Recent advances in management of chronic lymphocytic leukemia patients with a novel kinase inhibitor
Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in Western countries.1 In comparison, CLL is much rarer in Asian populations with an age-standardized incidence rate (ASIR) of less than 0.5 per 100,000 person years, or about 10% of ASIR cases in Western countries.2 At a recent webinar organized by the Hong Kong Society of Haematology, Professor Constantine S. Tam from the Peter MacCallum Cancer Centre and the University of Melbourne, Australia, introduced ibrutinib as a novel treatment among both relapsed/refractory (RR) and previously untreated CLL patients.†
Addressing the unmet need among CLL patients refractory to chemoimmunotherapy
Currently, the FCR (fludarabine, cyclophosphamide and rituximab) regimen is the recommended first-line treatment for CLL patients without 17p deletion (del(17p)).3 In elderly patients with coexisting conditions, chlorambucil can be prescribed instead to mitigate the treatment-related toxicities of FCR.1 In RR CLL patients after fludarabine treatment, alemtuzumab was demonstrated to induce an overall response rate (ORR) of only 30-40% with median survival of 1-2 years.4 For RR CLL patients resistant to both fludarabine and alemtuzumab, ofatumumab was demonstrated to induce an ORR of 50%; yet phase 3 and 4 studies indicated that this efficacy may be overestimated as the ORR was found to be 4% and 22%, respectively.5,6
The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib was approved by the United States Food and Drug Administration (US FDA) in 2014 as the first chemotherapy-free RR CLL treatment option of its kind available to patients regardless of treatment history, including those with del(17p).7 Del(17p) patients typically perform poorly on FCR chemotherapy. Ibrutinib significantly improved ORR, progression-free survival (PFS), and overall survival (OS) compared with ofatumumab as demonstrated in the recent RESONATE study. Furthermore, it was shown to restore bone marrow function in CLL patients with a significantly higher rate of sustained improvement in hematologic variables.1 Prof. Tam highlighted that this class of kinase inhibitor is not myelosuppressive, and is “very gratifying to give, especially for patients with large lymph nodes, who will feel them start to soften, often even after the first dose of ibrutinib”.
Ibrutinib as treatment for relapsed/refractory and previously untreated CLL
In the RESONATE study, 391 CLL or small lymphocytic lymphoma (SLL) patients who had at least one previous therapy or were inappropriate candidates for purine analogue treatment were recruited.5 Patients were randomly assigned to receive either oral ibrutinib (at a dose of 420mg once daily) or intravenous ofatumumab for up to 24 weeks at an initial dose of 300mg at week 1, followed by a dose of 2,000mg weekly for 7 weeks, and then every 4 weeks for 16 weeks.5
At a median follow-up of 9.4 months, ibrutinib significantly improved PFS (HR for progression or death=0.22, 95% CI: 0.15-0.32, p<0.001) and has demonstrated a significantly higher ORR when compared to ofatumumab (42.6% vs. 4.1%, p<0.001).5 At 12 months, the OS was 90% in the ibrutinib group and 81% in the ofatumumab group; at 6-year post-randomization follow-up, the median OS was longer in the ibrutinib arm when compared to the ofatumumab arm (67.7 vs. 65.1 months) despite extensive (68%) crossover to ibrutinib (HR=0.81, 95% CI: 0.60-1.10) (Figure 1).8
Building on the observed efficacy among RR CLL patients in the RESONATE study, ibrutinib was then compared against chlorambucil to confirm its efficacy in previously untreated CLL patients.1 The RESONATE-2 study enrolled 269 1L CLL or SLL patients who were 65 years of age or older and without del(17p).1 Patients were randomly assigned to receive either oral ibrutinib (at a dose of 420mg once daily) or oral chlorambucil on days 1 and 15 of each 28-day cycle.1
At a median follow-up of 18.4 months, ibrutinib resulted in significantly longer PFS when compared to chlorambucil (HR=0.16, 95% CI: 0.09-0.28, p<0.001).1 At 24 months, the OS was higher in the ibrutinib group than the chlorambucil group (98% vs. 85%), and the ORR was also higher with ibrutinib than with chlorambucil (86% vs. 35%, p<0.001).1 With a median follow-up of 60 months, PFS and OS benefits were sustained (HR for progression/death=0.15, 95% CI: 0.10-0.22, HR for death=0.45, 95% CI: 0.27-0.76) and the 5-year OS was observed to be 83% for ibrutinib and 68% for chlorambucil.9
From the results of both studies, ibrutinib was demonstrated to improve OS and PFS among both RR and 1L CLL patients, particularly for those who are elderly with significantly higher ORR compared to previous treatment options.1,5 Furthermore, when RR CLL patients were stratified by the number of prior lines, a poorer PFS was observed when ibrutinib was introduced later in the treatment regimen (Figure 2). Prof. Tam reinforced this observation, advising that “when you have a drug like ibrutinib which is highly potent, it is still better to use it as early-line therapy because the more refractory the disease, the less effective most drugs are”.
Ibrutinib preserved survival benefits in patients with high-risk clinical or genomic alterations
In addition to del(17p) mutations, CLL patients who have 11q deletion (del(11q)), TP53 mutation, or an unmutated immunoglobulin heavy chain variable region (IGHV) are also known to have poor outcome when treated with standard chemoimmunotherapy.8 In the 6-year follow-up of the RESONATE study, the PFS benefit with ibrutinib versus ofatumumab was preserved in the genomic high-risk RR CLL population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs. 8.0 months; HR=0.110; 95% CI: 0.080-0.152), which represented 82% of patients (Figure 3).8 In particular, CLL patients with del(11q) appeared to have no decrement in benefit from continuous ibrutinib therapy with a median PFS of 60.7 months, which was longer than the median PFS of the overall ibrutinib cohort.8 Similarly, ibrutinib’s survival benefit was also shown to extend to high-risk 1L CLL patients with TP53 mutation, del(11q) and/or undeleted IGHV in the 5-year follow-up of the RESONATE-2 study (PFS HR=0.08, 95% CI: 0.05-0.15, OS HR=0.37, 95% CI: 0.18-0.74).9
Other recent CLL drugs
Acalabrutinib is another BTK-inhibitor that was approved by the US FDA in November 2019 for CLL treatment. In the phase 3 ASCEND trial, the 12-month PFS was 88% for acalabrutinib and 68% for idelalisib plus rituximab or bendamustine and rituximab (HR=0.31, 95% CI: 0.20-0.49) among RR CLL patients.10 Further studies are required to evaluate acalabrutinib’s efficacy and safety.
Venetoclax is a B-cell lymphoma 2 (Bcl-2) antagonist that induces CLL cell apoptosis and was approved by the US FDA in May 2019. Unlike ibrutinib which is generally continued long term, venetoclax utilization can result in complete CLL remission and is recommended to be given for up to 2 years for RR CLL patients. An indicator of deep remission is the eradication of minimal residual disease (MRD) in blood or marrow, which can be achieved by venetoclax therapy. In the Phase 3 MURANO study, RR CLL patients were randomized to 6 cycles of venetoclax-rituximab (VenR) followed by 400mg of venetoclax daily or 6 cycles of bendamustine + rituximab (BR) for 2 years.11 29 out of 194 (15%) patients in the venetoclax arm discontinued therapy due to adverse events.11 Although VenR recipients had superior 4-year PFS (57.3% vs. 4.6%, HR=0.19, 95% CI: 0.14-0.25) and increased rates of undetectable MRD compared to BR recipients (62% vs. 13%), 6 (3.7%) out of 162 patients in the VenR arm developed high-MRD by the end of the trial.12 There was an increasing trend in MRD among Ven patients a year before trial completion, indicating that clinical progression was not due to stopping therapy but to patients developing resistance to Venetoclax.
Message to physicians
BTK inhibitors often do not result in complete remissions and are usually administered long term. Prof. Tam expressed that it is reassuring that no new safety signals emerged over the extended ibrutinib treatment duration of 5-6 years, and that the incidence of the majority of adverse events decreased over time.8,9 Over 6 years of follow-up, the prevalence of any grade ≥3 AEs among RR CLL patients with ibrutinib decreased from 62% in the first year to 48% in the second year and remained stable thereafter.8 This observation was similar among 1L CLL patients, with an initial decrease from 58% to 39% and remaining stable thereafter up to 5 years.9
Based on clinical experience, up to 66% of CLL patients on ibrutinib will experience minor bleeding while up to 6% of patients will experience major bleeding.13 Consequently, Prof. Tam cautioned the use of ibrutinib in combination with multiple antiplatelet agents, emphasizing that “[ibrutinib] is possibly the most potent antiplatelet drug ever discovered”. He strongly recommended stopping ibrutinib 7 days peri major surgery and 3 days peri minor surgery to avoid the risk of bleeding. He further elaborated that acute bleeds can be managed with platelet transfusion. Prof. Tam added that the adverse effects of myelosuppression including neutropenia, thrombocytopenia and anemia are very rare for this drug class and typically only occur in the first year of therapy.
Up to 7% of CLL patients will develop atrial fibrillation (AF) which is challenging to manage. Prof. Tam further elaborated that there is often a reversible causative factor such as pneumonia or electrolyte imbalance, and that they can be managed with appropriate treatment while continuing on ibrutinib. Prof. Tam recommended rate control with beta-blockers as many anti-arrhythmic drugs have interactions with ibrutinib. When selecting an anticoagulant, Prof. Tam suggested apixaban or rivaroxaban due to their minimal ibrutinib interactions. Finally, the risk of infection with ibrutinib is generally lower for ibrutinib compared to chemotherapy.
While chemoimmunotherapies, the current standard of care, have restricted use in patient population with moderate ORR at best, ibrutinib has conferred significant PFS and OS benefits with good ORR among 1L RR CLL patients regardless of prior treatment history. In addition to del(17p), the efficacy of ibrutinib therapy was shown to be preserved among patients with other high-risk clinical and genomic alterations. Given its long term efficacy and safety data supported by multiple clinical studies, ibrutinib should be considered as a preferred regimen for the initial treatment of CLL.
† This article is sponsored by Janssen, a division of Johnson & Johnson (HK) Ltd
Click here or scan the QR code to watch the lecture
This is an independent editorial article, published and distributed through unrestricted educational support from the pharmaceutical community, for the purpose of continuing medical education only. The views expressed in this publication reflect the experience and/or opinion of the author(s) and are not necessarily those of editors, publisher and sponsor(s). Because of rapid advances in medicine, independent verification of clinical diagnoses, medical suitability and dosage should be made before treatment prescription. The appearance of advertisement, if any, has no influence on editorial content or presentation and does not imply the endorsement of products by the publication, or its authors and editors.
- Burger JA et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015;373(25):2425-2437.
- Chan TS-Y et al. Clinicopathological features and outcome of chronic lymphocytic leukaemia in Chinese patients. Oncotarget. 2017;8(15):25455-25468.
- Eichhorst B et al. Chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus bendamustine and rituximab (BR) in previously untreated and physically fit patients (pts) with advanced chronic lymphocytic leukemia (CLL): results of a planned interim analysis of the CLL10 trial, an international, randomized study of the german CLL study group (GCLLSG). Blood. 2013;122(21):526-526.
- Tse E, Gill HS. Management of Chronic Lymphocytic Leukaemia. Hong Kong J Radiol. 2011;14(Suppl):S56-62.
- Byrd JC et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223.
- Moreno C et al. Ofatumumab in poor-prognosis chronic lymphocytic leukemia: a phase IV, non-interventional, observational study from the European Research Initiative on Chronic Lymphocytic Leukemia. Haematologica. 2015;100(4):511-516.
- Lymphoma Research Foundation. About Lymphoma. https://lymphoma.org/aboutlymphoma/cll/cllfdaupdates. Accessed September 10, 2020.
- Munir T et al. Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019;94(12):1353-1363.
- Burger JA et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798.
- Ghia P et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861.
- Kater AP et al. Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study. J Clin Oncol. 2019;37(4):269-277.
- Seymour JF et al. Four-Year Analysis of Murano Study Confirms Sustained Benefit of Time-Limited Venetoclax-Rituximab (VenR) in Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL). Blood. 2019;134(Supplement_1):355-355.
- Stephens DM, Byrd JC. How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia. Blood. 2019;133(12):1298-1307.