National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2020 Highly morbid forms report

Abstract

Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting "irreversible" fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required.

Keywords: Allogeneic hematopoietic cell transplantation; Chronic graft-versus-host disease; Consensus; Gastrointestinal tract; Lung; Ocular; Sclerosis; Skin.

Figure 1.

Potential Longitudinal Trial Design Proposal for Highly Morbid Manifestations of chronic GVHD using BOS as example. The proposed study approach aims to simultaneously address identified fundamental knowledge gaps in several domains, including (1) description of clinical evolution and clinical phenotypes, (2) early detection and predictive biomarker discovery, (3) mechanisms of disease through translational work, and (4) evaluation of novel treatments. High-risk patients are enrolled at a pre-diagnosis phase based on biomarker and clinical risk factors and followed over time through phases of chronic GVHD. Patients may also enter the longitudinal cohort at the time of chronic GVHD diagnosis, and if they develop a highly morbid manifestation, they are followed in that specific cohort category and may be enrolled on clinical trials. Longitudinal clinical data and serial tissue samples and specimens will be collected. In this Figure, lung disease is used as an example for the enrollment entry, interventions, endpoints, and data and samples to be collected. This schema can be easily expanded to reflect skin, GI, and other manifestations with relevant data collection and treatment agents. SOC indicates standard of care; f/u, follow-up; HRCT, high-resolution chest tomography; BAL, bronchoalveolar lavage; 6MWT, 6-minute walk test.

Figure 2.

Potential longitudinal trial design proposal for oGVHD. OSDI indicates ocular surface disease index; VAS, visual analog scale.