Survival and Therapeutic Outcomes in T-Cell Prolymphocytic Leukemia (T-PLL): A Collaborative Multi-Center Study Cohort
Authors: Braunstein Zachary , McLaughlin Eric , Lingamaneni Prasanth , Barta Stefan K. , Cao Miao , Chang Tiffany , Ganesan Nivetha , Luu Binh , Mehta-Shah Neha , Shree Tanaya , Watkins Marcus P. , Zain Jasmine , Allen Pamela B. , Paulino Darina , Adams Brittany , Wang Jie , Feng Amber , Marchi Enrica , Roberts Nathan , Wilcox Ryan A. , Gutierrez Marc Gabriel , Frosch Zachary AK , Sklarz Tammarah , Sethi Tarsheen , Foss Francine M. , Beaven Anne W , Haverkos Bradley M. , Treitman Rachel , Stevens Patrick , Mishra Anjali , Stuver Robert , Hampel Paul J , Brammer Jonathan E. 
Published: December 2024

Introduction: T-PLL is a rare, aggressive malignancy with poor prognosis and limited therapies. Outside of prospective trials utilizing alemtuzumab, data is derived primarily from small retrospective series, and limited data on survival outcomes and therapeutic efficacy, particularly beyond frontline therapy are available. In this large multi-center series, with comprehensive clinical data, we evaluated survival and therapeutic outcomes in T-PLL patients, with a focus on identification of prognostic subgroups of T-PLL, that will inform future investigations into the biology and treatment of this disease.
Methods: We retrospectively evaluated all patients diagnosed with T-PLL at 15 academic cancer centers throughout the USA between 2000-2023 using the recent TPLL-ISG staging and response criteria with overall response rate (ORR) defined as CR and PR. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier methods and cox proportional hazard models. Single-cell RNA sequencing (scRNAseq) was performed using the standard 10X Genomics platform.
Results: 377 patients, with a median follow-up time of 29 months (range: 0-196) were evaluated. The median age at diagnosis was 64 and 51% were male. In evaluated patients (n=223), TCL1A was positive by cytogenetics or FISH in 82%. 61% of patients had CD4+CD8- T-PLL, 11% of patients had CD4-CD8+ T-PLL, and 24% of patients had CD4+CD8+ T-PLL, with 4% unknown. 175 patients (46.4%) had known nodal involvement at diagnosis identified by PET or CT scan.
Among treated patients (n=342, 91%), using TPLL-ISG criteria, the ORR to any frontline treatment was 67% (49% CR, 18% PR). Median OS and PFS was 19 months and 10 months in responding patients from the start of treatment initiation. For those treated with frontline alemtuzumab (n=250), the ORR was 74% (58% CR), with a median OS and PFS of 18 and 12 months. 20 patients (5%) were treated with a combination of alemtuzumab/pentostatin frontline with an ORR of 85% (70% CR), which was superior to alemtuzumab alone (ORR 74%, 58% CR). Patients that had frontline chemotherapy (excluding pentostatin, n=48) had a worse ORR of 35% (15% CR) (p&lt;0.001), and a worse PFS of 4 months (p=0.002), when compared to those who received alemtuzumab. Among patients in 1st CR/PR (n=226), 44% (n=99) received an allograft and had an improved 3-year OS of 50% vs 17%, (HR=0.67, 95%CI 0.48-0.93), and 50% improvement in PFS (HR 0.48, 0.33-0.68) compared to those who did not receive an allograft.
For patients that received second line treatment (n=176, 52%), re-treatment with alemtuzumab (n=33) produced a 46% ORR (21% CR). Other active second-line treatments included: pentostatin (n=23; 44% ORR, 17% CR), ruxolitinib-based regimens (n=4; 25% ORR, 0% CR), venetoclax-based regimens (n=13; 39% ORR, 8% CR), bendamustine (n=10; 30% ORR, 0% CR), and nelarabine (n=4; 75% ORR, 50% CR).
In subgroup survival analysis, TCL1A+ patients had a worse OS and PFS when compared to TCL1A- patients (23 months vs 43 months; p=0.02), and (14 months vs 24 months; p=0.02) respectively, with HR 1.58 (1.08, 2.31) (p=0.02) for OS and HR 1.62 (1.09-2.40) (p=0.02) for PFS. Furthermore, CD4- T-PLL had worse OS (16 months vs 25 months) when compared to CD4+ patients [HR 1.57 (1.08, 2.27), p=0.02]. Single cell RNA seq in 13 patients, including 3 TCL1A- patients, with a total of 66,269 T-PLL cells, demonstrated a unique RNA signature between the CD4+/- and TCL1A+/- patients, suggesting these represent unique molecular subtypes of T-PLL.
Conclusions: In this large, multi-center study of T-PLL, frontline treatment with a combination of alemtuzumab/pentostatin improved response rates and OS. Further, among patients who attained a CR, allograft improved OS & PFS vs no allograft. In relapsed T-PLL, retreatment with alemtuzumab had a high ORR, and we report significant activity of multiple novel/alternative agents with the largest reported numbers to date. Intriguingly, TCL1A+, and CD4- T- PLL had worse OS/PFS, and scRNAseq confirmed unique molecular signatures in these populations, suggesting these represent novel molecular subtypes of T-PLL with prognostic significance. These studies form the foundation for future, targeted, therapeutic studies in this rare, aggressive disease with few treatment options.