humans; Leukemia; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma

Topics: Animals; Benzyl Compounds; Brain; DDT; Electron Spin Resonance Spectroscopy; Free Radicals; Humans; Kinetics; Leukemia; Liver; Lung Neoplasms; Lymphocytes; Mathematics; Melphalan; Mercaptopurine; Mice; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Nitrosourea Compounds; Rats; Thiotepa; Time Factors

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

Topics: Antibiotics, Antineoplastic; Busulfan; Chlorambucil; Chromosome Aberrations; Chromosome Disorders; Humans; Leukemia; Melphalan; Phosphorus Isotopes; Polycythemia Vera

Topics: Adenocarcinoma; Autoimmune Diseases; Autopsy; Bone Marrow; Breast Neoplasms; Female; Humans; Immunoglobulin G; Leukemia; Melphalan; Middle Aged; Multiple Myeloma

Topics: Agammaglobulinemia; Antibodies; Antigens, Bacterial; Blood Protein Disorders; Blood Proteins; Busulfan; Chlorambucil; Electrophoresis, Paper; Hodgkin Disease; Humans; Immunodiffusion; Immunoelectrophoresis; Immunoglobulin A; Immunoglobulins; Immunosuppression Therapy; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Mannomustine; Melphalan; Primary Myelofibrosis; Radiation Effects; Saliva; Skin Tests; Spleen; Time Factors

Topics: Adult; Aged; Cyclophosphamide; Female; Humans; Leukemia; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Urethane

Topics: Alkylating Agents; Female; Humans; Leukemia; Melphalan; Multiple Myeloma; Thiotepa

Topics: Aged; Bone Marrow Cells; Clone Cells; Cyclophosphamide; Erythrocytes; Female; Humans; Immunoglobulin G; Immunoglobulin M; Leukemia; Male; Melphalan; Middle Aged; Multiple Myeloma; Waldenstrom Macroglobulinemia

Topics: Adenoma; Adolescent; Adult; Aged; Anemia, Hypochromic; Anemia, Macrocytic; Anemia, Sideroblastic; Blood Protein Disorders; Chlorambucil; Female; Hemoglobinometry; Humans; Immunosuppressive Agents; Kidney Neoplasms; Leukemia; Lupus Erythematosus, Systemic; Male; Melphalan; Multiple Myeloma; Polycythemia; Pyridoxine; Waldenstrom Macroglobulinemia

Topics: Antineoplastic Agents; Cyclophosphamide; Fluorouracil; Humans; Leukemia; Mechlorethamine; Melphalan; Methotrexate; Substance-Related Disorders; Vinblastine; Vincristine

Topics: Aged; Autopsy; Cyclophosphamide; Female; Humans; Leukemia; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged

Topics: Adult; Antineoplastic Agents; Busulfan; Chlorambucil; Hodgkin Disease; Humans; Leukemia; Lymphoma; Male; Mechlorethamine; Melphalan; Vinblastine

Topics: Age Factors; Aminopterin; Animals; Antineoplastic Agents; Busulfan; Chlorambucil; Cyclophosphamide; Dactinomycin; Drug Tolerance; Graft vs Host Disease; Immunosuppressive Agents; Leukemia; Melphalan; Mercaptopurine; Methotrexate; Mice; Plants, Medicinal; Plants, Toxic; Podophyllin; Podophyllum; Skin Transplantation; Thioguanine; Transplantation, Homologous

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

Topics: Adolescent; Antineoplastic Agents; Busulfan; Child; Cyclophosphamide; Drug Therapy; Humans; Infant; Leukemia; Leukemia, Myeloid; Melphalan; Mercaptopurine; Multiple Myeloma; Neoplasms; Phosphorus Isotopes; Prednisone

Topics: Animals; Dactinomycin; Floxuridine; Leukemia; Melphalan; Mercaptopurine; Methotrexate; Mitomycins; Neoplasm Metastasis; Pyrimidines; Sarcoma, Experimental; Thiotepa

Topics: Adolescent; Child; Child, Preschool; Humans; Leukemia; Melphalan

Topics: Abdominal Neoplasms; Angiography; Breast Neoplasms; Geriatrics; Gold; Humans; Injections; Iodine Isotopes; Leukemia; Lymphatic Metastasis; Lymphatic System; Lymphography; Lymphoma; Lymphoma, Non-Hodgkin; Melanoma; Melphalan; Methotrexate; Neoplasms; Radioisotopes; Radionuclide Imaging; Retroperitoneal Neoplasms; Scandium; Thiotepa; Yttrium

Topics: Animals; Antineoplastic Agents; Cyclophosphamide; Fluorouracil; Leukemia; Leukemia, Experimental; Melphalan; Mercaptopurine; Mice; Neoplasms; Neoplasms, Experimental; Oncogenic Viruses; Pharmacology; Research; Triethylenemelamine

Topics: Animals; Leukemia; Leukemia, Experimental; Melphalan; Mice; Pharmacology; Research

Topics: Cyclophosphamide; Leukemia; Leukemia, Experimental; Leukemia, Lymphoid; Lymphocytes; Melphalan; Mice; Moloney murine leukemia virus; Oncogenic Viruses; Radiation Effects; Research; Triethylenemelamine

Topics: Blood Protein Disorders; Blood Protein Electrophoresis; Cyclophosphamide; Drug Therapy; gamma-Globulins; Geriatrics; Hospitals, General; Humans; Leukemia; Leukemia, Lymphoid; Lymphocytes; Melphalan; Multiple Myeloma; Myeloma Proteins; Neoplasms; Vascular Diseases; Waldenstrom Macroglobulinemia

Topics: Animals; Cyclophosphamide; Leukemia; Leukemia, Experimental; Melphalan; Moloney murine leukemia virus; Oncogenic Viruses; Radiation Effects; Triethylenemelamine

Topics: Allografts; Antineoplastic Agents; Leukemia; Leukemia, Experimental; Melphalan; Mercaptopurine; Radiation; Spleen; Transplantation; Transplantation, Homologous; Triethylenemelamine

Topics: Adolescent; Child; Geriatrics; Head and Neck Neoplasms; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mandibular Neoplasms; Maxillary Neoplasms; Melanoma; Melphalan; Multiple Myeloma; Neoplasms; Orbital Neoplasms; Plasmacytoma; Sarcoma; Sarcoma, Kaposi

Topics: Antineoplastic Agents; Genetic Diseases, X-Linked; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Hairy Cell; Lymphatic Diseases; Lymphoma; Melphalan; Nitrogen Mustard Compounds; Severe Combined Immunodeficiency

Topics: Animals; Antineoplastic Agents; Antiviral Agents; Cyclophosphamide; Fluorouracil; Leukemia; Leukemia, Experimental; Leukemia, Lymphoid; Melphalan; Mercaptopurine; Mice; Oncogenic Viruses; Pathology; Pharmacology; Rauscher Virus; Research; Splenomegaly; Thiosemicarbazones; Vincristine

Topics: Alkylating Agents; Animals; Antineoplastic Agents; Carcinoma 256, Walker; Carcinoma, Hepatocellular; Chemistry, Pharmaceutical; Leukemia; Leukemia, Experimental; Liver Neoplasms; Lung Neoplasms; Melphalan; Neoplasms, Experimental; Nitrogen Mustard Compounds; Pharmacology; Phenylalanine; Research; Skin Neoplasms

Topics: Acute Disease; Antineoplastic Agents; Leukemia; Melphalan

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