Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, <1% at 6 months, and ≤0.1% from 12 months onward define optimal response, whereas >10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome–positive [Ph+] >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.

No abstract

Dasatinib, administered once daily, as compared with imatinib, administered once daily, induced significantly higher and faster rates of complete cytogenetic response and major molecular response. Since achieving complete cytogenetic response within 12 months has been associated with better long-term, progression-free survival, dasatinib may improve the long-term outcomes among patients with newly diagnosed chronic-phase CML. (ClinicalTrials.gov number, NCT00481247.)

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available firstline). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

BACKGROUND Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma. METHODS We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee. RESULTS The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib. CONCLUSIONS Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.)

A B S T R A C T PurposeThis multicenter, randomized, open-label, phase III trial compared the efficacy and safety of decitabine with treatment choice (TC) in older patients with newly diagnosed acute myeloid leukemia (AML) and poor-or intermediate-risk cytogenetics. Patients and MethodsPatients (N ϭ 485) age Ն 65 years were randomly assigned 1:1 to receive decitabine 20 mg/m 2 per day as a 1-hour intravenous infusion for five consecutive days every 4 weeks or TC (supportive care or cytarabine 20 mg/m 2 per day as a subcutaneous injection for 10 consecutive days every 4 weeks). The primary end point was overall survival (OS); the secondary end point was the complete remission (CR) rate plus the CR rate without platelet recovery (CRp). Adverse events (AEs) were recorded. ResultsThe primary analysis with 396 deaths (81.6%) showed a nonsignificant increase in median OS with decitabine (7.7 months; 95% CI, 6.2 to 9.2) versus TC (5.0 months; 95% CI, 4.3 to 6.3; P ϭ .108; hazard ratio [HR], 0.85; 95% CI, 0.69 to 1.04). An unplanned analysis with 446 deaths (92%) indicated the same median OS (HR, 0.82; 95% CI, 0.68 to 0.99; nominal P ϭ .037). The CR rate plus CRp was 17.8% with decitabine versus 7.8% with TC (odds ratio, 2.5; 95% CI, 1.4 to 4.8; P ϭ .001). AEs were similar for decitabine and cytarabine, although patients received a median of four cycles of decitabine versus two cycles of TC. The most common drug-related AEs with decitabine were thrombocytopenia (27%) and neutropenia (24%). ConclusionIn older patients with AML, decitabine improved response rates compared with standard therapies without major differences in safety. An unplanned survival analysis showed a benefit for decitabine, which was not observed at the time of the primary analysis.

Purpose We report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating long-term efficacy and safety outcomes of patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with dasatinib or imatinib. Patients and Methods Patients with newly diagnosed CML-CP were randomly assigned to receive dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260). Results At the time of study closure, 61% and 63% of dasatinib- and imatinib-treated patients remained on initial therapy, respectively. Cumulative rates of major molecular response and molecular responses with a 4.0- or 4.5-log reduction in BCR-ABL1 transcripts from baseline by 5 years remained statistically significantly higher for dasatinib compared with imatinib. Rates for progression-free and overall survival at 5 years remained high and similar across treatment arms. In patients who achieved BCR-ABL1 ≤ 10% at 3 months (dasatinib, 84%; imatinib, 64%), improvements in progression-free and overall survival and lower rates of transformation to accelerated/blast phase were reported compared with patients with BCR-ABL1 greater than 10% at 3 months. Transformation to accelerated/blast phase occurred in 5%and 7%of patients in the dasatinib and imatinib arms, respectively. Fifteen dasatinib-treated and 19 imatinib-treated patients had BCR-ABL1 mutations identified at discontinuation. There were no new or unexpected adverse events identified in either treatment arm, and pleural effusion was the only drug-related, nonhematologic adverse event reported more frequently with dasatinib (28% v 0.8% with imatinib). First occurrences of pleural effusion were reported with dasatinib, with the highest incidence in year 1. Arterial ischemic events were uncommon in both treatment arms. Conclusion These final results from the DASISION trial continue to support dasatinib 100 mg once daily as a safe and effective first-line therapy for the long-term treatment of CML-CP.

ELN Foundation and France National Cancer Institute.