Post-transplantation Benadamustine and Cyclophosphamide in Patients With Refractory Myeloid Malignancies

Phase 2

Completed

• Conditions: Chronic Myeloid Leukemia; Myeloproliferative Neoplasm; Myeloid Leukemia, Acute; Myelodysplastic Syndromes
• Interventions: Drug: Bendamustine Hydrochloride; Drug: Cyclophosphamid

• Registration Number: NCT04943757
• Lead Sponsor: St. Petersburg State Pavlov Medical University

Brief Summary

Prognosis of patients undergoing salvage allogeneic stem cell transplantation for refractory leukemia or other refractory myeloid malignanies is poor. One of the approaches to augment graft-versus-leukemia effect the use of post-transplantation bendamustine in graft-versus-host disease prophylaxis. Despite high frequency of responses and durable remissions after this approach majority of patients develop a serious complication - cytokine release syndrome, which can be life-threatening in some patients. On the other hand post-transplantation cyclophocphamide was reported to abort cytokine release syndrome that sometimes occurs after graft transfusion in patients after haploidentical graft transfusion. The aim of this study is to evaluate if the combination of post-transplantation bendamustine (PTB) and post-transplantation cyclophosphamide (PTCY) facilitates comparable graft-versus leukemia effect to PTB, but with better safety profile and reduced incidence of severe cytokine release syndrome.

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: 2021-06-29
• Primary Completion: 2024-05-30
• Study Completion: 2024-05-30
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-10
• Last Update Posted: 2024-10-14

Recruitment & Eligibility

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

Inclusion Criteria

• Patients with indication for allogeneic hematopoietic stem cell transplantation
• Patients with 5-10/10 HLA-matched related or unrelated 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
• Diagnosis:

Acute myeloid leukemia Chronic myeloid leukemia, Ph+ Myelodysplastic Syndromes Myeloprolipherative neoplasms

• Salvage hematopoietic stem cell transplantation defined as:
• Acute myeloid leukemia: >5% of clonal blasts despite adequate previous induction therapy or allogeneic stem cell transplantation Myelodysplastic Syndrome: >10% of blasts despite previous therapy with -7 or complex karyotype, or p53 mutation Chronic myeloid leukemia: blast crisis or acceleration phase despite at least 3 previous lines of TKIs Myeloprolipherative neoplasms : high tumor burden despite previous therapy, including >20 000 WBC/ ul or splenomegaly >15 cm
• No severe concurrent illness

Exclusion Criteria

• 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
PTBCy graft-versus-host disease prophylaxis	Cyclophosphamid	Days +3 through +4: Bendamustine 50 mg/m2 iv x 2 days; Days +3 through +4: Cyclophosphamide 25 mg/kg iv x 2 days; Days +5 through +35: Mycophenolate mofetil 30 mg/kg/day, maximum 3 g/day, iv or po x 30 days; Days +5 through +100: Tacrolimus 0.03 mg/kg/day with further correction by concentration
PTBCy graft-versus-host disease prophylaxis	Bendamustine Hydrochloride	Days +3 through +4: Bendamustine 50 mg/m2 iv x 2 days; Days +3 through +4: Cyclophosphamide 25 mg/kg iv x 2 days; Days +5 through +35: Mycophenolate mofetil 30 mg/kg/day, maximum 3 g/day, iv or po x 30 days; Days +5 through +100: Tacrolimus 0.03 mg/kg/day with further correction by concentration

Primary Outcome Measures

Name	Time	Method
Event-free survival analysis [ Time Frame: 1 year ]	1 year	Measure: Kaplan-Meier estimate of death or relapse, or graft failure

Secondary Outcome Measures

Name	Time	Method
Incidence of HSCT-associated adverse events (safety and toxicity)	100 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.
Non-relapse mortality analysis	1 year	Cumulative incidence of patients with mortality without hematological relapse of malignancy
Incidence of moderate and severe chronic GVHD	1 year	Cumulative incidence of patients with moderate and severe chronic GVHD according to NIH 2015 criteria
Relapse rate analysis	1 year	Cumulative incidence of patients with relapse
- Incidence of Cytokine release syndrome	100 days	Proportion of patients with cytokine release syndrome according to ASBMT Consensus Grading for Cytokine Release Syndrome, 2018
Incidence of acute GVHD grade II-IV	125 days	Cumulative incidence of patients with acute GVHD II-IV grade
Overall survival analysis	1 year	Kaplan-Meier estimate of death from all causes

Trial Locations

Locations (1)

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