Eltrombopag With Standard Immunosuppression 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 younger patients, but most are not suitable candidates for
transplantation due to advanced age or lack of a histocompatible donor. Comparable long-term
survival in SAA is attainable with immunosuppressive treatment with horse anti-thymocyte
globulin (h-ATG) and cyclosporine (CsA). However, of those patients treated with h-ATG/CsA,
one quarter to one third will not respond, and 30-40% of responders relapse. The majority of
the hematologic responses observed following initial h-ATG/CsA are partial, with only a few
patients achieving normal blood counts. Furthermore, analysis of our own extensive clinical
data suggests that poor blood count responses to a single course of ATG (non-robust
responders), even when transfusion-independence is achieved, predicts a worse prognosis than
when robust hematologic improvement is achieved (protocol 90-H-0146). The explanation for
partial recovery and relapse are not fully understood, but incomplete elimination of
auto-reactive T cells and insufficient stem cell reserve are both possible. Furthermore,
10-15% of SAA patients treated with standard immunosuppression will develop an abnormal
karyotype in follow-up, with monosomy 7 being most common, which portends progression to
myelodysplasia and leukemia. In contrast, malignant clonal evolution is rare in complete
responders to immunosuppression. Although horse ATG/CsA represented a major advance in the
treatment of SAA, refractoriness, incomplete responses, relapse, and clonal evolution limit
the success of this modality. Thus, newer regimens are needed to address these limitations,
and provide a better alternative to stem cell transplantation.

One approach to augment the quality of hematologic responses is to improve underlying stem
cell function. Previous attempts to improve responses in SAA with hematopoietic cytokines
including erythropoietin, G-CSF, and stem cell factor, have failed. Thrombopoietin (TPO) is
the principal endogenous regulator of platelet production. In addition, TPO also has
stimulatory effects on more primitive multilineage progenitors and stem cells in vitro and in
animal models. Eltrombopag (Promacta ), an oral 2nd generation small molecule TPO-agonist, is
currently approved for treatment of chronic immune thrombocytopenic purpura (ITP), chronic
hepatitis C-associated thrombocytopenia, and severe aplastic anemia who have had an
insufficient response to immunosuppressive therapy. Eltrombopag increases platelets in
healthy subjects and in thrombocytopenic patients with chronic ITP and hepatitis C virus
(HCV) infection. Our Branch recently completed a pilot study of eltrombopag in refractory
SAA. We saw encouraging clinical results in a cohort of patients who have failed on average
two prior immunosuppressive regimens (Olnes et al. ASH Annual Meeting Abstracts, San Diego,
CA, 2011, oral presentation and N Engl J Med 2012;367:11-9.1). Of the twenty-five SAA
patients treated with eltrombopag by mouth for three months, eleven (44%) patients met
protocol criteria of clinically meaningful hematologic responses, without significant
toxicity. Nine patients demonstrated an improvement in thrombocytopenia (>20k/ L increase or
transfusion independence), hemoglobin improved in two patients (>1.5g/dL or achieved
transfusion independence, and four patients had a significant response in their neutrophil
count. When responders continued the drug beyond three months, the hematologic response to
eltrombopag increased; a trilineage response was observed in four patients, and a bilineage
response occurred in another four, with median follow-up of 13 months. These results suggest
that stem cell depletion, a major component of the pathophysiology of SAA, might be directly
addressed by eltrombopag administration. The aim of the current study would be to improve the
hematologic response rate and its quality, as well as prevent late complications such as
relapse and clonal progression, by addition of eltrombopag to standard immunosuppressive
therapy.

This trial will evaluate the safety and efficacy of combining eltrombopag with standard
hATG/CSA as first line therapy in patients with SAA. The primary endpoint will be the rate of
complete hematologic response at six months. Secondary endpoints are relapse, robust
hematologic blood count recovery at 3, 6, and 12 months, survival, clonal evolution to
myelodysplasia and leukemia, marrow stem cell content and hematological response of relapse
patients that re-start treatment.

-INCLUSION CRITERIA:

1. Severe aplastic anemia characterized by Bone marrow cellularity less than 30 percent
(excluding lymphocytes)

AND

At least two of the following:

- Absolute neutrophil count less than 500/microL

- Platelet count less than 20,000/microL

Absolute reticulocyte count less than 60,000/microL

2. Age greater than or equal to 2 years old

3. Weight greater than 12 kg

EXCLUSION CRITERIA:

1. Known diagnosis of Fanconi anemia

2. Evidence of a clonal disorder on cytogenetics performed within 12 weeks of study
entry. Patients with super severe neutropenia (ANC less than 200 /microL) will not be
excluded initially if cytogenetics are not available or pending. If evidence of a
clonal disorder consistent with myelodysplasia is later identified, the patient will
go off study.

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

4. SGOT or SGPT >5 times the upper limit of normal

5. Subjects with known liver cirrhosis in severity that would preclude tolerability of
cyclosporine and eltrombopag as evidenced by albumin < 35g/L

6. Hypersensitivity to eltrombopag or its components

7. Infection not adequately responding to appropriate therapy

8. 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

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

10. Current pregnancy, or unwillingness to take oral contraceptives or use a barrier
method of birth control or practice abstinence to refrain from pregnancy if of
childbearing potential during the course of this study

11. Inability to understand the investigational nature of the study or to give informed
consent or does not have a legally authorized representative or surrogate that can
provide informed consent.