Ruxolitinib for Steroid-refractory GVHD

Study Overview
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Brief Summary
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Steroid-refractory acute GVHD (srGVHD) is one of the causes of mortality after allogeneic stem cell transplantation, while steroid-refractory chronic GVHD significantly increases morbidity, aggravates quality of life and may also impact survival. Currently there is no standard treatment of srGVHD. One of the most promising agents is Janus kinase (JAK) inhibitor ruxolitinib, which in the retrospective study demonstrated excellent response rate and survival of patients with either acute or chronic srGVHD. This study prospectively evaluates the efficacy of ruxolitinib in srGVHD patients.

Official Title
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Treatment of Steroid-refractory Acute and Chronic Graft-versus-host Disease With Inhibitor of Janus Kinases

Conditions
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Graft Vs Host Disease

Intervention / Treatment
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* Drug: Ruxolitinib Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of graft-versus-host disease established based on tissue biopsy Steroid-refractory acute or chronic graft-versus-host disease according to EBMT/ELN criteria (T. Ruutu et al, 2014) Age 1 to 70 years Karnofsky index >30%. Ability for oral drug intake Life expectancy > 1 month Signed informed consent Exclusion Criteria: Severe organ dysfunction: AST or ALT >5 upper normal limits (excluding cases related to liver GVHD), creatinine >2 upper normal limits Requirement for vasopressor support at the time of enrollment Uncontrolled bacterial or fungal infection at the time of enrollment Pregnancy Somatic or psychiatric disorder making the patient (or legal guardian) unable to sign informed consent

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ruxolitinib treatment<br>Ruxolitinib 10 mg bid for adults and children with body weight > 40 kg, 0.15 mg/kg bid for children with body weight < 40 kg. | Drug: Ruxolitinib Oral Tablet<br>* Dose reduction criteria for acute GVHD: grade 4 neutropenia or grade 4 thrombocytopenia related to ruxolitinib administration based on the decision of attending physician. Dose reduction criteria for chronic GVHD: grade 3 neutropenia, grade 3 thrombocytopenia or anemia requiring transfusion, related to ruxolitinib administration based on the decision of attending physician. Reduced dose schedule: 5 mg bid for adults and children with body weight > 40 kg, 0.08 mg/kg bid for children with body weight < 40 kg. Treatment discontinuation criteria: complete response; absence of response after 28 days or progressive disease after 7 days for acute GVHD; absence of response after 84 days or progressive disease after 28 days for chronic GVHD; life-threatening complications.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | Partial response for acute GVHD is defined as the improvement of at least one stage in the severity of aGVHD in one organ without deterioration in any other organ. A response had to last for at least 3 weeks. Partial response for chronic GVHD was defined as reduction in GVHD National Institute of Health (NIH) severity score at east for one organ without deterioration in any other organ. A complete response was defined as the absence of any symptoms related to GVHD. Overall response is defined as presence of partial or complete response | 84 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-month overall survival | Time from start of ruxolitinib until death or 6 months, summarized using Kaplan-Meier estimates. | 6 months | 
| Toxicity based NCI CTC grades | Toxicity parameters based on NCI CTCAE 4.03 grades: nasea, vomiting, anemia, thrombocytopenia, leukopenia, neutropenia, hepatotoxicity (liver function tests), nephrotoxicity (creatinine), neurotoxicity (attending physician assessment), hemorrhagic cystitis (attending physician assessment). | 6 months | 
| Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence |  | 6 months | 
| GVHD relapse incidence after complete response | Time from stopping ruxolitinib until recurrence of GVHD or 6 months, summarized using cumulative incidence estimates. | 6 months | 
| Relapse incidence of underlying hematologic malignancy | Time from starting ruxolitinib until hematologic relapse or 12 months, summarized using cumulative incidence estimates | 12 months | 
| Quality of life measured by FACT BMT ver. 4 questionnaire in adults |  | 6 months | 
| Quality of life measured by PedQL Stem Cell transplant module ver.1.0 questionnaire in children |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute graft-versus-host disease, chronic graft-versus-host disease, Steroid-refractory GVHD, ruxolitinib, JAK inhibitors