Addition of JSP191 (C-kit Antibody) to Nonmyeloablative Hematopoietic Cell Transplantation for Sickle Cell Disease and Beta-Thalassemia

This is an interventional treatment trial for Sickle Cell Anemia focused on measuring Myeloid Chimerism, Lymphoid Cells, Myeloid Cells, Donor Leukocyte Engraftment, Non-Myeloablative Conditioning Read More

• INCLUSION CRITERIA:

Recipient: patients must fulfill one disease category under inclusion criteria 1 and all of criteria 2

1. Patients with sickle cell disease at high risk for disease related morbidity or mortality, defined by having an end-organ damage (A, B, C, D, or E) or complication(s) not ameliorated by SICKLE CELL-SPECIFC THERAPIES (F):

A. Stroke defined as a clinically significant neurologic event that is accompanied by an infarct on cerebral MRI OR an abnormal trans-cranial Doppler examination (>=200 m/s); OR

B. Sickle cell related renal insufficiency defined by a creatinine level >=1.5 times the upper limit of normal (see table below) and kidney biopsy consistent with sickle cell nephropathy OR nephrotic syndrome OR creatinine clearance <60mL/min/1.73m2 for patients <16 years of age or <50mL/min for patients >16 years of age OR requiring peritoneal or hemodialysis. OR

Age (Years) Upper limit of normal serum creatinine (mg/dl)

<= 5 0.8

5 < age <= 10 1.0

10 < age <= 15 1.2

> 15 1.3

C. Tricuspid regurgitant jet velocity (TRV) of >=2.5 m/s in patients >=18 years of age at least 3 weeks after a vaso-occlusive crisis; OR

D. Recurrent tricorporal priapism defined as at least two episodes of an erection lasting >=4 hours involving the corpora cavernosa and corpus spongiosa; OR

E. Sickle hepatopathy defined as EITHER ferritin >1000mcg/L OR direct bilirubin >0.4 mg/dL at baseline in patients >18 years of age; OR

F. Any one of the below complications:

Complication - Eligible for HSCT

• Vaso-occlusive crises- More than 1 hospital admission per year while on a therapeutic dose of sickle cell treatment /medication
• Acute chest syndrome (ACS)- Any ACS while on sickle cell treatment /medication
• Osteonecrosis of 2 or more joints- And on sickle cell treatment /medication where total hemoglobin increase less than 1 g/dL or fetal hemoglobin increases <2.5 times the baseline level
• Red cell alloimmunization- Total hemoglobin increase <1 g/dL while on therapeutic doses of sickle cell treatment /medication

Patients with beta-thalassemia who have grade 2 or 3 iron overload, determined by the presence of 2 or more of the following:

• portal fibrosis by liver biopsy
• inadequate chelation history (defined as failure to maintain adequate compliance with chelation with deferoxamine initiated within 18 months of the first transfusion and administered subcutaneously for 8-10 hours at least 5 days each week)

• hepatomegaly of greater than 2 cm below the costochondral margin or by other imaging scans

  2. Non disease specific

  • Ages >=4 years (>=18 years for phase 1 portion of the study)
  • 6/6 HLA matched family donor available
  • Ability to comprehend and willing to sign an informed consent, assent obtained from minors
  • Negative serum or urine -HCG, when applicable
  • Agree to use birth control throughout the study and 12 months after drug product infusion.
• Female subjects must agree to use a medically acceptable method of birth control such as oral contraceptive, intrauterine device, barrier and spermicide, or contraceptive implant/injection from start of screening through 12 months after drug product infusion.

• Male subjects must agree to use effective contraception (including condoms) from start of screening through 12 months after drug product infusion.

  3. Patients and Capacity to Consent

  • Subject provides informed consent prior to initiation of any study procedures.

  • Subject understands and agrees to comply with planned study procedures.

    4. Donor

Fully matched human leukocyte antigen (HLA) donors at A, B, C, and DR loci (8 of 8 or 10 of 10) are intended for this study. Donors age 4 or older and >=20 kg, eligible to donate hematopoietic stem cells, who are additionally willing to donate blood for research are eligible for this study. 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 eligible donors, but is Abbreviated Title: CD117 Antibody in MRD HCT for beta globin disorders not required for a donor to make a stem cell donation, so it is possible that not all donors will enroll onto this study.

EXCLUSION CRITERIA:

Recipient exclusion criteria

• ECOG performance status of 3 or more, or Lanksy performance status of <40 (See Appendix A).
• Diffusion capacity of carbon monoxide (DLCO) <35% predicted (corrected for hemoglobin and alveolar volume).
• Baseline oxygen saturation of <85% or PaO2 <70
• Left ventricular ejection fraction: <35% estimated by ECHO
• Transaminases >5x upper limit of normal for age
• 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
• Major anticipated illness or organ failure incompatible with survival from PBSC transplant.
• Pregnant or breastfeeding

Donor exclusion criteria

• Pregnant or breastfeeding
• Cognitively impaired subjects