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NCT Number: NCT02799147

GVHD Prophylaxis With Post-transplantation Bendamustine in Refractory Leukemia

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.

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Key information

Conditions

Leukemia, Acute Lymphoblastic Acute Myeloid Leukemia Hematologic Diseases Hemic and Lymphatic Diseases Immune System Diseases Immunoproliferative Disorders Leukemia Leukemia, Biphenotypic, Acute Leukemia, Lymphoid Leukemia, Myeloid Leukemia, Myeloid, Acute Lymphatic Diseases Lymphoproliferative Disorders Mixed-Lineage Acute Leukemias Neoplasms Neoplasms by Histologic Type Precursor Cell Lymphoblastic Leukemia-Lymphoma

Age range

18 year–60 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

First Pavlov State Medical University of St. Petersburg

Saint Petersburg, 197089, Russia

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

allogeneic stem cell transplantation

Procedure

Other names: HSCT

Fludarabine monophosphate

Drug

busulfan

Drug

Bendamustine

Drug

Primary outcomes

  1. Engraftment rate

    Time frame: 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 outcomes

  1. Relapse rate analysis

    Time frame: 365 days

  2. Non-relapse mortality analysis

    Time frame: 365 days

  3. Incidence of acute GVHD, grades II-IV

    Time frame: 180 days

  4. Incidence of chronic GVHD, moderate and severe (NIH criteria)

    Time frame: 365 days

  5. Overall survival analysis

    Time frame: 365 days

  6. Event-free survival analysis

    Time frame: 365 days

  7. Toxicity (NCI CTCAE 4.03)

    Time frame: 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

  8. Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence

    Time frame: 100 days

Sponsors and collaborators

Lead sponsor

St. Petersburg State Pavlov Medical University

Other

Registry information

Official study title

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

Important dates

Study start
2016
Primary completion
2020
Study completion
2020
First posted
Jun 14, 2016
Registry last updated
Nov 23, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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