Real-world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: data from 95 consecutive patients treated in a compassionate use program. A study from the Swedish Chronic Lymphocytic Leukemia Group

Abstract

Ibrutinib, a Bruton's tyrosine kinase inhibitor is approved for relapsed/refractory and del(17p)/TP53 mutated chronic lymphocytic leukemia. Discrepancies between clinical trials and routine healthcare are commonly observed in oncology. Herein we report real-world results for 95 poor prognosis Swedish patients treated with ibrutinib in a compassionate use program. Ninety-five consecutive patients (93 chronic lymphocytic leukemia, 2 small lymphocytic leukemia) were included in the study between May 2014 and May 2015. The median age was 69 years. 63% had del(17p)/TP53 mutation, 65% had Rai stage III/IV, 28% had lymphadenopathy ≥10cm. Patients received ibrutinib 420 mg once daily until progression. At a median follow-up of 10.2 months, the overall response rate was 84% (consistent among subgroups) and 77% remained progression-free. Progression-free survival and overall survival were significantly shorter in patients with del(17p)/TP53 mutation (P=0.017 and P=0.027, log-rank test); no other factor was significant in Cox proportional regression hazards model. Ibrutinib was well tolerated. Hematomas occurred in 46% of patients without any major bleeding. Seven patients had Richter's transformation. This real-world analysis on consecutive chronic lymphocytic leukemia patients from a well-defined geographical region shows the efficacy and safety of ibrutinib to be similar to that of pivotal trials. Yet, del(17p)/TP53 mutation remains a therapeutic challenge. Since not more than half of our patients would have qualified for the pivotal ibrutinib trial (RESONATE), our study emphasizes that real-world results should be carefully considered in future with regards to new agents and new indications in chronic lymphocytic leukemia. IntroductionChronic lymphocytic leukemia (CLL), the most common leukemia in adults, is characterized by a clonal expansion of CD5 + and CD23 + B-lymphocytes which accumulate in blood, bone marrow and lymphoid tissues. Chemoimmunotherapy is the standard first-line treatment, but patients with del(17p) or TP53 gene muta- The CLL cell receives survival and proliferation signals from the microenvironment, and the B-cell receptor (BCR) is a key factor in this interaction. Bruton´s tyrosine kinase (BTK) is a non-receptor tyrosine kinase and plays a crucial role in BCR signalling. Ibrutinib is an oral, selective and irreversible inhibitor of BTK. It binds to the cysteine-481 amino acid of the BTK enzyme. Real -world results of ibrutinib in patients with5 Next-generation BTK inhibitors are under clinical development with promising early results. 6In the first phase 2 study of ibrutinib, 71% of patients with relapsed or refractory CLL achieved a partial response (PR) according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria, 7 and an additional 18% of patients had PR with lymphocytosis (PR-L). 8 The response was independent of clinical and genomic risk factors including del(17p). The 3-year followup of this study reported no late occurring toxicity, and progression was...

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

“…Long‐term results from this study (median follow‐up, 47 months) showed a median PFS of 32 months for this high‐risk patient subgroup (Jain et al , 2016). In a real‐world study of ibrutinib‐treated patients enrolled in a compassionate‐use programme, the estimated 10‐month PFS and OS rates were 71% and 78%, respectively, for 50 patients with del(17p) (Winqvist et al , 2016). In a real‐world study of ibrutinib‐treated patients in a named patient scheme, the estimated 12‐month discontinuation‐free progression and OS rates were 71% and 84%, respectively for 90 patients with del(17p) (UK CLL Forum 2016).…”

“…Although ibrutinib undoubtedly represents a significant advance in the treatment of patients with CLL and del(17p), it nevertheless appears that many R/R patients with del(17p) will ultimately relapse with ibrutinib therapy (Byrd et al , 2015; Winqvist et al , 2016). There may be a plateau in the rate of RT in patients, suggesting that the risk of developing RT is biologically determined.…”

“…Since the initial study, many more patients with del(17p) CLL have been treated with ibrutinib, including in real‐world settings (Mato et al , 2016, UK CLL Forum 2016; Winqvist et al , 2016). To provide a more robust description of outcomes in the prospective trials in this important high‐risk patient population, we conducted a combined analysis of 243 patients with R/R del(17p) CLL who received treatment with single‐agent ibrutinib (420 mg) in 1 of 3 prospective clinical studies (Byrd et al , 2013, 2014, 2015; O'Brien et al , 2014, 2016a).…”

Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: a UK and Ireland analysis of outcomes in 315 patients

“…Furthermore, the multi-center Swedish experience presented data on 95 CLL patients treated for a median of 10.2 months, with a 10 month PFS of 77% and OS of 83%. 9 There are a number of potential reasons why the rates of ibrutinib discontinuation and survival are likely to be worse in a real-world setting than in a clinical trial. Patients treated outside of a clinical trial are more likely to have poorer performance status and more comorbidities.…”

Effects of ibrutinib treatment on murine platelet function during inflammation and in primary hemostasis

“…Despite an excellent safety profile and high tolerability, a large number of patients have bleeding as a side effect. [1][2][3] These events are typically low grade, presenting as mucosal or skin bleeding; 1,3 however, more severe bleeding has been reported, and is a concern when scheduling surgery or if anti-coagulants are needed, such as in patients with atrial fibrillation.…”