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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Identification of patient sub-groups with smoldering multiple myeloma (SMM) at high risk of progression to active disease (MM) is an important goal. 18F-FDG PET/CT (positron emission tomography (PET) integrated with computed tomography (PET/CT) using glucose labelled with the positron-emitting radionuclide (18)F) allows for assessing early skeletal involvement. Identification of osteolytic lesions by this technique has recently been incorporated into the updated International Myeloma Working Group criteria for MM diagnosis. However, no data are available regarding the impact of focal lesions (FLs) without underlying osteolysis on time to progression (TTP) to MM. We hence prospectively studied a cohort of 120 SMM patients with PET/CT. PET/CT was positive in 16% of patients (1 FL: 8, 2 FLs: 3, >3 FLs: 6, diffuse bone marrow involvement: 2). With a median follow-up of 2.2 years, 38% of patients progressed to MM, in a median time of 4 years, including 21% with skeletal involvement. The risk of progression of those with positive PET/CT was 3.00 (95% confidence interval 1.58-5.69, P=0.001), with a median TTP of 1.1 versus 4.5 years for PET/CT-negative patients. The probability of progression within 2 years was 58% for positive versus 33% for negative patients. In conclusion, PET/CT positivity significantly increased the risk of progression of SMM to MM. PET/CT could become a new tool to define high-risk SMM.

Purpose: To evaluate the role of 18F-FDG PET/CT in 282 symptomatic multiple myeloma patients treated up-front between 2002 and 2012.Experimental Design: All patients were studied by PET/CT at baseline, during posttreatment follow-up, and at the time of relapse. Their median duration of follow-up was 67 months.Results: Forty-two percent of the patients at diagnosis had >3 focal lesions, and in 50% SUV max was >4.2; extramedullary disease was present in 5%. On multivariate analysis, ISS stage 3, SUV max >4.2, and failure to achieve best complete response (CR) were the leading factors independently associated with shorter progression-free survival (PFS) and overall survival (OS). These 3 variables were used to construct a prognostic scoring system based on the number of risk factors. After treatment, PET/ CT negativity (PET-neg) was observed in 70% of patients, whereas conventionally defined CR was achieved in 53%. Attainment of PET-neg favorably influenced PFS and OS. PET-neg was an independent predictor of prolonged PFS and OS for patients with conventionally defined CR. Sixty-three percent of patients experienced relapse or progression; in 12%, skeletal progression was exclusively detected by systematic PET/CT performed during follow-up. A multivariate analysis revealed that persistence of SUV max >4.2 following first-line treatment was independently associated with exclusive PET/CT progression.Conclusions: PET/CT combined with ISS stage and achievement or not of CR on first-line therapy sorted patients into different prognostic groups. PET/CT led to a more careful evaluation of CR. Finally, in patients with persistent high glucose metabolism after first-line treatment, PET/CT can be recommended during follow-up, to screen for otherwise unidentifiable progression.

The median age of chronic myeloid leukemia (CML) patients is ϳ 60 years, and age is still considered an important prognostic factor, included in Sokal and EURO risk scores. However, few data are available about the long-term outcome of older patients treated with imatinib (IM) frontline. We analyzed the relationship between age and outcome in 559 early chronic-phase CML patients enrolled in 3 prospective clinical trials of Gruppo Italiano Malattie Ematologiche dell'Adulto CML Working Party, treated frontline with IM, with a median follow-up of 60 months. There were 115 older patients (> 65 years; 21%). The complete cytogenetic and major molecular response rates were similar in the 2 age groups. In older patients, event-free survival (55% vs 67%), failurefree survival (78% vs 92%), progressionfree survival (62% vs 78%), and overall survival (75% vs 89%) were significantly inferior (all P < .01) because of a higher proportion of deaths that occurred in complete hematologic response, therefore unrelated to CML progression (15% vs 3%, P < .0001). The outcome was similar once those deaths were censored. These data show that response to IM was not affected by age and that the mortality rate linked to CML is similar in both age groups. This trial was registered at www. clinicaltrials.gov as #NCT00514488 and #NCT00510926. (Blood. 2011;117(21): 5591-5599)