Pharmacologic Pretransplant Immunosuppression (PTIS) + Reduced Toxicity Conditioning (RTC) Allogeneic Stem Cell Transplantation in Inherited Hematologic Disorders

Pharmacologic Pretransplant Immunosuppression (PTIS) + Reduced Toxicity Conditioning (RTC) Allogeneic Stem Cell Transplantation in Inherited Hematologic Disorders

To assess the outcomes of NRM when administering pharmacologic pretransplant immunosuppression (PTIS) followed by pretransplant reduced toxicity conditioning (RTC) and an allogeneic stem cell transplant (allo-SCT) and post-transplant graft-versus-host disease prophylaxis based on post-transplant cyclophosphamide (PT-Cy) in patients with inherited blood disorders.

Objectives

Primary:

To estimate the 100-day non-relapse mortality (NRM) rate when administering pharmacologic pretransplant immunosuppression (PTIS) followed by pretransplant reduced toxicity conditioning (RTC) and an allogeneic stem cell transplant (allo-SCT) and post-transplant graft-versus-host disease prophylaxis based on post-transplant cyclophosphamide (PT-Cy) in patients with inherited blood disorders.

Secondary outcomes include the following:

i. Immune reconstitution ii. Infectious complications iii. Quality of life (QOL) at 3 months,100 days, and 1 year post-transplant iv. OS, EFS, and GRFS v. Incidence of aGVHD at day 100. vi. Rate of chronic GVHD within the first-year post transplantation. vii. Rate of Graft failure

Inclusion Criteria:

1. The first six patients will be ages >12 years old and <35 years old. Thereafter in a second stage, patients ages 2 to 50 years old will be included.

2. Patient with a matched related donor or who has a related haploidentical donor identified.

3. Performance score of at least 70 by Karnofsky or 0 to 1 by ECOG (age > 12 years), or Zubrod or Lansky Play Performance Scale of at least 70 (age <12 years).

4. Adequate major organ system function as demonstrated by:

   1. Serum creatinine clearance equal or more than 50 ml/min (calculated with Cockroft-Gault formula).
   2. Bilirubin equal or less than 1.5 mg/dl except for Gilbert's disease. ALT and/or AST equal or less than 3x institutional ULN. Conjugated (direct) bilirubin less than 2x upper limit of normal.
   3. Left ventricular ejection fraction equal or greater than 50%.
   4. Diffusing capacity for carbon monoxide (DLCO) equal or greater than 50%
   5. Predicted, corrected for hemoglobin. For children < 7 years of age who are unable to perform PFT, oxygen saturation > 92% on room air by pulse oximetry.

5. Patient or the patient's legal representative, parent(s) or guardian should be able to provide written informed consent. Assent of a minor if participant's age is at least seven and less than eighteen years.

6. Sexually active males and females of childbearing potential must agree to use a form of contraception considered effective and medically acceptable by the Investigator.

Exclusion Criteria:

1. HIV positive; active hepatitis B or C.
2. Uncontrolled infections.
3. Liver cirrhosis. However mild fibrosis will be allowed i.e. fine reticulin or Grade 1, with bridging fibrosis.
4. CNS involvement within 3 months.
5. Positive pregnancy test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization.
6. Inability to comply with medical therapy or follow-up.
7. Will restrict eligibility to a maximum BMI of ≤40
8. Patient with a known history of allergic reactions to any constituents of the cell product, including a known history of allergic reactions to DMSO.
9. Prior allo-SCT
10. Other active malignancy/cancer diagnosis in remission for at least 2yrs. Malignancies not being excluded are as follows: Ductal carcinoma in situ (DCIS), Basal cell carcinoma (BCC), Cervical intraepithelial neoplasia (CIN)