BLOG: Management of chronic GVHD evolves from challenges to collaborative solutions
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Chronic graft-versus-host disease is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation.
This is due both to the chronic GVHD itself and the immunosuppressive agents used for its treatment.
This condition is created by us performing the transplant procedure, and in persons who are cured of their malignancy. Therefore, we have a responsibility to our patients to find better treatments.
Steroids are still considered first-line therapy for chronic GVHD. However, only 40% to 50% of patients with chronic GVHD respond adequately to first-line treatment. The rest become steroid-refractory or steroid-dependent, requiring further lines of therapy.
There has been a remarkable development in the field of chronic GVHD in terms of better understanding of pathophysiology and development of novel treatments.
However, the selection of immunosuppressive agent for steroid-refractory chronic GVHD still is largely based on institutional or physician preference, prior treatments, toxicity profile, drug interactions and convenience.
Even though there are three FDA-approved agents for steroid-refractory chronic GVHD — and many others sporadically used — there is insufficient evidence to recommend one agent over another. We still lack knowledge and experience to fully understand whether one agent is better than other for specific chronic GVHD manifestations, in what order to use them, how to switch between them, what should be a taper, or whether we can effectively combine them to allow for lower steroid dose and potentially lowering the dose of each agent.
The answer to all of these questions can be summed up in two words: clinical trials!
The future of chronic GVHD advancement will come from translational science with the identification of biomarker-based immune profiles and development of more personalized, biologically-based treatments that would be less broadly immunosuppressive, more immunomodulatory and potentially organ-specific.
Eventually, clinical trials comparing and/or combining agents that demonstrate activity in single-arm studies will be needed.
When designing such trials, the potential benefit of the agent or a combined therapy will need to outweigh the risk for adverse events and the burden of (yet another) “novel” therapy. In addition, these trials will need to be rigorously designed, preferably blinded, and multicenter in nature.
Our recent experience with large trials that resulted in the FDA approval of three novel agents demonstrate the feasibility of multi-institutional collaboration in chronic GVHD research.
However, I believe the ultimate answer to the question about management of persistent and recurrent chronic GVHD is that we don’t allow it to develop.
Studies already are being initiated incorporating these new agents in the upfront setting for newly diagnosed chronic GVHD and as a steroid-sparing approach. Further, additional research is needed to improve our prophylactic interventions and pre-emptive therapies of early, evolving chronic GVHD.
To address these challenges, the third NIH Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD was initiated in 2019/2020. Four working groups concentrate on etiology and prevention, pre-emptive approaches, systemic treatments and highly morbid forms of chronic GVHD.
In addition, the consensus project underlined the need for effective partnership and collaboration among all involved stakeholders, including patients/patient advocates, providers, industry and governmental agencies.
References:
- Hamilton BK, et al. Hematology Am Soc Hematol Educ Program. 2021;doi:10.1182/hematology.2021000301.
- Pavletic SZ, et al. Transplant Cell Ther. 2021;doi:10.1016/j.jtct.2021.02.034.
- Wolff D, et al. Bone Marrow Transplant. 2021;doi:10.1038/s41409-021-01389-5.
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