Clinical Predictors of Response in Chronic Graft-Versus-Host Disease: Results From the "Predicting the Quality of Response to Specific Treatments (PQRST)" Trial.

Background

Allogeneic hematopoietic cell transplant (HCT) is a potentially curative therapy for advanced hematologic malignancies and bone marrow failure syndromes. Despite advances in graft‐versus‐host disease (GVHD) prophylaxis, clinically significant chronic GVHD remains a common long‐term complication of transplantation, with an estimated incidence of up to 30% with modern GVHD prophylaxis regimens [ 1 ]. Chronic GVHD is a leading cause of late morbidity and mortality, and impaired quality of life after HCT. The cumulative incidence of non‐relapse mortality in patients with chronic GVHD has previously been estimated to be 22% at 5 years, with an increase over time to a projected 40% at 12 years, with causes of death primarily attributed directly to chronic GVHD or related infections [ 2 ].

Patients with chronic GVHD may suffer from organ dysfunction and adverse effects not only from the disease itself affecting target organs but also the therapies used to treat GVHD, which can subsequently cause physical, functional, and psychosocial deficits, ultimately with disability and poor quality of life [ 3 , 4 , 5 ]. Initial chronic GVHD therapy consists primarily of systemic corticosteroids; however, symptom recurrence is common when steroids are tapered [ 6 ], and only a third of patients have durable remissions off immunosuppression [ 7 ]. Among those who are able to discontinue systemic immunosuppression, the median duration of chronic GVHD therapy is estimated to be about 5 years [ 6 ]. Furthermore, most patients receive multiple lines of therapy without consensus on the best therapy beyond steroids.

Significant advances have been made in understanding the pathogenesis of chronic GVHD, which is now felt to be a complex series of processes involving interactions of alloreactive donor cells and early inflammation, driven by innate immune cells and persisting B‐ and T‐cell dysregulation resulting in chronic inflammation, and aberrant recipient tissue repair and fibrosis [ 8 ]. This understanding has led to the approval of novel, less broadly immunosuppressive therapies targeting specific pathogenic pathways. Since 2017, four agents have been FDA‐approved for steroid‐refractory chronic GVHD treatment: ibrutinib, a BTK inhibitor and the first agent to be approved in 2017 [ 9 ]; ruxolitinib, a JAK1/2 inhibitor [ 10 ] and belumosudil, a ROCK2 inhibitor [ 11 ], both approved by the FDA in 2021; and most recently, axatilimab, a CSF‐1R inhibitor, approved in 2024. Despite relatively favorable response rates in this challenging population, there remain significant gaps in understanding the pleomorphic nature of chronic GVHD and varying organ‐specific responses to therapies. A major limitation in the field is the gap in knowledge of how to use clinical disease phenotypes and biologic markers to rationally choose agents for first, second, or third‐line therapy and subsequent sequence of therapies to achieve optimal response and durable disease control.

The Chronic GVHD Consortium conducted this prospective observational trial of patients with moderate to severe chronic GVHD requiring first, second‐, or third‐line therapy to identify predictors of treatment response. This paper focuses on clinical predictors of response.

Methods

Study Design

This is a prospective cohort study of patients with chronic GVHD [ 12 ] who were starting first‐, second‐, or third‐line “index” therapy between July 2020 and August 2025 ( NCT04431479 ). The index therapy must have been started for chronic GVHD within 2 weeks of the baseline visit and had to be based on one of the following classes of therapy: prednisone‐based therapy (prednisone started at > 0.25 mg/kg/day or the dose increased to > 0.5 mg/kg/day), BTK inhibitors (e.g., ibrutinib, acalabrutinib), JAK inhibitors (e.g., ruxolitinib, itacitinib, baricitinib), belumosudil, axatilimab, mTOR inhibitors (sirolimus), calcineurin‐inhibitors (cyclosporine or tacrolimus), extracorporeal photopheresis, monoclonal CD20 antibodies (e.g., rituximab, ofatumumab), methotrexate, or mycophenolate mofetil. These agents were chosen as potential index therapies to include FDA approved and most commonly used therapies and to minimize heterogeneity in treatment as much as possible. A new line of therapy was defined as one or more systemic agents intended to start at the same time to treat chronic GVHD, or if prednisone was increased by > 0.5 mg/kg/day from prior dose. Other dose adjustments were not considered a new line of therapy.

Patients were eligible for this study if they were ≥ 18 years of age and recipients of an allogeneic HCT for any indication, from any donor, with any graft source, conditioning regimen, and GVHD prophylaxis. Concurrent acute GVHD manifestations were allowed if at least one classic chronic GVHD manifestation was also present (i.e., overlap subtype) [ 13 ]. Exclusion criteria included any evidence of relapsed primary malignancy, uncontrolled psychiatric disorders, or life expectancy < 6 months. The protocol was approved by a central Institutional Review Board (IRB) at the Fred Hutchinson Cancer Center. All participants provide written informed consent. The trial was registered at clinicaltrials.gov: NCT04431479 .

Patients were evaluated at the start of index treatment, and subsequent time points (1, 3, and 6 months after start of therapy) or at the time of treatment change if before 6 months and were graded per 2014 NIH consensus conference scoring (0–3) and response criteria. Patient‐reported outcomes were collected and medical records review performed at each study visit. Sociodemographic information (race, ethnicity, age, sex, relationship status, education, work status, and family income) was collected by self‐report at the baseline assessment. Research blood samples were collected at enrollment, 1 month, and if a new systemic immunosuppressive treatment was started before 6 months [ 12 , 14 ].

Clinical Endpoints

Clinical endpoints included calculated NIH‐, provider, and patient‐best responses (Table S1 ) by and at 6 months; failure‐free survival; and clinical predictors of these responses. Responders included those who achieved a complete (CR) or partial response (PR) prior to starting a next systemic therapy and within 6 months of starting index medication. Anyone who did not achieve a CR or PR by 6 months or who started a next systemic treatment prior to achieving a CR or PR was a non‐responder to the index therapy. Nine patients with missing response data (died [ N = 4] or withdrew [ N = 5]) were considered non‐evaluable.

Patient‐Reported Outcomes (PRO)

Participants completed the 30‐item Lee Symptom Scale (LSS), a validated patient‐reported chronic GVHD symptom scale captured on a five‐point Likert scale. Patients also completed the Patient Reported Outcomes Measurement Information System (PROMIS)‐29 and the PROMIS‐Global. The PROMIS‐29 is a 30‐item assessment measuring physical and social function, anxiety, depression, fatigue, pain, and sleep disturbance. The PROMIS‐Global is a 10‐item measurement assessing a total global physical and mental function with a score for each. For analyses assessing change in quality of life, improvement or worsening of the modified LSS summary symptom score by 6 points or more [ 15 ] or the PROMIS Physical or Mental Functioning scales by 5 points or more compared to baseline is considered a clinically significant change. The PROMIS‐29 measures were included in analyses of predictors of response.

Statistical Analysis

Descriptive statistics were used to summarize baseline transplant and chronic GVHD features, as well as PROs. Failure‐free survival was estimated from the start of the index medication, with failures defined as relapse, death, or addition of next systemic therapy (or increase in steroids > 0.5 g/kg) for any reason for treatment of chronic GVHD. Overall survival (OS) was defined as the time from the start of index medication to death from any cause. Non‐relapse mortality was defined as the time from the start of index medication to death with relapse as a competing risk. Patients lost to follow up or surviving as of last contact were censored.

Cox regression and logistic regression models were used to identify risk factors for FFS and NIH response by 6 months, respectively. Potential predictors included age, sex, family income, patient‐reported LSS and PROMIS, HCT‐Comorbidity index (CI), disease, graft, donor type, conditioning regimen, GVHD prophylaxis, index line of therapy, severity of GVHD, GVHD organ involvement, and index treatment. NIH‐calculated, clinician‐reported and patient‐reported changes in chronic GVHD activity at 6 months were investigated for their ability to predict 1 year FFS, NRM and survival.

Results

Baseline Patient and GVHD Characteristics

Between July 2020 and August 2025, 181 patients with chronic GVHD were prospectively enrolled from 10 transplant centers within the Chronic GVHD Consortium and had at least 6 months of follow‐up for analysis. Accrual is still ongoing to enroll and collect additional data on patients treated with axatilimab which was only FDA‐approved in August 2024. Baseline characteristics are shown in Table 1 . Median age at enrollment was 62 years (interquartile range [IQR] 52–68), and almost all patients underwent HCT for malignant disease, most received a peripheral blood stem cell graft (89%), and their GVHD prophylaxis was calcineurin inhibitor (CNI)‐based in combination with methotrexate (40%) or mycophenolate mofetil (34%). Median time from HCT to enrollment was 17 months (IQR 10–34), and median follow up after enrollment was 15 months (IQR 7–29).

GVHD characteristics at time of enrollment are shown in Table 2 . Chronic GVHD was first diagnosed at a median of 9 months post‐HCT (IQR 6–14) and was moderate or severe in the majority (95%) of patients; many (61%) also had prior acute or late acute GVHD. Skin, eyes, and mouth were most commonly involved with > 50% of patients affected. Of those with skin ( N = 115) involvement, 66 had sclerotic manifestations. Patients were most commonly starting first (47%) or second (35%) line therapy. Index treatment by line of therapy is shown in Table 3 and although prednisone, ruxolitinib, and belumosudil were the most common agents used across first, second‐ and third‐line therapies, there is a wide range of different agents used, including 39/181 (21.5%) combination therapies, reflecting significant practice variation. Most combination therapies were started within 2 weeks of each other, as defined by the protocol to be considered one new index line of therapy. Other agents, including ibrutinib and ECP, were much less common. Only four patients received axatilimab, likely reflecting the timing of its FDA‐approval and availability. Of note, for first line therapy, 58/85 (68%) started prednisone but 30/85 (35%) received prednisone in combination with another agent. There were no clear differences in choice of agent based on organ involvement and the most common agent used across all organs was ruxolitinib (data not shown).

Response and Survival Outcomes

Best responses by 6 months by all response criteria were high, but not durable. Best calculated NIH response was 72%, clinician‐reported response was 76% and patient reported response was 71%. At 6 months however, almost half of responders had lost their response and CR/PR rates were 40% (Table 4 ). Median time to best response was 35 days (NIH and patient), and 36 days (provider). These responses were largely driven by mouth and skin and much less commonly by esophagus and upper and lower GI, although all organs responded. On average, more than one organ contributed to each patient's response. In contrast, eye, skin, joint and mouth were the organs most likely to account for progression (Table S2 ). We further evaluated responses to specific agents in common organs of interest (sclerotic skin, mouth, and eye). Highest responses for sclerotic skin (60% [3/5]) and eye (83% [5/6]) were seen with extracorporeal photopheresis but the sample size was very small. Oral responses were seen across several agents (Table S3 ).

In contrast, best response and response at 6 months when defined by validated PRO measures was lower, for example 53% and 30% for the LSS (Table 4 ). In addition, the response measures agreed 74%–78% of the time with modest correlations between the various response measures when comparing responders and non‐responders, for example, in best response by 6 months: NIH response vs. clinician‐reported 0.36, NIH response vs. patient‐reported 0.37, clinician‐reported vs. patient‐reported 0.45, with no evidence that one measure consistently over‐ or under‐estimated response compared to the others, p = 0.30, p = 0.88, p = 0.19, respectively, by McNemar's test.

Six‐, 12‐ and 18‐month estimates for FFS, NRM, and OS are shown in Table 5 . There were no differences in FFS by index therapy (prednisone, ruxolitinib or belumosudil) or line of therapy (first, second, or ≥ third line) (Table S4 ). We analyzed FFS by index therapies for first line therapy only and found no differences whether patients were treated with prednisone alone, prednisone in combination with other agents, or non‐steroidal therapies upfront. Landmark analysis at 6 months demonstrated that NIH‐calculated and clinician‐reported response (CR/PR) was correlated with slightly higher but not statistically different 1 year FFS across all clinician‐based response measures. Unexpectedly, patient reported improvement at 6 months was associated with worse but not statistically different FFS, 68% (53%–80%) versus stable/worsening 75% (46%–90%) (Table S5 ).

Predictors of Response and FFS

Although several clinical variables were analyzed for their association with NIH response, only PROMIS 29 fatigue demonstrated a statistically significant association with NIH‐response, where worse fatigue was associated with worse response (Table 6 ). Specific organ involvement, severity, line of therapy, choice of therapy, LSS scores, and patient, disease, and transplant variables were not found to significantly predict response.

The only variable associated with shorter FFS was worse PROMIS physical health score, both in univariable and multivariable analysis (OR 0.6, 95% CI 0.5–0.8, p < 0.001). The only factor associated with best LSS response (defined by decrease of ≥ 6 points) in multivariate analysis was higher baseline LSS summary scores (higher symptom burden), OR 2.1 per 10 points, 95% CI 1.5–2.9, p < 0.001. Worse PROMIS physical health response was predicted by worse baseline score (OR 0.6 per 10 points, 95% CI 0.4–0.9, p = 0.02). PROMIS mental health improvement was associated with higher PROMIS 29‐depression, 1.6 per 10 points, 95% CI 1.1, 2.4, p = 0.02.

In the FFS analysis, the most common event defining the N = 103 “failures” was initiation of a new medication N = 88 (85%), with a smaller number of relapses N = 9 (9%) and deaths N = 6 (6%). In multivariable analysis, only lower physical health by PROMIS was significantly associated with worse FFS (HR 0.6, 95% CI 0.6–0.8, p < 0.001).

Discussion

The Chronic GVHD Consortium “Predictors of Quality of Response to Therapy” study aims to better identify and understand predictors of treatment response to personalize future therapy in this pleiomorphic disease. This paper focuses on clinical predictors of response and reports failure‐free survival in a contemporary era. In this real‐world study, we found that best ORR within the first 6 months was similar to clinical trials with 60%–80% CR/PR but by 6 months, both response and FFS were only about 40%. Decline in response was seen across all NIH, clinician‐reported, and patient‐reported criteria. Overall NRM was low at 6% by 12 months, but still increased over time. Despite novel FDA‐approved therapies, FFS at 6‐ (66%) and 12 months (48%) was similar to a previous report by Palmer et al. (FFS 63% at 6 months and 45% at 12 months) and Inamoto et al. (FFS 68% at 6 months and 54% at 12 month for initial treatment) describing older agents [ 16 , 17 ]. Of note, the impact of length of time on any given therapy, or sequence of therapies, was not investigated, and the overall longer‐term benefit of novel agents over historic therapies remains to be seen. Nevertheless, it is interesting that in this analysis, FFS and NRM up to 1 year has not changed over time despite advances in the understanding of chronic GVHD and development of novel agents. Further investigation into the reason for this is still needed. Furthermore, although we demonstrated patient‐reported fatigue was associated with lower response rates, we did not find any other clinical predictors of response despite extensive evaluation of clinical information.

The most common medications used in this study were corticosteroids, ruxolitinib and belumosudil for any line of therapy, although corticosteroid use as index treatment decreased in subsequent lines of therapy. Axatilimab was only approved in 2024, and few patients in our cohort received this medication. The study is currently enrolling patients treated with axatilimab to further enrich this cohort. We did not find any evidence that clinicians tailored therapy to any specific organ manifestation. Instead, providers continue to have significant variations in practice, and used several different agents and combinations, particularly in first‐line therapy. In investigating common organs of interest (sclerotic skin, mouth, and eyes), we also did not find any pattern of therapies used.

This analysis did not identify any strong clinical predictors of relapse or death, although median follow‐up was only 15 months. Six‐month response was associated with better FFS at 1 year; but no specific therapy or line of therapy was associated with FFS. In multivariate analysis, only PROMIS physical health predicted FFS, which may be more of an indicator of baseline poor physical functioning and not GVHD biology or treatment responsiveness. This highlights once again the importance of patient‐reported outcomes and quality of life measures in chronic GVHD, both as predictors of outcomes and as meaningful measures of successful treatment. Our results show that correlation between clinician‐assessed and patient‐reported responses is modest, and discrepancies should be anticipated, possibly reflecting that clinicians and patients perceive or value changes differently.

We acknowledge several limitations of this study. Eligible patients were starting initial, second‐ or third‐line therapies for chronic GVHD, and the phenotype for these cases may differ by nature or line of therapy in their response pattern. While further elucidating these phenotypes and responses is part of the overarching aims of the study, heterogeneity in the cohort complicates the analysis. The study was also impacted by the COVID‐19 pandemic, and while enrollment continued during this time period, the speed of enrollment and completeness of data were compromised. Haploidentical and mismatched unrelated donors and post‐transplant cyclophosphamide (PTCy) GVHD prophylaxis were under‐represented in our cohort, reflecting the years of accrual and possibly the lower likelihood of cGVHD when PTCy is used. The cohort had very few patients treated with axatilimab so we continue to accrue these patients. Furthermore, the simplification of defining and categorizing “index therapy” into groups which differ markedly in response kinetics and toxicity, and treating them as a single categorical variable may mask therapy‐specific predictors.

Nevertheless, this initial report from the Chronic GVHD consortium PQRST cohort demonstrates and confirms favorable but unfortunately not durable responses with contemporary therapies. Although clinical trials have consistently shown that many chronic GVHD therapies achieve meaningful early responses, those studies largely emphasized best overall response rates and short‐term improvement. Our real‐world cohort reinforces a less visible but clinically important reality: responses across therapies are often not durable, regardless of line of therapy. This study highlights the ongoing challenge of sustaining benefit over time and the persistent need for more durable and phenotype‐informed/biologically‐based treatment strategies. Additional studies to further detail organ involvement and biologic phenotypes and their responsiveness to specific therapies are ongoing with the goal of better personalizing treatment approaches and improving durable control of chronic GVHD.

Funding

This work was supported by the National Institutes of Health (CA118953).

Conflicts of Interest

B.K.H. received consulting fees from Incyte and Sanofi; research funding from Incyte; adjudication committee for CSL Behring. P.A.C. has received consulting fees from Incyte, Mesoblast, and Sanofi; research funding from Sanofi. J.P. has received consulting fees from Incyte, Sanofi, and Deciphera; research funding from BMS, CTI Biopharma, Incyte, Sanofi, Johnson & Johnson, and AstraZeneca. G.C. received consulting fees from Sanofi. N.F. has received consulting fees for Incyte, Johnson & Johnson, Omeros, and Sanofi and serves on the speaker bureau for Incyte. Medical Monitor: Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Co‐Chair: CIBMTR Chronic GVHD Committee. C.L.K. has served on the advisory boards for Incyte, Mesoblast, and Sanofi. She has served on the GVHD adjudication committee for a clinical trial performed by CSL Behring. C.J.L. has received consulting fees from Incyte, Sanofi, Jazz; research funding from Incyte. She is on a clinical trial steering committee for Incyte. S.J.L. has received consulting fees from Novartis, Incyte, Sanofi, Orca Bio, Sonoma, GSK; research funding from 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). The remaining authors declares no conflicts of interest.

Supporting information

Table S1: Response definitions.

Table S2: Organs accounting for NIH response (A) or progression (B) by visit.

Table S3: Best organ response by Index medication regardless of line of therapy.

Table S4: Failure‐free Survival (FFS) by index therapy.

Table S5: Subsequent failure‐free survival (FFS) at 1 year, based on six‐month response.

Acknowledgments

This work was supported by the National Institutes of Health (CA118953). This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH). The contributions of the NIH author are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the author and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

Supplementary Materials

Table S1: Response definitions.

Table S2: Organs accounting for NIH response (A) or progression (B) by visit.

Table S3: Best organ response by Index medication regardless of line of therapy.

Table S4: Failure‐free Survival (FFS) by index therapy.

Table S5: Subsequent failure‐free survival (FFS) at 1 year, based on six‐month response.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.