Doris M. Ponce, MD
Memorial Sloan Kettering Cancer Center, New York City, New York

Key Takeaways

  • Patients with chronic graft-versus-host disease (cGVHD) have several unmet treatment needs and gaps, including drugs to elicit better treatment response, treatment customization according to organ affection, and reduction in treatment toxicities.
  • While the US Food and Drug Administration (FDA) has approved 3 subclasses of drugs for the treatment of steroid-refractory cGVHD (SR-cGVHD), each has contraindications for certain subsets of patients and evidence suggests they may work better in combination, though further clinical trials are required to confirm this theory.
  • Currently, new treatment pathways are under investigation, including macrophage activation inhibition and immunomodulatory effect by costimulatory blockade of T cytotoxic T cells.

Current first-line therapy for cGVHD involves the use of corticosteroids, but many patients who undergo these therapies become refractory to steroids or dependent on steroids. The FDA’s recent approval of 3 drugs for the treatment of cGVHD has expanded treatment options for patients, but gaps remain in treatment response, treatment toxicity reduction, and other areas. Doris M. Ponce, MD, a hematologic oncologist, associate attending physician, and the program director of GVHD at Memorial Sloan Kettering Cancer Center in New York City, focuses on investigating novel therapies to prevent and treat cGVHD. In this article, Dr Ponce discusses how she treats cGVHD, how the recently approved drugs for the treatment of cGVHD can be integrated into treatment options for patients, and potential future developments for the treatment of cGVHD.

Chronic GVHD is a major cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT).1 What are some of the most pressing current gaps and unmet needs for the treatment of SR-cGVHD?

The upfront treatment of cGVHD includes the use of systemic corticosteroids, which are associated with several toxicities, and more than half of patients with cGVHD develop SR-cGVHD or steroid-dependent cGVHD (SD-cGVHD).2 Thus, upfront treatment optimization to avoid SR-cGVHD is a current gap in the treatment paradigm.
In patients with established cGVHD, the current unmet needs include:

  • Treatment response, as we most commonly only achieve a partial response and therefore symptoms of cGVHD are still present, so treatment optimization to achieve a deeper response is needed;
  • Treatment customization according to organ affection, as patients are currently treated similarly — eg, visceral vs skin involvement have different pathophysiology, but we currently lack individualized therapy;
  • Reduction in treatment toxicities;
  • Reduction in polypharmacy;
  • Improvement in quality of life; and
  • Early initiation of second-line therapy in patients with SR-cGVHD or SD-cGVHD.

Pretreatment evaluation of cGVHD includes assessing organ system involvement and documenting the extent and severity of disease. Can you describe the National Institutes of Health (NIH) criteria for diagnosing and scoring the severity of cGVHD?

The NIH criteria for diagnosing and scoring cGVHD includes a standardized approach for individual organ scoring and global overall cGVHD severity. There are currently 8 organs or sites evaluated in the scoring system: skin, mouth, eyes, genitalia, gastrointestinal (GI) tract, liver, lungs, and muscles/fascia/joints. Each organ or site is scored on a 4-point scale (0 to 3) based on symptoms, with 0 representing no involvement and 3 consistent with severe impairment. Mild cGVHD is classified as disease limited to 1 or 2 organs involved with no more than a score of 1 and without lung involvement. Moderate cGVHD describes 3 or more organs involved with no more than a score of 1, any organ having a score of 2, or lung score of 1. In the presence of a lung score of 2 or 3, or at least 1 organ with a score of 3, the patient is classified as having severe cGVHD.3

More than half of patients with cGVHD develop SR-cGVHD or SD-cGVHD. Thus, upfront treatment optimization to avoid SR-cGVHD is a current gap in the treatment paradigm.

There are several drugs that are now FDA-approved for SR-cGVHD. Can you discuss the differences in the drug subclass types and how treatment choices are guided?

There are currently 3 drugs that are FDA-approved for the treatment of SR-cGVHD or SD-cGVHD:
Ibrutinib is a selective and irreversible dual inhibitor of Bruton’s tyrosine kinase (BTK) protein and interleukin-2 inducible T cell kinase (ITK).4 The BTK inhibition prevents downstream activation of the B cell receptor (BCR) pathway and subsequently blocks cell growth, proliferation, and survival of B cells. ITK contributes to proximal T cell receptor signaling. Thus, ibrutinib inhibits B and T cell activation.5
Ruxolitinib is a potent and selective Janus kinase (JAK) 1 and 2 inhibitor.6 In cGVHD, the intracellular JAK 1/2 pathway leads to transcription of proinflammatory cytokines, mediation of inflammatory neutrophil migration, and upregulation of major histocompatibility complex (MHC) class II expression, which further promotes T cell expansion. Interferon gamma (IFN-γ) mediates alloreactive T cell infiltration into target organs. Overall, the inhibition of the JAK/signal transducers and activators of transcription (JAK/STAT) pathway prevents further inflammation and damage to target organs.7
Belumosudil is a selective rho-associated coiled-coil-containing protein kinase-2 (ROCK2) inhibitor.8 Activation of ROCK2 results in the upregulation of STAT3 phosphorylation and subsequent T-helper 17 (Th17)-specific transcription factors. Inhibition of ROCK2 allows for the resolution of immune dysregulation by restoring immune homeostasis. This results in a shift from proinflammatory Th17 cells to increased regulatory T cells (Tregs). Additionally, activation of ROCK2 results in the polymerization of globular actin to fibrous actin (F-actin) via profibrotic mediators. Inhibition of ROCK2 by belumosudil abrogates this profibrotic process in patients with cGVHD.9
Treatment options are guided by several factors such as line of therapy; if they are for second-line, ibrutinib or ruxolitinib are indicated, whereas belumosudil is approved after second-line therapy. Additionally, comorbidities and potential drug toxicities can guide treatment selection. As an example, in the presence of cardiac arrhythmia or risk of bleeding, ibrutinib should be avoided, whereas in the presence of profound cytopenia or cytomegalovirus reactivation, ruxolitinib should not be an initial drug of choice; if we see severe GI dyspepsia, belumosudil may exacerbate these symptoms.
In the future, treatment selection based on organ involvement or individual needs may be a consideration. However, the latter requires further investigation.

What treatment goals do you discuss with patients with SR-cGVHD? Are discussions centered on sustained reduction or complete elimination of symptom burden, disability, and disease activity?

My initial discussions are centered on treatment goals and expectations. The initial goal is to achieve symptom stability without further progression, followed by gradual improvement. Because most of the patients who respond to cGVHD therapy will achieve a partial response, the possibility of partial vs complete resolution of symptoms needs to be part of the conversation. We discuss the length of therapy, potential side effects, and quality of life issues. I aim to reduce the symptoms burden and, when possible, place an emphasis on topical therapy to enhance treatment response. We discuss the rehabilitation process and mental health considerations as well.

Can you discuss emerging research evaluating new treatment approaches to SR-cGVHD, which may include combined treatment approaches?

The current FDA-approved drugs for the treatment of SR-cGVHD have only been tested in combination with corticosteroids. However, it is possible that combining these drugs with each other or with other treatments that have potential therapeutic effects, such as pirfenidone, may enhance treatment response. There is interest in the blood and marrow transplant field for a combined treatment approach, and future clinical trials should consider evaluating the safety and efficacy of a combined regimen. Until then, rigorous evaluation under a clinical trial is needed to recommend any treatment combination. Other pathways under investigation include macrophage activation inhibition by the drug axatilimab,10 and immunomodulatory effect by costimulatory blockade of T cytotoxic T cells by abatacept.11 These drugs, if proven to be safe and effective, may provide additional therapeutic options for patients who have failed current approved therapies in cGVHD. Overall, cGVHD involves a complex pathophysiology with tissue damage, T cell and B cell activation, immune response dysregulation, impaired tolerance, and aberrant tissue repair.

Treatment goals for SR-cGVHD
Treatment goals for SR-cGVHD include symptom stability, gradual improvement, partial resolution, and quality of life.

How do you determine when withdrawal of therapy can be done while limiting recurrence of cGvHD?

The tapering of immunosuppression therapy can vary among centers. The determinants include cGVHD treatment response and drug-related toxicities. The initial step is to decrease the immunosuppressant associated with major toxicities, such as corticosteroids. Once this is achieved and cGVHD signs and symptoms remain quiescent, other immunosuppressants can be tapered. An overall approach is to taper the noncorticosteroid drugs after 6 months of therapy in patients who achieved a complete or partial response and have discontinued corticosteroids for at least 8 weeks. If a patient has a cGVHD flare, the taper should be held and the drug dose increased for symptom management. It is common to require immunosuppressant dose adjustment in the process of tapering. The important aspect to remember is the gradual approach with close clinical observation.
This Q&A was edited for clarity and length.


Doris M. Ponce, MD, reported affiliations with CareDx, Evive Biotechnology (Shanghai) Ltd, Gerson Lehrman Group, Ceramedix, Guidepoint Global Advisors, Incyte Corporation, and Kadmon-Sanofi Holdings, Inc.


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8. RezurockTM. Prescribing information. Kadmon Pharmaceuticals, LLC; 2021. Accessed April 18, 2023.

9. Zanin-Zhorov A, Blazar BR. ROCK2, a critical regulator of immune modulation and fibrosis has emerged as a therapeutic target in chronic graft-versus-host disease. Clin Immunol. 2021;230:108823. doi:10.1016/j.clim.2021.108823
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Reviewed June 2023