Haploidentical hematopoietic stem cell transplantation irrespective of the conditioning intensity 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 7-20% of graft failures in different diseases. Fludarabine and busulfan conditioning is the most commonly used approach for a variety of diseases. In two previously completed trials of addition of either bendamustine and ruxolitinib to conditioning we observed low rates of primary graft failure with both approaches. The study is the direct randomized comparisons of these two approaches with the primary aim of reducing composite events of primary graft failure, relapse and non-relapse mortality. The stratas for the study are Disease Risk Index (DRI) and the age of the haploidentical donor (\<35 vs ≥35).
Patients must have an indication for allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for malignant disease
Diagnosis: acute myeloid leukemia, acute lymphoblastic leukemia, mixed lineage acute leukemia, lymphoblastic lymphoma, chronic myeloid leukemia, myelodysplastic syndromes, myeloprolipherative neoplasm
Age ≥18
Malignant disease in hematologic response: <5% of clonal blasts in the bone marrow and no clonal blasts in peripheral blood.
Titer of anti-donor anti-HLA antibodies ≥ 5000 at the time of inclusion
Moderate or severe cardiac disease: ejection fraction <50%, unstable angina, stable angina NYHA class III or IV, chronic heart failure NYHA class III or IV, Lawn grade V arrhythmia, myocardial infarction within 3 months before inclusion
Stroke within 3 months of inclusion, unless related to the underlying malignancy
Severe decrease in pulmonary function: FEV1 <50% or DLCO<50% of predicted or respiratory distress or need for oxygen support;
Parallel
Bendamustine Hydrochloride
DrugDays -7 through -6: Bendamustine 90 mg/m2 iv x 2 days
Ruxolitinib
DrugDays -7 through -2: ruxolitinib 5 mg tid per os
Event-free survival
Measure: Kaplan-Meier estimate of either relapse, primary or secondary graft failure or death from all causes
Cumulative incidence of primary and secondary graft failure
Cumulative primary and secondary graft failure, competing risk is death and relapse
Incidence of HSCT-associated adverse events (safety and toxicity)
Toxicity assessment is based on presence of NCI CTC AE 5.0 event grades 3-5. Veno-occlusive disease incidence and severity assessment is based on EBMT criteria 2020. Transplant-associated microangiopathy incidence assessment is based on Harmonization criteria by Schoettler et al. All toxicity measurements will be aggregated as severity scores
Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence
proportion of patients, requiring systemic treatment for bacterial, viral and fungal disease
Cumulative incidence of acute GVHD grade II-IV
Cumulative incidence of patients with acute GVHD II-IV grade, competing risk is death, relapse and primary graft failure
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