Abatacept Abrogates the Risk of Acute GvHD in Both Matched and Mismatched Transplantation for Haemoglobinopathies and Bone Marrow Failure

Introduction: Allogeneic hematopoietic stem cell transplantation [HCT] is a well-established curative therapy for hemoglobinopathies and bone marrow failure syndromes [BMF]. Advances in conditioning regimens and prophylaxis have reduced the incidence of graft versus host disease [GvHD]. However, GVHD remains the most important factor of morbidity and impacts long-term outcomes. This is particularly important with the advent of HLA-mismatched and haploidentical HCT leading to universal availability of curative treatment for these indications where there is no advantage for a graft versus leukaemia effect. Abatacept is a fusion protein cytotoxic T cell-lymphocyte-4-immunoglobulin [CTLA4-Ig] that induces co-stimulatory blockade of CD80 and CD86 on antigen presenting cells modulating T-cell activation. Abatacept has been shown to result in a reduction of severe GvHD and improved outcomes in the malignant HCT setting [Watkins et al 2021].

Aims: We hypothesised that the addition of abatacept for 6 months to GvHD prophylaxis would result in a reduced rate of acute GVHD in children undergoing HCT for hemoglobinopathies and BMF with improved outcomes.

Methods: Between June 2023 and June 2024, 35 consecutive T cell replete HCT received abatacept prophylaxis: 10 mg/kg [day -1, day +5, day +14, day +28, day +60, day +90, day +120, day +150. Results were compared to HCT outcomes from the previous four years. 16 procedures were matched related, 9 matched unrelated, 5 matched unrelated and 5 haploidentical HCT. 15 children had sickle cell disease, 8 transfusion dependent thalassemia, 4 for Diamond-Blackfan anemia, 2 Fanconi anemia, 2 congenital dyserythropoietic anemia and 4 for severe aplastic anemia. The outcomes were compared to a historical control group of 66 consecutive HCT between January 2020 and May 2023 at the same institution using the same conditioning regimens but without abatacept prophylaxis. The median age was the 11 years of age in both groups (abatacept group range 2-18 years and control group 2-19 years). The source of stem cells consisted of 31 bone marrow and 4 PBSC in the abatacept group whereas the control group had no PBSC use. The median follow-up was 6.4 months (0.95 - 12.9) for the abatacept group and 15.9 months for the control group (1.5 - 42.5). Estimates for the probability were calculated using the Kaplan-Meier statistical approach.

Results: All patients in the abatacept group engrafted and are alive whereas there were 2 cases of graft failure (3%) and 3 deaths (4.5%) in the control group. Median neutrophil engraftment was 16.5 days (11-28) in the abatacept group and 13 days (9-29). The probability of acute GVHD grade II-IV was significantly lower in the abatacept group: 6.6% (2 cases) versus 39.7% in the control group (26 cases), p <0.001. There were no cases of acute GvHD grade III-IV in the abatacept group whereas there were 11 (16.8%) of which one was grade 4 in the control group, P 0.016. This was associated with a median cessation of immunosuppression of 180 days (108-295) in the abatacept group (n = 13) versus 216 days (106-523) in the control group. The OS and EFS at 1 year was 100% for the abatacept group whereas the 96.8% and 93.6% respectively for the control group.

Conclusion: Abatacept reduces the risk of grade II-IV acute GVHD in both matched and mismatched pediatric HCT for non-malignant disorders including hemoglobinopathies and bone marrow failure syndromes. Further, abatacept resulted in a reduction in the duration of immunosuppression. It is particularly effective in abrogating the risk of severe acute GvHD. It was well tolerated with no associated toxicity with its use.

References: WatkinB, Qayed M, McCracken C, et al. Phase II trial of costimulation blockade with abatacept for prevention of acute GVHD. J Clin Oncol. 2021. ;39(17):1865-1877.

de la Fuente:Sanofi: Membership on an entity's Board of Directors or advisory committees; Vertex: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MAAT Pharma: Membership on an entity's Board of Directors or advisory committees; Sangamo: Membership on an entity's Board of Directors or advisory committees.