Unusual extramedullary relapses under imatinib mesylate treatment in chronic myeloid leukemia

There are at least four distinct African and one Asian chromosomal backgrounds (haplotypes) on which the sickle cell mutation has arisen. Additionally, previous data suggest that the beta(S)/Bantu haplotype is heterogeneous at the molecular level. Here, we report the presence of the (A)gamma -499 T-->A variation in sickle cell anemia chromosomes of Sicilian and North African origin bearing the beta(S)/Benin haplotype. Being absent from North American beta(S)/Benin chromosomes, which were studied previously, this variation is indicative for the molecular heterogeneity of the beta(S)/Benin haplotype.     

The effects of imatinib mesylate treatment before allogeneic transplantation for chronic myeloid leukemia

The impact of imatinib mesylate (IM) treatment for chronic myeloid leukemia (CML) on subsequent allogeneic transplantation is uncertain. To better understand this relationship, we retrospectively compared 145 patients with CML receiving IM for a minimum of 3 months before allogeneic hematopoietic cell transplantation (HCT) to 231 patients with CML who did not. IM treatment was associated with no increase in early hepatotoxicity or engraftment delay after HCT compared with the historical cohort. In addition, there was no statistically significant difference in the IM-treated cohort compared with the historical cohort with regard to overall survival, disease-free survival, relapse, and nonrelapse mortality. For chronic-phase (CP) patients, IM response prior to HCT was associated with post-HCT outcome. Patients who underwent transplantation in CP with a suboptimal response or a loss of response on IM had a statistically significant higher hazard of mortality when compared with CP patients who achieved a complete cytogenetic response (CCR) or major cytogenetic response (MCR) on IM (HR=5.31, 95% confidence interval [CI] 1.13-25.05, P=.03). These data indicate that pre-HCT IM is not associated with increased transplant-related morbidity (TRM) or poorer outcomes. However, patients with a suboptimal or loss of IM response before HCT do worse, suggesting a more aggressive disease course for these patients.     

Sudden blastic transformation in patients with chronic myeloid leukemia treated with imatinib mesylate

Sudden blastic transformation (SBT) has been reported in 0.5% to 2.5% of patients treated with interferon-alpha (IFN-alpha) during the first 3 years of therapy. Imatinib is now standard therapy for patients with chronic myeloid leukemia in chronic phase. We investigated the occurrence of SBT among patients treated with imatinib. Among 541 patients treated with imatinib in chronic phase, 23 developed blast phase, which was of sudden onset (ie, occurring in patients previously in complete cytogenetic remission) in 4 patients (17%; 0.7% of the total), 2 lymphoid and 2 myeloid. Patients with SBT were found to have low-risk features more often at the time of presentation and had achieved optimal response with imatinib. Three of the 4 patients underwent allogeneic stem cell transplantation and achieved a molecular remission. SBT is still a rare event, probably less common than that observed with IFN-alpha therapy. Continuous monitoring of patients treated with imatinib is mandatory.     

Efficacy and pharmacokinetics of imatinib mesylate in a child with chronic myeloid leukemia

A 6-year-old girl with chronic myeloid leukemia (CML) was treated with imatinib 230 mg/m2/day and its pharmacokinetics were investigated. The patient had a complete hematologic response on day 21, but had a minor cytogenetic response and the CML progressed to a blast crisis on day 133. At present, she has maintained complete cytogenetic remission with allogenetic peripheral blood stem cell transplantation. The pharmacokinetics revealed that the maximum concentration (1.4 micrograms/ml); time to maximum concentration (5.1 h); half-life (11.0 h); trough concentration (0.4 microgram/ml); and, area under the concentration-time curve (28.1 micrograms.h/ml) were inferior to those for adult patients in the 400 mg/day group. This observation suggests that a suboptimal plasma concentration might be related to resistance to imatinib and/or blast crisis.     

Successful treatment with imatinib mesylate for Philadelphia chromosome-positive refractory acute myeloid leukemia

A 51-year-old man was diagnosed as having Philadelpha (Ph) chromosome-positive acute myeloid leukemia (AML) with major-BCR/ABL mRNA. He achieved complete remission after induction chemotherapy. Five months later, he was again positive for the Ph chromosome despite additional chemotherapy. He was therefore treated with imatinib mesylate, a specific inhibitor of BCR/ABL tyrosine kinase, at a dose of 600 mg/day. However, the treatment was interrupted because of thrombocytopenia, skin eruption and face edema. After the patient recovered from these side effects, imatinib was readministered at a dose of 400 mg/day and a complete cytogenetic response was achieved. Imatinib is expected to be an effective drug for Ph chromosome-positive AML.     

Practical aspects of the treatment of chronic myelogenous leukemia with imatinib mesylate

Imatinib mesylate (Gleeve; formerly known as STI-571; Novartis Pharmaceuticals, Basel, Switzerland) is a protein tyrosine kinase inhibitor that has been approved by the US Food and Drug Administration for chronic-phase chronic myeloid leukemia (CML) that is refractory to or intolerant of interferon-alpha, and with accelerated and blast-phase CML. Imatinib is remarkably effective as treatment for chronic-phase and accelerated-phase CML at doses of 400 mg and 600 mg daily, respectively. Although dramatic responses are noted in patients with myeloid blast crisis, lymphoid blast crisis, and Philadelphia chromosome-positive acute lymphoblastic leukemia, the responses are usually incomplete and of short duration. The role of imatinib in relation to allogeneic stem cell transplantation is discussed, recognizing that the data on which any decisions can be made are relatively immature. At this time, it remains to be seen whether the chronic phase of CML can be extended sufficiently long in some patients so that they are functionally "cured," and whether doses of imatinib higher than 400 mg daily will improve response rates in chronic-phase CML. The feasibility of combining imatinib with other agents also needs to be examined, as does the utility of molecular monitoring of response. Finally, developing methods to overcome resistance to imatinib is a looming challenge.     

Myelodysplastic syndromes and acute leukemia developing after imatinib mesylate therapy for chronic myeloid leukemia

During therapy with imatinib, some patients with chronic myeloid leukemia (CML) develop chromosomal abnormalities in Philadelphia chromosome (Ph)-negative cells. These abnormalities are frequently transient and their clinical consequence is unclear. Although some reports have suggested that the abnormalities might be associated with secondary myelodysplastic syndrome (MDS), the diagnosis has not always been established using standard criteria. We report 3 cases of patients treated with imatinib for CML who were subsequently found to have chromosomal abnormalities in Ph-negative cells. One of them developed acute myelogenous leukemia (AML) and the other 2 developed high-risk MDS that rapidly transformed to AML. These cases were identified in a total study group of 1701 patients. Although these occurrences are rare, the findings highlight the need for close monitoring of patients with CML treated with imatinib.     

High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia

Imatinib mesylate (STI571) is effective in chronic phase chronic myelogenous leukemia (CML). However, most patients treated with 400 mg imatinib daily have variable levels of residual molecular disease. We treated 114 patients with newly diagnosed chronic phase CML with 400 mg imatinib twice daily. Overall, 109 patients (96%) had a major cytogenetic response (Philadelphia chromosome [Ph] < 35%), and 103 (90%) had a complete response (Ph 0%). With a median follow-up of 15 months, no patient has progressed to accelerated or blastic phase. The estimated 2-year survival rate was 94%. By quantitative polymerase chain reaction (QPCR) studies, 71 (63%) of 112 patients showed BCR-ABL/ABL percentage ratios decrease to less than 0.05%, and 31 (28%) to undetectable levels. Compared with standard-dose imatinib, high-dose imatinib was associated with significantly better complete cytogenetic response (P =.0005), major molecular response (QPRC < 0.05%; P =.00001), and complete molecular response (undetectable BCR-ABL; P =.001). High-dose imatinib was well tolerated but resulted in more frequent myelosuppression; 82% of patients continue to receive 600 mg or more of imatinib daily. In conclusion, high-dose imatinib induced higher rates of complete cytogenetic response and of molecular response in patients with newly diagnosed chronic phase CML.     

Efficacy and prognosis of chronic myeloid leukemia treated with imatinib mesylate in a Chinese population

There is limited data from developing countries on the current status of imatinib treatment for chronic myeloid leukemia (CML), thus we retrospectively analyzed 116 Chinese CML patients who received imatinib between 2003 and 2008. The response rates for 102 patients in chronic phase were: complete hematologic, 94.1%; complete cytogenetic, 69.6%; and complete molecular response, 54.9%. For 14 patients in the accelerated phase, the respective response rates were 85.7, 35.7 and 28.6%. The 3-year progression-free survival and 5-year overall survival were 73.3 and 74.8%. Although skin hypopigmentation occurs as the most common side effect (77.6%), imatinib is still well tolerated. In addition to the known pretreatment characteristics of spleen size, leukocyte and platelet counts, disease phase and Sokal scores, we found that delayed therapy, variant Philadelphia chromosome translocations and IM-related grade 3/4 leucopenia were associated with an inferior cytogenetic response. Four factors emerged as predictors of disease progression: molecular response, cytogenetic response, disease phase and disease duration prior to imatinib treatment, but only the latter three remained significant after multivariate analysis. The results indicate that the suboptimal outcome in Chinese patients is associated with delayed imatinib therapy, so the importance of the optimal treatment opportunity for CML should be emphasized.