Calcineurin Inhibitor–Free GVHD Prevention Posttransplant Yields Strong Results

A novel 3-drug regimen for preventing graft-vs-host disease (GVHD) after allogeneic stem cell transplantation without a calcineurin or mTOR inhibitor has shown promising efficacy and tolerability, according to findings presented at the 2026 European Blood and Marrow Transplantation Society (EBMT) conference in Madrid, Spain.¹

Interim results of the ABC phase 1/2b clinical trial (NCT06681922) showed that posttransplant cyclophosphamide (PTCy), bortezomib (Velcade), and abatacept (Orencia) led to low GVHD incidence and favorable survival outcomes. Additionally, reducing the dose of PTCy appeared to enhance engraftment speed without worsening GVHD rates.

“We all can agree that an ideal GVHD prevention regimen should be effective, nontoxic, practical, and cost effective, and I will submit to you that it should also be of short duration to allow for early introduction of maintenance strategies,” A. Samer Al-Homsi, MD, MBA, system chief of blood and marrow transplant and cellular therapy at the Northwell Health Cancer Institute in New York, explained in his presentation.

Trial Background

The trial of PTCy, bortezomib, and abatacept did not include calcineurin inhibitors such as tacrolimus or cyclosporine or mTOR inhibitors such as sirolimus, which are standard components of most current prophylaxis regimens but carry significant toxicity and complicate the early introduction of posttransplant maintenance therapies.

Al-Homsi described these 3 agents as having activity early in the cascade of events leading to GVHD. Cyclophosphamide plus bortezomib showed an advantage, as did cyclophosphamide, abatacept, and a shortened course of tacrolimus.^2,3 This led to the ABC trial’s investigation of abatacept, bortezomib, and cyclophosphamide, with rabbit antithymocyte globulin given to patients receiving grafts from unrelated donors.¹ The phase 1 3+3 design led to a 3-dose 10 mg/kg abatacept regimen being adopted for phase 2. After the first 25 patients, PTCy was decreased from 50 mg/kg to 37.5 mg/kg. The regimen was completed by day +28 following transplant.

Strong GVHD and Survival Outcomes Across 60 Patients

With a data cutoff of February 15, 2026, and a median follow-up of 16.2 months, 60 of an intended 74 patients had been enrolled across 2 cohorts: matched related or unrelated donor transplants and mismatched (7/8) unrelated donor transplants of peripheral blood stem cells. The study population had a median age of 59 years, and the majority carried intermediate to high-risk disease, with acute myeloid leukemia representing the most common diagnosis. The primary end point was the incidence of grade 2 to 4 acute GVHD by day 120.

By day +180, the estimated cumulative incidence of grade 2 to 4 acute GVHD was 4.8% in the matched donor cohort and 18.5% in the mismatched cohort, with no grade 3 or 4 events occurring in either group. At 1 year, moderate and severe chronic GVHD incidence was 10.2% and 12.5% in the matched and mismatched cohorts, respectively.

At 1 year, overall survival was 91.3% (95% CI, 80.4-96.3%), progression-free survival was 78.2% (64.8-87.1%), and GVHD- and relapse-free survival was 70.9% (56.7-81.2%). The 1-year cumulative incidence of relapse was 17.7%, and treatment-related mortality was 5.2%; at 2 years, these were 20.9% and 13.6%, respectively. There were 5 cases of disease relapse and 6 of treatment-related mortality, which included 2 deaths that were attributed to suicide and complications related to a liver transplant.

Reduced PTCy Dose Speeds Engraftment Without Apparent Cost

A key secondary finding concerned the impact of the mid-trial protocol amendment that reduced the PTCy dose from 50 mg/kg to 37.5 mg/kg on days +3 and +4. In the 35 patients receiving the lower dose, median time to neutrophil engraftment was 15 days compared with 17 days in the 25 patients who received full-dose PTCy (P =.004), and median platelet engraftment occurred at 22 vs 25.5 days (P =.04). No primary or secondary graft failure was observed in either group, and full donor chimerism was achieved in 94.8% of patients by day +100.

Importantly, reducing the PTCy dose did not appear to compromise immune reconstitution. Recovery of CD3+, CD4+, CD8+, and CD19+ lymphocyte subsets was comparable between the 2 dose groups at days +30, +100, and +180. Dose reduction did not appear to significantly affect GVHD incidence: grade 2 to 4 acute GVHD occurred in 4% vs 11.8% of full- and reduced-dose patients respectively (P =.29), and moderate-to-severe chronic GVHD in 12% vs 9.47% (P =.87).

Safety Profile

Adverse events were primarily infectious. Cytomegalovirus reactivation requiring preemptive therapy occurred in 31.7% of patients, Epstein-Barr virus in 16.7%, and adenovirus in 3.3%. One patient developed posttransplant lymphoproliferative disorder, which responded to rituximab (Rituxan), and 1 case of sinusoidal obstructive syndrome resolved with treatment. No dose-limiting toxicities were reported during the phase 1 dose-escalation of abatacept, and a 3-dose schedule (days +5, +14, and +28) was adopted for phase 2.

Implications

The investigators concluded that the ABC regimen represents an effective, nontoxic, and short-duration approach to GVHD prevention that may facilitate earlier immune reconstitution and timely initiation of posttransplant maintenance therapy, advantages that have been difficult to achieve with calcineurin inhibitor-based platforms. The finding that PTCy dose reduction accelerates engraftment without apparent compromise in GVHD control or immune recovery adds a potentially clinically meaningful refinement to the regimen.

The trial is ongoing and still enrolling additional patients to the mismatched donor cohort. Al-Homsi said it would be compared with a propensity score–matched control when full results are reported and could potentially be investigated in a randomized study.

“The key here is to get rid of tacrolimus completely and to shorten the duration of prevention,” said Al-Homsi in his presentation. “Now our attention should shift from prevention of GVHD with all these results that you are seeing with different presentations, so we can focus more on relapse and try to introduce early maintenance strategies to hopefully decrease the risk of relapse, which remains a major problem…in the field of allogeneic transplant.”

REFERENCES

1. Al-Homsi AS, Boisclair S, Cole K, et al. Post-transplant cyclophosphamide dose reduction within an entirely calcineurin and mTOR inhibitor-free GVHD prophylaxis regimen: interim results of the ABC phase I-IIb trial. Presented at: 2026 EBMT Annual Meeting; March 22-25, 2026; Madrid, Spain.OS12-07.

2. Bruno B, Cirrone F, Cole K, et al. Post-transplant high dose cyclophosphamide and bortezomib as graft-versus-host disease prophylaxis following allogeneic hematopoietic stem cell transplantation. Blood. 2021;138(suppl 1):3892. doi:10.1182/blood-2021-151809

3. Al-Homsi AS, Cirrone F, Wo S, et al. PTCy, abatacept, and a short course of tacrolimus for GVHD prevention after haploidentical transplantation. Blood Adv. 2023;7(14):3604-3611. doi:10.1182/bloodadvances.2023010545