Abatacept prevents graft-versus-host disease in sickle cell patients after alloSCT

In a small series of 13 older children with sickle cell disease, adding abatacept to the regimen after stem cell transplantation (SCT) appeared to be safe and effective to prevent graft-versus-host disease (GVHD) [1].

Dr Niketa Shah (Yale University, USA) presented the multicentre trial, which had a primary objective of determining event-free survival in patients treated with abatacept after SCT. The unmet need that the authors tried to address is that a major cause of mortality following unrelated donor SCT in sickle cell disease patients >13 years is GVHD.

To that end, 13 children with sickle cell disease (ages 7-21 years) underwent SCT due to stroke (n=6), ≥3 severe vaso-occlusive pain crises (n=4), or ≥2 acute chest syndrome episodes per year (n=3). Patients received conditioning with hydroxyurea, proximal alemtuzumab (starting day −12 or earlier), fludarabine, and melphalan in patients with HLA-matched unrelated donors (-A, -B, - C, and -DRB1). Thiotepa (8 mg/kg) was added in HLA-mismatched SCT. GVHD prophylaxis included a calcineurin inhibitor and methotrexate. Abatacept (10 mg/kg) was administered on days -1, +5, +14, +28, +60, +100, +180, +270, and +365 based on efficacy described against acute GVHD with early dosing after SCT for malignant disorders.

The conditioning regimen was well tolerated. One patient had primary graft rejection after infection (7%). All other patients engrafted; neutrophils recovered at median of 18 days (10-24), and platelets at median of 28 days (16-39). All engrafted patients survived free of sickle cell disease with median follow-up of 12 months (range 4-59). At day +100, myeloid lineage donor chimerism was >95% in all patients, and lymphoid donor chimerism varied between 39% and 100% in all patients. Two-year overall survival and event-free survival was 100% and 92.3% (95% CI 6.57-35.7), respectively. The day+100 incidence of grade 2-4 and 3-4 acute GVHD incidence was 23% and 15%, respectively. One-year incidence of chronic GVHD was 38%. However, only 1 patient (7%) developed extensive chronic GVHD. One patient (7%) developed posterior reversible encephalopathy syndrome and recovered. Viral replication in blood was detected in 7 of 13 patients (7 cytomegalovirus; 1 Epstein-Barr virus reactivation). No patient developed Epstein-Barr virus-related post-transplant lymphoproliferative disease or required Epstein-Barr virus-related intervention.

The observations are preliminary, based on a small patient cohort, and are not placebo-controlled. Nevertheless, these early observations support a role for abatacept in the low incidence of severe acute GVHD (15% vs 17% grade 3-4) despite mismatched donors, low incidence of extensive chronic GVHD (7% vs 38%), and no mortality despite patient age (10/13 were >13 years old). The engraftment, safety, and immune reconstitution profile continue to be monitored in this ongoing trial now accruing in a phase 2 cohort.

1. Shah N, et al. Abstract 370, ASH 2019, 7-10 December, Orlando, USA.

Posted on 5 March 202017 May 2024