In leukemias, the monitoring techniques on the response after the treatment have clinical importance for evaluating new therapeutic approaches and identifying the risk of relapse. In this study, genetic changes before and after chemotherapy in interphase and metaphase nuclei of bone morrow of adults with provisional diagnosis of leukemia were compared to understand the molecular characterization and pathogenesis of the leukemia for the classification of diagnosis and prognosis. We examined bone morrow cells of 47 chronic myeloid leukemia (CML) cases (29 of 47 at the time of diagnosis, 31 of 47 after chemotherapy) with the bcr/abl translocation probes and of 10 acute promyelocytic leukemia (APL) cases (7 of 10 at the time of diagnosis, 4 of 10 after chemotherapy) with the PML/RARalpha translocation probes by using dual color-flourescence in situ hybridization (DC-FISH). For each case, 400 interphase nuclei and 11 to 25 metaphases nuclei were analysed. The ratios of translocations before and after chemotherapy were compared between interphase and metaphase nuclei. After chemotherapy, though, translocations were detected in interphase nuclei of 29 of the 31 CML and 4 of the 4 APL cases, these translocations were determined in metaphase nuclei of only 14 of the 31 CML and 1 of the 4 APL cases with very low ratios (p < 0.01). The results showed that the rates of translocation positive interphase nuclei were higher than the rates of translocation positive metaphase nuclei (p < 0.01) after chemotherapy, so there may be some factors effecting proliferative activity of metaphase formation in leukemias.

Chronic myeloid leukaemia is associated with a specific translocation between chromosomes 9 and 22 that results in the formation of a chimaeric gene. This gene, when transcribed, produces the BCR-Abl oncoprotein which has tyrosine kinase activity and the ability to prevent apoptosis, but has no effect on cellular proliferation. Imatinib mesylate, an inhibitor of the BCR-Abl transcript modelled on the ATP binding pocket of the Abl oncoprotein, prevents phosphorylation of effector molecules and induces apoptosis. Imatinib has limited effectiveness when BCR-Abl cells are in the quiescent cell-cycle state of G0. A life-long regimen of imatinib should reduce the risk of relapse from cells leaving G0. Up-regulation of BCR-Abl expression, ATP binding pocket mutations, up-regulation of MDR1 and over-expression of Pgp are all thought to limit the effectiveness of imatinib. Advanced BCR-Abl positivity is associated with complex mutations, which are thought to have a cumulative effect on the BCR-Abl oncoprotein in disrupting normal signal transduction, making these cells refractory to monotherapy alone. Combination therapy is thought to overcome this. Research studies have identified imatinib as a potential treatment option for a diverse range of malignancies associated with BCR-Abl, platelet-derived growth factor receptor (PDGFr) and c-Kit pathways. This may extend the application of this special therapy in the future.

OBJECTIVES: To evaluate the effectiveness of imatinib as first-line treatment for chronic myeloid leukaemia (CML) compared with interferon-alpha (IFN-alpha), hydroxyurea and bone marrow transplantation (BMT), and the cost-effectiveness of imatinib compared with IFN-alpha and hydroxyurea. DATA SOURCES: Electronic databases. REVIEW METHODS: Selected studies and full-text articles were screened and rigorously selected. Survival was the key outcome measure. Surrogate outcome measures included haematological (blood) response and cytogenetic (bone marrow) response (CR). As no published cost-effectiveness studies were found that compared imatinib and IFN-alpha, an independent Markov model was constructed and this was compared with models submitted to the National Institute for Clinical Excellence by the manufacturer of imatinib. RESULTS: Intention-to-treat analysis showed that imatinib was associated with complete CR at 12 months follow-up of 68% compared with 20% for the IFN-alpha plus Ara-C group. The estimated proportion of people taking imatinib who had not progressed to accelerated or blast phases at 12 months was 98.5%, and 93.1% for IFN-alpha plus Ara-C. Overall survival was not statistically significantly different. Withdrawal due to side-effects was 2% for imatinib and 5.6% for IFN-alpha plus Ara-C. Cross-over due to intolerance was 0.7% and 22.8% for imatinib and for IFN-alpha plus Ara-C, respectively. Quality of life was better in the imatinib group than the IFN-alpha group when assessed at 1, 3 and 6 months. Median survival across the four IFN-alpha versus hydroxyurea studies was 66 and 56.2 months, respectively. Median complete CR was 6% for IFN-alpha and 0 for hydroxyurea. Median withdrawal due to side-effects was 24% and 4% for IFN-alpha and hydroxyurea, respectively. Four out of the five studies comparing BMT and IFN-alpha showed a long-term survival advantage for BMT over IFN-alpha, but a short-term disadvantage. In four of the five studies comparing BMT and IFN-alpha, median survival had not yet been reached in the BMT groups in 6–10 years. Median survival in the IFN-alpha arms ranged from 5.2 to 7 years. The BMT group gained a survival advantage over IFN-alpha at 3–5.5 years. In the BMT group death due to transplant-related complications ranged from 36 to 45%. The incremental cost-effectiveness ratio (ICER) of imatinib compared with IFN-alpha from the independent model was GBP26,180 per quality-adjusted-life-years (QALY) gained and was relatively robust. Imatinib was less cost-effective than hydroxyurea with an ICER of GBP86,934. CONCLUSIONS: Imatinib appears to be more effective than current standard drug treatments in terms of cytogenetic response and progression-free survival, with fewer side-effects. However, there is uncertainty concerning longer term outcomes, the development of resistance to imatinib, the duration of response and the place of imatinib relative to BMT. New issues are continually arising, such as optimal management pathways and combination therapies. Recommendations for research include: long-term follow-up data from the first- and second-line imatinib trials; investigation into specific subgroups, e.g. high-risk patients, the elderly, children or those eligible for BMT; long-term comparisons of imatinib with BMT performed in early stages of CML; the use of imatinib in combination with other therapies, and further detailed economic studies. Investigation of the impact of CML and imatinib on quality of life is also important.

Primary (nonreactive) eosinophilia is operationally classified as either a “clonal” or an “idiopathic” process. Clonal eosinophilia stipulates the presence of cytogenetic, molecular, or bone marrow histologic evidence of acute leukemia or a chronic myeloid disorder. Idiopathic eosinophilia is a diagnosis of exclusion that is made after ruling out both “secondary” (reactive) and clonal eosinophilia. Hypereosinophilic syndrome is a subclass of idiopathic eosinophilia that requires the documentation of both sustained eosinophilia (> or = 1500/microL for at least 6 months) and target-organ damage. A series of novel observations in the last 5 years have warranted a refined approach to the diagnosis as well as the treatment of clonal eosinophilic disorders, including systemic mastocytosis. At the center of these new developments are mutations involving the platelet-derived growth factor receptor genes (PDGFRA and PDGFRB), which have been pathogenetically linked to clonal eosinophilia, and their presence predicts complete as well as durable treatment responses to imatinib mesylate. The bone marrow histologic phenotype of these imatinib-sensitive eosinophilic disorders includes systemic mastocytosis, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, and atypical chronic myeloproliferative disorder.

To determine the optimal dose, dose-limiting toxicities, and pharmacokinetics of imatinib mesylate in children with refractory or recurrent Philadelphia chromosome-positive (Ph+) leukemias. Oral imatinib mesylate was administered daily at dose levels ranging from 260-570 mg/m2 in consecutive 28-day courses of therapy. Serial blood samples for plasma pharmacokinetic studies were collected on days 1 and 8 of course 1. Thirty-one patients between 3-20 years of age with refractory Ph+ leukemias received 479 courses (median 6, range 1-46) of imatinib. The most common toxicities associated with imatinib administration, which occurred in < 5% of courses, were grade 1 or 2 nausea, vomiting, fatigue, diarrhea and reversible increases in serum transaminases. One patient at the 440 mg/m2 dose level had dose-limiting weight gain. There were no other first course dose-limiting toxicities. A maximum tolerated dosage was not defined. Among twelve CML patients evaluable for cytogenetic response, 10 had a complete response and 1 had a partial response. Among ten ALL patients evaluable for morphologic response, seven achieved an M1 and one achieved an M2 bone marrow. Pharmacokinetic analyses revealed that there was marked interpatient variability in the pharmacokinetic parameters. Daily oral imatinib mesylate is well tolerated in children with Ph+ leukemias at doses ranging from 260 to 570 mg/m2. Doses of 260 and 340 mg/m2 provide systemic exposures similar to those of adults who are treated with daily doses of 400 and 600 mg, respectively.

Topotecan, a topoisomerase-I inhibitor is an active drug in the treatment of AML and MDS. To evaluate its toxicity and efficacy in a combination regimen with cytarabine, we conducted a clinical phase I/II trial in patients with relapsed acute myeloid leukemia (AML) or relapsed or newly diagnosed MDS RAEB, RAEB-t or CMML. Twenty-one patients (11 AML, 10 MDS/CMML) entered the study and were treated with 1.25 mg/m2 topotecan as continuous intravenous infusion daily for 5 days and cytarabine 1.0 g/m2 by infusion over 2 h daily for 5 days (TA). Cycles were repeated on day 28. The median observation time was 131 weeks (range: 36-196 weeks). A total of 37 cycles of TA were administered. In 1 patient, the dose of TA had to be reduced and in 1 patient, there was a treatment delay for the second cycle, both because of hematologic toxicity. The most frequent non-hematologic side-effect of TA was fever, which occurred in 17 patients (89%) with temperatures over 38 degrees C. None of the patients died due to any treatment-related toxicities, but 2 patients (10%) died within 1 month due to disease progression. A CR was achieved in 7 patients (33%), 3 of whom were MDS and 4 AML. A partial remission was reported in 8 patients (38%), no change of disease in 2 patients (10%) and progressive disease in 4 patients (19%). The median remission duration was 18 weeks (range 2-161 weeks) for MDS patients and 11 weeks (range 2-49 weeks) for AML patients. The time to progression for patients of 60 years and older (n = 10) was 16 weeks (range 2-49 weeks) and the survival was 32 weeks (range 2-119 weeks). TA is a feasible and efficacious chemotherapeutic combination for the treatment of MDS RAEB, RAEB-t, CMML and AML. For patients of 60 years and older, this regimen is also a safe option.