mercaptopurine and Leukemia--Myelomonocytic--Acute

Topics: Aged; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Dendritic Cells; Disease Progression; Doxorubicin; Humans; Immunophenotyping; Leukemia, Myelomonocytic, Acute; Lymph Nodes; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Methotrexate; Middle Aged; Prednisone; Prognosis; Remission Induction; Skin Neoplasms; Transplantation, Homologous; Vincristine

Among 11 JMML children, two had an abnormal karyotype, and nine had a normal karyotype at onset. In one patient with trisomy 8 and four patients with a normal karyotype, a new clone with an aberrant karyotype emerged 1-14 months after 6-mercaptopurine (6-MP) therapy as shown by G-banding analyses. Fluorescence in situ hybridization disclosed that an abnormal clone existed in approximately 3-6% of bone marrow cells at onset or before 6-MP therapy in all the four cases examined, and increased to approximately 12-90% during the treatment. In culture with granulocyte-macrophage colony-stimulating factor, cytogenetically abnormal clones that proliferated during 6-MP therapy possessed significantly less sensitivity to the antimetabolite, compared with cells that decreased in numbers after the therapy. A PTPN11 mutation was detected in all of granulocyte-macrophage colonies irrespective of karyotypic aberration in one patient, whereas approximately 80% of erythroid colonies and 20% of mixed colonies possessed neither a PTPN11 mutation nor chromosomal abnormalities. The appearance of chromosomal aberrations shown by G-banding during 6-MP therapy in some JMML cases may result, in part, from the growth of a 6-MP-refractory clone that already exists at onset. It is possible that treatment with 6-MP promotes progression of the disease.

Topics: Antineoplastic Agents; Chromosome Aberrations; Chromosome Banding; Genes, ras; Humans; In Situ Hybridization, Fluorescence; Intracellular Signaling Peptides and Proteins; Leukemia, Myelomonocytic, Acute; Mercaptopurine; Mutation; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatases

The authors describe a young boy with juvenile myelomonocytic leukemia (JMML) who relapsed 45 days after HLA and killer immunoglobulin-like receptor (KIR) mismatched unrelated donor bone marrow transplant (MMUD-BMT) and subsequently developed life-threatening graft-versus-host disease (GvHD). Treatment with 6-mercaptopurine (6-MP) appeared to control severe GvHD and possibly prevented recurrence of leukemic relapse.

Topics: Antimetabolites, Antineoplastic; Busulfan; Cyclophosphamide; Graft vs Host Disease; Graft vs Leukemia Effect; Hematopoietic Stem Cell Transplantation; Histocompatibility; HLA-B Antigens; HLA-B52 Antigen; HLA-C Antigens; Humans; Infant; Leukemia, Myelomonocytic, Acute; Male; Melphalan; Mercaptopurine; Receptors, Immunologic; Receptors, KIR; Remission Induction; Secondary Prevention; Transplantation Conditioning; Transplantation, Homologous

Forty-six children with juvenile myelomonocytic leukemia (JMML) diagnosed between 1978 and 1993 in 12 centers were retrospectively studied. There is no evidence that any conventional treatment influences the long-term evolution of JMML. Among 28 patients treated without bone marrow transplantation (BMT), 26 died (median survival: 17 months), two are alive, one in complete remission (CR) after intensive chemotherapy. Allogenic BMT is the best treatment: 18 patients underwent BMT, 11 are in CR (at 9, 15, 22, 25, 41, 45, 49, 53, 66, 90 and 108 months). Conditioning regimens using chemotherapy alone may cure some patients (3/6) occasionally despite autologous reconstitution (1/3); if relapse occurs, a second BMT may be curative (2/3). Among the 12 patients conditioned immediately with TBI, six are in CR, one is in relapse, five died (one of them in durable autologus CR from Schwannoma). It is our opinion that splenectomy is of therapeutic value and seems not to have influenced the incidence of infections complications. We found no argument in favor of intensive chemotherapy before conditioning. Results with HLA-matched unrelated donors are satisfactory. One patient relapsed at 4 months after an unrelated BMT and entered a new CR after discontinuation of cyclosporine.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Etoposide; Female; Follow-Up Studies; Humans; Hydroxyurea; Immunologic Factors; Infant; Interferons; Isotretinoin; Leukemia, Myelomonocytic, Acute; Life Tables; Male; Mercaptopurine; Remission Induction; Retrospective Studies; Splenectomy; Transplantation Conditioning; Treatment Outcome; Whole-Body Irradiation

We report a case of therapy-related acute myeloid leukemia (t-AML), M4 FAB subtype, with t(10;11)(p14;q21) chromosome abnormality developed in a patient treated for acute promyelocytic leukemia (APL) after 4 years of continuous complete remission (CCR). Two distinct forms of t-AML have been described: the classical type and the second type. Our case has many characteristics in common with the second type of t-AML such as: exposure to topoisomerase II active agents (idarubicin (IDA), mitoxantrone (MITOX), etoposide (VP16)), M4 FAB subtype, a latency period of 39 months and absence of a preleukemic phase. However, it differs in the chromosome 11 breakpoint (band q21 instead of q23) and absence of ALL-1 (Hrx, MLL, Htrx) gene involvement. This can represent the second observation of t-AML occurring after treatment for APL.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Chromosomes, Human, Pair 10; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Cytarabine; Etoposide; Female; Humans; Idarubicin; Karyotyping; Leukemia, Myelomonocytic, Acute; Leukemia, Promyelocytic, Acute; Mercaptopurine; Methotrexate; Mitoxantrone; Neoplasms, Second Primary; Remission Induction; Thioguanine; Translocation, Genetic

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

The chemicals 6-mercaptopurine (6-MP) and methotrexate (MTX) are the cornerstones in the maintenance treatment of acute lymphoblastic leukemia. The intracellular metabolism of 6-MP to 6-thioguanosine nucleotides (TGN) via 6-thioinosine 5'-monophosphate (TIMP) is crucial for its cytotoxic effect. MTX inhibits purine de novo synthesis and thereby increases the intracellular PRPP being a substrate for the phosphoribosylation of 6-MP to TIMP. Hypoxanthine has been shown to inhibit the uptake of 6-MP over the cell membrane and the phosphoribosylation of 6-MP to TIMP. We have previously shown that the conversion of TIMP to TGN decreases at 6-MP concentrations above 5 microM in vitro. The aim of the present study was therefore to investigate the effect of MTX increasing the PRPP and TIMP concentrations and of hypoxanthine decreasing the TIMP concentration on the formation of TGN from TIMP. Murine myelomonocytic leukemia cells (WEHI-3b) were treated with 6-MP in vitro. The drug concentration was kept constant by continuous addition of 6-MP during the experiment. With this technique, the concentration of TGN begins to decrease already at 6-MP concentrations above 2 microM. The addition of 0.2 microM MTX 6 h before 6-MP strongly inhibited the purine de novo synthesis, decreased the ATP, and increased the PRPP concentration 4-fold. The intracellular concentrations of TIMP and to a lesser extent TXMP also increased. The concentrations of the TGN were, however, basically unaffected by the preincubation with MTX. Simultaneous addition of 20-50 microM hypoxanthine and 6-MP decreased the accumulation of all cellular 6-MP metabolites. It is concluded that the synergistic cytotoxic effect of the combination of 6-MP and MTX is not based on biochemical modulation of the 6-MP metabolism by MTX.

Topics: Animals; Drug Interactions; Extracellular Space; Hypoxanthine; Hypoxanthines; Inosine Monophosphate; Kinetics; Leukemia, Experimental; Leukemia, Myelomonocytic, Acute; Mercaptopurine; Methotrexate; Mice; Phosphoribosyl Pyrophosphate; Purines; Thionucleotides; Tumor Cells, Cultured; Xanthines

A 21-year-old man was admitted to our hospital because of anorexia and general malaise in July, 1988. On admission, the white blood cell count of 18,600/microliters with 72% leukemic cells. The bone marrow aspirate showed 76.8% immature monocytes, 10% mature and immature eosinophils. Leukemic cells were 66.6% myeloperoxidase positive cells, and 20.6% naphthylbutyrate esterase positive cells. The lysozyme activity in urine was high. Cytogenetic analysis revealed the presence of 46 XY inv (16) (p13 q22). Under the diagnosis of acute myelomonocytic leukemia with eosinophilia (M4Eo) associated with inv (16) (p13 q22), one course of DCMP induction therapy was performed. After complete remission, the bone marrow aspirate showed disappearance of inv (16) (p13 q22), and associated with decreased residual leukemic cells.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Chromosome Inversion; Chromosomes, Human, Pair 16; Cytarabine; Daunorubicin; Humans; Injections, Spinal; Karyotyping; Leukemia, Myelomonocytic, Acute; Male; Mercaptopurine; Methotrexate; Prednisolone; Remission Induction

A subacute myelomonocytic leukemia was diagnosed in 28-month-old cotwins. At this age, their spontaneously dividing cells had a normal karyotype. A few months later, after treatment with 6-mercaptopurine, the following karyotypes were observed: 50,XX, +X, +13, +19, +21 in one and 51,XX, +X, +X, +10, +19, +21 in the other. After bone marrow transplantation, both relapsed although they had received high doses of chemo- and radiotherapy. One developed a clone 46,XX,del(20q), which acquired other clonal rearrangements. The other child developed two different abnormal clones, both with unbalanced rearrangement of chromosome 13. Some of these clones may correspond to immature erythroblasts. The gain of chromosomes, especially for #13, which occurred independently in the cotwins by various mechanisms and at different periods during the disease, is very striking. It may indicate the existence of a strong selective advantage for trisomic 13 cells and may be related to the genetic constitution of the patients.

Topics: Bone Marrow Transplantation; Chromosome Aberrations; Chromosome Disorders; Chromosomes, Human, Pair 13; Diseases in Twins; Female; Humans; Infant; Karyotyping; Leukemia, Myelomonocytic, Acute; Mercaptopurine; Twins; Twins, Monozygotic

A case of AML (M 4) with t(6; 11) showed recovery to myelodysplastic syndrome (MDS)-like bone marrow after one course of DCMP regimen. Dysplastic changes of three cell-lineages were observed and micromegakaryocytes were markedly increased in number. Recovering hematopoiesis was incomplete. During MDS-like phase, t(6; 11) disappeared, reverting to normal karyotypes. Low dose ara-C regimen did not show any effect. AML soon relapsed with reappearance of t(6; 11). MDS-like abnormal hematopoiesis has recently been reported to occur after remission induction therapy or at the time of relapse. G-6PD isozyme study revealed in a remission case of AML that hematopoiesis still consisted of abnormal clone in spite of karyotypic normalization. The abnormal hematopoiesis observed in our case can be referred to such a clonal disorder predominating after disappearance of blastic component of AML. It seems important to reveal what proportion of de novo AMLs shows such an abnormal hematopoiesis and to establish suitable therapeutic approach.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 6; Cytarabine; Daunorubicin; Female; Humans; Karyotyping; Leukemia, Myelomonocytic, Acute; Mercaptopurine; Middle Aged; Myelodysplastic Syndromes; Prednisolone; Remission Induction; Translocation, Genetic