Nonmyeloablative Haploidentical Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Sickle Cell Disease
Nonmyeloablative Haploidentical Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Sickle Cell Disease
Background:

 Peripheral blood stem cell transplantation procedures are used for people with sickle cell
 disease. Researchers want to improve the success and reduce the complications for these
 procedures. This might allow more people to have a transplant.

 Objective:

 To see if a new transplant regime is effective, safe and well tolerated in people with sickle
 cell disease.

 Eligibility:

 Adults at least 18 years old with sickle cell disease and certain complications.

 A relative who is a half tissue match.

 Design:

 Participants will be screened with medical history, physical exam, and blood tests.
 Recipients will also have:

 -  Heart, lung, and mental health tests

 -  Chest x-rays

 -  Bone marrow taken from the pelvic bone

 -  Eyes and teeth checked

 Recipients will have a large central line inserted into a vein for up to 6 months.

 Donors will have their veins tested and have an IV inserted for 1 day or on rare occasions 2
 days.

 Donors will get a drug to activate bone marrow. It will be injected for about 6 days.

 Donors will have at least 1 five-hour procedure where bone marrow stem cells will be
 collected. Blood will be taken from a vein in one arm or in rare cases from a groin vein and
 put through a machine. Some blood will be saved and the rest will be returned. Stem cells
 will be taken from the saved blood in a lab and frozen until ready to give to the recipient.

 Recipients will have:

 -  Stems cells collected and frozen

 -  Hygiene lessons

 -  Bone density scans

 -  Low-dose radiation

 -  Drugs for their immune system

 -  Donor cells infused through their central line

 -  Transfusions

 After about 30 days, recipients will leave the hospital. They must stay near NIH for 3 months
 after the transplant and have frequent visits. After returning home, they will have 8 visits
 over 5 years, then be contacted yearly.

 ...
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.
 Four of 4 patients transplanted remain free of SCD.

 Our main limitation has been a lack of HLA-matched sibling donors in the majority of
 patients. We performed a study in which patients with severe SCD who lacked a suitable donor
 underwent a search for a matched unrelated donor or umbilical cord donor. The vast majority
 of patients were not found to have an appropriate alternative donor. We therefore seek to
 develop a safe nonmyeloablative regimen to be applied to the haploidentical setting so that
 family members can serve as donors and greatly expand the donor pool.

 We developed a nonmyeloablative haploidentical PBSC transplant protocol which included 3
 cohorts, with stopping rules built in for regimen failure, defined as graft rejection or
 severe GVHD. All included 400 cGy total body irradiation (TBI) in divided doses 1 and 2 days
 prior to transplant, alemtuzumab, and sirolimus. The first cohort included no
 cyclophosphamide. The 2nd included one dose of cyclophosphamide given at 50mg/kg on day 3
 post-transplant, and the 3rd included 100mg/kg cyclophosphamide given in divided doses on
 days 3 and 4 post-transplant. The engraftment rate and percentage of patients who remained
 free of SCD improved with each successive cohort. However, the graft rejection rate in the
 3rd cohort remained high at 50%. To attempt to reduce the rate of graft rejection in the
 haploidentical setting, this protocol will add PC to the conditioning regimen.

 In this protocol, we propose PBSC transplantation in patients with SCD considered at high
 risk for complications from or ineligible for standard bone marrow transplantation, with
 allogeneic peripheral blood stem cells from a haploidentical donor using a novel
 immunosuppressive regimen without myeloablation in an attempt to further decrease the
 transplant-related morbidity/mortality. The low intensity nonmyeloablative conditioning
 regimen will consist of a relatively low radiation dose for therapeutic radiation,
 Alemtuzumab (Campath ), Sirolimus (Rapamune ), Cyclophosphamide (Cytoxan ), and pentostatin
 (Nipent ) as a strategy to provide adequate immunosuppression to allow sufficient engraftment
 for clinical remission with a lower risk of GVHD development. T-cell replete, donor-derived,
 granulocyte colony-stimulating factor (G-CSF)- mobilized PBSC will be used to establish
 hematopoietic and lymphoid reconstitution.

 The primary endpoint of this study is the percentage of patients at 100 days post-transplant
 who have not rejected their grafts, and who are without severe GVHD (defined as grade 3 and
 higher acute GVHD and moderate to severe chronic GVHD). Other endpoints include degree of
 donor-host chimerism necessary for long-term graft survival and disease amelioration,
 incidence of acute and chronic GVHD, incidence of graft rejection, transplant-related
 morbidity, as well as disease-free and overall survival.
-  INCLUSION CRITERIA-RECIPIENTS:

 Patients with any type of sickle cell disease who are at high risk for disease-related
 morbidity or mortality, defined by having severe end-organ damage (A, B, or C) or
 potentially modifiable complication(s) not ameliorated by hydroxyurea (D):

 A. Stroke defined as a clinically significant neurologic event that is accompanied by an
 infarct or hemorrhage on cerebral MRI or cerebral arteriopathy requiring chronic
 transfusion therapy; OR

 B. Tricuspid regurgitant jet velocity (TRV) of greater than or equal to 2.5 m/s at baseline
 (without vaso-occlusive crisis) and/or pulmonary hypertension; OR

 C. Sickle hepatopathy defined as either ferritin >1000 mcg/L and platelet count <
 250,000/uL (without vaso-occlusive crisis) OR direct bilirubin > 0.4 mg/dL and platelet
 count <250,000/uL (without vaso-occlusive crisis)

 D. Any one of the below complications:

 -  Complication-Vaso-occlusive crises; Eligible for HSCT-Recurrent vaso-occlusive pain
 crises (at least 2 per year for the last 2 years) despite hydroxyurea

 -  Complication-Acute chest syndrome; Eligible for HSCT-any ACS while on hydroxyurea.

 Non-disease specific:

 A. Age greater than or equal to 18 years

 B. Haploidentical relative donor available

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

 D. Negative serum beta-HCG

 E. Ejection fraction greater than or equal to 35%

 F. Glomerular filtration rate >60 mL/min/1.73m^2 by cystatin C-based or iothalamate-based
 or other equivalent GFR testing

 G. Adjusted DLCO greater than or equal to 35%

 EXCLUSION CRITERIA RECIPIENT: (any of the following would exclude the subject from
 participating)

 1. Available 6/6 HLA-matched sibling donor

 2. ECOG performance status of 3 or more (See Appendix A)

 3. Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking
 medication and progression of clinical symptoms) within one month prior to starting
 the conditioning regimen.

 4. Patients with fever or suspected minor infection should await resolution of symptoms
 before starting the conditioning regimen.

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

 6. Pregnant or breast-feeding

 7. Donor specific anti-HLA antibodies (DSAs) greater than or equal to 2000 Mean
 Fluorescence Intensity (MFI)

 8. Patients seronegative for EBV who have EBV seropositive donors

 INCLUSION CRITERIA-DONOR:

 Haploidentical relative donor deemed suitable and eligible, and willing to donate, per
 clinical evaluations who are additionally willing to donate blood for research. Related
 donors will be evaluated in accordance with existing Standard NIH Policies and Procedures
 for determination of eligibility and suitability for clinical donation. Note that
 participation in this study is offered to all related donors, but is not required for a do
 le that not all related donors will enroll onto this study.

 EXCLUSION CRITERIA-DONOR:

 None