This multicenter prospective study seeks to determine if daratumumab given, prior to HLA-identical sibling donor transplantation using alemtuzumab, low dose total-body irradiation, and sirolimus, can prevent pure red blood cell aplasia with an acceptable safety profile in patients with anti-donor red blood cell antibodies, achieving an event-free survival similar to transplanted patients without such antibodies.
Patients with SCD age 2-24.99 years who have a healthy HLA-identical sibling donor with major ABO incompatibility OR patients with RBC alloantibodies against other donor RBC antigens.
Patients must have an absolute neutrophil count of 1 x 109/L and a platelet count of 100 x 109/L.
Lansky/Karnofsky score of, at least, 70.
History of an abnormal transcranial Doppler measurement defined as TCD velocity ≥200 cm/sec by the non-imaging technique measured at a minimum of two separate occasions.
Life expectancy less than 6 month
Pregnant or breastfeeding patients.
Infectious Disease: 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 for HIV and patients with active or resolved Hepatitis B or C determined by serology and/or NAAT are excluded.
Liver: Direct (conjugated) bilirubin > 1.5 mg/dL. Transaminases >5x upper limit of normal for age.
Single group
Daratumumab
DrugDaratumumab is a cytotoxic monoclonal antibody (IgG1k) to CD38 and is commercially approved to treat multiple myeloma. CD38 is expressed on several types of blood cells including B-cells, antibody-secreting plasma blasts and plasma cells. As a result, it has been used to treat antibody-mediated diseases, including children with antibody-mediated cytopenias post-HCT.
Alemtuzumab
DrugAlemtuzumab is a humanized monoclonal antibody specific to lymphocyte antigens. It is a recombinant DNA-derived humanized monoclonal antibody (Campath-1H) that is directed against the 21-28 kD cell surface glycoprotein, CD52.
Sirolimus
DrugSirolimus is an mTOR inhibitor immunosuppressant used to prevent organ transplant rejections as well as treat lymphangioleiomyomatosis and adults with perivascular epithelioid cell tumors.
Total Body Irradiation
RadiationTotal body irradiation is a form of radiotherapy used primarily as part of the preparative regimen for haematopoietic stem cell transplantation. The radiation is given in a low dose so that normal tissues can repair themselves.
To determine the event-free survival of children and adolescents with SCD undergoing nonmyeloablative HCT who received 4 doses of pre-HCT daratumumab for donor-directed red blood cell antibodies.
Event-free survival rate at 1 year with events including death, graft failure (donor myeloid chimerism \<10% or second HCT), grade II-IV GVHD, and serious pure red blood cell aplasia (persistent reticulocytopenia and need for red blood cell transfusion support after day +100).
To evaluate changes in antibodies to red blood cell antigens pre and post exposure to daratumumab and HCT.
Antibodies titers against donor red blood cell antigens pre and post exposure to daratumumab. Anti-A and Anti-B titers, RBC alloantibody testing at baseline, day -7, day 0, day +30, and day +100.
To characterize the safety of adding pre-HCT daratumumab to the conditioning regimen, as defined by adverse events grade 3 or greater.
Proportion of patients with infusion reactions and grade 3 adverse events related to daratumumab, and infections requiring treatment in the first year post-HCT, with comparison to historical controls on the SUN study.
To compare alemtuzumab levels, in mcg/mL, post-HCT among patients treated with daratumumab, with patients not treated with daratumumab on the SUN study.
Testing alemtuzumab levels on day 0, +7, +14 and +30.
To compare immune reconstitution among patients treated with daratumumab, with patients not treated with daratumumab on the SUN study.
Testing immune cell subsets at day +180 and +365.
To compare donor chimerism (lymphoid vs myeloid) post-HCT among patients treated with daratumumab, with patients not treated with daratumumab on the SUN study.
Testing donor chimerism at day +30, +60, +100, +150, +180, +270 and +365.
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Children's National Research Institute
Lead sponsor
Alberta Children's Hospital
Collaborator
The Hospital for Sick Children
Collaborator
Levine Children's Hospital
Collaborator
Ann & Robert H Lurie Children's Hospital of Chicago
Collaborator
Nationwide Children's Hospital
Collaborator
Children's Hospital at Montefiore
Collaborator
Doris Duke Charitable Foundation
Collaborator
Janssen Pharmaceuticals
Collaborator
