PracticeUpdate: Haematology & Oncology

LEUKAEMIA 24

Drug sequencing strategy needed for CLL Blood Take-home message

settings; front-line (HR 2.8, CI1.3–6.3 p=0.01), relapsed-refractory (HR 2.8, CI 1.9–4.1 p<0.001), del17p (HR 2.0, CI 1.2–3.4 p=0.008), and com- plex karyotype (HR 2.5, CI 1.2–5.2 p=0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS as compared to chemoimmunotherapy (CIT). Furthermore, patients who discontinued ibrutinib due to pro- gression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3–1.0, p=0.06). CONCLUSIONS In the largest real-world experi- ence of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Further, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to CIT combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimise treatment algorithms. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leu- kemia: results from a multi-center study of 683 patients. Blood 2016 Dec 01;128(22)4400, AR Mato, BT Hill, N Lamanna, et al. or worse adverse events in the idelalisib group were neutropenia (124 [60%] of 207 patients) and febrile neutropenia (48 [23%]), whereas in the placebo group they were neutropenia (99 [47%] of 209) and thrombocytopenia (27 [13%]). An increased risk of infection was reported in the idelalisib group compared with the placebo group (grade ≥3 infections and infestations: 80 [39%] of 207 vs 52 [25%] of 209). Serious adverse events, including febrile neutropenia, pneumonia, and pyrexia, were more com- mon in the idelalisib group (140 [68%] of 207 patients) than in the placebo group (92 [44%] of 209). Treatment-emergent adverse events leading to death occurred in 23 (11%) patients in the idelalisib group and 15 (7%) in the placebo group, including six deaths from infections in the idelalisib group and three from infections in the placebo group. INTERPRETATION Idelalisib in combination with bendamustine plus rituximab improved progres- sion-free survival compared with bendamustine plus rituximab alone in patients with relapsed or refractory chronic lymphocytic leukaemia. However, careful attention needs to be paid to management of serious adverse events and infections associated with this regimen during treatment selection. Idelalisib or placebo in combination with benda- mustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol 2017 Jan 27;[EPub Ahead of Print], AD Zelenetz, JC Barrientos, JR Brown, et al.

• This retrospective study compared patients with chronic lymphocytic leukaemia (n= 683) treated with kinase inhibitors (ibrutinib and idelalisib) and venetoclax. Patients treated with ibrutinib had improved progression-free survival when it was used as front-line therapy and when it was used in the treatment of relapsed/refractory, del(17p), and complex karyotype leukaemias. • Ibrutinib is superior to idelalisib, and, in the event of ibrutinib treatment failure, venetoclax appeared superior to idelalisib and chemoimmunotherapy. Studies are needed to confirm and optimise the ordering of treatment with kinase inhibitors and venetoclax in this patient population. Abstract and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS).

BACKGROUND Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the US. However, there is no guidance as to their opti- mal sequence. PATIENTS AND METHODS We conducted a multi- center, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival,

RESULTS A total of 683 patients were identified. Baseline characteristics were similar in the ibru- tinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81% respec- tively. With a median follow up of 17 months (range 1–60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (vs idelalisib) as first KI had a significantly better PFS in all

Idelalisibwith bendamustine and rituximab improves outcomes of relapsed/refractory CLL The Lancet Oncology Take-home message

• This was a multicentre, placebo-controlled, double-blinded phase III study evaluating safety and efficacy of adding idelalisib to bendamustine plus rituximab in 416 patients with relapsed/refractory chronic lymphocytic leukaemia (rrCLL). Median progression-free survival (PFS) was 20.8 months and 11.1 months in the treatment and placebo groups, respectively (P < 0.0001). Rates of febrile neutropenia were higher in the treatment group (23% vs 13%). • The addition of idelalisib to bendamustine plus rituximab improved PFS in rrCLL, with increased toxicity rates. Abstract

m 2 intravenously on days 1 and 2 for six 28-day cycles; rituximab: 375 mg/m 2 on day 1 of cycle 1, and 500 mg/m 2 on day 1 of cycles 2–6) in addition to either twice-daily oral idelalisib (150 mg) or placebo until disease progression or intolerable study drug-related toxicity. Ran- domisation was stratified by high-risk features (IGHV, del[17p], or TP53 mutation) and refractory versus relapsed disease. The primary endpoint was progression-free survival assessed by an independent review committee in the intention- to-treat population. FINDINGS Between June 26, 2012, and Aug 21, 2014, 416 patients were enrolled and randomly assigned to the idelalisib (n=207) and placebo (n=209) groups. At a median follow-up of 14 months (IQR 7-18), median progression-free sur- vival was 20.8 months (95% CI 16.6-26.4) in the idelalisib group and 11.1 months (8.9-11.1) in the placebo group (hazard ratio [HR] 0.33, 95% CI 0.25-0.44; p<0.0001). The most frequent grade 3

BACKGROUND Bendamustine plus rituximab is a standard of care for the management of patients with relapsed or refractory chronic lym- phocytic leukaemia. New therapies are needed to improve clinically relevant outcomes in these patients. We assessed the efficacy and safety of adding idelalisib, a first-in-class targeted phosphoinositide-3-kinase δ inhibitor, to ben- damustine plus rituximab in this population. METHODS For this international, multicentre, double-blind, placebo-controlled trial, adult patients (≥18 years) with relapsed or refractory chronic lymphocytic leukaemia requiring treat- ment who had measurable lymphadenopathy by CT or MRI and disease progression within 36 months since their last previous therapy were enrolled. Patients were randomly assigned (1:1) by a central interactive web response system to receive bendamustine plus rituximab for a maximum of six cycles (bendamustine: 70 mg/

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