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You Make the Call: How would you treat a patient with end-stage lung cGVHD and worsening hypoxia?

March 28, 2023

April 2023

Gary J. Schiller, MD

Gary J. Schiller, MD
Professor of Medicine,
Director, Hematological Malignancy/Stem Cell Transplant Program
Department of Medicine
David Geffen School of Medicine at UCLA




A patient of mine underwent a matched unrelated donor allogeneic hematopoietic cell transplant for B-cell acute lymphoblastic leukemia about 10 years ago and has a long history of chronic graft-versus-host disease (cGVHD) of the lung. His treatment regimen for the past year has been tacrolimus, ruxolitinib, and belumosudil, along with FAM (inhaled fluticasone, azithromycin, and montelukast). At this point, he has end-stage lung cGVHD, is on 3 L of oxygen by nasal cannula, and is homebound.

In the past he was treated with corticosteroids, ibrutinib, and etanercept. He was also treated with extracorporeal photopheresis for a long time, but this was no longer feasible due to insurance coverage and the distance from his home to the clinic. Recently, his lung GVHD has worsened in terms of hypoxia, and he has declined hospice care. My questions are:

  • Is there a role of the combined use of ruxolitinib and belumosudil?
  • Is there a suggestion for a different treatment regimen for lung cGVHD?
  • Is there a role for lung transplant with severe lung cGVHD?


This question is one that we confront periodically. Although steroids are used as first-line agents in treating the immune dysregulation of cGVHD, complete response is uncommon. This clinical lack of response may have to do with the mechanisms that sustain cGVHD and which include both T-cell and B-cell activation and cytokine-mediated chronic inflammation.1 Ruxolitinib is specifically approved for the treatment of steroid-refractory acute GVHD, so it is not surprising that JAK pathway inhibition is utilized in steroid-refractory cGVHD, for which ibrutinib has regulatory approval as well. The label for ruxolitinib in the setting of cGVHD is for treatment after lack of response to one or two lines of systemic therapy. Therapies directed at B-cell activation have gained some currency in cGVHD.2 Rituximab has some efficacy in steroid-refractory cGVHD, where proteasome inhibitors have activity as well.

At the time belumosudil was studied, concomitant use of other drugs was permitted, and randomization was only stratified by the severity of cGVHD and prior exposure to ibrutinib, not ruxolitinib.3 The drug is attractive since it is an oral inhibitor of ROCK2, a kinase that is operative in the adaptive immune response that leads to fibrosis and, in the setting of cGVHD, abnormal tissue repair (fibrosis). There were some patients who previously received ruxolitinib in the phase II registration trial, but they constituted less than 30% of the subjects. In the published table that accompanies the article, there was one patient on concomitant ruxolitinib and belumosudil, one patient on concomitant rituximab and belumosudil, and two patients on imatinib and study drug. Of course, since approval, we have had patients on both, along with stable corticosteroids, as was required in the study. I do not know whether concurrent use of ruxolitinib affects metabolism or mechanism of action with belumosudil; the authors wrote that they permitted some concurrent immunosuppressive medications because they did not expect drug-drug interactions, but ruxolitinib was not among them. 

This patient seems to have chronic pulmonary scarring because of cGVHD, and the only therapy that might be considered useful in this late-stage fibrosis is lung transplantation. It is hard to imagine the process being reversible given its long history. I would recommend exploring whether this patient is a candidate for orthotopic lung transplant.4


  1. Shapiro RM, Antin JH. Therapeutic options for steroid-refractory acute and chronic GVHD: an evolving landscape. Expert Rev Hematol. 2020;13(5):519-532.
  2. Martini DJ, Chen YB, DeFilipp Z. Recent FDA approvals in the treatment of graft-versus-host disease. Oncologist. 2022;27(8):685-693.
  3. Cutler C, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study. Blood. 2021;138(22):2278-2289.
  4. Vogl UM, Nagayama K, Bojic M, et al. Lung transplantation for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation: a single-center experience. Transplantation. 2013;95(4):623-628.


A 45-year-old female patient who is pregnant has a history of catheter-related upper extremity deep vein thrombosis (DVT) during a hospitalization for COVID-19 in 2021. As of note, she was taking estrogen at the time. She also has a history of three first-trimester miscarriages, as well as a miscarriage of twin sons. She has a family history that is positive for venous thromboembolism, with a maternal aunt who experienced a DVT in her 50s. She is heterozygous for prothrombin gene mutation. Hereditary thrombophilia testing and testing for antiphospholipid syndrome have been done, both of which were negative.

The patient is currently 11 weeks pregnant after in vitro fertilization and implantation. She has been on estrogen supplementation for pregnancy support, but this will be ending within a few weeks. She has also been taking enoxaparin 40 mg SQ daily. Once she is off estrogen, would you recommend that she continue enoxaparin up to the time of delivery and then for six weeks postpartum, or discontinue it at that time and restart it after delivery through six weeks postpartum?

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Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.


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