Eltrombopag + Immunosuppression for Severe Aplastic Anemia

Overseen By Bhavisha Patel, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Must be taking: Horse-ATG, Cyclosporine

Must not be taking: Chemotherapy, Hematological drugs

Disqualifiers: Fanconi anemia, Clonal disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 3-6 months

207 Participants Needed

Trial Summary

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on active chemotherapeutic treatment or take drugs with hematological effects, you will not be eligible to participate.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on active chemotherapy or drugs with blood-related effects, you may not be eligible to participate.

What data supports the idea that Eltrombopag + Immunosuppression for Severe Aplastic Anemia is an effective treatment?

The available research shows that adding eltrombopag to the standard immunosuppressive therapy, which includes horse antithymocyte globulin and cyclosporine, improves the treatment's effectiveness for severe aplastic anemia. Specifically, eltrombopag increased the rate of overall and complete responses when used as part of the initial treatment. This combination is more effective than using eltrombopag alone, which has a response rate of 40% to 50% in patients who did not respond to initial immunosuppression. In comparison, the standard treatment without eltrombopag has a response rate of 60% to 70%, but adding eltrombopag seems to enhance these outcomes. ^{1 2 3 4 5}

What data supports the effectiveness of the drug combination Eltrombopag and Immunosuppression for Severe Aplastic Anemia?

Research shows that adding eltrombopag to standard immunosuppressive therapy, which includes horse antithymocyte globulin and cyclosporine, improves the treatment's effectiveness in patients with severe aplastic anemia. Eltrombopag, when used with immunosuppression as a first-line treatment, increases the rate of overall and complete responses. ^{1 2 3 4 5}

What safety data exists for Eltrombopag and immunosuppression in severe aplastic anemia?

Eltrombopag, when added to standard immunosuppressive therapy (horse ATG plus cyclosporine), has shown improved efficacy in severe aplastic anemia. It has been approved for patients 2 years and older, although safety data in pediatric cohorts is limited. Eltrombopag as a single agent has shown hematologic response rates of 40% to 50% in those refractory to initial immunosuppression. When combined with immunosuppression as frontline therapy, it increased overall and complete response rates, with a favorable comparison in clonal cytogenetic abnormalities to immunosuppression alone. Longer follow-up is needed to better define long-term risks. ^{1 2 4 6 7}

Is the combination of Eltrombopag and immunosuppression safe for humans?

Eltrombopag, when combined with immunosuppressive therapy like horse antithymocyte globulin and cyclosporine, has been used in severe aplastic anemia and generally shows good safety with improved response rates. However, longer follow-up is needed to fully understand long-term safety, especially in children. ^{1 2 4 6 7}

Is the drug combination of Cyclosporine and Horse-ATG promising for treating Severe Aplastic Anemia?

Yes, the combination of Cyclosporine and Horse-ATG is promising for treating Severe Aplastic Anemia. It is a standard treatment that shows good response rates, and when combined with the drug Eltrombopag, it can significantly improve patient outcomes, leading to high response rates and better survival. ^{1 2 3 6 8}

What makes the drug combination of eltrombopag, cyclosporine, and horse-ATG unique for treating severe aplastic anemia?

The combination of eltrombopag with cyclosporine and horse-ATG is unique because eltrombopag, a thrombopoietin receptor agonist, enhances the effectiveness of standard immunosuppressive therapy, leading to higher overall and complete response rates and achieving transfusion independence in many patients. ^{1 2 4 6 8}

What is the purpose of this trial?

Background: * 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 counts. Objectives: - To test the safety and effectiveness of adding eltrombopag to standard immunosuppressive therapy for severe aplastic anemia. Eligibility: - Individuals at least 2 years of age who have severe aplastic anemia that has not yet been treated. Design: * 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.

Research Team

Neal S Young, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Eligibility Criteria

This trial is for individuals aged 2 years and older with severe aplastic anemia who haven't been treated yet. They must have specific low blood cell counts, weigh over 12 kg, and not have certain liver issues or infections. People with prior immunosuppressive therapy, pregnancy, or severe concurrent diseases can't participate.

Inclusion Criteria

Weight greater than 12 kg

I am at least 2 years old.

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

Exclusion Criteria

My liver is too weak for certain medications due to low albumin levels.

I do not have severe health issues that would stop me from tolerating the treatment.

Hypersensitivity to eltrombopag or its components

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive horse-ATG and cyclosporine, with eltrombopag added at different times depending on the cohort

3-6 months

Frequent visits for blood tests and monitoring

Follow-up

Participants are monitored for safety, effectiveness, and potential clonal evolution after treatment

18-24 months

Regular visits for monitoring and blood tests

Extension Cohort

Participants in the extension cohort receive continued treatment with eltrombopag and cyclosporine

6 months

Treatment Details

Interventions

• Cyclosporine
• Eltrombopag
• Horse-ATG

Trial Overview The trial tests the addition of a drug called Eltrombopag to standard treatment (horse-ATG and cyclosporine) for severe aplastic anemia. Participants are divided into groups receiving Eltrombopag at different times and durations alongside their standard care.

Participant Groups

Group I: Extrension Cohort Experimental Treatment 1 Intervention

Receive horse ATG days 1- 4, receive CsA day 1 to month 6 at higher dose, then reduced dose for 18 months, and receive eltrombopag day 1 to month 6

Group II: Cohort 3: hATG, CsA (dose reduced), EPAG day 1 to month 6 Experimental Treatment 1 Intervention

Receive horse ATG days 1- 4, receive CsA day 1 to month 6 at higher dose, then reduced dose for 18months, and receive eltrombopag day 1 to month 6

Group III: Cohort 2: hATG, CsA, EPAG Day 14 to Month 3 Experimental Treatment 1 Intervention

Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 3

Group IV: Cohort 1: hATG, CsA, EPAG Day 14 to Month 6 Experimental Treatment 1 Intervention

Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 6

Cyclosporine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Neoral for:

• Prevention of organ rejection in kidney, liver, heart, lung, pancreas, and bone marrow transplants
• Treatment of severe psoriasis
• Treatment of nephrotic syndrome

Approved in United States as Neoral for:

• Prevention of organ rejection in kidney, liver, and heart transplants
• Treatment of severe rheumatoid arthritis
• Treatment of severe psoriasis

Approved in Canada as Neoral for:

• Prevention of organ rejection in kidney, liver, heart, lung, pancreas, and bone marrow transplants
• Treatment of severe psoriasis
• Treatment of nephrotic syndrome

Approved in Japan as Neoral for:

• Prevention of organ rejection in kidney, liver, and heart transplants
• Treatment of severe rheumatoid arthritis
• Treatment of severe psoriasis

Who Is Running the Clinical Trial?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

Findings from Research

In a phase 3 trial involving 197 previously untreated patients with severe aplastic anemia, the addition of eltrombopag to standard immunosuppressive therapy significantly improved the complete response rate at 3 months from 10% to 22%.

Eltrombopag also accelerated the time to response, with patients receiving it showing a median time to first response of 3.0 months compared to 8.8 months for those not receiving it, all without increasing the incidence of severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia. Peffault de Latour, R., Kulasekararaj, A., Iacobelli, S., et al.[2023]

Horse antithymocyte globulin plus cyclosporine is the standard treatment for severe aplastic anemia, achieving hematologic response rates of 60% to 70%.

Eltrombopag, when used alone or in combination with immunosuppressive therapy, shows promising response rates of 40% to 50% and enhances overall response rates, indicating its potential as an effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent Advances and Long-Term Results of Medical Treatment of Acquired Aplastic Anemia: Are Patients Cured? Scheinberg, P.[2021]

In a study of 89 aplastic anemia patients, the combination of cyclosporine (CSA) and eltrombopag (EPAG) showed similar overall response rates to the combination of CSA, EPAG, and antithymocyte globulin (ATG), indicating that CSA + EPAG may be an effective alternative treatment.

The CSA + EPAG combination resulted in fewer side effects compared to the standard treatment with ATG, with a mortality rate of 7.8% in the ATG group and no deaths in the CSA + EPAG group, suggesting a potentially safer option for newly diagnosed patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclosporine plus eltrombopag in the treatment of aplastic anemia with or without antithymocyte immunoglobulin: A multicenter real-world retrospective study. Chen, M., Liu, Q., Gao, Y., et al.[2023]

In a phase II study involving 20 patients with severe aplastic anemia, rabbit anti-thymocyte globulin showed similar response rates to horse anti-thymocyte globulin, with no significant differences in efficacy or early mortality rates over 12 months.

Key predictors of treatment response included the presence of a paroxysmal nocturnal hemoglobinuria clone and a higher pretreatment reticulocyte count, while factors like younger age and higher neutrophil and lymphocyte counts were linked to better overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of rabbit anti-thymocyte globulin in severe aplastic anemia. Afable, MG., Shaik, M., Sugimoto, Y., et al.[2021]

The standard treatment for severe aplastic anemia, horse anti-thymocyte globulin plus cyclosporine, achieves a hematologic response in 60 to 70% of patients, but there is a significant risk of relapse (30 to 40%) and clonal evolution (10 to 15%).

Despite advances in treatment options, no new regimens have significantly improved hematologic response rates or reduced relapse and clonal evolution, making the current standard therapy still the most effective initial approach for managing severe aplastic anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current management of severe acquired aplastic anemia. Scheinberg, P.[2016]

Eltrombopag, a thrombopoietin receptor agonist, has shown significant efficacy in treating severe aplastic anemia (SAA), with 40% to 50% of patients recovering blood counts and achieving transfusion independence after initial immunosuppressive therapy.

When eltrombopag was combined with horse antithymocyte globulin (ATG) and cyclosporine as a first-line treatment, it resulted in approximately 90% overall response rates and 40% complete response rates, especially when all medications were started simultaneously.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of eltrombopag in severe aplastic anemia. Scheinberg, P.[2019]

In a study of 25 pediatric patients with severe aplastic anemia, the addition of eltrombopag to standard immunosuppressive therapy showed a satisfactory hematological response, with 29% achieving complete response at 6 and 12 months.

The combination therapy was well tolerated, with no significant differences in infection rates between the groups, although one patient experienced transient liver enzyme elevation, indicating a need for monitoring but not major safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eltrombopag in children with severe aplastic anemia. Lesmana, H., Jacobs, T., Boals, M., et al.[2022]

Eltrombopag, a thrombopoietin receptor agonist, has shown significant efficacy in treating severe aplastic anemia (SAA), with 40% to 50% of patients recovering blood counts and achieving transfusion independence after initial immunosuppressive therapy.

When used in combination with horse antithymocyte globulin (ATG) and cyclosporine as a first-line treatment, eltrombopag resulted in about 90% overall response rates and 40% complete response rates, especially when all medications were started simultaneously.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of eltrombopag in severe aplastic anemia. Scheinberg, P.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Recent Advances and Long-Term Results of Medical Treatment of Acquired Aplastic Anemia: Are Patients Cured? [2021]

3. England pubmed.ncbi.nlm.nih.gov

Cyclosporine plus eltrombopag in the treatment of aplastic anemia with or without antithymocyte immunoglobulin: A multicenter real-world retrospective study. [2023]

4. Italy pubmed.ncbi.nlm.nih.gov

Efficacy of rabbit anti-thymocyte globulin in severe aplastic anemia. [2021]

5. Brazil pubmed.ncbi.nlm.nih.gov

Current management of severe acquired aplastic anemia. [2016]

6. United States pubmed.ncbi.nlm.nih.gov

Activity of eltrombopag in severe aplastic anemia. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Eltrombopag in children with severe aplastic anemia. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Activity of eltrombopag in severe aplastic anemia. [2019]