Current Prophylaxis and Treatment of Gvhd: Analysis of a Large Real-World Cohort. Spanish Group of Hematopoietic Transplantation and Cellular Therapy (GETH/TC)
Authors: Martinez Munoz Maria Carmen , Bento De Miguel Leyre , Salas Maria Queralt , Montoro Juan , Sanz Jaime , Lopez Corral Lucia , Pérez López Estefanía , Pascual Maria Jesús , García-Cadenas Irene , Suarez-Lledo Maria , Bermúdez Arancha , Peña Felipe , Carretero Carlos , Jiménez Lorenzo María-José , González Pedro Antonio , Sampol Mayol Antonia , Heras Inmaculada , Zudaire Teresa , Balsalobre Pascual , Filaferro Silvia , Cedillo Angel , Solano Carlos , Jurado Chacón Manuel 
Published: December 2024

INTRODUCTION
Graft-versus-host disease (GVHD) remains a serious complication of allogeneic hematopoietic stem cell transplantation (alloHSCT), associated with high morbidity and mortality. In recent years, there have been significant advances in both the prophylaxis and treatment of GVHD. In light of the clinical heterogeneity, the paucity of randomized prospective studies, and the emergence of new prophylactic and therapeutic regimens, an analysis and update of the incidence, clinical behavior, and therapeutic management of GVHD in real-life settings is imperative. We present preliminary results of a study promoted by GETH/TC, with the primary objective of evaluating the incidence of acute GVHD (aGVHD) and chronic GVHD (cGVHD). Secondary objectives include analyzing the prevalence, population characteristics, clinical features, efficacy, and safety profile of treatments used in real-world settings in Spain.

METHODS
This retrospective study analyzed alloHSCT procedures performed in 13 Spanish centers, selected for their high activity and for reporting at least 95% of their cases during the period 2018-2020 through the EBMT/GETH registry.

RESULTS
A total of 1,550 alloHSCTs were included (56% males, median age 54 years [IQR 43-62]), with the majority (89%) using peripheral blood stem cell grafts. Forty-one percent received myeloablative and 59% reduced intensity conditioning regimens. The most frequent diagnoses were AML (36%), MDS (13%), and ALL (12%). Donor types included HLA-matched sibling (33%), HLA-matched unrelated (30%), mismatched related or unrelated (10%), and haploidentical (28%). GVHD prophylaxis was PTCy-based in 1,015 (66%) patients, ATG-based in 106 (7%), CNI + MTX in 202 (13%), CNI + Sirolimus in 103 (7%), and others in 124 (8%).
Cumulative incidences (CI) at day +100 of grade II-IV and grade III-IV aGVHD were 29% and 7%, respectively. In the univariate analysis, the use of PTCy-based or ATG-based GVHD prophylaxis was associated with a lower CI of grade II-IV aGVHD (PTCy vs. ATG HR 1.34 [95% CI 0.92-1.92], P=0.12; PTCy vs. CNI + MTX HR 2.26 [95% CI 1.79-2.84], P&lt;0.001; and PTCy vs. CNI + Sirolimus HR 2.12 [95% CI 1.58-2.83], P&lt;0.001). In comparison with PTCy, the CI of grade III-IV aGVHD was higher for ATG-based group (HR 1.90 [95% CI 1.04-3.25], P=0.034) and for CNI + MTX (HR 1.66 [95% CI 1.02- 2.67], P=0.040), with no differences for CNI + Sirolimus group (HR 1.71 [95% CI 0.94-3.09], P=0.077). Corticosteroids were the most frequently (76%) used first-line treatment for aGVHD. A higher probability of refractoriness to first-line treatment was observed in the ATG-based (44%) and CNI + MTX (32%) groups compared to the PTCy-based (28%) and CNI + Sirolimus (14%) groups (P=0.05). The most frequently utilized salvage treatments were extracorporeal photopheresis (ECP) and ruxolitinib, in that order.
The 3-year CI of moderate-severe cGVHD was 27%. Compared with PTCy, CNI + MTX had a higher risk of cGVHD (HR 1.95 [95% CI 1.51-2.51], P&lt;0.001), with no differences when compared with ATG-based (HR 1.42 [95% CI 0.93-2.14], P=0.098) and CNI + Sirolimus groups (HR 1.28 [95% CI 0.88-1.85], p=0.190). Corticosteroids were the most commonly used first-line treatment. No differences in the probability of response were observed according to the GVHD prophylaxis group. A total of 240 patients required second-line treatment, with ruxolitinib followed by ECP being the most used therapies.
With a median follow-up of 47.8 months, the 3-year overall survival (OS) and relapse-free survival (RFS) were 62% and 54%. Developing grade II-IV or moderate-severe cGVHD was associated to significant higher non-relapse mortality (HR 2.52 [95% CI 2.02-3.14], P&lt;0.001; HR 2.11 [95% CI 1.52-2.92], P&lt;0.001, respectively), and lower OS (HR 1.72 [95% CI 1.45-2.03], P&lt;0.001; HR 5.41 [95% CI 4.45-6.59], P&lt;0.001, respectively).

CONCLUSIONS
The preliminary analysis of this large series of alloHSCTs reveals that, irrespective of donor type, Spanish centers tend to prefer the use of PTCy for GVHD prophylaxis. The rates of aGVHD and cGVHD were lower than previously reported in the literature, and this may be attributable to the widespread use of PTCy in our setting. The development of aGVHD or cGVHD is linked to a higher mortality rate and poorer survival outcomes, underscoring the necessity for enhanced strategies to prevent this adverse event. Further statistical analysis of the data is currently being performed.