Venetoclax in Combination With Chemo‐Immunotherapy in Richter Transformation: <i>A Real‐Life</i> Experience

The prognosis of Richter Transformation (RT) with standard chemo-immunotherapy (CIT) remains poor. Several previous experiences with Venetoclax (V) in combination with CIT demonstrated the feasibility and safety of V-CIT based regimens in RT. This is a retrospective, observational multicenter study aimed to assess the efficacy and safety of the real-life use of V-CIT in the treatment of RT. Response assessments were evaluated according to the Lugano 2014 criteria. 20 consecutive patients treated with V-CIT based regimens from October 2018 to July 2024, were included. Median age was 63.5 years (33-73), with 75% of males. 11/17 were IGHV unmutated and 8/18 carried a mutation for Tp53 and/or a del17p. The median time from CLL diagnosis to RT was 6.5 years (0-17). A clonal relationship was demonstrated in 16/16 evaluable patients. The median number of prior treatments for CLL was 2 (0-4): CIT in 10, BTKi in 10, V based treatment in 4, no previous therapy in 5. V was associated with R-DA-EPOCH, R-CHOP, and BFM in 10, 9 and 1 patients for a median number of 4 cycles (1-6). ORR was 55% with 10 CR (50%) and 1 PR (5%). 3 patients had progressive disease (PD) and 1 died for multiorgan failure. 7 patients received allogeneic-HSCT consolidation. At a median follow up of 11.5 months (1-78), 10 patients, including 5 who received HSCT, are alive in CR; median PFS and OS were not reached. All patients experienced grade 3-4 hematological toxicities: neutropenia (100%), anemia (50%) and thrombocytopenia (25%). Non-hematological toxicities included: febrile neutropenia (15%), covid19 (25%), other infections (30%), nausea (10%), thrombotic/hemorrhagic events (10%). Data from this real-life experience confirm the feasibility and the activity of V-CIT based combination in younger fit RT patients, where the high rate of initial response may allow a significant proportion to receive allogeneic-HSCT consolidation. New studies with V combinations are ongoing and the comparison with this real-life data may be worthwhile to better understand their therapeutic impact.