Transplantation for Patients With Sickle Cell Disease From Mismatched Family Donors of Bone Marrow

Phase 2

Completed

Conditions: Sickle Cell Disease

Interventions: Procedure: Bone Marrow Transplant (BMT)
Drug: Hydroxyurea
Drug: Thiotepa
Drug: Fludarabine monophosphate
Drug: Cyclophosphamide
Other: Rabbit Anti-thymocyte Globulin
Radiation: Total Body Irradiation

Registration Number: NCT02757885

Lead Sponsor: Emory University

Brief Summary: The purpose of this study is to learn if it is possible and safe to treat persons with severe sickle cell disease (SCD) by bone marrow transplant (BMT) from human leukocyte antigen (HLA) half-matched related donors. Preparation before transplant includes the chemotherapy drugs hydroxyurea, fludarabine, thiotepa, anti-thymocyte globulin, and cyclophosphamide. It also includes radiation.

Detailed Description: The purpose of this study is to learn if it is possible and safe to treat persons with severe sickle cell disease (SCD) by bone marrow transplant (BMT) from human leukocyte antigen (HLA) half-matched related donors. Preparation before transplant includes the chemotherapy drugs hydroxyurea, fludarabine, thiotepa, anti-thymocyte globulin, and cyclophosphamide. It also includes radiation.

Investigators also seek to understand the side effects of BMT in adolescents and young adults with SCD and measure how often serious side effects occur including those that are expected and unexpected. After transplant, investigators will measure the health of the body organs that ordinarily would have been damaged by having SCD in addition to testing the lungs, brain, and kidneys.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 10

Inclusion Criteria

Disease severity: Participants with SCD who have 1 or more of the following (i-v).
- Clinically significant neurologic event (stroke) or any neurological deficit lasting > 24 hours;
- History of two or more episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea);
- History of three or more severe pain crises per year in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea);
- Administration of regular red blood cell (RBC) transfusion therapy, defined as receiving 8 or more transfusions per year for ≥ 1 year to prevent vaso-occlusive clinical complications (i.e. pain, stroke, and ACS). Patients on chronic transfusion who have to discontinue transfusion because of allo-sensitization will be eligible.
- An echocardiographic finding of tricuspid valve regurgitant jet (TRJ) velocity ≥ 2.7 m/sec. Patients under the age of 18 years must have cardiac catheterization proven pulmonary arterial hypertension to qualify on this eligibility criterion.
Age: Patients must be 15 - 40 years of age inclusive OR if younger than 15 years must be pubertal
Adequate physical function as measured by:
- Karnofsky/Lansky performance score ≥ 60
- Cardiac function: Left ventricular ejection fraction (LVEF) > 40% or LV shortening fraction > 26% by cardiac echocardiogram or by MUGA scan.
- Pulmonary function: Pulse oximetry with a baseline O2 saturation of ≥ 85% and DLCO > 40% (corrected for hemoglobin).
- Renal function: Serum creatinine ≤ 1.5 x the upper limit of normal for age as per local laboratory and 24 hour urine creatinine clearance > 70 mL/min/1.73 m2 or GFR > 70 mL/min/1.73 m2 by radionuclide GFR.
- Hepatic function: Serum conjugated (direct) bilirubin < 2 x upper limit of normal for age as per local laboratory and ALT and AST < 5 x upper limit of normal as per local laboratory. Patients with hyperbilirubinemia as a consequence of hyperhemolysis, or who experience a sudden, profound change in the serum hemoglobin after a RBC transfusion, are not excluded.
- For participants with a suitable donor who meet eligibility criteria and are willing to proceed to HCT, if they have received chronic transfusion therapy for ≥ 1 year and have clinical evidence of iron overload by serum ferritin or MRI, an evaluation by liver biopsy is required. Histological examination of the liver must document the absence of cirrhosis, bridging fibrosis, and active hepatitis. The absence of bridging fibrosis will be determined using the histological grading and staging scale
Suitable Donor: To undergo transplantation on this study, participants must have an adult first degree relative who shares at least 1 human leukocyte antigen (HLA) haplotype with the participant, does not have SCD or other hemoglobinopathy, and is in good health; if these criteria are met, they will be allowed to serve as donors. Relatives with sickle cell trait are not excluded as donors. When more than 1 donor is available, the donor with the fewest HLA allele mismatches will be chosen, unless the patient had donor anti-HLA antibodies or there was a medical reason to exclude the donor. If donor anti-HLA antibodies are detected, the next best related match will be chosen. Umbilical cord blood or peripheral blood stem cell donors will not be accepted.

Exclusion Criteria

Availability of HLA matched sibling or 8 of 8 HLA-A, B, C and DRB1 matched unrelated donor
Presence of donor specific antibodies in the patient
Histological examination of the liver must document the absence of cirrhosis, bridging fibrosis and active hepatitis. The absence of bridging fibrosis will be determined using the histological grading and staging scale as described by Ishak and colleagues (1995). The presence of bridging fibrosis will be an exclusion criterion.
Uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment
Seropositivity for HIV
Previous hematopoietic cell transplantation (HCT)
Participation in a clinical trial in which the patient received an investigational drug or device or off-label use of a drug or device within 3 months of enrollment
Demonstrated lack of compliance with prior medical care
Unwilling to use approved contraception for at least 6 months after transplant
A history of substance abuse in the last 5 years that interferes with care
Pregnant or breast-feeding females at the time of consideration for HCT

Donor Selection Criteria:

Preference will be given to related marrow donors who are 2-4 (out of 8) HLA antigen mismatched and towards whom the recipient does not have donor specific antibodies. Donors will sign an informed consent disclosing that the marrow donation will be used by a patient participating in this study. The donor must be matched with the recipient for at least 4 of 8 HLA alleles (HLA -A, -B, -C and -DRB1 by allele-level DNA methodology). The target total nucleated cell count (TNC) is 3.5-8.0 x 108/kg of recipient weight. Marrow will be collected without mobilization. Mobilized peripheral blood stem cell (HPC-A) collections will not be permitted. Donors must undergo hemoglobinopathy screening by electrophoresis; donors who have a hemoglobinopathy will be excluded but trait condition is acceptable.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Bone Marrow Recipient	Fludarabine monophosphate	Single arm open label study: Participants with sickle cell disease (SCD) will receive bone marrow from a human leukocyte antigen (HLA) mismatched donor.
Bone Marrow Recipient	Bone Marrow Transplant (BMT)	Single arm open label study: Participants with sickle cell disease (SCD) will receive bone marrow from a human leukocyte antigen (HLA) mismatched donor.
Bone Marrow Recipient	Rabbit Anti-thymocyte Globulin	Single arm open label study: Participants with sickle cell disease (SCD) will receive bone marrow from a human leukocyte antigen (HLA) mismatched donor.
Bone Marrow Recipient	Total Body Irradiation	Single arm open label study: Participants with sickle cell disease (SCD) will receive bone marrow from a human leukocyte antigen (HLA) mismatched donor.
Bone Marrow Recipient	Hydroxyurea	Single arm open label study: Participants with sickle cell disease (SCD) will receive bone marrow from a human leukocyte antigen (HLA) mismatched donor.
Bone Marrow Recipient	Thiotepa	Single arm open label study: Participants with sickle cell disease (SCD) will receive bone marrow from a human leukocyte antigen (HLA) mismatched donor.
Bone Marrow Recipient	Cyclophosphamide	Single arm open label study: Participants with sickle cell disease (SCD) will receive bone marrow from a human leukocyte antigen (HLA) mismatched donor.

Primary Outcome Measures

Name	Time	Method
Event-free Survival (EFS) Rate	Up to One Year	Event-free Survival (EFS) is defined as the survival with stable donor erythropoiesis with no new clinical evidence of sickle cell disease (SCD). Primary or late graft rejection with disease recurrence or death will count as events for this endpoint.
Rate of Disease Recurrence	Up to One Year	Disease recurrence is defined as the return of sickle erythropoiesis (HbS level \> 70%) and the absence of donor cell representation.
Late Graft Rejection Rate	Day 42 Post transplant up to 1 year	The absence of donor hematopoietic cells in peripheral blood beyond day 42 up to 1 year in a patient who had initial evidence of hematopoietic recovery with \> 20% donor cells will be considered a late graft rejection.
Primary Graft Rejection Rate	Day 42	Primary graft rejection is defined as the absence of donor cells assessed by peripheral blood chimerism assays on day 42. Primary graft rejection can be accompanied by pancytopenia and marrow aplasia or by autologous hematopoietic reconstitution without aplasia.

Secondary Outcome Measures

Name	Time	Method
Cumulative Incidence of Neutrophil Engraftment and Platelet Engraftment.	Up to One Year	Cumulative incidence of Neutrophil Engraftment and Platelet Engraftment. Neutrophil engraftment is defined as the first of 3 measurements on different days when the patient has an absolute neutrophil count of ≥ 500/µL after conditioning. Platelet engraftment is defined as the first day of a minimum of 3 measurements on different days that the patient has achieved a platelet count \> 50,000/µL and did not receive a platelet transfusion in the previous 7 days.
Overall Survival Rate	Up to One Year	Overall survival is defined as survival with or without sickle cell disease (SCD) after hematopoietic cell transplantation (HCT).
Chimerism Rate Following Hematopoietic Cell Transplantation for Sickle Cell Disease	Up to One Year	Genomic DNA extracted from peripheral blood will be analyzed for variable number of tandem repeats (VNTR) to detect donor engraftment in myeloid and lymphoid fractions.
Veno-occlusive Disease (VOD) Rate	Up to One Year	VOD is diagnosed by the presence of ≥ 2 of the following with no other identifiable cause for liver disease: 1. Jaundice (direct bilirubin ≥ 2 mg/dL or \> 34 μmol/L) 2. Hepatomegaly with right upper quadrant pain 3. Ascites and/or weight gain (\> 5% over baseline)
Rate of Central Nervous System (CNS) Toxicity	Up to One Year	CNS toxicity will be defined as seizures, CNS hemorrhage, or PRES. PRES is defined as an increased diffusion coefficient in areas of T2 hyperintensity on diffusion-weighted imaging in the context of clinical symptoms or physical findings including headache, seizures, visual disturbances, and altered level of consciousness.
Infection Rate	Up to One Year	Significant infections will be recorded including but not limited to bacterial or fungal sepsis, CMV reactivation with/without clinical disease, adenovirus infection, EBV PTLD, other significant viral reactivations or community-acquired viral infections and invasive mold infections.
Frequency of Idiopathic Pneumonia Syndrome (IPS)	Up to One Year	IPS is diagnosed by evidence of widespread alveolar injury: 1. Radiographic evidence of bilateral, multi-lobar infiltrates (by chest x-ray or CT scan); AND 2. Evidence of abnormal respiratory physiology based upon oxygen saturation (SpO2) \< 93% on room air or the need for supplemental oxygen to maintain oxygen saturation ≥ 93%; AND 3. Absence of active lower respiratory tract infection
Frequency of Stroke	Up to One Year	An overt stroke is defined as a focal neurologic event and neurologic deficit lasting \> 24 hours with neuroimaging changes.