Characterization of BCL-2 alternative proteins and outcome in patients with peripheral T-cell lymphoma (PTCL).
Authors: Marques-Piubelli Mario L. , Solis Luisa Maren , Malpica Luis , Gouni Sushant , Nair Ranjit , Chihara Dai , Iyer Swaminathan Padmanabhan , Wistuba Ignacio Ivan , Vega Francisco , Strati Paolo 
Published: June 2021

e19531 Background: The outcome of patients with PTCL, NOS is generally very poor, and the identification of biologically rational targets, which may translate into effective and non-toxic treatment strategies, is a high priority. The pro-survival BCL-2 family members BCL-2, BCL-XL (BCL2L1), BCL-W (BCL2L2), BCL2A1 and MCL-1 contribute to tumor maintenance, progression, and chemo-resistance across a range of cancers, but their contributions in PTCL, NOS are poorly understood. Methods: Patients with PTCL, NOS treated between 09/2000 and 09/2019 and with available tissue biopsy were included in the study. Diagnosis was retrospectively confirmed by two expert hematopathologists. BCL-2, BCL-XL, BCL-W, BCL2A1 and MCL-1 expression was assessed by immunohistochemistry (IHC), and the percentage of positive tumor cells assessed by standard microscopy. The 2014 Lugano Classification was used to define response to therapy. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and were compared using log-rank test between patient groups. Results: Twenty-seven patients were included in the study: 67% were male, 52% ≥ 65 year old, and 48% had stage IV disease; 59% were previously treated and 41% received > 2 lines of therapy, including stem cell transplant (SCT) in 19%. The median expression of BCL-2, BCL-XL, BCL-W, BCL2A1 and MCL-1 by IHC was: 30% (range: 0-100%), 10% (range: 0-90%), 100% (range: 40-100%), 20% (range: 0-90%), and 70% (range: 1-100%), respectively. BCL-2A1 was significantly higher in previously treated patients (35% vs 5%, p = 0.02), and in those who had previously received > 2 lines of therapy (40% vs 5%, p = 0.02). Twenty-four (89%) patients were treated after tissue biopsy, 17 (63%) with chemotherapy, 7 (26%) with biological therapy, and 6 (22%) received subsequent SCT. Five (24%) patients achieved complete remission (CR); only BCL-W associated with response, a higher expression (quartiles 3 and 4) being observed among patients not achieving CR (median 100% vs 90%, p = 0.07). After a median follow-up of 28 months (95% CI, 14-42 months), 22 (81%) patients progressed or died, and median PFS was 4 months (95% CI, 2-6 months); only BCL-W associated with PFS, a shorter median PFS being observed for patients with higher expression (3 months vs 7 months, p = 0.001). At most recent follow-up, 17 (63%) patients died, and median OS was 6 months (95% CI, 1-12 months). only BCL-W associated with OS, a shorter median OS being observed for patients with higher expression (4 months vs not reached, p = 0.004). Conclusions: High expression of BCL-W associates with significantly worse outcome in patients with PTCL, NOS. While clinical trials investigating the safety and efficacy of BCL-2 inhibition in PTCL, NOS are ongoing, these results suggest that concomitant BCL-W inhibition may be beneficial, and functional studies aimed at confirming these findings are highly needed.