Clinical trial NCT02799147: GVHD Prophylaxis With Post-transplantation Bendamustine in Refractory Leukemia
Official title: Dose-escalation Study of Graft-versus-host Disease Prophylaxis With High-dose Post-transplantation Bendamustine in Patients With Refractory Acute Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Leukemia, Acute Lymphoblastic
Acute Myeloid Leukemia
Mixed-Lineage Acute Leukemias
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
Lead sponsor: St. Petersburg State Pavlov Medical University
Sponsor class: OTHER
First posted: 2016-06-14
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Engraftment rate
timeFrame: 60 days
Secondary outcomes:
measure: Relapse rate analysis
timeFrame: 365 days
measure: Non-relapse mortality analysis
timeFrame: 365 days
measure: Incidence of acute GVHD, grades II-IV
timeFrame: 180 days
measure: Incidence of chronic GVHD, moderate and severe (NIH criteria)
timeFrame: 365 days
measure: Overall survival analysis
timeFrame: 365 days
measure: Event-free survival analysis
timeFrame: 365 days
measure: Toxicity (NCI CTCAE 4.03)
timeFrame: 100 days
measure: Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence
timeFrame: 100 days
Other outcomes:
Locations:
city: Saint-Petersburg
country: Russian Federation
facility: First Pavlov State Medical University of St. Petersburg
Study officials:
affiliation: St. Petersburg State Pavlov Medical University
name: Boris V. Afanasyev, Professor
role: STUDY_DIRECTOR
References:
citation: Stokes J, Hoffman EA, Zeng Y, Larmonier N, Katsanis E. Post-transplant bendamustine reduces GvHD while preserving GvL in experimental haploidentical bone marrow transplantation. Br J Haematol. 2016 Jul;174(1):102-16. doi: 10.1111/bjh.14034. Epub 2016 Mar 31.