Eltrombopag Combined With Cyclosporine as First Line Therapy in Patients With Severe Acquired Aplastic Anemia

The purpose of this study was to evaluate the efficacy and safety of eltrombopag in combination with cyclosporine alone as first-line therapy on overall hematologic response

This was an interventional phase II, single-arm, multicenter, open-label, study to investigate the efficacy and safety of the combination of eltrombopag and cyclosporine in treatment-naive, adult subjects with severe aplastic anemia (SAA) as first line therapy.

Eligible subjects received eltrombopag and cyclosporine for up to 6 months. Participants who achieved hematologic response any time on or before 6 months were considered as responders; else they were considered as non-responders.

Responders at Month 6 discontinued eltrombopag and started to taper cyclosporine until relapse or Month 24, whichever was early. Responders who relapsed prior to 6 months and non-responders discontinued the treatment at 6 months and were followed-up for 30 days.

Responders who started to taper cyclosporine and relapsed prior to 24 months discontinued cyclosporine and were followed-up for 30 days.

Eligibility Criteria:
Inclusion Criteria:

1. Patient had signed the Informed Consent (ICF) prior to any screening procedures
2. Patient was male/female ≥18 years old at the time of informed consent and able to swallow a tablet.
3. Patient had SAA characterized by:

   1. Bone marrow cellularity \<30% (excluding lymphocytes) and
   2. At least two of the following (peripheral blood):

      * Absolute neutrophil count \<500/µL
      * Platelet count \<20,000/µL
      * Absolute reticulocyte count \<60,000/µL
4. Normal ECG defined as the following as determined via the mean of a triplicate ECG

   * Resting heart rate: 50-90 bpm
   * QTcF at screening \<450 msec (for male patients), ≤460 msec (for female patients)

Exclusion Criteria:

1. Diagnosis of Fanconi anemia.
2. Evidence of a clonal hematologic bone marrow disorder on cytogenetics by central review
3. Prior immunosuppressive therapy with cyclosporine, alemtuzumab, rabbit or horse ATG and thrombopoietin receptor (TPO-R) agonists.
4. Hypersensitivity to eltrombopag or cyclosporine or their components.
5. AST or ALT \>3 x ULN.
6. Serum creatinine, total bilirubin, or alkaline phosphatase \>1.5 x ULN.
7. Patient with liver cirrhosis.
8. Patients who were human immune deficiency virus (HIV), hepatitis C virus or hepatitis B surface antigen (HBsAg) positive. HCV-RNA negative patients were allowed to be enrolled.
9. 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 consent, be compliant with study procedures, tolerate protocol therapy, or that death within 30 days is likely.
10. Patients with cancer who were not considered cure, were on active chemotherapeutic treatment or who took drugs with hematological effects.
11. Administration of an investigational drug within 30 days or 5 half-lives, whichever was longer, preceding the first dose of study treatment.
12. Pregnancy statements and contraception requirements:

    Pregnancy or nursing (lactating) women Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant (or female partners of male patients), unless they were using highly effective methods of contraception during dosing and for 3 months after stopping medication.
13. Not able to understand the investigation nature of the study or to give informed consent.
14. Clinically significant ECG abnormality including cardiac arrhythmias (e. g. ventricular tachycardia) complete left bundle branch block, high grade atrioventricular block, or inability to determine the QTcF interval on the ECG.
15. Presence of cardiac disease, or family history of idiopathic sudden death or congenital long QT syndrome.
16. Risk factors for Torsades de Pointe including uncorrected hypokalemia or hypomagnesemia, or use of concomitant medication(s) with a known risk to prolong the QT interval that could not be discontinued or replaced by safe alternative medication per www.qtdrugs.org.
17. ECOG performance status of ≥2.
18. Patients under the age of 40 must be referred for consideration of allogeneic bone marrow transplantation (HSCT) if (human leukocyte antigen) HLA matching had been done and a suitable matched sibling donor was available and the patient was willing to undergo transplantation (i.e. patients who did not have a HLA match or were not medically fit, not willing or unable to undergo transplantation were considered for enrollment).