melphalan and Preleukemia

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

Our previous results have indicated that mice whose plasmacytoma regressed following curative melphalan chemotherapy manifested various persistent immunohematological abnormalities including immunosuppression, myeloproliferation, as well as excessive production of and response to growth factors. Mice not bearing plasmacytoma treated with an identical dose of melphalan chemotherapy did not exhibit such abnormalities. In the present study we show that plasmacytoma-regressor mice (PRM) contain preleukemic cells which do not progress to leukemia in these mice. However, adoptive transfer of splenocytes originating in PRM to preirradiated but otherwise untreated syngeneic recipients resulted in the development of overt leukemia in these recipients. The presence of leukemia in the primary recipient mice was ascertained by blood counts as well as by spleen histology. Furthermore, splenocytes from the irradiated primary recipients adoptively transferred to non-irradiated secondary recipients caused leukemia formation in 100% of the secondary recipients. Sex chromosome analysis of the leukemic cells in the irradiated primary recipients clearly showed that they originated in the PRM donors. Two leukemic lines were established from leukemias developing in the secondary recipients and both expressed surface markers of hematopoietic progenitor cells as well as markers of T cells. We suggest that PRM could serve as an animal model to investigate development of chemotherapy-related leukemia in humans.

Topics: Animals; Antineoplastic Agents, Alkylating; Female; Karyotyping; Leukocyte Count; Male; Melphalan; Mice; Mice, Inbred BALB C; Phenotype; Plasmacytoma; Preleukemia; Spleen; Time Factors

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

As typical disorders of the elderly, myelodysplastic syndromes (MDSs) are relatively unusual in childhood. Nevertheless, up to 17% of cases of pediatric acute myeloid leukemia may have a preleukemic phase. In young patients, the goal of treatment is eradication of the preleukemic malignant clone and reconstitution of normal hematopoiesis. Allogeneic bone marrow transplantation (BMT) has proved to be capable of this, but the optimal conditioning treatment to achieve eradication remains to be defined. Between May 1989 and June 1993, eight consecutive pediatric patients with MDS received a marrow transplant from an HLA-identical, mixed lymphocyte culture (MLC) non-reactive sibling. Diagnosis at time of presentation was refractory anemia with excess of blasts (RAEB) in two patients, RAEB in transformation (RAEB-t) in three, and juvenile chronic myelogenous leukemia (JCML, the pediatric counterpart of adult chronic myelomonocytic leukemia) in the remaining three children. Conditioning regimen consisted of busulfan, cyclophosphamide and melphalan, three alkylating agents potentially capable of killing also dormant preleukemic stem cells. The preparative regimen was very well tolerated, and all patients engrafted promptly. Six out of eight patients (75%) are alive and well with a median observation time of 20 months (range 8-34 months). Serial karyotype monitoring and molecular analyses have demonstrated a full chimerism of donor cells and the complete disappearance of trisomy 8 detected before transplant in three cases. All surviving patients have a Karnofsky score of 100%. One boy, affected by RAEB-t with monosomy 7 resistant to treatment with low-dose ara-C, relapsed 11 months after BMT, evolved in AML and died from progressive leukemia. Another patient with RAEB died on day +95 after BMT due to interstitial pneumonia of unclear etiology. This study confirms that allogeneic BMT is the treatment of choice in pediatric patients with MDS, and suggests that the employed conditioning regimen is a safe and effective means for eradicating the preleukemic malignant clone. Particularly noteworthy is that the three children with JCML obtained a complete remission and one of them is now a long-term survivor.

Topics: Adolescent; Anemia, Refractory, with Excess of Blasts; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Infant; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Melphalan; Myelodysplastic Syndromes; Preleukemia; Remission Induction; Transplantation, Homologous

A complete hematologic remission was achieved in a patient with therapy-related preleukemia and transfusion-dependent pancytopenia after treatment with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). The patient remained in remission for nearly 1 year despite the discontinuation of GM-CSF treatment. Several lines of evidence suggest that normal hematopoiesis was restored after GM-CSF treatment. First, the cytogenetic anomaly, which was present before GM-CSF, completely disappeared after three cycles of treatment. Cytogenetic conversion was documented by conventional karyotypic evaluation of mitotic bone marrow cell preparations as well as by premature chromosome condensation analysis of the nonmitotic cells of bone marrow and peripheral blood. Second, the growth pattern and cycle status of bone marrow granulocyte-macrophage (CFU-GM) and erythroid (BFU-E) progenitor cells were found to be normal during remission. Third, X chromosome-linked restriction fragment length polymorphism-methylation analysis of DNA from mononuclear cells (greater than 80% lymphocytes) and mature myeloid elements showed a polyclonal pattern. These findings suggest that restoration of hematopoiesis in this patient after GM-CSF treatment may have resulted from suppression of the abnormal clone and a selective growth advantage of normal elements.

Topics: Adenocarcinoma; Blotting, Southern; Bone Marrow; Colony-Stimulating Factors; DNA; Erythrocyte Count; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Hematocrit; Hematopoiesis; Humans; Karyotyping; Leukocyte Count; Melphalan; Middle Aged; Platelet Count; Preleukemia; Recombinant Proteins

Clinical effects of a low dose of behenoyl ara-C (LD-BHAC) and K-18, an IgG-melphalan conjugate, were studied in hypoplastic leukemia (HL). Among 8 cases of HL treated with LD-BHAC regimen, in which 50 mg BHAC was administered daily by one-hour drip infusion for 14 days, 4 achieved complete remission (CR) and 2, partial remission (PR). The response rate (CR + PR) was 75%. Hematological toxicities were observed in most of the cases. The peak level of serum ara-C concentration, 3.62-18.9 ng/ml (mean: 11.74 ng/ml), was observed at cessation of infusion, and an ara-C level of 2.75-48.9 ng/ml (mean: 3.45 ng/ml) was still present in the blood 6 hours after cessation of infusion. Six cases of HL were treated with K-18. Eight tablets of K-18, containing 30 mg per tablet, were given daily. Two of 6 cases achieved CR with little hematological toxicities. LD-BHAC and K-18 can be expected in the treatment of hypoplastic leukemia and its related diseases such as hypoplastic preleukemia in the aged.

Topics: Adult; Aged; Antineoplastic Agents; Cytarabine; Drug Evaluation; Humans; Immunoglobulin G; Immunotoxins; Infusions, Intravenous; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Preleukemia

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 case of myelodysplasia (refractory anaemia with excessive blasts) arising 7 years after a 3 year period of intermittent monthly treatment cycles with melphalan for multiple myelomas is reported. This is another example of preleukaemic syndrome possibly caused by melphalan. Among the possible pathogenetic mechanisms, the incidence of cyclic episodes of medullary hypoplasia are emphasised.

Topics: Blood Transfusion; Erythrocyte Transfusion; Female; Humans; Melphalan; Middle Aged; Multiple Myeloma; Myeloproliferative Disorders; Platelet Transfusion; Prednisone; Preleukemia; Time Factors

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