The GAIA/CLL13 study is a phase 3 trial that answers several important questions about how to treat patients with chronic lymphocytic leukaemia.1,2 In The Lancet Oncology, Moritz Fürstenau and ...colleagues now report updated 4-year follow up data in an exploratory analysis.1 In the study, treatment-naive, fit patients with chronic lymphocytic leukaemia were randomly assigned to one of four treatment groups. The initial report of this study showed improved progression-free survival with venetoclax–obinutuzumab and venetoclax–obinutuzumab–ibrutinib compared with chemoimmunotherapy and established venetoclax–obinutuzumab as a preferred regimen for fit patients, since previous studies had been in patients with comorbidities.2,3 With additional follow-up (median of 50·7 months IQR 44·6–57·9), progression-free survival was still significantly improved for venetoclax–obinutuzumab (hazard ratio HR 0·47 97·5% CI 0·32–0·69, p<0·0001) and venetoclax–obinutuzumab–ibrutinib (0·30 0·19–0·47, p<0·0001) versus chemoimmunotherapy, and not for venetoclax–rituximab versus chemoimmunotherapy (p=0·10).1 The continued clear progression-free survival benefit of venetoclax-obinutuzumab over chemoimmunotherapy (estimated 4-year progression-free survival of 81·8% 97·5% CI 75·8–87·8 vs 62·0% 54·4–69·7) continues to support ending the use of chemoimmunotherapy in chronic lymphocytic leukaemia.1 What is reported for the first time in the updated analysis is a longer progression-free survival with venetoclax–obinutuzumab than with venetoclax–rituximab (HR 0·57 97·5% CI 0·38–0·84; p=0·011).1 Coupled with the finding that venetoclax–rituximab has no progression-free survival improvement compared with chemoimmunotherapy, this new evidence calls into question the use of venetoclax–rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia. The safety profile of venetoclax–obinutuzumab was more favourable and had a lower discontinuation rate than venetoclax–obinutuzumab–ibrutinib (14 6% of 229 vs 31 13% of 231).1 However, there might be a benefit for some patients because those with IGHV unmutated chronic lymphocytic leukaemia had a significantly longer progression-free survival with triple therapy than with venetoclax–obinutuzumab (HR 0·58 95% CI 0·36–0·94) and this difference might continue to widen over time.1 These results raise questions as to how the MRD-guided triple therapy approach used in GAIA/CLL13 compares with fixed-duration triple therapy and to venetoclax–ibrutinib, which is well studied and a standard of care regimen in Europe.6–8 Review of outcomes across trials can provide some information regarding the relative benefits of these treatments, but phase 3 trials studying these will be needed to determine the best approach.
In an exploratory analysis of the phase II CAPTIVATE study, previously untreated patients with chronic lymphocytic leukemia with a higher-risk feature of immune globulin heavy chain variable (IGHV) ...unmutated status, del(17p), and/or TP53 mutation had similar efficacy and safety outcomes compared with patients without a higher-risk feature when treated with fixed-duration ibrutinib and venetoclax. See related article by Allan et al., p. 2593.
Ibrutinib is associated with dramatic efficacy against B-cell malignancies. Yet, it has been linked with potentially limiting cardiotoxicity, including emerging reports of profound hypertension ...(HTN). The long-term incidence, severity, and impact of HTN development with ibrutinib are unknown. Therefore, in 562 consecutive patients treated with ibrutinib for B-cell malignancies from 2009 through 2016, we assessed the new/incident or worsened HTN (systolic blood pressure BP cutoff, 130 mm Hg). Observed incident HTN rates were compared with Framingham-heart–predicted incident HTN rates. We also evaluated the relationship of HTN to the development of other major adverse cardiovascular events (MACEs), including arrhythmia, myocardial infarction, stroke, heart failure, and cardiovascular death. Further, we assessed the effects of different antihypertensive classes on ibrutinib-related HTN. Overall, 78.3% of ibrutinib users developed new or worsened HTN over a median of 30 months. New HTN developed in 71.6% of ibrutinib users, with a time to 50% cumulative incidence of 4.2 months. Among those without preceding HTN, 17.7% developed high-grade HTN (BP >160/100 mm Hg). In multivariate regression, new or worsened HTN was associated with increased MACEs (hazard ratio HR, 2.17; 95% confidence interval CI, 1.08-4.38). No single antihypertensive class was associated with prevention or control of ibrutinib-related HTN. However, antihypertensive initiation was associated with a lower risk of a MACE (HR, 0.40; 95% CI, 0.24-0.66). Collectively, these data suggest that ibrutinib is associated with a substantial increase in the incidence and severity of HTN, and that HTN development carries a higher risk of subsequent cardiotoxic events.
•Among lymphoid malignancy patients treated with ibrutinib, the subsequent incidence of new hypertension is nearly 72%.•Development of new or worsened HTN after ibrutinib initiation associates with a more than twofold increased risk of other cardiac events.
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Whether BTK inhibitors are effective when used after venetoclax in patients with chronic lymphocytic leukemia is an important unanswered question. In a large retrospective cohort study examining ...outcomes for next line treatment after venetoclax, BTK inhibitors were found to result in durable responses in patients who were not previously BTK inhibitor resistant.
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Targeted therapies including the engineered afucosylated anti-CD20 monoclonal antibody obinutuzumab, Bruton's tyrosine kinase inhibitor ibrutinib, and B-cell lymphoma protein 2 inhibitor venetoclax ...have demonstrated significant clinical activity in chronic lymphocytic leukemia (CLL) and, based on their complementary mechanisms, are ideal for combination. However, combining venetoclax with other active agents raises safety concerns, as it may increase the risk for tumor lysis syndrome. To minimize this risk, we designed and implemented a fixed-duration regimen using sequentially administered obinutuzumab followed by ibrutinib (cycle 2) and venetoclax (cycle 3), for a total of fourteen 28-day cycles. This phase 1b study included 12 patients with relapsed or refractory CLL. We tested 3 dose levels of venetoclax and identified the doses of all 3 agents approved by the US Food and Drug Administration for use in the combination. Adverse events were consistent with known toxicities of the individual agents, with hematologic adverse events being most frequent. No clinically significant tumor lysis syndrome occurred. The overall response rate was 92% (95% confidence interval, 62%-100%), with 42% (5/12) achieving a complete remission or complete remission with incomplete marrow recovery. There were 6 patients with no detectable CLL in both the blood and bone marrow at the end of treatment. We found this regimen to be safe and tolerable in CLL, and capable of inducing deep responses, justifying future study in our ongoing phase 2 cohorts of relapsed or refractory and treatment-naive patients, as well as larger phase 3 trials currently in planning. This trial was registered at www.clinicaltrials.gov as #NCT02427451.
•Cytoreduction with obinutuzumab and ibrutinib followed by the addition of venetoclax has acceptable safety with no tumor lysis syndrome.•This combination has preliminary activity including complete remissions with undetectable residual disease in relapsed or refractory CLL.
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B-cell receptor signalling inhibition by targeting Bruton tyrosine kinase (BTK) is effective in treating chronic lymphocytic leukemia (CLL). The BTK inhibitor ibrutinib may be intolerable for some ...patients. Acalabrutinib is a more selective BTK inhibitor that may be better tolerated by patients who are intolerant to ibrutinib. A phase 2 study of acalabrutinib was conducted in patients with relapsed/refractory CLL who were ibrutinib-intolerant and had continued disease activity. Intolerance was defined as having discontinued ibrutinib due to persistent grade 3/4 adverse events (AEs) or persistent/recurrent grade 2 AEs despite dose modification/interruption. Patients received oral acalabrutinib 100 mg twice daily until disease progression or intolerance. Sixty patients were treated. Overall response rate to acalabrutinib was 73% and three patients (5%) achieved complete remission. At median follow-up of 35 months, the median progressionfree and overall survival were not reached; 24-month estimates were 72% and 81%, respectively. The most frequent AEs with acalabrutinib were diarrhea (53%), headache (42%), contusion (40%), dizziness (33%), upper respiratory tract infection (33%), and cough (30%). Most common reasons for acalabrutinib discontinuation were progressive disease (23%) and AEs (17%). Most patients with baseline samples (49/52; 94%) and all with on-treatment samples (3/3; 100%) had no detectable BTK and/or PLCG2 mutations. Acalabrutinib is effective and tolerable in most patients with relapsed/refractory CLL who are intolerant of ibrutinib. Acalabrutinib may be useful for patients who may benefit from BTK inhibitor therapy but are ibrutinib intolerant.
Chronic lymphocytic leukemia (CLL) is associated with perturbed immune function and increased risk for second primary malignancies (SPM). Ibrutinib and acalabrutinib (BTKi) are effective therapies ...for CLL resulting in partial restoration of immune function. The incidence of and risk factors for SPM in CLL patients receiving BTKi are not yet characterized. We retrospectively determined the incidence of SPM in CLL patients treated with ibrutinib or acalabrutinib at our institution between 2009 and 2017, assessed for association between baseline characteristics and SPM incidence, and compared the observed to expected cancer incidence among age, sex, and year matched controls without CLL. After a median of 44 months follow-up, 64/691 patients (9%) were diagnosed with SPM (excluding non-melanoma skin cancer NMSC). The 3-year cumulative incidence rate was 16% for NMSC and 7% for other SPM. On multivariable analysis, smoking was associated with increased SPM risk (HR 2.8 95% CI: 1.6-4.8) and higher baseline CD8 count was associated with lower SPM risk (HR 0.9 for 2-fold increase 95% CI: 0.8-0.9). The observed over expected rate of SPM was 2.2 95% CI: 1.7-2.9. CLL patients treated with BTKi remain at increased risk for SPM, and secondary cancer detection is an important consideration in this population.
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