Primary Myelofibrosis, Myeloproliferative Disorders
Conditions
Keywords
Myelofibrosis, Ruxolitinib, Cyclophosphamide, Immunosuppressive Agents, Immune System Diseases, Busulfan, Fludarabine, Antineoplastic Agents, Alkylating, Myeloablative Agonists, Hematopoietic Stem Cell Transplantation, Allogeneic
Brief summary
A number of groups have demonstrated very low incidence of acute and chronic graft-versus-host disease (GVHD) with post-transplantation cyclophosphamide (PTCy) in haploidentical and unrelated allogeneic stem cell transplantation (SCT). Still the relapse of the underlining malignancy is a problem after this prophylaxis. Ruxolitinib is currently one of the most promising drugs in the treatment of steroid-refractory GVHD. On the other hand, its primary indication is myelofibrosis, and it was demonstrated that ruxolitinib before allogeneic SCT might improve the outcome. This pilot trial evaluates whether the combination of PTCy and ruxolitinib facilitates adequate GVHD control, and decreases the risk of graft failure and disease progression in myelofibrosis patients.
Interventions
PROCEDUREAllogeneic hematopoietic stem cell transplantation
Day 0: Infusion of unmanipulated graft
DRUGBusulfan
Days -5 through -3: Busulfan 1 mg/kg po qid №10
Days -7 through -2: 30 mg/m2/day iv qd x 6 days
DRUGCyclophosphamide
Day +3 and +4: 50 mg/kg/day iv qd
DRUGRuxolitinib
Days -8 through -2 15 mg tid
Sponsors
St. Petersburg State Pavlov Medical University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Patients must have an indication for allogeneic hematopoietic stem cell transplantation * Diagnosis: Primary myelofibrosis Secondary myelofibrosis * Signed informed consent * Matched related, 8-10/10 HLA-matched unrelated or haploidentical donor available. The HLA typing is performed by the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. * No second tumors * 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 acute graft-versus-host disease, grades II-IV | 180 days |
| Incidence of chronic GVHD, moderate and severe (NIH criteria) | 365 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival analysis | 365 days | Summarized using Kaplan-Meier and cumulative incidence estimates. |
| Event-free survival analysis | 365 days | Event is defined as relapse or death in the specified time frame. Summarized using Kaplan-Meier and cumulative incidence estimates. |
| Incidence of primary or secondary graft failure | 60 days | — |
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.03 | 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 | — |
| Relapse rate analysis | 365 days | Summarized using Kaplan-Meier and cumulative incidence estimates. |
| Non-relapse mortality analysis | 365 days | Non-relapse mortality is defined as any death in absence of relapse or progressive disease. Summarized using Kaplan-Meier and cumulative incidence estimates. |
Countries
Russia
Outcome results
None listed