Bendamustine, followed by obinutuzumab and idelalisib in chronic lymphocytic leukemia (<scp>CLL2‐BCG</scp>): Final analysis of a multicenter, open‐label <scp>phase‐II</scp>‐trial
Authors: Paula Cramer, Julia von Tresckow, Anna‐Maria Fink, Sandra Robrecht, Adam Giza, Eugen Tausch, Lothar Müller, Wolfgang Knauf, Matthias Zingerle, Othman Al‐Sawaf, Petra Langerbeins, Kirsten Fischer, Karl‐Anton Kreuzer, Michael Kneba, Clemens‐Martin Wendtner, Stephan Stilgenbauer, Barbara Eichhorst, Michael Hallek
Journal: American Journal of Hematology (2024)

Treatment regimen an iwCLL and MRD response. The therapeutic armamentarium for chronic lymphocytic leukemia (CLL) has improved dramatically in the recent years: the CD20 antibodies, inhibitors of BTK and Bcl2, as well as their combinations have replaced chemoimmunotherapy in first-line and relapse therapy. Idelalisib, an inhibitor of the δ-isoform of the phosphatidyl-inositol-3-kinase in the B-cell receptor signaling pathway, plays only a minor role in the treatment of CLL because of an increased risk of serious (opportunistic) infections. The CLL2-BCG study is part of a series of phase-II trials conducted by the German CLL Study Group which evaluate a sequential treatment consisting of an optional debulking with bendamustine, followed by an induction and a maintenance with a targeted agent combined with an anti-CD20 antibody. These trials used a measurable residual disease (MRD)-guided discontinuation strategy called "sequential triple-T concept" (tailored, targeted treatment aiming at a total eradication of CLL).1-5 The CLL2-BCG study tested bendamustine, followed by obinutuzumab and idelalisib. The CLL2-BCG trial is a prospective, open-label, multicenter phase-II-trial initiated by the German CLL Study Group with the University of Cologne, Germany, being the legal sponsor (participating sites and recruitment: Table S1 and Figure S1). The sequential treatment started with an optional debulking with 2 cycles bendamustine (recommended for patients with absolute lymphocyte counts ≥25 000/μL or lymph nodes ≥5 cm without contraindications). In the induction (8 months) obinutuzumab was administered 4-weekly and in the maintenance phase (up to 24 months) 12 weekly, while idelalisib was taken continuously from the second cycle onwards. Treatment was stopped in case of a deep response with a complete remission and undetectable MRD in peripheral blood in two assessments within an interval of 3 months (study design: Figure S2). Otherwise this combination was continued for a maximum of 32 months, until unacceptable toxicity, or progression and/or new CLL treatment. Initially, the study recruited an all-comer population of treatment-naive and relapsed/refractory CLL patients irrespective of their physical fitness, comorbidities and high-risk genetic markers. Due to an increased rate of infections in other idelalisib trials, recruitment was later limited to patients with relapsed/refractory CLL with high-risk features such as TP53 deletion/mutation and/or ineligibility for ibrutinib treatment, for whom only few alternative therapies were available (eligibility criteria: Supporting information S1 p2-3). Furthermore, all first-line patients had to discontinue treatment with idelalisib, but were allowed to continue with obinutuzumab according to the treatment schedule if considered reasonable by the treating physician. The primary endpoint was the overall response rate (ORR) at the end of induction. Analyses were performed in a descriptive manner without confirmatory testing as the number of enrolled patients was relevantly lower than initially planned. All analyses are based on the final dataset of the trial as of 1st September 2022 with a median observation time of 37 months (range: 1–51 months). All patients provided written informed consent. The study was approved by the health authorities and the institutional review board of each participating site, was registered with ClinicalTrials.gov number NCT02445131. Between May 2015 and September 2019, a total of 48 patients were enrolled, including 33 (70%) with an unmutated IGHV, 19 (40%) with a TP53 mutation or deletion and 15 (42%) with a complex karyotype with ≥3 aberrations (patient's characteristics: Table S2). Sixteen patients (33%) had treatment-naive CLL and 32 (67%) relapsed/refractory CLL with a median of 2 (range: 1–10) prior therapies, 10 patients had received at least one treatment with a targeted agent (Figure S3a,b). Thirty-eight patients (79%) received bendamustine for debulking, but eight discontinued treatment before the induction due to safety concerns with idelalisib. Forty patients (83%) received at least one dose of induction therapy (efficacy population), 33 completed the six cycles of induction treatment and 27 also continued with maintenance treatment (consort diagram: Figure S4). Nine patients had suboptimal treatment exposure because they discontinued idelalisib due to the novel safety data during or shortly after the induction. The mean dose intensity of the planned dose of idelalisib was 43% in the induction and 5% in the maintenance in the first-line cohort, and 76% in the induction and 58% in the maintenance in the relapsed/refractory cohort. While the mean dose intensity for obinutuzumab in induction and maintenance was 88% and 89% of the planned dose in the first-line and 94% and 78% in the relapsed/refractory patients, respectively (see also Table S3). At the end of induction, 32 of 40 patients responded (ORR 80%, 95% confidence interval 64%–91%), including all 19 patients (100%) from the first-line and 22 of the 30 patients (73%) in the relapsed/refractory cohort (Figure 1A and Table S4a). Nine patients (23%, three patients with previously untreated and six with relapsed/refractory CLL) achieved undetectable MRD (<10−4) in peripheral blood (Figure 1B and Table S4a). After debulking, an iwCLL response was already achieved in 19 of 38 patients (50%) (Table S4b). At the end of maintenance treatment, the ORR was 85% (23 of 27 patients), including three patients with a CR according to iwCLL criteria, another seven were only lacking a CT scan and/or bone marrow examination. Fifteen patients had undetectable MRD in peripheral blood, including 5 in the first-line and 10 in the relapsed/refractory cohort. Five patients with relapsed/refractory CLL also had undetectable MRD in bone marrow, the other 22 patients did not undergo a bone marrow biopsy (Figure 1A,B, Table S4c). Seven of 27 patients improved their MRD level during maintenance treatment, including six with a conversion to undetectable MRD (Table S5). Among the 10 patients who had already received a targeted agent, eight completed the full six cycles of induction treatment and three of them achieved a PR at the final restaging after induction, including one each with an undetectable, intermediate and high MRD level. With continued maintenance treatment, two patients remained in a PR and one patient progressed, the patient with the intermediate MRD level converted to undetectable MRD. The estimated rate of progression-free survival (PFS, defined as the time between registration and first disease progression or death) after 3 years was 69% in the first-line and 41% in the relapsed/refractory cohort (Figure S5). The median PFS from termination of maintenance treatment was not reached for eight patients who stopped treatment early due to a deep remission with undetectable MRD levels, with an estimated PFS rate of 75% after 1 year since treatment discontinuation. Five of them are still in remission after a median time of almost 2 years after end of treatment (Figure S6). The estimated rate of overall survival (OS, defined as the time between registration and death) after 3 years was 90% in the first-line and 78% in relapsed/refractory patients (Figure S7). Of the nine deaths, seven were fatal infections, but three infections were considered unrelated because they occurred either more than half a year after end of treatment or after disease progression/start of subsequent treatment (Table S6). A total of 599 adverse events (AEs) were reported for the entire study duration in 46 of all 48 patients (96%), according to investigator assessment, 315 (53%) were related to study drug and 130 (22%) were serious AEs (Table S7). Sixty-nine AEs (in 30 patients) led to a temporary interruption of one or both study drugs, 22 (in 15 patients) to dose reductions and 19 (in 13 patients) to a permanent discontinuation of one drug or all treatment. During bendamustine debulking, a total of 98 AEs occurred in 30 of 38 patients (79%), most common were infections, cytopenias and gastrointestinal disorders (Table S8). With obinutuzumab and idelalisib, 284 AEs occurred in 39 of 40 patients (98%) in the induction and 150 AEs in 25 of 27 patients (93%) in the maintenance phase. Most common toxicities during induction and maintenance were infections (91 episodes in 35 patients [88%], including 19 patients [48%] with a CTC grade III or higher), followed by cytopenias and gastrointestinal disorders (Table S9). The known relevant, sometimes severe and fatal toxicities of idelalisib were observed also in this trial, but no unexpected or cumulative toxicities occurred with the combination of idelalisib and obinutuzumab and with the prior debulking with bendamustine. The safety measures taken during the conduct of the trial led to a lower than planned treatment intensity. Also, the patient cohort is smaller and a high proportion of patients had adverse risk factors and/or extensive prior therapy. In light of this, the overall response rate at the end of the induction treatment (primary endpoint of the trial) of 80% is in the expected range. However, the rate of undetectable MRD of 23% is relatively low, partly because a relevant proportion of patients (28%) did not undergo MRD testing. The iwCLL and MRD response was improved with maintenance treatment in five and seven patients, respectively. Eight patients were able to stop maintenance treatment early due to a deep remission as defined by protocol and a relevant number of them remained in remission for a clinically meaningful time. The responses among the 10 patients with a prior therapy with targeted agents were disappointing, which underlines the high medical need to develop novel therapeutic approaches for these patients. Thus, this combination should be used with caution and only if all other treatment options are exhausted, that is, covalent BTK inhibitors, venetoclax and novel therapeutic alternatives, for example, the non-covalent BTK inhibitor pirtobrutinib, T-cell-engaging bispecific antibodies (e.g., epcoritamab) or cellular therapies have failed or cannot be used. Paula Cramer, Julia von Tresckow, Barbara Eichhorst and Michael Hallek were responsible for the conception and design of the study; Paula Cramer, Julia von Tresckow, Anna-Maria Fink, Sandra Robrecht, Othman Al-Sawaf, Petra Langerbeins and Kirsten Fischer were responsible for the trial management; Paula Cramer, Julia von Tresckow, Eugen Tausch, Lothar Müller, Wolfgang Knauf, Matthias Zingerle, Othman Al-Sawaf, Petra Langerbeins, Michael Kneba, Clemens-Martin Wendtner, Stephan Stilgenbauer, Barbara Eichhorst and Michael Hallek were responsible for the recruitment and treatment of patients; Paula Cramer, Julia von Tresckow, Anna-Maria Fink, Sandra Robrecht and Adam Giza had access to the raw data; Paula Cramer performed a central review of all clinical data; Eugen Tausch, Karl-Anton Kreuzer, Michael Kneba and Stephan Stilgenbauer performed the laboratory analyses; Sandra Robrecht and Adam Giza performed the statistical analysis. All authors interpreted the data; Paula Cramer wrote the first draft of the manuscript and all authors approved the final manuscript. The authors wish to express their gratitude towards all patients participating in the trial, as well as the physicians and trial staff at the sites (participating sites: Supporting information S1 p1). Also, we thank the study management team with the project managers Tanja Annolleck, Johanna Wesselmann, Miriam Schüler-Aparicio and Angelina Glatt, the safety managers Sabine Frohs, Tanja Annolleck and Berit Falkowski, the data managers Olga Korf, Florian Drey, Viktoria Monar and Irene Preißler-Stodden, the statisticians Jasmin Bahlo, Can Zhang, and Gracia Braun, as well as Dr. Birgit Fath and the monitors from the "competence network malignant lymphoma" ("Kompetenznetz Maligne Lymphome"). The CLL2-BCG trial is an investigator-initiated trial with the University of Cologne being the legal sponsor; financial support and the study drugs were provided by the pharmaceutical companies Gilead and F. Hoffmann-LaRoche. Researchers interested in accessing the de-identified clinical data of this study may submit a formal request to the corresponding author which should include a detailed research proposal, objectives, and an explanation of how the data will be used. Researchers accessing the data will be required to sign a data sharing agreement outlining the terms and conditions of use. Data S1. Supporting Information. 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.