Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Biphenotypic Acute Leukemia, Lymphoblastic Lymphoma, Myelodysplastic Syndromes, Myeloproliferative Neoplasm
Conditions
Brief summary
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).
Interventions
DRUGBendamustine Hydrochloride
Days -7 through -6: Bendamustine 90 mg/m2 iv x 2 days
DRUGRuxolitinib
Days -7 through -2: ruxolitinib 5 mg tid per os
Sponsors
St. Petersburg State Pavlov Medical University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* 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. * 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
Exclusion criteria
* 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; * Severe organ dysfunction: AST or ALT \>5 upper normal limits, bilirubin \>1.5 upper normal limits, creatinine \>2 upper normal limits * Creatinine clearance \< 40 mL/min * Uncontrolled bacterial or fungal infection at the time of enrollment defined by CRP\> 70 mg/L * Requirement for vasopressor support at the time of enrollment * Karnofsky index \<70% * Pregnancy * Somatic or psychiatric disorder making the patient unable to sign informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free survival | 2 years | Measure: Kaplan-Meier estimate of either relapse, primary or secondary graft failure or death from all causes |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of HSCT-associated adverse events (safety and toxicity) | 125 days | 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 | 100 days | proportion of patients, requiring systemic treatment for bacterial, viral and fungal disease |
| Cumulative incidence of acute GVHD grade II-IV | 125 days | Cumulative incidence of patients with acute GVHD II-IV grade, competing risk is death, relapse and primary graft failure |
| Incidence of moderate and severe chronic GVHD | 2 years | Cumulative incidence of patients with moderate and severe chronic GVHD according to NIH 2015 criteria, competing risk is death, relapse and primary graft failure |
| Cumulative incidence of primary and secondary graft failure | 365 days | Cumulative primary and secondary graft failure, competing risk is death and relapse |
| Overall survival analysis | 2 years | Measure: Kaplan-Meier estimate of death from all causes |
| GVHD-relapse-free survival analysis | 2 years | Measure: Kaplan-Meier estimate of death, acute GVHD grade III-IV, severe chronic GVHD or relapse |
| Relapse cumulative incidence analysis | 2 years | Cumulative incidence of patients with relapse, competing risk is non-relapse mortality |
| Non-relapse mortality analysis | 2 years | Cumulative incidence of patients with mortality without hematological relapse of malignancy |
Countries
Russia
Contacts
Primary ContactIVAN SERGEEVICH MOISEEV
Backup ContactYulia Vlasova
Outcome results
None listed