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4640 A Prospective, Phase-II Study to Evaluate the Efficacy and Safety of Obinutuzumab, Ibrutinib, and Venetoclax (GIVeRS) in Patients with Richter's Syndrome

Program: Oral and Poster Abstracts
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, clinical trials, Clinical Research, Combination therapy, Therapies
Monday, December 11, 2023, 6:00 PM-8:00 PM

Tamar Tadmor1,2*, Ohad Benjamini3*, Neta Goldschmidt4*, Natalia Kreiniz, MD5*, Osnat Bairey6*, Reut Harel, MD7*, Tsofia Inbar8*, Ofir Wolach, MD9,10* and Yair Herishanu, MD11*

1Technion, Ruth and Bruce Rappaport Faculty of Medicine,, Haifa,, Israel
2Hematology, Bnai-Zion Medical Center, Haifa, Haifa, ISR
3Sheba Medical Center–Tel HaShomer, Ramat Gan, Israel
4Department of Hematology, Hadassah Medical Center, Jerusalem, Jerusalem, ISR
5Hematology, Bnai Zion Medical Center, Haifa, Israel
6Davidoff Cancer Center, Rabin Medical Center,, Petach Tikva, ISR
7Department of Hematology, Emek Medical Center, Afula, Ein-Dor, Israel
8Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus,, Haifa, Israel
9Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah-Tikva, Israel
10Rabin Medical Center, Institute of Hematology, Davidoff Cancer Center, Petah Tikva, Israel
11Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel

Background: Richter's syndrome (RS) is an aggressive histologic transformation of chronic lymphocytic leukemia (CLL), most commonly to diffuse large B-cell lymphoma (DLBCL). RS is characterized by a rapid clinical course, low responses to therapy, and poor long-term survival. Chemoimmunothreapy for RS achieves overall response rates of 40% to 60%, and median progression-free survival (PFS) and overall survival (OS) of 3 to 10 months and 6 to 21 months, respectively. More recently, single targeted agents of either ibrutinib or venetocolax have been shown some clinical activity in RS. Furthermore, ibrutinib combined with venetoclax with or without anti-CD20 antibodies has a synergistic activity in CLL, resulting in deep and prolong responses along with a good safety profile.

Methods: This is a prospective phase 2, open-label, non-randomized, single-arm, multi-center study aimed to assess the efficacy and safety of ibrutinib, venetoclax, and obinutuzumab in treatment-naïve or relapsed/refractory patients with biopsy-confirmed RS to DLBCL (NCT04939363). The experimental regimen consisted of 12 months of fixed-duration treatment with obinutuzumab, ibrutinib, and venetoclax. Obinutuzumab was administered at a dose of 100 mg intravenously on day 1, 900 mg on day 2, and then 1000 mg on day 8 and 15 of cycle 1. On day 1 of the subsequent five cycles, obinutuzumab at a dose of 1000 mg was administered. Ibrutinib was administered at a dose of 560mg orally daily initiated together with the first obinutuzumab infusion on day 1 of cycle 1 and was continued throughout the 12 treatment 28-day cycles. Venetoclax was given at a dose of 400 mg orally daily for 12 treatment cycles after an accelerated ramp-up phase from day 15 in cycle 1. The primary endpoint was investigator-assessed overall response rate (ORR) defined as the proportion of patients who achieve complete metabolic response (CR) and partial metabolic response (PR) determined by PET-CT imaging at 6 months per Lugano 2014 criteria. Other key endpoints included; investigator-assessed ORR at 3 and 12 months, PFS, Duration of response (DOR), OS, and safety.

Results: From August 2021 until the data cut-off on July 20, 2023, a total of 10 patients with RS were enrolled. Median age was 76.0 (range, 62‒88) years and 70% were male. Six patients were treatment-naïve, 4 had relapsed/refractory RS, 50% had extra-nodal disease, 70% had elevated LDH, 70% were double or triple expressors, and the median number of prior therapies among the R/R patients was 1 (Table 1). Median follow-up was 255 days (95% CI, 158.7-351.3), median treatment duration was 160 days (range: 29-362) and treatment is still ongoing in 3 patients. At 3 and 6 months, the ORRs were 70.0% (7/10) and 22.2% (2/9), respectively, and CR rates (CRRs) were 40.0% (4/10) and 11.1% (1/9), respectively. At the data cutoff, 6/10 (60.0%) patients progressed and 5/10 (50.0%) died. The median PFS was 162 days (95% CI, 66.9-257.1), median DOR 272 days, and median OS was 228 days (95% CI: 184.2-271.8). The causes of death included RS in 2 patients and one case each of Covid-19, secondary malignancy, and general deterioration. Most common related treatment-emergent AEs (TEAEs) of all grades were neutropenia 40%, thrombocytopenia 50%, diarrhea 40%, and skin rash 50%, 2 patients developed Covid-19 who recovered during the protocol. None of the patients developed tumor lysis syndromes.

Conclusions: In patients with RS triplet treatment with ibrutinib, venetoclax, and obinutuzmab was well tolerated, achieved high rates of early metabolic response (ORR-70% and CRR-40%) at 3 months. Given the high early response rate but subsequent progression, this triplet therapy may serve as a bridge to consolidation with cellular therapy.

Disclosures: Tadmor: janssen,: Research Funding; Abbvie, ROCHE, Janssen, AstraZeneca, takeda: Consultancy, Honoraria. Benjamini: Abbvie, Janssen, AstraZeneca: Consultancy. Wolach: Teva: Consultancy; Medison: Honoraria; Gilead: Consultancy; Astellas: Consultancy, Honoraria; BWH: Patents & Royalties: Inhibition of JAK-STAT signaling inhibits formation of neutrophil extracellular traps (NETs); US11426405B2; Abbvie: Consultancy, Honoraria, Research Funding. Herishanu: Abbvie: Honoraria; Lilly: Honoraria; AstraZeneca: Honoraria; Roche: Honoraria; Janssen: Honoraria, Research Funding.

*signifies non-member of ASH