Procedure: Radiotherapy
N/A
Drug: Alemtuzumab (Campath® (Registered Trademark))
N/A
Drug: Sirolimus (Rapamune® (Registered Trademark))
N/A

Nonmyeloablative allogeneic peripheral blood stem cell transplants are currently being investigated in phase I/II trials assessing engraftment, efficacy, and toxicity at a number of transplant centers. Preliminary data, including our own experience with over 100 patients, have shown a high rate of complete donor engraftment with a relatively low toxicity profile. The decreased risk of transplant-related complications associated with nonmyeloablative transplants expands eligibility to patients with nonmalignant hematological disorders curable by allogeneic transplantation; however, significant toxicity with current regimens persists including severe GVHD leading to significant morbidity and mortality. Moreover, mixed chimerism has been shown to be sufficient to induce clinical remissions in children with nonmalignant hematologic disorders undergoing conventional allogeneic transplantation. Therefore, newer regimens need to be developed that are more applicable to patients with non-malignant disorders in whom no graft vs. leukemia effect is needed, and where mixed chimerism is sufficient for disease amelioration.

In this protocol, we propose transplantation in patients with severe congenital anemias including sickle cell anemia (SCA), thalassemia, or Diamond Blackfan anemia (DBA), considered at high risk for complications from or ineligible for standard BMT, with allogeneic peripheral blood stem cells from an HLA identical sibling using a novel immunosuppressive regimen without myeloablation in an attempt to further decrease the transplant related morbidity/mortality. The low intensity nonmyeloablative conditioning regimen will consist of low dose radiation, Alemtuzumab (Campath® (Registered Trademark)) and Sirolimus (Rapamune® (Registered Trademark)) as a strategy to provide adequate immunosuppression to allow sufficient engraftment for clinical remission with a lower risk of graft versus host disease development. T-cell replete, donor-derived, granulocyte colony stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSC) will be used to establish hematopoietic and lymphoid reconstitution, with additional T-cell infusions in those patients with unstable engraftment.

The primary endpoint of this study is donor engraftment. Other end points include degree of donor-host chimerism necessary for long-term graft survival and disease amelioration, incidence of acute and chronic graft versus host disease (GVHD), incidence of graft rejection, transplant related morbidity, as well as disease-free and overall survival.

• INCLUSION CRITERIA:

RECIPIENTS:

Must fulfill one disease category from below

Disease Specific:

Patients with sickle cell anemia (Hb SS, SC, or Sb-thal(o)) at high risk for disease related morbidity or mortality, defined by having irreversible end organ damage (A, B, or C) or potentially reversible complication(s) not ameliorated by hydroxyurea (D):

• Previous neurologic event (either symptomatic or found by imaging alone), OR
• Sickle cell related renal failure, creatinine clearance less than 20 mg/ml or requiring peritoneal or hemo-dialysis, OR
• Pulmonary hypertension, measured by tricuspid regurgitant jet velocity (TRV) of greater than 2.5m/s, OR
• any of the below complications
• more than 2 hospital admissions for pain crises per year for the last 2 years
• a previous acute chest syndrome
• stage I or II sickle chest: Stage I patients have normal oxygen saturation but 80% of predicted normal pulmonary function tests. Stage II patients also have normal oxygen saturation but 60% of predicted normal pulmonary function tests
• evidence of renal damage as defined as having an elevated creatinine of 1.5 x normal, or reduced creatinine clearance, which is still greater than 50% of normal
• osteonecrosis of multiple joints
• red cell alloimmunization

AND

-having failed hydrosyurea, as defined by a failure to achieve a hematologic response and/or clinical response where clinical/hematologic response is defined as a significant decrease in the number of crises experienced after a 6 month trial or a 2-3 fold increase in the hemoglobin F level unless has renal insufficiency preventing hydroxyurea use.

Patients with thalassemia who have grade 2 or 3 iron overload, determined by the presence of 2 or more of the following:

• portal fibrosis by liver biopsy
• inadequate chelation history (defined as failure to maintain adequate compliance with chelation with desferoxamine initiated within 18 months of the first transfusion and administered subcutaneously for 8-19 hours at least 5 days each week)
• Hepatomegaly of greater than 2 cm below the costochondral margin

Patients with Diamond Blackfan Anemia, who are refractory to or intolerant of coritcosteriods and are transfusion dependent

Non-Disease specific:

• Ages 16-65
• 6/6 HLA matched family donor available
• Ability to comprehend and willing to sign an informed consent
• Negative serum B-HCG

INCLUSION CRITERIA:

DONOR

6/6 HLA identical family donor

Ages greater than or equal to 2 and weight greater than 18 kg (in so far that the weight difference between recipient and donor does not exceed a reasonable likelihood of being able to obtain an adequate cell dose from the donor within two aphereses)

Fit to receive G-CSF and give peripheral blood stem cells (normal blood counts, normotensive and no history of stroke)

Ability to comprehend and willing to sign an informed consent; assent obtained from minors

EXCLUSION CRITERIA:

RECIPIENT

(any of the following would exclude the subject from participating)

Age less than 16 years

ECOG performance status of 3 or more.

Diffusion capacity of carbon monoxide (DLCO) less than 60% predicted.

Left ventricular ejection fraction: less than 40% estimated by ECHO.

Transaminases greater than 5x upper limit of normal

Psychiatric disorder or mental deficiency severe enough as to make compliance with the BMT treatment unlikely, and making informed consent impossible.

Major anticipated illness or organ failure incompatible with survival from PBSC transplant.

Pregnant or lactating

EXCLUSION CRITERIA:

DONOR:

(any of the following would exclude the donor from participating)

Pregnant or lactating

Donor unfit to receive filgrastim G-CSF and undergo apheresis. (Uncontrolled hypertension, history of congestive heart failure or unstable angina, thrombocytopenia)

HIV positive

Hemoglobin SS, SC, or Sbeta thal0, or beta thalassemia intermedia

Abnormal Red Cell Adenosine Deaminase level collected on donors for Diamond Blackfan Anemia recipients.