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

Phase 2

Completed

• Conditions: Leukemia, Acute Lymphoblastic; Myeloid Leukemia, Acute; Myelodysplastic Syndromes; Myeloproliferative Neoplasm; Lymphoblastic Lymphoma; Biphenotypic Acute Leukemia
• Interventions: Drug: Fludarabine; Drug: Bendamustine Hydrochloride; Drug: Busulfan; Drug: Cyclophosphamide; Drug: Mycophenolate Mofetil; Drug: Tacrolimus 5Mg Cap

• Registration Number: NCT04942730
• Lead Sponsor: St. Petersburg State Pavlov Medical University

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2021-01-21
• Study First Submitted: 2021-06-21
• Study First Submitted QC: 2021-06-21
• Study First Posted: 2021-06-28
• Primary Completion: 2024-04-30
• Study Completion: 2024-04-30
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-06
• Last Update Posted: 2024-05-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 50

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
FluBuBe	Tacrolimus 5Mg Cap	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
FluBuBe	Fludarabine	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
FluBuBe	Bendamustine Hydrochloride	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
FluBuBe	Busulfan	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
FluBuBe	Mycophenolate Mofetil	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
FluBuBe	Cyclophosphamide	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

Primary Outcome Measures

Name	Time	Method
- Incidence of primary and secondary graft failure	100 days	Proportion of patients with primary and secondary graft failure defined by the absence of donor chimerism

Secondary Outcome Measures

Name	Time	Method
- Event-free survival analysis	2 years	Kaplan-Meier estimate of death or relapse
- Relapse rate analysis	2 years	Cumulative incidence of patients with relapse
- Overall survival analysis	2 years	Kaplan-Meier estimate of death from all causes
- Incidence of HSCT-associated adverse events (safety and toxicity)	125 days	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.
- Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence	[ Time Frame: 100 days ] [ Designated as safety issue: Yes ]	Proportion of patients, requiring systemic treatment for bacterial, viral and fungal disease
- Incidence of acute GVHD grade II-IV	125 days	Cumulative incidence of patients with acute GVHD II-IV grade
- Incidence of moderate and severe chronic GVHD	365 days	Cumulative incidence of patients with moderate and severe chronic GVHD according to NIH 2015 criteria.
- Non-relapse mortality analysis	2 years	Cumulative incidence of patients with mortality without hematological relapse of malignancy

Trial Locations

Locations (1)

RM Gorbacheva Research Institute; 🇷🇺 Saint Petersburg, Russian Federation