Abstract
PURPOSE:
Sclerotic chronic graft-versus-host disease (cGVHD) represents a highly morbid and refractory form of cGVHD, and novel therapies for sclerotic cGVHD are critically needed. This study aimed to determine the efficacy of ruxolitinib in patients with corticosteroid refractory sclerotic cGVHD.
PATIENTS AND METHODS:
In a single-arm multicenter phase II trial (n=47), adults with sclerotic cGVHD refractory to corticosteroids and ≥1 additional line of systemic therapy for cGVHD received ruxolitinib for ≥6 months (ClinicalTrials.gov identifier: NCT03616184). The primary endpoint was complete or partial response in skin and/or joint defined according to the 2014 NIH cGVHD Consensus Criteria.
RESULTS:
Following the use of ruxolitinib for a median of 11 months, partial response (PR) in skin and/or joints was noted in 49% (95% CI 34–64%) at 6 months with 45% having joint and fascia response and 19% having skin response. The duration of skin/joint response was 77% (95% CI: 48%–91%) at 12 months. Overall cGVHD PR was noted in 47% (95% CI 32–61%). Improvement in Lee symptom scale summary and skin subscale scores was noted in 38% of patients. With a cumulative incidence of treatment failure of 20.8% (95% CI 10.0–34.1%), non-relapse mortality of 2.2% (95% CI 0.17%–10.3%) and no recurrent malignancy, failure-free survival was 77.1% (95% CI 61.3%–87.0%) at 12 months. Ruxolitinib was overall well tolerated with no new safety signals.
CONCLUSION:
The use of ruxolitinib was associated with relatively high rates of skin/joint responses and overall cGVHD responses, improvement in patient-reported outcomes, low non-relapse mortality and high failure-free survival in patients with refractory sclerotic cGVHD. Ruxolitinib offers an effective treatment option for refractory sclerotic cGVHD.
Keywords: Chronic graft-versus-host disease, scleroderma, salvage therapy, ruxolitinib, clinical trial, fibrosis, sclerosis
Introduction
Chronic graft-versus-host disease (cGVHD) occurs in up to one-half of the recipients of allogeneic stem cell transplantation.1,2 Commonly involved organs include skin, mouth, eyes, gut, liver, lung, joint and fascia.1,2 While the risk of cGVHD increased between 1990s to early 2000s,3 the use of novel GVHD prophylaxis strategies that incorporate post-transplant cyclophosphamide and antithymocyte globulin is decreasing the risk of cGVHD.4,5
Sclerotic cGVHD represents a highly morbid form of cGVHD,6 which is associated with pain, poor health-related quality of life and high rates of disability due to contractures, chronic skin ulcers, and pulmonary restriction.6–8 It is frequently refractory to initial and subsequent treatments, thus representing an area of unmet need.6,7 While sclerotic cGVHD biology differs from other forms of cGVHD and involves progressive tissue fibrosis, clinical trials focusing specifically on sclerotic cGVHD are sparse.6 Prior studies evaluating the role of tyrosine kinase inhibitors or rituximab were relatively small or retrospective.9–12 In a randomized clinical trial focusing on sclerotic cGVHD, rituximab versus imatinib resulted in clinical benefit in only a quarter of patients.13 The National Institute of Health (NIH) cGVHD Consensus Project has highlighted the importance of studying various phenotypes of cGVHD separately to advance a “precision” medicine approach to treating cGVHD.6,14 Specifically, treatment trials of sclerotic cGVHD are considered a high priority.6
Ruxolitinib is an oral inhibitor of Janus Kinase (JAK) 1 and 2, which is now approved by the US Food and Drug Administration (FDA) for treatment of cGVHD following failure of systemic therapy.15 Initial evidence demonstrated that ruxolitinib may be effective in patients with sclerotic cGVHD.16,17 For these reasons, we designed a multicenter phase II trial to test the hypothesis that ruxolitinib is an effective treatment for corticosteroid refractory sclerotic cGVHD.
Patients and Methods
Patient Eligibility
Eligibility criteria included adults aged ≥18 years with sclerotic cGVHD who had superficial or deep skin sclerosis, fasciitis, or joint contractures. Patients should have received either a systemic corticosteroid for ≥12 months and at least one additional line of systemic therapy, or a corticosteroid and at least two additional lines of therapy for cGVHD. Other inclusion criteria included Karnofsky performance status score ≥60, absolute neutrophil count greater than 1000/μL, and platelet count ≥50,000/μL. Key exclusion criteria included total bilirubin >1.5 × the upper limit of the normal range, creatinine clearance <30 mL/min, uncontrolled infection, or uncontrolled cardiopulmonary conditions.
Study Design and Treatment
This phase II trial enrolled patients between November 2018 and June 2021 from five centers in the United States (Supplemental Table 1). Ruxolitinib 10 mg twice daily was administered orally continuously for 6 months. Patients who had at least partial response or stable disease at 6 months could extend treatment for another 6 months. At the end of 6 months, or 12 months for patients on the extended treatment, ruxolitinib was tapered over one month before discontinuation. Ruxolitinib dose was reduced by 50% in patients using strong CYP3A4 inhibitors.
Patients underwent blood counts and serum chemistry testing 2 and 4 weeks after treatment initiation, then monthly during the first 6 months of treatment. Patients were evaluated for cGVHD activity using the 2014 NIH cGVHD Consensus Criteria18 and patient-reported outcomes (PROs) were captured at baseline, at the end of 3 and 6 months after starting ruxolitinib. Patients who maintained complete or partial response at the end of 6 months were followed every 3 months until treatment failure, or for a total of 2 years.
The study was registered with ClinicalTrials.gov identifier (NCT03616184) and funded by Incyte. The institutional review board or independent ethics committee at each center approved the study. The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent.
All authors reviewed and approved the submitted manuscript.
Study End Points
The primary endpoint was complete or partial response in skin and/or joint defined according to the 2014 NIH cGVHD Consensus Criteria.18 Secondary endpoints included overall cGVHD response, treatment failure, failure-free survival (FFS), non-relapse mortality (NRM), steroid dose reduction and PROs. Overall cGVHD response was defined as an improvement in cGVHD at ≥1 organ/site without progression in any other organ/site.18 Treatment failure was defined as an addition of another systemic therapy, relapse, or NRM. We defined FFS as the absence of relapse, NRM or addition of another systemic therapy.19 We used the Lee Symptom Scale20 and Scleroderma Health Assessment Questionnaire (SHAQ)13,21–23 to capture PROs. A clinically meaningful cutoff of ≥7 for the summary score and ≥11 for the skin subscale of the Lee Symptom Scale was used to determine changes from baseline to 6 months after treatment.20,24 A cutoff of ≥0.2 defined clinically meaningful change in disability and other indices derived from the SHAQ.23 Peripheral blood was collected from patients at enrollment, 3 and 6 months after initiation of ruxolitinib to analyze changes in various proinflammatory cytokines and lymphocyte populations (Supplemental Figure 1, Supplemental Table 2).
Statistical Analysis
Sample size justification:
A two-stage minimax design was planned to test the null hypothesis that the overall response rate in skin and/or joint p≤0.25 versus the alternative that p≥0.45. In the first stage, 18 patients were planned to be enrolled; if 4 or fewer responded, the trial would stop for futility. At stage two, an additional 24 patients were planned to be enrolled for a combined total of 42 from both stages. If 15 or fewer responded out of 42 patients at the end of stage two, then no further investigation would be warranted. If 16 or more patients responded, then further investigation would be warranted. This design achieves 84% power with a significance level of 0.044. A total sample size of 47 was enrolled to account for 10% dropout.
The efficacy and safety analyses were done in the full set of 47 patients, all of whom received at least one dose of ruxolitinib. Descriptive statistics were computed for patient characteristics. Mean, standard deviation (SD), median and range are reported for continuous variables, and frequencies and percentages are used to describe categorical variables. Skin and/or joint responses and overall cGVHD responses are reported as a proportion and 95% exact confidence interval (CI). Duration of response was defined as time from initial skin/joint response at or prior to 6-month visit to treatment failure or death. The Kaplan-Meier method was used to estimate overall survival and FFS distributions. Cumulative incidence methods are used to estimate the distribution of relapse and NRM, with death without relapse and death with relapse as competing events, respectively. We calculated the average percent change in the corticosteroid dose for each patient, and the number and proportion of patients with a dose reduction greater than 50%. All adverse events were summarized at the patient level. Descriptive statistics were computed for PROs, Lee Symptom Scale, and SHAQ at study enrollment and 6 months. Changes in PROs from study enrollment to 6 months were assessed with paired t-tests or Wilcoxon sign-rank test depending on whether test assumptions were met. The difference in peripheral blood lymphocyte populations between the 6-month value and baseline was calculated for each patient. Because this difference deviated from normality, a Wilcoxon signed-rank test was used to analyze the data. Median, quartiles, and range are presented. A repeated measures model was used to analyze the cytokines in serum values at baseline, 3 months, and 6 months. Because the data deviated from normality, a log-transformation was applied prior to analysis. Back-transformed least squares means and 95% confidence intervals are presented.
Study Results
Baseline characteristics:
We consented 49 patients; two did not meet eligibility criteria. The study participants (n=47) had a median age of 62 years (range 23–76) (Table 1). Forty percent of the participants were female and 91% were white. Most patients had intermediate (60%) or low (17%) disease risk index. Most (87%) patients had received peripheral blood grafts from matched unrelated (66%) or related (23%) donors. A total of 66% of patients had prior acute GVHD. The median time from diagnosis of cGVHD to enrollment was 39 months. All patients had classic cGVHD, which was mostly severe (85%) or moderate (13%) per the 2014 NIH consensus criteria. Patients had received a median of 3 (range 2–6) prior lines of treatment (Supplemental Table 3).
Table 1.
Baseline characteristics of the patients
| Characteristics | Total (N=47) |
|---|---|
| Age in years, median (range) | 62 (23–76) |
| Male, n (%) | 28 (60%) |
| Race | |
| White | 43 (91%) |
| Indication for transplant, n (%) | |
| Acute myeloid leukemia | 9 (19%) |
| Myelodysplastic syndrome | 11 (23%) |
| Acute lymphocytic leukemia | 8 (17%) |
| Non-Hodgkin lymphoma | 4 (9%) |
| Others | 15 (32%) |
| Disease Risk Index | |
| Very High | 1 (2%) |
| High | 7 (15%) |
| Intermediate | 28 (60%) |
| Low | 8 (17%) |
| Other* | 3 (6%) |
| Conditioning intensity, n (%) | |
| Myeloablative | 22 (47%) |
| Nonmyeloablative | 9 (19%) |
| Reduced intensity | 16 (34%) |
| Donor type, n (%) | |
| Related | 13 (28%) |
| Unrelated | 34 (72%) |
| HLA matching, n (%) | |
| Matched sibling | 11 (23%) |
| Matched unrelated | 31 (66%) |
| Other | 5 (11%) |
| Stem cell source, n (%) | |
| Peripheral blood | 41 (87%) |
| Bone marrow | 6 (13%) |
| Time from transplant to enrollment in months, median (range) | 51 (19–139) |
| Prior acute GVHD | 31 (66%) |
| Time from chronic GVHD diagnosis to enrollment in months, median (range) |
39 (6.4–133) |
| Chronic GVHD severity, n (%) | |
| Severe | 40 (85%) |
| Moderate | 6 (13%) |
| Mild | 1 (2%) |
| Organs involved at enrollment | |
| Number of organs involved, median (range) | 5 (1–7) |
| ≥3 organs involved, n (%) | 44 (94%) |
| Eyes, n (%) | 40 (85%) |
| Skin, n (%) | 47 (100%) |
| Mouth, n (%) | 25 (53%) |
| Joints and/or fascia, n (%) | 42 (89%) |
| Lungs, n (%) | 13 (28%) |
| Upper gastrointestinal, n (%) | 3 (6%) |
| Esophagus, n (%) | 15 (32%) |
| Lower gastrointestinal, n (%) | 3 (6%) |
| Liver, n (%) | 19 (40%) |
| Karnofsky Performance Status, median (range) | 80 (60–100) |
| 60–70 | 8 (17%) |
| 80–90 | 38 (81%) |
| 100 | 1 (2%) |
| Prior therapies for chronic GVHD, median (range) | 3 (2–6) |
| ≥3 prior therapies, n (%) | 74% |
Other includes aplastic anemia (n=2) and unknown (n=1).
GVHD chronic graft-versus host disease, N number
Follow-up and treatment characteristics:
The CONSORT diagram (Fig. 1) shows patient disposition. The median follow-up was 11.9 months (ranges 0.9–24.4 months). Patients received ruxolitinib for a median of 11 months (range <1–14 months); with one patient receiving treatment for 14 months, which was deemed a protocol violation. Seventy-six percent of patients (n=36) received ruxolitinib for ≥6 months. Fifty-five percent of patients (n=26) missed at least 1 dose of ruxolitinib, and 23% (n=11) patients had at least 1 dose modification (10 patients had dose reduction; one patient had dose increase after stopping azole antifungal).
Figure 1. CONSORT diagram showing patients’ disposition.
N indicates number of patients.
Safety:
An adverse event of any grade was noted in 66% of patients (32% related to ruxolitinib), and a grade ≥3 adverse event was reported in 40% (13% related to ruxolitinib) (Table 2). Adverse events observed in ≥10% of patients included diarrhea, nausea, vomiting, fatigue, lung infection, skin infection, upper respiratory infection, and weight gain. Grade ≥3 adverse events noted in ≥5% of patients included lung infection and hypertension.
Table 2.
Treatment-emergent adverse events
| Adverse event | N (% out of 47 patients) | Possibly or Probably Related N (% out of 47 patients) |
|---|---|---|
| Any grade | 31 (66%) | 15 (32%) |
| Grade ≥3 adverse event | 19 (40%) | 6 (13%) |
| Serious adverse event* | 13 (28%) | 3 (6%) |
| All grade adverse event in ≥10% | ||
| Diarrhea | 5 (11%) | 0 (0%) |
| Nausea | 9 (19%) | 2 (4%) |
| Vomiting | 6 (13%) | 0 (0%) |
| Fatigue | 7 (15%) | 2 (4%) |
| Lung infection | 5 (11%) | 3 (6%) |
| Skin infection | 5 (11%) | 3 (6%) |
| Upper respiratory infection | 8 (17%) | 5 (11%) |
| Weight gain | 5 (11%) | 5 (11%) |
| Grade ≥3 adverse event ≥5% | ||
| Lung infection | 4 (9%) | 2 (4%) |
| Hypertension | 3 (6%) | 0 (0%) |
N number
Thirteen patients had at least one serious adverse event, grade ≥3 with a total of 25 serious adverse events: lung infection (n=3), and one episode each of generalized edema, chest pain, abdominal pain, enterocolitis, nausea, fever, sudden death, cholecystitis, catheter-related infection, sepsis, fracture, influenza, cutaneous basal cell carcinoma, toe ischemia, cellulitis, syncope, hallucination, adult respiratory distress syndrome, dyspnea, hypoxia, respiratory failure and thromboembolic event.
Efficacy:
Partial response (PR) in skin and/or joint was noted in 49% (95% CI 34–64%) (n=23/47) at 6 months (Figure 2a). Other patients had stable disease (19%, 9/47), progression (19%, 9/47), and missing data (13%, 6/47). A total of 19% of patients (n=9/47) had PR in skin; none had complete response (CR). Forty-five percent had CR or PR in joints and fascia (n=21/47) with three patients having CR. Skin/joint PRs were seen across all subgroups, but PRs were particularly high among 12 patients who had received <3 prior lines of therapy (75%, 95% CI 50–99%) (Figure 2b). PRs were seen in 36% of patients (17/47) by 3 months, the first response assessment timepoint. Three patients on extended treatment who had stable disease or mixed response at 6 months had PR by 9 months. No new PRs were noted after 9 months. The duration of response at 12 months was 77% (95% CI: 48%–91%) (Figure 3a).
Figure 2. a. Skin and/or joint responses at 6 months. Figure 2b. Forest plot for subgroup analyses of skin/joint partial responses based on baseline factors. Figure 2c. Overall chronic GVHD responses at 6 months.
A higher percentage of patients had overall cGVHD progression, as compared to progression in skin/joint, because of progression in organs other than skin/joint.
Figure 3. a. Duration of responses (DOR). Figure 3b. Cumulative incidence of treatment failure (upper curve) and non-relapse mortality (lower curve). Figure 3c. Overall survival (upper curve) and failure-free survival (lower curve).
Overall cGVHD PR was noted in 47% (95% CI 32–61%) (n=22/47) at 6 months (Figure 2c); other responses included stable disease (13%, 6/47), progression (38%, 13/47), and missing data (13%, 6/47). PRs were noted in all organs involved at baseline (Supplemental Table 4). Fifteen patients had received ibrutinib prior to enrollment in the study. Among these 15 patients, 7 patients (47%) had PR in skin and/or joint, and 9 patients (60%) had overall cGVHD PR.
Twenty-four percent of patients taking corticosteroid at baseline (9/37) had >50% reduction in corticosteroid dose at 6 months after treatment initiation. The mean steroid dose (measured as prednisone equivalent) at baseline was 19.7 mg (n=37, SD=16.1) and at 6 months was 8.3 mg (n=29, SD=6.8), corresponding to an average percent reduction of 35.2% (SD=42.2%). Five patients (13%) had cessation of steroid use by 6 months.
The cumulative incidence of treatment failure was 15.2% (95% CI 6.6%–27.1%) at 6 months and 20.8% (95% CI 10.0–34.1%) at 12 months (Figure 3b). The cumulative incidence of NRM was 2.2% (95% CI 0.17%–10.3%) at 6 and 12 months. Malignancy relapse was not observed. FFS was 82.6% (95% CI 68.2–90.9%) at 6 months and 77.1% (95% CI 61.3%–87.0%) at 12 months (Figure 3c). Overall survival was 97.8% (95% CI 85.3–99.7%) at 6 and 12 months.
Patient-reported outcomes:
An improvement in the summary score of Lee symptom scale was noted in 38% of patients, and improvement in the skin subscale score was observed in 38% (Figures 4a and 4b). A total of 30% of patients had improvement in the standard disability index of the SHAQ (Figure 4c). Improvement in overall disease activity, breathing and pain visual analogue scale of the SHAQ was seen in 40%, 23% and 26% of patients, respectively. Approximately, one-third of patients had missing data on PROs. A significant correlation between improvement in PROs and objective responses was not established but the number of patients in each response category was small (Supplemental Table 5).
Figure 4. Patient-reported outcomes. Fig 4a. Changes in Lee symptom scale or LSS (summary score) from baseline to 6-month posttreatment. Fig 4b. Changes in Lee symptom scale, skin subscale score from baseline to 6-month posttreatment. Fig 4c. Changes in Scleroderma Health Assessment Questionnaire indices from baseline to 6-month posttreatment.
Correlative studies:
CD8+ CD95 activated T cells (induces apoptosis) increased from pre-treatment to 6 months after treatment (p=0.027). Several cytokine levels (e.g. interleukins-6 and 4) were elevated at baseline, compared to expected normal serum levels,25,26 and dropped 6 months after treatment but these or any other changes in serum cytokine levels (n=26) or lymphocyte population (n=12) over time did not reach statistical significance (Supplemental Tables 6 and 7).
Discussion
Sclerotic cGVHD represents an area of unmet need with limited prospective clinical trial data. In a heavily pretreated patient population with sclerotic cGVHD, the use of ruxolitinib was associated with skin/joint responses and overall cGVHD responses in about half of the patients. Similar rates of response were noted in patients who had previously received ibrutinib. PRs were particularly high at 75% among 12 patients who had received <3 prior lines of therapy. PRs were seen within 3 months but took up to 6–9 months after treatment initiation in some patients. At 1 year, the duration of response was 77%, FFS was high at 77%, and NRM was low at 2%. No malignancy relapse was noted in a population with mostly low to intermediate disease risk index. Ruxolitinib was overall well tolerated. While a grade ≥3 adverse event was observed in 40%, 13% had a grade ≥3 adverse event related to the study treatment. Treatment discontinuation due to an adverse event was noted in only 1 patient (9%).
While the study met the primary endpoint, PR in skin (19%) was lower than PR in joints/fascia (45%), which is at least in part because of the sensitivity of the NIH skin response criteria. Hence, PROs can provide valuable insights regarding the impact of sclerotic cGVHD, and changes in response to therapy.18 Compared to the NIH skin responses, improvement in the skin subscale of the Lee symptom scale was noted in 38% of patients, highlighting the efficacy in improving skin symptoms. No validated PRO measures currently exist specifically for patients with sclerotic cGVHD; however, the SHAQ is a validated measure in scleroderma.13,21–23 Thirty-percent of patients had improved by the standard disability index of the SHAQ. Altogether, these results demonstrate objective improvement in refractory sclerotic cGVHD and improvement in PROs with ruxolitinib.
Within the limitations of cross-trial comparisons, the NIH skin/joint response rates with ruxolitinib compared favorably to a significant clinical response rate (improvement in skin sclerosis or joint range of motion) of 27% vs. 26% at 6 months achieved in a randomized phase II trial with rituximab vs. imatinib.13 The 6-month rates of treatment failure was 65% in the imatinib arm and 58% in the rituximab arm; however, the definition for treatment failure (less than a significant clinical response rate, or study treatment discontinuation due to cGVHD progression, or treatment intolerance) was different.13 This difference in treatment failure definition precludes comparison with the treatment failure rate of 15.2% at 6 months with ruxolitinib. Two phase I/II trials demonstrated skin/joint response rates of 47% and 65% with glasdegib in patients with refractory sclerotic cGVHD; however, treatment intolerance, particularly dose limiting toxicity-defining muscle cramping, precluded dose escalation in one trial and resulted in closure of the second trial.27 The results of our study cannot be compared with other studies using novel agents,28,29 which were not tested in patients with sclerotic cGVHD.
The study has several strengths and a few limitations. The strengths include a multicenter phase II trial designed specifically for sclerotic cGVHD, use of the 2014 NIH response criteria, and incorporation of validated PROs. The trial results demonstrate favorable outcomes associated with the use of ruxolitinib in this highly morbid subset of refractory sclerotic cGVHD. The limitations include missing data, particularly for PROs, and missing specimen collection for correlative studies, which were in part related to the coronavirus disease 2019 pandemic and in part due to assessments or specimen collection missed by the study team. Missingness of data was not continuously monitored, which did not allow attempts to obtain the data. Another key challenge associated with the correlative studies included loss of cell viability during storage or shipping. To avoid inflating response rates, we considered patients with missed response assessments to be nonresponders. We measured levels of various cytokines and lymphocyte populations before and after the use of ruxolitinib. The purpose of these laboratory tests was to highlight how JAK-STAT inhibition decreases the levels of proinflammatory cytokines and subsets of T-lymphocytes that contribute to cGVHD, as noted in prior studies.16,17 However, missed specimen collection or collection of poor quality specimens decreased the power of the planned correlative studies. Although incorporating biological markers in clinical trials is highly desirable,14 the study results highlight the challenges associated with biomarker incorporation in an early phase trial.
In conclusion, the use of ruxolitinib was associated with relatively high rates of skin/joint responses and overall cGVHD responses, low NRM and high FFS in patients with refractory sclerotic cGVHD. One-third of patients reported improvement in symptom burden. Despite these results, many patients did not respond to treatment, and progression of cGVHD led to treatment discontinuation in seven patients prior to 6 months. Toxicities were generally manageable, and two-thirds of patients continued beyond 6 months. A randomized trial comparing ruxolitinib to the best available therapy can establish the superiority of ruxolitinib over other agents in sclerotic cGVHD. However, such a trial is unlikely to be conducted. Additionally, given that only half of patients with sclerotic cGVHD respond to ruxolitinib, it may be prudent to focus on designing trials to improve treatment efficacy. As such, future studies should consider using ruxolitinib or other novel drugs such as belumosudil or axatilimab earlier in the treatment course, as patients with sclerotic cGVHD who are less heavily treated may respond better. Also, trials combining novel drugs should be tested to further improve efficacy. Until such studies are conducted, based on the results of this trial, single-agent ruxolitinib offers an effective option for sclerotic cGVHD, thus meeting a hitherto unmet need.
Supplementary Material
Context.
Key Objective:
To determine the efficacy of ruxolitinib in patients with corticosteroid refractory sclerotic cGVHD, a highly morbid and refractory form of cGVHD.
Knowledge Generated:
In this multicenter phase II trial, the use of ruxolitinib was associated with partial responses in skin and/or joints in 49% and improvement in Lee symptom scale summary and skin subscale scores in 38% of patients at 6 months. With relatively low rates of non-relapse mortality (2.2%), treatment failure (20.8%) and no malignancy relapse, failure-free survival was 77% at 12 months.
Relevance (written by Charles Craddock):
Ruxolitinib represents an important and well tolerated new treatment option in corticosteroid refractory sclerotic cGVHD. Strategies permitting earlier therapeutic intervention and the development of combination regimens with emerging novel therapies have the potential to further improve patient outcomes.
Acknowledgements
The authors would like to extend our gratitude to all the patients who participated in this clinical trial, to the investigators and research personnel at all the cancer centers, to research personnel at Dr. Ram Mahato’s laboratory at the University of Nebraska Medical Center, and to Taylor Johnson, Peggy Heires and other Clinical Trial Office staff at the Fred & Pamela Buffett Cancer Center for their support in managing the multicenter trial. The authors would also like to thank Bharti Sethi, who was a significant contributor in Ram Mahato’s laboratory and was instrumental in completing multiple laboratory experiments related to this study.
This work was supported by grant and drug support from Incyte. The Clinical Trial Office, and the Protocol Review and Monitoring System Office at the Fred & Pamela Buffett Cancer Center are supported by a grant from the National Cancer Institute (P30 CA036727). During the study time period, VRB was supported by a grant from the National Institute of General Medical Sciences, 1 U54 GM115458, which funds the Great Plains Institutional Development Award (IDeA) Clinical Translational Research (CTR) Network. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Footnotes
Disclosure of Conflicts of Interest
VRB reports participating in the Safety Monitoring Committee for Protagonist, serving as an Associate Editor for the journal, Current Problems in Cancer, and as a contributor for BMJ Best Practice, and receiving consulting fees from Imugene, research funding (institutional) from MEI Pharma, Actinium Pharmaceutical, Sanofi U.S. Services, Abbvie, Pfizer, Incyte, Jazz, and National Marrow Donor Program, and drug support (institutional) from Chimerix for a trial. HKC reports participating on ad hoc advisory boards for Incyte, clinical steering committee for Incyte, regional consulting for Sanofi, and research funding support by Opna. BKH reports participating on ad hoc advisory board for Incyte, Sanofi, and Rigel, Data Safety Monitoring Board for Angiocrine, and adjudication committee for CSL Behring. KG reports participating in advisory board for Novartis Pharmaceutics, Autolus and ImCheck Therapeutics. TN reports participating in advisory board for Medexus (uncompensated), and receiving clinical trial support (institutional) from Novartis and drug support for a clinical trial (institutional) from Karyopharm. SJL has received consulting fees from Mallinckrodt, Equillium, Kadmon, Novartis, Incyte; research funding from Amgen, AstraZeneca, Incyte, Kadmon, Pfizer, Sanofi and Syndax, and drug supply from Janssen. She is on clinical trial steering committees for Incyte and Sanofi. She is on the Board of Directors of the National Marrow Donor Program (uncompensated). There are no conflicts of interest for other authors.
Statement of prior presentations: Presented in an abstract form at the 2022 American Society of Hematology Annual Meeting in New Orleans.
Data Sharing Statement: Researchers interested in the original data should contact the corresponding author or University of Nebraska Medical Center Investigator-Initiated Trial Office at iitoffice@unmc.edu. A Data Use Agreement will be required.
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