Leukemia, Chronic Myeloid, Myelodysplastic Syndromes, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
Conditions
Keywords
Cyclophosphamide, Thymoglobulin, Myelodysplastic Syndromes, Immunosuppressive Agents, Immune System Diseases, Busulfan, Fludarabine, Tacrolimus, Mycophenolate mofetil, Antineoplastic Agents, Alkylating, Myeloablative Agonists, Hematopoietic Stem Cell Transplantation, Allogeneic Transplantation, Leukemia, Chronic Myeloid, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
Brief summary
Purpose There is a growing evidence of high efficacy of post-transplantation cyclophocphomide (PTCy)-based GVHD prophylaxis in haploidentical and matched related and unrelated bone marrow transplantation. There is limitted, but growing data on safety and efficacy of this prophylaxis in unrelated and peripheral blood stem cell transplantations. Use of PTCy in chronic myeloproliferative neoplasms and myelodisplatic syndrome is of particular interest. On the one hand, PTCy could reduce the incidence of chronic GVHD and long-term bormidity. On the other hand, there is a concern, that PTCy can increase the incidence of graft failures in this group of patients. Currently published data indicate that low-dose Thymoglobulin-based prophylaxis is the most promissing compatitor in terms of acute and chronic GVHD control. So there is a rationale to randomize Thymoglobulin and PTCy as GVHD prophilaxis. Pre-transplant assesment of moratlity (PAM)-index will be used as the strata for randomization, as it is the paramter that takes into account the most important factors effecting survival. The conditioning regimen and the other two components of GVHD prophylaxis (mycophenolate mofetil and tacrolimus) will be identical in the two arms of the study.
Interventions
PROCEDUREUnrelated allogeneic stem cell transplantation
DRUGBusulfan
DRUGTacrolimus
DRUGMycophenolate mofetil
DRUGCyclophosphamide
DRUGThymoglobulin
Sponsors
St. Petersburg State Pavlov Medical University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
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 * Diagnosis: Chronic myeloid leukemia Myelodysplastic Syndromes Myeloprolipherative neoplsm unclassified Atypical chronic myelogenous leukemia * Signed informed consent * Patients with 10/10 HLA-matched 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. Mismatches in these loci are not allowed. * Peripheral blood stem cells as graft source * No second tumors * No prior history of Thymoglobulin exposure or no history of anaphylactic shock after Thymoglobulin administration * 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of primary graft failure | 60 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of chronic GVHD, moderate and severe (NIH criteria) | 365 days | — |
| Non-relapse mortality analysis | 365 days | — |
| Event-free survival analysis | 365 days | — |
| Incidence of acute GVHD, grades II-IV | 365 days | — |
| Relapse rate analysis | 365 days | — |
| Toxicity (NCI CTCAE 4.03) | 100 days | Toxicity parameters based on NCI CTCAE 4.03 grades: hepatotoxicity (liver function tests), nephrotoxicity (creatinine), neurotoxicity (attending physician assessment), mucositis (attending physician assessment), hemorrhagic cystitis (attending physician assessment), cardiotoxicity (ECG, echocardiography). Additional toxicity parameters: incidence and severity of veno-occlusive disease, incidence of transplant-associated microangiopathy |
| Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence | 100 days | — |
| Overall survival analysis | 365 days | — |
Countries
Russia
Outcome results
None listed