Real-World Ruxolitinib and Corticosteroid Treatment Patterns in Patients with Chronic Graft-Versus-Host Disease in the United States

Ruxolitinib was approved in September 2021 for chronic graft-versus-host disease (cGVHD) after failure of 1–2 lines of systemic therapy in adult and pediatric patients ≥12 years of age. Real-world data describing the use of ruxolitinib and how it impacts corticosteroid use in patients with cGVHD following allogeneic hematopoietic stem cell transplantation (alloHSCT) across various practices require further investigation. This retrospective study was carried out by Dr. Jingbo Yu and describes real-world characteristics and treatment patterns of ruxolitinib and corticosteroids in patients with cGVHD after alloHSCT in the United States.

This was a retrospective claims data analysis that included commercial, Medicare/Medicare Advantage, and Medicaid health plan members who received an alloHSCT and had a cGVHD diagnosis, ruxolitinib use for cGVHD treatment (earliest claim was the index date), and health insurance coverage ≥6 months before and ≥6 months after the index date (or less due to death). Patients were followed until the earliest of death, end of continuous plan enrollment, or end of study period. Ruxolitinib and corticosteroid dosages and treatment length were determined using prescription refills in pharmacy claim records.

A total of 471 patients who had cGVHD and started ruxolitinib treatment between July 2019–August 2022 were included in this analysis. Median (IQR) age was 46 (26–60) years, with 15.3% <18 years. Approximately 60% were male, 59.2% had commercial insurance, 28.0% had Medicaid, and 4.5% had Medicare. Patients were followed for a median (IQR) of 465 (316–694) days from ruxolitinib initiation.

Patients initiated ruxolitinib after a median (IQR) of 116 (26–255) days (83.5 days in pediatric patients, 119 days in adults) from cGVHD diagnosis. A total of 213 (45%) patients started ruxolitinib as second-line treatment following treatment with corticosteroids. Median ruxolitinib starting dosage was 10 mg/day for pediatric and adult patients (pediatric IQR: 5–10; adult IQR: 10–20). Among patients who had a ruxolitinib refill, 58.4% had a dose change; of those, 55.9% had a dose increase and 44.1% had a dose decrease in their first dose change. Kaplan-Meier analysis showed median length of ruxolitinib treatment across all lines of therapy was 245 days (95% CI: 210–300). At the end of follow-up, 33.1% of patients remained on ruxolitinib treatment for a median of 389 days (IQR: 260–591).

Median corticosteroid daily dosing decreased 69% over time from median (IQR) 40.0 (18.4–61.0) mg pre-index to 12.5 (5.0–40.0) mg at 180 days post-index across all patients. Patients who initiated ruxolitinib early (1–29 days post-cGVHD) were more likely to taper steroids (72.3%) than those who initiated ruxolitinib later (30–100 or 101+ days; 59.3% and 58.5%, respectively; P=0.030). Median corticosteroid daily dose pre-index was 40 mg for early ruxolitinib initiators and day 30–100 ruxolitinib initiators, and 25 mg for day 101+ ruxolitinib initiators. Median corticosteroid daily dose by 180 days post-index was lowest for ruxolitinib early initiators (10 mg) versus 20 mg for day 30–100 ruxolitinib initiators and 15 mg for day 101+ ruxolitinib initiators. Furthermore, the number of patients with steroid complication-related healthcare resource utilization (HCRU) was numerically less after initiation of ruxolitinib compared with before ruxolitinib treatment for ambulatory visits (68.4% vs 78.8%), emergency room visits (12.5% vs 15.3%), and inpatient stays (37.2% vs 56.1%), respectively.

In real-world practice, patients treated with ruxolitinib for cGVHD start at a median dose of 10 mg daily, with most patients receiving dose adjustments as necessary. Overall, patients received ruxolitinib for a median of 8 months, with 33.1% of patients continuing ruxolitinib for a median duration of over 1 year, suggesting long-term safety and ongoing clinical benefit of treatment. Patients had a 69% reduction in corticosteroids over the 6 months after initiating ruxolitinib and a decrease in steroid complication-related HCRU, suggesting ongoing clinical benefit of ruxolitinib in reducing steroid dose and related complications

Serial Clinical and Biomarker Monitoring during Treatment Can Stratify Patients with Low Risk Gvhd

The majority of patients respond to steroid treatment for graft-vs-host disease (GVHD), but the typically high doses and prolonged courses can cause substantial morbidity. GVHD can be classified at onset into two groups with significant differences in treatment response and non-relapse mortality (NRM) by clinical criteria (Minnesota risk) but the more favorable standard risk group still experiences high rates of treatment failure and NRM [MacMillan, BBMT 2015]. The authors (Dr. Nikolaos Katsivelos et al) previously validated a serum biomarker-based (ST2+REG3α) risk stratification system, MAGIC algorithm probabilities (MAPs), that can stratify patients both at initiation and during treatment into risk groups for treatment response and NRM [Hartwell, JCI Insight 2017, Srinagesh, Blood Adv 2019]. GVHD that is Minnesota standard risk and has a low MAP (i.e., Ann Arbor 1) at start of treatment represents a low risk group with >80% response rate to steroids and ~10% NRM [Etra, Blood 2023]. The authors hypothesized that serial monitoring of GVHD symptom severity and MAPs twice (days (d) 7 and 14) in patients with clinical and biomarker defined low risk GVHD could further stratify patients into clinically meaningful groups.

The authors retrospectively determined MAPs at d7 and 14 in 450 patients with low risk GVHD who participated in a prospective, multi-center, observational trial and were treated with systemic steroids between 2015-2023. MAPs <0.291 at days 7 and 14 were defined as low risk based on a previously validated threshold [Major-Monfried Blood 2018]. Clinical responses were scored as complete (CR), partial (PR), or non-response (NR) by standard criteria. Initiation of second line therapy was considered NR. Patients were categorized into three groups (A-C) based on clinical responses and MAPs at days d7 and 14. A: CR/PR by d14 and low MAP at both d7+14; B: stable or worse GVHD (NR) by d14 with low MAP at both d7 and 14; C: any response with a high MAP at d7 or 14. The endpoints were clinical response at day 28 (overall response rate, ORR=CR or PR), regardless of earlier response status, and 6-month NRM.

The median age of the study population was 54 years (range: 0-79); 19% of patients received PT-Cy for GVHD prophylaxis. Target organ involvement was skin ± upper GI (66%), lower GI (23%), isolated UGI (11%), and skin+liver (1%), and GVHD severity was grade I (35%), II (61%), and III (4%) at start of treatment. Patients in group A (n=310, 69%), clinical responders with low MAPs through day 14, had excellent d28 ORR (93%) and very low NRM (4%). GVHD in this group was considered ultra-low risk (ULR) and subset analyses revealed highly consistent d28 ORR and NRM, regardless of target organ severity, age (<18, 18-59, >60), HCT-CI score, conditioning intensity, and GVHD prophylaxis. Group B patients comprised clinical non-responders with low MAPs through day 14 (n=112, 25%); half of them responded by d28 and their NRM was low (8%), albeit double that of group A (p=0.079). Group C was small (n=28, 6%) and included both clinical responders (n=20, 4%) and clinical non-responders (n=8, 2%) who had at least one high MAP through day 14. Their d28 ORR was 54% but NRM increased four-fold (32%) and was significantly worse than patients who maintained low MAPs regardless of clinical response (p<0.001).

Serial monitoring by clinical response and biomarkers during the first two weeks of treatment identifies a small number of high risk patients whose GVHD is initially low risk (group C). This group experiences high NRM regardless of clinical response to steroid treatment and may benefit from treatment escalation. Patients with low risk GVHD who do not have an early clinical response to steroids but maintain low MAPs, (group B) have reasonably good long-term outcomes with standard treatment. Finally, serial monitoring identifies a very large subset of patients with ULR GVHD (group A) who respond exceptionally well to standard treatment and experience very low rates of 6-month NRM regardless of pre-transplant characteristics and GVHD prophylaxis. Such patients may benefit from treatment de-escalation strategies such as shorter courses of lower dose steroids, a strategy we are currently testing in a clinical trial (NCT05090384).

Identification of High-Risk Patients and Establishment of a Clinical Prediction Model for Frontline Steroid Failure in Chronic Graft-Versus-Host-Disease

Contemporary practice for frontline chronic graft-versus-host disease (cGvHD) treatment predominantly involves the use of systemic corticosteroids. Treatment with newer agents for cGvHD including ruxolitinib, belumosudil or axatilimab may benefit patients at high risk of treatment failure. The authors that carried out the study (Dr. Arjun Pandey et al) aimed to delineate high risk characteristics associated with frontline systemic steroid treatment failure in patients with cGvHD.

The authors conducted a retrospective review of 267 consecutive patients who were diagnosed with cGvHD and were treated with frontline systemic corticosteroids after allogenic stem cell transplant (allo-SCT) at Princess Margaret Cancer Centre in Toronto, Canada. They collected data including demographics, disease and transplant characteristics as well as characteristics and classification of cGvHD using NIH Consensus Criteria. The primary outcome of this analysis was failure free survival (FFS); failure was defined as 1) systemic treatment change, 2) relapse or 3) non-relapse mortality. The Kaplan-Meier method was used with log rank test for univariate analysis and the Cox proportional hazard regression model for multivariate analysis using a modified version of R.

The median age of the 267 included patients was 51 (range: 19-71); 107 patients (40%) were female. 186 patients (70%) had a myeloid malignancy. With regards to transplant characteristics, 171 patients (64%) had a matched related donor, and 249 patients (93%) received stem cell transplant from a peripheral blood source. 48 patients (20%) underwent T-cell depletion and 94 patients (35%) underwent reduced intensity conditioning. The proportion of patients with mild, moderate and severe cGvHD according to NIH criteria was 82 (31%), 140 (52%) and 45 (17%) respectively. More than one organ was involved in 226 patients (85%), with the skin (n=167, 63%), liver (n=163, 61%) and mouth (n=131, 49%) being the most common organs involved.

The median follow-up duration was 2.6 years amongst survivors. FFS was 61.7% [95% CI: 55.6-67.3] at 6 months, 37.8% [31.7-43.8] at 1 year, and 26.6% [20.9-32.5] at two years; median time to failure among the 267 patients was 252 days [217, 321]. Age, sex, and type of underlying condition were not significant predictors of FFS. With regards to transplant characteristics, no significant association was observed between FFS and any of: stem cell source (bone marrow vs. peripheral blood), donor-to-recipient sex or donor/recipient CMV status, T-cell depletion, reduced-intensity conditioning or type of GvHD prophylaxis. On univariate analysis, history of acute GvHD grade III-IV, severe cGvHD NIH global score at time of initial diagnosis, involvement of more than one organ, and mouth or GI involvement were each associated with shorter median time to failure; of these, acute GvHD grade III-IV (140 days vs. 291 days; HR: 1.46, [1.01, 2.13], p=0.047), severe cGvHD at initial diagnosis (164 days vs. 294 days, HR: 1.75, [1.20, 2.55], p=0.004) and involvement of more than one organ (226 days vs. 508 days, HR: 1.75, [1.11, 2.75], p=0.02) were each associated with significantly shorter median time to failure on multivariate analysis. Matched related donor status was associated with significantly longer median time to failure on both univariate and multivariate (329 days vs. 189 days, HR: 0.63, [0.47, 0.85], p=0.02) analysis. We developed a risk score, assigning one point for each of the high-risk characteristics associated with frontline steroid treatment failure (severe acute or chronic GvHD, involvement of more than one organ and unrelated donor). With increasing points on the score, a progressively shorter median time to failure was observed: risk score 0-1 (n=136: 346 days [291, 673]), 2 (n=85: 217 days [164, 304]), 3-4 (n=36: 103.5 days [59-179], p<0.001). Increasing points on the score were also associated with reduced FFS at 1 (data not shown) and 2 years: risk score 0-1 (n=136: 38.3% [29.5, 47.0]), 2 (n=85: 16.1% [8.3-26.2]), 3-4 (n=36: 8.5% [1.8-22.1], p<0.001).

Unrelated donor use, severe acute/chronic GvHD and ≥2 involved organs are high risk characteristics for frontline steroid failure. Future research should assess interventions including incorporation of newer agents such as ruxolitinib, belumosudil or axatilimab in addition to corticosteroids in these high-risk patients.

Age Is a Crucial Determinant of GFRS with Incidence of Severe Chronic GVHD Reducing over Time in Haemopoietic Cell Transplantation for Transfusion Dependent Thalassaemia: Real World Data from 2010-2021. an Analysis of the European Society for Blood and Bone Marrow Transplantation Hemoglobinopathy Working Party

Allogeneic hematopoietic cell transplantation (HCT) is the best established curative option for transfusion dependent thalassemia (TDT). This has been at least in part due to the real world outcomes identified by EBMT (Baronciani, BMT 2016; 51:536-41). However, these require updating as they were limited to the 2000-2010 period and no data exists on the incidence of severe GVHD, particularly important with advent of gene therapy.

In this study, carried out by Donatella Baronciani et al, data on pediatric and adult patients with TDT receiving a HCT from January 2010 to December 2021 were extracted by the EBMT Hemoglobinopathy registry database. Only first transplants were included. Data are expressed as median with range unless specifically indicated. Event free survial (EFS, defined as being alive and free of subsequent HCT, GVHD and event free survival), GRFS (defined as abence of second HCT, grade III-IV acute and extensive chronic GVHD) and overall survival (OS) were evaluated using Kaplan-Meier. GVHD outcomes and subsequent HCT were estimated using cumulative incidence function with death as competing risks. Differences between outcomes were tested by log-rank and Gray tests and multivariable Cox models were using for adjustement including age at HCT in class, year in periods and donor type.

2,807 consecutive patients were transplanted in centers distributed accross 36 countries in Europe, Asia and Africa: 2,601 children (up to 18 years of age) and 206 adults. Median age at transplant of children was 6.7 years (range 0.5-18) and in adults 22.1 years (18-44.8). 55.1% children were male and 44.9% female, and 51.7% adults were male whereas 48.3% were female.

The number of matched related, mismatched related and unrelated transplants were 1,879 (72.7%), 156 (6%) and 551 (21.3%) for children and 143 (69.4%), 14 (6.8%) and 49 (23.8%) for adults. 69.2% of children received bone marrow as the stem cell source whereas 59.3% adults received PBSC. The most common conditioning regimen for children was BuCy based (34.7%) for children whereas for adults it was FluBu (45.3%), a quarter of both groups using BuTreo based.

After a median follow up of 24 months, the 2 years OS and EFS were 92.1% (90.8 - 93.3) and 87.4% (85.7 - 88.9) for children and 84.4% (78.1 - 89) and 80.8% (73.9 - 86.1) for adults, respectively. Acute GVHD grade III/IV and chronic GVHD extensive occurred in 8.4% (7.2 - 9.6) and 4.4% (3.5 - 5.6) of children and 9.5% (5.8 - 14.3) and 7.2% (3.5 - 12.7) of adults, respectively. In multivariable analysis, impact of age of patient and donor type were statistically significant for age on overall survival and both on overall and severe GVHD; whereas year of HCT (before or after 2015) had a significant protective effect on severe chronic GVHD and overall survival. Compared to the class 0-4 years old, the impact on GRFS of age were HR 0.87 (0.65-1.16, p= 0.33) for the group 4-7 years, HR 0.96 (0.73-1.27, p = 0.8) for 7-12 years, HR 1.59 (1.2-2.1, p = <0.001) for 12-18 years and HR 1.63 (1.15-2.32, p = 0.006) for the group ≥18 years.

Real world data confirms allogeneic HCT as a curative therapy for TDT with high rate of cure. Age continues to be a crucial determinant of outcomes of HCT with best GFRS achieved in those transplanted up to 12 years of age. There has been a significant reduction in the risk of severe chronic GVHD over time despite almost a third of HCT being with alternative donors.