Safah Explores Disease Features and Treatment Options for Chronic GVHD

Case-Based Roundtable Meetings SpotlightCase-Based Roundtable Meetings Spotlight: December 2, 2022
Pages: 36

During a Targeted Oncology case-based roundtable event, Hana Safah, MD, discussed chronic graft-vs-host disease in terms of diagnosis, phases, risk assessment, and treatment options.

case summary
Hana Safah, MD

Professor of Clinical Medicine

Section of Hematology and Medical Oncology

Director, Stem Cell Transplantation Program and the Leukemia and Lymphoma Programs

Tulane University School of Medicine

New Orleans, LA

Hana Safah, MD

Professor of Clinical Medicine

Section of Hematology and Medical Oncology

Director, Stem Cell Transplantation Program and the Leukemia and Lymphoma Programs

Tulane University School of Medicine

New Orleans, LA

Targeted OncologyTM: Can you discuss some of the features of chronic GVHD regarding transplant source, organ involvement, and scoring?

SAFAH: We know that…with bone marrow transplant [BMT], the patient might suffer from prolonged time to engraftment and hospitalization. At this point, I’m presenting the stem cell source and the risk of what type of GVHD to expect, and the burden of chronic GVHD on the patients.1 Also, from a similar study, when we look at chronic GVHD across organs, we see that the incidence is [higher] with the PBSCT compared with the BMT, in all organs involved.2

Now, when we do chronic GVHD assessment, we use other tools, and here we look at specific signs and symptoms that are related to [each] organ [system].2 In the skin, we look for tightness, we look for pruritus, we look for discoloration. We look at sweat glands and ability to sweat. For mucocutaneous, we look for dryness in the mouth and the eyes. Also, we look for lesions in the mouth: mucositis-like ulcers, sores. Weight loss is a very important sign when it comes to evaluating chronic GVHD.

In 2014, the National Institutes of Health [NIH] standardized the way we do scoring for chronic GVHD.3 What we do now when we evaluate patients for chronic GVHD is use the NIH Clinical Scoring System where we score the organs on a 4-point scale, 0 to 3. And what is included here that was not included in acute GVHD is the performance status. It’s very important to measure clinical performance status, and we report that using the ECOG or the Karnofsky [performance statuses], because chronic GVHD and the symptom burden related to [it] can affect performance status, physiology, and functionality.

When we do the scoring, we score them as mild, moderate, and severe, and it’s mostly dependent on the number of organs involved.2 So, if it’s 1 to 2, it’s mild, especially if there is no lung [involvement]. However, between the moderate and severe, it’s usually the number of organs— 3 or more—and the lung score. If it’s lung score 1, it’s moderate. If it is 2 or 3, it becomes severe.

Can you discuss the pathophysiology of the different phases of chronic GVHD?

When we look at chronic GVHD, it’s very important to remember it goes through phases.4 I think of it as 3 phases.

The early inflammatory phase starts when we give the patient the high-dose chemotherapy, with or without radiation, and that results in tissue injury and the release of the microbial component. Tissue injury, along with the release of the microbial components in the gut, results in activation of the host antigen-presenting cells. These activated cells, along with release of the inflammatory cytokines, result in the activation of the donor T cells.

Then we move into phase 2, where we have the thymic injury, and that’s why we probably have more GVHD in older patients compared with younger patients.4 So, with the thymic injury we end up with the selection of donor T cells that have an autoreactivity and alloreactivity. At the same time, we have loss of peripheral and central tolerance with decrease in the Tregs [regulatory T cells] as well as Bregs [regulatory B cells].

At the same time, when we look at the lymph nodes, the donor T follicular helper cells start promoting the expansion of the B cells.4 These B cells usually are aberrant B cells that are producing antihost antibodies or immunogenicity, resulting in aberrant plasma cells that are releasing these antibodies that are causing more inflammation—a form of auto[antibodies] and alloantibodies that are leading to more inflammation and activation of the macrophage.

[This] leads to the third phase where…as part of what we call tissue repair in severe inflammation, we end up with fibrosis and scarring.4 By understanding those phases, and what the players are in these phases, we’re trying to come up with treatments that can target every player—the ones that are causing the pathology and the disease.

Can you review some of the treatment options for chronic GVHD?

Because of [our improved understanding of the pathophysiology], we now have more effective and less toxic therapy. For instance, looking at ibrutinib [Imbruvica], which was listed on the NCCN [National Comprehensive Cancer Network] options: ibrutinib is a BTK [Bruton tyrosine kinase] inhibitor, and can affect the B cells as well as the T cells.5,6 But, looking at belumosudil [Rezurock], as a ROCK2 [rho-associated coiled-coil–containing protein kinase-2] inhibitor, it inhibits the STAT[signal transducer and activator of transcription]3 and STAT5 pathways.

Looking at ruxolitinib [Jakafi] as a JAK[Janus kinase]1/ JAK2 inhibitor, it also inhibits the STAT1/3 pathway that is related. All of them do have an effect on the treatment of chronic GVHD, whether decreasing the cell proliferation, cell survival—in all of them—and decreasing the cytokine production. Whereas with ibrutinib, there is a decrease in the antibody production, because of its effect on the B cells. And with the belumosudil as well as ruxolitinib, there is also expansion of Treg with the decrease in the T helper 17 cells and activation and proliferation.

When we look at the available treatments for chronic GVHD, the first-line treatment approach is usually, when we have a mild case of chronic GVHD, supportive treatment and topical treatment, whether it’s topical steroids or using a specific type of dexamethasone [Decadron] eye rinse, or dexamethasone mouth rinse for mild dryness of the mouth. However, when we start treating moderate to severe systemic disease, this is when we need systemic treatment. And the first-line therapy for systemic disease is steroids.7,8

This is when we’re looking at the NIH criteria of having more than 3-organ involvement, or more than 1 organ with a moderate score, or when we have lung involvement, or any organ with severe 3 score.3 Always, when we start treatment, we wait for response. It is very important to monitor for infection while on steroid treatment. It’s best to start them on prophylaxis, whether covering for viral, bacterial, or fungal infection, especially when they’re on high-dose steroids, and continue supportive care.

What we’re missing in GVHD in general, whether it’s acute or chronic, and what we’re missing very much in chronic GVHD are studies that will tell us what the best supportive care for these patients would be. In fact, we don’t have very good guidelines in the treatment of chronic GVHD. We speak of supportive care: doing stretching exercises for the joints, talking to the dietitian to improve weight loss and increase protein intake. [In addition, there is] the use of antidiarrheals and vaginal creams, working with an obstetrician-gynecologist. Again, it would be nice to have more evidence-based guidelines on how to do the supportive care for these patients.

We see that for chronic GVHD we do have several options. Some of them are approved by the FDA, especially ruxolitinib, which carries the category 1 recommendation from the NCCN.9 [Category 2A recommendations include] belumosudil as well as ibrutinib.10,11

poll: GVHD treatment

Can you discuss the evidence for ibrutinib in chronic GVHD?

Looking at ibrutinib, it was [initially investigated in] a phase 1b/2, single-arm trial [NCT02195869].12,13 The trial was completed and led to the initial approval. It included 42 patients. When we look at those patients, 85% had more than 2 organs [with involvement] at baseline, with involvement of mucocutaneous being most of them. There were some who had gastrointestinal [GI] involvement at 36%; again, very few [with] liver [or] lung involvement. These patients had to fail at least 3 lines of prior regimens. Overall, the outcome was based on overall response rate [ORR] and there was a 69% best ORR at a median of 26-month follow-up; 69% sustained more than 20 weeks of that response; 11 of 18 of those who suffered from sclerosis did respond to the treatment; 64% tapered prednisone to less than 0.15 mg/kg per day during the study. This was a very important point when we evaluate a new available therapy, so that it helps us taper steroids as soon as possible.

Looking at ibrutinib on follow-up studies, in the iNTEGRATE study [NCT02959944], they had 193 patients.14 This time they used ibrutinib up front, and the arms were ibrutinib plus prednisone vs prednisone plus placebo. The primary analysis: at median follow-up of 25 months, the 48-week response rate was 41% vs 37% [P = .54], the duration of response [DOR] was 16 [months] vs 10 months [P = .12], and there was no significant difference in the event-free survival for the up-front therapy [P = .1].

However, looking at the iMAGINE trial [NCT03790332], they included 59 patients and they included pediatric [patients], [aged] 1 to 22 years.15 It was a single-arm trial where they included patients who had failed at least 1 line of therapy, and the treatment was ibrutinib 240 mg/m2. The primary analysis was at median follow-up of 20 months. They had a 24-week ORR of 44%, and 61% sustained response for more than 20 weeks.

Again, when you look at the response curve, patients who were treatment naive did very well compared [with] patients with relapsed/ refractory. Looking at the complete response [CR] rate, it was, in all patients, 8% compared with 69% partial response [PR].

What led to the approval of ruxolitinib for chronic GVHD?

The FDA approved the use of ruxolitinib for chronic GVHD on September 22, 2021, after failure of 1 or 2 lines of systemic therapy, in adults and pediatric patients who are 12 years and older.9

The use of ruxolitinib in chronic GVHD was based on a phase 3 REACH3 trial [NCT03112603].16 It was an open-label, randomized, multicenter trial. They recruited 329 patients who had undergone allogeneic stem cell transplantation and had steroid-refractory or steroid-dependent chronic GVHD. Patients received ruxolitinib at 10 mg twice daily on the ruxolitinib arm vs the investigator’s choice of therapy. They followed all patients for overall response at week 24.

These are the characteristics of the patients who were included.16 Fifty percent received unrelated [donor] stem cell transplantation; 45% had failed steroids only; 40% had failed steroids plus calcineurin inhibitor; and 15% failed steroids, calcineurin inhibitors, and other. When we look at the investigator’s treatment of choice, including ECP [extracorporeal photopheresis], methotrexate, MMF [mycophenolate mofetil (CellCept)], sirolimus [Rapamune], infliximab [Remicade], rituximab [Rituxan]—whatever we use in our practice— including ibrutinib and imatinib [Gleevec]. The efficacy data revealed that the ORR at week 24 was 49.7% of the patients receiving ruxolitinib vs 25.6% in the patients receiving the treatment of choice [Figure 116], and there was a significant difference, clinically significant [odds ratio, 2.99; 95% CI, 1.86-4.80; P < .001]. Ruxolitinib showed superior efficacy over control but led to a higher incidence of grade 3 thrombocytopenia and anemia.

ORR at 24 weeks-REACH3

At week 24…the CR rate was almost double in the ruxolitinib compared [with] the control arm.16 Looking at week 24 symptom improvement, it was 24.2% with ruxolitinib vs 11.0% in the control arm. Looking at best ORR at any time during the 24 weeks, you see it was 76.4% in the ruxolitinib arm vs 60.4% in the control arm, with a better CR rate in the ruxolitinib arm [Figure 216]. Keep in mind that there was a crossover allowed. Sixty-one patients who crossed over from the control arm to the ruxolitinib arm also had a response, and the best ORR was similar to what we see in the overall intent-to-treat population, 78.7% at data cutoff, 4 CRs plus 44 PRs, consistent with a best overall response for ruxolitinib in the randomized population.

Looking at failure-free survival, we see that again, from the Kaplan-Meier curve, the median duration was more than 18.6 months in the ruxolitinib arm compared [with] 5.7 months in the control arm [HR, 0.37; 95% CI, 0.27-0.51; P < .001].16 Looking at the DOR from the Kaplan-Meier curve, it was not reached in the ruxolitinib arm vs 6.24 months in the control arm.

[In terms of] adverse events [AEs]: [there are] the cytopenias.16 Ruxolitinib can cause cytopenias, so there was more anemia and thrombocytopenia in the ruxolitinib arm vs the control arm, especially with grade 3. These patients need close follow-up and support.

best ORR in REACH3

Can you discuss the data supporting the use of belumosudil for chronic GVHD?

The ROCK inhibitor belumosudil was approved based on the ROCKstar trial [NCT03640481], which was a phase 2, multicenter, open-label trial that included patients older than 18 years with active chronic GVHD.17 Those patients had to fail between 2 and 5 lines of prior systemic therapy, so they were [very] sick with their chronic GVHD and refractory to treatment. They had to have a stable steroid dose of at least 14 days. They were randomized to receive 200 mg once daily vs 200 mg twice daily, and at the end, the FDA approved the drug to be given as 200 mg once daily.

The primary end point was looking at ORR. [In terms of] baseline characteristics, the majority of patients had mucocutaneous, but there were some patients with [involvement in] lungs, esophagus, upper GI, lower GI, and a few in the liver. Looking at the patient characteristics, they included patients who had failed prior ibrutinib as well as prior ruxolitinib.

The ORR was around 76% in the intent-to-treat population. But all the subgroups that were evaluated benefited from the treatment with the belumosudil, including the patients who had failed previous ibrutinib and previous ruxolitinib.

When we look at the response by organ, we see improvement in all organs, whether it is the fascia and the GI tract or the mucocutaneous. The majority had very good complete remission seen mostly in the GI tract, followed by, as we see usually, the mucocutaneous organs. I was impressed also by the liver [response], but [there were fewer patients] with [involvement in] the liver and the lungs.

Looking at the overall survival and failure-free survival, the failure-free survival at 6 months was reported at 75% and at 1 year it was 56%.17 Two-year overall survival was 89%.

It is a well-tolerated drug. Most patients were maintained on a good relative dose intensity of more than 95%.17 When we look at grade 3 and 4 AEs, we see pneumonia, hypertension, and hyperglycemia. Looking at cytopenias: anemia of grade 3 to 4 was in 3%, neutropenia was 2%, and thrombocytopenia was 2%. It is well tolerated, especially when it comes to cytopenias. There was 1 case of EBV [Epstein-Barr virus] viremia and 1 case of CMV [cytomegalovirus] reactivation.


1. Anasetti C, Logan BR, Lee SJ, et al; Blood and Marrow Transplant Clinical Trials Network. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012;367(16):1487-1496. doi:10.1056/NEJMoa1203517

2. Flowers MED, Martin PJ. How we treat chronic graft-versus-host disease. Blood. 2015;125(4):606-615. doi:10.1182/blood-2014-08-551994

3. Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. the 2014 diagnosis and staging working group report. Biol Blood Marrow Transplant. 2015;21(3):389-401.e1. doi:10.1016/j.bbmt.2014.12.001

4. Hamilton BK. Updates in chronic graft-versus-host disease. Hematology Am Soc Hematol Educ Program. 2021;2021(1):648-654. doi:10.1182/hematology.2021000301

5. Zeiser R, Lee SJ. Three US Food and Drug Administration-approved therapies for chronic GVHD. Blood. 2022;139(11):1642-1645. doi:10.1182/blood.2021014448

6. NCCN. Clinical Practice Guidelines in Oncology. Hematopoietic cell transplantation, version 2.2022. Accessed November 21, 2022.

7. Sullivan KM, Witherspoon RP, Storb R, et al. Prednisone and azathioprine compared with prednisone and placebo for treatment of chronic graft-v-host disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation. Blood. 1988;72(2):546-554.

8. Akpek G, Lee SM, Anders V, Vogelsang GB. A high-dose pulse steroid regimen for controlling active chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2001;7(9):495-502. doi:10.1053/bbmt.2001.v7.pm11669216

9. FDA approves ruxolitinib for chronic graft-versus-host disease. FDA. September 21, 2021. Accessed November 21, 2022.

10. FDA approves belumosudil for chronic graft-versus-host disease. FDA. July 16, 2021. Updated February 2, 2022. Accessed November 21, 2022.

11. FDA expands ibrutinib indications to chronic GVHD. FDA. August 2, 2017. Accessed November 21, 2022.

12. Miklos D, Cutler CS, Arora M, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130(21):2243-2250. doi:10.1182/blood-2017-07-793786

13. Waller EK, Miklos D, Cutler C, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy: 1-year update of a phase 1b/2 study. Biol Blood Marrow Transplant. 2019;25(10):2002-2007. doi:10.1016/j.bbmt.2019.06.023

14. Miklos D, Abu Zaid M, Cooney JP, et al. Ibrutinib vs placebo in combination with corticosteroids in patients with new-onset chronic graft-versus-host disease (cGVHD): results from the randomized, double-blind phase 3 iNTEGRATE study. Abstract presented at: European Hematology Association Congress 2021; June 9, 2021; Virtual. Abstract S235. Accessed November 21, 2022.

15. Carpenter PA, Kang HJ, Yoo KH, et al. Ibrutinib treatment of pediatric chronic graft-versus-host disease: primary results from the phase 1/2 iMAGINE study. Transplant Cell Ther. 2022;28(11):771.e1-771.e10. doi:10.1016/j.jtct.2022.08.021

16. Zeiser R, Polverelli N, Ram R, et al; REACH3 Investigators. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med. 2021;385(3):228-238. doi:10.1056/NEJMoa2033122

17. 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. Published correction in Blood. 2022;139(11):1772.

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