Efficacy of idelalisib and rituximab in relapsed/refractory chronic lymphocytic leukemia treated outside of clinical trials. A report of the Gimema Working Group

Abstract Because the efficacy of new drugs reported in trials may not translate into similar results when used in the real‐life, we analyzed the efficacy of idelalisib and rituximab (IR) in 149 patients with relapsed/refractory chronic lymphocytic leukemia treated at 34 GIMEMA centers. Median progression‐free survival (PFS) and overall survival were 22.9 and 44.5 months, respectively; performance status (PS) ≥2 and ≥3 previous lines of therapy were associated with shorter PFS and overall survival (OS). 48% of patients were on treatment at 12 months; the experience of the centers (≥5 treated patients) and PS 0–1 were associated with a significantly longer treatment duration (p = 0.015 and p = 0.002, respectively). TP53 disruption had no prognostic significance. The overall response rate to subsequent treatment was 49.2%, with median OS of 15.5 months and not reached in patients who discontinued, respectively, for progression and for toxicity (p < 0.01). Treatment breaks ≥14 days were recorded in 96% of patients and adverse events mirrored those reported in trials. In conclusion, this real‐life analysis showed that IR treatment duration was longer at experienced centers, that the ECOG PS and ≥3 lines of previous therapy are strong prognostic factor and that the overall outcome with this regimen was superimposable to that reported in a randomized trial.


| INTRODUCTION
The introduction of kinase targeted treatment has represented a major advance in the management of patients with relapsed refractory (R/R) chronic lymphocytic leukemia (CLL), including patients with genetically defined high-risk disease and fludarabine-refractory disease. [1][2][3] The majority of R/R patients can be effectively treated with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, which has been associated with a 71% overall response rate (ORR) and a 75% estimated progression-free survival (PFS) rate at 26 months, with a 7-year PFS of 34%. 4,5 The selective PI3Kdelta inhibitor idelalisib given as single agent produced objective responses in 81% of patients who had received a median of five previous lines of treatment. 6 The combination of idelalisib and rituximab (IR) in a Phase 3 trial including patients who were deemed ineligible to further chemoimmunotherapy showed a 93% PFS rate at 24 weeks, 7 a median PFS of 20.3 months and a median overall survival (OS) of 40.6 months. 8 In another Phase 3 trial, a median PFS of 15.8 months was reported with IR 9 and an increased incidence of adverse events leading to treatment interruptions and/or discontinuation in the majority of patients was noted. 8,9 Therefore, expert opinions for the management of adverse events have been proposed to improve adherence to this regimen. 10,11 The efficacy of new drugs reported in clinical trials may not translate into similar results when used in the day-to-day real-life practice. 12,13 This prompted us to carry out an observational RIGOLIN ET AL.
-327 retrospective-prospective study on the long-term efficacy and safety of IR in R/R CLL patients treated outside of clinical trials in 34 centers of the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) cooperative study group.
Accepting the limitations of observational studies, we included, in addition to PFS, the most objective endpoints for this analysis, i.e., the percentage of patients on treatment at different time points and OS, and also investigated how baseline clinical and biologic features could impact on the outcome of treatment and analyzed outcome after idelalisib discontinuation.

| Patients
Patients treated with IR between 2014 and 2017 at GIMEMA centers were selected for this analysis from local pharmacy databases and/or from unit-specific databases. The inclusion criteria in this observational retrospective study were (i) diagnosis of CLL according to the National Cancer Institute (NCI) recommendations, 14 (ii) age ≥18 years, (iii) one previous treatment with alkylating agents and/or purine analogues with or without monoclonal antibodies, (iv) progression requiring therapy, 14 (v) treatment with at least one dose of IR. Patients were excluded if they had a Richter's syndrome transformation, HIV infection, active HCV, or HBV infection. The study was registered at ClinicalTrials.gov (NCT03545035) and was approved by the local Ethics Committees.

| Study design and endpoints
Data were obtained from the medical files and entered into case record forms by the treating physicians. Computerized and manual consistency checks were performed by the data managers of the GIMEMA Data Center. Treatment response and disease progression were assessed according to the NCI criteria. 14 The primary endpoint was PFS at 12 months from the start of treatment. Subjects who withdrew from the study without progression were censored at the date of the last assessment. Subjects without postbaseline assessments but known to be alive were censored at the time of the first dose of the study drug. Secondary endpoints were (i) the ORR, assessed in all patients who started treatment, (ii) OS calculated from the date of the first dose of the study drug up to the date of death from any cause, and (iii) the percentage of patients on treatment at 12 months. Patients without follow-up assessment were censored at the day of the last treatment administration. Being aware of the difficulty in obtaining a detailed description of adverse events (AEs) in a retrospective analysis, we asked clinicians to report any clinically significant AE deemed possibly related to idelalisib and/or rituximab according to the NCI Common Terminology Criteria for AE version 4.0.  tests were two-sided, accepting p < 0.05 as indicative of a statistically significant difference. All analyses were performed using the SAS system software (version 9.4) and R statistical software.

| Patients
One-hundred and forty-nine R/R CLL patients from 34 Italian centers were included in the study (Table S1). Twelve centers reported data on at least five patients (69.8% of the total population) and the remaining 22 centers reported less than five patients (30.2% of the total patient population). Forty-five percent of cases had received three or more previous lines of therapy, previous exposure to ibrutinib occurred in 12.9% of the patients.
The baseline characteristics are shown in Table 1

| Treatment with IR
At a median follow-up of 39.4 months, the median PFS was 22.9 months (95% CI 20.5-28.8, Figure 1A). Factors predicting for a shorter PFS at univariate analysis (  (Table S2).
The median OS was 44.5 months (95% CI 32.5-NA; Figure 2A). In univariate analysis, a shorter OS was associated with a PS ≥ 2 (me-  Figure 2C) with a borderline significance for U-IGHV (p = 0.07). TP53 disruption and the size of the centers had no impact on OS. PS ≥ 2 (p < 0.001) and ≥3 lines of therapy (p = 0.046) were associated with a shorter OS at multivariate analysis (Table 3).
Forty-eight percent, 24.3%, and 11.8% of patients were still receiving the study drug at 12, 24, and 36 months, respectively. respectively, p < 0.0001, Figure 3A). Among patients who received a subsequent treatment, the OS was better when discontinuation was  Figure 3B).

| Safety
A detailed report of grade 3-5 AE in 117 patients is shown in

| DISCUSSION
To minimize selection and attrition biases as well as imprecise reporting of data inherent to observational studies, 15 To answer this question, we carried out an analysis based on a relatively large dataset of CLL patients treated off-trial with IR and followed for a prolonged period of time in 34 centers of the Italian GIMEMA cooperative group. Our study provides therefore a real-life evaluation of data reflecting a widespread utilization of IR in our country, with a majority of the investigators reporting less than five treated patients. We were able to analyze the efficacy and tolerability of this combination with a minimum follow-up for living patients of 12 months and to assess the outcome after IR discontinuation.  That being said, it is worth noting that PS ≥ 2 and as well ≥3 previous lines of therapy were associated with a shorter OS and PFS in our analysis and the a trend for shorter PFS was noted when comparing centers that included <5 patients and centers with ≥5 patients treated with IR. Our data also confirm that IR was not associated with an inferior PFS and OS in patients carrying a TP53 disruption. Because the unmutated IGHV configuration was associated with shorter PFS at univariate analysis in our study and with a significantly shorter OS in the randomized study comparing IR versus placebo plus rituximab, 8  The number of medical comorbidities did not portend inferior outcomes in our study, thus confirming in a real-world setting the findings of a previous report of patients treated with idelalisib in clinical trials. 23 The incidence of grade 3-4 infections and pneumonia (29.7% and 17%, respectively), diarrhea and colitis (27.1%), increased transaminase levels (5.9%) is similar to that observed in trials 8,19 and in a report describing the outcome in 68 patients treated in the UK and Ireland. 22 The relatively low incidence of neutropenia (33.1%) may reflect the policy not to perform routine blood counts in the clinical practice at many centers.
The long follow-up of our study allowed to document a 49.2% ORR in 59 patients who received a subsequent treatment, with a higher probability of response in patients who had received ≤2 lines of treatment prior to IR and with an encouraging median OS in patients who discontinued due to toxicity.
In conclusion, we hereby report the largest real-life experience with IR in patients with R/R CLL treated and followed for a prolonged period of time at many centers across our country. contributed to the acquisition of data revised, critically the manuscript, and approved the submitted and final version.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1002/hon.2861.