Dose-escalation Study of Graft-versus-host Disease Prophylaxis With High-dose Post-transplantation Bendamustine in Patients With Refractory Acute Leukemia
Overview
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- St. Petersburg State Pavlov Medical University
- Enrollment
- 27
- Locations
- 1
- Primary Endpoint
- Engraftment rate
Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 60 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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-DQB
- •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
Arms & Interventions
280 mg/m2 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.
Intervention: Allogeneic stem cell transplantation (Procedure)
280 mg/m2 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.
Intervention: Fludarabine monophosphate (Drug)
280 mg/m2 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.
Intervention: Busulfan (Drug)
280 mg/m2 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.
Intervention: Bendamustine (Drug)
200 mg/m2 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
Intervention: Allogeneic stem cell transplantation (Procedure)
200 mg/m2 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
Intervention: Fludarabine monophosphate (Drug)
200 mg/m2 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
Intervention: Busulfan (Drug)
200 mg/m2 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
Intervention: Bendamustine (Drug)
140 mg/m2 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.
Intervention: Allogeneic stem cell transplantation (Procedure)
140 mg/m2 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.
Intervention: Fludarabine monophosphate (Drug)
140 mg/m2 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.
Intervention: Busulfan (Drug)
140 mg/m2 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.
Intervention: Bendamustine (Drug)
Outcomes
Primary Outcomes
Engraftment rate
Time Frame: 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 Outcomes
- Incidence of acute GVHD, grades II-IV(180 days)
- Non-relapse mortality analysis(365 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)
- Relapse rate analysis(365 days)
- Event-free survival analysis(365 days)
Investigators
Ivan S Moiseev
Vice-director for science of R.M. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation
St. Petersburg State Pavlov Medical University