thioguanine-anhydrous and Blast-Crisis

An in vitro synergism between different inducers of AML cell differentiation has been previously observed. Therefore, we treated 53 myelodysplastic (MDS) patients with a low dose combination of cis-retinoic acid (cRA, 20-40 mg/day) and 1,25 alpha (OH)2 cholecalciferol [(OH)2D3, 1-1.5 micrograms/day] +/- intermittent 6-thioguanine (30 mg/m2/day). The latter was reserved for patients with bone marrow (BM) blast excess (> or = 5%). The treatment was well tolerated, without major toxicity. Among 25 patients with BM blasts less than 5%, we observed one complete, eight partial and four minor responses (response rate 52%) with a median response duration of 8 months (2 +/- 24). Median survival, which did not correlate with response, is projected at 76 months. Thirty-one patients with BM blast excess (> or = 5%), including three of the previous group who progressed to refractory anemia with excess of blasts (RAEB), were treated with the three-drug protocol. One complete, 12 partial and six minor responses were obtained (response rate 61%) with a median response duration of 6 months (2-29+). A significant difference in survival (P < 0.005) was observed between the 19 responders (median 25 months) and the 12 non-responders (median 9 months). A reduction in the transfusion need was observed in 41% of the transfusion-dependent patients with blast excess and in 53% of those without blast excess. Therefore, combined differentiating therapy seems more effective than previously reported single agent treatments and should be considered for a larger randomized study to assess its actual impact on survival of MDS patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Blood Transfusion; Bone Marrow Transplantation; Cholecalciferol; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Remission Induction; Survival Analysis; Thioguanine; Tretinoin

6-Thioguanine (6-TG) was administered as a continuous i.v. infusion for 7 days to 24 patients with relapsed or refractory acute leukemia or in the blast phase of chronic granulocytic leukemia. The daily dose of 6-TG was escalated from 37.5 mg/m2 to 160 mg/m2. Stomatitis was dose-related and dose-limiting with a maximum tolerated dose of 120 mg/m2 daily. Cutaneous reactions were dose-related but not dose-limiting. The recommended dose for phase II trials in acute leukemia is 120 mg/m2 per day as a continuous infusion for 7 days. There were two complete and four partial remissions among all patients. At the suggested phase II dose of 120 mg/m2 there were two complete remissions and one partial remission in five evaluable patients.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Blast Crisis; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine

To evaluate whether children with acute myeloblastic leukemia (AML) presenting with extramedullary infiltration (EMI) have different clinical, morphologic features and prognosis from children without EMI, a 127 consecutive previously untreated children with AML were entered in this study. Fifty-one children (40%) had EMI at diagnosis and 27% of these showed multiple site involvement. Twenty-seven of 127 children (21%) presented myeloid tumors. No age related differences in the incidence of EMI was noted. However, analysis of clinical and biological features at diagnosis showed that WBC count > or =50 x 10(9) l(-1), hepatosplenomegaly >5 cm, FAB AML-M4 and AML-M5 subtypes and CD13, CD14 expression of bone marrow (BM) leukemic cells (>20%) were more frequent in children with EMI. Two consecutive treatment protocols were used. In both protocols remission was achieved with combined high-dose methylprednisolone (HDMP) as a differentiating and apoptosis inducing agent with mild cytotoxic chemotherapy (low-dose cytosine arabinoside (LD Ara-C), weekly mitoxantrone and Ara-C or 6-thioguanine). Administration of short-course (4-7 days) HDMP (20-30 mg/kg per day) alone resulted in a remarkable decrease in peripheral blood, BM blasts and in the size of EMI in responding patients. In both protocols, remission rate in patients with EMI was 71 and 80%, which was lower than that of the patients without EMI (87 and 89%). This may be attributed to the higher frequency of unfavorable features in children with EMI. However, in patients who presented with myeloblastoma and treated with a more intensive post-remission therapy (AML-94), the 4-year disease-free survival (DFS) and event-free survival (EFS) rates were not found to be significantly different from children who had no EMI (P>0.05). Whereas, the outcome of children who presented with gingival infiltration did not improve. In further studies, the prognostic significance of different localisation of EMI and the effect of addition of HDMP to cytotoxic chemotherapy should be explored in larger series.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Bone Marrow Cells; CD13 Antigens; Child; Child, Preschool; Cytarabine; Female; Humans; Leukemia, Myeloid; Leukemic Infiltration; Lipopolysaccharide Receptors; Male; Methylprednisolone; Mitoxantrone; Prognosis; Remission Induction; Survival Rate; Thioguanine; Treatment Outcome

T(8;9) is a relatively new translocation that has been reported in a few patients with chronic myeloid leukemia (CML) but never in acute myeloid leukemia (AML). We report here a patient who presented with AML with t(8; 9). He lacked the Philadelphia chromosome but tested positive for the gene by the polymerase chain reaction method. This confirmed the diagnosis of CML with blast crisis, and appropriate treatment could be instituted

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Bone Marrow Transplantation; Child, Preschool; Chromosomes, Human, Pair 8; Chromosomes, Human, Pair 9; Combined Modality Therapy; Cytarabine; Daunorubicin; Ethmoid Sinus; Etoposide; Fusion Proteins, bcr-abl; Humans; Karyotyping; Leukemia, Myeloid, Accelerated Phase; Male; Meninges; Mitoxantrone; Remission Induction; Sacrococcygeal Region; Sarcoma, Myeloid; Thioguanine; Translocation, Genetic

We report on a 49 year old female with primary extra-medullary manifestation of a acute myeloid leukemia in the lungs without leukemic signs. The disease was diagnosed by detection of leukemic blast cells in bronchoalveolar lavage. Chemotherapy with the TAD-VP-scheme resulted in partial remission. The patient died in systemic early relapse. To our knowledge this is the first description of primary isolated extra-medullary manifestation of a acute myeloid leukemia in the lungs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Bronchoalveolar Lavage Fluid; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Middle Aged; Prednisolone; Radiography; Thioguanine; Vincristine

Topics: Antineoplastic Agents; Blast Crisis; Cell Survival; Child; Cytarabine; Dexamethasone; Down Syndrome; Doxorubicin; Etoposide; Humans; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Treatment Outcome; Tumor Cells, Cultured

Activity of BCL-2 protein may be antagonised by BAX protein expression, thereby affecting cellular sensitivity to chemotherapeutic drugs. We analysed the BCL-2 protein expression of blast cells from 19 patients by flow cytometry and immunocytochemistry. This was compared to in vitro sensitivity to the anthracyclines and antimetabolites using the MTT assay. We found a significant correlation between BCL-2 expression and in vitro response to two antimetabolite drugs. One of 7 patients (14%) whose cells were sensitive to ara-C expressed BCL-2 compared to 4/4 patients (100%) whose cells were resistant to ara-C in vitro (p = 0.05). Furthermore, none of the three patients whose cells were sensitive to 6-TG expressed BCL-2 compared to 6/9 patients (67%) whose cells were resistant in vitro (p = 0.045). We found no other correlation between BCL-2 expression and any other chemotherapeutic drug analysed. The ratio of BCL-2 to BAX may be more relevant clinically, therefore cells from a further 9 patients were analysed for both proteins. Whilst there was no overall relationship between BCL-2/BAX ratios and sensitivity to ara-C and 6TG, individual patients could be identified whose blast cells were resistant to ara-C and had high BCL-2/BAX ratios. Further analysis of the significance of these ratios to drug resistance may be of future prognostic value.

Topics: Apoptosis; bcl-2-Associated X Protein; Blast Crisis; Bone Marrow Cells; Cytarabine; Flow Cytometry; Humans; Immunohistochemistry; Leukemia, Myeloid, Acute; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Thioguanine

Since May 1996 all Nordic countries have been participating in a study of childhood acute myeloid leukemia (AML). The aim is to correlate the in vitro sensitivity of leukemic cells and individual plasma concentrations of cytotoxic drugs with clinical effect. Blast cells from bone marrow and/or peripheral blood are tested against a panel of cytotoxic agents using the fluorometric microculture cytotoxicity assay (FMCA). Plasma concentrations of cytotoxic drugs are analysed during induction therapy. Bone marrow samples from the participating centres generally reached the analysing laboratory within 24 hours. 61 out of 71 (86%) samples were successfully analysed, 47 de novo AML and 14 relapses. Relapsing patients tended to have a more resistant test profile than newly diagnosed patients. Steady state plasma levels of doxorubicin, etoposide and 6-thioguanine nucleotide varied about 10-fold between patients. The intra-individual variation was much less, suggesting that dose adjustment based on pharmacokinetic data might be useful in the future.

Topics: Amsacrine; Antineoplastic Agents; Blast Crisis; Bone Marrow; Cell Survival; Child; Cytarabine; Doxorubicin; Drug Screening Assays, Antitumor; Erythrocytes; Etoposide; Humans; Leukemia, Myeloid, Acute; Recurrence; Scandinavian and Nordic Countries; Thioguanine

We have previously described a case of clonality switch in a female patient with acute myeloid leukemia (AML) by X-chromosome inactivation analysis. She presented with refractory anemia with excess blasts in transformation but soon progressed to overt AML. Following induction chemotherapy, she went into complete remission but later relapsed into a second myelodysplastic phase. Analysis of her X-linked DNA polymorphism patterns at presentation and relapse showed that hematopoiesis was clonal, but the genotypes of the two clones was different. She remains clinically well and has a virtually normal blood count more than 5 years from presentation. We now report an update of this unique case and discuss the implications of this finding within the context of a multicellular origin of leukemia.

Topics: Adult; Anemia, Refractory, with Excess of Blasts; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Bone Marrow; Clone Cells; Cyclophosphamide; Cytarabine; Daunorubicin; Disease Progression; Dosage Compensation, Genetic; Female; Hematopoiesis; Heterozygote; Humans; Leukemia, Myeloid, Acute; Neoplastic Stem Cells; Prednisolone; Remission Induction; Thioguanine; Vincristine

A total of 40 patients presenting with chronic myeloid leukaemia in blastic transformation were treated with a non-aggressive chemotherapy regimen consisting of vincristine, cytosine arabinoside and thioguanine. Remissions were achieved by 3/10 (30%) patients displaying lymphoid transformation (remission duration, 2, 3, and 5 months, respectively) and by 5/30 (17%) subjects exhibiting myeloid changes (duration 2+, 4, 4, 5 and 7 months, respectively). Myelosuppression was the major toxicity and non-haematological toxicities were mild and acceptable. The median survival of patients exhibiting lymphoid and myeloid blastic transformation as measured from the time of transformation was 6 and 3 months, respectively, but the difference was not statistically significant. Three subjects displaying lymphoid transformation and five showing myeloid changes survived for greater than 12 months after the time of transformation.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Child; Cytarabine; Daunorubicin; Doxorubicin; Female; Humans; Hydroxyurea; Leukemia; Leukemia, Myeloid, Chronic-Phase; Male; Methotrexate; Middle Aged; Remission Induction; Thioguanine; Vincristine