mercaptopurine and Chromosome-Deletion

Acute myelofibrosis (AMF), as defined by an acute panmyelopathy associated with marked megakaryocytic hyperplasia and marrow fibrosis, appears to be a stem cell disorder. Even though it is most difficult to distinguish from various myeloproliferative and myelodysplastic disorders as well as acute myelogenous leukemia, it has rarely been reported to terminate as acute lymphoblastic leukemia (ALL). Only five cases have been reported in the literature; two from the pediatric literature and only three from the adult literature. Of the three adult cases, two were defined by light microscopy alone. Among the cases with follow-up (3/5), all died within 2 weeks to 2 months of diagnosis. We report an additional case in an adult; the ALL was defined by morphology, flow cytometric immunophenotyping, and cytogenetic analysis. The interval from diagnosis of AMF to ALL was 3 months. Our patient was treated with standard therapy for ALL, was in complete remission at last follow-up (3 months off maintenance therapy), and represents the only reported case who attained a complete remission. There are too few cases to determine the prognostic significance of termination of AMF in an acute leukemia of lymphoid origin vs. myeloid origin.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Blast Crisis; Bone Marrow; Chromosome Deletion; Chromosomes, Human, Pair 5; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Disease Progression; Flow Cytometry; Humans; Immunophenotyping; Male; Mercaptopurine; Methotrexate; Neoplastic Stem Cells; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Primary Myelofibrosis; Remission Induction; Vincristine

We report here a 71 year-old female presenting with acute myeloblastic leukemia (FAB-M1) after treatment of essential thrombocythemia with Vercyte. Conventional cytogenetic techniques showed a complex karyotype, 44,XX,-5,-7,-11,add(11)(q23),-14,+mar,+r. The use of several fluorescent in situ hybridizations (FISH) lead to the identification of these complex rearrangements. The marker was found to be tricentric, with pericentromeric material of chromosome 7 inserted in the short arm of chromosome 5, resulting in monosomy 5q and 7q. The derivative chromosome 11 was dicentric and had subtelomeric sequences of 11p on both ends; several copies of the MLL gene were located in two different regions separated by a centromere of chromosome 11. Twenty-one cases, including ours, of myelodysplastic syndromes and acute myelogenous leukemia with MLL amplification present in hsr or dmin were found in the literature. Most of these patients shared some characteristics: they were old, they had de novo acute myeloid leukemia (AML) with a complex karyotype and a short survival, 90% of them having also a del(5q). Therefore, the simultaneous presence of MLL amplification and del(5q) appears to be a nonrandom association that could be the signature of AML in elderly patients with a poor prognosis.

Topics: Aged; Chromosome Deletion; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 5; Chromosomes, Human, Pair 7; Cytogenetic Analysis; Fatal Outcome; Female; Gene Amplification; Histone-Lysine N-Methyltransferase; Humans; In Situ Hybridization, Fluorescence; Karyotyping; Leukemia, Myeloid, Acute; Mercaptopurine; Myeloid-Lymphoid Leukemia Protein; Pipobroman; Prognosis; Sensitivity and Specificity; Thrombocytosis

Hepatic dysfunction is a rare presentation of leukemia in children. Because most chemotherapy agents are metabolized by the liver, this complication may have major adverse consequences and effective treatment could be compromised.. The MEDLINE database and current management guidelines from the United States Pediatric Cooperative Cancer Groups were reviewed and analyzed. Data from two institutional cases are described.. Although previous literature is not informative, our experience suggests that children with leukemia and moderate hepatic dysfunction may tolerate aggressive chemotherapy.. Current protocol guidelines for dose modification for liver disease may be overly stringent and modification may be beneficial.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Biopsy; Child, Preschool; Cholestasis, Intrahepatic; Chromosome Deletion; Daunorubicin; Hepatomegaly; Humans; Liver; Liver Function Tests; Male; Mercaptopurine; Methotrexate; Practice Guidelines as Topic; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Remission Induction; Thrombocytopenia; Ultrasonography; Vincristine

A 65-year-old man with Crohn's disease died of acute myeloblastic leukemia after treatment for 11.8 years with 6-mercaptopurine, 1.5 mg/kg/day (100 mg/day). On cytogenetic analysis, most of the malignant bone marrow cells had deletion of chromosome 7, the most frequently reported cytogenetic abnormality in chemotherapy-related acute leukemia. This finding, together with previous reports of acute leukemia and other malignancies following prolonged treatment with azathioprine or 6-mercaptopurine for nonmalignant conditions including inflammatory bowel disease, indicates that long-term use of these drugs for inflammatory bowel disease may increase the risk of malignancy. However, the magnitude of the risk is unknown.

Topics: Aged; Chromosome Deletion; Chromosomes, Human, Pair 7; Crohn Disease; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Mercaptopurine

We report a patient with acute myelomonocytic leukemia (AMMoL) who showed two independent point mutations of the N-ras gene at codons 12 and 13. Longitudinal analysis revealed that one mutation at codon 13 was detectable throughout his disease course and the other at codon 12 emerged as a second mutation 14 months after the diagnosis was made, at the refractory stage. Cloning to vector and subsequent sequencing confirmed that these mutations occurred in different alleles. Chromosome findings showed a simple abnormal karyotype at presentation and further karyotypic aberrations during his disease course, concomitantly with the second mutation of the N-ras gene. These findings revealed a close relationship among the disease progression, karyotypic evolution and a newly-appearing N-ras mutation.

Topics: Aclarubicin; Alleles; Antineoplastic Combined Chemotherapy Protocols; Chromosome Deletion; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 9; Codon; Cytarabine; Daunorubicin; Disease Progression; Doxorubicin; Etoposide; Fatal Outcome; Genes, ras; Genetic Vectors; Humans; Karyotyping; Leukemia, Myelomonocytic, Acute; Male; Mercaptopurine; Middle Aged; Mitoxantrone; Point Mutation; Prednisolone; Vinblastine; Vincristine

Dominant-lethal effects of 6-mercaptopurine on male mice were studied using eight doses, ranging from 150 to 482 mg/kg. Effects of the 150-mg/kg dose were studied over the entire spermatogenic cycle, and those of the higher doses for matings made between days 28.5 and 41.5 after treatment. It was found that, with low doses, there was only one period in which clearcut increases in induced dominant-lethal mutations were detected, namely in matings that occurred 32.5 to 35.5 days after treatment. With higher doses, effects could be detected beyond that period through day 39.5. Spermatozoa utilized for matings during the period of greatest response were presumably derived from germ cells that were in late differentiating spermatogonial and early meiotic spermatocyte stages at the time of treatment. These results are similar to those of Ray and Hyneck. To date, 6-mercaptopurine is unique in inducing dominant lethality only at these particular stages. A study of chromatid aberration induction in the treated males themselves was carried out for 150 and 250 mg/kg doses of 6-mercaptopurine over the period of 9 to 16 days after treatment. A considerable increase in ischromatid and chromatid deletions was observed in diakinesis-metaphase-I spermatocytes on days 14 and 15 after treatment. For reasons discussed, the cells sampled at this may be assumed to have been in early meiosis (preleptotene), with some in late differentiating spermatogonial stages, at the time of treatment. The rough agreement in sensitive cell type for dominant lethality and chromatid aberration induction suggests that chromatid deletions are the cause of dominant lethality in this study. Conservative estimates of the frequency of dominant lethality expected from the chromatid aberration frequencies tend to substantiate this suggestion.

Topics: Animals; Chromosome Aberrations; Chromosome Deletion; Chromosome Inversion; Dose-Response Relationship, Drug; Genes, Dominant; Genes, Lethal; Injections, Intraperitoneal; Male; Meiosis; Mercaptopurine; Mice; Mutagens; Spermatogenesis