melphalan and Leukemia--Erythroblastic--Acute

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: 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

Here we show the antimyeloma cytotoxicity of adaphostin and carried out expression profiling of adaphostin-treated multiple myeloma (MM) cells to identify its molecular targets. Surprisingly, c-Jun was the most up-regulated gene even at the earliest point of analysis (2 h). We also observed adaphostin-induced c-Abl cleavage in immunoblot analysis. Proteasome inhibitor bortezomib, but not melphalan or dexamethasone, induced similar effects, indicating unique agent-dependent mechanisms. Using caspase inhibitors, as well as caspase-resistant mutants of c-Abl (TM-c-Abl and D565A-Abl), we then showed that c-Abl cleavage in MM cells requires caspase activity. Importantly, both overexpression of the c-Abl fragment or c-Jun and knockdown of c-Abl and c-Jun expression by small interfering RNA confirmed that adaphostin-induced c-Jun up-regulation triggers downstream caspase-mediated c-Abl cleavage, inhibition of MM cell growth, and induction of apoptosis. Finally, our data suggest that this mechanism may not only be restricted to MM but may also be important in a broad range of malignancies including erythroleukemia and solid tumors.

Topics: Adamantane; Apoptosis; Benzamides; Boronic Acids; Bortezomib; Caspase Inhibitors; Caspases; Cell Growth Processes; Dexamethasone; Humans; Hydroquinones; Imatinib Mesylate; Leukemia, Erythroblastic, Acute; Melphalan; Multiple Myeloma; Piperazines; Proto-Oncogene Proteins c-abl; Proto-Oncogene Proteins c-jun; Pyrazines; Pyrimidines; Transfection; Up-Regulation

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

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

A 42-year-old woman with Crow-Fukase syndrome developed acute myeloid leukemia (M6: FAB classification) following treatment with alkylating agents (a total of 2,500 mg of melphalan and 9,800 mg of cyclophosphamide). Chromosome analysis of the bone marrow showed 49,XX,der(1;7)(q10;p10), +8, +19, +21 in therapy-related myelodysplastic syndrome with additional chromosomes 8, and 12 and two additional chromosomes 21 in acute leukemia. Because of the risk of therapy-related leukemia, alkylating agents should be used with caution in the treatment of Crow-Fukase syndrome.

Topics: Adult; Alkylating Agents; Chromosome Aberrations; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 7; Cyclophosphamide; Female; Humans; Leukemia, Erythroblastic, Acute; Melphalan; Myelodysplastic Syndromes; POEMS Syndrome; Translocation, Genetic; Trisomy

Topics: Adult; Bone Marrow Transplantation; Cyclophosphamide; Epilepsy, Tonic-Clonic; Fever; Graft vs Host Disease; Humans; Leukemia, Erythroblastic, Acute; Male; Melphalan; Mitoxantrone; Multiple Myeloma; Purpura, Thrombotic Thrombocytopenic; Whole-Body Irradiation

A case of secondary erythroleukemia treated with apparent success with androgen is reported. The patient is 63-year-old Japanese female. She had a history of multiple myeloma and had been treated with melphalan, vincristine and prednisolone. She developed erythroleukemia 88 months after the initiation of chemotherapy, while her myeloma was a complete remission. She was treated first with vitamin D3 with no beneficial effect and subsequently with 0.5 mg/kg of mepitiostane. A hematologic improvement began two months from the initiation of androgen therapy, and a complete remission of erythroleukemia was attained thereafter. A chromosomal abnormality of bone marrow cells, which was observed at the time of developing erythroleukemia, also disappeared after the treatment. She remained in good condition and hematologic remission under the androgen therapy at the latest follow-up, 1-year after the development of erythroleukemia. Androgen therapy may be considered as a useful treatment for secondary erythroleukemia.

Topics: Androstanols; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Leukemia, Erythroblastic, Acute; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone; Remission Induction; Vincristine

The hydrolysis of melphalan in cell culture medium at 37 degrees C has been studied. Degradation of melphalan proceeded via monohydroxy-melphalan (MOH) to dihydroxymelphalan [M(OH)2] with a half-life of 66 min for melphalan and 58 min for MOH. The half-life for melphalan was similar to the terminal half-life of the drug in vivo. The effect of the two metabolites, MOH and M(OH)2, on the chemosensitivity of K562 leukaemia cells during continuous exposure to melphalan was also examined. M(OH)2 had no potentiating effect on melphalan cytotoxicity at concentrations up to 100 micrograms/ml. MOH also had little effect on cell kill at concentrations higher than those commonly achieved during in vitro chemosensitivity assays. The LD50 for 1 h exposure to melphalan was twice that for continuous exposure: this also suggests no interference by MOH and M(OH)2. These data suggest that continuous exposure of melphalan in in vitro chemosensitivity assays is probably preferable to the arbitrary 1 h drug exposure time commonly employed.

Topics: Culture Media; Drug Resistance; Half-Life; Humans; Hydrolysis; Leukemia, Erythroblastic, Acute; Melphalan; Staining and Labeling; Time Factors; Tumor Cells, Cultured; Tumor Stem Cell Assay

Since the beginning of the seventies there have been an increasing number of reports of second malignancies in patients treated with cytotoxic agents. The commonest of these malignancies are acute nonlymphocytic leukemias. Such occurrences are also known in patients with multiple myeloma treated with melphalan. In a 74-year-old female with multiple myeloma treated with melphalan for 19 months, erythroleukemia developed 23 months after the start of treatment. The second malignancy has almost entirely displaced the myeloma cells in the marrow. In consequence, the paraprotein gradient in electrophoresis diminished in size.

Topics: Aged; Blood Protein Electrophoresis; Bone Marrow; Bone Marrow Examination; Female; Humans; Leukemia, Erythroblastic, Acute; Melphalan; Multiple Myeloma; Paraproteins; Time Factors

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

Topics: Adenocarcinoma; Aged; Breast Neoplasms; Female; Humans; Leukemia, Erythroblastic, Acute; Melphalan; Pulmonary Fibrosis; Radiotherapy; Remission, Spontaneous

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: Female; Humans; Leukemia, Erythroblastic, Acute; Melphalan; Middle Aged; Myxedema; Skin Diseases

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: Aged; Female; Humans; Leukemia, Erythroblastic, Acute; Melphalan; Multiple Myeloma

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

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

Topics: Humans; Leukemia, Erythroblastic, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma

Topics: Aged; Alkylating Agents; Biopsy; Bone Marrow; Chlorambucil; Female; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Lymphoid; Male; Melphalan; Middle Aged; Multiple Myeloma; Uracil Mustard; Waldenstrom Macroglobulinemia

Topics: Aged; Androgens; Autopsy; Blood Cell Count; Bone Marrow Cells; Humans; Leukemia, Erythroblastic, Acute; Male; Melphalan; Waldenstrom Macroglobulinemia

Topics: Adult; Blood Coagulation; Blood Protein Disorders; Blood Protein Electrophoresis; Cryoglobulins; Humans; Immunoglobulin M; Leukemia, Erythroblastic, Acute; Male; Melphalan; Time Factors

Topics: Blood Protein Disorders; Cryoglobulins; Cyclophosphamide; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid; Melphalan

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