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Background Most older patients with acute myeloid leukemia (AML) who attain morphologic remission with intensive chemotherapy (IC) will eventually relapse and post-relapse prognosis is dismal. In the pivotal QUAZAR AML-001 trial, oral azacitidine maintenance therapy significantly prolonged overall survival by 9.9 months (P P Methods QUAZAR AML-001 is an international, placebo-controlled randomized phase 3 study. Patients aged ≥ 55 years with AML and intermediate- or poor-risk cytogenetics at diagnosis, who had attained first complete remission (CR) or CR with incomplete blood count recovery (CRi) within 4 months before study entry, were randomized 1:1 to receive oral azacitidine 300 mg or placebo once-daily for 14 days in repeated 28-day cycles. Safety was assessed in all patients who received ≥ 1 dose of study drug. Results A total of 469 patients received oral azacitidine (n = 236) or placebo (n = 233). Median age was 68 years. Patients received a median of 12 (range 1–80) oral azacitidine treatment cycles or 6 (1–73) placebo cycles. Gastrointestinal AEs were common and typically low-grade. The most frequent grade 3–4 AEs during oral azacitidine therapy were hematologic events. AEs infrequently required permanent discontinuation of oral azacitidine (13%), suggesting they were effectively managed with use of concomitant medications and oral azacitidine dosing modifications. Conclusion Oral azacitidine maintenance had a generally favorable safety profile. Prophylaxis with antiemetic agents, and blood count monitoring every other week, are recommended for at least the first 2 oral azacitidine treatment cycles, and as needed thereafter. Awareness of the type, onset, and duration of common AEs, and implementation of effective AE management, may maximize treatment adherence and optimize the survival benefits of oral azacitidine AML remission maintenance therapy. Trial registration This trial is registered on clinicaltrials.gov: NCT01757535 as of December 2012.

Background: Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor.\ud \ud Methods: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of the oral formulation of azacitidine (CC-486, a hypomethylating agent that is not bioequivalent to injectable azacitidine), as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Patients who were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for hematopoietic stem-cell transplantation were randomly assigned to receive CC-486 (300 mg) or placebo once daily for 14 days per 28-day cycle. The primary end point was overall survival. Secondary end points included relapse-free survival and health-related quality of life.\ud \ud Results: A total of 472 patients underwent randomization; 238 were assigned to the CC-486 group and 234 were assigned to the placebo group. The median age was 68 years (range, 55 to 86). Median overall survival from the time of randomization was significantly longer with CC-486 than with placebo (24.7 months and 14.8 months, respectively; P

Background:\ud All studies of treatment-free remission (TFR) in patients with chronic myeloid leukaemia have discontinued tyrosine kinase inhibitor (TKI) treatment abruptly and have focussed on patients with stable MR4 (BCR-ABL to ABL ratio ≤0·01%). We aimed to examine the effects of gradual treatment withdrawal and whether TFR is feasible for patients with less deep but stable remission.\ud \ud Methods:\ud The De-Escalation and Stopping Treatment with Imatinib, Nilotinib, or sprYcel (DESTINY) study is a non-randomised, phase 2 trial undertaken at 20 UK hospitals. We recruited patients (aged ≥18 years) with chronic myeloid leukaemia in first chronic phase, who had received TKI therapy for 3 years or more, with three or more BCR-ABL quantitative PCR transcript measurements (BCR-ABL to ABL1 ratio) less than 0·1% (major molecular response [MMR]) in the 12 months before entry. Patients with all PCR measurements less than 0·01% were assigned to the MR4 group. Patients with results between 0·1% and 0·01% were allocated to the MMR group. TKI treatment was de-escalated to half the standard dose for 12 months, then stopped for a further 24 months, with frequent PCR monitoring. Recurrence was defined as the first of two consecutive samples with PCR measurement greater than 0·1%, which required treatment recommencement at full dose. The primary endpoint was the proportion of patients who could first de-escalate their treatment for 12 months, and then stop treatment completely for a further 2 years, without losing MMR. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985.\ud \ud Findings:\ud Treatment at entry was imatinib (n=148), nilotinib (n=16), or dasatinib (n=10), for a median of 6·9 years (IQR 4·8–10·2). Between Dec 16, 2013, and May 6, 2015, we enrolled 49 patients into the MMR group and 125 into the MR4 group. In the MR4 group, 84 (67%) patients reached the 36-month trial completion point and recurrence-free survival was 72% (95% CI 64–80). In the MMR group, 16 (33%) entrants completed the study and recurrence-free survival was 36% (25–53). No disease progression was seen and two deaths occurred due to unrelated causes. All recurrences regained MMR within 5 months of treatment resumption.\ud \ud Interpretation:\ud Initial de-escalation before discontinuation might improve the success of TFR protocols, although the mechanism of its benefit is not yet clear. The findings also suggest that TFR merits further study in patients with stable MMR.\ud \ud Funding:\ud Newcastle University and Bloodwise.

In the phase III study RESONATE, ibrutinib reduced the risk of progression and improved overall survival versus ofatumumab in previously treated patients with CLL/SLL. In this novel analysis of patient well-being including patient-reported outcomes, ibrutinib reduced disease burden while preserving parameters of hematologic and immunologic function in RESONATE. These results suggest that ibrutinib can improve quality of life while prolonging survival. Background: Ibrutinib compared with ofatumumab significantly improves progression-free and overall survival in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients and Methods: Measures of well-being were assessed in RESONATE, where previously treated patients with CLL/SLL were randomized to receive ibrutinib 420 mg/day (n = 195) or ofatumumab (n = 196) for up to 24 weeks. Endpoints included hematologic function, Functional Assessment of Chronic Illness TherapyeFatigue (FACIT-F), disease-related symptoms, European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 (EORTC QLQ-C30), and medical resource utilization. Results: With up to 24 months' follow-up (median, 16.4 months), 79% of cytopenic patients showed sustained hematologic improvement (82% with improved platelet count, 69% with improved hemoglobin) on ibrutinib versus 43% on ofatumumab (P = 3 hypertension occurred in 6%, grade >= 3 atrial fibrillation in 4%, major hemorrhage in 2%, and tumor lysis syndrome in 1% of patients. Conclusion: Ibrutinib led to significant improvements in hematologic function and disease symptomatology versus ofatumumab, and can restore quality of life while prolonging survival in relapsed/refractory CLL/SLL. (C) 2018 The Authors. Published by Elsevier Inc.

Background:\ud \ud Discontinuation of tyrosine kinase inhibitor (TKI) therapy is feasible for some patients with chronic myeloid leukaemia with deep molecular responses; however, patients with stable major molecular response (MMR), but not MR4, have not been studied, nor has the effect of treatment de-escalation rather than outright cessation. We aimed to examine the effects of treatment de-escalation as a prelude to complete cessation, not only in patients with MR4 or greater, but also in those with MMR but not MR4.\ud Methods:\ud \ud We did this interim analysis of a non-randomised, phase 2 trial at 20 hospitals in the UK. We recruited patients (aged ≥18 years) with chronic myeloid leukaemia in first chronic phase who had received TKI for 3 years or more and were either in stable MR4 (BCR-ABL1:ABL1 ratio 0·1%) on two consecutive samples. The primary endpoint of this interim analysis was the proportion of patients who lost MMR on de-escalation and regained MMR on TKI resumption. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985.\ud Findings:\ud \ud Between Dec 16, 2013 and April 10, 2015, we enrolled 174 patients into the MMR cohort (n=49) or the MR4 cohort (n=125). During the 12 months of half-dose therapy, 12 patients (7%) had molecular recurrence, all of whom regained MMR within 4 months of full-dose TKI resumption (median time to recovery 77 days). Recurrence was significantly lower in the MR4 cohort (three [2%; 90% CI 0·2–4·8] of 121 evaluable patients) than in the MMR cohort (nine [19%; 90% CI 9·5–28·0] of 48 evaluable patients; hazard ratio 0·12, 90% CI 0·04–0·37; p=0·0007), but was unrelated to previous TKI or TKI therapy duration. Adverse events (eg, lethargy, diarrhoea, rash, and nausea) improved during the first 3 months of de-escalation, though not thereafter. 16 serious adverse events were reported, including one fatality due to worsening pre-existing peripheral arterial occlusive disease in a patient who had received only imatinib.\ud Interpretation:\ud \ud TKI de-escalation is safe for most patients with excellent responses to TKI therapy, and is associated with improvement in symptoms. These findings show that lower TKI doses might maintain responses in these patients, implying that such patients could be unnecessarily overtreated. Studies of more ambitious de-escalation are warranted.