High Complete Responses with Combination of Platinum-Based Regimen with BTK Inhibitors in Richter's Syndrome: University of Miami - Case Series
Authors: Pongas Georgios , Alasfour Maryam , Soong Deborah , Alderuccio Juan Pablo , Lossos Izidore S. 
Published: December 2024

Background: Richter's Syndrome (RS) is a rare and aggressive complication of Chronic Lymphocytic Leukemia (CLL) affecting 2-10% of patients, where CLL transforms to an aggressive Lymphoma, most commonly Diffuse large B-cell Lymphoma (90%) (DLBCL). Despite advancements in CLL treatments, RS outcomes remain poor, as complete responses are achieved in only 20% of patients, and less than 20% experience long-term survival with chemoimmunotherapy (CIT). Herein, we present our institutional experience with case series of RS with DLBCL treated with RICE (rituximab, ifosfamide, carboplatin and etoposide) chemotherapy in combination with BTKi and examine their outcomes.
Methods: A retrospective study was performed for RS patients with DLBCL transformation at the Sylvester Comprehensive Cancer Center, from 1/1/2015 until 4/25/24. We included patients with RS with DLBCL transformation that were treated with RICE chemotherapy in combination with covalent BTK inhibitors. Demographic, pathologic (TP53 mutations, FISH with 17p del and complex karyotype) and clinical data, including response rates, progression free survival (PFS) and overall survival (OS) were collected. Median PFS (mPFS) and median OS (mOS) were calculated with IBM SPSS.
Results: We identified 12 patients (pts) with RS with DLBCL transformation that were treated with RICE chemotherapy in combination with BTKi. The average age was 61 yo (53-71), 9 were white, 8 had 17p deletion (3 negative, one unknown), 6 had TP53 mutations (4 unknown, 2 negative), 5 had complex karyotype (2 unknown). Seven pts received RICE + BTKi for front line therapy of the RS. Three of these 7 pts developed RS while they were on BTKi treatment for CLL, whereas the remaining 4 were BTKi naive. Five pts received RICE + BTKi for relapsed and refractory RS (R/R RS) and 3 of them were BTKi naïve, whereas 1 was refractory to RCHOP + BTKi for RS and 1 had disease progression (DP) on BTKi for CLL. In total, 7 pts with RS were BTKi naïve, whereas 5 pts were previously treated with a BTKi (3 for CLL, 1 for RS and 1 for both CLL and RS). The overall response rates to RICE + BTKi was 83% with 58% patients achieving a CR. The mPFS was 54 months (95%CI=27.3-81) and the median OS was 57 months (95%CI=32.2-82.2). The ORR among the BTKi naive pts was 86% (6pts) with 71% (5pts) achieving a CR. Those 5 pts with CR subsequently received Allogeneic-Hematopoietic Stem Cell Transplantation (Allo-HSCT) (4) or CAR-T (1). Three of BTKi naive pts are alive and remain in CR (2 Allo-HSCT and 1 CAR-T) with no additional treatment, whereas 2 died from infections related to Allo-HSCT and 2 from RS progression. Among the BTKi pre-treated patients, the ORR was 80% (4pts), with 40% (2pts) achieving a CR. All the 4 pts that responded were able to be consolidated with Allo-HSCT (2 CR, 1 PR) and 1pt (PR) with CAR-T. Three of the BTKi pretreated pts are alive and remain in CR (2 allo-HSCT and 1 CAR-T) with no additional therapy, whereas 1 died due to infections related to allo-HSCT and 1 from RS progression. Overall, the 2-year OS among the BTK naive and BTK pre-treated patients following the treatment with RICE + BTKi was 40% and 60% respectively.
Conclusion: The management of RS pose significant challenges, resulting in generally poor outcomes when treated with the traditional CIT regimens alone. In this retrospective study we described superior complete responses with the RICE in combination with covalent BTK inhibitors allowing patients to proceed with consolidative Allo-HSCT or CAR-T. Future clinical trials, should consider investigating the combination of platinum-based chemotherapies with BTK inhibitors as we aim to improve the response rates and survival outcomes in RS.