Hematopoietic Stem Cell Transplant for Sickle Cell Disease
Condition: Sickle Cell Disease; Sickle Cell Anemia; SCD
MeSH terms: Anemia, Sickle Cell
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This is a phase I/II study of patients with sickle cell disease. It aims to find out if
      people with sickle cell disease can be cured by changing their immune system before they have
      blood stem cell transplants. Doctors will give patients a new drug (fludarabine) to see if
      this drug changes patients immune system and reduces the patient's cells (host) from
      rejecting donor cells (graft) after the patient gets a Hematopoietic (blood) stem cell
      transplant.
    

Detailed description: 
      Primary Objective

      1. To evaluate the safety and feasibility of hematopoietic stem cell transplant (HSCT) after
      treatment with fludarabine in adult patients with Sickle Cell Disease (SCD).

      Secondary Objective(s), in HSCT for SCD

        1. To evaluate the rates of disease-free and overall survival in both MSD and alternate
           graft donor (MUD, haploidentical, or cord blood-derived) recipients

        2. To evaluate fertility in matched sibling and alternate-donor graft recipients

        3. To evaluate GVHD rates in MSD and Alternate Graft Donor recipients in SCD.

        4. To evaluate cerebral, pulmonary, renal, and generalized vasculopathy before and after
           HSCT in SCD.

        5. To evaluate hematopoiesis and erythropoiesis before and before HSCT in SCD.

        6. Modulation of SCD Phenotype by Allogeneic Transplantation. Rigorous clinical follow-up
           will be performed, per routine care, to evaluate those consequences of SCD that will be
           modified by allogeneic transplantation in the short-term (4-12 weeks), in the
           medium-term (12-24 weeks) and in the long-term (>24 weeks). Short-term changes would
           include disappearance of stress hematopoiesis and erythropoiesis; medium- and long-term
           changes would include effects on pain, fertility (TSH, LH), cognition (routine cognitive
           assessments), and end-organ damage (including urine albumin-to-creatinine ratios and
           tricuspid regurgitant jet velocities, as indicated).

      Procedures:

      The study will start with at least 10 and up to 25 patients. They will be given the lowest
      starting dose of fludarabine. This is done to make sure it is safe. Researchers will watch
      the patients during what is called the dose-limiting toxicity (DLT) period. Their safety will
      be monitored by a Safety Monitoring Committee, which is made up of people who run research
      studies. The study will not take new patients until the DLT period is done.

      If at least 3 of the 10 patients enrolled do not benefit, the maximum tolerated dose (MTD)
      will be considered exceeded. After the DLT period is complete, patients will receive a stem
      cell transplant from a genetically matched donor. Patients will be continued to be monitored
      for a year after the transplant.

      To prepare for the transplant patients will have to undergo the following treatments:

        -  an exchange transfusion

        -  a stem cell graft infusion from either a:

             -  perfectly matched sibling donor (called MSD),

             -  perfectly matched but unrelated donor (called MUD),

             -  a half-matched related donor (called Haploidentical), or

             -  a cord blood donor

        -  rabbit antithymocyte globulin (ATG)

        -  cytoxan (a type of chemotherapy)

        -  Fludarabine (you get this medicine a few weeks before transplant and again, as part of
           the routine chemotherapy treatment). This is the main drug being studies in this
           research

        -  total body irradiation (also called TBI)

        -  tacrolimus, mycophenolate (MMF) and/or methotrexate (MTX). These drugs will weaken your
           immune system. They are given to lower your chances of getting GVHD and rejecting the
           donor cells.

      Patients will be in the study for approximately 14 months.
    

Intervention name(s): Fludarabine; Hematopoietic Stem Cell Transplant (HSCT)
Intervention type(s): Drug; Procedure
Intervention description(s): the study will begin with enrollment of an initial safety cohort of at least 10 subjects at the lowest dose, after which enrollment will pause until the dose-limiting toxicity (DLT) period has been completed. If a patient experiences DLT, defined as failure to engraft. In which case, the patient may be advanced to two higher doses.; Three weeks after Immunomodulation patients will be infused with matched bone marrow from a sibling, unrelated donor, haploidentical donor, or cord blood. Patients will be followed for the following year.
Other intervention name(s): Fludarabine monophosphate
Intervention MeSH terms: Fludarabine; Fludarabine phosphate
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Sickle Cell Disease; Sickle Cell Anemia; GvHD; fludarabine