melphalan and Leukemia--Radiation-Induced

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

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

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

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

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

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

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

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: 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