Sequential Treatment with Bendamustine, Obinutuzumab (GA101) and Ibrutinib in Chronic Lymphocytic Leukemia (CLL): Final Results of the CLL2-BIG Trial of the German CLL Study Group (GCLLSG)

Abstract

Introduction: The GCLLSG has demonstrated the efficacy of a sequential therapy with bendamustine followed by obinutuzumab (or GA101; G) and ibrutinib (I) according to a "sequential triple-T" concept [Hallek M., Blood 2013] using a tailored and targeted treatment aiming at total eradication of minimal residual disease (MRD) in CLL [von Tresckow J, Leukemia 2019]. Here we present the results of the final analysis of the CLL2-BIG trial after the end of maintenance therapy. Methods: This phase-II trial investigated the efficacy and safety of a novel regimen for physically fit and unfit CLL patients (pts) requiring treatment, irrespective of high-risk genetics. 62 pts were to be recruited according to a predefined allocation for the two strata of first-line (1L) and relapse/refractory (RR) treatment. Six cycles of induction therapy with G and I were administered followed by maintenance therapy with continuous I and G every three months until achievement of an MRD-negative complete remission or up to 24 months. Pts with an absolute lymphocyte count ≥ 25.000/µl and/or lymph nodes ≥ 5cm were scheduled to receive two cycles of bendamustine before start of induction. The primary endpoint was the overall response rate 3 months after the start of last induction cycle administered; secondary endpoints included the best response rate, MRD evaluations as well as survival and safety parameters (graded per the NCI CTCAE v.4 criteria). Results: 66 pts were enrolled. Five pts completed less than two cycles of induction therapy and were therefore excluded from the full analysis set as defined by study protocol. Patient characteristics are shown in Table 1. Of note, half of the pts had received prior therapies and two thirds had a high/very-high CLL-IPI. At the end of induction, ORR was 100% and 29 pts (47.5%) achieved MRD-negativity (<10-4 by 4-color-flow cytometry) in peripheral blood (PB), as previously published. 59 of 61 pts (96.7%) started maintenance therapy. Response is shown in Figure 1 and was improved in 16 pts, with 6 pts (9.8%) achieving a complete remission (CR) or CR with incomplete recovery of the bone marrow (CRi) and 55 pts (90.2%) a PR by iwCLL criteria, including 54.1% patients who were lacking a bone marrow biopsy or CT scan but fulfilled all other criteria for CR/CRi (clinical CR). 42 pts (71.2%) were MRD negative in PB at the last staging during maintenance therapy. 11 pts discontinued maintenance therapy early due to AE (6 pts (10.2%)), progressive disease (PD), refusal of further treatment (2 pts (3.4%) each) or physician´s decision (1 pt (1.7%)). 15 pts (25.4%) completed 24 months and 33 pts (55.9%) stopped due to MRD negativity after a median time of 15.6 months on study. PFS and OS are shown in Figures 2 and 3. In 1L pts 4 PD (13.3%) and no deaths occurred while among RR pts 8 PD (25.8%) and 7 deaths were reported (3 due to infections, 2 due to progression of CLL, 1 due to comorbidity and 1 due to infection and unknown cause). Among pts who stopped treatment due to MRD negativity, 5 pts relapsed after a median duration of 16.4 months off treatment and 1 pt died after 8.7 months, respectively. During maintenance therapy, no grade 5 AE occurred. 151 (45.5%) of 332 CTC grades 1 - 4 AE were deemed as related to study drugs. Due to AE, I was dose modified in 26 pts (44.1%), G in 1 pt (1.7%). All grade 3-4 toxicities observed are shown in Table 2. Conclusion: The depth of response of the BIG regimen can be improved by maintenance therapy with I and G, leading to a rate of undetectable MRD in the PB in 71.2% of pts. Among 33 pts who discontinued treatment due to MRD negativity only 5 pts relapsed and 1 pt died so far. The data demonstrate that the BIG protocol using an MRD guided concept for treatment discontinuation yields very good results, in particular in 1L CLL pts. Disclosures Von Tresckow: Celgene: Other: Travel support; AbbVie: Consultancy, Honoraria, Other: Travel support; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding. Cramer:Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Other: travel support, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Roche: Honoraria, Other: travel support, Research Funding; mundipharma: Other: travel support. Langerbeins:Mundipharma: Other: travel support; Roche: Honoraria, Other: travel support; Janssen: Honoraria, Other: travel support, Research Funding; AbbVie: Honoraria, Other: travel support; Sunesis: Honoraria. Fink:Celgene: Research Funding; Roche: Other: travel grants; Janssen: Membership on an entity's Board of Directors or advisory committees. Al-Sawaf:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Illmer:Roche: Other: travel support. Tausch:AbbVie: Consultancy, Honoraria, Other: travel support, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Ritgen:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding. Fischer:Roche: Other: travel grants; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wendtner:Gilead Sciences, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffman-La Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Research Funding, Speakers Bureau. Kreuzer:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Stilgenbauer:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Other: Travel support; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffmann La-Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau. Böttcher:AbbVie: Honoraria, Other: travel support; Becton Dickinson: Honoraria; Celgene: Other: tavel support; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Eichhorst:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; BeiGene: Research Funding; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hallek:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Obinutuzumab (GA101) is not registered for Treatment of relapsed/rferactory CLL

Efficacy and Safety of the Combination of Tirabrutinib and Entospletinib With or Without Obinutuzumab in Relapsed Chronic Lymphocytic Leukemia

“…10 Within the heterogeneous population of the CLL2-BIG trial, the combination of ibrutinib plus obinutuzumab with an optional bendamustine debulking yielded an ORR of 100% with 9.8% CR. 11 These reported CR rates are consistent with those presented here.…”

“…Acalabrutinib plus obinutuzumab resulted in 4 of 22 relapsed/refractory patients who achieved partial response attaining bone marrow MRD negativity at 12 months 13 . Within the CLL2‐BIG trial, an increase of uMRD in the peripheral blood from 47.5% at the end of 6 months of induction therapy to 71.2% after up to 24 months of maintenance therapy was observed 11,14 . This observation suggests that primary endpoint evaluation in this trial may have been premature.…”

“…In contrast to frontline therapy, the combination of zanubrutinib, another next‐generation BTK inhibitor, and obinutuzumab achieved an ORR of 92%, including 7 CRs (28%) in patients with relapsed/refractory CLL or small lymphocytic lymphoma after a median follow‐up of 29 months 10 . Within the heterogeneous population of the CLL2‐BIG trial, the combination of ibrutinib plus obinutuzumab with an optional bendamustine debulking yielded an ORR of 100% with 9.8% CR 11 . These reported CR rates are consistent with those presented here.…”

“…13 Within the CLL2-BIG trial, an increase of uMRD in the peripheral blood from 47.5% at the end of 6 months of induction therapy to 71.2% after up to 24 months of maintenance therapy was observed. 11,14 This observation suggests that primary endpoint evaluation in this trial may have been premature. While MRD rates improved overall beyond week 25, improvement of CR rates could not be detected, since later computerized tomography scan or bone marrow biopsies were not required per protocol.…”

Efficacy and Safety of Tirabrutinib and Idelalisib With or Without Obinutuzumab in Relapsed Chronic Lymphocytic Leukemia

“… 10 Additional CD20 antibody administration may increase uMRD rates: MRD in the peripheral blood increased from 47.5% after 6 months with ibrutinib plus obinutuzumab to 71.2% after up to 24 months. 11 , 12 Whether TIO uMRD rates will continue to improve over time and responses will be durable remains to be seen.…”