Background: Abatacept blocks CD28-CD80/86 axis and prevents T-cell co-stimulation. In early studies, abatacept has shown promising results when added to methotrexate and tacrolimus in matched and mismatched donor SCT. Further promising results have been demonstrated with a combination of post-transplant cyclophosphamide (PTCy), abatacept, and a short course of tacrolimus to improve the results of GvHD prevention in the setting of haploidentical SCT. Based on this data we initiated a phase Ib-II clinical trial of the efficacy and toxicity of the Abatacept/Tacrolimus/PTCy combination for patients who received HLA-mismatched grafts and Abatacept/Tacrolimus combination for patients who received HLA-matched grafts.

Aim: assess the frequency of acute and chronic GVHD grade II-IV.

Patients received G-CSF mobilized peripheral blood grafts from related and unrelated donors. GvHD prevention consisted of PTCy 50mg/kg IV on day +3 and +4, abatacept 10mg/kg IV on day -1, +5, +14 and +28 and tacrolimus. Tacrolimus was started on day -1 at 0.02 mg/kg/day by continuous IV and adjusted thereafter to maintain a trough level of 5-12 ng/mL. Tacrolimus taper was planned to begin on day +90 and complete by day +120 in the absence of GvHD. All patients received standard supportive care including acyclovir and co-trimoxazole until CD4-count >200 cells/muL, posaconazole/voriconazole until day +60, and if CMV positive by serology, ganciclovir 5 mg/kg per day until day +100. G-CSF was administered routinely until neutrophil engraftment.

From Oct 2020 to Jul 2022, 51 patients were enrolled. The median age was 44 years (23-64) M/F 49%/51%. Diagnosis: AML 23,5% (12/51), B-NHL 17,6% (9/51), HD 17,6% (9/51), ALL 15,6% (8/51), MDS 9,8% (5/51), MF 5,9% (3/51), CLL 4% (2/51), MM 4% (2/51), AA 2% (1/51). Disease status before conditioning: 30/51 had CR, 15/51 - PR, 6/51- active disease. Conditioning regimens: Treo/Flu for AML, ALL, MDS and MF (28/51, 55%), Benda/Flu for B-NHL, HD, CLL and MM (22/51, 43%), Flu/Cy/ATG for AA (1/51, 2%). RIC/MAC: 65%/35%. 29,4% (15/51) of patients received cryopreserved products. Median times to ANC and platelet engraftment were 15 (8-60) and 18 days. 2 patients had primary graft failure (absence of engraftment > 28 days, non-response MDS before SCT and B-NHL, both 5/10, both older than 60). In both cases, a second HSCT was performed from the same donors. In the first case (non-response MDS), repeated HSCT without any effect and the patient died, in the second case, there was graft engraftment with the restoration of blood parameters. 1 patient (ETP ALL, mismatched related donor 5/10) had poor graft function. Transfusion of purified CD34+ cells (Miltenyi Biotec) from the same donor was accompanied by restoration of hematopoiesis.

With a median follow-up was 154 days (25-641) with 34 patients having >120 days, 23 >180 days, and 7 >365 days of follow-up, 13,7% (7/51) patients developed acute GvHD grade II-IV (mostly skin, gut, liver). 9,8% (5/51) of patients developed chronic GvHD grade II-IV (skin, lungs, mucous eyes, liver, joints). 47% (24/51) completed tacrolimus taper by day +120. 3 patients switched from tacrolimus to sirolimus and one to prednisone due to intolerance or toxicity. 3 patients with MF received ruxolitinib from day +30 as a treatment for MF (no signs of GVHD of any grade). All patients with GvHD grade II-IV received systemic steroids. 7 patients received ruxolitinib, 3 - MMF, 4 - rituximab, 1 - daratumumab, 2 - ibrutinib, 1 - acalabrutinib and 2 - imatinib. CMV activation rate was 35,3%. There were 1 case of BK virus and 1 case of JC virus (patient with HD after aGVHD and cGVHD). 2 patients developed thrombotic microangiopathy (one received tacrolimus, one did not).

During the observation period, 25,5% (13/51) patients died: 3 due to COVID-19, 4 due to relapse/progression, 3 from infectious complications (2 sepsis and 1 PML due to JCPyV), 1 from non-engraftment, and 1 due to uncontrolled AIHA.

Summary: our preliminary results suggest that Abatacept/Tacrolimus +- PTCy is feasible and seems to offer very promising outcomes with low rates of acute and chronic GvHD grade II-VI. Based on this and previous trials we need a phase III clinical trial to evaluate abatacept. In our practice, abatacept-based immunosuppressive therapy has become routine. Additional reducing mortality is possible due to the widespread use of anti-covid antibodies and the exclusion of patients with a lack of response to disease therapy.

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.

© 2022 by The American Society of Hematology
2022
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