CATCHing chronic GVHD

In this issue of Blood Advances, Pidala et al¹ report the clinical outcomes from the Chronic GVHD Consortium CATCH study, which was designed to characterize the contemporary incidence and clinical onset of chronic graft-versus-host disease (cGVHD). The investigators aimed to identify pre–allogeneic stem cell transplantation (alloHSCT) and early post–alloHSCT risk factors, as well as the earliest manifestations of cGVHD to establish a foundation for future trials investigating preemptive interventions for incipient and subclinical cGVHD and organ-specific biomarker studies. This prospective, longitudinal observational study systematically describes the clinical course of 208 patients from before alloHSCT through the first 12 months after alloHSCT enrolled at 7 US centers between November 2019 and April 2024.

Despite recent advances in the prevention and treatment of cGVHD, it remains the leading cause of nonrelapse mortality, while also imposing a substantial psychosocial and socioeconomic burden.² The global incidence is estimated to range from 20% to 40%,² and is influenced by pre-alloHSCT risk factors, GVHD prophylaxis strategies, dysbiosis, and prior acute GVHD.² Its multifaceted pathophysiology is characterized by acute inflammation, chronic immune dysregulation, and aberrant tissue repair, which ultimately leads to irreversible organ damage in many patients.³ With the advent and Food and Drug Administration approval of the targeted therapies such as ruxolitinib, ibrutinib, belumosudil, and axatilimab⁴ early treatment aimed at interrupting this harmful alloimmune cascade before irreversible tissue injury occurs has emerged as a potential promising strategy. This paradigm, however, necessitates the ability to identify patients at risk through reliable biomarker-based risk stratification or detection of subclinical cGVHD.⁵ Against this background, the CATCH study addresses a critical unmet need and represents an important step toward earlier diagnosis and intervention.

Pidala et al report a cumulative cGVHD incidence of 54% at 24 months, with 38% of patients requiring systemic immunosuppression after a median follow-up of 28 months. These relatively high estimates reflect an anticipated cGVHD risk-enriched cohort after the exclusion of patients with established low-risk characteristics, such as those receiving antithymocyte/anti–T-lymphocyte globulin prophylaxis. Moreover, although most donors were HLA-matched unrelated (71%) or mismatched/haploidentical (15%), only 38% of recipients received posttransplantation cyclophosphamide (PTCy)–based GVHD prophylaxis. According to previous studies (eg, the study by Bolanos-Meade et al⁶), the cGVHD incidence after PTCy was distinctly lower (34.5% at 2 years), with disproportionately reduced need for immunosuppression (17.2% at 2 years). Interestingly, cGVHD developed earlier in recipients of PTCy than in those receiving non-PTCy prophylaxis (8.4 vs 10.1 months). Whether this finding reflects patient selection or distinct cGVHD pathophysiology remains uncertain.

Another relevant finding is the significant proportion of patients presenting with mild cGVHD onset not requiring immediate systemic immunosuppression (56%). This poses a challenge for exclusively symptom-based, preemptive immunosuppressive interventions possibly compromising the graft-versus-leukemia (GVL) effect in patients with malignant disorders, given that mild cGVHD has been repetitively associated with superior overall survival compared with no cGVHD.² The high proportion of patients with mild cGVHD also underlines the need to use contemporary controls when planning future preemptive trials. Additional biomarker-driven patient selection aimed at identifying the subgroup that would progress to moderate cGVHD, or interventions that preserve the GVL effect, could provide a solution.⁵ Conversely, only a minority of patients (8%) had severe cGVHD at diagnosis, demonstrating the protracted evolution of the disease, which can be captured in most cases before significant organ impairment manifests.

At cGVHD onset, ocular manifestations (41%) surpassed cutaneous manifestations (32%) in frequency, which is sobering as ocular cGVHD is associated with early nonreversibility and morbidity.⁷ Further complicating matters, in contrast to skin lesions, early ocular changes are frequently nonspecific, and histopathological confirmation is rarely feasible. A recently identified factor contributing to the persistently high incidence of ocular cGVHD is the detrimental effect of laminar airflow and air conditioning. Although protecting patients from airborne pathogens, these environmental conditions concomitantly desiccate the ocular surface, thereby promoting a proinflammatory environment and inducing ocular cGVHD.⁸

Skin manifestations occurred earliest after alloHSCT (median, 6.3 months) and presented as rash or erythema in most cases (32%), whereas only 7% and 3% of patients, respectively, had cGVHD-defining lichen planus-like features or ichthyosis. This predominance of nonspecific cutaneous findings may complicate the early clinical diagnosis of cGVHD, especially in the absence of other diagnostic organ manifestations. Although cGVHD is diagnosed clinically, these results underscore the potential need for diagnostic biomarker, including potential histopathological confirmation.

Interestingly, although pulmonary cGVHD, another highly morbid form,⁷ represented the second earliest manifestation (median, 7.0 months), the median interval between initial involvement and the initiation of immunosuppression was relatively prolonged (median, 1.7 months). These findings suggest that opportunities for earlier recognition and interventions may exist and underline the importance of routine pulmonary function testing. Notably, the authors identified only a limited number of atypical early cGVHD manifestations, consistent with our own single-center experience, in which atypical cGVHD occurred late after transplantation (median, 379 days after alloHSCT).⁹

An independent association (P = .001) of serial patient-reported outcome measure (PROM) assessment with subsequent development of cGVHD requiring immunosuppression supports their value for the early detection of emerging cGVHD.¹ Furthermore, the routine integration of PROMs into clinical care, including digital approaches, may facilitate disclosure of sensitive symptoms (ie, genital involvement) while promoting patient empowerment.

Additionally, despite the routine use of letermovir prophylaxis, the CATCH study unexpectedly identified donor cytomegalovirus seropositivity as an independent risk factor for cGVHD requiring immunosuppression (P = .02), warranting further investigation.

Over the past decade, considerable efforts have been made to identify diagnostic, predictive, and prognostic biomarkers for cGVHD. A range of serological and cellular biomarker signatures have been proposed, although none have yet been integrated into clinical routine.¹⁰ By incorporating serial biomarker samples with detailed clinical phenotyping, the CATCH study has the potential to advance this field and provide important insights into biomarker-guided risk stratification and early diagnosis. However, these biomarker data are not included in the present report and are eagerly awaited.

In summary, Pidala et al provide valuable contemporary data on the incidence, early clinical manifestations, and risk factors of cGVHD. These findings may enable timely therapeutic intervention before clinically overt and irreversible organ damage develops.

Conflict-of-interest disclosure: M.F. received honoraria from Novartis and Sanofi; and travel support from Novartis and Medac. D.W. received honoraria from Novartis, Incyte, Sanofi, Behring, Neovii, and Therakos; and a research grant from Novartis.