Diagnosis Of cGVHD Research Articles

Oral Chronic Graft-Versus-Host Disease: Pathogenesis, Diagnosis, Current Treatment, and Emerging Therapies.

Chronic graft-versus-host disease (cGvHD) is a multisystem disorder that occurs in recipients of allogeneic hematopoietic (alloHCT) stem cell transplants and is characterized by both inflammatory and fibrotic manifestations. It begins with the recognition of host tissues by the non-self (allogeneic) graft and progresses to tissue inflammation, organ dysfunction and fibrosis throughout the body. Oral cavity manifestations of cGVHD include mucosal features, salivary gland dysfunction and fibrosis. This review synthesizes current knowledge on the pathogenesis, diagnosis and management of oral cGVHD, with a focus on emerging trends and novel therapeutics. Data from various clinical studies and expert consensus are integrated to provide a comprehensive overview.

Treatment-Sensitive and Treatment-Dependent Chronic Graft-versus-Host Disease Yield Superior Failure-Free and Overall Survival Compared to Treatment-Resistant Chronic Graft-versus-Host Disease

Response to treatment of chronic graft-versus-host disease (cGVHD) may help predict prognosis and outcomes. We hypothesized that the response of cGVHD to treatment and the ability to taper immunosuppression define distinct treatment response categories that differ in terms of risk factors and prognosis. Our aim was to determine specific clinical characteristics and outcomes associated with 3 distinct cGVHD treatment response groups based on the response to and duration of immunosuppressive therapy (IST) as treatment-sensitive (TS), treatment-resistant (TR), and treatment-dependent (TD) cGVHD. This retrospective single-institution cohort study included 1142 consecutive adult and pediatric recipients of allogeneic hematopoietic cell transplantation (HCT) performed for malignant and nonmalignant disorders at the University of Minnesota between 2008 and 2016. All donor, graft, conditioning regimen, and GVHD prophylaxis strategies were included, but only patients who commenced systemic treatment within 30 days of cGVHD diagnosis were included. A total of 185 patients who developed cGVHD necessitating IST within 30 days of cGVHD diagnosis were included in this analysis. At 1 year after cGVHD onset, 13% of the patients were TS, 27% were TD, and 60% were TR (including 14% deceased), whereas at 2 years after cGVHD onset, 29% were TS, 5% were TD, and 66% were TR (including 22% deceased). In a landmark analysis starting at 1 year after cGVHD onset, 5-year failure-free survival (FFS) and overall survival (OS) were lowest in the TR group (FFS, 38%; OS, 70%), with comparable outcomes in the TD (74% and 82%, respectively) and TS (79% for both) groups. Compared to no cGVHD, TR cGVHD was associated with worse OS at 5 years after cGVHD (hazard ratio, 2.09 versus no cGVHD; 95% confidence interval, 1.3 to 3.3; P < .01). Our findings suggest that refining cGVHD classification into 3 treatment response states defines important predictors of early and late clinical outcomes and identifies patients needing more effective treatment.

Genital chronic graft-versus-host disease: an unmet need that requires trained gynecologists

Objective Menopause and chronic graft-versus-host disease (cGvHD) are the leading causes of morbidity after allogeneic hematopoietic stem cell transplantation (alloHSCT). Genitalia are one of the target organs of cGvHD causing sexual dysfunction and local symptoms, which may impair women’s quality of life. The aim of this study is to describe the prevalence and clinical characteristics of genital cGvHD. Methods A retrospective cross-sectional observational study was performed including 85 women with alloHSCT. All women were diagnosed and counseled by a trained gynecologist. Health-related quality of life was assessed by the Cervantes Short-Form Scale and sexual function was evaluated by the Female Sexual Function Index. Results Seventeen women (20%) included in the study were diagnosed with genital cGvHD. The main complaints were vulvovaginal dryness (42.2%) and dyspareunia (29.4%), the presence of erythema/erythematous plaques (52.9%) being the most frequent sign. Median time from transplant to diagnosis of genital cGvHD was 17 months among those with mild involvement, 25 months for moderate and 42 months for severe forms. Mortality was 29.4% in patients who developed cGvHD with genital involvement versus 8.8% among those without (p = 0.012). Conclusion Early gynecological evaluation might allow to identify patients with mild forms of genital cGvHD, potentially enabling better management and improved outcomes.

Impact of Center Volume on Chronic Graft Versus Host Disease in Patients With Allogeneic Stem Cell Transplantation

BackgroundChronic graft-versus-host disease (cGVHD) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT), negatively impacting quality of life (QoL) and increasing the risk of death. Complexity in cGVHD diagnosis and treatment causes significant variations in cGVHD management strategies across medical centers and physicians despite the existence of published guidelines. Thus, we hypothesized that center volume is associated with cGVHD incidence and outcomes after cGVHD develops. ObjectiveThis study aimed to evaluate the effect of center volume on the incidence of cGVHD in patients who underwent HSCT and outcomes in patients with cGVHD. Study DesignOur retrospective study included 28,786 patients who underwent their first HSCT (overall cohort) and 7,664 who developed cGVHD (cGVHD cohort). We categorized institutions into quartiles (very low, low, high, and very high) using the number of HSCTs performed during the study period. We assessed cGVHD incidence in overall cohort and overall survival (OS) in cGVHD cohort. ResultsThe very high-volume group showed significantly higher cGVHD incidence (adjusted hazard ratio [HR], 1.38; 95% confidence interval [CI]: 1.30–1.46) compared to the very low-volume group. However, the cGVHD incidence was similar among very low-, low- and high-volume groups. Low, high, and very high-volume groups showed significantly higher OS with adjusted HRs of 0.83 (95% CI: 0.73–0.94), 0.69 (95% CI: 0.61–0.79), and 0.68 (95% CI: 0.60–0.76), respectively, compared with the very low-volume group. ConclusionIn conclusion, we revealed a higher incidence of cGVHD in the very high-volume group and a poor survival outcome in the very low-volume group in patients with cGVHD.

Real-World Outcomes of Pfts in Screening for Lung Involvement in Chronic Gvhd Post-Allogeneic Stem Cell Transplant: A Retrospective Study of 387 Patients in British Columbia, Canada

Introduction: Lung involvement in chronic graft versus host disease (cGVHD) is an uncommon but potentially devastating complication with significant morbidity and mortality in patients who have received an allogeneic hematopoietic stem cell transplant (alloHSCT). Unfortunately, early detection remains difficult as early lung cGVHD tends to be asymptomatic or present with nonspecific symptoms such as cough or mild shortness of breath. In British Columbia (BC), Canada, routine pulmonary function tests (PFTs) have been employed in the screening of lung cGVHD in this population at an interval of every 3-4 months for the first 2-3 years after alloHSCT. However, it is unknown whether routine screening 1) improves detection of lung cGVHD, and 2) enables earlier intervention to lead to better outcomes. We aimed to assess the real-world outcomes of lung cGVHD screening and compared the characteristics and clinical results of patients who had lung cGVHD detected via routine PFT screening, versus those who were detected after development of symptoms. Methods: A retrospective chart review was conducted on all adult patients who underwent an alloHSCT at BC, Canada between June 2017 and January 2021. Patients were followed until August 2022. Patients were excluded if they had primary graft failure or if they died within 100 days after transplant. All types of pulmonary GVHD were included analysis and cases were established by the treating clinician in the clinical record. NIH consensus criteria were used to grade cGVHD severity. Statistical significance was calculated using the Chi square test for categorical variables and T-test for continuous variables. Results: Among 387 eligible consecutive patients who underwent alloHSCT, 189 (49%) developed cGVHD, with 33 (9%) cases of lung involvement. The mean time to diagnosis of lung cGVHD from the date of transplant was 13 ± 8 months. There were 16 cases of lung cGVHD (48%) that were initially detected by routine screening, while 17 cases (52%) were first detected due to clinical symptoms that developed in between screening visits or after the screening period ended (two patients developed symptoms at 27 months and 43 months respectively). Patient characteristics are presented on Table 1. Lung involvement was the first cGHVD sign in 17/33 (51%) of patients, with 5 (15%) detected by routine screening and 12 (36%) due to symptoms. At time of diagnosis of lung involvement, 12/33 (36%) of patients were already on systemic immunosuppression for cGVHD with 9 (56%) of these cases detected from screening and 3 (18%) from symptoms (p=0.02). All patients had a maximum overall cGVHD severity by NIH criteria of 2-3. Sixteen of 33 (48%) patients had a lung cGVHD score by NIH criteria of 2-3 at diagnosis, with a mean FEV1 of 54% ± 15, compared to 17 (52%) patients with a score of 1 and mean FEV1 of 78% ± 12. The NIH score at diagnosis was not significantly different between those picked up by routine screening versus symptoms (p=0.76). Eighteen of 33 (55%) patients had a maximum lung cGVHD score by NIH criteria of 2-3, with the mean lowest FEV1 of 52% ± 15, compared to 15 patients (45%) with a maximum lung cGVHD score of 1, with the mean lowest FEV1 of 77% ± 10. Similarly, the maximum NIH lung cGVHD score were not significantly different between those picked up by routine screening versus symptoms (p=0.08). However, patients picked up on screening were more likely to have significant clinical improvements in lung function (4/16 [25%] versus 0/17 [0%], p=0.03), and less likely to die from lung cGVHD (0/16 [0%] versus 5/17 [29%], p=0.02). Conclusions: Routine screening PFTs are effective for early diagnosis of asymptomatic lung cGVHD, and are associated with improved outcomes compared to patients who were diagnosed after symptoms developed. Since a significant number of these patients were not previously receiving immunosuppression for other cGVHD, this suggests a potential benefit in screening all patients every 3 months, regardless of prior GVHD status.

Treatment- Sensitive, Dependent, and Refractory Chronic Gvhd: Incidence and Clinical Outcomes

Introduction Chronic graft-versus-host disease (cGVHD) remains a limitation to the long-term success of allogeneic hematopoietic cell transplantation (HCT). The clinical characteristics and outcomes associated with treatment-sensitive, -dependent, and -refractory cGVHD are unknown. We investigated risk factors associated with distinct cGVHD treatment response groups and analyzed the impact of treatment response on clinical outcomes of cGVHD following HCT. Methods The study population included 185 consecutive adult and pediatric patients who developed cGVHD after first allogeneic HCT for malignant and non-malignant disorders at the University of Minnesota between 2008 and 2016. All graft and donor sources, GVHD prophylaxis strategies, and conditioning regimens were included. Only cGVHD cases that started treatment within 30 days of diagnosis are included. We defined cGVHD diagnosis and overall severity using the 2014 NIH Consensus Criteria. We predefined treatment response categories as either treatment-sensitive (TS), -dependent (TD), or -refractory (TR) at 6, 12, and 24 months after cGVHD onset. TS requires clinical improvement after 12 months of initial therapy with discontinuation of therapy by 24 months. TR criteria include disease progression during therapy, addition of new systemic therapies, or death before 6 months of cGVHD treatment. TD patients meet TS criteria, however still require systemic therapy 24 months after initiation of cGVHD therapy. Outcomes by response group were analyzed in a landmark analysis at the time at which treatment response was determined, excluding any with the event of interest (relapse, death) before the landmark time. To compare treatment response categories with a no-cGVHD control group, the landmark time was set to the median day of cGVHD onset (day 220) plus treatment response category ascertainment time (e.g. 12 months). Disease-free survival (DFS) was defined as survival without relapse or death. Failure-free-survival (FFS) after cGVHD was defined as survival without relapse, death, or new systemic treatment initiated more than 30 days after cGVHD onset. Results Patient and transplant characteristics are shown in Table 1. Among 1142 allografts, 222 (19%) developed cGVHD and of those 185 (83%) received systemic cGVHD therapy within 30 days of onset and were included in this analysis. Median time to onset of cGVHD was 216 days (range 71-945) with 7.4 years median time follow up time after cGVHD. The 3-year cumulative incidence of mild, moderate, and severe cGVHD was 3.4%, 11.5%, and 4.4%, respectively. The distribution of treatment response categories as TS, TD, or TR cGVHD are shown at 6, 12, and 24 months in the Sankey plot (Figure 1). Patients were most often TD at 6 months after diagnosis and transitioned to TS or TR by 24 months. Patients with moderate and severe cGVHD were equally likely to be either TD or TR at 6 months. By 12 months, most severe cGVHD cases were TR, while the TD group consisted mostly of moderate cGVHD cases. Patients with prior aGVHD, especially maximum grade III-IV aGVHD, were more likely to have TR cGVHD at 12 months. Patients over 18 were more likely to have TD or TR cGVHD. We noted no other significant risk factors associated with treatment response groups. The most common second-line cGVHD therapy used in addition to systemic corticosteroids was largely sirolimus, followed by cyclosporine and tacrolimus. We analyzed clinical outcomes by treatment response at 12 months from cGVHD diagnosis. 10-year FFS was lowest in TR followed by TD and TS groups (38%, 66%, 79%, respectively; P=0.01). Similarly, both 10-year overall survival and DFS were lowest in TR group followed by TD and TS groups. 10-year NRM was highest in TR and TD groups compared to the TS group (33%, 23%, 5%, respectively; P=0.13). In multivariate analysis, TR cGVHD was associated with worse overall survival at 12 months after cGVHD (HR 2.5 vs. no cGVHD; 95% CI, 1.7-3.7; P &amp;lt; .01) Conclusions We identified TR cGVHD as a significant risk factor for lower OS and FFS at 12 months post-diagnosis. TS and TD cGVHD groups showed similar prognoses, both better than the TR group. Our findings suggest that cGVHD treatment response states are important predictors of clinical outcomes. Additionally, we have shown that long term follow-up after cGVHD treatment is necessary to determine treatment sensitivity and therefore predict long term outcomes.

Early Elevation of Absolute Eosinophil Count after Allogeneic Hematopoietic Stem Cell Transplantation Is Associated with Chronic Graft-Versus-Host Disease in Children

BACKGROUND Chronic graft-versus-host disease (cGVHD) is the most frequent late complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with non-relapse mortality. If recipients with cGVHD are not properly treated at the appropriate time, cGVHD can lead to severe complications. Therefore, early prediction of cGVHD is required to improve quality of life among the pediatric survivors who undergo allo-HSCT. The significance of eosinophilia in peripheral blood after allo-HSCT remains to be elucidated. Previous studies found that eosinophilia after allo-HSCT reduced the risk of relapse of malignancies or non-relapse mortality and was also associated with cGVHD. However, the subjects of these reports were mainly adults and there were limited data focused on eosinophilia after allo-HSCT in children. The aim of this study was to evaluate whether an early elevation of absolute eosinophil count after allo-HSCT was associated with the development of cGVHD in children. METHODS A total of 165 consecutive patients who received allo-HSCT in our institute were included. Patients who had previously received allo-HSCT, relapsed or died before day 100, and did not achieve engraftment, were excluded. Eosinophilia was defined as an eosinophil count of more than 500 /µL in peripheral blood within 60 days of stem cell infusion. The primary outcome of the present study was the development of cGVHD. RESULTS In our cohort, eosinophilia was detected in 67 patients (40.6%), with a median maximum eosinophil count of 1,050 /µL (range, 504 - 7,812 /µL) at a median of 40 days (range, 24 - 59 days), while median maximum eosinophil count in those without eosinophilia was 189 /µL (range, 0 - 495 /µL). There were no significant differences between the patients with or without eosinophilia in disease type, graft source, donor type, conditioning regimen, and GVHD prophylaxis and treatment. The median time from day 0 to the date of diagnosis of cGVHD was 120 days (range, 100 - 1,302 days). The cumulative incidence rate of cGVHD at 3 years in the entire cohort was 39.3% (95% confidence interval: 32.2 - 47.4). Patients with eosinophilia had a higher 3-year cumulative incidence rate of cGVHD, compared with those without eosinophilia (49.1% vs. 32.7%, P = 0.007). Cox proportional hazards model analysis with adjustments for the potential confounding factors of HLA mismatched donor, unrelated donor, aGVHD, use of ATG as conditioning regimen revealed that eosinophilia was associated with an increased risk of cGVHD (adjusted hazard ratio: 2.12; 95% confidence interval: 1.16-3.85, P = 0.014). In the 165 patients who underwent allo-HSCT, there was no significant difference in 5-year overall survival (OS) between the eosinophilia and the non-eosinophilia groups (80.1% vs. 80.5%, P=0.76). In the 121 patients with malignant diseases, there was no significant difference in 5-year OS between the eosinophilia and the non-eosinophilia groups (75.5% vs. 76.3%, P = 0.70). There was also no significant difference in 5-year disease-free survival between the eosinophilia and the non-eosinophilia groups (69.1% vs. 77.1%, P = 0.34). On the other hand, there was a significant difference in 5-year GVHD-free relapse-free survival between the eosinophilia and the non-eosinophilia groups (41.1% vs. 62.4%, P = 0.04). DISCUSSION &amp; CONCLUSION In the present study, we revealed that an early elevation of absolute eosinophil count after allo-HSCT was associated with cGVHD in children. Because eosinophilia after allo-HSCT occurs before the development of cGVHD, early eosinophilia after allo-HSCT may predict the development of cGVHD in children.

A diagnostic classifier for pediatric chronic graft-versus-host disease: results of the ABLE/PBMTC 1202 study.

The National Institutes of Health Consensus criteria for chronic graft-versus-host disease (cGVHD) diagnosis can be challenging to apply in children, making pediatric cGVHD diagnosis difficult. We aimed to identify diagnostic pediatric cGVHD biomarkers that would complement the current clinical criteria and help differentiate cGVHD from non-cGVHD. The Applied Biomarkers of Late Effects of Childhood Cancer (ABLE) study, open at 27 transplant centers, prospectively evaluated 302 pediatric patients after hematopoietic cell transplant (234 evaluable). Forty-four patients developed cGVHD. Mixed and fixed effect regression analyses were performed on diagnostic cGVHD onset blood samples for cellular and plasma biomarkers, with individual markers declared relevant if they met 3 criteria: an effect ratio ≥1.3 or ≤0.75; an area under the curve (AUC) of ≥0.60; and a P value <5.814× 10-4 (Bonferroni correction) (mixed effect) or <.05 (fixed effect). To address the complexity of cGVHD diagnosis in children, we built a machine learning-based classifier that combined multiple cellular and plasma biomarkers with clinical factors. Decreases in regulatory natural killer cells, naïve CD4 T helper cells, and naïve regulatory T cells, and elevated levels of CXCL9, CXCL10, CXCL11, ST2, ICAM-1, and soluble CD13 (sCD13) characterize the onset of cGVHD. Evaluation of the time dependence revealed that sCD13, ST2, and ICAM-1 levels varied with the timing of cGVHD onset. The cGVHD diagnostic classifier achieved an AUC of 0.89, with a positive predictive value of 82% and a negative predictive value of 80% for diagnosing cGVHD. Our polyomic approach to building a diagnostic classifier could help improve the diagnosis of cGVHD in children but requires validation in future prospective studies. This trial was registered at www.clinicaltrials.gov as #NCT02067832.

Real-world experience with low-dose IL-2 for children and young adults with refractory chronic graft-versus-host disease

AbstractThe majority of patients with chronic graft-versus-host disease (cGVHD) are steroid refractory (SR), creating a need for safe and effective therapies. Subcutaneous low-dose interleukin-2 (LD IL-2), which preferentially expands CD4+ regulatory T cells (Tregs), has been evaluated in 5 clinical trials at our center with partial responses (PR) in ∼50% of adults and 82% of children by week 8. We now report additional real-world experience with LD IL-2 in 15 children and young adults. We conducted a retrospective chart review of patients with SR-cGVHD at our center who received LD IL-2 from August 2016 to July 2022 not on a research trial. The median age at start of LD IL-2 was 10.4 years (range, 1.2-23.2 years) at a median of 234 days from cGVHD diagnosis (range, 11-542 days). Patients had a median of 2.5 (range, 1-3) active organs at LD IL-2 start and received a median of 3 (range, 1-5) prior therapies. The median duration of LD IL-2 therapy was 462 days (range, 8-1489 days). Most patients received 1 × 106 IU/m2 per day. There were no serious adverse effects. The overall response rate in 13 patients who received >4 weeks of therapy was 85% (complete response, n = 5; PR, n = 6) with responses in diverse organs. Most patients significantly weaned corticosteroids. Tregs preferentially expanded with a median peak fold increase of 2.8 in the ratio of Tregs to CD4+ conventional T cells (range, 2.0-19.8) by 8 weeks on therapy. LD IL-2 is a well-tolerated, steroid-sparing agent with a high response rate in children and young adults with SR-cGVHD.

Prognostic Value of Cutaneous Disease Severity Estimates on Survival Outcomes in Patients With Chronic Graft-vs-Host Disease

Prior studies have demonstrated an association between cutaneous chronic graft-vs-host disease (cGVHD) and mortality. Assessment of the prognostic value of different measures of disease severity would assist in risk stratification. To compare the prognostic value of body surface area (BSA) and National Institutes of Health (NIH) Skin Score on survival outcomes stratified by erythema and sclerosis subtypes of cGVHD. Multicenter prospective cohort study from the Chronic Graft-vs-Host Disease Consortium including 9 medical centers in the US, enrolled from 2007 through 2012 and followed until 2018. Participants were adults and children with a diagnosis of cGVHD requiring systemic immunosuppression and with skin involvement during the study period, who had longitudinal follow-up. Data analysis was performed from April 2019 to April 2022. Patients underwent continuous BSA estimation and categorical NIH Skin Score grading of cutaneous cGVHD at enrollment and every 3 to 6 months thereafter. Nonrelapse mortality (NRM) and overall survival (OS), compared between BSA and NIH Skin Score longitudinal prognostic models, adjusted for age, race, conditioning intensity, patient sex, and donor sex. Of 469 patients with cGVHD, 267 (57%) (105 female [39%]; mean [SD] age, 51 [12] years) had cutaneous cGVHD at enrollment, and 89 (19%) developed skin involvement subsequently. Erythema-type disease had earlier onset and was more responsive to treatment compared with sclerosis-type disease. Most cases (77 of 112 [69%]) of sclerotic disease occurred without prior erythema. Erythema-type cGVHD at first follow-up visit was associated with NRM (hazard ratio, 1.33 per 10% BSA increase; 95% CI, 1.19-1.48; P < .001) and OS (hazard ratio, 1.28 per 10% BSA increase; 95% CI, 1.14-1.44; P < .001), while sclerosis-type cGVHD had no significant association with mortality. The model with erythema BSA collected at baseline and first follow-up visits retained 75% of the total prognostic information (from all covariates including BSA and NIH Skin Score) for NRM and 73% for OS, with no statistical difference between prognostic models (likelihood ratio test χ2, 5.9; P = .05). Conversely, NIH Skin Score collected at the same intervals lost significant prognostic information (likelihood ratio test χ2, 14.7; P < .001). The model incorporating NIH Skin Score instead of erythema BSA accounted for only 38% of the total information for NRM and 58% for OS. In this prospective cohort study, erythema-type cutaneous cGVHD was associated with increased risk of mortality. Erythema BSA collected at baseline and follow-up predicted survival more accurately than the NIH Skin Score in patients requiring immunosuppression. Accurate assessment of erythema BSA may assist in identifying patients with cutaneous cGVHD at high risk for mortality.

Clinical characteristics of oral chronic graft-versus-host disease according to the 2014 National Institutes of Health (USA) consensus criteria.

Chronic graft-versus-host disease (cGVHD) is a serious and common complication of allogeneic hematopoietic cell transplantation (alloHCT). The oral cavity is the second most common site affected by cGVHD. In 2014, the 2005 National Institutes of Health (NIH) consensus criteria were revised to address areas of controversy. The aim of this study was to evaluate the clinical characteristics of oral cGVHD using the 2014 NIH consensus criteria. The baseline data of oral manifestation of patients, who were diagnosed with oral cGVHD, in the first dental visit were analyzed (n=22). The oral mucosal disease was evaluated by NIH modified Oral Mucosa Rating Scale (OMRS) and Thongprasom sign score. The salivary gland disease and sclerotic disease were determined by the presence of signs and symptoms. The functional impact was assessed by the organ-specific severity score. The median time from transplant to oral cGVHD diagnosis was 11.9 months. White striae with an erosive area was found in 72.7% of the patients. The mean ± SD of NIH modified OMRS was 6.1 ± 3.0. The most common and severely affected site of lichen planus-like features was buccal mucosa. Xerostomia, superficial mucocele and limited mouth opening were found in 18.2%, 9.1%, and 9.1%, respectively, of the patients. Almost all patients (90.9%) had partial limitation of oral intake. There were no significant differences in NIH modified OMRS or organ-specific severity score among the patient characteristic groups. Moreover, there was no association between the oral manifestations of cGVHD and the patient characteristics. The most common oral manifestation of cGVHD was white striae with an erosive area of oral mucosal disease, followed by xerostomia, superficial mucocele, and limited mouth opening. The 2014 NIH consensus criteria for diagnostic and severity assessment are informative and feasible in real-world practice.

Characterization of Real-World Chronic Graft-Versus-Host-Disease Patients Receiving Belumosudil

Introduction Chronic graft-versus-host-disease (cGVHD) is a common complication of hematopoietic stem cell transplant (HSCT). cGVHD is characterized by inflammation and fibrosis that negatively impact multiple organ systems, resulting in substantial morbidity and mortality. While many systemic therapies are available to treat cGVHD, these therapies are associated with adverse events that may limit treatment adherence or lead to discontinuation. In July 2021, the Rho-associated coiled-coil kinase 2 (ROCK2) inhibitor belumosudil was approved by the United States Food and Drug Administration for the treatment of cGVHD for patients 12 years and older after failure of at least two prior lines of systemic therapy based on the efficacy observed in a randomized, open-label, multicenter trial (NCT03640481). Characteristics of patients being treated with belumosudil outside of a clinical trial have not been described previously. The objective of this study is to understand the real-world, non-clinical trial use of belumosudil for patients with cGVHD. Methods This retrospective study describes cGVHD patients recorded in the Komodo closed claims dataset between January 2016 and March 2022. The final cohort of interest included patients who were diagnosed with cGVHD (≥1 medical claim with the International Classifications of Disease Version 10 [ICD-10] diagnosis code D89.811), received belumosudil (≥1 claims with National Drug Code 79802020030), and were 12 years of age or older in the year of belumosudil initiation. Patients were required to have at least 36 months of continuous medical and pharmacy enrollment prior to their initial belumosudil prescription to ensure a complete medical diagnosis, treatment, and healthcare utilization history. Results A total of 151 patients were identified [median (interquartile range) age of 53 (40-62) years old; 54% female]. Sixty percent (92/151) of the patients had an HSCT within the 36-month observation period, and 73% (67/92) of the patients with an observable HSCT also had a diagnosis for a hematologic cancer in the 3 months prior to their HSCT. The median times from HSCT (in those with a recorded event) and cGVHD diagnoses (in all patients available) to belumosudil initiation were 3.2 (1.7-4.0) and 1.5 (0.5-3.1) years, respectively. During the 36 months pre-belumosudil treatment, common diagnoses included dyspnea (81%, 123/151), cytopenia (79%, 119/151; includes anemia, neutropenia, and thrombocytopenia), and "complications of stem cell transplant" (76%, 115/151; ICD-10 code T86.5). In the 12 months immediately prior to belumosudil initiation, the mean (standard deviation) Charlson Comorbidity Index score was 3.6 (2.2); a median of 9 (4-20) cGVHD-related healthcare encounters occurred; and nearly half of all patients had a hospitalization (all-cause 48%, 73/151; cGVHD-related, 27%, 41/151), with the most frequent primary diagnoses for admission attributed to respiratory illnesses and transplant complications. The majority of patients had received ≥3 lines of cGVHD treatment (85%, 128/151) in the 36 months pre-belumosudil, with a median of 5 (4-6) systemic therapies. Combination therapies containing either calcineurin inhibitors (17%; 25/151) or ruxolitinib (15% 23/151) were the most common lines of therapy immediately prior to belumosudil prescription. Use of strong Cytochrome P450 Family 3 Subfamily A (CYP3A) inducers was not observed during the observation period. In the 12 months prior to belumosudil initiation, 55% (83/151) patients were prescribed proton pump inhibitors. For the first belumosudil prescription that a patient received, 74% (111/151) of patients received once-daily dosing, and 26% (40/151) of patients received twice-daily dosing. Conclusions In this real-world data, prior to receiving belumosudil, patients received a median of 5 lines of systemic therapies at a median of 1.5 years from cGVHD diagnosis. Patients displayed multiple comorbidities and frequent hospitalizations that could complicate clinical management with existing cGVHD therapies. There is an unmet need for safe and effective treatment for cGVHD patients. Further research is needed to describe outcomes for patients being treated with belumosudil.

Racial, Ethnic and Socioeconomic Disparity in Outcomes of Patients with Chronic Graft-Versus-Host Disease: A CIBMTR Analysis

Introduction: Prior studies have demonstrated that racial/ethnic minority groups and patients with low socioeconomic status (SES) have worse overall survival (OS) after allogeneic hematopoietic stem cell transplant (allo-HCT). Whether the racial and SES disparity in outcomes persists and possibly may even be exacerbated in allo-HCT recipients with chronic graft-versus-host disease (cGVHD) is unknown. Certain aspects of cGVHD such as the need for long term care, prolonged immunosuppressive treatment, and close follow up for complications may exacerbate racial and SES disparities. In the current study, we analyzed the association of race/ethnicity and SES with the incidence of cGVHD and compared the long-term outcomes of allo-HCT survivors with cGVHD by race/ethnicity and SES. Methods: The study population comprised 14,825 adults with acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), myelodysplastic syndrome (MDS), or myeloproliferative neoplasm (MPN) who received first allo-HCT between 2008-2018 in the United States. Residential ZIP code at the time of allo-HCT was used to estimate annual household income as the measure of SES. Patients with relapse of the primary disease prior to diagnosis of cGVHD were excluded. The incidence of cGVHD was calculated using the cumulative incidence estimator. Cox regression models were used to determine whether race/ethnicity and SES were associated with overall survival (OS), treatment related mortality (TRM) and relapse among patients with cGVHD. A stepwise backward variable selection was used to develop models for each outcome with a threshold of 0.05 for retention in the model. The main variable was then forced into the models. Interactions between the main variable and the adjusted covariates were tested at the significance level of 0.01. Results: Patients were reported to be Non-Hispanic White (W) (n=11,796), Non-Hispanic Black (B) (n=1,009), Hispanic (H) (n=1,325), and Asian (A) (n=695). A total of 5,600 relapse-free allo-HCT recipients developed cGVHD. There was no significant difference in cumulative incidence of cGVHD based on race/ethnicity (p=0.49, Table 1) or SES (p=0.44). In the multivariable analysis, we observed no significant differences in OS (p=0.15), TRM (p=0.11) and relapse (p=0.03) in patients with cGVHD based on race and ethnicity adjusted for patient-, disease- and transplant-related covariates. SES (household income, with or without adjustment for health insurance status) was significantly associated with OS (p<0.0001) and TRM (p=0.0006). More specifically, the highest quartile of household income (≥ $80,000) was associated with improved OS (HR 0.78, CI 0.71-0.86, p< 0.0001) and reduced TRM (HR 0.75, CI 0.66-0.86, p< 0.0001) compared with the lowest household income quartile (< $48,000) (Table 2). There was no association between the SES and relapse among patients with cGVHD (p=0.29). Conclusions: Our study highlights that low SES, regardless of race/ethnicity, has a negative impact on outcomes after diagnosis of cGVHD. Disparities in outcomes solely based on race/ethnicity were not evident among patients with cGVHD. Future studies are needed to determine if people with low SES and cGVHD have disproportionately worse outcomes than those with low SES without cGVHD. If they do, then optimizing the health care resources available to cGVHD patients with low SES may improve long-term outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effect of CMV Reactivation and Letermovir Use on Chronic Gvhd Incidence Following Haploidentical Donor Transplantation with Post-Transplant Cyclophosphamide

A recent CIBMTR analysis describing the increased incidence of CMV infection following post-transplant cyclophosphamide (PTCy) (Goldsmith et al. Blood 2021, 137(23):3291-3305) also demonstrated higher chronic graft-versus-host disease (cGVHD) rates in PTCy recipients following CMV reactivation. The authors suggested that CMV reactivation may potentially negate the known protective effect of PTCy on cGVHD incidence. However, such an analysis can be confounded by the close association of cGVHD and CMV reactivation making cause-and-effect associations challenging. In the hopes of better understanding this association, we analyzed 346 consecutive PTCy-based haploidentical donor transplants (HAPLO) performed at a single institution between Jan 2012 to June 2021. We first evaluated the effect of CMV reactivation on cGVHD incidence utilizing both a D+100 and D+180 landmark analysis. Secondly, we analyzed the effect of routine CMV prophylaxis with letermovir, which was initiated in all HAPLO recipients starting Jan 2018, on cGVHD incidence. Given that letermovir reduces the risk of CMV reactivation, we hypothesized that pre-letermovir cGVHD rates in HAPLO recipients should be higher if CMV reactivation was a true causative risk factor for cGVHD. Baseline characteristics of HAPLO recipients included median age 53 (range, 19-80), 58% male, 52% non-Hispanic white , HCT-CI ≥3 in 60% and CMV-seropositive in 76%. Myeloablative conditioning was used in 42% of transplants. CMV viremia requiring preemptive therapy occurred in 155 patients, with a median time to reactivation of 40 days (range 1-645) with 86% of reactivations occurring before day +100. Patients receiving letermovir prophylaxis had lower CI of CMV viremia when measured at day +100 (17% vs. 57%) and day +180 (26% vs. 57%) respectively compared to patients not receiving letermovir. There was no difference in baseline characteristics between those receiving and not receiving letermovir prophylaxis. Compared with contemporaneously treated MRD and MUD recipients receiving conventional GVHD prophylaxis, the CI of cGVHD was lower following PTCy-based HAPLO (28% vs. 46% and 43% respectively). The CI of cGVHD did not differ in HAPLO recipients with or without CMV reactivation, whether using a day +100 or day +180 landmark analysis. Similarly, there was no difference in cGVHD incidence in HAPLO recipients that received CMV prophylaxis with letermovir vs. those that did not (see figure). A subsequent analysis evaluating the CI of moderate-to-severe grade cGVHD showed similar findings with no effect of either CMV reactivation or letermovir use. Cox multi-variable analysis evaluating CMV reactivation as a time-dependent covariate confirmed the lack of effect of CMV viremia on cGVHD incidence (HR 1.1, p=0.65). In summary, our large single-center analysis of PTCy-based HAPLO recipients did not confirm the prior CIBMTR findings of increased cGVHD incidence following CMV reactivation. Furthermore, cGVHD incidence was not influenced by letermovir prophylaxis despite significantly lower rates of CMV reactivation. We speculate that the previously published association of higher cGVHD rates with CMV reactivation after PTCy-based transplants may represent an epiphenomenon, whereby CMV reactivation in some patients may predate the clinical diagnosis of cGVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

JAK/Rock Inhibitor TQ05105 for Glucocorticoid-Refractory or -Dependent Chronic Graft-Versus-Host Disease：Preliminary Analysis Results of a Phase 1b/2 Study

Introduction: Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation that is a leading cause of morbidity, mortality, and impaired quality of life. It is an immune-mediated inflammatory and fibrotic disorder. The Janus kinase (JAK) signaling pathways play an important role in immune-cell activation and tissue inflammation during cGVHD. The rho-associated coiled-coil-containing protein kinase-2 (ROCK2) signaling pathway regulates Th17/regulatory T cells balance and controls profibrotic pathways involving in progression of cGVHD. TQ05105 is a novel, oral dual JAK1/2 and ROCK1/2 inhibitor targeting inflammatory and fibrotic components of cGVHD. Selective JAK/ROCK inhibition with TQ05105 may offer a novel approach to the management of cGVHD. Methods: This phase1b/2, multicenter, open-label study of TQ05105 enrolled moderate or severe glucocorticoid-refractory or -dependent cGVHD patients who had received at least one prior lines of therapy (LOTs). This trial consist of 2 parts：a phase 1b dose escalation phase using a standard 3+3 design to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Phase 2 of this study is a expansion of TQ05105 at RP2D. The initial dose is 10mg BID, then reduced to 5mg BID in the event of unacceptable toxicity and increased to 15mg BID in the absence of dose limited toxicity. The primary endpoint of Phase 1b portion of the study was safety and RP2D. The key secondary end points were the best overall response (BOR, complete or partial response) defined per the 2014 NIH Consensus criteria, failure-free survival (FFS) at 6 month and improved score on the modified Lee Symptom Scale (LSS). Results: From May 2021, through May 2022, 22 patients were enrolled. Median age was 33 years (16-89), 63.6% male. The median time from cGVHD diagnosis to enrollment was 36 months. Patients enrolled in 10mg BID (n=7) and 15mg BID (n=15) had received a median of 4 prior lines of cGVHD therapy, respectively. 77.3% of patients had severe cGVHD. 57.1% of patients in 10mg BID and 53.3% in 15mg BID had involvement of ≥ 4 organs. The most frequently involved organs in 10mg BID and 15mg BID, respectively, are eyes (100%, 86.7%), mouth (57.1%, 93.3%), lungs (57.1%, 86.7%), skin (57.1%, 53.3%), and Joints and/or fascia (57.1%, 46.7%). The median treatment duration was 165 days (29-370). TQ05105 was well tolerated without dose-limiting toxicities in two doses. The RP2D was not determined and enrollment is ongoing. Commonly reported AEs (≥20%) were Epstein-Barr virus infections (36.4%), pulmonary infection (31.8%), upper respiratory tract infection (31.8%), leukopenia (27.3%), neutropenia (27.3%), hypercholesterolemia (27.3%). Grade 3 or higher AEs were reported in 10 patients and SAEs in 7 patients. No apparent increase in incidence of infection was observed. No cases of cytomegalovirus (CMV) infection or reactivation were reported with TQ05105. As of the data cutoff, there was no death and no relapse. Of the 22 patients, the BOR was 100% (7 of 7) in 10mg BID and 73.3% (11 of 15) in 15mg BID, and median duration of response was not reached. Responses were rapid, with 45% of responders achieving a response by the first assessment (at 4 weeks). Responses were achieved across key subgroups in 10mg BID and 15mg BID, with BOR of 100% (4 of 4) and 72.7% (8 of 11) in patients with ≥ 4 organs involved, 100% (6 of 6) and 73.3% (11 of 15) in patients who had received ≥ 2 prior systemic LOTs, 100% (4 of 4) and 76.9% (10 of 13) in patients who were refractory to their last LOT before enrollment，100% (5 of 5) and 66.7%(8 of 12) in patients with severe cGVHD. The FFS rate was 88.9% (95%CI, 43.3%-98.4%) at 6 months. During TQ05105 treatment, 85.7% (6 of 7) in 10mg BID and 53.3% (8 of 15) in 15mg BID reduced corticosteroids (CS) dose. 8/22 (36.4%) patients discontinued CS. 57.1% (4 of 7) and 26.7% (4 of 15) of patients in 10mg BID and 15mg BID, respectively, achieved an improvement (≥ 7 points reduction) in the LSS Score, including both responders and non-responders. Conclusion: TQ05105 is well-tolerated for cGVHD and yielding high rates of clinical response, improving quality-of-life, reducing corticosteroids dose. The data indicated that TQ05105 may be proved to be a potential, effective therapy for patients with glucocorticoid-refractory or -dependent cGVHD. (Funded by Chia Tai Tianqing Pharmaceutical Group Co., Ltd. ClinicalTrials.gov number, NCT04944043) Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase I/II Clinical Trials of Donor-Derived Purified Regulatory T Cells for the Treatment of Steroid-Refractory Chronic Graft Versus Host Disease

Introduction Chronic Graft versus Host Disease (cGvHD) remains a major complication of hematopoietic stem cells transplantation (HSCT) causing significant morbidity and mortality. We performed Phase I/II clinical trials to access the feasibility, safety and efficacy of infusing donor regulatory T cells (Treg) for the treatment of steroid-refractory/dependent cGvHD under the auspices of the EC-funded consortium TREGeneration.This is the first presentation of the Lisbon (iMM) and Seville (SAS) cohorts. Methods Treg were purified using CliniMACS (Miltenyi Biotec®) from fresh leukapharesis from the original HSCT donor by CD8 and CD20 depletion, followed by CD25bright positive selection. The dose escalation protocol comprised sequential groups of 3 (SAS) or 5 (iMM) patients per center receiving 0.5x106 (Dose A), 1x106 (Dose B) or 2-3x106 (Dose C) donor Treg/kg. After Phase I, 5 patients per center were included at the MTD, as a preliminary Phase II trial. We report feasibility and toxicity results on 33 patients (n=19, iMM; n=14, SAS) and efficacy on 31 patients (n=19, iMM; n=12, SAS) evaluable at month 12 post infusion (n=8, moderate; n=23, severe). Patients were classified according to the NIH 2014 cGVHD criteria (Jagasia, MH et al, BBMT, 2015). Scores for the skin, eye, modified oral mucosa, GI tract, liver, lung, joint/fascia and cGvHD severity were used to calculate clinical responses at 3, 6 and 12 months, whereupon the final response was recorded. cGVHD treatment at iMM comprised primarily steroids and MMF, while all patients at SAS were on a ruxolitinib-containing regimen and had not obtained at least a partial response. Blood was collected for lymphocyte subsets monitoring by flow cytometry, evaluation of tissue damage biomarkers, homeostatic, pro-inflammatory and suppressive cytokines (sIL-2Ra, CXCL9/MIG, MMP3, Osteopontin, CXCL10/IP-10, CSTB, sCD13, Elafin, sTM, ST2, BAFF, IL-1R antagonist, IL-2, IL-7, IL-10, IFN-γ, TNF-α, CXCL11/I-TAC, IL-6, IL-17A/CTLA8 and TGF-β) by Multiplex, and tracking of infused Treg clonotypes by deep-level TCR RNA-based Next Generation Sequencing (NGS). Univariate tests were carried out using Fisher's exact test for categorical variables. t-test or Mann-Whitney tests were used for continuous variables as per normality analysis. Since no multiple testing correction was carried out, there were no corrections for multiple comparison or adjustments for other covariates. Results and Conclusions Donor Treg products preparation was feasible. Nevertheless, due to the paucity of circulating Treg, dose C required 2 separate leucapheresis in most patients. At SAS, achieving more than 1.5x106 donor Treg/kg was possible for only 4 patients. At iMM, the QC criteria were met in 20/20 products (mean Treg purity 67%; CD8 depletion 4.5 and 4 times for CD20). At SAS, 1 product did not meet the purity criteria and was not infused, the remaining 14 products were infused (mean purity 73%; CD8 log depletion of 4.9 and of 6.5 times for CD20). Infused cell doses were calculated based on Treg purity (CD4+CD25++CD127lowFoxP3+). There were no dose limiting toxicities and dose C was used whenever reached in the Phase II trial. Efficacy analysis revealed that 22 out of 31 evaluable patients (70.9%) showed either complete response (CR) or partial response (PR) at month 12, whereas 29% progressed (P) or did not respond (NR). The median time from infusion to response was 6 months. The same efficacy trend was observed irrespective of a previous failure to ruxolitinib. Time from cGvHD diagnosis to Treg infusion was significantly associated with response in the iMM cohort (p=0.003). Interestingly, the Treg dose influenced outcomes. Hence, when patients receiving A+B doses (<1 x106Treg/Kg) were compared to patients receiving >1.3x106 Treg/Kg, 10/18 (56%) of patients in lower doses responded versus 12/13 (92%) in higher Treg doses (p=0.045). Furthermore, 39% of patients had the daily dose of prednisolone tapered by at least 50%. Exploratory TCR tracking analysis revealed the persistence of infused Treg clones in 18 of the 20 patients analyzed thus far up to one year after infusion. In summary, we report the feasibility and safety of donor Treg infusion in patients with moderate/severe cGVHD. Meaningful responses were observed in over 2/3 of the patients, further suggesting that early treatment with Treg is associated to improved clinical outcomes. Our results set the stage for larger Phase II trial. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Ruxolitinib for Treatment of Steroid Refractory Sclerotic Chronic Graft-Versus-Host Disease (cGVHD): Results of a Multicenter Phase II Trial

Background: Sclerotic cGVHD is a highly morbid form of cGVHD, often refractory to standard and secondary therapies and associated with significant decline in patients' quality of life and functioning. We conducted a single-arm phase II multicenter trial to test the hypothesis that ruxolitinib is effective treatment for steroid refractory sclerotic cGVHD (ClinicalTrials.gov ID: NCT03616184). Methods: Eligibility criteria included adults with cGVHD and skin, joint and/or fascia sclerosis, who had received systemic corticosteroids for >12 months and at least one additional line of therapy, or systemic corticosteroids and at least two additional lines of therapy. Subjects received oral ruxolitinib 10 mg twice daily for 6 months, which was subsequently tapered over another month. Treatment could be extended up to 12 months in patients deriving clinical benefit. The primary objective was to determine the proportion of patients with an NIH-defined response in skin or joints at 6 months. A sample size of 47 patients (estimated 10% drop out) had α of 0.044 and a power of 84% to test the null hypothesis response rate of 25% (Clin Cancer Res. 2016; 22: 319-327) compared to an alternative of 45%. Other endpoints included overall response, non-relapse mortality (NRM), treatment failure (administration of additional systemic therapy, malignancy relapse or mortality), glucocorticoid dose reduction, and patient-reported outcomes (PROs) (Lee symptom scale and Scleroderma Health Assessment Questionnaire). Results: 49 patients were consented between November 2018- June 2021; 2 patients were screen failures. Baseline characteristics of 47 patients included a mean age of 58 (range 23-76) years, 40% female, and 91% white. 87% had peripheral blood as a graft source. 66% had matched unrelated donor transplant. 66% had prior acute GVHD. Median time from cGVHD diagnosis to enrollment was about 48 months. All patients had classic cGVHD at enrollment. Severity included mild (2%), moderate (13%) or severe (85%). Patients had received a mean of 3 prior lines of treatment. Patients received a mean of 8.6 cycles of ruxolitinib. 13% had missing data that precluded response assessment; these patients were considered non-responders. Partial responses (PR) in skin or joint (primary endpoint) were seen in 49% (95% CI 34-64%) at 6 months; other responses included stable disease (19%), progression (19%) and missing (13%) (Fig 1). No complete responses were observed in skin or joint. Overall cGVHD partial responses were seen in 47% (95% CI 32-61%); other responses included stable disease (13%), mixed responses/progression (27%) and missing (13%). PR/CR in individual organs (among those with organ involvement after excluding missing data) were as following: eye (12/32, 37%), mouth (9/17, 53%), esophagus (5/9, 55%), upper GI (2/3, 67%), lower GI (2/3, 67%), lung (1/9, 11%), and liver (5/14, 36%). 24% (95% CI 11.8-41.2%) had >50% reduction in glucocorticoid dose from baseline to 6 months. The cumulative incidences of treatment failure and NRM at 6 months were 15.2% (95% CI 6.6- 27.1%) and 2.2% (95% CI 0.2-10.3%). No patients have had relapse of malignancy. 6-month failure free survival was 84.8% (95% CI 70.7-92.4%) (Fig 2). Any grade and grade 3 or higher adverse events occurred in 55% (n=26) and 36% (n=17) of patients. 6 out of 17 grade 3 or higher adverse events were considered possibly or probably related to ruxolitinib. AE occurring in >10% of patients included dry eye, diarrhea, nausea, vomiting, infection, upper respiratory tract infection, weight gain, laboratory and other abnormalities. PRO analyses are ongoing and will be presented. Discussion: The trial met its primary endpoint with half of adults with moderate-severe sclerotic cGVHD achieving partial responses in skin or joint as well as overall cGVHD responses. The use of ruxolitinib was associated with high rates of failure-free survival. In conclusion, the use of ruxolitinib results in high rate of responses in highly morbid sclerotic form of cGVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Early Versus Late Treatment with Ruxolitinib in Patients with Steroid-Refractory Chronic Graft-Versus-Host Disease: A Post Hoc Analysis from the Randomized, Phase 3 REACH3 Study

Background: Chronic graft-versus-host-disease (cGVHD) occurs in a relevant proportion of long-term survivors after allogeneic hematopoietic stem cell transplantation and is a leading cause of morbidity and nonrelapse mortality. Standard first-line treatment for cGVHD is systemic corticosteroids; however, approximately 40%-60% of patients either do not respond or become refractory and require additional systemic therapy. Ruxolitinib is an oral, selective Janus kinase (JAK)1/JAK2 inhibitor approved for steroid-refractory (SR)-cGVHD in adult and pediatric patients aged ≥12 years after failure of ≤2 lines of systemic therapy. In the phase 3 pivotal REACH3 trial, compared with best available therapy (BAT), ruxolitinib significantly improved response rates and allowed for steroid tapering among patients with SR-cGVHD. The impact of timing of ruxolitinib initiation on treatment response and patient outcomes needs further investigation. Methods: REACH3 (NCT03112603) was a phase 3 randomized, open-label, multicenter study in which SR-cGVHD patients aged ≥12 years with moderate or severe SR or steroid-dependent cGVHD were randomized to receive either ruxolitinib 10 mg twice daily or investigator-selected BAT. This post hoc analysis examined overall response rate (ORR [complete response (CR) + partial response (PR)]) at Week 24, best overall response (BOR) at any time, and duration of response (DOR) between early (≤14 days from SR-cGVHD), late (>14-28 days), very late (>28 days), or late and very late (>14 days) study treatment initiation. Subgroups were defined based on time from SR-cGVHD to randomization. DOR was measured as the time from first documented CR or PR among those with response at Week 24. Odds ratio (OR) and 95% CI for ORR and BOR were calculated using stratified Cochran-Mantel-Haenszel test or Wald confidence limits. DOR was analyzed with the Kaplan-Meier method. Results: Overall, 165 patients were randomized to ruxolitinib (n=88, 77, 47 for early, late-and-very-late [>14 days], and very late, respectively) and 164 to BAT (n=85, 79, 46). Median age ranged from 47-51 years between subgroups, and most patients were male (range between subgroups, 52.9%-66.2%). Approximately half of patients had experienced prior acute GVHD (range between subgroups, 47.8%-55.8%). Patients had moderate (42.9%) or severe (56.8%) SR-cGVHD at time of study entry; mean time from cGVHD diagnosis to randomization ranged from 154.3-346.0 days between subgroups. Ruxolitinib was superior to BAT in all time-to-treatment subgroups for ORR (early: OR, 2.83 [95% CI: 1.49, 5.37]; late-and-very-late: OR, 3.10 [95% CI: 1.51, 6.34]; very late: OR, 3.41 [95% CI: 1.30, 8.95]; Table). There was a trend toward higher rate of CR for ruxolitinib treatment vs BAT regardless of treatment delay. DOR represented as probability of loss of response over time is presented in the Figure. Ruxolitinib was superior to BAT for BOR of CR or PR up to Week 24 in late-and-very-late (OR, 2.92 [95% CI: 1.46, 5.87]) and very late subgroups (OR, 2.72 [95% CI: 1.13, 6.52]) and numerically greater in the early treatment subgroup (OR, 1.59 [95% CI: 0.80, 3.15]; Table). No differences in ORR, BOR (Table), or DOR were observed between ruxolitinib time-to-treatment subgroups. Conclusions: These data demonstrate that ruxolitinib provides clinical benefit compared with BAT regardless of time elapsing between onset of SR-cGVHD and treatment start. These findings confirm ruxolitinib as an effective treatment option compared with BAT that leads to durable responses in patients with cGVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CT-275 Incidence and Characteristics of Chronic GVHD in Haploidentical Stem-Cell Transplantation With Post-Transplantation Cyclophosfamide: Experience of the Spanish Group of Hematopoietic Transplantation and Cell Therapy (GETH-TC)

Chronic graft-versus-host-disease (cGVHD) is a relevant cause of late morbidity and mortality related to allogenic-stem-cell transplantation in long-term survivors. GVHD prophylaxis using post-transplantation cyclophosphamide (PTCy) has improved haploidentical stem-cell transplantation (haplo-HSCT) outcomes; however, data related to characteristics, risk factors, or cGVHD outcomes are limited. In this study, we analyze the incidence, risk factors and disability related to cGVHD in patients undergoing haplo-HSCT PTCy. Retrospective multicenter analysis of 389 consecutive patients that underwent haplo-HSCT-PTCy at 7 Spanish transplant centers from 2007 to 2020. cGVHD diagnosis was made following the NIH criteria and Disability related to cGVHD was defined as Fatobene et al criteria. Median age was 48 years (5-74), and 62% were males. AML and HL were the most common indications for transplantation (37%, 22%). 36% received a previous transplant. The median follow-up was 35 months (3-102). Cumulative incidence of aGVHD and aGVHD III-IV at day +180 was 66% and 20%. The 2-year OS was 59%, 2-year PFS 54%, 2 year-GRFS was 45%. 95 patients developed cGVHD, cumulative incidence of cGVHD and cGVHD moderate-severe was 34% and 10% at 3 years. 42 patients required systemic treatment. In the univariate analysis of risk factors for cGVHD in patients alive on day +100, female donor (p=0.034), female donor and male recipient (p=0.041), DRI low (p=0.026), myeloablative conditioning (p=0-047), previous aGVHD (p=0.014), and the use of radiotherapy in conditioning (p=0.004) were identified. Busulfan conditioning was identified as a protective factor (p=0.036). In multivariate analysis, the presence of previous GVHD (p=0.031) and the protective power of conditioning with busulfan (p=0.036) remains statistically significant. cGVHD according to NIH at 3 years, moderate cGVHD showed a higher OS (p=0.054), higher PFS (p=0.004) and lower relapse than the rest of the groups (p=0.035). Receiving one line of treatment (p=0.043) and use of bone marrow were the only risk factors identified for these patients. Haplo-HPT with Cy-post shows a low, but not negligible incidence of cGVHD, and its use represents an alternative for some patients. The development of moderate cGVHD is a protective factor in this transplant modality. The characterization of predictive factors of this subgroup is relevant given the results.

ORAL CHRONIC GRAFT-VERSUS-HOST DISEASE IN A COVID-19 PATIENT: A CASE REPORT OF A RAPID AND PROGRESSIVE DISEASE

Chronic graft-versus-host disease (cGVHD) is a common complication in patients undergoing haploidentical hematopoietic stem cell transplantation (haploHSCT). The aim was to relate a recent case of a rapid and progressive oral cGVHD after COVID-19. A 35-year-old man developed oral cGVHD only in the lips 190 days after haploHSCT for acute myelomonocytic leukemia. COVID-19 was diagnosed 263 days after haploHSCT and 5 days after donor lymphocyte infusion with improvement in his clinical condition after 1 week. Moreover, the patient reported rough changes in oral mucosa in 24 hours. Oral clinical exam showed extensive lichen planus–like changes in the whole oral mucosa in association with xerostomia, leading to a clinical oral cGVHD diagnosis. Both cGVHD and COVID-19 share high levels of inflammatory markers in their physiopathology, including interleukin 6 and TH-17 immune response. COVID-19 could contribute to oral lesions in association with donor lymphocytes.