Three Immunosuppressive Treatment Regimens for Severe Aplastic Anemia

Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder
characterized by pancytopenia and a hypocellular bone marrow. Allogeneic bone marrow
transplantation offers the opportunity for cure in 70% of patients, but most patients are
not suitable candidates for hematopoietic stem cell transplantation (HSCT) due to advanced
age or lack of a histocompatible donor. For these patients, comparable long term survival is
attainable with immunosuppressive treatment with anti-thymocyte globulin (ATG) and
cyclosporine (CsA). However, of those patients treated with horse ATG(h-ATG)/CsA, one
quarter to one third will not respond, and about 50% of responders relapse. Auto-reactive T
cells may be resistant to the effect of ATG/CsA (non-responders), while in others residual
auto-reactive T cells expand post-treatment, leading to hematopoietic stem cell destruction
and recurrent pancytopenia (relapse). As long term survival is correlated to response rates
and robustness of hematopoietic recovery, novel immunosuppressive regimens that can achieve
hematologic response and decrease relapse rates are needed.

This trial will compare the effectiveness of three immunosuppressive regimens as first line
therapies in patients with SAA with early hematologic response as the primary endpoint, as
well as assess the role of extended CsA treatment after h-ATG in reducing numbers of late
events of relapse and clonal evolution. Randomization is employed to obtain an equal
distribution of subject to each arm; comparisons of early hematologic responses will be made
among the rates observed among the three concurrent arms (rabbit-ATG [r-ATG] versus standard
h-ATG; alemtuzumab vs standard h-ATG). For long course CSA, comparison of primary end points
will be to well established historic relapse rate of 38% at 2-3 years and a cumulative rate
of clonal evolution of 15%.

In the original design subjects were randomized to one of three different regimens: h-ATG +
6 months CsA followed by an 18 month CsA taper; r-ATG + 6 months CsA; or alemtuzumab
(Campath). Subjects failing to respond to r-ATG will be crossed over to alemtuzumab
(Campath), and subjects failing alemtuzumab (Campath) will be crossed over to r-ATG.
Subjects failing to respond to h-ATG + CsA taper will go off study and be evaluated for
eligibility for a second course of immunosuppression on companion protocol 03-H-0249, which
similarly randomizes subjects between r-ATG and alemtuzumab (Campath) as salvage therapy.

The Campath arm was closed to new accrual for lack of efficacy on 4/10/2008. Subsequently,
new accruals will be randomized to h-ATG + 6 months CsA followed by an 18 month CsA taper or
r-ATG + 6 months CsA. Subjects failing to respond to h-ATG + CsA taper will go off study and
be evaluated for eligibility for a second course of immunosuppression on companion protocol
03-H-0249, which similarly randomizes subjects between r-ATG and alemtuzumab (Campath ) as
salvage therapy. Subjects who fail to respond to r-ATG + 6 months CsA will be offered
treatment with h-ATG as salvage therapy or will go off-study to alternative treatments or
stem cell transplant (from sibling or unrelated donor).

The primary endpoint will be hematologic response, defined as no longer meeting criteria for
SAA, at 6 months. Secondary endpoints are relapse, robustness of hematologic recovery at 6
months, response at 3 and 12 months, survival, clonal evolution to PNH, myelodysplasia and
acute leukemia. Long-course CSA will be assessed separately for its efficacy in reducing
late events of relapse and evolution by comparison to historical control data.

-INCLUSION CRITERIA:

1. Severe aplastic anemia characterized by bone marrow cellularity less than 30%
(excluding lymphocytes) and at least two of the following:

- Absolute neutrophil count less than 500/microliter

- Platelet count less than 20,000/microliter

- Absolute reticulocyte count less than 60,000/microliter

2. Age greater than or equal to 2 years old

3. Weight greater than 12 kg

EXCLUSION CRITERIA:

1. Diagnosis of Fanconi's anemia

2. Evidence of a clonal disorder on cytogenetics. Patients with super severe neutropenia
(ANC less than 200/microliter) will not be excluded initially if cytogenetics are not
available or pending. If evidence of a clonal disorder is later identified, the
patient will go off study.

3. Prior immunosuppressive therapy with ATG, ALG, alemtuzumab, or high dose
cyclophosphamide.

4. Infection not adequately responding to appropriate therapy.

5. Serologic evidence of HIV infection.

6. Failure to discontinue the herbal supplements Echinacea purpurea or Usnea barbata
(Old Man's Beard) within 2 weeks of enrollment.

7. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary,
infectious, or metabolic disease of such severity that it would preclude the
patient's ability to tolerate protocol therapy, or that death within 7-10 days is
likely.

8. Potential subjects with cancer who are on active chemotherapeutic treatment or who
take drugs with hematological effects will not be eligible.

9. Current pregnancy, or unwillingness to take oral contraceptives or refrain from
pregnancy if of childbearing potential.

10. Not able to understand the investigational nature of the study or give informed
consent.