GVHD Prophylaxis With Post-transplantation Bendamustine in Refractory Leukemia

Acute Myeloid Leukemia Clinical Trial

Official title:

Dose-escalation Study of Graft-versus-host Disease Prophylaxis With High-dose Post-transplantation Bendamustine in Patients With Refractory Acute Leukemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02799147
• Other study ID #: 05/16-n
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: June 2016
• Est. completion date: November 2020

Study information

• Verified date: November 2020
• Source: St. Petersburg State Pavlov Medical University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 27
• Est. completion date: November 2020
• Est. primary completion date: November 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Acute Lymphoblastic
• Leukemia, Biphenotypic, Acute
• Leukemia, Myeloid, Acute
• Mixed-Lineage Acute Leukemias
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Procedure:
• Allogeneic stem cell transplantation

Drug:
• Fludarabine monophosphate

• Busulfan

• Bendamustine

Locations

Country	Name	City	State
Russian Federation	First Pavlov State Medical University of St. Petersburg	Saint-Petersburg

Sponsors (1)

Lead Sponsor	Collaborator
St. Petersburg State Pavlov Medical University

Country where clinical trial is conducted

Russian Federation, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Engraftment rate	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.	60 days
Secondary	Relapse rate analysis		365 days
Secondary	Non-relapse mortality analysis		365 days
Secondary	Incidence of acute GVHD, grades II-IV		180 days
Secondary	Incidence of chronic GVHD, moderate and severe (NIH criteria)		365 days
Secondary	Overall survival analysis		365 days
Secondary	Event-free survival analysis		365 days
Secondary	Toxicity (NCI CTCAE 4.03)	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	100 days
Secondary	Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence		100 days