Unrelated Umbilical Cord Blood Transplantation With Coinfusion of Mesenchymal Stem Cells
Condition: Allogeneic Stem Cell Transplantation
Study type: Interventional

Summary: 
      A pilot study to assess the feasibility of unrelated umbilical cord blood transplantation
      with coinfusion of third-party mesenchymal stem cells after myeloablative or nonmyeloablative
      conditioning in patients with hematological malignancies.

      This is a multicenter single arm, phase I-II pilot study. The primary objective of this study
      is to determine the feasibility of Umbilical Cord Blood (UCB) Hematopoietic Stem Cell
      Transplantation (HSCT) with co-infusion of third party mesenchymal stem cells as assessed by
      the treatment-related mortality at d100 after transplant.

      Patient inclusion criteria:

      Age 15-60 yrs, Patients for whom allogeneic stem cell transplantation is the preferred
      treatment option, with the following hematological malignancies: acute myeloid leukemia,
      acute lymphoblastic leukemia, high risk myelodysplastic syndrome, advanced
      lymphoproliferative disorders, chronic myeloid leukemia (refractory or intolerant to
      second-line tyrosine kinase inhibitors), multiple myeloma, Informed consent given, Patient
      exclusion criteria, Previous allogeneic transplant, Progressive malignant disease,
      Significant organ damage as a contraindication to allotransplantation, Significant
      psychiatric or neurological disorder, Uncontrolled viral, fungal or bacterial infection,
      Pregnancy, HIV positive, Patients will receive either myeloablative or reduced intensity
      conditioning. One or 2 cord blood transplants will be transplanted, followed by infusion of a
      third-party mesenchymal stem cell transplant, Adverse event reporting Belgian Hematology
      Society (BHS) transplant committee will establish a protocol review committee which will
      organize a central monitoring of the study. Within the context of allogeneic Hematopoietic
      Stem Cell Transplantation (HSCTx) many severe events are likely to occur.

      Statistics and stopping rules: The trial will be stopped at any time that there is reasonable
      evidence that the true rate of day +100 nonrelapse mortality exceeds 0.40. It is the
      intention to include an initial 20 patients.
    

Detailed description: 
      PROTOCOL SYNOPSIS

      Title of the study A pilot study to assess the feasibility of unrelated umbilical cord blood
      transplantation with coinfusion of third-party mesenchymal stem cells after myeloablative or
      nonmyeloablative conditioning in patients with hematological malignancies.

      Design of the study This is a multicenter single arm, phase I-II pilot study.

      Primary objective The primary objective of this study is to determine the feasibility of UCB
      HSCT with co-infusion of third party mesenchymal stem cells as assessed by the
      treatment-related mortality at d100 after transplant.

      Secondary objectives

        -  Chimerism at multiple time points

        -  Hematopoietic recovery (neutrophil and platelet engraftment)

        -  Immune recovery

        -  Incidence of acute and chronic graft-versus-host disease (GVHD)

        -  Infectious complications

        -  Disease free survival

        -  Relapse incidence

        -  Overall survival

      Graft criteria

        -  No peripheral blood or marrow donor available at the 9/10 compatibility level using high
           resolution typing techniques

        -  Adequate cord blood transplant available:

           a)Single cord blood

        -  Minimal 4/6 match (DR1-high, A-low, B-low)

        -  Minimal 2 (6/6), 2.5 (5/6) or 3 (4/6) x 10exp7 nucleated cells per kg in the graft
           b)Double cord blood

        -  At least 4/6 common antigens shared by recipient and the 2 cord blood transplants

        -  Minimal 3x 10exp7 nucleated cells per kg in the combined graft

      Patient inclusion criteria

        -  Age 15-60 yrs

        -  Allogeneic stem cell transplantation is the preferred treatment option:

           a)High risk acute myeloid leukemia (AML) in first complete remission (CR)

        -  Preceding myelodysplastic syndrome

        -  High risk karyotypes (e.g. monosomy 5 or 7, complex)

        -  Feline McDonough Sarcoma (FMS)-like tyrosine kinase 3 (FLT3) alteration

        -  > 2 cycles to obtain CR

        -  Erythroblastic or megakaryocytic leukemia b)High risk acute lymphoblastic leukemia (ALL)
           in first CR

        -  High risk karyotypes (e.g. t[9;22], t[4;11], t[1;19], complex)

        -  Mixed lineage leukemia (MLL) rearrangements c)Acute leukemia in second or third
           remission d)High risk myelodysplastic syndrome: International Prognostic Scoring System
           (IPSS) Intermediate-2 or high risk e)Advanced lymphoproliferative disorders

        -  Diffuse large B-cel non-Hodgkin lymphoma (NHL) or mantle cell NHL or B-prolymphocytic
           leukemia

             -  Sensitive relapse after autologous HSCTx

        -  T-prolymphocytic leukemia

        -  Chronic lymphocytic leukemia

             -  Refractory to fludarabine

             -  Adverse karyotypes (del p17) f)Chronic myeloid leukemia

        -  Refractory or intolerant to second-line tyrosine kinase inhibitors g)Multiple myeloma

        -  Advanced disease (selected cases)

        -  Informed consent given

      Patient exclusion criteria

        -  Previous allogeneic transplant

        -  Progressive malignant disease

        -  Significant organ damage as a contraindication to allotransplantation

             -  Creatinine clearance < 60 ml/min

             -  Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) > 3x normal value
                and/or serum bilirubin >3 mg/dL

             -  Cardiac failure (LVEF < 50%)

             -  Clinical relevant pulmonary disease: Diffusing capacity of lung for carbon monoxide
                (DLCO) < 50% normal

        -  Significant psychiatric or neurological disorder

        -  Uncontrolled viral, fungal or bacterial infection

        -  Pregnancy

        -  HIV positive

      Study procedure Patients will receive either myeloablative or reduced intensity conditioning.
      One or 2 cord blood transplants will be transplanted, followed by infusion of a third-party
      mesenchymal stem cell transplant

      Adverse event reporting BHS transplant committee will establish a protocol review committee
      which will organize a central monitoring of the study. Within the context of allogeneic HSCTx
      many severe events are likely to occur.

      Statistics and stopping rules The trial will be stopped at any time that there is reasonable
      evidence that the true rate of day +100 nonrelapse mortality exceeds 0.40. It is the
      intention to include an initial 20 patients.
    

Intervention name(s): cord blood transplantation
Intervention type(s): Other
Intervention description(s): One or two cord blood transplants with co-infusion of third-party mesenchymal stem cells after pre-transplant preparative regimen
Intervention model: Single Group Assignment
Intervention model description: Patients will receive either myeloablative or reduced intensity conditioning. One or 2 cord blood transplants will be transplanted, followed by infusion of a third-party mesenchymal stem cell transplant
Masking: None (Open Label)
Primary purpose: Treatment