Post-transplant cyclophosphamide-based graft-verses-host disease (GVHD) prophylaxis is associated with a low incidence of fibrotic chronic GVHD after allogeneic hematopoietic cell transplantation across diverse donor types

Abstract Background: Chronic graft-versus-host disease (cGVHD) remains the leading cause of non-relapse mortality (NRM) in patients who undergo allogeneic stem cell transplantation (alloHCT), with a 50-70% incidence after calcineurin inhibitor (CNI) and methotrexate-based prophylaxis. Fibrotic manifestations of cGVHD, such as scleroderma, joint facial involvement, and bronchiolitis obliterans syndrome (BOS), are associated with significant morbidity and mortality. Post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis can significantly reduce the incidence of cGVHD compared to conventional GVHD prophylaxis strategies in reduced-intensity conditioning (RIC) setting (Bolanos Mead et al., NEJM 2023), with recent trends showing increasing utilization of PTCy as the preferred GVHD prophylaxis strategy across all donor and conditioning types. However, its specific impact in preventing fibrotic cGVHD is not well-defined. Methods: This single-center, retrospective study included adult patients (>18 years) who underwent first alloHCT using PTCy-based GVHD prophylaxis at City of Hope (COH) between January 1, 2020, and December 31, 2023 (n=531). Patients receiving concurrent ATG or Jak inhibitors, bone marrow graft, second HCT, and those with relapses prior to cGVHD onset were excluded. The final cohort included 462 patients who underwent haploidentical (haplo), mismatched unrelated donor (mMUD), or matched unrelated donor (MUD) alloHCT. Primary endpoints included incidence, severity, and cGVHD organ involvement, focusing on fibrotic features of the skin, lungs and joint fascia using the 2014 NIH consensus criteria (Jagasia et al., BBMT 2015). Secondary endpoints were NRM, overall survival (OS) and systemic immunosuppression treatment patterns. Patient data were extracted from the COH database and verified through chart review under IRB-approved protocol. Results: Median age at HCT was 56 years (range: 19-82), 66% recipients were male, and the most common indication for HCT was AML (39%) among 201 patients who developed cGVHD. Conditioning regimens were myeloablative (46%, n=93) or non-myeloablative/RIC (54%, n=108). Most patients received tacrolimus and mycophenolate mofetil (88%) or sirolimus (10%) in combination with PTCy. Disease risk index was low-intermediate in 68%, KPS ≥90 in 75%, and HCT-CI 0–2 in 56%. Donor types included haplo (n=102), mMUD (n=63), and MUD (n=45). Grade 2-4 acute GVHD prior to cGVHD onset occurred in 39% (n=78) patients. Median time to cGVHD onset was 161 days (range: 63-1181). With a median duration of follow-up of 22.5 months, 43% (n=201/462) patients developed cGVHD. Two-year cumulative cGVHD incidence was 46% (haplo), 40% (mMUD) and 40% (MUD). Based on the 2014 NIH criteria, the majority of cGVHD cases were mild (59%, n=118) and moderate (28%, n=56). Severe cGVHD was seen in the remaining patients (13%, n=27). Most patients had 1-2 organs involved (86%), while multiorgan involvement (>4 organs) was rare (7%). The most commonly affected organs were the skin (71%), mouth (30%), and eyes (22%), with similar distribution across all donor types. Fibrotic manifestations were infrequent, with scleroderma observed in 7 (3%) patients, severe joint or fascia involvement in 2 (1%) patients, and BOS in 11 (5%) patients. In patients who developed moderate-severe cGVHD, corticosteroids were used as first-line therapy in 88% (n=73/83) patients. In patients who failed frontline corticosteroids, 71 (85%) patients received novel agents, with ruxolitinib being the most frequently used first-line salvage agent in 70 (84%) patients, followed by infrequent use of other therapies—ECP, rituximab or belumosudil (n=8 each, 9.5%). The 2-year OS rate was similar across donor types and was 85% for haplo (95% CI: 77-93%), 77% for mMUD (95% CI: 67-89%), and 82% for MUD (95% CI: 70-95%) [p=0.089]. The 2-year NRM rate was 9% for haplo (95% CI: 5-18%), 16% for mMUD (95% CI: 9-29%), and 10% for MUD (95% CI: 4-26%) [p=0.21] and similar across all donor types. Conclusion: PTCy-based GVHD prophylaxis is associated with a lower incidence of moderate-to-severe cGVHD, particularly fibrotic GVHD subtypes, when compared to conventional CNI-based prophylaxis regimens. Most patients who developed cGVHD responded to corticosteroids or ruxolitinib. Our data supports the efficacy and versatility of PTCy in GVHD prevention across different donor types.