Venetoclax-based therapies in patients with Relapsed/Refractory T-cell prolymphocytic leukemia

Abstract

Abstract Background: T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T lymphocytes with high rates of relapse and poor outcomes. Despite high response rates in the frontline with alemtuzumab and allogeneic stem cell transplantation (SCT), effective strategies for relapsed/refractory (R/R) disease remain a critical unmet need. BCL2 inhibition with venetoclax (VEN) may be an effective strategy in R/R T-PLL. Methods We conducted a retrospective study of patients (pts) with R/R T-PLL who received VEN-based regimens as part of 1st or later-line salvage therapy. Treatment response was assessed according to the T-PLL International Study Group Consensus Criteria. Results 35 pts with R/R T-PLL, median age 66 years (range, 43–88), were included. At the time of relapse, 33 pts (94%) had elevated LDH, with 17 (49%) having values >2x the ULN. 28 pts (80%) had extramedullary disease, including 23 (66%) with lymph node involvement. Among 28 pts with BM involvement, the median infiltration was 70% (3–100). Of the 33 pts with cytogenetic data, 20 (61%) had complex karyotype, 20 (61%) had inv(14)(q11.2q32) or t(14;14)(q11;q32), and 17 (52%) had abnormalities involving chromosome 8. TCL1 rearrangement by FISH was detected in 25 of 31 tested pts (81%). Among 25 pts with next generation sequencing (NGS) at the time of VEN initiation, 13 (52%) harbored mutations in JAK3, 5 (20%) STAT5B, and 4 (16%) each in ATM and JAK1. All pts had previously received alemtuzumab, and 9 (26%) had undergone SCT. The median number of prior lines of therapy before VEN initiation was 1 (range, 1–5); 19 pts (54%) were treated with VEN-based therapy in 1st salvage while 16 pts (46%) were treated in 2nd or later salvage. VEN was combined with cladribine (+/- additional agents) in 17 pts (49%), including 8 (23%) who also received ruxolitinib. Nine pts (26%) were treated with VEN and pentostatin (+/- alemtuzumab), 3 (9%) with FCM (fludarabine, cyclophosphamide, mitoxantrone), 2 (6%) with alemtuzumab alone, 2 (6%) with ruxolitinib alone, and 1 (3%) each with bendamustine or as monotherapy. The median VEN dose equivalent was 600 mg (range, 100–1200 mg). All pts underwent rapid dose escalation over a median of 3 days. Overall, 8 pts (23%) achieved complete response (CR) or CR with incomplete hematologic recovery (CRi), including 3 pts who lacked bone marrow assessment but met all other CR/CRi criteria. An additional 8 pts (23%) achieved partial response (PR), resulting in an overall response rate (ORR) of 46%. The ORR was 42% and 50% for pts in 1st salvage vs. 2nd or greater salvage. The ORR for VEN combinations with cladribine, pentostatin, or FCM were 47%, 56%, and 33%, respectively. Among responders, 3 pts (19%) had measurable residual disease (MRD) negativity by flow cytometry. Six pts (17%) died before response assessment, primarily due to rapid disease progression. The median duration of response (DOR) was 1.9 months (95% CI, 0.9–3.0). One pt proceeded to SCT following CR to VEN-based therapy. With a median follow-up of 16 months (m), the median OS for the entire cohort was 4.3 m (95% CI, 3.3-6.5). The median OS was 6.8 m (95% CI, 4.0–12.4) among overall responders and 8.0 m (95% CI, 6.8–NR) for those who achieved CR/CRi. Among pts treated in 1st salvage, the median time from initiation of frontline therapy to VEN-based salvage therapy was 2.6 m, compared to 11.7 m for those treated with VEN in later salvage lines. Pts with a longer time from diagnosis to VEN-based salvage therapy (> 12 m vs. <12 m) had a longer median OS: 6.4 vs 3.7 m, respectively (p=0.003). Similarly, pts with a DOR >18 m to frontline therapy had a longer median OS with VEN-based salvage therapy of 7.5 m vs 3.7 m for those with a DOR <18 m (p=0.005). Tumor lysis syndrome (TLS) occurred in 3 pts (9%), including 2 (6%) with clinical TLS. Grade 3-4 neutropenia occurred in 26 pts (74%), and thrombocytopenia in 27 pts (77%). Eighteen pts (51%) experienced infectious complications including 13 bacterial, 6 viral, and 2 fungal infections. Conclusion Pts with R/R T-PLL continue to face poor prognosis. VEN-based therapies demonstrate encouraging response rates in this refractory, proliferative, heavily pretreated population, with improved survival observed among responders and those with longer duration of 1st remission. However, OS remains short, highlighting the need for prospective trials to optimize VEN-based treatment and post remission strategies in these pts.