Improving the Results of Bone Marrow Transplantation for Patients With Severe Congenital Anemias

Nonmyeloablative allogeneic peripheral blood stem cell (PBSC) transplants are currently being
investigated in phase I/II trials assessing engraftment, efficacy, and toxicity at a number
of transplant centers. Preliminary data 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
graft-versus-host-disease (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 beta-globin disorders
including sickle cell disease (SCD), and beta-thalassemia, considered at high risk for
complications from or ineligible for standard BMT, with allogeneic PBSCs 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 ) and Sirolimus (Rapamune ) as a strategy to provide adequate immunosuppression to
allow sufficient engraftment for clinical remission with a lower risk of GVHD development.
T-cell replete, donor-derived, granulocyte colony stimulating factor (filgrastim, G-CSF)
mobilized PBSCs will be used to establish hematopoietic and lymphoid reconstitution.

The primary endpoint of this study is treatment success at one year, defined as full donor
type hemoglobin on hemoglobin electrophoresis for patients with SCD and
transfusion-independence for patients with beta-thalassemia. Other end points include degree
of donor-host chimerism necessary for long-term graft survival and disease amelioration,
incidence of acute and chronic graft-vs-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 disease at high risk for disease related morbidity or mortality,
defined by having irreversible end organ damage (A, B, C, D or E) or potentially reversible
complication(s) not ameliorated by hydroxyurea (F):

A. Stroke defined as a clinically significant neurologic event that is accompanied by and
infarct on cerebral MRI

OR

an abnormal trans-cranial Doppler examination ( greater than or equal to 200m/s);

OR

B. Sickle cell related renal insufficiency defined by a creatinine level greater than or
equal to 1.5 times the upper limit of normal and kidney biopsy consistent with sickle cell
nephropathy OR nephritic syndrome OR creatinine clearance less than 60mL/min/1.73m(2) for
patients less than or equal to 16 years of age or less than 50mL/min for patients greater
than or equal to 16 years of age OR requiring peritoneal or hemodialysis

OR

Age is less than or equal to 5 years of age with the upper limit of normal serum creatinine
0.8mg/dl

Age is greater than 5 years or less than or equal to 10 years of age with the upper limit
of normal serum creatinine 1.0mg/dl

Age is greater than 10 years and less than or equal to 15 years of agethe the upper limit
of normal serum creatinine 1.2mg/dl

Age greater than 15 years of age with the upper limit of normal serum creatinine 1.3mg/dl

C. Tricuspid regurgitant jet velocity (TRV) of greater than or equal to 2.5m/s in patients
greater than or equal to 18 years of age at least 3 weeks after a vaso- occlusive crisis,
OR

D. Recurrent tricorporal praipism defined as at least two episodes of an erection lasting
greater than or equal to 4 hours involving the corpora cavernosa and corpus spongiosa, OR

E. Sickle hepatopathy defined as EITHER ferritin greater than 100mcg/L OR direct bilirubin
greater than 0.4 mg/dL at baseline in patients greater than or equal to 18 years of age; OR

F. Any one of the below complications:

1. Vaso-occlusive crisis:

- Eligible for hydroxyurea at least 3 hospital admissions in the last year

- Eligible for HSCT More than 1 hospital admission per year while on maximal
tolerated dose of hydroxyurea

2. Acute Chest Syndrome (ACS):

- Eligible for hydroxyurea: 2 prior ACS while greater than 3 years of age and
adequately treated for asthma

- Eligible for HSCT: any ACS while on hydroxyurea*

3. Osteonecrosis of 2 or more joints:

- Eligible for hydroxyurea: And significantly affecting their quality of life by
Karnofsky score 50-60

- Eligible for HSCT: And on hydroxyurea* where total hemoglobin increase less than
1g/dL or fetal hemoglobin increases less than 2.5 time the baseline level

4. Red cell alloimmunization:

- Eligible for hydroxyurea: Transfusion dependent

- Eligible for HSCT: Total hemoglobin increase less htan 1 g/dL while on
hydroxyurea*

- hydroxyurea at maximum tolerated dose

Patients with beta-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 8-10 hours at least 5 days each
week)

- Hepatomegaly of greater than 2 cm below the costochondral margin

NON-DISEASE SPECIFIC:

- Ages greater than or equal to 4 years

- 6/6 HLA matched family donor available

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

- Negative serum beta-HCG

- Pediatric patients less than 16 years of age must decline myeloablative bone
marrow transplantation

DONOR:

6/6 HLA identical family donor

Weight greater than or equal to 20 kg (in so far that 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 (adequate blood counts,
stable blood pressure, 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)

ECOG performance status of 3 or more or Lansky performance status of less than 40.

Diffusion capacity of carbon monoxide (DLCO) less than 35% predicted. (corrected for
hemoglobin and alveolar volume)

Baseline oxygen saturation or less than 85 % or PaOa2 less than 70

Left ventricular ejection fraction: less than 35% estimated by ECHO.

Transaminases greater than 5 times the upper limit of normal for age

Evidence of uncontrolled bacterial, viral or fungal infections (currently taking
medication and progression of clinical symptoms) within one month prior to starting
the conditioning regimen

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

Pregnant or lactating

Major ABO mismatch

DONOR:

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

Pregnant or breastfeeding

HIV positive

Hemoglobin S greater than or equal to 50%, or beta-thalassemia intermedia