Combination Therapy with Nelarabine, Peg-Asparaginase and Venetoclax for Adults Patients with Relapsed/Refractory T-Cell ALL
Authors: Khaire Niranjan Shiwaji , Jabbour Elias , Kadia Tapan M. , Short Nicholas J. , Borthakur Gautam , Pemmaraju Naveen , Daver Naval , Kebriaei Partow , Paul Shilpa , Shah Vishrut , Garris Rebecca , Sasaki Koji , Ravandi Farhad , Jain Nitin 
Published: December 2024

Introduction

Nelarabine, an antimetabolite drug is approved for treatment for relapsed/refractory (R/R) T-ALL/LBL. When used as a single agent in this setting, the response rates (CR/CRi) range from 31 to 36% with median overall survival (OS) ranging from 4.6 to 8 months (DeAngelo,2007; Gokbuget, 2011; Candoni 2020). We report our experience of nelarabine combined with peg-asparaginase and venetoclax for adult patients (pts) with R/R T-ALL/LBL.

Methods & Results

We retrospectively identified a total of 12 pts with R/R T-ALL/LBL who were treated with at least 1 cycle of combination therapy with nelarabine, peg-asparaginase and venetoclax (NEL-PEG-VEN) from August 2018 to December 2021 at MD Anderson Cancer Center, Houston.

The median age of the population was 47 years (range, 21-64 years) and 8 (67%) were male. The pathological diagnosis at baseline was T-ALL/LBL in 10 pts and T/Myeloid MPAL in 2 pts. 3 (25%) pts had ETP and 1 (8.3%) pt had near-ETP immunophenotype. 3 (25%) pts had complex cytogenetics and NGS revealed NOTCH1/FBXW7 mutations in 7 (58%) and TP53 in 3 (25%) pts. Majority of the pts (n=9) received hyper-CVAD based therapy as initial line of treatment. Time from first therapy to use of NEL-PEG-VEN was a median of 3 months (range, 1.2 to 104 months). Median number of prior lines of therapy was 1.5 (1 prior Rx, n=6; 2 prior Rx, n=5; 3+ prior line Rx, n=1). The number of pts with prior exposure to nelarabine, peg-asparaginase and venetoclax were 2 (16%), 2 (16%) and 4 (32%), respectively. Two pts had received prior allogeneic stem cell transplant (allo-SCT).

The most common dosing regimen used was nelarabine at 650 mg/m2 for 5 days with peg-asparaginase as a single dose of 1000-1500 IU/m2 (cap 3750 IU) on the fifth day. Venetoclax was most commonly dosed at 400 mg daily for 7-14 days. Median number of cycles of NEL-PEG-VEN administered was 1 (range, 1-2). A total of 6/12 (50%) pts had a response (2 CR, 3 CRh, 1 CRi) while 1 pt had aplastic marrow, 1 pt had MLFS, and 4 had refractory disease. Among the responders, 4/6 achieved MRD negative remission by flow cytometry (10-4 sensitivity) after 1 cycle of NEL-PEG-VEN. Notably, 5 of the 6 pts who responded to the therapy proceeded to an allo-SCT with median interval of 3.6 months from NEL-PEG-VEN initiation. The median OS of the whole cohort was 9.1 months. Among the responders (n=6), median RFS was 23 months. Among the 5 pts who underwent allo-SCT, 2/5 had a post-transplant relapse while the other three are alive and in remission at 33-, 34- and 62-months post NEL-PEG-VEN regimen. One pt had grade 4 neurotoxicity in the form of ascending sensorimotor polyradiculopathy causing paraparesis, and 1 pt had grade 3 neurotoxicity in the form of transient ischemic attacks.

Conclusions

The novel combination of nelarabine, peg-asparaginase and venetoclax is an effective nelarabine-based therapy for adults with R/R T-ALL/LBL. In our cohort of 12 pts, we observed an ORR of 6/12 (50%) of whom 5/6 (83%) could go on to receive allo-SCT. The median OS of the whole cohort was 9.1 months and the median RFS of the responders was 23 months. NEL-PEG-VEN regimen is an effective therapy in getting this difficult to treat population into a remission, allowing them to proceed with a potentially curative allo-SCT.