Oral chronic graft-versus-host disease (cGVHD) as a potential clinical marker of the graft-versus-leukemia (GVL) effect in allogeneic hematopoietic stem cell transplantation: A prospective single-center study

Abstract Background: Allogeneic stem cell transplantation (HSCT) is a well-established and life-saving therapeutic procedure for many patients with hematological malignancies, inborn errors of metabolism, or bone marrow failure syndromes. Chronic graft-versus-host disease (cGVHD) is a major complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), affecting up to 40-60% of recipients. Oral involvement is common (80%) and significantly impairs quality of life (QoL); however, its potential prognostic implications have not been fully elucidated. Given the established association between cGVHD and the graft-versus-leukemia (GVL) effect, we hypothesized that oral cGVHD might serve as a clinically relevant marker of favorable disease control. Objectives: The aim of this study was to assess the association between oral cGVHD and post-transplant outcomes, including overall survival (OS), disease-free survival (DFS), non-relapse mortality (NRM), and relapse incidence, and to characterize the clinical features and prognostic value of oral involvement. Methods: We conducted a prospective monocentric study including patients who underwent allo-HSCT between October 2023 and May 2025 in the hematology department of CHU de Nice. Oral evaluations were performed at pre-transplantation visit and at days +30, +100, 6 months and one-year post-transplant. Oral cGVHD was graded according to the 2014 NIH M-OMRS consensus criteria. Saliva samples were collected for future biomarker analysis. Clinical outcomes were compared between patients with and without oral cGVHD. Univariate and multivariate analyses were conducted using the Cox proportional hazards model. Statistical analysis were performed using IBM SPSS statistics. Results: Among the 54 patients median age was 57.6 years and male/female ratio was 1:1. The median time between transplantation and diagnosis was 8 months. Tobacco use was reported in 8 patients (14.8%). Comorbidities were present in 45 patients (83%). Peripheral blood stem cells (PBSC) were the main source of stem cells in 98% of cases (53 patients), with only 2% (1 patient) receiving umbilical stem cells. Regarding donor characteristics, 70.4% were male (38 donors) and 29.6% female (16 donors). The CMV donor/recipient matching was positive/positive in 24% of cases, negative/negative in 35.2%, negative/positive in 31.5%, and positive/negative in 9.3%. Concerning donor-recipient relationships, 53.7% (29) were unrelated 10/10 HLA-matched donors, 9.3% (5) were unrelated but non-10/10 matched, 25.9% (14) were geno-identical related donors, and 11.1% (6) were haplo-identical related donors. Fifty two patients (96.3%) developed acute GVHD (aGVHD), and 46 (85%) developed cGVHD, including 35 patients (76%) with oral involvement. Oral cGVHD was distributed in a non-significative way between mild, moderate and severe scores according to the NIH M-OMRS assessment. The underlying disease was AML in 20 cases, T-ALL in 3 cases, ALL B in 1 case, ALL B PHI + in 3 cases, Myelodysplasia in 7 cases, Myelofibrosis in 12 cases, T cell Lymphoma in 1 case, anaplastic T cell lymphoma in 3 cases, NK/T cell Lymphoma in 1 case, follicular lymphoma in 1 case and Hodgkin Lymphoma in 1 case and 1 patient with an SCD. Thirty-five patients were in RC1 state while 16 were RC2, 2 were RC3 and 1 RC4. Although the median follow-up was 15.11 months, the estimated 2-year OS was significantly higher in patients with oral cGVHD compared to those without (72.3% vs. 33%, p=0.01). DFS was also significantly improved (48.4% vs. 0%, p=0.003). NRM occurred later in patients with oral cGVHD (mean 620 vs. 410 days, p=0.002). Importantly, oral cGVHD was not associated with increased NRM. Patients without oral cGVHD appeared to experience a higher cumulative relapse rate over time, although this was not statistically significant(p=0.243). Conclusions: In this prospective study, oral cGVHD emerged as a potential surrogate marker of the GVL effect, associated with significantly improved OS and DFS without an increase in NRM. These findings suggest that mild to moderate oral cGVHD may reflect a balanced and beneficial immune response. Ongoing analyses, including salivary biomarkers, aim to validate early diagnostic tools and optimize post-transplant management strategies.