Ruxolitinib for Newly Diagnosed Bronchiolitis Obliterans Syndrome

Study Overview
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Brief Summary
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Lung is one of the target organs in chronic graft versus host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Bronchiolitis obliterans syndrome (BOS) after allo-HSCT was a clinical syndrome characterized by persistent airflow restriction which is the result of lung cGVHD. BOS is one of the main causes of late mortality after allo-HSCT, severely restricting the daily activities and respiratory function of patients. It limits the quality of life and increased the non-relapse mortality (NRM) after allo-HSCT. Currently, the first-line treatment for BOS is FAM ( oral fluticasone, azithromycin and montelukast). However, more than 50% of patients develop as steroids resistant (SR)-BOS, and SR-BOS has a poor prognosis and irreversible impaired lung function. Ruxolitinib is an effective drug in the treatment of SR-cGVHD. This is a phase Ⅱ prospective clinical study to explore the efficacy and safety of ruxolitinib as a first-line treatment for newly diagnosed BOS after allo-HSCT.

Detailed Description
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The incidence of chronic graft versus host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) was 30%-70%, Which extremely limited the quality of life and the survival of patients after allo-HSCT. Lung is one of the target organs in cGVHD after allo-HSCT. Bronchiolitis obliterans syndrome (BOS) after allo-HSCT was a clinical syndrome characterized by persistent airflow restriction which is the result of lung cGVHD. BOS is one of the main causes of late mortality after allo-HSCT, severely restricting the daily activities and respiratory function of patients. It limits the quality of life and increased the non-relapse mortality (NRM) after allo-HSCT. Currently, the first-line treatment for BOS is FAM ( oral fluticasone, azithromycin and montelukast). However, more than 50% of patients develop as steroids resistant (SR)-BOS, and SR-BOS has a poor prognosis and irreversible impaired lung function. Ruxolitinib is an effective drug in the treatment of SR-cGVHD. This is a phase Ⅱ prospective clinical study to explore the efficacy and safety of ruxolitinib as a first-line treatment for newly diagnosed BOS after allo-HSCT.

Official Title
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Ruxolitinib for Newly Diagnosed Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation

Conditions
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Bronchiolitis Obliterans Syndrome, Hematologic Malignancy

Intervention / Treatment
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* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female; 18-65 years old Diagnosis of BOS after allo-HCT defined as the 2014 NIH criteria Life expectancy > 6 months at the time of enrollment At least 4 weeks since initiation of the most recent systemic therapy for cGVHD or BOS The ability to understand and willingness to sign a written consent document Exclusion Criteria: Recurrent malignancy or disease progression requiring anticancer therapy Currently receiving or have previously received ruxolitinib for chronic GVHD therapy Known history of allergy to ruxolitinib or its excipients Hepatic dysfunction: transaminases (ALT, AST) > 5X ULN and/or total bilirubin > 3X ULN Hematologic dysfunction: absolute neutrophil count <1000/μL, platelet cout <30*10E9/L, and/or Hgb < 8 g/dL Renal dysfunction: calculated creatinine clearance < 30 mL/min (Cockcroft-Gault formula) previously received second-line treatment or any drugs in clinical trials for cGVHD

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: treatment group<br>Ruxolitinib twice daily treatment, combined with steroids 1mg/kg/day for two weeks, and tampering 0.25 mg/kg/day every week | Drug: Ruxolitinib<br>* Oral ruxolitinib twice daily<br>* Other names: Ruxolitinib twice daily;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| absolute FEV1 increase | The proportion of participants with a sustained, absolute FEV1 increase by ≥ 10% after 3 months of treatment with ruxolitinib (compared to baseline measure prior to study enrollment) | 3 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| treatment failure rate | The proportion of participants who do not experience a sustained, absolute decrease in FEV1 by ≥ 10% after 3 months of treatment with ruxolitinib (compared to baseline measure prior to study enrollment) | 3 Months | 
| absolute FEV1 increase | The proportion of participants with a sustained, absolute FEV1 increase by ≥ 10% after treatment with ruxolitinib (compared to baseline measure prior to study enrollment) | 6 Months, 9 Months, 12 Months and 24 Months | 
| Improvements in chronic GVHD organ specific manifestations | mprovements in chronic GVHD organ specific manifestations will be categorized according to the NIH chronic GVHD consensus criteria. | 6 Months, 9 Months, 12 Months and 24 Months | 
| Overall Survival | The proportion of patients survival at two years after enrollment of ruxolitinib treatment | 2 years | 
| cGVHD progression-free survival | Participants alive without cGVHD progression are censored at the date of last disease evaluation | 2 years | 
| The incidence and types of serious adverse events | Adverse events are graded according to Common Terminology Criteria for Adverse Events (CTCAE v4) | From the start of treatment until 30 days after the end of treatment, up to 2 years | 
| The change of systemic corticosteroid dose over time | The change of systemic corticosteroid dose over time during the treatment of BOS | From the start of treatment until the end of treatment, up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allogeneic Hematopoietic stem cell transplantation, chronic graft versus host disease, bronchiolitis obliterans syndrome