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Dasatinib is effective second line treatment for patients with chronic myeloid leukemia (CML) resistant or intolerant to imatinib. We report here the first experiences with dasatinib therapy in 71 CML patients resistant or intolerant to imatinib from the real clinical practice of 6 hematological centers in the Czech Republic. Dose 100 mg daily and 70 mg twice daily was administered to patients with chronic phase (CP) and advanced phases (AP) CML. In chronic phase (n=46), complete hematological reponse (CHR) was achieved in 97%, major cytogenetic reponse (MCgR) in 77% and complete cytogenetic response (CCgR) in 67%. Major molecular reponse (MMR) was achieved in 19/31 patients in median of 10 months. In advanced phase (n=25), CHR was attained in 77%, MCgR in 39%, CCgR in 33% and MMR in 2/18 patients. Eleven different baseline mutations were followed up in 15 patients. Dasatinib eliminated mutations in most of the patients, but 3 patients acquired a new one. Novel mutations were detected under dasatinib therapy in 2 patients. Dasatinib was well tolerated, cytopenias were common and was managed by dose modification. The estimated progression free survival (PFS) at 12 months was 97+/-3% in CP and 62+/-21% in AP. The median time to treatment failure was 605 days in AP while it was not reached in CP patients. Our clinical experiences, described here, confirmed that dasatinib is associated with high response rates especially in imatinib resistant or intolerant CML patients in chronic phase.

To date, all of the chromosomal deletions that cause alpha-thalassemia remove the structural alpha genes and/or their regulatory element (HS -40). A unique deletion occurs in a single family that juxtaposes a region that normally lies approximately 18-kilobase downstream of the human alpha cluster, next to a structurally normal alpha-globin gene, and silences its expression. During development, the CpG island associated with the alpha-globin promoter in the rearranged chromosome becomes densely methylated and insensitive to endonucleases, demonstrating that the normal chromatin structure around the alpha-globin gene is perturbed by this mutation and that the gene is inactivated by a negative chromosomal position effect. These findings highlight the importance of the chromosomal environment in regulating globin gene expression.

To date, all of the chromosomal deletions that cause alpha-thalassemia remove the structural alpha genes and/or their regulatory element (HS -40). A unique deletion occurs in a single family that juxtaposes a region that normally lies approximately 18-kilobase downstream of the human alpha cluster, next to a structurally normal alpha-globin gene, and silences its expression. During development, the CpG island associated with the alpha-globin promoter in the rearranged chromosome becomes densely methylated and insensitive to endonucleases, demonstrating that the normal chromatin structure around the alpha-globin gene is perturbed by this mutation and that the gene is inactivated by a negative chromosomal position effect. These findings highlight the importance of the chromosomal environment in regulating globin gene expression.

In 1993 the EORTC-LCG activated a randomized study comparing HD-CLB and FAMP in untreated B-CLL patients with advanced disease as defined by elevated Total Tumor Mass score (TTM) [Jaksic et al. Br J Haematol 1981, 49: 405] and/or bone marrow failure. Stage was also assessed according to the International Workshop CLL criteria. Patients over 75 years and those with severe concomitant diseases were ineligible. HD-CLB and FAMP were both administered for 18 weeks. HD-CLB consisted of 10 mg/m2/day, with dose reduction based on peripheral cell count, according to a toxicity-tailored schedule. FAMP was used at the dose of 25 mg/m2/day for 4 consecutive days every 3 weeks for 6 courses. Non responding patients were crossed to the alternate regimen and responding cases did not receive any further therapy. The main end-points of the study were clinical, hematological and bone marrow response rate, toxicity and survival. Criteria of response were defined according to the recommendations of the NCI-sponsored working group and by TTM reduction. We report the results on at present 71 evaluable patients (out of 82 patients randomized) with a median actuarial follow-up of 32 months. Median age was 61 years, 62% were males, median TTM size was 11.7 and distribution frequency of patients in Rai stage 0, I, II, III, IV was 3, 23, 43, 14 and 17%, respectively. All parameters were well balanced between treatment arms. Response rates achieved were comparable (ptrend = 0.315): COMPLETE PARTIAL MINIMAL NO RESP TOTAL HD-CLB 14 (41%) 16 (47%) 3 (9%) 1 (3%) 34 FAMP 15 (40%) 13 (35%) 5 (14%) 4 (11%) 37 TOTAL 29 29 8 5 71 Interestingly, the response rate was not significantly influenced by the Rai or Binet stages, TTM score, or by the presence of bone marrow failure. Grade 3/4 overall hematological toxicity was observed in 73% and 51% of cases treated with HD-CLB and FAMP, respectively (ptrend = 0.023). Treatment interruption and dose change was significantly more frequent in HD-CLB arm, in line with strict guidelines of the toxicity tailored design. As a consequence, median total dose actually delivered was only 62% of full theoretical dose in HD-CLB arm compared with 100% in FAMP arm. The observed hematological toxicity did not translate in clinical toxicity. Moreover, moderate to major infections were more frequent in FAMP arm (37%) vs. 12% in HD-CLB arm (ptrend = 0.043). One mild hemorrhage was reported in patients on HD-CLB, and 2 mild and 1 gross hemorrhage in patients on FAMP. Non hematological toxicity was negligible and consisted of allergy in 3 patients (all in HD-CLB), mild to moderate pulmonary (1 in HD-CLB, 5 in FAMP), mild to moderate hepatic (4 in HD-CLB, 2 in FAMP) and mild renal toxicity (1 in HD-CLB, 1 in FAMP arm). Overall survival rate at 2.5 years was 83% (SE = 7%) for patients on HD-CLB vs. 65% (SE = 9%) on FAMP (Logrank p = 0.29). In conclusion, both regimens are feasible, and the overall response rate was quite high (ą 80%). Response and survival of used FAMP schedule is comparable to other reported FAMP monotherapy series. Response and survival on HD-CLB is at least not inferior, suggesting that dose intensive chlorambucil being a simple, well tolerated and safe program may be effectively used for front-line treatment of patients with advanced B-CLL.