Bone Marrow Transplantation vs Standard of Care in Patients With Severe Sickle Cell Disease (BMT CTN 1503)
Condition: Sickle Cell Disease
MeSH terms: Anemia, Sickle Cell
Study type: Interventional
Phase: Phase 2

Summary: 
      This is a clinical trial that will compare survival and sickle related outcomes in
      adolescents and young adults with severe sickle cell disease after bone marrow
      transplantation and standard of care. The primary outcome is 2-year overall survival.
    

Detailed description: 
      This is a prospective phase II multi-center trial of hematopoietic stem cell transplantation
      or standard of care based on availability of HLA-matched related or unrelated donor after
      confirmation of clinical eligibility. In order to minimize bias assignment to either
      treatment arm, clinical eligibility to both treatment arms are similar and donor availability
      is not known at referral. HLA typing and donor search is initiated upon confirmation of
      clinical eligibility for the study. Additionally, all analyses of primary and secondary
      endpoints will follow the Intent-to-Treat principle to address potential bias introduced by
      participants with donors not proceeding to transplantation or those without a matched donor
      receiving transplantation with less well-matched donors.

      The primary outcome is 2-year overall survival. Our hypothesis is that patients who receive
      bone marrow transplantation will experience early deaths but that this will plateau by 2
      years after transplantation. Patients who receive standard of care will not experience early
      death but will succumb to their disease at a rate much higher than the general population.
      Therefore, the goal of the study is to establish that the difference in the proportion of
      patients surviving is not significantly more than 15% lower in the donor arm at 2-years after
      assignment to treatment arm.

      Secondary endpoints will compare changes in sickle cell disease related events (pulmonary
      hypertension, cerebrovascular events, renal function, avascular necrosis, leg ulcer) and
      functional outcomes [6-minute walk distance (6MWD), health-related quality of life, cardiac
      function, pulmonary function, and mean pain intensity as assessed by a multidimensional
      electronic pain diary] from baseline to 2-years after assignment to treatment arms.

      Additionally for patients assigned to the donor arm and expected to undergo transplantation,
      hematopoietic recovery, graft rejection, acute and chronic graft-versus-host disease, other
      significant transplant-related complications and disease-free survival will be reported.
    

Intervention name(s): Busulfan; Fludarabine; r-ATG; Hematopoietic Cell Transplant; Tacrolimus; Methotrexate; Standard of Care; Alemtuzumab; Total Body Irradiation (TBI); Sirolimus; Melphalan; G-CSF
Intervention type(s): Drug; Drug; Drug; Procedure; Drug; Drug; Procedure; Drug; Drug; Drug; Drug; Drug
Intervention description(s): A:
Busulfan dose will be 3.2 mg/kg administered as a single daily dose IV on days -8 through -5 with dosing adjusted using targeted pharmacokinetics.; A:
Fludarabine dose will be 35 mg/m^2/day administered IV on days -7 through -3 (total fludarabine dose is 175 mg/m^2).
C:
Fludarabine 30mg/m2 IV dose will be given on Days -8, -7, -6, -5, -4; A:
r-ATG will be administered IV on day -6 at 0.5mg/kg, on day -5 at 1 mg/kg and on days -4, -3 and -2 at 1.5mg/kg (total r-ATG dose is 6 mg/kg).; A,B,C:
Day 0 is the day of transplantation.; A:
Tacrolimus commences on day -3 and extends through day +180 after transplantation with doses adjusted to maintain appropriate levels according to institutional guidelines.
C:
Tacrolimus at therapeutic doses through Day 180, then taper per institutional guidelines; A:
Methotrexate will be administered intravenously on day+1 at 15mg/m^2, day+3 at 10mg/m^2, day+6 at 10mg/m^2, and day+11 at 10mg/m^2.
C:
Methotrexate IV 7.5 mg/m2 dose will be given on Days +1, 3, +6 following transplant; Continue to receive standard of care treatment per patient's SCD physician.; B:
Alemtuzumab 0.03 mg/kg IV dose will be given on Day -7, Alemtuzumab 0.1 mg/kg IV dose will be given on Day -6, Alemtuzumab 0.3 mg/kg IV dose will be given on Day -5,-4,-3
C:
Alemtuzumab test dose 3 mg IV once 24 hours prior to 1st dose of Alemtuzumab Alemtuzumab 10 mg IV, 15 mg IV, 20 mg IV given on Days -22 through Day -18. Alemtuzumab doses may be administered between Days -22 and -18 but are required to be on three consecutive days.; Total Body Irradiation 300 cGY on Day -2; Sirolimus at therapeutic doses through day 180, then taper per institutional guidelines if donor CD3+ >50%; C:
Melphalan 140 mg/m2 IV dose will be given on Day -3; G-CSF 5 μg/kg/day continue until neutrophil engraftment.
Other intervention name(s): Busulfex; Fludara; Rabbit antithymocyte globulin; Bone Marrow Transplant; BMT; HCT; Prograf®; MTX; Lemtrada; Rapamune; Alkeran; Granulocyte colony-stimulating factor
Intervention MeSH terms: Sirolimus; Methotrexate; Fludarabine; Melphalan; Busulfan; Alemtuzumab; Tacrolimus; Antilymphocyte Serum; Thymoglobulin; Lenograstim
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Patients are enrolled without a known donor. All patients have 180 days from confirmation of eligibility to confirm a donor. Patients with a donor will be assigned to the Donor Arm and receive HCT; patients without a donor will be assigned to the no donor arm and continue receiving standard of care for their SCD.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Sickle Cell Disease; Young Adults; Phase II Trial; Hematopoietic Cell Transplantation (HCT); Human Leukocyte Antigen (HLA)