PTCy and Ruxolitinib GVHD Prophylaxis in Myelofibrosis

Study Overview
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Brief Summary
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A number of groups have demonstrated very low incidence of acute and chronic graft-versus-host disease (GVHD) with post-transplantation cyclophosphamide (PTCy) in haploidentical and unrelated allogeneic stem cell transplantation (SCT). Still the relapse of the underlining malignancy is a problem after this prophylaxis. Ruxolitinib is currently one of the most promising drugs in the treatment of steroid-refractory GVHD. On the other hand, its primary indication is myelofibrosis, and it was demonstrated that ruxolitinib before allogeneic SCT might improve the outcome. This pilot trial evaluates whether the combination of PTCy and ruxolitinib facilitates adequate GVHD control, and decreases the risk of graft failure and disease progression in myelofibrosis patients.

Official Title
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Graft-versus-host Disease Prophylaxis With Post-transplantation Cyclophosphamide and Ruxolitinib in Patients With Myelofibrosis

Conditions
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Primary Myelofibrosis, Myeloproliferative Disorders

Intervention / Treatment
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* Procedure: Allogeneic hematopoietic stem cell transplantation
* Drug: Busulfan
* Drug: Fludarabine monophosphate
* Drug: Cyclophosphamide
* Drug: Ruxolitinib
* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have an indication for allogeneic hematopoietic stem cell transplantation Diagnosis: Primary myelofibrosis Secondary myelofibrosis Signed informed consent Matched related, 8-10/10 HLA-matched unrelated or haploidentical donor available. The HLA typing is performed by the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. No second tumors No severe concurrent illness Exclusion Criteria: Moderate or severe cardiac dysfunction, left ventricular ejection fraction <50% Moderate or severe decrease in pulmonary function, FEV1 <70% or DLCO<70% of predicted Respiratory distress >grade I Severe organ dysfunction: AST or ALT >5 upper normal limits, bilirubin >1.5 upper normal limits, creatinine >2 upper normal limits Creatinine clearance < 60 mL/min Uncontrolled bacterial or fungal infection at the time of enrollment Requirement for vasopressor support at the time of enrollment Karnofsky index <30% Pregnancy Somatic or psychiatric disorder making the patient unable to sign informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
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: PTCy and ruxolitinib<br> | Procedure: Allogeneic hematopoietic stem cell transplantation<br>* Day 0: Infusion of unmanipulated graft<br>* Other names: HSCT;Drug: Busulfan<br>* Days -5 through -3: Busulfan 1 mg/kg po qid №10<br>Drug: Fludarabine monophosphate<br>* Days -7 through -2: 30 mg/m2/day iv qd x 6 days<br>Drug: Cyclophosphamide<br>* Day +3 and +4: 50 mg/kg/day iv qd<br>* Other names: Cytoxan;Drug: Ruxolitinib<br>* Days -8 through -2 15 mg tid<br>Drug: Ruxolitinib<br>* Days +5 through +100: 7.5 mg bid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of acute graft-versus-host disease, grades II-IV |  | 180 days | 
| Incidence of chronic GVHD, moderate and severe (NIH criteria) |  | 365 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of primary or secondary graft failure |  | 60 days | 
| Non-relapse mortality analysis | Non-relapse mortality is defined as any death in absence of relapse or progressive disease. Summarized using Kaplan-Meier and cumulative incidence estimates. | 365 days | 
| Overall survival analysis | Summarized using Kaplan-Meier and cumulative incidence estimates. | 365 days | 
| Event-free survival analysis | Event is defined as relapse or death in the specified time frame. Summarized using Kaplan-Meier and cumulative incidence estimates. | 365 days | 
| Relapse rate analysis | Summarized using Kaplan-Meier and cumulative incidence estimates. | 365 days | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.03 | Toxicity parameters based on NCI CTCAE 4.03 grades: hepatotoxicity (liver function tests), nephrotoxicity (creatinine), neurotoxicity (attending physician assessment), mucositis (attending physician assessment), hemorrhagic cystitis (attending physician assessment), cardiotoxicity (ECG, echocardiography). Additional toxicity parameters: incidence and severity of veno-occlusive disease, incidence of transplant-associated microangiopathy | 100 days | 
| Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence |  | 100 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelofibrosis, Ruxolitinib, Cyclophosphamide, Immunosuppressive Agents, Immune System Diseases, Busulfan, Fludarabine, Antineoplastic Agents, Alkylating, Myeloablative Agonists, Hematopoietic Stem Cell Transplantation, Allogeneic