Eltrombopag With Standard Immunosuppression for Severe Aplastic Anemia

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Brief Title

Eltrombopag With Standard Immunosuppression for Severe Aplastic Anemia

Official Title

Eltrombopag Added to Standard Immunosuppression in Treatment-Naive Severe Aplastic Anemia

Brief Summary


        -  Severe aplastic anemia is a rare and serious blood disorder. It happens when the immune
           system starts to attack the bone marrow cells. This causes the bone marrow to stop
           making red blood cells, platelets, and white blood cells. Standard treatment for this
           disease is horse-ATG and cyclosporine, which suppress the immune system and stop it from
           attacking the bone marrow. However, this treatment does not work in all people. Some
           people still have poor blood cell counts even after treatment.

        -  Eltrombopag is a drug designed to mimic a protein in the body called thrombopoietin. It
           helps the body to make more platelets. It may also cause the body to make more red and
           white blood cells. Studies have shown that eltrombopag may be useful when added to
           standard treatment for severe aplastic anemia. It may help improve poor blood cell


      - To test the safety and effectiveness of adding eltrombopag to standard immunosuppressive
      therapy for severe aplastic anemia.


      - Individuals at least 2 years of age who have severe aplastic anemia that has not yet been


        -  Participants will be screened with a physical exam, medical history, and blood tests.
           Blood and urine samples will be collected.

        -  Participants will start treatment with horse-ATG and cyclosporine. Treatment will be
           given according to the standard of care for the disease.

        -  Cohort 1: After 14 days, participants will start taking eltrombopag. They will take
           eltrombopag for up to 6 months.

        -  Cohort 2: After 14 days, participants will start taking eltrombopag. They will take
           eltrombopag for up to 3 months.

        -  Cohort 3 and Extension Cohort: Participants will start taking eltrombopag on Day 1. They
           will take eltrombopag for up to 6 months.

        -  Participants may receive other medications to prevent infections during treatment.

        -  Treatment will be monitored with frequent blood tests. Participants will also fill out
           questionnaires about their symptoms and their quality of life.

Detailed Description

      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

      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.

Study Phase

Phase 1/Phase 2

Study Type


Primary Outcome

Rate of Complete Hematologic Response

Secondary Outcome

 Rate of Response at 3 and 12 Months Then Yearly; Rate of Relapse; Rate of Clonal Evolution to PNH, MDS and AML; Rate of Survival; Rate of Response for Relapse Subjects That Re-start Treatment and Effects of CsA Dose Starting at Month 6 to Month 24.


Severe Aplastic Anemia


Cohort 1: hATG, CsA, EPAG Day 14 to Month 6

Study Arms / Comparison Groups

 Cohort 1: hATG, CsA, EPAG Day 14 to Month 6
Description:  Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 6


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

July 2, 2012

Completion Date

January 30, 2024

Primary Completion Date

January 30, 2018

Eligibility Criteria


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


             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


          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

          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.




2 Years - 95 Years

Accepts Healthy Volunteers



Neal S Young, M.D., (301) 496-4462, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

National Heart, Lung, and Blood Institute (NHLBI)



Study Sponsor

Neal S Young, M.D., Principal Investigator, National Heart, Lung, and Blood Institute (NHLBI)

Verification Date

April 2022