Reduced Intensity Transplantation for Severe Sickle Cell Disease

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:

• 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.
• 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).
• History of two or more episodes of acute chest syndrome (ACS) in the 2-years period preceding enrollment.
• 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.
• History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment in the last 12 months.
• History of two or more episodes of priapism (erection lasting ≥4 hours or requiring emergent medical care).
• Administration of regular RBC transfusions (≥8 transfusions in the previous 12 months).
• 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.