Real‐world results of ibrutinib in relapsed/refractory <scp>CLL</scp> in <scp>F</scp>rance: Early results on a large series of 428 patients
Authors: Loic Ysebaert, Thérèse Aurran‐Schleinitz, Caroline Dartigeas, Marie‐Sarah Dilhuydy, Pierre Feugier, Anne‐Sophie Michallet, Olivier Tournilhac, Jehan Dupuis, Pierre Sinet, Claire Albrecht, Florence Cymbalista
Journal: American Journal of Hematology (2017)

To the Edior: Ibrutinib is an inhibitor of Bruton's tyrosine kinase approved for the treatment of chronic lymphocytic leukemia (CLL), in relapsed/refractory but also now frontline setting.1 Here, we report on the largest series of poor prognosis relapsed CLL patients included in the French Temporary Authorization for Use procedure (ATU, between December 2013 and November 2014). A total of 428 patients were included in 106 centers throughout France (including 72% in University Hospitals, and 28% in smaller secondary or tertiary Centers) and received ibrutinib 420 mg daily. Main baseline characteristics are summarized in Table 1. Accordingly, to the real-life setting, median age was 70 years (35% aged ≥75 years), 92.9% had advanced Binet stage B/C, and 45.1% of patients had either del17p and/or TP53 mutation. At baseline, 54.2% of patients had at least one significant comorbidity. The most common were vascular disorders (24.5%, with 21% having arterial hypertension), metabolism and nutrition disorders (16.6%), cardiac disorders (11.2%), and/or neoplasms (11%). As a consequence, 14% of patients were taking an anti-thrombotic drug at the time of ibrutinib exposure. In total, 372 patients had several points of follow-up during the first months of therapy, and were therefore suitable for ORR/safety evaluations. Among them, 54 had permanent treatment discontinuations, included 8 due to disease progression (Supporting Information Figure 1). Median follow-up was 3 months (1-10 months). Due to age, comorbidities, and number of previous therapies, many of these patients wouldn't have been recruited in a clinical trial. The best overall response rate was 88.5%, including 37.9% of partial response and 44.1% of partial response + lymphocytosis. Some patients were reported in complete response by physicians but without confirmation by bone marrow biopsy. About 10% had stable disease and 1.5% showed disease progression. Safety was also evaluated, 73.4% patients experienced ≥1 adverse event (AE) of mild-to-moderate severity, but 33.2% experienced ≥1 serious adverse event (SAE) (34% if aged >75y), mostly ibrutinib-related. A summary of selected adverse events of interest with ibrutinib is presented in the Supporting Information Table 2. Twenty-five patients died during follow-up. Despite the short follow-up inherent to the 11-months inclusion period of the ATU, the findings are consistent with ibrutinib registration studies,1, 2 confirming the good safety and efficacy of ibrutinib in a real-world setting. At initiation of treatment, concomitant antithrombotic therapy included anti platelet in 36, heparin in 13, and others (vitamine K antagonists, direct oral coagulants) in 10 patients. The frequency of serious hemorrhagic events was low, occurring in 1.6% of patients overall and 2.6% of patients who were receiving concomitant antithrombotic therapy during ibrutinib treatment (n = 78). As shown in Supporting Information Figure 2, these data are in concordance with those from published clinical trials in the R/R setting.3 The data presented in this article represent the largest real-life cohort obtained through the French ATU program of 428 CLL patients treated with ibrutinib, physicians being from both public and private practice. The response rates are consistent with those observed in the clinical trial RESONATE (ibrutinib vs ofatumumab). In this phase 3 study randomizing ibrutinib versus ofatumumab, 2% of participants had a complete response, 68% had a partial response, 15% had a partial response with lymphocytosis (resulting in an 85% response rate), 11% had stable disease, and 1% showed disease progression in the ibrutinib arm based on investigator assessment.2 As a comparison, evaluation of the ATU of ofatumumab in France has yielded disappointing results.4 In a very similar cohort of 95 ibrutinib treated patients in a Swedish compassionate use program (median age 69 years, 65% with del17p/TP53 mutations, same profile of previous therapies), response rate was 84% and PFS was 77% at a median follow-up of 10.2 months. These response rates and survivals obtained in hundreds of real-life patients (from compassionate use programs in France, UK, and Sweden) favorably compare with the results claimed from clinical trials. Previous reports claimed that CLL patients treated with chemo-immunotherapy or ofatumumab alone may benefit from similar outcomes in real life, but experience more side effects than reported in trials, due to the burden of comorbidities (especially renal impairment), or reduced relative dose-intensity. In our series, ibrutinib was well tolerated including in the elderly population, with no unexpected AE, except more cardiac disorders including atrial fibrillation (AF) (6.5% in all population, and 9.3% above 75 years). Data pooled from clinical trials showed that 6.5% of 756 patients receiving ibrutinib for CLL and mantle cell lymphoma had atrial fibrillation.5 Our experience in patients >75 years suggests that chronic, medically treated atrial fibrillation before initiation of therapy does not impact on outcomes with ibrutinib, but that patients with peripheral arteriopathy/myocardial infarction and taking anticoagulants should be managed more carefully.6 Overall, despite inherent limitations of a real-world analysis (eg, the declarative nature of data collection and the absence of data monitoring), the findings from data collected in this ATU confirm and extend previous reports on ibrutinib safety and efficacy in the context of controlled studies after a short follow-up. Authors would like to acknowledge all physicians and patients for their participation. All the co-authors collected the clinical data. Andrew Lane (Lane Medical Writing) drafted the initial version and was funded by Janssen France. The final manuscript was prepared by the authors. LY: Roche, Abbivie, Gilead, Janssen. TA: Janssen, Gilead, Roche, Abbvie. CD: Janssen, Mundipharma, Gilead. MSD: Roche, Janssen, Gilead, Abbvie. PF: Janssen. ASM: no. OT: Janssen, Gilead, Mundipharma, Roche. JD: Abbvie, Celgene. FC: Janssen, Gilead, Abbvie, Roche. PS and CA are employees of Janssen-Cilag. Additional Supporting Information may be found online in the supporting information tab for this article. FIGURE S1 Reasons for drug permanent discontinuation in 54/372 patients. FIGURE S2 Frequency of serious hemorrhagic events. TABLE S2 Summary of selected adverse events of interest with ibrutinib. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.