Haploidentical Transplantation With Pre-Transplant Immunosuppressive Therapy for Patients With Sickle Cell Disease

A Pilot Study of Pre-transplant Immunosuppressive Therapy for Haploidentical Transplants in Patients With Sickle Cell Disease

This is a study to evaluate the safety and toxicity of a treatment regimen consisting of 2 cycles of pre-transplant immunosuppressive therapy followed by myeloablative preparative regimen and allogeneic hematopoietic stem cell transplantation from a haploidentical donor in patients with sickle cell disease.

The overall goal of this study is to expand the donor pool for hematopoietic stem cell transplantation in sickle cell disease using haploidentical donors, and to develop a non-toxic, myeloablative regimen, with the goal of achieving a consistent donor chimerism utilizing pre-transplant immunosuppressive therapy.

All patients will receive an haploidentical hematopoietic stem cell transplant with the following conditioning and GvHD prevention:

Pre-transplant immunosuppressive therapy:

2 cycles of Fludarabine and Dexamethasone x 5 days each cycle

Conditioning regimen:

rATG daily x 3 days, Fludarabine daily x 6 days and Busulfan daily x 4 days

GVHD prophylaxis:

Cyclophosphamide day +3 and +4, Tacrolimus and Mycophenolate mofetil

Inclusion criteria

• Diagnosis: Patients with sickle cell anemia (Hgb SS or SB° Thalassemia) with baseline Hgb S more than 60%.
• Disease status:
• Significant neurologic event (stroke) or any neurological deficit lasting > 24 hours; or increased transcranial Doppler velocity (>200 m/s).
• History of one 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 one or more severe vaso-occlusive 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).
• Recurrent priapism requiring medical therapy.
• Osteonecrosis of two or more joints despite the institution of supportive care measures.
• Prior treatment with regular 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 acute chest syndrome)
• Echocardiograph finding of tricuspid valve regurgitation jet (TRJ) velocity ≥ 2.5 m/sec.
• Ages 1 to 30.
• Child Bearing Potential- Transplantation could be teratogenic and/or lethal to the developing fetus. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation. Should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately.
• Informed Consent/Assent: All subjects must have the ability to understand and the willingness to sign a written informed consent.
• The recipient must have a related donor who is genotypically haploidentical on HLA-A, B, C and DRB1 loci.
• No HLA matched sibling or 10/10 matched unrelated donor is available.

Exclusion criteria:

• Any uncontrolled illness including ongoing or active bacterial, viral or fungal infection.
• Patients may not be receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to any in the pre- or post-transplant regimen.
• Pregnant women are excluded from this study.
• Patients with any active malignancy are ineligible for this study, other than non-melanoma skin cancers.
• Medical problem or neurologic/psychiatric dysfunction which would impair patient ability to be compliant with the medical regimen and to tolerate transplantation or would prolong hematologic recovery which in the opinion of the principal investigator would place the recipient at unacceptable risk.
• Prior autologous or allogeneic transplant.
• Fully HLA-matched related or unrelated donor is available to donate.
• Non-Compliance: Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.