Belumosudil for the Treatment of Chronic Graft-versus-Host Disease: A Single Center Real-World Experience

doi:10.21203/rs.3.rs-4922719/v1

Chronic graft-versus host disease (cGVHD) remains a major complication post-allogeneic stem cell transplantation (HCT). Belumosudil, a ROCK2 inhibitor was approved for cGVHD with 2–5 prior lines of therapy. We retrospectively analyzed 45 patients who received belumosudil at City of Hope Medical Center. Prior to belumosudil, the median age was 59 yrs with 3 prior lines of therapy (range 1–6). GVHD severity was predominantly moderate (37.8%) and severe (46.7%). Many patients had a prior history of ruxolitinib (71.1%), with concurrent use of belumosudil occurring in 51.1% of patients. ORR at 6-months and 12 months were 31.1% and 33.4% respectively. The best ORR at any point during belumosudil was 46.7% (CR 6.7% + PR 40%) and median FFS was 11.2 months. Infection occurred in 42% of patients, with 27% of patients requiring hospitalization to manage infection. Patients with concurrent ruxolitinib had higher infection rates (60.9% vs. 22;7%, p = 0.0156) and hospitalization (47.8% vs. 4.5%, p = 0.0017). Most infections were viral and considered mild requiring no hospitalization to manage the infection. Real-world experience with belumosudil supports the use in the treatment of cGVHD based on the ORR, promising FFS, and good tolerability in patients who have progressed on multiple prior lines of therapy.

Health sciences/Medical research

Health sciences/Diseases/Haematological diseases/Haematological cancer

Belumosudil

Chronic Graft versus Host Disease

Hematopoietic cell transplantation

Chronic graft-versus-host-disease (cGVHD) remains a major complication after allogeneic hematopoietic stem cell transplantation (HCT) that results in significant morbidity and mortality post-HCT [1]. The overall incidence of cGVHD ranges from 30–50% depending on the GVHD prophylaxis regimen and the donor graft source [2]. Clinical symptoms can develop in multiple organs over three biologic phases: (1) early inflammation due to tissue injury (2) late inflammation due thymic injury and loss of peripheral tolerance in addition to T- and B-cell dysregulation leading to chronic inflammation (3) abnormal tissue repair and fibrosis [3, 4]. Treatment of cGVHD is often prolonged, with a median treatment duration of 2–3.5 years and in patients with multiorgan involvement many lines of treatment are needed for symptom management [3–5]. Corticosteroids are widely accepted as first-line therapy, however more than half of patients with cGVHD will require a second agent within two years [3–6]. There is no consensus on preferred second-line therapy after failure of frontline steroids. For steroid-refractory (SR) chronic GVHD, there are now three approved drugs available including ibrutinib, ruxolitinib, and belumosudil [7].

Belumosudil is an oral selective rho-associated coiled-coil kinase 2 (ROCK) inhibitor approved by the United States Food and Drug Administration in 2021 for the treatment of cGVHD after failure of at least two prior lines of systemic therapy in patients 12 years or older [8]. ROCK2 modulates the balance between proinflammatory, T-helper 17 (Th17) and T-helper follicular cells (Thf), in addition to upregulating anti-inflammatory regulatory T-cell (Treg) subsets. Inhibition of ROCK2 downregulates STAT3 and other Th17-specific transcription factors, while upregulating STAT5 in conventional T-cells (Tcon), and anti-inflammatory cytokines such as IL-10; thereby restoring immune homeostasis in cGVHD patients. Additionally, fibrotic pathways are inhibited by the prevention of stress fiber formation/polymerization, and finally cytoplasmic sequestration of myocardium-related transcription factor (MRTF) results in reduced expression of transcription factors associated with proinflammatory and fibrotic pathways. Collectively, ROCK2 inhibition results in upregulation of Treg:Tcon ratio and inactivation of Th17/Thf and decrease in myofibroblasts-induced production of collagen, thus inhibiting both inflammatory and fibrotic pathways and resulting in clinical benefit [9–11].

Belumosudil was approved based the results of the pivotal ROCKstar trial, which was a phase 2 study of belumosudil at two dose levels of 200 mg once or twice daily in patients with moderate to severe cGVHD, who had previously been treated with 2–5 prior lines of therapy [12]. Most patients in this study had advanced cGVHD and up to a third of patients had progression on prior treatment with ruxolitinib or ibrutinib. The drug was well-tolerated in this study with no significant myelosuppression or CMV reactivation in treated patients. The major adverse effects included infections (53%), GI complications (42%), and constitutional symptoms (48%). The best overall response rate was 74% (95% CI: 62–84%) in the 200 mg once daily dose cohort, and this was selected as the FDA-approved dose. The 12-month failure-free survival (FFS) was 57% (95% CI: 44–68) and time to next treatment was 16.6 months. Responses were seen in all subgroups of interest including patients with severe cGVHD, > 3 prior lines of therapy, and those with prior exposure to ruxolitinib or ibrutinib. Patients on treatment also had improvement in modified Lee cGVHD symptom scale (mLSS) and reduction of prednisone and calcineurin inhibitor doses. Furthermore, Lee et al. recently reported that these responses were durable on long-term follow-up of 3 years [13]. An additional open-label study of belumosudil at 200 mg/day from a Japanese group reported results in 21 patients showing similar efficacy and safety [14].

However, there have been no reports to date describing the safety/efficacy data in real-world non-clinical trial setting. Herein, we report our experience of using belumosudil in SR-cGVHD patients treated with FDA-approved dose of 200 mg once daily. One of the interests was to evaluate the safety and efficacy of the combination of ruxolitinib and belumosudil in patients with cGVHD as ruxilitinib had to be stopped before belumosudil in the ROCKstar trial.

We conducted a retrospective analysis of 45 consecutive patients who received commercial supply of belumosudil at FDA-approved doses for treatment of cGVHD at City of Hope Medical Center (COH) between the period of August 2021 to November 2022, after the drug was FDA approved. The study was approved by COH institutional review board. Baseline characteristics were collected and included age, gender, disease, donor type, conditioning regimen, GVHD prophylaxis regimen, prior cGVHD therapies and median lines of therapy prior to initiation of belumosudil.

Primary outcome was overall response rates (ORR) to belumosudil at six months and twelve months, based on the NIH Consensus Response Criteria Working Group [15]. Our study utilized overall response rate as the primary outcome to allow for comparison with the ROCKstar trial. Complete response (CR) was defined as resolution of all manifestations related to chronic GVHD in a specific organ and a partial response (PR) was defined as improvement of GVHD score of a specific organ without achieving a CR. Stable disease (SD) was defined as no improvement in GVHD score, but not experiencing any progression of GVHD and mixed response (MR) was improvement of one organ but progression of another organ. Overall response rate (ORR) was defined as the number of patients who experienced either a CR or PR. The GVHD scoring system used in this study was based on the criteria developed by 2014 Diagnosis and Staging Working Group [16]. Secondary outcomes incidence of steroid dose reduction or discontinuation, median time to failure, and failure-free survival (FFS). Failure with belumosudil was defined as either discontinuation of belumosudil, progression of GVHD, disease relapse, or death, which ever occurred first. FFS was censored at the last follow-up if patients were known to be alive and free of any abovementioned events. A safety analysis included the incidence of belumosudil discontinuation, incidence of infection, and a descriptive analysis of toxicity experienced with belumosudil. The incidence of infections was based on the number of patients with a positive culture (i.e. blood, urine, respiratory) that required treatment, positive serologies (i.e. serum or respiratory aspergillus galactomannan antigen), or CT or X-ray imaging suggestive of infection.

Descriptive statistics were used for baseline characteristics and outcomes. The associations of baseline characteristics and response were examined using Chi-square tests or Fisher’s exact tests whenever appropriate. Kaplan-Meir curves and log-rank tests were used to examine the associations between baseline characteristics and failure-free survival. All tests were 2-sided at 0.05 significance levels.

Baseline characteristics are summarized in Table 1. Briefly, the median age of patients prior to initiating belumosudil was 59 years (range 19-78). The most common indications for allo-HCT were AML (n=18; 40%) and ALL (n=10; 22%). Donor type was predominantly matched-unrelated donors (n=19; 42.2%) and mismatched-unrelated (n=12; 26.7%) with most patients receiving peripheral blood stem cell graft (n=41; 91.1%). Over half the patients received myeloablative conditioning (n=25; 55.6%) with tacrolimus and sirolimus (n=32; 71.1%) being the most common GVHD prophylaxis regimen utilized. Patients initiated on belumosudil most often had skin (n=34; 75.6%), eyes (n=22; 48.9%), mouth (n=21; 46.7%), and joints (n=17; 37.8%) involvement with cGVHD. Baseline severity of GVHD based on organ and global scores are summarized in Table 2. Based on the NIH consensus criteria, 21 patients (46.7%) presented with severe GVHD, and 17 patients (37.8%) had moderate cGVHD when belumosudil was introduced. Prior to the start of belumosudil, patients were on a median of three prior lines of therapy (range 1-6) with many patients previously treated with ruxolitinib (n=32; 71.1%). The time from HCT to belumosudil and onset of cGVHD to belumosudil were 35 months (range 6-160) and 24 months (range 0-147) respectively. In this report, 23 patients (51.1%), were concurrently treated using ruxolitinib and belumosudil combination. Before initiating belumosudil, patients with a prior history of using ruxolitinib (n=9) had received a median of 206 days (range 60-1183) of treatment, whereas patients treated concurrently with ruxolitinib and belumosudil (n=23) received a median 461 days (range 78-1226) of ruxolitinib treatment. In addition, 78% of patients (n=35) were receiving a corticosteroid concurrently at a median dose of 10 mg/day (approximately 0.15 mg/kg/day, range 1-40 mg/day) within a month prior to initiating belumosudil.

Median follow-up for this study at the time of analysis for all patients was 22.9 months (range 2.8-27.5). The ORR to belumosudil in this heavily pretreated population was 31.1% at 6 months and increased slightly to 33.4% at 12 months. The best ORR at any time during treatment with belumosudil was 46.7% (CR=3, PR=18), with a median time to best response occurring at a median of 108.5 days (range 48-367) after starting therapy. Stable disease was seen in thirteen patients at 6 months (28.9%) and eight patients at 12 months (17.8%), with FFS of 48.9% at 12 months. The response rate to belumosudil by organ involvement and global response rate as defined by NIH Consensus Response Criteria Working Group can be seen in Figure 1. Patients with skin cGVHD/scleroderma (n=34) had ORR of 14.7% at both 6 months and 12 months with three patients achieving a CR and two patients achieving a PR. Stable disease of skin cGVHD was maintained in 19 patients at 6 months (55.9%) and 11 patients (52.9%) at 12 months. Patients with joint/fascia cGVHD (n=17) had an ORR of 5.9% at 6 months (CR=1, no PR) which increased to 23.5% at 12 months (CR=3, PR=1), and stable disease was noted in eleven patients (64.7%) at 6 months which decreased to six patients (41.2%) at 12 months. Response to mouth cGVHD was promising with ORR of 19.0% and 23.8% at 6 and 12 months respectively with CR rates of 14.3% and 23.8% at 6 months and 12 months respectively. Lastly, ocular cGVHD demonstrated ORR of 33% at both 6 months and 12 months with stable disease seen in 42.9% and 23.8% at 6 months and 12 months respectively, with many patients on topical treatments as an adjunct to belumosudil. The ORR in other GVHD target organs (e.g. liver, gastrointestinal, lungs) was limited and difficult to assess as the sample sizes were small. The median time to failure to belumosudil was found to be 4.7 months (range 0.7-14) and median FFS was 11.2 months (Figure 1). At the time of our analysis, there was a decrease in corticosteroid dose in 13 patients (28.9%) and 9 patients were able to discontinue the corticosteroid (20%). Patients with prior ruxolitinib exposure (n=32) had a 12-month ORR of 25% (8/32) compared to ORR of 38.5% (5/13) in ruxolitinib naïve patients (p=0.4726). When we analyzed patients receiving concomitant ruxolitinib and belumosudil (n=23) to those receiving only belumosudil, the 12-month ORR was similar at 21.7% and 36.4% respectively (p=0.3368).

Eight patients (17.8%) discontinued belumosudil at a median time of 94 days (range 21-791) due to adverse effects, the most common reason for discontinuation included gastrointestinal toxicity (n=5) and other reasons for discontinuation included bleeding (n=1), infection (n=1), and muscle weakness (n=1). Belumosudil was well-tolerated by most patients in our study, however documented infection occurred in 42% (n=19) of patients with 27% (n=12) of cases requiring hospitalization to manage the infection. Infection rates were 60.9% (n=14) in the group of patients who received concurrent ruxolitinib and belumosudil compared to 22.7% (n=5) in the belumosudil only group (p=0.0156) with higher incidence of hospitalization in the concurrently treated group (47.8% vs. 4.5%, p=0.0017). Of the 19 patients who experienced an infection, 94.7% (n=18) were viral, 42.1% (n=8) were bacterial, and 15.8% (n=3) were fungal. Many of the viral infections were mild, with 72% of viral infections (13/18) not requiring hospitalization for medical treatment, with viral infections that included: respiratory syncytial virus 27.8% (n=5), rhinovirus 27.8% (n=5), SARS-CoV-2 27.8% (n=5), influenza 11.1% (n=2), BK virus 11.1% (n=2) in the urine, mucocutaneous herpes 11.1% (n=2), parvovirus 5.6% (n=1), and parainfluenza 5.6% (n=1). One patient with SARS-CoV-2 infection required hospitalization and treatment with remdesivir in combination with dexamethasone for severe respiratory symptoms. There were two cases of CMV reactivation, with one patient requiring treatment with ganciclovir. All the fungal infections were due to aspergillosis, as one patient had documented aspergillus fumigatus on bronchoscopy and the other two patients presented with a positive galactomannan antigen result (one patient through blood test and the other with bronchoscopy). Death occurred in four patients while on belumosudil, with three of the deaths attributed to progressive cGVHD.

Overall, our single center experience using belumosudil in patients with advanced cGVHD showed similar adverse effect profile but lower ORR of 46.7% when compared to the results of the ROCKstar study. There are some similarities between our study and the ROCKstar study, most notably that complete response rates were rarely seen, as only 6% of patients were able to achieve resolution of all cGVHD manifestations within 12 months of initiation belumosudil [12]. In addition, the study population in our report is similar to the ROCKstar trial, as our patients had been treated with a median of three prior lines of therapy (range 1–6) and consisted primarily of patients with NIH severe cGVHD. However, our study had some important differences in that significantly more patients in our study had prior exposure to ruxolitinib (71%). The predominance of advanced disease and prior ruxolitinib exposure in patients treated in our study may have contributed to lower ORR responses compared to ROCKstar study where only 30% patients were previously treated with ruxolitinib. We did note higher ORR in patients who were ruxolitinib naïve compared to patients with prior exposure to ruxolitinib, but this did not reach statistical significance, which could be due to the small sample size in our study. In addition, our study included a subgroup of patients that were treated concurrently with belumosudil and ruxolitinib and the 12-month ORR was 21.7%. Most patients tolerated the combination well and no unusual toxicities were noted, however the combination was associated with significantly higher infection rates and hospitalization due to infection. Recently, Pusic et al. reported their experience of using concomitant ruxolitinib with belumosudil in 14 patients and reported an ORR of 43% (with no complete responses), which was also lower than the responses seen in the ROCKstar study [17]. Subsequently, there have been some retrospective studies that demonstrate success with combination therapy after failure with either ruxolitinib or belumosudil as single agent [18–20]. Based on these results, it appears that the combination of both FDA approved agents warrants further investigation with prospective studies to determine which patient subgroups would benefit the most from the combination.

The most recent CIBMTR data suggests that the numbers of allogeneic transplantations continue to rise annually, underlying the importance to develop more effective therapies and novel drug combinations to treat cGvHD, as this post HCT complication remains the most common cause for late non-relapse mortality [2–3, 21–23]. Fortunately, three oral agents are now approved for the treatment of cGVHD, specifically ruxolitinib, ibrutinib, and belumosudil [7]. Ruxolitinib was approved in 2021 as second-line in steroid-refractory patients based on results of a Phase 3 study (REACH3) demonstrating superior 6-month ORR of 49.7% compared to the control group at 25.6% [24, 25]. Safety analysis results revealed the most common Grade ≥ 3 adverse events revolved around myelosuppression, with the incidence of infection of any type found to be 63.6% and Grade ≥ 3 infections occurring in 19.4% of patients. We subsequently demonstrated in a retrospective study an ORR of 43.4% at 12 months with infection rates at 52% in cGVHD patients treated with commercial ruxolitinib at our center [26]. In our study, the drug discontinuation rate and adverse effect profile were similar to that reported in ROCKstar trial except for increased infectious complication in patients who were treated concurrently with belumosudil and ruxolitinib. Appropriate antimicrobial prophylaxis and close monitoring for infections is needed for patients treated with combination therapy.

Based on the efficacy of these novel agents in steroid refractory setting, attempts are being made to move these novel agents to the upfront/newly diagnosed cGVHD setting. A Phase 3 study using steroids alone or steroids with ibrutinib for frontline treatment of patients with cGVHD (iNTEGRATE study) unfortunately showed response rates were no different in combination arm compared to placebo [27]. Similarly, the GRAVITAS-309 trial combining prednisone with itacitinib (a JAK1 inhibitor) was stopped due to increase in complications in the combination arm [28]. Both belumosudil (NCT06143891) and ruxolitinib (NCT06388564) are now being studied in the frontline setting in combination with steroid and/or axatilimab (a monoclonal antibody targeting colony stimulating factor-1 receptor) for newly diagnosed cGVHD. Early introduction of these novel agents may increase the depth of NIH responses with more patients potentially benefitting from less exposure to steroids and higher CR. Overall, belumosudil is an attractive option in the management in cGVHD with low infectious complications, less myelosuppression, and a fast onset of clinical responses (median time to first response 1.8 months), thus making this agent a good choice for upfront therapy [12]. Despite the high ORR reported in the ROCKstar and other smaller studies, most responses are partial, and patients eventually progress and require addition lines of therapy as was noted in the ROCKstar trial and our retrospective study as well [13, 14, 29].

Our study is limited by its retrospective design, reliance on physician documentation of cGVHD symptoms, and interobserver variability. In addition, our study did not control for site-directed therapies, which might have contributed to improved NIH disease severity scores especially in sites like the skin, mouth and eye that may benefit from on topical treatment for successful management, thus overestimating the true impact belumosudil in these sites. The results of our study also did not account for quality-of-life improvements with belumosudil as many patients acknowledged feeling better while on belumosudil, but we were unable to quantify this improvement retrospectively. Lee et al. published their pooled analysis of two studies that showed patient-reported outcomes with belumosudil had a strong positive correlation with response to therapy and supported the use to document clinically meaningful benefit [30].

Real-world experience clinical reports are important as they bridge the gap between controlled clinical research and everyday medical practice, helping clinicians make treatment decisions. Here despite our limitations, we summarize the largest cohort of patients analyzing the real-world impact of belumosudil for the treatment of cGVHD. Our results show that belumosudil does provide benefit based on the ORR of 33.4% at 12 months, a median failure-free survival 11.2 months, and good tolerability with a 17.8% discontinuation rate in patients with advanced cGVHD who have progressed on multiple prior lines of therapy. Thus, belumosudil should be considered as an option for salvage therapy for the treatment of cGVHD and additional studies are ongoing to study the role of this agent upfront.

Declarations of interest

The authors have no competing interests if not stated below. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data Availability Statement

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Funding:

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author Contributions:

Badri Modi and Dat Ngo: study design, extracting and analyzing data, interpreting results, manuscript writing

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Table 1: Baseline Characteristics (N=45) in 45 patients who received belumosudil for treatment of cGVHD

Characteristic

Median age, years (range)

59 (19-78)

Gender, n (%)

Male
Female

20 (44.4)

25 (55.6)

Ethnicity, n (%)

Caucasian
Hispanic
African-American
Asian

27 (60.0)

11 (24.4)

5 (11.1)

2 (4.4)

Disease, n (%)

Acute myeloid leukemia
Acute lymphoblastic leukemia
Non-Hodgkins Lymphoma
Myelodysplastic syndrome/Myeloproliferative neoplasm
Other

18 (40.0)

10 (22.2)

9 (20.0)

5 (11.1)

3 (6.7)

Donor type, n (%)

Matched related donor
Matched unrelated donor
Mismatch unrelated donor
Haploidentical donor

11 (24.4)

19 (42.2)

12 (26.7)

3 (6.7)

Donor source, n (%)

Peripheral blood stem cell
Bone marrow
Not available

41 (91.1)

2 (4.4)

Conditioning, n (%)

Myeloablative
Non-myeloablative/Reduced intensity
Not available

25 (55.6)

19 (42.2)

1 (2.2)

GVHD prophylaxis regimen, n (%)

Tacrolimus/Sirolimus
Tacrolimus/Methotrexate
PTCy/Tacrolimus/MMF
Other

32 (71.1)

6 (13.3)

3 (6.7)

4 (8.9)

Corticosteroids within 1 mos. prior to belumosudil, n (%)

Median dose of corticosteroids, mg (range)

35 (77.8)

10 (1.5-40)

Prior ruxolitinib use, n (%)

32 (71.1)

Concurrent ruxolitinib prior to belumosudil, n (%)

22 (48.9)

Prior GVHD medication, n (%)

Mycophenolate mofetil
Extracorporeal photopheresis
Ibrutinib
Rituximab
Interleukin-2
Others

15 (33.3)

13 (29.9)

7 (15.6)

5 (11.1)

2 (4.4)

13 (28.9)

Median number lines of therapy, n (range)

3 (1-6)

Median time from HCT to belumosudil use, months (range)

35 (6-160)

Table 2: Baseline cGVHD Severity (n=45) in 45 patients who received belumosudil for treatment of cGVHD

		Score, n (%)
Organ	Total, n (%)	3 (severe)	2 (moderate)	1 (mild)
Skin	34 (75.6)	12 (26.7)	16 (35.6)	6 (13.3)
Mouth	21 (46.7)	3 (6.7)	5 (11.1)	13 (28.9)
Eyes¹	22 (48.9)	3 (6.7)	8 (17.8)	10 (22.2)
Joints/Fascia	17 (37.8)	5 (11.1)	5 (11.1)	7 (15.6)
Lungs	6 (13.3)	4 (8.9)	1 (2.2)	1 (2.2)
Liver	5 (11.1)	1 (2.2)	0 (0)	4 (8.9)
Gastrointestinal	2 (4.4)	0 (0)	1 (2.2)	1 (2.2)
Global severity score	45 (100)	21 (46.7)	17 (37.8)	7 (15.6)

¹One patient had eye cGVHD but unable to determine severity

Table 3: Primary and secondary outcomes in 45 patients who received belumosudil for treatment of cGVHD

ORR during treatment with belumosudil, n (%) CR PR	21 (46.7) 3 (6.7) 18 (40.0)
Median time to best response, days (range)	108.5 (48-367)
Decrease in steroid dose, n (%) Discontinue steroids, n (%)	13 (28.9) 9 (20.0)
Median time to failure (i.e. discontinuation, progression, relapse, death), months (range)	4.7 (0.7-14.0)
Failure due to progression/ineffectiveness, n (%)	15 (33.3)
Median duration of treatment with belumosudil, months (range)	15.7 (0.7-27.5)
Discontinued belumosudil due to adverse effect, n (%)	8 (17.8)
All-cause mortality, n (%)	4 (8.9)

Yes

SUPPLEMENTALAPPENDIX.docx

Belumosudil for the Treatment of Chronic Graft-versus-Host Disease: A Single Center Real-World Experience

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Abstract

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INTRODUCTION

METHODS

RESULTS

DISCUSSION

Declarations

Declarations of interest

Data Availability Statement

Funding:

Author Contributions:

References

Tables

Additional Declarations

Supplementary Files

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