Background: Richter's syndrome (RS) is a rare histologic transformation of chronic lymphocytic leukemia (CLL), most commonly to diffuse large B-cell lymphoma (DLBCL). It is characterized by an aggressive clinical course and dismal prognosis. Treatment is usually based on regimens traditionally used for de novo DLBCL like R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-DA-EPOCH (rituximab and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin). The outcomes with chemo-immunotherapy in RS are poor, achieving a complete response rate (CRR) of about 20% to 30% of patients and median progression-free survival (PFS) and overall survival (OS) in the range of 6 and 12 months, respectively.

Methods: This is a phase 2, open-label, non-randomized, single-arm, multi-center study aimed to assess the efficacy and safety of 12-month fixed duration obinutuzumab, ibrutinib, and venetoclax (GIVe) in patients with DLBCL-type RS (NCT04939363). Obinutuzumab was administered IV for 6 cycles, starting with 100 mg on day 1 and 900 mg on day 2, 1000 mg on day 8 and on day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6. ibrutinib 560 mg daily was administered orally from day 1 of cycles 1 through 12. The daily oral venetoclax regimen was initiated on day 11 of cycle 1, starting with an accelerated ramp-up, thereafter continuing at 400 mg daily until completion of cycle 12. The primary endpoint was investigator-assessed 6-month overall metabolic response rate per Lugano 2014 criteria. Other key secondary endpoints included complete metabolic response (CMR) rate, PFS, OS, and safety.

Results: From August 2021 until the data cut-off on July 7, 2024, a total of 12 patients with RS were enrolled, with a median age of 78.0 years (range, 62-87), 8 (67%) were males, 8 (67%) were treatment-naïve, 4 (37%) had relapsed/refractory disease, 5 (42%) had extra-nodal disease, 8 (67%) had elevated LDH, and 9 (75%) were double or triple-expressors (Table 1). Among the 10 patients who were evaluable for response, the 3-month and 6-month OMR rates were 70.0% (7/10) and 37.5% (3/8), respectively, and the 3-month and 6-month CMR rates were 40.0% (4/10) and 25% (2/8), respectively. During a median follow-up of 23 months (range, 1-32), 6/12 (50 %) progressed and 10/12 (83.3 %) died. Median PFS was 4.4 months (95% CI, 1-11.9) and median OS was 7.8 months (95% CI: 1-32). Causes of death included RS (n=3), intractable diarrhea (n=2), infections (n=2; one case of sepsis and one case of Covid-19 during the next-line therapy with bendamustine plus rituximab), neurological deterioration (n=2), and acute myeloid leukemia (n=1). Most common related treatment-emergent adverse events (TEAEs) of all grades were neutropenia 40%, thrombocytopenia 50%, diarrhea 40%, and skin rash 50%, 2 patients developed Covid-19 and recovered during the treatment period of the study. None of the patients developed tumor lysis syndrome or atrial fibrillation.

Conclusions: In elderly patients with RS, 12-month fixed duration obinutuzumab, ibrutinib, and venetoclax treatment achieved high 3-month metabolic responses. Despite the early encouraging response, the duration of response, PFS, and OS were short. This three-drug regimen appears to be less well tolerated in elderly patients with RS

Disclosures

Tadmor:Janssen, roche, abbvie, astra, takeda, novartis, beigene, medison: Consultancy, Research Funding. Goldschmidt:Abbvie, Janssen, AstraZeneca: Consultancy. Sarid:Abbvie, Janssen, AstraZeneca: Consultancy, Honoraria. Wolach:Pfizer: Honoraria; Teva: Honoraria; Amgen: Honoraria; Medison: Honoraria; Abbvie, Janssen,: Consultancy, Honoraria, Research Funding; Astellas: Honoraria. Herishanu:Abbvie, Janssen, AstraZeneca: Consultancy, Honoraria.

This content is only available as a PDF.
2024
Sign in via your Institution