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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of adding eltrombopag, a drug that boosts blood cell production, to the standard treatment for severe aplastic anemia. Severe aplastic anemia is a rare condition where the immune system attacks bone marrow, reducing blood cell production. Participants will receive traditional immunosuppressive therapy with horse-ATG (anti-thymocyte globulin) and cyclosporine, along with eltrombopag, to determine if it improves their blood cell counts. Those with untreated severe aplastic anemia might be suitable for this trial. As a Phase 1, Phase 2 trial, the study focuses on understanding how the treatment works and measuring its effectiveness in an initial group of patients.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Studies have shown that eltrombopag, when combined with standard treatment for severe aplastic anemia, can improve low blood cell counts. Eltrombopag mimics a natural protein in the body to boost blood cell production. Research indicates that eltrombopag is generally safe and well-tolerated. It has been used successfully in individuals with severe aplastic anemia, restoring blood cell levels without major safety concerns.

The other treatments in the trial, cyclosporine and horse-ATG, form part of the standard treatment for severe aplastic anemia. Cyclosporine is considered relatively safe, and horse-ATG has been used for over 30 years with a good safety record. Both treatments reduce the immune system's activity to prevent it from attacking the bone marrow, which is essential for treating this disorder. While side effects can occur, they are generally well-understood and closely monitored during treatment.

Overall, the treatments in this study, including eltrombopag, have shown promise in terms of safety for individuals with severe aplastic anemia. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for severe aplastic anemia?

Researchers are excited about the treatment combination of eltrombopag with immunosuppression for severe aplastic anemia because it offers a novel approach to boosting blood cell production. While traditional treatments like immunosuppressive therapy with cyclosporine and horse anti-thymocyte globulin (ATG) focus on dampening the immune system's attack on the bone marrow, eltrombopag introduces a unique mechanism by stimulating the production of blood cells directly through the thrombopoietin receptor. This dual-action approach not only addresses the underlying immune issues but also actively encourages bone marrow recovery, potentially leading to faster and more robust blood cell production. This could be a game-changer for patients who need quicker responses and better outcomes from their treatment.

What evidence suggests that adding eltrombopag to standard immunosuppressive therapy might be an effective treatment for severe aplastic anemia?

Research has shown that adding eltrombopag to standard treatments may improve blood cell counts in people with severe aplastic anemia. In this trial, participants will receive different combinations of eltrombopag, horse-ATG, and cyclosporine. Studies have found that eltrombopag alone works for 40-50% of patients who did not respond to earlier treatments. When combined with standard treatments, the overall response appears even better. This combination has proven effective for patients who have not been treated before and have severe or very severe aplastic anemia. Standard treatments like horse-ATG and cyclosporine already work well for 60-70% of patients. Eltrombopag may enhance these results by helping the bone marrow produce more blood cells. ^{4 5 6 7 8}

Who Is on the Research Team?

Neal S Young, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Are You a Good Fit for This Trial?

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

I am at least 2 years old.

Weight greater than 12 kg

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

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

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

Hypersensitivity to eltrombopag or its components

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 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 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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5280860/

Outcome of Cyclosporine Monotherapy in Patients ... In a study by Gluckman et al. [2], cyclosporine was as effective as anti-thymocyte globulin (ATG) in patients with severe aplastic anemia (SAA). Compared to ATG ...

2. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/5648/505200/Outcomes-of-Antithymocyte-Globulin-and

Outcomes of Antithymocyte Globulin and Cyclosporine for ... The findings of our study demonstrate that ATG plus CsA is an effective and safe treatment option for patients with SAA, especially in the older patient ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05399732

Study Details | NCT05399732 | Efficacy and Safety in ... This randomized control study aimed to compare the 6-month efficacy and safety of the combination of luspatercept and cyclosporine versus cyclosporine ...

4. frontiersin.org frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1378432/full

The state of the art in the treatment of severe aplastic anemia Long-term outcome of pediatric patients with severe aplastic anemia treated with antithymocyte globulin and cyclosporine. J Pediatr. (2008) 153:814–9. doi ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S259009862400006X

Treatment response and its predictors of ... There is limited data on predictors of response to anti-thymocyte globulin and cyclosporine in patients with severe or very severe aplastic anemia.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38687471/

The long-term outcomes and safety of severe aplastic ... The long-term outcomes and safety of severe aplastic anemia treated with porcine antilymphocyte globulin plus cyclosporine, with or without thrombopoietin ...

7. nature.com nature.com/articles/s41408-025-01328-3

Efficacy and safety of immunosuppressive therapy versus ... This trial compared antithymocyte globulin (ATG) + cyclosporine A (CsA) + avatrombopag (AVA) and CsA + AVA in older adults with severe aplastic anemia (SAA).

8. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/1347/502724/Atgam-Efficacy-and-Safety-in-Moderate-to-Very

Atgam Efficacy and Safety in Moderate-to-Very Severe ... This ATGAM Temporary Use Authorization program was a retrospective, multicenter study to report safety and efficacy surveillance data on ATGAM use in patients ...