Horse ATG/CsA in Aplastic Anemia Patients Unresponsive to or With a Suboptimal Response to Rabbit ATG/CsA Treatment

Severe aplastic anemia (SAA), characterized by pancytopenia and a hypocellular bone marrow,
is effectively treated by immunosuppressive therapy, usually a combination of antithymocyte
globulin (ATG) and cyclosporine (CsA). Survival rates following this regimen are equivalent
to those achieved with allogeneic stem cells transplantation. However, approximately 1/3 of
patients will not show blood count improvement after ATG/CsA. General experience and small
pilot studies have suggested that such patients benefit from further immunosuppression.
Furthermore, analysis of our own clinical data suggests that patients with minimal blood
count responses to a single course of ATG, even when transfusion independence is achieved,
have a markedly worse prognosis than patients with robust hematologic improvement.

The majority of the experience in the US and worldwide has been with horse ATG (h-ATG) plus
CsA as initial therapy in SAA. Rabbit ATG (r-ATG) plus CsA has been employed successfully in
about 1/3 of cases in those who are refractory to initial h-ATG/CsA (current NHLBI Protocol
03-H-0249). In recent years, h-ATG and r-ATG have been used interchangeably in
treatment-naive patients, and initial therapy with r-ATG/CsA is now frequent in the US and
the only option in Europe and Japan, where h-ATG is no longer available. An active NHLBI
randomized study is comparing the efficacy of h- and r-ATG as initial therapy in SAA, and the
results from a recently completed interim analysis suggest that the hematologic response rate
ultimately may not be comparable between these two agents (Protocol 06-H-0034). There is no
published report on the outcome of repeat immunosuppressive therapy in those patients
refractory to initial r-ATG/CsA, and thus the management of these patients is uncertain. We
therefore propose this study of h-ATG/CsA in SAA patients who are refractory or have a
suboptimal response to r-ATG.

The primary endpoint will be the response rate at 3 months where response is defined as no
longer meeting criteria for SAA.

The primary objective is to evaluate the effectiveness (response rate) at 3 months of a
second course of immunosuppression with h-ATG/CsA in subjects refractory to or with a
suboptimal response to a course of r-ATG/CsA or cyclophosphamide at least 3 months post
treatment.

Secondary objectives include robustness of hematologic recovery, relapse, response rate at 6
months, clonal evolution and overall survival.

The primary endpoint will be changes in absolute neutrophil count, platelet count,
reticulocyte count at 3 months.

Secondary endpoints will include time to relapse, changes in cytogenetics, time to death.

- All patients 2 years old or over with SAA who have failed initial immunosuppression
with r-ATG/CsA and are not candidates for a matched sibling marrow transplantation
will be considered for enrollment. Patients who have a suitable matched sibling donor
will be referred for consideration of allogeneic bone marrow transplantation. Patients
not willing to undergo transplantation will be considered for enrollment. Eligibility
will be determined on another screening Hematology Branch protocol (97-H-0041) or
another active Hematology branch protocol. The time between determination of
eligibility and signing consent to participate on this protocol and initiate treatment
on this protocol will not exceed 90 days.

INCLUSION CRITERIA:

1. Diagnosed with SAA characterized by:

1. Bone marrow cellularity < 30% (excluding lymphocytes)

2. At least two of the following:

i. Absolute neutrophil count <500/ microL

ii. Platelet count <20,000/ microL

iii. Reticulocyte count <60,000/ microL

2. Failure to respond to an initial course of r-ATG/CsA or cyclophosphamide at least 3
months post-treatment or a suboptimal response to initial therapy defined by both
platelet and reticulocyte count < 50,000 /microL at 3 months post-treatment

3. Age greater than or equal to 2 years of age

EXCLUSION CRITERIA:

1. Diagnosis of Fanconi anemia. Patients with very severe neutropenia (ANC < 200 /microL)
will not be excluded initially if results of Fanconi anemia testing are not available
or pending. If evidence of Fanconi anemia is later identified, the subject will go off
study.

2. Evidence of a clonal disorder on cytogenetics. Patients with very severe neutropenia
(ANC < 200/uL) will not be excluded initially if results of cytogenetics are not
available or pending. If evidence of a clonal disorder is later identified, the
subject will go off study.

3. Patients who received prior course(s) of alemtuzumab will not be excluded.

4. Infection not adequately responding to appropriate therapy

5. HIV seropositivity

6. 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.

7. Subjects with cancer who are on active chemotherapeutic treatment or who take drugs
with hematological effects will not be eligible

8. Serum creatinine > 2.5 mg/dL

9. Current pregnancy, breast-feeding or unwillingness to refrain from pregnancy if of
child bearing potential

10. Inability to understand the investigational nature of the study or give informed
consent