GVHD Prophylaxis With Post-transplantation Bendamustine in Refractory Leukemia

Study Overview
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Brief Summary
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Several groups have demonstrated very low incidence of acute and chronic graft-versus-host disease (GVHD) with post-transplantation cyclophosphamide (PTCy) in haploidentical, unrelated and related allogeneic stem cell transplantation (SCT). Nonetheless for majority of the grafts, except for 10/10 HLA-matched bone marrow, with this type of prophylaxis require concomitant administration of calcineurin inhibitors±MMF, which delays immune reconstitution and development of graft-versus-leukemia (GVL) effect. So, despite reduction of transplant-related mortality, use of PTCy doesn't lead to the reduction of relapse incidence. This is particularly important for relapsed or refractory acute leukemia patients, where, despite all efforts to intensify conditioning regimens, relapses after SCT occur in more than 50% of patients, and long-term survival rarely exceeds 10-20%. In preclinical model of haploidentical SCT the substitution of post-transplantation cyclophosphamide with bendamustine, led to comparable GVHD control, but significantly augmented GVL effect. To test this hypothesis and improve the outcome of allogeneic SCT in refractory acute leukemia patients we initiated a pilot trial with high-dose post-transplantation bendamustine for GVHD prophylaxis. The selection of doses is based on the previous dose-escalation studies. Additional immunosuppression could be added for mismatched grafts.

Official Title
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Dose-escalation Study of Graft-versus-host Disease Prophylaxis With High-dose Post-transplantation Bendamustine in Patients With Refractory Acute Leukemia

Conditions
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Leukemia, Acute Lymphoblastic, Acute Myeloid Leukemia, Mixed-Lineage Acute Leukemias

Intervention / Treatment
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* Procedure: Allogeneic stem cell transplantation
* Drug: Fludarabine monophosphate
* Drug: Busulfan
* Drug: Bendamustine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Diagnosis: Acute Myeloblastic Leukemia Acute Lymphoblastic Leukemia Mixed-Lineage Acute Leukemias Disease, refractory to at list one course of induction chemotherapy or immunotherapy More than 5% clonal blasts in the bone marrow or peripheral blood at the time of inclusion 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 No previous autologous or allogeneic stem cell transplantations Exclusion Criteria: Karnofsky index <70% 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 >1.5 upper normal limits Creatinine clearance < 60 mL/min Uncontrolled bacterial or fungal infection at the time of enrollment, defined by CRP level >70 mg/L or positive procalcitonin in patient with adequate empirical antibacterial and antifungal therapy. Requirement for vasopressor support at the time of enrollment 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: 60 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 280 mg/m2 bendamustine<br>10 patients Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -6 through -3: Busulfan 1 mg/kg po qid №14 Day 0: Infusion of unmanipulated graft Day +3 and +4: Bendamustine 140 mg/m2/day iv. | Procedure: Allogeneic stem cell transplantation<br> <br> * Other names: HSCT;Drug: Fludarabine monophosphate<br> <br> Drug: Busulfan<br> <br> Drug: Bendamustine<br> <br> |
| Experimental: 200 mg/m2 bendamustine<br>10 patients Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -6 through -3: Busulfan 1 mg/kg po qid №14 Day 0: Infusion of unmanipulated graft Day +3 and +4: Bendamustine 100 mg/m2/day iv | Procedure: Allogeneic stem cell transplantation<br> <br> * Other names: HSCT;Drug: Fludarabine monophosphate<br> <br> Drug: Busulfan<br> <br> Drug: Bendamustine<br> <br> |
| Experimental: 140 mg/m2 bendamustine<br>10 patients Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -6 through -3: Busulfan 1 mg/kg po qid №14 Day 0: Infusion of unmanipulated graft Day +3, +4: Bendamustine 70 mg/m2/day iv. | Procedure: Allogeneic stem cell transplantation<br> <br> * Other names: HSCT;Drug: Fludarabine monophosphate<br> <br> Drug: Busulfan<br> <br> Drug: Bendamustine<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Engraftment rate | Engraftment is defined as the first of 3 consecutive days with an ANC>500 per μl and WBC>1000 per μl. Platelet engraftment is not mandatory for the endpoint. | 60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse rate analysis |  | 365 days | 
| Non-relapse mortality analysis |  | 365 days | 
| Incidence of acute GVHD, grades II-IV |  | 180 days | 
| Incidence of chronic GVHD, moderate and severe (NIH criteria) |  | 365 days | 
| Overall survival analysis |  | 365 days | 
| Event-free survival analysis |  | 365 days | 
| Toxicity (NCI CTCAE 4.03) | 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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Allogeneic Transplantation, Hematopoietic Stem Cell Transplantation, Leukemia, Acute Lymphoblastic, Acute Myeloid Leukemia, Mixed-Lineage Acute Leukemias, Immune System Diseases, Immunosuppressive Agents, Myeloablative Agonists, Busulfan, Fludarabine, Antineoplastic Agents, Alkylating, Bendamustine Hydrochloride