Repeat Peripheral Blood Stem Cell Transplantation for Patients With Sickle Cell Disease and Falling Donor Myeloid Chimerism Levels
Repeat Peripheral Blood Stem Cell Transplantation for Patients With Sickle Cell Disease and Falling Donor Myeloid Chimerism Levels
Background:

 Sickle cell disease can often be treated with blood stem cell transplants. But for some
 people the disease returns. This study will give a second transplant to people whose disease
 has returned but still have some donor cells in their body.

 Objective:

 To cure people s sickle cell disease by giving a second treatment that makes more room in
 their bone marrow for donor cells.

 Eligibility:

 People ages 4 and older with sickle cell disease who had a transplant but the disease
 returned, and their donor relatives

 Design:

 Participants will be screened with medical history, physical exam, and blood tests.

 Recipients will also be screened with heart and breathing tests, x-rays, a bone marrow
 sample, and teeth and eye exams. They must have a caregiver.

 Donors will have 7-8 visits. They will take a drug for 5-6 days to prepare them for the
 donation. For the donation, blood is taken from a vein in the arm or groin. The stem cells
 are collected. The rest of the blood is returned. This may be repeated.

 Recipients will get a long IV line in their arm or chest for about 1-2 months. They will take
 drugs to help their body accept the donor cells. They will get the donor cells and red blood
 cell transfusions through the line. They will stay in the hospital about 30 days after the
 transfusion of donor cells.

 In first 3 months after the infusion, recipients will have many visits. Then they will have
 visits every 6 months to 1 year for 5 years. During those visits they will repeat some of the
 screening tests....
Nonmyeloablative allogeneic peripheral blood stem cell (PBSC) transplants are currently being
 investigated in phase I/II trials assessing engraftment, efficacy, and toxicity at a number
 of transplant centers. Our ongoing protocol for patients with severe congenital anemias,
 particularly sickle cell disease (SCD), and an HLA-matched sibling donor has had excellent
 preliminary results. None of the patients who engrafted had sickle-related events or any
 evidence of graft versus host disease (GVHD). There was no significant toxicity associated
 with the conditioning regimen. An additional protocol is ongoing for patients with high risk
 of graft rejection which employs pentostatin and oral cyclophosphamide (PC) pre-transplant to
 further deplete recipient lymphocytes in an attempt to decrease the rate of graft rejection,
 and to date the engraftment rate has substantially improved. Our first haploidentical
 transplant protocol showed improving engraftment and success rates with the addition of
 post-transplant cyclophosphamide, but with a median follow-up of 5 years, the disease-free
 survival was at best 50%. Our new haploidentical transplant protocol has had some encouraging
 early results in the first 5 patients transplanted.

 Based on 67 patients undergoing HLA-matched sibling or haploidentical PBSC transplants at the
 NIH, we sought to determine what donor chimerism level is necessary to reverse SCD. Three of
 the patients had falling donor myeloid chimerism (DMC) levels, and when the DMC level fell
 below 20%, all 3 patients had return of their SCD. Our mathematical model showed that only
 20% DMC (which tracks with donor erythroid chimerism) is necessary due to vast differences in
 donor and recipient red blood cell (RBC) survival. As all 3 patients had persistent but
 insufficient donor chimerism levels, we performed a PBSC boost using the same donor and
 busulfan/alemtuzumab conditioning. Haploidentical patients received CD34-selected PBSCs and
 HLA-matched sibling patients received unmanipulated PBSCs. All 3 patients now remain free of
 SCD with DMC levels of 100% at 1, 2.5, and 3.5 years post-transplant. Therefore, in this
 protocol, we propose repeat PBSC transplants using CD34-selected PBSCs in patients with a
 haploidentical donor and unmanipulated PBSCs in patients with an HLA-matched sibling donor
 from the same donor in a population of patients who have falling DMC and return of SCD.
-  INCLUSION CRITERIA:

 Inclusion criteria- recipient

 1. Patient with history of SCD who underwent allogeneic hematopoietic stem cell
 transplantation (HSCT)

 2. Patient with recurrent SCD defined as HbS greater than or equal to 50% for donors with
 sickle cell trait and greater than or equal to 10% for donors with HbAA with recurrent
 clinical manifestations (for example but not limited to recurrent painful crises,
 acute chest syndrome, priapism, or severe anemia)

 3. Persistent donor chimerism levels

 4. Age greater than or equal to 4 years

 5. Negative beta-HCG

 6. Ejection fraction greater than or equal to 35%

 7. DLCO greater than or equal to 35%

 Inclusion- donor

 1. Original donor from the patient s prior transplant

 2. Age greater than or equal to 18 years

 3. Fit to receive filgrastim (G-CSF) and to give peripheral blood stem cells (blood
 counts and blood pressure within DTM standards)

 4. Ability to comprehend and willing to sign an informed consent

 EXCLUSION CRITERIA:

 Exclusion criteria- recipient

 1. ECOG performance status of 3 or more (see Appendix B)

 2. Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking
 medication and progression of clinical symptoms) within one month prior to signing the
 consent

 3. Patients with fever or suspected minor infection should await resolution of symptoms
 before signing the consent

 4. Major anticipated illness or organ failure incompatible with survival from PBSC
 transplant

 5. Pregnant or breastfeeding

 6. Baseline alanine aminotransferase or direct bilirubin >3x upper limit of normal

 7. History of liver cirrhosis

 8. History of secondary malignancies (other than localized skin cancer)

 Exclusion- donor

 1. Pregnant or breastfeeding

 2. HIV positive

 3. Hemoglobin S >50%

 4. History of congestive heart failure, unstable angina, or stroke