Benadamustine, Fludarabine and Busulfan Conditioning in Recipients of Haploidentical Stem Cell Transplantation (FluBuBe)

Study Overview
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Brief Summary
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Haploidentical hematopoietic stem cell transplantation irrespective of the conditioning and graft-versus-host disease prophylaxis is associated with high frequency of primary and secondary graft failure. Different technologies of with replete or depleted graft are associated with 10-20% of graft failures. Fludarabine and busulfan conditioning is the most commonly used approach for a variety of disease. Furthermore combination of fludarabine and bendamustine was sufficient to facilitate engraftment in patients with chronic lymphocytic leukemia and lymphomas. The aim of the study is to evaluate whether addition of bendamustine to fladarabine and busulfan conditioning reduces the risk of primary graft failure after haploidentical allograft.

Official Title
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Benadamustine, Fludarabine and Busulfan Conditioning in Recipients of Haploidentical Stem Cell Transplantation (FluBuBe)

Conditions
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Leukemia, Acute Lymphoblastic, Myeloid Leukemia, Acute, Biphenotypic Acute Leukemia, Lymphoblastic Lymphoma, Myelodysplastic Syndromes, Myeloproliferative Neoplasm

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Bendamustine Hydrochloride
* Drug: Busulfan
* Drug: Cyclophosphamide
* Drug: Mycophenolate Mofetil
* Drug: Tacrolimus 5Mg Cap


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 with myeloablative conditioning for malignant disease Patients with 5-9/10 HLA-matched related donor available. The donor and recipient must be identical by the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. Peripheral blood stem cells or bone marrow as a graft source No second malignancies requiring treatment No severe concurrent illness Exclusion Criteria: Titer of anti-HLA antibodies ≥ 5000 at the time of inclusion 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: 75 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: FluBuBe<br>Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days; Days -7 through -6: Bendamustine 130 mg/m2 iv x 2 days; Days -5 through -3: Busulfan 1 mg/kg po qid x 3 days; Days +3 through +4: Cyclophosphamide 50 mg/kg iv x 2 days; Days +5 through +35: Mycophenolate mofetil 45 mg/kg/day, maximum 3 g/day, iv or po x 30 days; Days +5 through +150: Tacrolimus 0.03 mg/kg/day with further correction by concentration | Drug: Fludarabine<br>* 30 mg/m2/day iv x 6 days, days -7 through -2 of HSCT<br>Drug: Bendamustine Hydrochloride<br>* 130 mg/m2 iv x 2 days, Days -7 through -6 of HSCT<br>Drug: Busulfan<br>* 1 mg/kg po qid x 3 days, Days -5 through -3<br>Drug: Cyclophosphamide<br>* 50 mg/kg iv x 2 days, Days +3 through +4<br>Drug: Mycophenolate Mofetil<br>* 45 mg/kg/day, maximum 3 g/day, iv or po x 30 days, Days +5 through +35<br>Drug: Tacrolimus 5Mg Cap<br>* 0.03 mg/kg/day iv or po, Days +5 through +100 with with further correction by concentration. Target concentration 5-15 ng/ml.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| - Incidence of primary and secondary graft failure | Proportion of patients with primary and secondary graft failure defined by the absence of donor chimerism | 100 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| - Incidence of HSCT-associated adverse events (safety and toxicity) | Toxicity assessment is based on NCI CTC AE 5.0 grades. Veno-occlusive disease incidence and severity assessment is based on EBMT criteria 2016. Transplant-associated microangiopathy incidence assessment is based on Cho et al. criteria. All toxicity measurements will be aggregated as severity scores. | 125 days | 
| - Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence | Proportion of patients, requiring systemic treatment for bacterial, viral and fungal disease | [ Time Frame: 100 days ] [ Designated as safety issue: Yes ] | 
| - Incidence of acute GVHD grade II-IV | Cumulative incidence of patients with acute GVHD II-IV grade | 125 days | 
| - Incidence of moderate and severe chronic GVHD | Cumulative incidence of patients with moderate and severe chronic GVHD according to NIH 2015 criteria. | 365 days | 
| - Non-relapse mortality analysis | Cumulative incidence of patients with mortality without hematological relapse of malignancy | 2 years | 
| - Overall survival analysis | Kaplan-Meier estimate of death from all causes | 2 years | 
| - Event-free survival analysis | Kaplan-Meier estimate of death or relapse | 2 years | 
| - Relapse rate analysis | Cumulative incidence of patients with relapse | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fludarabine, Bendamustine, Busulfan, Myeloablative Agonists, Hematopoietic Stem Cell Transplantation, Allogeneic, Antineoplastic Agents, Alkylating