Post-transplantation Benadamustine and Cyclophosphamide in Patients With Refractory Myeloid Malignancies

Study Overview
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Brief Summary
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Prognosis of patients undergoing salvage allogeneic stem cell transplantation for refractory leukemia or other refractory myeloid malignanies is poor. One of the approaches to augment graft-versus-leukemia effect the use of post-transplantation bendamustine in graft-versus-host disease prophylaxis. Despite high frequency of responses and durable remissions after this approach majority of patients develop a serious complication - cytokine release syndrome, which can be life-threatening in some patients. On the other hand post-transplantation cyclophocphamide was reported to abort cytokine release syndrome that sometimes occurs after graft transfusion in patients after haploidentical graft transfusion. The aim of this study is to evaluate if the combination of post-transplantation bendamustine (PTB) and post-transplantation cyclophosphamide (PTCY) facilitates comparable graft-versus leukemia effect to PTB, but with better safety profile and reduced incidence of severe cytokine release syndrome.

Official Title
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Graft-versus-host Disease Prophylaxis With Combination of Post-transplantation Benadamustine and Cyclophosphamide in Patients With Refractory Myeloid Malignancies (PTBCy)

Conditions
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Myeloid Leukemia, Acute, Chronic Myeloid Leukemia, Myelodysplastic Syndromes, Myeloproliferative Neoplasm

Intervention / Treatment
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* Drug: Bendamustine Hydrochloride
* Drug: Cyclophosphamid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with indication for allogeneic hematopoietic stem cell transplantation Patients with 5-10/10 HLA-matched related or unrelated 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 Diagnosis: Acute myeloid leukemia Chronic myeloid leukemia, Ph+ Myelodysplastic Syndromes Myeloprolipherative neoplasms Salvage hematopoietic stem cell transplantation defined as: Acute myeloid leukemia: >5% of clonal blasts despite adequate previous induction therapy or allogeneic stem cell transplantation Myelodysplastic Syndrome: >10% of blasts despite previous therapy with -7 or complex karyotype, or p53 mutation Chronic myeloid leukemia: blast crisis or acceleration phase despite at least 3 previous lines of TKIs Myeloprolipherative neoplasms : high tumor burden despite previous therapy, including >20 000 WBC/ ul or splenomegaly >15 cm 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: PTBCy graft-versus-host disease prophylaxis<br>Days +3 through +4: Bendamustine 50 mg/m2 iv x 2 days; Days +3 through +4: Cyclophosphamide 25 mg/kg iv x 2 days; Days +5 through +35: Mycophenolate mofetil 30 mg/kg/day, maximum 3 g/day, iv or po x 30 days; Days +5 through +100: Tacrolimus 0.03 mg/kg/day with further correction by concentration | Drug: Bendamustine Hydrochloride<br>* 50 mg/m2 iv Days +3 through +4 after allogeneic hematopoietic stem cell transplantation<br>Drug: Cyclophosphamid<br>* 25 mg/kg iv Days +3 through +4 after allogeneic hematopoietic stem cell transplantation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival analysis [ Time Frame: 1 year ] | Measure: Kaplan-Meier estimate of death or relapse, or graft failure | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| - Incidence of Cytokine release syndrome | Proportion of patients with cytokine release syndrome according to ASBMT Consensus Grading for Cytokine Release Syndrome, 2018 | 100 days | 
| 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. | 100 days | 
| 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 | 1 year | 
| Relapse rate analysis | Cumulative incidence of patients with relapse | 1 year | 
| Non-relapse mortality analysis | Cumulative incidence of patients with mortality without hematological relapse of malignancy | 1 year | 
| Overall survival analysis | Kaplan-Meier estimate of death from all causes | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bendamustine, Cyclophosphamide, Graft-versus-host disease, Graft-versus-leukemia effect, Refractory, Acute Myeloid leukemia, Hematopoietic Stem Cell Transplantation, Allogeneic