A Randomized Phase II Trial Comparing a Calcineurin Inhibitor-Free Graft-Versus-Host Disease Prophylaxis Regimen with Post-Transplantation Cyclophosphamide and Abatacept to Standard of Care

Abstract

Background: Graft versus host disease (GVHD) is one the major causes of mortality and morbidity after an allogeneic stem cell transplantation. We hypothesized that we can induce post-transplant tolerance by using the combination of post-transplant cyclophosphamide (PTCy) and abatacept (CTLA4Ig) for GVHD prophylaxis. PTCy when given on Days +3 and +4 can eliminate host-reactive donor T cells. CTLA4Ig blocks the costimulatory signals given through CD28 to naïve donor T cells thus favoring an anergic phenotype that promotes tolerance towards recipient derived antigens. CTLA4Ig gives an activating signal to NK cells and therefore has the ability to preserve the graft-versus-tumor effect. Methods: We have initiated a 50 patient randomized clinical trial. Patients with hematologic malignancies in need of a transplant and with an 8/8 matched donor are randomized 1:1 to tacrolimus and methotrexate for GVHD prophylaxis (standard of care arm) or PTCy on days +3 and +4 followed by CTLA4Ig on days +5, +14,+28, +56, +84, +112, +140 and +168. Patients are stratified by conditioning regimen (myeloablative vs reduced intensity) and by donor type (matched sibling vs matched unrelated donor). The primary endpoint is chronic GVHD at 1 year as a marker of tolerance induction. Secondary endpoints include acute GVHD rate, relapse rate, overall survival, GVHD-relapse-free-survival, transplant related mortality and infection rate. Post-transplantation immune reconstitution studies include measuring T cell and NK cell phenotype, PD-1 expression, and alloreactivity to recipient and third party at predetermined time points. Results: 25 patients have been treated on this study, 10 of which are on the experimental arm. Patients on the experimental arm have been followed for up to 516 days post-transplant. So far no cases of chronic GVHD or grade 3-4 acute GVHD have been observed in the experimental arm. All the patients have engrafted and there have been no treatment related deaths. Conclusions: The combination of PTCy and CTLA4Ig for GVHD prophylaxis is feasible. This ongoing study will examine its ability to induce post-transplant tolerance. Disclosures Tzachanis: Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Partner: Consultancy; Fate Therapeutics: Research Funding; Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Incyte: Research Funding; EUSA: Consultancy; Takeda: Consultancy, Speakers Bureau; Magenta: Consultancy; Kyowa Kirin: Consultancy. Goodman: Seattle Genetics: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria. Mangan: Elevate Bio: Other: ad board. OffLabel Disclosure: abatacept: using as part of graft versus host disease prophylaxis

A Difficult Case of Calcineurin Inhibitor Neurotoxicity Post-Haploidentical HCT With a Successful Novel Solution: Cytotoxic T-Lymphocyte-Associated Protein 4-Immunoglobulin Blockade for GVHD Prophylaxis

“…These studies also showed successful GVHD prevention with CTLA4-Ig blockade, leading to abatacept FDA approval in 2021 for select patients undergoing MUD and 7/8 HLA MMUD HCT. Our institutional experience in a randomized clinical trial has also found that omission of CNIs with a prophylactic regimen of PTCy and abatacept significantly decreased risk of acute and cGVHD, with a more favorable toxicity profile compared with traditional GVHD prophylaxis 24 . Furthermore, in haploidentical HCT, a phase 1b-2 clinical trial investigating PTCy and abatacept with CNI tacrolimus found low rates of grades 3 to 4 aGVHD (4.4%) and one year moderate-to-severe cGVHD (25.9%) rates 25 .…”

“…Pre-clinical studies suggest that CTLA4-Ig blockade allows NK cell activity and thus the GVL effect remains preserved. Furthermore, our institutional experience found no significant difference in overall survival (OS), GVHD-relapse-free OS, or disease-free survival in the abatacept arm versus the CNI containing standard-of-care arm at one year post HCT 24 . Collectively this suggests that the GVL effect remains preserved with use of CTLA4-Ig blockade-based GVHD prophylactic regimens.…”

Graft-versus-host disease: teaching old drugs new tricks at less cost

“…A different phase II randomized clinical trial (NCT03680092) is comparing GVHD prophylaxis with PTCy and abatacept (CNI-free regimen) with CNI/mini dose MTX in 8/8 MRDs or MUDs. Preliminary results were presented at the 63 rd ASH Annual Meeting in 2021 ( 80 ). In this trial, patients in the PTCy arm received abatacept on days +5, +14, +28, +56, +84, +112, +140, and +168.…”