Calcineurin Inhibitor-Free Interventions BMT CTN 1301 for Prevention of Graft-versus-Host Disease (BMT CTN 1301)
Condition: Acute Leukemia; Myelodysplasia
MeSH terms: Preleukemia; Myelodysplastic Syndromes; Graft vs Host Disease
Study type: Interventional
Phase: Phase 3

Summary: 
      The study is designed as a three arm randomized Phase III, multicenter trial comparing two
      calcineurin inhibitor (CNI)-free strategies for Graft-versus-Host Disease (GVHD) prophylaxis
      to standard tacrolimus and methotrexate (Tac/Mtx) in patients with hematologic malignancies
      undergoing myeloablative conditioning hematopoietic stem cell transplantation.
    

Detailed description: 
      Chronic Graft-versus-Host Disease (GVHD) is a complication that affects many hematopoietic
      stem cell transplant (HSCT) survivors; it occurs when the new cells from a transplant attack
      the recipient's body. The current standard GVHD prophylaxis regimen for patients with
      hematologic malignancies undergoing HSCT involves a combination of immunosuppressive agents
      given for the first 6 months after transplant. Often, patients develop GVHD and continue on
      these agents for much longer periods. The combination of calcineurin inhibitors (tacrolimus
      and cyclosporine A) with methotrexate (MTX) is the most common GVHD prophylaxis used
      worldwide in the context of myeloablative conditioning transplants. This regimen demonstrates
      better control of acute GVHD, but is less effective against chronic GVHD. Management of
      chronic GVHD remains a challenge and it has become a significant health problem in transplant
      survivors with more frequent use of mobilized peripheral blood stem cells. Additionally,
      several issues arise with the standard approach including various toxicity symptoms and side
      effects, increased risk of thrombotic microangiopathy due to CNI, no prevention of other
      infectious diseases, and no prevention for disease relapse.

      This standard strategy of Tac/MTX will be used as a control in comparison to two other
      treatment plans both utilizing CNI-free methods: CD34 selected T-cell depletion in peripheral
      blood stem cell (PBSC) grafts, and infusion of bone marrow (BM) grafts followed by
      post-transplant Cyclophosphamide (PTCy). Study participants will be randomized to one of
      these three treatment arms.
    

Intervention name(s): Unmanipulated Bone Marrow Graft with Tacrolimus/Methotrexate; Mobilized CD34-selected Peripheral Blood Stem Cell graft; Unmanipulated Bone Marrow Graft with Cyclophosphamide; Cyclophosphamide; Tacrolimus; Methotrexate
Intervention type(s): Procedure; Procedure; Procedure; Drug; Drug; Drug
Intervention description(s): Unmanipulated BM grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.; Mobilized CD34-selected PBSC grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.; Unmanipulated BM grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.; Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide.
Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow infusion) and on Day 4 post-transplant (approximately 24 hours after Day 3 cyclophosphamide). Cyclophosphamide will be given as an IV infusion over 1-2 hours (depending on volume).; Tacrolimus will be given orally or intravenously per institutional standards starting Day -3. The dose of tacrolimus may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of tacrolimus (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tacrolimus taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD.; Methotrexate will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of methotrexate should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices. Leucovorin rescue is allowed according to institutional practices.
Other intervention name(s): Cytoxan®; Prograf®; FK506; MTX
Intervention MeSH terms: Cyclophosphamide; Methotrexate; Tacrolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Acute Leukemia; Myelodysplasia; GVHD Prophylaxis; Chronic GVHD