Reduced Intensity Transplantation for Severe Sickle Cell Disease

Reduced Intensity Related Donor Peripheral Blood Derived Hematopoietic Progenitor Cell Transplantation for Patients With Severe Sickle Cell Disease

This study is being done to test a transplant method that may have fewer side effects (or less toxic, less harmful) than conventional high dose chemotherapy conditioning-based transplants for children and young adults with Sickle Cell Disease (SCD). Patients less than or equal to 25 years old with SCD who would likely benefit from allogeneic hematopoietic cell transplantation (HCT) will be included in this study. Patients with a suitable HLA matched sibling donor (MSD) will be enrolled on the MSD arm while patients without an eligible MSD who have a suitable haploidentical (HAPLO) donor available will be enrolled on the HAPLO arm of the study.

Primary Objective

To assess the donor T-cell chimerism at 1-year post transplant in each respective arm (MSD, HAPLO) of the trial.

Secondary Objectives

• Assess the overall survival and 1-year, 2-year and 3-year post-transplant graft versus host disease (GVHD)-free SCD-free survival.
• Estimate the primary and secondary graft rejection rate at 1-year, 2-year and 3-year post- transplant.
• Estimate the incidence and severity of acute and chronic (GVHD).
• Estimate the incidence of SCD recurrence after transplant
• Assess the neutrophil and platelet recovery kinetics post-transplant.

Exploratory Objectives

• Record immune reconstitution parameters, including chimerism analysis, quantitative lymphocyte subsets, T cell receptor excision circle (TREC) analysis, V-beta spectratyping, and lymphocyte phenotype and function.
• Conduct longitudinal examination of impact of HCT on patient health-related quality of life (HRQL) and adjustment, and parental adjustment.
• Examine impact of HCT on patient cognitive and academic function.
• Determine factors that influenced the decision to undergo HCT, explore perceptions of the HCT experience, and assess decisional satisfaction/regret.
• Develop and evaluate an objective/quantitative imaging biomarker to assess organ (liver and heart) function/disease status and changes following HCT.
• Develop and evaluate an objective/quantitative imaging biomarker to determine cerebral blood flow and oxygen extraction fraction following HCT.

This is a prospective single center phase II study of a reduced intensity conditioning based hematopoietic cell transplant for patients with sickle cell disease. In this study, patients with SCD who would be expected to benefit from an allogeneic HCT will receive an unmanipulated peripheral blood derived hematopoietic stem and progenitor cell (HSPC) graft from either an MSD or HAPLO donor after a reduced intensity conditioning regimen comprising of alemtuzumab, thiotepa and low dose total body irradiation. All patients will receive a pre-conditioning phase comprising of hydroxyurea and azathioprine to reduce the risk of graft rejection. GVHD prophylaxis will consist of sirolimus. Patients on the HAPLO arm will also receive two doses of post-transplant cyclophosphamide. All patients will receive regularly scheduled low dose donor lymphocyte infusions till donor lymphocyte chimerism reaches at least 90% donor. The main objective of this study is to improve graft function and immune reconstitution after a reduced intensity conditioning based transplant.

Inclusion Criteria for Transplant Recipient

• Age less than or equal to 25 years.

• Patients with a suitable HLA-matched sibling donor (MSD) can be enrolled on MSD arm of the trial. Patients with single haplotype matched (≥ 3 of 6) family member donor can be enrolled on HAPLO arm of the trial, if they do not have a suitable HLA-matched sibling donor (MSD) available for progenitor cell donation.

• Patients with SCD (any genotype) who meet any ONE of the following criteria:

  1. History of an abnormal transcranial Doppler measurement defined as TCD velocity ≥ 200 cm/sec by the non-imaging technique (or ≥ 185 cm/sec by the imaging technique) measured at a minimum of two separate occasions.
  2. History of cerebral infarction on brain MRI (overt stroke, or silent stroke if ≥3 mm in one dimension, visible in two planes on fluid-attenuated inversion recovery T2- weighted images).
  3. History of two or more episodes of acute chest syndrome (ACS) in the 2-years period preceding enrollment.
  4. History of two or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in the last 12 months.
  5. History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment in the last 12 months.
  6. History of two or more episodes of priapism (erection lasting ≥4 hours or requiring emergent medical care).
  7. Administration of regular RBC transfusions (≥8 transfusions in the previous 12 months).
  8. At least two episodes of splenic sequestration requiring red blood cell transfusion or splenectomy after at least one episode of splenic sequestration.

Exclusion Criteria for Transplant Recipient

• Karnofsky or Lansky performance score <60.
• Pregnant or breastfeeding patients.
• Uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms) within 1 month prior to conditioning. Patients with febrile illness or suspected minor infection should await clinical resolution prior to starting conditioning. Patients with confirmed seropositivity or positive NAAT for HIV are excluded.
• Serum conjugated (direct) bilirubin >3x upper limit of normal for age as per local laboratory. Participants with hyperbilirubinemia or elevated AST as the result of hyperhemolysis, or a severe drop in hemoglobin post blood transfusion, are not excluded as long as it downtrends and return to acceptable limits subsequently.
• Left ventricular shortening fraction <25% or ejection fraction <40% by echocardiogram.
• Estimated creatinine clearance less than 50 mL/min/1.73m2.
• Diffusion capacity of carbon monoxide (DLCO) <35% (adjusted for hemoglobin). Baseline oxygen saturation <85% or PaO2 <70.
• Presence of anti-donor specific HLA antibodies unresponsive to desensitization as defined below.

HLA antibody presence and specificity will be determined by solid phase immunoassays. An anti-donor specific HLA antibody test will be considered positive when the mean fluorescence intensity (MFI) is:

• >1,000 for donor specific antibodies to HLA-A, -B, and DRB1. or
• >2,000 for donor specific antibodies to HLA-C, DQB1 and DPB1.

A participant with presence of anti-donor specific HLA antibodies may be provisionally enrolled on the study if desensitization (see Appendix H) is begun concurrently with pre-conditioning. Response to desensitization will be defined as:

• decreasing anti-donor specific HLA antibody titer with an MFI of less than 5,000 and
• negative C1q-binding anti-HLA antibody assay.

Inclusion Criteria for Donor

• An HLA-matched sibling donor for MSD arm and at least single haplotype matched (≥ 3 of 6) family member for HAPLO arm.
• HIV negative.
• Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female).
• Not breast feeding.
• Donor should not have clinically significant hemoglobinopathy. Donors with sickle cell trait are acceptable.