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

Study Overview
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Brief Summary
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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.

Detailed Description
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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

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

Conditions
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Stem Cell Transplantation

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Dexamethasone
* Drug: Cyclophosphamide
* Drug: Bortezomib
* Drug: Rituximab
* Drug: Busulfan
* Drug: Cyclophosphamide (Cy)
* Drug: Tacrolimus (or cyclosporine)
* Drug: Mycophenolate mofetil (MMF)
* Drug: Rabbit ATG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Patient with a matched related donor or who has a related haploidentical donor identified. 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). Adequate major organ system function as demonstrated by: Serum creatinine clearance equal or more than 50 ml/min (calculated with Cockroft-Gault formula). 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. Left ventricular ejection fraction equal or greater than 50%. Diffusing capacity for carbon monoxide (DLCO) equal or greater than 50% 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. 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. 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: HIV positive; active hepatitis B or C. Uncontrolled infections. Liver cirrhosis. However mild fibrosis will be allowed i.e. fine reticulin or Grade 1, with bridging fibrosis. CNS involvement within 3 months. Positive pregnancy test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization. Inability to comply with medical therapy or follow-up. Will restrict eligibility to a maximum BMI of ≤40 Patient with a known history of allergic reactions to any constituents of the cell product, including a known history of allergic reactions to DMSO. Prior allo-SCT 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I: Sequential Pharmacological PTIS<br> | Drug: Fludarabine<br>* 40 mg/m2/day i.v.- by vein<br>* Other names: Fludara™;Drug: Dexamethasone<br>* 25 mg/m2/day i.v.-by vein<br>Drug: Cyclophosphamide<br>* 100 mg/m2 IV-by vein<br>* Other names: Cytoxan™;Drug: Bortezomib<br>* Four doses of bortezomib at a dose of 1.3 mg/m2 -injection under the skin<br>* Other names: Velcade®;Drug: Rituximab<br>* Four doses of rituximab at a dose of 375 mg/m2- by vein<br>* Other names: Rituxan®;Drug: Busulfan<br>* 110 mg/m2 i.v-by vein<br>* Other names: Busulfex™;Drug: Cyclophosphamide (Cy)<br>* by vein<br>* Other names: Cytoxan™;Drug: Tacrolimus (or cyclosporine)<br>* by vein<br>|
| Experimental: Phase II: RTC Regimen and GVHD Prophylaxis Based on Post-Cy<br> | Drug: Fludarabine<br>* 40 mg/m2/day i.v.- by vein<br>* Other names: Fludara™;Drug: Cyclophosphamide<br>* 100 mg/m2 IV-by vein<br>* Other names: Cytoxan™;Drug: Busulfan<br>* 110 mg/m2 i.v-by vein<br>* Other names: Busulfex™;Drug: Cyclophosphamide (Cy)<br>* by vein<br>* Other names: Cytoxan™;Drug: Tacrolimus (or cyclosporine)<br>* by vein<br>Drug: Mycophenolate mofetil (MMF)<br>* given by PO<br>Drug: Rabbit ATG<br>* by vein<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the 100-day non-relapse mortality (NRM) rate when administering pharmacologic pretransplant immunosuppression (PTIS) followed by pretransplant reduced toxicity conditioning (RTC |  | through study completion, an average of 1 year |