Fausto Castagnetti

Frontline imatinib treatment of chronic myeloid leukemia: no impact of age on outcome, a survey by the GIMEMA CML Working Party

The median age of chronic myeloid leukemia (CML) patients is ~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 dellAdulto 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%), failure-free survival (78% vs 92%), progression-free 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.

Investigating factors associated with adherence behaviour in patients with chronic myeloid leukemia: an observational patient-centered outcome study

Background:Optimal adherence to imatinib therapy is of paramount importance to maximise treatment effectiveness in patients with chronic myeloid leukaemia (CML). The main objective of this study was to investigate patient-reported personal factors associated with adherence behaviour.Methods:Analysis was conducted on 413 CML patients receiving long-term therapy with imatinib. Adherence behaviour was measured with the Morisky Medication Adherence Scale and personal factors investigated included: quality of life, perceived social support, fatigue, symptom burden, psychological wellbeing and desire for additional information. Key socio-demographic and treatment-related factors were also taken into account. Univariate and multivariate logistic regression analyses were used to investigate factors associated with optimal adherence to therapy.Results:In all, 53% of patients reported an optimal adherence behaviour. The final multivariate model retained the following variables as independent predictors of optimal adherence to therapy: desire for more information (ref. no), odds ratio (OR)=0.43 (95% confidence interval (CI), 0.29–0.66; P<0.001), social support (higher score representing greater support), OR=1.29 (95% CI, 1.11–1.49; P<0.001) and concomitant drug burden (ref. no), OR=1.82 (95% CI, 1.18–2.80; P=0.006).Conclusion:This study suggests that a higher level of social support, satisfaction with information received and concomitant drug burden are the main factors associated with greater adherence to long-term imatinib therapy.

Variant Philadelphia translocations: molecular-cytogenetic characterization and prognostic influence on frontline imatinib therapy, a GIMEMA Working Party on CML analysis

Variant Philadelphia (Ph) chromosome translocations have been reported in 5%-10% of patients with newly diagnosed chronic myeloid leukemia (CML). Variant translocations may involve one or more chromosomes in addition to 9 and 22, and can be generated by 2 different mechanisms, 1-step and 2-step rearrangements, as revealed by fluorescence in situ hybridization. The prognostic significance of the occurrence of variant translocations has been discussed in previous studies. The European LeukemiaNet recommendations do not provide a warning for patients with variant translocations, but there is limited information about their outcome after therapy with tyrosine kinase inhibitors. To identify the role of variant translocations in early chronic phase (CP) CML patients treated with imatinib mesylate, we performed an analysis in a large series of 559 patients enrolled in 3 prospective imatinib trials of the Gruppo Italiano Malattie EMatologiche dellAdulto (GIMEMA) Working Party on CML. Variant translocations occurred in 30 patients (5%). Our data show that the presence of variant translocations has no impact on the cytogenetic and molecular response or on outcome, regardless of the involvement of different mechanisms, the number of involved chromosomes, or the presence of deletions. Therefore, we suggest that patients with variant translocations do not constitute a warning category in the imatinib era. This study is registered at www.clinicaltrials.gov as NCT00514488 and NCT00510926.

Incidence, risk factors and management of pleural effusions during dasatinib treatment in unselected elderly patients with chronic myelogenous leukaemia

To assess the most important features and clinical impact of pleural effusions, which are a common toxicity during dasatinib treatment and often impair its high efficacy, 172 unselected consecutive patients with chronic myelogenous leukaemia in chronic phase treated in 27 Italian centres, with dasatinib when aged >60u2009years for resistance/intolerance to imatinib, were examined. During treatment, 52/172 patients (30.2%) presented pleural effusion, which was grades 1–2 in 38 patients and grades 3–4 in 14 patients (8.1% of the entire cohort of patients), according to the WHO scale; in 14/52 patients (26.9%), there was a concomitant pericardial effusion. Pleural effusion was recurrent in 25/52 patients (48.0%). Median time from dasatinib to first pleural effusion was 11.0u2009months (interquartile range 3.6–18.6). Eleven patients (6.4%) required permanent dasatinib discontinuation. Only presence of concomitant pulmonary disease (u2009pu2009=u20090.035) and initial daily dose of dasatinib (140u2009mg vs 100u2009mg, pu2009=u20090.014) were significantly associated with pleural effusions. There were no differences among patients with or without pleural effusions as concerns response rates and overall survival. Pleural effusions were common in our unselected ‘real‐life’ population of elderly patients but were clinically manageable and did not seem to affect treatment results. Copyright

Dasatinib is safe and effective in unselected chronic myeloid leukaemia elderly patients resistant/intolerant to imatinib

To highlight dasatinib role in the elderly, 125 unselected patients with CP-CML aged >60 years resistant/intolerant to imatinib were retrospectively evaluated. Grade 3-4 haematological and extra-haematological toxicities were reported in 39 (31.2%) and 34 (27.2%) patients; grade 3-4 haematological toxicity was higher in patients with 140 mg starting dose (50.0% vs 19.6%, p=0.001). Grade 3-4 pleuro-pericardial effusions occurred in 10 patients (8.0%). Dose reductions were more common in patients with 140 mg (88.4% vs 26.7%, p<0.001). Of 122 evaluable patients, 72 (59.1%) had cytogenetic response [12 (9.8%) partial, 60 (49.3%) complete]. Overall, 38/60 patients in complete CyR also achieved a molecular response. Cumulative OS at 24 and 48 months were 93.1% (95% CI 88.4-97.8) and 84.2% (95% CI 74.6-93.7). Dasatinib, at the recommended dose of 100mg/day, is effective and safe also in unselected elderly subjects.

IDH2 somatic mutations in chronic myeloid leukemia patients in blast crisis

We read with interest a series of manuscripts,1, 2, 3, 4, 5, 6 reporting somatic mutations of the isocitrate dehydrogenase 1 and 2 enzyme isoforms (IDH1, IDH2) in patients with de novo acute myeloid leukemia (AML), in patients with chronic and blast phase Philadelphia chromosome-negative (Ph–) myeloproliferative neoplasms (MPNs) and in patients with early and accelerated phase myelodysplastic syndromes (MDSs).We have recently screened, by massively parallel sequencing, the transcriptome of a Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) patient

Outcome of 82 chronic myeloid leukemia patients treated with nilotinib or dasatinib after failure of two prior tyrosine kinase inhibitors

There have been few reports of a response to dasatinib or nilotinib after failure of two prior sequential tyrosine kinase inhibitors. We report the outcome of 82 chronic phase patients who received nilotinib or dasatinib as third-line alternative tyrosine kinase inhibitor therapy. Thirty-four patients failed to respond to nilotinib and were started on dasatinib as third-line tyrosine kinase inhibitor therapy while 48 patients were switched to nilotinib after dasatinib failure. Overall, we obtained a cytogenetic response in 32 of 82 patients and major molecular response in 13 patients; disease progression occurred in 12 patients. At last follow up, 70 patients (85.4%) were alive with a median overall survival of 46 months. Our results show that third-line tyrosine kinase inhibitor therapy in chronic myeloid leukemia patients after failure of two prior sequential tyrosine kinase inhibitors may induce a response that, in some instances, could prolong overall survival and affect event-free survival.

Evaluation of residual CD34+Ph+ progenitor cells in chronic myeloid leukemia patients who have complete cytogenetic response during first-line nilotinib therapy

Compared with imatinib, nilotinib is a potent breakpoint cluster region/v‐abl Abelson murine leukemia viral oncogene (bcr‐abl) kinase inhibitor, and it induces higher rate and rapid complete cytogenetic response (CCyR), yet no clinical data are available regarding its efficacy against chronic myeloid leukemia (CML) stem cells. Earlier studies demonstrated that clusters of differentiation 34–positive, Philadelphia chromosome–positive (CD34+Ph+) cells are detectable in about 45% of patients with CML, despite being on long‐term imatinib therapy and having achieved sustained CCyR.

DNA hypermethylation promotes the low expression of pro-apoptotic BCL2L11 associated with BCR-ABL1 fusion gene of chronic myeloid leukaemia

The authors declare no competing interests. Michelle A. Neller Andrew K. Sewell Scott R. Burrows John J. Miles Australian Centre for Vaccine Development, Human Immunity Laboratory and Cellular Immunology Laboratory, Queensland Institute of Medical Research Brisbane Queensland, Australia, T Cell Modulation Laboratory, Institute of Infection and Immunity Cardiff University School of Medicine Cardiff UK and School or Medicine, The University of Queensland Brisbane Queensland, Australia E-mail: john.miles@qimr.edu.au

Explaining the in vitro and in vivo differences in leukemia therapy

The majority of patients with chronic myeloid leukemia in early chronic phase (CML-ECP) who are treated with imatinib achieve a complete cytogenetic response with a significant reduction in the risk of progression to advanced phases. Recent studies show that therapy of CML-ECP with nilotinib leads to a faster and deeper response compared to imatinib. However, in vitro data indicates that there is no detectable difference in inhibition of signaling downstream of Bcr-Abl between the two agents, and that neither drug induces apoptosis of CML CD34+ cells. We use a computational model of hematopoiesis and CML combined with serial quantitative data of disease burden under imatinib and nilotinib therapy to explain this apparent disconnect between in vivo and in vitro responses. We show how a subtle difference in the differentiation rate of CML cells under therapy with either agent, with marginal impact onto the in vitro studies, translates into a significantly different reproductive fitness of treated cells in vivo, providing a sizeable difference, hence providing an explanation for the superior response observed with nilotinib.