Our results show that, irrespective of the hematologic response, monitoring for emerging mutations in the first months of therapy may play a role in detecting patients with worse prognosis, for whom a revision of the therapeutic strategy should be considered.

Nilotinib has a higher binding affinity and selectivity for BCR-ABL with respect to imatinib and is an effective treatment of chronic myeloid leukemia (CML) after imatinib failure. In a phase 2 study, 73 early chronic-phase, untreated, Ph ؉ CML patients, received nilotinib at a dose of 400 mg twice daily. The primary endpoint was the complete cytogenetic response (CCgR) rate at 1 year. With a median follow-up of 15 months, the CCgR rate at 1 year was 96%, and the major molecular response rate 85%. Responses were rapid, with 78% CCgR and 52% major molecular response at 3 months. During the first year, the treatment was interrupted at least once in 38 patients (52%). The mean daily dose ranged between 600 and 800 mg in 74% of patients, 400 and 599 mg in 18% of patients, and was less than 400 mg in 8% of patients. Dose interruptions were mainly due to nonhematologic and biochemical side effects. Myelosuppression was irrelevant. One patient progressed to blastic crisis after 6 months; one went off-treatment for lipase increase grade 4 (no pancreatitis). Nilotinib is safe and very active in early chronic-phase CML. These data support a role for nilotinib for the frontline treatment of CML. This study was registered at ClinicalTrials.

T he striking efficacy of imatinib mesylate in chronic myeloid leukemia (CML) 1,2 has established this therapy as the new standard of care for the disease. However, resistance is an emerging problem which has prompted the design of several second-generation Bcr-Abl inhibitors. One of these, dasatinib , is now in advanced clinical development. 4 In vitro assays 5,6 and crystallographic studies 7 have suggested that the less stringent conformational requirements for Bcr-Abl binding are likely to render dasatinib active against many of the kinase domain mutants responsible for imatinib resistance. One remarkable exception appears to be the T315I, which has been shown to disrupt a hydrogen bond critical for dasatinib binding and to create steric hindrance which interferes with the entrance of the inhibitor into the ATP-binding site. In order to assess which pre-existent or emerging mutations are associated with decreased clinical efficacy of dasatinib, we analyzed BCR-ABL kinase domain sequences before and during treatment in Philadelphia chromosome-positive (Ph + ) leukemia patients who failed to respond to or relapsed during dasatinib therapy. Design and MethodsIn a phase II program (sponsored by Bristol-Myers Squibb) we treated with dasatinib 70 mg twice daily a total of 45 patients with either CML (n=35) or Ph + acute lymphoblastic leukemia (ALL) (n=10) who were resistant to or intolerant of imatinib. Their median age was 50 years (range, 18-74), the median duration since the diagnosis of CML was 32 months (range, 4-158); and the median duration of imatinib treatment was 17 months (2-57). At the time of writing, with a median follow-up of 12 months (range, 1-19), 21 patients have shown evidence of either primary or acquired resistance, defined as a failure to achieve a hematologic response or loss of hematologic response during treatment, respectively. All the patients provided written informed consent to their participation in this study. Hematologic response was assessed according to the criteria already described for the phase I study.4 Cytogenetic ABSTRACT Brief ReportThe emergence of resistance to the Bcr-Abl inhibitor imatinib mesylate in patients with Philadelphia chromosome-positive (Ph + ) leukemia has prompted the development of second-generation compounds active against several imatinib-insensitive mutant forms of Bcr-Abl, including dasatinib (BMS-354825; Bristol-Myers Squibb). In order to assess which pre-existent or emerging kinase domain mutations are associated with decreased clinical efficacy of desatinib, we analyzed BCR-ABL kinase sequences before and during treatment in 21 Ph + patients who failed to respond to or relapsed during dasatinib therapy. In all patients but one, resistance to dasatinib was invariably found to be associated with mutations at residue 315 and/or at residue 317. Hematology and Medical Oncology "L. e A. Seràgnoli", S. OrsolaMalpighi Hospital, Massarenti 9, 40138 Bologna, Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selec...

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NCT00510926, NCT00514488, NCT00769327, NCT00481052.

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BackgroundImatinib mesylate is the first line treatment for chronic myeloid leukemia. In patients with advanced phase of the disease, the advent of imatinib significantly increased survival. However, few long-term data, based on large, prospective and controlled trials are available on the outcome of these patients. Design and MethodsWe conducted a phase II trial of imatinib 600 mg daily in patients with chronic myeloid leukemia in blast crisis. The return to chronic phase was defined as <15% blasts and <30% blasts plus promyelocytes in blood or bone marrow and <20% peripheral basophils. A complete hematologic response required the normalization of platelet and white cell differential counts and absence of extramedullary involvement. Cytogenetic response was assessed by the standard banding technique and rated as usual. ResultsNinety-two patients were enrolled (20 with lymphoid blast crisis and 72 with myeloid blast crisis). Forty-six patients (50%) returned to chronic phase, and 24 patients (26%) achieved also a complete hematologic response. Sixteen patients (17%) had a cytogenetic response (9 complete, 1 partial, and 6 minor or minimal). The complete cytogenetic response was subsequently lost by all but two patients between 2 and 12 months after first having achieved it: the median duration of complete cytogenetic response was 7 months. All responses were sustained for a minimum of 4 weeks. The median survival of all the patients was 7 months. After a median observation time of 66 months, seven (8%) patients are alive. Three of these patients are on imatinib treatment (1 in complete hematologic remission, 1 in partial cytogenetic response and 1 in complete cytogenetic remission). Three patients are in complete remission after allogeneic stem cell transplantation. One patient is alive in blast crisis, on therapy with a second-generation tyrosine kinase inhibitor. ConclusionsImatinib was effective and safe in the short-term treatment of chronic myeloid leukemia in blast crisis, but longer-term outcome was not significantly influenced (ClinicalTrials.gov identifier: NCT00514969). Key words: chronic myeloid leukemia, blast crisis, imatinib, outcome, long-term.Citation: Palandri F, Castagnetti F, Testoni N, Luatti S, Marzocchi G, Bassi S, Breccia M, Alimena G, Pungolino E, Rege-Cambrin G, Varaldo R, Miglino M, Specchia G, Zuffa E, Ferrara F, Bocchia M, Saglio G, Pane F, Alberti D, Martinelli G, Baccarani M, and Rosti G on follow-up. Haematologica 2008; 93:1792-1796 This is an open-access paper.Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg: outcome of the patients alive after a 6-year follow-up © F e r r a t a S t o r t i F o u n d a t i o n IntroductionBlast crisis (BC) is the terminal phase of chronic myeloid leukemia (CML), a clonal myeloproliferative disease characterized by a reciprocal t(9;22)(q34;q11) chromosomal translocation, which creates the Philadelphia chromosome (Ph) and leads to the expression of the BCR-ABL fusion protein, whose deregulated constitutive tyrosi...

for the GIMEMA Working Party on Chronic Myeloid Leukemia Since interferon-␣ and imatinib (IM; STI571, Glivec, Gleevec) are effective for the treatment of chronic myeloid leukemia (CML), and their mechanisms of action are different, we designed an exploratory study investigating the effects of a standard IM dose (400 mg/d) and a variable pegylated interferon-␣ (PegIFN) dose (50 g/wk, 100 g/ wk, and 150 g/wk). The criteria for dose adjustment were designed so as to ensure the delivery of the IM dose and to protect life quality. There were 76 patients with previously untreated Philadelphia (Ph)-positive CML enrolled in the study. There were 3 patients who discontinued IM and 45 patients who discontinued PegIFN. The severity of adverse events increased with increasing PegIFN dose. The IM dose could be administered to the patients who were assigned to receive 50 g/wk or 100 g/wk PegIFN but not to those who were assigned to receive 150 g/wk. The median administered dose of PegIFN ranged between 32 g/wk and 36 g/wk. The cytogenetic response was 70% complete (Ph-neg 100%) and 83% major (Ph-neg > 65%). The BCR/ ABL transcript was reduced by at least 3 logs in 68% of complete cytogenetic responders. These data of toxicity, compliance, and efficacy may assist in the design and preparation of prospective studies.