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

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.

Study Overview

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

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ivan S Moiseev, MD, Prof.; Phone Number: +79217961951; Email: moisiv@mail.ru
• Study Contact Backup: Name: Alexandr D Kulagin, MD, Prof.; Phone Number: +78123386265; Email: bmt-director@1spbgmu.ru

Study Locations

• Russian Federation
  • Saint Petersburg, Russian Federation, 197022
    • Recruiting
    • RM Gorbacheva Research Institute
    • Contact: Alexandr Kulagin; Phone Number: +78123386265; Email: bmt-director@1spbgmu.ru

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: FluBuBe; 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

Drug: Fludarabine; 30 mg/m2/day iv x 6 days, days -7 through -2 of HSCT; Drug: Bendamustine Hydrochloride; 130 mg/m2 iv x 2 days, Days -7 through -6 of HSCT; Drug: Busulfan; 1 mg/kg po qid x 3 days, Days -5 through -3; Drug: Cyclophosphamide; 50 mg/kg iv x 2 days, Days +3 through +4; Drug: Mycophenolate Mofetil; 45 mg/kg/day, maximum 3 g/day, iv or po x 30 days, Days +5 through +35; Drug: Tacrolimus 5Mg Cap; 0.03 mg/kg/day iv or po, Days +5 through +100 with with further correction by concentration. Target concentration 5-15 ng/ml.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
- Incidence of primary and secondary graft failure	Proportion of patients with primary and secondary graft failure defined by the absence of donor chimerism	100 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
- 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. criteria. All toxicity measurements will be aggregated as severity scores.	125 days
- Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence	Proportion of patients, requiring systemic treatment for bacterial, viral and fungal disease	[ Time Frame: 100 days ] [ Designated as safety issue: Yes ]
- 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.	365 days
- Non-relapse mortality analysis	Cumulative incidence of patients with mortality without hematological relapse of malignancy	2 years
- Overall survival analysis	Kaplan-Meier estimate of death from all causes	2 years
- Event-free survival analysis	Kaplan-Meier estimate of death or relapse	2 years
- Relapse rate analysis	Cumulative incidence of patients with relapse	2 years

Collaborators and Investigators

• Sponsor: St. Petersburg State Pavlov Medical University

Study record dates

Study Major Dates

• Study Start (Actual): January 21, 2021
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: June 21, 2021
• First Submitted That Met QC Criteria: June 21, 2021
• First Posted (Actual): June 28, 2021

Study Record Updates

• Last Update Posted (Actual): July 20, 2022
• Last Update Submitted That Met QC Criteria: July 19, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Allogeneic; Hematopoietic Stem Cell Transplantation; Bendamustine; Fludarabine; Busulfan; Antineoplastic Agents, Alkylating; Myeloablative Agonists
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Leukemia, Lymphoid; Leukemia, Myeloid; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Acute Disease; Myeloproliferative Disorders; Leukemia, Biphenotypic, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Bendamustine Hydrochloride; Fludarabine; Tacrolimus; Mycophenolic Acid; Busulfan
• Other Study ID Numbers: 06/21-n

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Request for sharing data with the study plan for the data will be evaluated under common conditions by Pavlov University Ethical Committee.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No