Clinical Case of the Month – Sclerotic cGvHD: What Next?

Title: Selecting Next-Line Therapy for Persistent, Function-Limiting Sclerotic Chronic Graft-versus-Host Disease

Submitted by: Sergio Rodriguez Rodriguez, MD, Dennis Dong Hwan Kim, MD, PhD

Physician expert perspective: Sergio Rodriguez Rodriguez, Clinical Fellow; Dennis Dong Hwan Kim, Staff Hematologist, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada.

Clinical Case Summary

A 68-year-old woman with chronic myelomonocytic leukemia underwent matched-related donor allogeneic hematopoietic cell transplantation in February 2024, with post-transplant cyclophosphamide, mycophenolate mofetil, and cyclosporine as graft-versus-host disease (GvHD) prophylaxis; she achieved a sustained complete remission and full donor chimerism. Chronic GvHD, assessed as moderate-to-severe at diagnosis, complicated her post-transplant course; manifestations involved the liver, oral mucosa, lungs, and skin, including progressive fibrotic/sclerotic skin manifestations. 

Hepatic involvement initially responded to corticosteroids, but skin sclerosis and impaired range of motion persisted. Subsequent treatment included prednisone, ruxolitinib, extracorporeal photopheresis (ECP), and belumosudil; dupilumab was prescribed for eczema. Oral and hepatic involvement normalized, and pulmonary function remained stable.

By mid-2026, after more than 30 ECP sessions and approximately 6 months of belumosudil (including 1 month of combination therapy with ruxolitinib, after which ruxolitinib was discontinued due to drug-coverage limitations), sclerotic skin disease remained functionally limiting, without meaningful improvement. This raised the question of whether additional systemic treatment is appropriate for persistent, function-limiting sclerosis despite control of other manifestations. At the last assessment before therapy modification, the NIH global cGvHD was moderate-to-severe, with persistent facial and arm skin tightness, and a photographic range of motion (P-ROM) of 22/25 (elbow and shoulder with limitation).

Question

Given the persistence of fibrotic manifestations despite multiple therapies, which of the following is an evidence-supported next-line systemic treatment option for this patient?

1. Increase prednisone to 0.5 mg/kg/day
2. Continue belumosudil and ECP for up to nine months of belumosudil treatment
3. Initiate axatilimab as the next-line systemic treatment
4. Discontinue all cGvHD-directed treatment as the cGvHD is stable
5. Administer donor lymphocyte infusion

Expert Perspective

This case illustrates an inadequate response of sclerotic manifestations rather than uniform failure of all previous treatment: oral and hepatic disease improved, while skin involvement remained disabling. Persistent limitations may reflect ongoing cGvHD activity, residual tissue damage, or both. Before escalation, assessment should document serial NIH skin and joint/fascia scores, P-ROM, daily-activity limitations, and symptom burden. Stable sclerosis alone does not establish treatment failure, and conventional skin response measures have limited sensitivity to clinically meaningful change [1]. Clinical decisions should consider how much disability is plausibly modifiable, rather than relying on the number of prior treatment lines alone.

Among the listed choices, axatilimab is an evidence-supported next-line option when further treatment is deemed necessary. It blocks colony-stimulating factor-1 receptor (CSF-1R), targeting the monocyte/macrophage biology implicated in cGvHD inflammation and fibrosis [2]. This differs from JAK1/2 inhibition with ruxolitinib and ROCK2 inhibition with belumosudil; however, belumosudil has also been reported to have immunomodulatory and antifibrotic effects [3]. 

The AGAVE-201 trial randomized 241 previously treated patients across three axatilimab doses [4]. In the FDA efficacy analysis of 79 patients receiving 0.3 mg/kg intravenously (IV) every two weeks, 59 (75%) achieved a response through cycle 7 day 1, all of them partial. An exploratory analysis found a decrease of at least 7 points in the modified Lee Symptom Scale in 56% [5]. Responses were observed after previous ruxolitinib or belumosudil exposure. 

Organ-specific findings require careful interpretation. An exploratory AGAVE-201 analysis reported improvement in sclerotic skin features in 25% of evaluable patients receiving 0.3 mg/kg every two weeks, whereas 73% had at least one-point improvement in the patient-reported thickened-skin item [5,6]. The median time to first skin response was 3.7 months in an exploratory organ-specific analysis [6], compared with 1.5 months for first overall response in the FDA analysis [5]. Based on the available information, symptom improvement should not be equated with objective reversal of sclerosis. Durability endpoints also differ. The FDA reported a median response duration of 1.9 months, counting progression, death, or new systemic treatment as events. Separately, an estimated 60% of responders had no death or new systemic treatment for at least 12 months after response [5]. 

Regarding the alternative options, continuing belumosudil and ECP (B) is not intrinsically inappropriate: the ROCKstar trial documented some responses after six to twelve months of treatment [3]. The decision to introduce a new therapy was guided by persistent functional limitation and the patient’s treatment priorities. Increasing the prednisone dose (A) would add further exposure despite the inadequate improvement in sclerosis, without a new inflammatory flare to justify re-escalation. Treatment withdrawal (D) should not be based on disease stability alone, particularly when function-limiting manifestations persist. Donor lymphocyte infusion (E) is not a cGvHD treatment and carries a risk of inducing GvHD [7].

Axatilimab was started at 0.3 mg/kg IV every two weeks, infused over 30 minutes. The US prescribing information specifies a maximum dose of 35 mg per infusion [8]. Belumosudil 200 mg daily and prednisone 5 mg daily were continued. The team monitored safety concerns, including enzyme elevations, infections, edema, and infusion-related reactions. We assessed aspartate aminotransferase and alanine aminotransferase, alkaline phosphatase, creatine phosphokinase, amylase, and lipase before treatment and every two weeks. We checked blood counts before each treatment and monitored for infection at every clinical assessment. Dose modifications should follow the applicable recommendations [8].

Axatilimab was initiated in July 2026. At the assessment before cycle 2, day 15, the patient reported improved skin tightness. Other organ manifestations remained stable, and no new clinical concerns were noted. This represents an early patient-reported improvement; longer follow-up and serial objective assessments are needed to evaluate changes in sclerosis and function. The treatment goal remains meaningful improvement in symptoms and function, while maintaining control of other organs and limiting toxicity.

Correct Answer  –  C

References

1. Markova A, Lee SJ, Modi B, Baumrin E, Rosenstein RK, Tkaczyk ER, Lehman JS, Inamoto Y, Carpenter PA, Schultz KR, Pidala JA, Martin P, Pusic I, Goklemez S, Stockmann C, Pinal-Fernandez I, Paczesny S, Harris A, Ponce DM, Holtzman NG, Jurdi NE, Pavletic SZ, Cowen EW. Toward Better Response Assessment of Cutaneous Chronic Graft-Versus-Host Disease: A Report from the National Institutes of Health Consensus Project Task Force. Transplant Cell Ther. 2026 Jun;32(6):644.e1-644.e19. doi: 10.1016/j.jtct.2026.01.009. Epub 2026 Jan 13. PMID: 41539488; PMCID: PMC12858292.
2. Kitko CL, Arora M, DeFilipp Z, Zaid MA, Di Stasi A, Radojcic V, Betts CB, Coussens LM, Meyers ML, Qamoos H, Ordentlich P, Kumar V, Quaranto C, Schmitt A, Gu Y, Blazar BR, Wang TP, Salhotra A, Pusic I, Jagasia M, Lee SJ. Axatilimab for Chronic Graft-Versus-Host Disease After Failure of at Least Two Prior Systemic Therapies: Results of a Phase I/II Study. J Clin Oncol. 2023 Apr 1;41(10):1864-1875. doi: 10.1200/JCO.22.00958. Epub 2022 Dec 2. PMID: 36459673; PMCID: PMC10082302.
3. Cutler C, Lee SJ, Arai S, Rotta M, Zoghi B, Lazaryan A, Ramakrishnan A, DeFilipp Z, Salhotra A, Chai-Ho W, Mehta R, Wang T, Arora M, Pusic I, Saad A, Shah NN, Abhyankar S, Bachier C, Galvin J, Im A, Langston A, Liesveld J, Juckett M, Logan A, Schachter L, Alavi A, Howard D, Waksal HW, Ryan J, Eiznhamer D, Aggarwal SK, Ieyoub J, Schueller O, Green L, Yang Z, Krenz H, Jagasia M, Blazar BR, Pavletic S. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study. Blood. 2021 Dec 2;138(22):2278-2289. doi: 10.1182/blood.2021012021. Erratum in: Blood. 2022 Mar 17;139(11):1772. doi: 10.1182/blood.2022015598. PMID: 34265047; PMCID: PMC8641099.
4. Wolff D, Cutler C, Lee SJ, Pusic I, Bittencourt H, White J, Hamadani M, Arai S, Salhotra A, Perez-Simon JA, Alousi A, Choe H, Kwon M, Bermúdez A, Kim I, Socié G, Chhabra S, Radojcic V, O'Toole T, Tian C, Ordentlich P, DeFilipp Z, Kitko CL; AGAVE-201 Investigators. Axatilimab in Recurrent or Refractory Chronic Graft-versus-Host Disease. N Engl J Med. 2024 Sep 19;391(11):1002-1014. doi: 10.1056/NEJMoa2401537. PMID: 39292927.
5. Le RQ, Godder K, Wang J, Collazo JS, Konicki R, Choe M, Feng M, Przepiorka D, Vallejo J, Shah A, Liu J, Gehrke BJ, Wilson W, Siegel A, Wu Y, Kuo CY, Ray M, Pazdur R, Theoret MR, de Claro RA. FDA Approval Summary: Axatilimab for Adult and Pediatric Patients Weighing at Least 40 Kilograms with Chronic GVHD after Two Prior Lines of Systemic Therapy. Clin Cancer Res. 2025 Sep 2;31(17):3607-3612. doi: 10.1158/1078-0432.CCR-25-0896. PMID: 40577088; PMCID: PMC12247180.
6. Kitko CL, Cutler C, DeFilipp Z, et al. Axatilimab for Chronic Graft-Versus-Host Disease: Responses in Fibrosis-Dominant Organs in AGAVE-201. Poster P1321 presented at the European Hematology Association 2024 Hybrid Congress; 13-16 June 2024; Madrid, Spain. Exploratory conference analysis.
7. Koster EAS, von dem Borne PA, van Balen P, et al. Risk factors for graft-versus-host-disease after donor lymphocyte infusion following T-cell depleted allogeneic stem cell transplantation. Front Immunol. 2024;15:1335341. doi:10.3389/fimmu.2024.1335341.
8. Incyte Corporation. NIKTIMVO (axatilimab-csfr) injection: US prescribing information. Wilmington, DE: Incyte Corporation. Revised June 2026. Accessed 8 September 2026.
   

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