Ibrutinib in very elderly patients with relapsed/refractory chronic lymphocytic leukemia: A real‐world experience of 71 patients treated in France: A study from the French Innovative Leukemia Organization (FILO) group
Authors: Anne‐Sophie Michallet, Arnaud Campidelli, Helene Lequeu, Marie‐Sarah Dilhuydy, Olivier Tournilhac, Luc‐Matthieu Fornecker, Jehan Dupuis, Florence Cymbalista, Sophie De Guibert, Alain Delmer, Jean‐Pierre Vilque, David Ghez, Veronique Leblond, Fabien Subtil, Pierre Feugier, Loic Ysebaert
Journal: American Journal of Hematology (2017)

In first-line therapy, 20% of patient with chronic lymphocytic leukemia (CLL) are even 80 years old or over, rendering therapeutic decisions often challenging. Due to the common comorbidity burden and frequency of adverse cytogenetics associated with this elderly population, these patients are often excluded from clinical trials participation. Ibrutinib, a first-in-class inhibitor of Bruton's tyrosine kinase, has been approved for the treatment of relapsed/refractory CLL, including those with del(17)/TP53 mutations in the first-line setting. However, a few very elderly patients have been included in ibrutinib clinical trials. Nevertheless, these studies reported overall response rates of >80%, with unprecedented progression-free survival (PFS)/overall survival (OS), significantly superior to those achieved in other relapse/refractory ibrutinib trials using immunochemotherapy or immunotherapy alone, irrespective of age, and associated with relatively mild toxicity. Despite these impressive results, real-world data from everyday clinical practices is highly sought after for concrete evidence regarding the impact of ibrutinib therapy in our very-elderly patient management. In France, 428 patients received ibrutinib from December 2013 to November 21, 2014, being accorded temporary authorization for use (ATU) from the French National Agency for Medicines and Health Product Safety (ANSM). We herein describe the key baseline characteristics and outcomes involving 71 patients aged >75 years, the oldest cohort ever reported outside clinical trials. The patient data was collected from medical files by primary care physicians and entered into electronic case report forms. The study protocol was approved by the French Innovative Leukemia Organization scientific committee and by relevant health authorities. The study was conducted in accordance with national ethical recommendations, as well as the Declaration of Helsinki. The patients eligible for ibrutinib ATU all experienced relapsed/refractory active disease (according to iwCLL 2008 criteria) and were scheduled to receive 420 mg/day ibrutinib. Endpoints were survival and ibrutinib-related safety. Since no bone marrow biopsy was performed at months 6-12, the recorded responses are only partial, irrespective of lymphocytosis. At the latest follow-up (as of December 2015), PFS was calculated from ibrutinib initiation to, either relapse or death, duration of response from ibrutinib initiation to relapse, and OS from ibrutinib initiation to death due to any cause. The median age was 79 years, thus 8-10 years higher than that of patients included in clinical trials or real-life practice cohorts to date. The median number of previous therapies was three (range: 1-9), including FC/FCR in 73.2%, R-bendamustine in 46.5%, rituximab in 86%, ofatumumab in 8.5%, and alemtuzumab in 26.7%. This population was heavily pretreated and at very high risk, with 26.2% exhibiting 17p deletions and 19.4% p53 mutations. In total, 70/71 patients started ibrutinib at 420 mg/day and one at 280 mg/day. Of the 71 patients, 37 (52.1%) had to either reduce (40.8%) or even temporarily stop ibrutinib (26.8%) within the first treatment year. The median time to dose reduction was 8 weeks (range: 2-52). Drug withdrawal was defined as a therapy discontinuation for over 7 days, eventually followed by either reduced dosing or full dose resumption at 420 mg/day. The most common causes for drug reduction/withdrawal were infection (10.5%), programmed surgery (8%), arthralgia (13%), bleeding (3%), diarrhea (5.2%), atrial fibrillation (2.6%), and hematological toxicity (15.8%). Out of 39 patients, 10 were restarted on full dose at 420 mg/day after toxicity had been resolved. Permanent ibrutinib discontinuation was reported in 32.4% of patients, following a median 5-month exposure (range: 1-16 months), due to CLL progression in only 5.6%. The primary safety concerns comprised infection (5.6%), bleeding (11.3%), cardiac problems (7%), and hematological toxicity (5.6%). At last follow-up, 63.4% of patients were alive on therapy, 15.5% alive off therapy, and 21.1% had died from various causes: 6/15 from CLL (including 3/6 Richter), 7/15 from infection, and 2/15 from heart disease. Efficacy analysis at months 6 and 12 revealed increasing partial response rates PR) (38.8% and 57.8%, respectively), along with decreasing rates of PR + lymphocytosis (46.9% and 35.6%, respectively), stable disease (8.2% and 2.2%, respectively), and progressive disease (6.1% and 4.4%, respectively), as presented in Table 1. Overall response rates were 85.7% and 93.4% at 6 and 12 months, respectively, thereby confirming the RESONATE trial findings.1, 2 The safety profile proved relatively well-known3 and manageable by means of dose reduction, consisting of grade 1-2 bleeding (19%), cardiac toxicity (7%), diarrhea (24%), and myalgia/arthralgia (20%), frequencies decreasing over the first 6 months. It should be noted that infection was reported in 21% of cases within the first 6 months, its incidence decreasing to 10.5% after 12 months, in line with the Sun et al. results.4 The PFS and OS rates at 12 months were 77% and 91%. The estimated median OS was 21 months, seemingly unprecedented in this age population. These outcomes were not impacted by CLL-related factors. Reducing the ibrutinib dose did not affect clinical outcomes (Supporting Information 1). Though fewer patients achieved >90% target occupancy at <420 mg/day, there was still a clear correlation between this biological endpoint, chosen due to no dose-limiting toxicity achieved in the first human ibrutinib studies, and objective response rates (ORR) or survival rates. The only factor influencing PFS (HR = 4.430; P = .016) and duration of response (HR= 4.931, P = .024) was arteritis/myocardial ischemia antecedents (Supporting Information 2). This parameter had no impact on OS. The drug withdrawal for >7 days tended to be associated with reduced response duration, yet dose reduction from 420 to 280 mg/day did not demonstrate the same effect. In this series, the estimated median OS was 21 months. In this real-world cohort of very elderly patients, del(17p)/TP53 mutations were found to have a smaller impact on PFS/DoR than comorbidities (HR = 0.827, P = .683; HR = 0.631; P = 0.543) had. The predominant cause of permanent drug withdrawal was bleeding symptoms.5 In conclusion, our series from the French early access program supports the use of ibrutinib in very elderly patients, thereby confirming its efficacy profile requiring adequate toxicity management, with dose reductions often being efficient. All authors declare they have no conflicts of interest Conception and design: LY, PF, and ASM; Collection and assembly of data: LY, HL, AC, PF, and ASM; Provision of patients: LY, HL, AC, MSD, OT, LMF, JD, FC, SDG, AD, SG, JPV, DG, VL, PF, and ASM; Data analysis and interpretation: LY, FS, and ASM; Manuscript writing: LY and ASM; Final approval of manuscript: all authors Authors would like to thank all the FILO clinicians who entered the data into the electronic case report forms. This work was partly supported by Agence Nationale de la Recherche through the project CAPTOR (ANR-11-PHUC 0001). 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