Article

Need for More Research Into Chronic GVHD After Allogeneic HSCT Highlighted in New Review

Author(s):

Although the understanding of chronic graft-versus-host disease (GVHD) has improved in recent years, more work is needed to facilitate personalized treatments for patients after hematopoietic stem cell transplantation (HSCT).

Although chronic graft-versus-host disease (cGVHD) is still the leading cause of nonrelapse mortality and morbidity after allogeneic hematopoietic stem cell transplantation (allo-HSCT), the understanding of cGVHD and treatment options have improved in recent years. A review published in Blood Advances summarizes the current treatment landscape and stresses the need for additional research into personalized therapies for cGVHD.

GVHD is a significant complication of allo-HSCT and can be either acute or chronic. Steroids are the typical course of treatment, but patients who do not respond to steroids usually face a poor prognosis.

“Clinically, variability in organ involvement is compounded by a spectrum of clinical subtypes and variable posttransplant timing, which adds to the complexity of discerning underlying mechanisms and devising strategies to overcome cGVHD,” the authors wrote. “Taken together, these studies support the conclusion that the biology of cGVHD is complex and likely to be heterogenous.”

The review includes current and potential treatments for cGVHD, as well as possible approaches to research and development of future treatments. Various pathways involved in autoimmune conditions have provided potential therapeutic targets.

The first agent to earn FDA approval for cGVHD was the Bruton tyrosine kinase inhibitor ibrutinib, which was initially approved for B-cell malignancies but showed efficacy in steroid-refractory GVHD. However, clinical outcomes have been fairly modest in the clinical setting. Belumosudi, a selective ROCK2 inhibitor, and ruxolitinib, a JAK/STAT inhibitor, are also approved for steroid-refractory cGVHD.

In addition to the approved agents, several agents with various mechanisms have shown promise in preclinical research and are being evaluated for cGVHD. These include B-cell–targeted strategies such as spleen-associated tyrosine kinase inhibition, phosphoinositide-3 kinase delta inhibition, and B-cell­–activating factor inhibition.

Anti–colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody (mAb) therapy has also shown promise in cGVHD, and the CSF-1R mAb axatilimab is one agent currently in pivotal clinical trials after showing promising results in earlier research. Low-dose treatment with the cytokine signaling molecule interleukin-2 and/or adoptive transfer of ex vivo expanded regulatory T cells (Tregs) have also shown promise in improving the Treg deficiency that typically accompanies cGVHD.

Taking steps at the time of allo-HSCT may also help reduce the incidence of cGVHD, the authors wrote. Early immune modulations have been shown to have an impact on the onset of cGVHD that occurs months after allo-HSCT. T-cell depletion in vivo has been shown to reduce cGVHD incidence, as has ex vivo naïve T-cell depletion. In rodent models, posttransplant cyclophosphamide as prophylaxis reduced both acute and chronic GVHD, and human trials confirmed the efficacy of this approach. However, although cyclophosphamide prophylaxis is now widely used, its mechanism of action is not entirely understood.

There are ongoing clinical and clinical trials to identify therapy targets and prevention strategies for cGVHD. The review authors emphasize the importance of early diagnosis of the condition, highlighting that clinical findings may not always fit snugly into a particular category or phase of cGVHD due to its heterogeneous nature.

“While laboratory, imaging, cellular, molecular, and metabolic data are being gathered, clinical annotation and scoring will be essential to categorize and diagnose GVHD not simply by severity, but by biological subtypes,” the authors wrote. “With such data, rational therapy selection can yield the highest chance of efficacy for the individual patient.”

Identifying diagnostic and risk-assignment biomarkers for cGVHD should also be a key initiative, and biomarker panels for both acute and chronic GVHD are being tested, they noted.

Clinical trials encompassing a wider scope of subgroups based on transplant types and clinical presentations are needed to provide further insight into the mechanisms of cGVHD, and the latest technology should be implemented to assess samples in both preclinical and clinical studies, the authors added.

Overall, they concluded that cGVHD warrants further research with the latest technological tools to facilitate the development of effective, well-tolerated therapies for patients. Collaboration between preclinical and clinical researchers will be a key aspect of faster progress.

“There is a gap between clinical manifestations of cGVHD and understanding of biological and molecular features of disease. Closing this gap would allow biological stratification of disease, precise assessment of treatment responses, and will ultimately lead to the development of personalized therapies guided by detection of the active pathways in cGVHD initiation, maintenance, and progression,” the authors wrote.

Reference

Buxbaum NP, Socié G, Hill GR, et al. Chronic GvHD NIH Consensus Project Biology Task Force: evolving path to personalized treatment of chronic GvHD. Blood Adv. Published online November 2, 2022. doi:10.1182/bloodadvances.2022007611

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