Phase II Trial of Allogeneic Hematopoietic Cell Transplantation for Mature NK/T Cell Neoplasms – Potent Graft Vs Tumor Effect Affords Remission Even with Refractory Disease

Abstract

Introduction

Peripheral (mature) T and NK-cell lymphomas (PTCL) are aggressive and poorly responsive to chemotherapy. Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative cellular immunotherapy. Unfortunately, alloHCT remains understudied prospectively. Herein, we present the results of a prospective trial of alloHCT for PTCL.

Methods

This single-center, prospective phase II trial (NCT03922724) is being conducted at the NIH from April 18, 2019 to present. The data from all patients enrolled and evaluable through August 23, 2022 are included. Patients received reduced-intensity conditioning (RIC) incorporating distally-timed horse antithymocyte globulin, pentostatin, low-dose, hyperfractionated cyclophosphamide and 2-days of busulfan, followed by a T-cell replete PBSC graft, with PTCy, MMF, and sirolimus for GVHD prophylaxis. GCSF was given on day -12, -8, and -4 in a subset of patients (n=10, mRIC arm) and compared to the prior 21 patients (RIC arm). Endpoints included progression-free survival (PFS), overall survival (OS), cumulative incidences (CuIs) of acute GVHD (aGVHD), chronic GVHD (cGVHD), progression/relapse, and transplant-related mortality (TRM).

Results

Patients transplanted (n=31) were high-risk, in disease subtype, HCT-CI scores, and disease status at HCT (Fig 1). With median follow-up of 3.5 years for surviving patients, 1-year PFS was 53% (95% CI 29-72%) for the RIC arm and 60% (95% CI 25-83%) for the mRIC arm. For the whole cohort, the estimated 3-year PFS was 52% (95% CI 33-68%), with 3-year OS of 61% (95% CI 42-76%). The 3-year CuI of relapse was 18% (95% CI 6-34%) (Fig 2A), with 100-day and 1-year Cul of TRM of 17% (95% CI 6-32%) and 24% (95% CI 10-41%) respectively (Fig 2B). The Cul of TRM at 1 year was 11% (95% CI 2-29%) for patients ≤60 years but 56% (95% CI 17-82%) for patients >60, p=0.011 (Fig 2C). No patients developed grade III-IV aGVHD. The 1-year Cul of grades II-IV aGVHD was 16% (95% CI 6-31%) in all patients. The 2-year CuI of cGVHD was 23% (95% CI 10-39%) with 2-year Cul of 30% (95% CI 6-60%) for recipients of HLA-matched grafts and 19% (95% CI 5-39%) for recipients of HLA-mismatched grafts. Immune reconstitution was robust overall with 90% of surviving, engrafted patients having CD4+ T cells > 50 cells/uL by day +100. Immune subset recovery to normal levels was reached by day +60 for NK cells (Fig 3A), day +180 for CD8+ T Cells (Fig 3B), day +100-180 for B cells (Fig 3C), and 2 years for CD4+ T Cells (Fig 3D).

Conclusions

Despite most patients being transplanted with high-risk, active disease, and significant comorbidities, outcomes were promising, providing compelling justification for the role of alloHCT in PTCL, even when remission is not obtained pre-HCT. The prospective study of alloHCT for PTCL is ongoing at NCI, aiming to decrease early TRM in older patients and further harness the graft-versus-tumor effect to afford cure and good survivorship.