TMLI and Alemtuzumab for Treatment of Sickle Cell Disease

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorizedrepresentative

• Assent, when appropriate, will be obtained per institutional guidelines

• Registered into Risk Evaluation and Mitigation Strategies (REMS) program

• Age: 12-40 years

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2

• Have a diagnosis of sickle cell disease, be at a high risk for disease relatedmorbidity or mortality, which must be defined by one of the following disease statuscriteria:

• Significant neurologic event (stroke) or any neurological deficit lasting > 24hours; or increased transcranial Doppler velocity (> 200 m/s).

• History of one or more episodes of acute chest syndrome (ACS) in the 2-yearperiod preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea).

• History of one or more severe vaso-occlusive pain crises per year in the 2-yearperiod preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea).

• Recurrent priapism requiring medical therapy.

• Osteonecrosis of two or more joints despite the institution of supportive caremeasures.

• Prior treatment with regular red blood cell (RBC) transfusion therapy, definedas receiving 8 or more transfusions per year for > 1 year to preventvaso-occlusive clinical complications (i.e. pain, stroke, and acute chestsyndrome)

• Echocardiograph finding of tricuspid valve regurgitation jet (TRJ) velocity >= 2.5 m/sec.

• Have a related donor who is matched on at least 8/10 human leukocyte antigen (HLA)-A, B, C, and DRB1 Loci

• Total bilirubin =< 2.5 x upper limit normal (ULN( (unless has Gilbert's disease) (performed within 30 days prior to day 1 of protocol)

• Aspartate aminotransferase (AST) =< 1.5 x ULN (performed within 30 days prior to day 1 of protocol)

• Alanine aminotransferase (ALT) =< 1.5 x ULN (performed within 30 days prior to day 1of protocol)

• Creatinine clearance (CrCl) of >= 60 mL/min per 24 hour urine test or theCockcroft-Gault formula (performed within 30 days prior to day 1 of protocol)

• If not receiving anticoagulants: International Normalized Ratio (INR) OR Prothrombin (PT) =< 1.5 x ULN (performed within 30 days prior to day 1 of protocol)

• If on anticoagulant therapy: PT must be within therapeutic range of intendeduse of anticoagulants

• If not receiving anticoagulants: Activated Partial Thromboplastin Time (aPTT) =<1.5x ULN (performed within 30 days prior to day 1 of protocol)

• If on anticoagulant therapy: aPTT must be within therapeutic range of intendeduse of anticoagulants

• Left ventricular ejection fraction (LVEF) >= 50% (performed within 30 days prior today 1 of protocol)

• Note: To be performed within 28 days prior to Day 1 of protocol therapy.

• If able to perform pulmonary function tests: Forced expiratory volume in 1 second (FEV1), force vital capacity (FVC), and diffused lung capacity of carbon monoxide (DLCO) (diffusion capacity) >= 50% of predicted (corrected for hemoglobin)

• If unable to perform pulmonary function tests: Oxygen (O 2) saturation > 92% onroom air

• Note: To be performed within 28 days prior to Day 1 of protocol therapy.

• Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab)combo, hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigennegative), and syphilis (rapid plasma regain [RPR])

• If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed

• Meets other institutional and federal requirements for infectious disease titerrequirements

• Note Infectious disease testing to be performed within 28 days prior to day 1of protocol therapy

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

• If the urine test is positive or cannot be confirmed as negative, a serumpregnancy test will be require.

• Agreement by females and males of childbearing potential to use an effective methodof birth control or abstain from heterosexual activity for the course of the studythrough at least Six months after the last dose of protocol therapy.

• Childbearing potential defined as not being surgically sterilized (men andwomen) or have not been free from menses for > 1 year (women only)

• DONOR: Age =< 60 years

• DONOR: Medical history and physical examination confirm good health status asdefined by institutional standards

• DONOR: Serologies for: Hepatitis B (HBV) Core Antibody, HIV I/II Antibody, humanT-lymphotropic virus (HTLV) - I/II antibody, HCV antibody, Hepatitis B surfaceantigen, Serologic Test for Syphilis, HIV-1/HCV/HBV nucleic acid, West Nile virusnucleic acid, Trypanosoma cruzi antibody, Cytomegalovirus (CMV) antibody, (AKA:Donor Room Serologies)

• DONOR: Female donors of childbearing potential must have a negative serum or urinebeta human chorionic gonadotropin (b-HCG) test within 30 days of initiation ofconditioning, 30 days of patients admission for conditioning and 7 days ofmobilization or bone marrow harvest.

• DONOR: The donor must be informed of the investigational nature of this study andhave signed a consent form in accordance with Federal Guidelines and the guidelinesof the participating institution

Exclusion Criteria:

• Prior allogeneic or autologous stem cell transplant

• Patients who are receiving any other investigational agents, or concurrentbiological, chemotherapy, or radiation therapy.

• History of allergic reactions attributable to compounds of similar chemical orbiologic composition to study agent

• Patients with any active malignancy are ineligible for this study, other thannon-melanoma skin cancers

• Medical problem or neurologic/psychiatric dysfunction which would impair patientability to be compliant with the medical regimen and to tolerate transplantation orwould prolong hematologic recovery which in the opinion of the principalinvestigator would place the recipient at unacceptable risk.

• Active infection requiring antibiotics

• Females only: Pregnant or breastfeeding

• Any other condition that would, in the Investigator's judgment, contraindicate thepatient's participation in the clinical study due to safety concerns with clinicalstudy procedures

• Prospective participants who, in the opinion of the investigator, may not be able tocomply with all study procedures (including compliance issues related tofeasibility/logistics)

• DONOR: Evidence of active infection

• DONOR: Medical or physical reason which makes the donor unlikely to tolerate orcooperate with growth factor therapy and leukapheresis if donating peripheral stemcells or unlikely to tolerate general anesthesia and bone marrow collection ifdonating a bone marrow

• DONOR: Factors which place the donor at increased risk for complications fromleukapheresis or granulocyte colony-stimulating Factor (G-CSF) therapy if donatingperipheral stem cells or general anesthesia and bone marrow collection if donating abone marrow

• DONOR: Lactating female or, if of child-bearing potential, is unwilling to implementadequate birth control

• DONOR: HIV positive

• DONOR: Prior radiation therapy