mercaptopurine and Myelodysplastic-Syndromes

6-Mercaptopurine (6MP) has been regarded as nonleukemogenic, even though the cytotoxicity of 6MP depends on the incorporation of 6-thioguanine nucleotides (6TGN) into DNA. In hematopoietic cells this pathway competes with S-methylation catalyzed by thiopurine methyltransferase (TPMT). However, methylated 6MP metabolites inhibit purine de novo synthesis and thus may enhance incorporation of 6TGN into DNA. Approximately 10% of white individuals have low TPMT activity as a result of polymorphisms in the TPMT gene. The authors attempted to test the hypothesis that the degree of DNA damage during 6MP therapy might reflect variations in 6MP metabolism and pharmacokinetics.. The authors measured TPMT activity as well as erythrocyte levels of 6TGN (E-6TGN) and methylated 6MP metabolites (E-MeMP) during 6MP therapy in 439 children with acute lymphoblastic leukemia, 5 of whom later developed secondary myelodysplasia or acute myeloid leukemia (sMDS/AML).. The patients who developed sMDS/AML had significantly lower TPMT activity compared with the remaining patients (P = 0.03). The 55 patients with TPMT activity <14 U/mL red blood cells (RBC) (antimode of the bimodal distribution) had a 5-year risk of sMDS/AML of 9 +/- 6% versus 1 +/- 1% for the remaining patients (P = 0.002). Cox regression analysis identified TPMT activity and E-MeMP level as the strongest predictors of risk for sMDS/AML (global P value = 0.02). Patients with low TPMT activity and high E-MeMP levels had the highest risk. All 5 patients with sMDS/AML had E-6TGN and/or E-MeMP levels > the 90% percentiles or had TPMT activity < 14 U/mL RBC.. These data demonstrate an increased leukemogenic risk when 6MP is administered with other cytotoxic agents in patients with low TPMT activity, and indicate that not only high 6TGN levels but also high levels of methylated metabolites may lead to DNA damage.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Child; Child, Preschool; DNA Damage; Guanine Nucleotides; Humans; Immunophenotyping; Infant; Mercaptopurine; Methyltransferases; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk; Thionucleotides

Fourty children with MDS treated in seven centres of The Polish Children's Leukemia Lymphoma Study Group in period 1975-1998y were included to the study. In 16 children RAEB-T, in 2 CMML in 10 RA and in 12 RAEB were diagnosed. Our and literature data showed that BMT is the best therapy for children with MDS. For children, who don't have a donor for BMT. Roacutan therapy seems to be the most effective.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Cytarabine; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Infant; Male; Mercaptopurine; Myelodysplastic Syndromes; Treatment Outcome; Valproic Acid

Topics: Autoimmune Diseases; Azathioprine; Humans; Leukemia, Myeloid, Acute; Mercaptopurine; Myelodysplastic Syndromes

Topics: Autoimmune Diseases; Azathioprine; Humans; Leukemia, Myeloid, Acute; Mercaptopurine; Myelodysplastic Syndromes

Therapy-related myeloid neoplasms are a potentially life-threatening consequence of treatment for autoimmune disease (AID) and an emerging clinical phenomenon.. To query the association of cytotoxic, anti-inflammatory, and immunomodulating agents to treat patients with AID with the risk for developing myeloid neoplasm.. This retrospective case-control study and medical record review included 40 011 patients with an International Classification of Diseases, Ninth Revision, coded diagnosis of primary AID who were seen at 2 centers from January 1, 2004, to December 31, 2014; of these, 311 patients had a concomitant coded diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Eighty-six cases met strict inclusion criteria. A case-control match was performed at a 2:1 ratio.. Odds ratio (OR) assessment for AID-directed therapies.. Among the 86 patients who met inclusion criteria (49 men [57%]; 37 women [43%]; mean [SD] age, 72.3 [15.6] years), 55 (64.0%) had MDS, 21 (24.4%) had de novo AML, and 10 (11.6%) had AML and a history of MDS. Rheumatoid arthritis (23 [26.7%]), psoriasis (18 [20.9%]), and systemic lupus erythematosus (12 [14.0%]) were the most common autoimmune profiles. Median time from onset of AID to diagnosis of myeloid neoplasm was 8 (interquartile range, 4-15) years. A total of 57 of 86 cases (66.3%) received a cytotoxic or an immunomodulating agent. In the comparison group of 172 controls (98 men [57.0%]; 74 women [43.0%]; mean [SD] age, 72.7 [13.8] years), 105 (61.0%) received either agent (P = .50). Azathioprine sodium use was observed more frequently in cases (odds ratio [OR], 7.05; 95% CI, 2.35- 21.13; P < .001). Notable but insignificant case cohort use among cytotoxic agents was found for exposure to cyclophosphamide (OR, 3.58; 95% CI, 0.91-14.11) followed by mitoxantrone hydrochloride (OR, 2.73; 95% CI, 0.23-33.0). Methotrexate sodium (OR, 0.60; 95% CI, 0.29-1.22), mercaptopurine (OR, 0.62; 95% CI, 0.15-2.53), and mycophenolate mofetil hydrochloride (OR, 0.66; 95% CI, 0.21-2.03) had favorable ORs that were not statistically significant. No significant association between a specific length of time of exposure to an agent and the drug's category was observed.. In a large population with primary AID, azathioprine exposure was associated with a 7-fold risk for myeloid neoplasm. The control and case cohorts had similar systemic exposures by agent category. No association was found for anti-tumor necrosis factor agents. Finally, no timeline was found for the association of drug exposure with the incidence in development of myeloid neoplasm.

Topics: Aged; Aged, 80 and over; Arthritis, Rheumatoid; Autoimmune Diseases; Azathioprine; Case-Control Studies; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Incidence; Leukemia, Myeloid, Acute; Lupus Erythematosus, Systemic; Male; Mercaptopurine; Methotrexate; Middle Aged; Mitoxantrone; Mycophenolic Acid; Myelodysplastic Syndromes; Odds Ratio; Psoriasis; Retrospective Studies; Risk Factors; United States

We describe a patient diagnosed with acute myeloid leukemia (AML) and low activity of thiopurine methyltransferase (TPMT) who developed secondary myelodysplastic syndrome after treatment.. A 10-year-old boy presented with AML-M2 with t(8;21)(q22;q22) and genotyping revealing 3*B TPMT heterozygosity. The patient was treated according to the NOPHO-AML 2004 protocol. Two years after the treatment, the patient presented with neutropenia and thrombocytopenia. Bone marrow, including fluorescent in situ hybridization and retrospective aCGH analysis, verified therapy-related myelodysplastic syndrome with ring chromosome 6.. The clinical course of this patient raises the possibility that low-activity TPMT genotypes may influence 6TG toxicity in patients with AML and lead to an increased risk of developing secondary malignant neoplasms.

Topics: Antimetabolites, Antineoplastic; Child; Heterozygote; Humans; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Methyltransferases; Myelodysplastic Syndromes

Intensive chemotherapy for newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) is associated with significant treatment-related morbidity and mortality. Herein, we investigate how pretreatment characteristics relate to early adverse outcomes in such patients, studying 205 consecutive individuals receiving curative-intent induction chemotherapy with cytarabine and an anthracycline ("7 + 3"; n = 175) or a "7 + 3"-like regimen (n = 30). Among the entire cohort, baseline grade 4 neutropenia (i.e., absolute neutrophil count <500 cells/µL) was associated with development of fever (P = 0.04), documented infection (P < 0.0001), and bacteremia (P = 0.002) but not requirement for intensive care unit-level care; after exclusion of the 30 patients who received "7 + 3"-like induction, baseline grade 4 neutropenia remained associated with documented infection (P < 0.0001) and bacteremia (P = 0.0005). Among patients achieving a complete remission with the initial treatment cycle, grade 4 neutropenia was associated with delayed neutrophil count recovery (P < 0.0001). Low monocyte and lymphocyte counts at baseline were similarly associated with increased risk of documented infection or bacteremia. After adjustment for age, gender, disease type, cytogenetic/molecular risk, and performance status, the risk of fever, documented infection, or bacteremia was 1.87 (95% confidence interval: 1.04-3.34; P=0.04)-fold, 4.95 (2.20-11.16; P<0.001)-fold, and 3.14 (0.99-9.98; P=0.05)-fold higher in patients with initial grade 4 neutropenia. Together, our studies identify severe baseline neutropenia as a risk factor for infection-associated adverse events after induction chemotherapy and may provide the rationale for the risk-adapted testing of myeloid growth factor support in this high-risk AML/MDS patient subset.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bacteremia; Blood Cell Count; Critical Care; Cyclophosphamide; Cytarabine; Daunorubicin; Febrile Neutropenia; Female; Granulocyte Colony-Stimulating Factor; Humans; Immunocompromised Host; Infections; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Middle Aged; Myelodysplastic Syndromes; Proportional Hazards Models; Remission Induction; Retrospective Studies; Young Adult

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Budesonide; Chromosomes, Human, Pair 7; Combined Modality Therapy; Crohn Disease; Cytarabine; Drug Therapy, Combination; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Immunosuppressive Agents; Leukemia, Monocytic, Acute; Male; Mercaptopurine; Mesalamine; Methyltransferases; Monosomy; Myelodysplastic Syndromes; Prednisone; Young Adult

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Mercaptopurine; Methotrexate; Myelodysplastic Syndromes; Neoplasms, Second Primary; Prednisone; Remission Induction; Tretinoin; Vincristine

We retrospectively analyzed 126 acute myelogenous leukemia (AML) patients aged > or =60 years who had all been referred to the same hematological department between 1989 and 1999. In 76 de novo AML cases, 53 patients (median age, 72 years) were treated with combination chemotherapy (CT) for remission induction. Complete remission (CR) rate was 57.1%. The median overall survival (OS) was 16 months, and the rate of 3-year OS was 28%. The favorable prognostic factors were performance status < or =2, cholinesterase > or =100 IU, and intermediate or favorable karyotype (P < .01). Seventeen patients (median age, 78 years) with hypocellular bone marrow or poor general condition were treated with low-dose cytosine arabinoside (LDAraC). In these patients, the CR rate was 50% and the median OS was 11 months, with an OS estimate at 3 years of 14%. All patients with hypocellular bone marrow who received LDAraC for 21 days achieved CR. In 50 patients who developed AML following a myelodysplastic syndrome (MDS/AML), 22 patients (median age, 74 years) were treated with CT, and 14 (median age, 74 years) patients were treated with LDAraC. The CR rates were 22.7% and 21.4%, respectively, and the median OS durations were 8 months and 11 months, respectively. There were no significant factors that would indicate a good prognosis in MDS/AML patients.

Topics: Acute Disease; Age Factors; Aged; Allopurinol; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cholinesterases; Cytarabine; Daunorubicin; Disease Progression; Female; Humans; Japan; Karyotyping; Leukemia, Myeloid; Life Tables; Male; Mercaptopurine; Middle Aged; Myelodysplastic Syndromes; Neoplasm Proteins; Prognosis; Remission Induction; Risk Factors; Survival Analysis; Survival Rate

A retrospective analysis was performed on 76 consecutive elderly patients with acute leukemia aged 60 years or more (48 men, 28 women). Forty patients were 60-69 years old, 28 were 70-79 years old and 8 were > or = 80 years old. There were 55 patients with acute myelogenous leukemia (AML), 13 acute lymphoblastic leukemia (ALL) and 8 AML from myelodysplastic syndrome (MDS/AML). Patients were treated with the JALSG protocol, CAG regimen, or low-dose Ara-C regimen for AML, and DVP/M-CHOP protocol for ALL. The complete remission (CR) rates were 52.7% (29 of 55) in AML, 61.5% (8 of 13) in ALL, and 0% in MDS/AML. The median CR durations were 226, 85, 0 days, and the median survivals were 204, 177, 99 days, respectively. CR rates were 65.3% for the JALSG protocol, 62.5% for the CAG regimen and 25.0% for low-dose Ara-C regimen. According to age, CR was obtained 62.5% in patients aged 60-69 years and 33.3% in patients over 70 years old. Our results indicated that patients aged 60-69 years should be treated with intensive chemotherapy.

Topics: Aclarubicin; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Daunorubicin; DNA; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Retrospective Studies; Vincristine

We describe a patient with leukocytosis with all the stages of neutrophilic series, peripheral dominant myeloblast proliferation, marked dysplasia of myeloid and erythroid series, and extramedullary hematopoiesis of the lymph nodes. A cytogenetic study of the bone marrow cells showed normal karyotype, and molecular analysis of the leukemic cells showed negative for BCR-ABL by RT-PCR. After chemotherapy, the patient went into complete remission with a normal blood and bone marrow profile with no dysplasia. On relapse, the hematological findings showed a typical bone marrow dominant acute myeloid leukemia, with the leukemic cells having a chromosomal abnormality. The patient exhibited the combined features of myeloproliferative disorder, myelodysplastic syndrome, peripheral dominant myeloblast proliferation (so-called peripheral leukemia) and typical acute myeloid leukemia throughout the clinical course. This is thought to be a rare overlapping disease involving these distinct hematological conditions that do not usually occur in the same patient.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cytarabine; Daunorubicin; Disease Progression; Hematopoiesis, Extramedullary; Humans; Leukemia, Myeloid; Male; Mercaptopurine; Middle Aged; Myelodysplastic Syndromes; Myeloproliferative Disorders; Prednisolone; Preleukemia; Remission Induction

A 62 year old male patient was previously admitted to another hospital in February 1989 because of palpitation. Peripheral blood examination revealed pancytopenia. Although the number of nucleated cells in the bone marrow aspirate was in the normal range. It contained 2.2% of blastic cells and dysplastic cells. He was diagnosed to be myelodysplastic syndrome with refractory anemia. He subsequently received repeated blood transfusions and other symptomatic treatments as an outpatient until 1990. When he was admitted to our hospital because of severe pancytopenia. The numbers of WBC, RBC, and platelets were 2,000/microliters, 134 x 10(4)/microliters, 2.9 x 10(4)/microliters respectively. Bone marrow aspiration resulted in dry tap, and biopsy at the iliac bone showed remarkable fibrosis with marked decrease of normal hematopoietic cells. Chromosome analysis revealed multiple aberrations such as 47XY, +8, 13q-, 14p+, 48XY, +8, +9, 13q+. The patient was treated with BHAC-AMP combination chemotherapy. After 3 cycles of the therapy, pancytopenia was improved and chromosomal aberration disappeared. This case was considered to be an acute myelofibrosis developed from myelodysplastic syndrome and worth to reporting with a review of literature, because drastic combination chemotherapy was extremely effective.

Topics: Aclarubicin; Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Chromosome Aberrations; Cytarabine; Humans; Male; Mercaptopurine; Middle Aged; Myelodysplastic Syndromes; Prednisolone; Primary Myelofibrosis

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

Topics: Adult; Aged; Anemia, Refractory, with Excess of Blasts; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Male; Mercaptopurine; Middle Aged; Myelodysplastic Syndromes; Prednisolone; Remission Induction; Vincristine

It has been proposed that intensive chemotherapy ror RAEB is dangerous, and a small dose of ara-C therapy is recommended in many institutes for its ability to differentiate leukemic cells. Combination chemotherapy for RAEB, however, has not been completely evaluated. We introduced B-DOMP therapy, which is used in our hospital, for RAEB. B-DOMP therapy includes Behenoyl ara-C, daunomycin, oncovin, 6-MP and prednisolone, which achieved approximately 80% of complete remission of ANLL for adults. Five males and one female of RAEB, aged 40-74 (median 70), were treated by B-DOMP regimen. Two cases achieved complete remission, 2 remained in partial remission and 2 cases died within one month. In three cases, the cause of death was fungal pneumonia. It must be stressed that life-threatening pneumonia was common after chemo therapy for RAEB, and careful protection against fungal infection using laminarair flow is required.

Topics: Adult; Aged; Anemia, Refractory, with Excess of Blasts; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Infusions, Intravenous; Male; Mercaptopurine; Middle Aged; Myelodysplastic Syndromes; Prednisolone; Remission Induction; Vincristine