Phase II study of polatuzumab in combination with chemoimmunotherapy for richter transformation (PolaR-EPCH).

Abstract Background: Richter transformation (RT) is a rare complication observed in patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). It most commonly manifests as large B cell lymphoma (LBCL) in the setting of CLL/SLL. Historically, remission rates are low with short survival after standard chemoimmunotherapy (CIT). Polatuzumab vedotin (pola) is an antibody drug conjugate that targets CD79b and is approved in combination with CIT for LBCL. Despite low CD79b expression in CLL/SLL, we previously demonstrated a heterogenous but adequate CD79b staining pattern in primary RT specimens (Allan et al., 2019). We therefore hypothesized targeting RT with pola in combination with a standard CIT backbone could prove effective. We present preliminary efficacy and safety data of this combination (PolaR-EPCH). Methods: Eligible pts were ≥18 years with a confirmed LBCL-RT. Enrolled pts had measurable disease, adequate organ and bone marrow function, with an ECOG performance status of ≤2. Pts received 1.8mg/kg of pola and 375mg/m2 of rituximab (or biosimilar) intravenously (IV) on Day 1, 50mg/m2/day etoposide and 10mg/m2/day doxorubicin as continuous infusion on Day 1-4. Cyclophosphamide was given IV on Day 5 at 750mg/m2. Prednisone, 60 mg/m2 twice daily was given Day 1-5. Vincristine was omitted due to cross toxicity with pola. Growth factor support was mandatory for each cycle. All infusions repeated every 21 days for up to 6 cycles. Dose adjustments as done standard for dose-adjusted REPOCH were at investigator's discretion following institutional guidelines. Responses were assessed using Lugano 2014 criteria. After completion of therapy pts were allowed maintenance with approved CLL/SLL therapies or consolidation with allogenic stem cell transplant (allo) per investigator discretion. Adverse events (AEs) were graded by CTCAE version 4.3. The primary endpoint was complete remission (CR) rate. Secondary endpoints were safety, overall response rate (ORR), 1 year progression free survival (PFS), and 1 year overall survival (OS). Results: From 9/27/21-4/14/25, 15 pts enrolled and were treated. Median age was 68.8 years, (range, 47-84). Eight (53%) were female, 13 (86.7%) were white and 2 (13.3%) were black. Median time to RT from CLL/SLL diagnosis was 7 years (range 1.5-29.8). Median prior lines of therapy for CLL/SLL were 2 (range 0-5), 5 pts (33%) had prior CIT, 11 (73%) prior BTKi, and 9 (60%) prior BCL2i. Eight (53%) were IGHV unmutated, 8 (53%) were TP53 deleted or mutated, 8 (53%) had a complex karyotype defined as ≥3 clonal abnormalities, and 3 (23.1%) had NOTCH1 mutations. After a median follow-up of 18.7 months, 15 pts were evaluable for safety and 12 pts evaluable for response. Best ORR was 83.3% (95% confidence interval (CI) 51.6-97.9%), best CR rate was 50% (95% CI 21.1-78.9%). One year PFS was 70.9% (95% CI 50.4-99.8%) and median PFS was 22.6 months (95% CI 12.5-NR). One year OS was 70.9% (95% CI 50.4-99.8%), median OS was not reached (95% CI 12.5-NR). Of 8 pts that completed treatment, 5 started maintenance therapy, all receiving BTKi, 1 received allo. Fifteen pts were evaluable for safety and received at least one cycle. Median number of cycles was 6 (range 1-6) with 8 pts (53.3%) completing 6 cycles. Of the 7 pts (47%) who discontinued treatment early, 4 (27%) stopped due to AE (2 sepsis, 1 mucositis, 1 hepatic failure) and 3 (20%) due to progressive disease (PD). Overall, 6 pts (40%) have died. Deaths due to treatment related AE occurred in 2 pts (1 sepsis, 1 hepatic failure), and 4 pts died due to PD. All 15 pts had an AE. Most common any grade AEs were hematologic; thrombocytopenia 73% (60% ≥Grade3 (Gr3)), neutropenia 67% (67% ≥Gr3), anemia 60% (27% ≥Gr3). Infections, ≥Gr3 occurred in 8 (53%) pts, 4 pts (27%) had COVID19 all ≥ Gr3. Febrile neutropenia occurred in 9 pts (60%) (60% ≥Gr3) and peripheral neuropathy occurred in 4 pts (27%), none ≥Gr3. Conclusions: We report interim results with pola in combination with CIT for RT. The regimen demonstrates encouraging activity with high response rates, excellent 1 year survival rates, and with an expected but manageable toxicity profile. These results compare favorably to historical CIT standards. Hematologic toxicity, febrile neutropenia, and infections are common, requiring close monitoring of patients during treatment. Deaths due to AEs occurred but are consistent with previous reports of targeted agent CIT combinations in RT populations.