Hematopoietic Stem Cell Transplant for Sickle Cell Disease
Overview
- Phase
- Phase 1
- Intervention
- Fludarabine
- Conditions
- Sickle Cell Disease
- Sponsor
- Case Comprehensive Cancer Center
- Enrollment
- 4
- Locations
- 1
- Primary Endpoint
- Probability of Engraftment
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a study of patients with sickle cell disease. It aims to find out if people with sickle cell disease can be cured by changing their immune system before they have blood stem cell transplants. Doctors will give patients a new drug (fludarabine) to see if this drug changes patients immune system and reduces the patient's cells (host) from rejecting donor cells (graft) after the patient gets a Hematopoietic (blood) stem cell transplant.
Detailed Description
Primary Objective 1. To evaluate the safety and feasibility of hematopoietic stem cell transplant (HSCT) after treatment with fludarabine in adult patients with Sickle Cell Disease (SCD). Secondary Objective(s), in HSCT for SCD 1. To evaluate the rates of disease-free and overall survival in both MSD and alternate graft donor (MUD, haploidentical, or cord blood-derived) recipients 2. To evaluate fertility in matched sibling and alternate-donor graft recipients 3. To evaluate GVHD rates in MSD and Alternate Graft Donor recipients in SCD. 4. To evaluate cerebral, pulmonary, renal, and generalized vasculopathy before and after HSCT in SCD. 5. To evaluate hematopoiesis and erythropoiesis before and before HSCT in SCD. 6. Modulation of SCD Phenotype by Allogeneic Transplantation. Rigorous clinical follow-up will be performed, per routine care, to evaluate those consequences of SCD that will be modified by allogeneic transplantation in the short-term (4-12 weeks), in the medium-term (12-24 weeks) and in the long-term (\>24 weeks). Short-term changes would include disappearance of stress hematopoiesis and erythropoiesis; medium- and long-term changes would include effects on pain, fertility (TSH, LH), cognition (routine cognitive assessments), and end-organ damage (including urine albumin-to-creatinine ratios and tricuspid regurgitant jet velocities, as indicated). Procedures: The study will start with at least 10 and up to 25 patients. They will be given the lowest starting dose of fludarabine. This is done to make sure it is safe. Researchers will watch the patients during what is called the dose-limiting toxicity (DLT) period. Their safety will be monitored by a Safety Monitoring Committee, which is made up of people who run research studies. The study will not take new patients until the DLT period is done. If at least 3 of the 10 patients enrolled do not benefit, the maximum tolerated dose (MTD) will be considered exceeded. After the DLT period is complete, patients will receive a stem cell transplant from a genetically matched donor. Patients will be continued to be monitored for a year after the transplant. To prepare for the transplant patients will have to undergo the following treatments: * an exchange transfusion * a stem cell graft infusion from either a: * perfectly matched sibling donor (called MSD), * perfectly matched but unrelated donor (called MUD), * a half-matched related donor (called Haploidentical), or * a cord blood donor * rabbit antithymocyte globulin (ATG) * cytoxan (a type of chemotherapy) * Fludarabine (you get this medicine a few weeks before transplant and again, as part of the routine chemotherapy treatment). This is the main drug being studies in this research * total body irradiation (also called TBI) * tacrolimus, mycophenolate (MMF) and/or methotrexate (MTX). These drugs will weaken your immune system. They are given to lower your chances of getting GVHD and rejecting the donor cells. Patients will be in the study for approximately 14 months.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have one of the following inherited hemoglobin gene disorders:
- •a. Hemoglobin SS
- •b. Hemoglobin SC
- •c. Hemoglobin S-Beta-zero-Thalassemia or
- •d. Hemoglobin S-Beta-plus Thalassemia with an episode of multi-organ failure within 5 years of eligibility
- •Patients must meet one of the following risk criteria:
- •Low Risk (Red Light. Stop and consider therapy closely): Must have matched sibling donor grafts, failed conventional therapy as determined by the PI, and evidence for morbid disease (one of the following):
- •a. 2 or more painful episode/year (requiring Emergency Department or inpatient care) x 2 years or
- •b. 1 or more diagnoses of Acute Chest Syndrome within 5 years, or
- •c. 2-year mortality 5-10% or
Exclusion Criteria
- •Red cell alloimmunization to a degree that precludes extended transfusion
- •Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- •Subjects must not have evidence of impaired liver function due to iron overload, +/- hepatitis. Patients will be evaluated by liver consult if ferritin \>1500, history of hepatitis,or ALTis ≥3 X Upper limit of normal (ULN). Recommended evaluations could include liver biopsy if there is evidence for significant hepatic iron deposition or fibrosis/cirrhosis on T2\* MRI of the liver.
- •eGFR \<21 ml/min
- •≥2.0 liter-per-minute pm home oxygen requirement
- •An estimated Left Ventricular Ejection Fraction ≤40% (echo or MUGA)
- •Hepatic cirrhosis (Biopsy Proven)
- •HIV positive, ineligible because of the increased risk of lethal infections when treated with marrow suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
- •Pregnant or breastfeeding women are excluded from this study because the immunomodulatory treatment, preparative regimen, and anti-GVHD therapy contain agents with the potential for teratogenic or abortifacient effects.
- •Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms) within 1 month prior to starting the conditioning regimen. Patients with fever or suspected minor infection should await resolution of symptoms before starting the conditioning regimen.
Arms & Interventions
Immunomodulation with Fludarabine prior to HSCT
Fludarabine given beginning at 25mgm/m2 three times per day. Patients may be escalated up to 25mgm/m2 five times per day depending on dose-limiting toxicity
Intervention: Fludarabine
Immunomodulation with Fludarabine prior to HSCT
Fludarabine given beginning at 25mgm/m2 three times per day. Patients may be escalated up to 25mgm/m2 five times per day depending on dose-limiting toxicity
Intervention: Hematopoietic Stem Cell Transplant (HSCT)
Outcomes
Primary Outcomes
Probability of Engraftment
Time Frame: 42 Days after transplant
The number of patients with engraftment (as defined as recovery of ANC to 500 cells per cubic mm) compared to the total number of patients treated as a function of the patient's age.
Secondary Outcomes
- Follicular Stimulating Hormone Levels(1 year)
- Testosterone Levels(1 year)
- Graft versus Host Disease(1 year)
- Pulmonary Vasculopathy(1 year)
- Disease Progression(1 year)
- Overall Survival(1 year)
- Luteinizing Hormone Levels(1 year)
- Renal Vasculopathy(1 year)
- Cerebral Vasculopathy(1 year)
- Mean time to engraftment(42 Days after transplant)
- Hematopoiesis(1 year)
- Erythropoiesis(1 year)