Leukemia, Acute Lymphoblastic, Acute Myeloid Leukemia, Mixed-Lineage Acute Leukemias
Conditions
Keywords
Allogeneic Transplantation, Hematopoietic Stem Cell Transplantation, Leukemia, Acute Lymphoblastic, Acute Myeloid Leukemia, Mixed-Lineage Acute Leukemias, Immune System Diseases, Immunosuppressive Agents, Myeloablative Agonists, Busulfan, Fludarabine, Antineoplastic Agents, Alkylating, Bendamustine Hydrochloride
Brief summary
Several groups have demonstrated very low incidence of acute and chronic graft-versus-host disease (GVHD) with post-transplantation cyclophosphamide (PTCy) in haploidentical, unrelated and related allogeneic stem cell transplantation (SCT). Nonetheless for majority of the grafts, except for 10/10 HLA-matched bone marrow, with this type of prophylaxis require concomitant administration of calcineurin inhibitors±MMF, which delays immune reconstitution and development of graft-versus-leukemia (GVL) effect. So, despite reduction of transplant-related mortality, use of PTCy doesn't lead to the reduction of relapse incidence. This is particularly important for relapsed or refractory acute leukemia patients, where, despite all efforts to intensify conditioning regimens, relapses after SCT occur in more than 50% of patients, and long-term survival rarely exceeds 10-20%. In preclinical model of haploidentical SCT the substitution of post-transplantation cyclophosphamide with bendamustine, led to comparable GVHD control, but significantly augmented GVL effect. To test this hypothesis and improve the outcome of allogeneic SCT in refractory acute leukemia patients we initiated a pilot trial with high-dose post-transplantation bendamustine for GVHD prophylaxis. The selection of doses is based on the previous dose-escalation studies. Additional immunosuppression could be added for mismatched grafts.
Interventions
PROCEDUREAllogeneic stem cell transplantation
DRUGBusulfan
DRUGBendamustine
Sponsors
St. Petersburg State Pavlov Medical University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
\- Diagnosis: Acute Myeloblastic Leukemia Acute Lymphoblastic Leukemia Mixed-Lineage Acute Leukemias * Disease, refractory to at list one course of induction chemotherapy or immunotherapy * More than 5% clonal blasts in the bone marrow or peripheral blood at the time of inclusion * 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 * No previous autologous or allogeneic stem cell transplantations
Exclusion criteria
* Karnofsky index \<70% * 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 \>1.5 upper normal limits * Creatinine clearance \< 60 mL/min * Uncontrolled bacterial or fungal infection at the time of enrollment, defined by CRP level \>70 mg/L or positive procalcitonin in patient with adequate empirical antibacterial and antifungal therapy. * Requirement for vasopressor support at the time of enrollment * Pregnancy * Somatic or psychiatric disorder making the patient unable to sign informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Engraftment rate | 60 days | Engraftment is defined as the first of 3 consecutive days with an ANC\>500 per μl and WBC\>1000 per μl. Platelet engraftment is not mandatory for the endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Non-relapse mortality analysis | 365 days | — |
| Incidence of acute GVHD, grades II-IV | 180 days | — |
| Incidence of chronic GVHD, moderate and severe (NIH criteria) | 365 days | — |
| Relapse rate analysis | 365 days | — |
| Event-free survival 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