Outcome of chronic lymphocytic leukemia patients who switched from either ibrutinib or idelalisib to alternate kinase inhibitor: A retrospective study of the French innovative leukemia organization (FILO)
Authors: Sophie Godet, Caroline Protin, Jehan Dupuis, Caroline Dartigeas, Jean‐Noël Bastie, Charles Herbaux, Véronique Leblond, Sophie de Guibert, David Ghez, Annie Brion, Loïc Ysebaert, Alain Delmer, Anne Quinquenel
Journal: American Journal of Hematology (2017)

Novel drugs targeting B cell receptor (BCR) signaling, such as ibrutinib and idelalisib, have dramatically changed the outcome of patients with chronic lymphocytic leukemia (CLL), especially those with high-risk features. However, data from both clinical trials and “real life” studies show that a large proportion of patients has to withdraw therapy. In the phase 3 Resonate trial comparing ibrutinib to ofatumumab in patients with relapsed or refractory CLL, 26% of patients had discontinued ibrutinib after a median follow-up of 19 months.1 In the updated results of a phase 3 comparing idelalisib in combination with ofatumumab to ofatumumab as a single agent, only 29% of patients were still on therapy with a median follow-up of 16.1 months.2 For patients having discontinued a first kinase inhibitor (KI), subsequent therapy with the alternative KI may represent a valuable option. Only few data are currently available on the efficacy and safety of a second KI in this setting.3, 4 The aim of our multicentric retrospective study was to evaluate whether an alternative KI would represent a valuable option after first KI discontinuation, and if the reason for first KI discontinuation should impact the choice of subsequent treatment. Between June 2015 and February 2017, we collected the data of 48 CLL patients followed in 16 FILO centers who were successively treated with ibrutinib and idelalisib. The procedure was conducted in accordance with the declaration of Helsinki. The first KI was ibrutinib for 29 patients and idelalisib for 19 patients. Median age was 71 years. Most patients had previously been heavily treated. Study of common prognostic factors revealed unmutated immunoglobulin heavy chain variable (IGHV) genes in 24/27 patients (89%), 17p deletion as assessed by FISH in 19/46 patients (41%) and complex karyotype in 7/46 (15%) (Supporting Information Table S1). The overall response rate (ORR) to ibrutinib as the first KI was 80% and it was similar for idelalisib (89%, Figure 1A). Median time to treatment discontinuation of the first KI was 6 months (range 0.4–22.1) and was not significantly different for ibrutinib and idelalisib. Toxicity was the main reason of first KI discontinuation for both ibrutinib and idelalisib-treated patients (62% and 79% respectively). The adverse events observed in our patients were similar to those reported in prior studies, i.e bleeding, atrial fibrillation, infection, neutropenia for ibrutinib and diarrhea, neutropenia, transaminitis and toxidermia for idelalisib (Supporting Information Table S2). CLL progression was the second reason of KI discontinuation and occurred in 11 patients (38%) in the ibrutinib group and in 4 patients (21%) in the idelalisib group. The median time to treatment discontinuation was significantly longer for patients who discontinued the first KI due to CLL progression than for those who stopped KI because of AEs (10.9 months, range 4.4 to 15.1 versus 4.8 months, range 0.4 to 22, P < .005). The short median duration of first KI treatment might explain the relatively low number of KI discontinuation for progression, as progression on KI usually occurs later with an incidence increasing with time.5 (A) First and second KI treatment: response rates, time to and reasons for discontinuation. (B) PFS et OS according to the cause of discontinuation of first KI The ORR to idelalisib as the second KI was 72% while ORR to ibrutinib was 95%. At the time of last follow-up, 39 patients (81%) had discontinued the second KI. Significantly more patients treated with idelalisib as the second KI discontinued therapy by comparison with the patients having received ibrutinib after idelalisib withdrawal (93% versus 63%, P = .02) (Figure 1A). The median time to second KI discontinuation was 7.5 months (range 0.5 to NR) for patients treated with idelalisib and 17.4 months (range 1 to NR) for patients treated with ibrutinib. Toxicity was again the main reason of treatment discontinuation for both ibrutinib and idelalisib-treated patients. The most common AEs leading to second KI withdrawal were the same as those causing their discontinuation when given as first KI (Supporting Information Table S2). CLL progression occurred in 10 patients (37%) receiving idelalisib as second KI and in 2 patients (17%) secondarily treated with ibrutinib. Two patients developed Richter's transformation, one in each group (Figure 1A). Notably, three intolerant patients remained untreated for more than one year after the second KI discontinuation (28, 15 and 14 months), all of them having received idelalisib as the second KI. Treating patients with idelalisib for a definite period could therefore represent an interesting option in some instances, although it is not supported by clinical trials. The median follow-up of the entire cohort from the time of second KI initiation was 17.6 months (range 0.5 to 35). Twenty-five patients died during the follow-up, 19 patients (65%) in the ibrutinib-first group and 6 patients (32%) in the idelalisib-first group (P = .04). Thirty-seven percent of deaths are related to adverse events, mainly infections, and 24% to CLL progression. For the whole cohort, median PFS and OS from the time of initiation of alternate KI were 14.8 months and 19.9 months respectively (Supporting Information Figure S1). The reason for first KI discontinuation is of great interest. PFS was significantly longer for patients who discontinued first KI for intolerance (19.9 months) compared to patients who discontinued first KI for CLL progression (7.5 months) (P < .0001). These findings concerning PFS are consistent with the data previously reported by Mato et al.3 Moreover, in our study, the reason for first KI discontinuation also impacted overall survival, with a median OS of 29.1 months in first KI-intolerant patients versus 14.8 months in patients whose disease progressed on the first KI (P < .005) (Figure 1B). The BCL-2 inhibitor venetoclax may represent another therapeutic option after KI withdrawal, especially in case of CLL progression. Preliminary data of a phase 2 study showed an estimated 12-month PFS of 80% for patients previously treated with either ibrutinib or idelalisib, with 45% of patients achieving MRD negativity in the peripheral blood, and one patient achieving bone marrow negative MRD.6 As a conclusion, our data suggest that the use of an alternative KI after first KI discontinuation because of adverse events may be a reasonable option for CLL patients. The outcome is significantly worse for patients progressing while treated by kinase inhibitor, and venetoclax represents a better alternative treatment in this particular setting. The authors wish to thank the additional members of the FILO group who contributed to the study by reporting cases: Eric Durot (Reims), Pierre Feugier (Nancy), Stéphane Leprêtre (Rouen), Béatrice Mahé (Nantes), Anne-Sophie Michallet (Lyon), Philippe Rodon (Perigeux), Eric Van Den Neste (Bruxelles). 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