GVHD Prophylaxis With Post-transplantation Bendamustine in Refractory Leukemia
- Conditions
- Mixed-Lineage Acute LeukemiasLeukemia, Acute LymphoblasticAcute Myeloid Leukemia
- Interventions
- Procedure: Allogeneic stem cell transplantation
- Registration Number
- NCT02799147
- Lead Sponsor
- St. Petersburg State Pavlov Medical University
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 27
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description 280 mg/m2 bendamustine Allogeneic stem cell transplantation 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. 200 mg/m2 bendamustine Allogeneic stem cell transplantation 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 200 mg/m2 bendamustine Fludarabine monophosphate 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 280 mg/m2 bendamustine Fludarabine monophosphate 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. 140 mg/m2 bendamustine Allogeneic stem cell transplantation 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. 140 mg/m2 bendamustine Fludarabine monophosphate 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. 140 mg/m2 bendamustine Busulfan 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. 280 mg/m2 bendamustine Busulfan 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. 280 mg/m2 bendamustine Bendamustine 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. 200 mg/m2 bendamustine Busulfan 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 200 mg/m2 bendamustine Bendamustine 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 140 mg/m2 bendamustine Bendamustine 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.
- Primary Outcome Measures
Name Time Method Engraftment rate 60 days 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.
- Secondary Outcome Measures
Name Time Method Non-relapse mortality analysis 365 days Incidence of acute GVHD, grades II-IV 180 days Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence 100 days Incidence of chronic GVHD, moderate and severe (NIH criteria) 365 days Overall survival analysis 365 days Toxicity (NCI CTCAE 4.03) 100 days 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
Relapse rate analysis 365 days Event-free survival analysis 365 days
Trial Locations
- Locations (1)
First Pavlov State Medical University of St. Petersburg
🇷🇺Saint-Petersburg, Russian Federation