Cyclosporine + Eltrombopag for Aplastic Anemia

Overseen By Bhavisha A Patel, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 2

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

Must be taking: Cyclosporine, Eltrombopag

Must not be taking: Antiretrovirals, Chemotherapy

Disqualifiers: Fanconi anemia, Clonal disorder, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether starting with lower doses of two oral medications, Cyclosporine and Eltrombopag, provides a safe and effective treatment plan for people with severe aplastic anemia (SAA). In SAA, the immune system attacks the bone marrow, leading to low blood cell counts. The trial aims to determine if this approach can prepare patients for another treatment, horse anti-thymocyte globulin, which targets the immune system. It suits anyone 3 years or older who has not yet received immunosuppressive therapies and experiences symptoms like very low blood cell counts. As a Phase 2 trial, this research measures how well the treatment works in an initial, smaller group of people.

Do I need to stop my current medications to join the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss your specific situation with the trial coordinators.

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

Research has shown that using Cyclosporine and Eltrombopag together is generally safe for treating severe aplastic anemia. In earlier studies, when these two drugs served as the initial treatment for this condition, no unexpected safety problems emerged. People of all ages tolerated the treatment well. Thus, the combination of Cyclosporine and Eltrombopag is well-tolerated, with no major safety concerns reported. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for aplastic anemia?

Researchers are excited about using Cyclosporine and Eltrombopag together for treating aplastic anemia because this combination targets the condition differently from the usual treatments. While standard options like immunosuppressive therapy mainly dampen the immune system to prevent it from attacking the bone marrow, Eltrombopag specifically stimulates the bone marrow to produce more blood cells. This dual approach of suppressing the immune attack with Cyclosporine and boosting blood production with Eltrombopag could offer a more comprehensive treatment, potentially improving outcomes for patients with severe aplastic anemia.

What evidence suggests that this trial's treatments could be effective for severe aplastic anemia?

Research has shown that combining eltrombopag (EPAG) with cyclosporine (CsA) can improve blood counts in people with severe aplastic anemia (SAA). In this trial, participants will receive CsA and EPAG together. One study found that patients who took EPAG with standard treatment showed better blood cell improvements than those who did not. Another study suggested that the combination of CsA and EPAG benefits patients who cannot have or tolerate other treatments, such as horse anti-thymocyte globulin. Overall, this treatment combination appears promising for those with SAA who have limited treatment options. ^{3 5 6 7 8}

Who Is on the Research Team?

Bhavisha A Patel, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Are You a Good Fit for This Trial?

This trial is for people aged 3 and older with severe aplastic anemia, a condition where the bone marrow doesn't make enough blood cells. Participants must have specific low blood cell counts, weigh over 12Kg, and not have HIV, certain infections or cancers, heart issues, liver cirrhosis or be on conflicting medications. Pregnant women or those who can't use contraception are excluded.

Inclusion Criteria

I am at least 3 years old.

I have severe aplastic anemia with very low blood cell counts.

Weight >12Kg

Exclusion Criteria

I cannot swallow.

I am not pregnant or nursing.

I do not have serious heart conditions or recent heart issues.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Remote screening via telephone conference

Initial Treatment

Participants take a lower oral dose of CsA and EPAG for 6 months, with weekly telephone calls until they visit the Clinical Center

8 weeks

Weekly telephone calls

Standard Treatment

Participants may receive h-ATG at the Clinical Center for 4 days, with a central line placed

4 days

In-person at Clinical Center

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up visits at 3 months, 6 months, and annually for 5 years

5 years

In-person visits at 3 months, 6 months, and annually

What Are the Treatments Tested in This Trial?

Interventions

• Cyclosporine
• Eltrombopag
• Horse-Anti-thymocyte-Globulin

Trial Overview

The study tests if starting oral Cyclosporine (CsA) and Eltrombopag (EPAG) early before horse anti-thymocyte globulin (h-ATG) helps treat severe aplastic anemia. Patients take CsA twice daily and EPAG for six months; some may receive h-ATG at NIH Clinical Center.

How Is the Trial Designed?

Group I: Participants with Severe Aplastic Anemia in Early Initiation of Cyclosporine and Eltrombopag Experimental Treatment 3 Interventions

Treatment-naïve Severe Aplastic Anemia (SAA) participants start Cyclosporine (CsA) on Day 1 at 2 mg/kg/day. At initiation of Horse Anti-Thymocyte-Globulin (h-ATG), dosing increases to 3 mg/kg every 12 hours for those ≥12 years (6 mg/kg/day total) and 6 mg/kg every 12 hours for those \<12 years (12 mg/kg/day total). Actual body weight is used unless \>125% ideal body weight (IBW), where adjusted IBW applies. CsA is titrated to a trough of 200-400 mcg/L. At 6 months, responders reduce to 2 mg/kg/day through 24 months, with return to full dosing if relapse occurs. h-ATG is given at 40 mg/kg/day for 4 days IV, unless the patient already shows a complete response at the initial NIH visit after remote oral therapy. Eltrombopag (EPAG) starts on Day 1 at 150 mg/day for ages 12-17, 75 mg/day for ages 6-11, and 2.5 mg/kg/day for ages 3-5. For East and Southeast Asian patients, starting doses are reduced to 75 mg/day (ages 12-85), 37.5 mg/day (ages 6-11), and 1.25 mg/kg/day (ages 3-5).

Group II: Extension Cohort Experimental Treatment 3 Interventions

Treatment-naïve Severe Aplastic Anemia (SAA) participants start Cyclosporine (CsA) on Day 1 at 2 mg/kg/day. At initiation of Horse Anti-Thymocyte-Globulin (h-ATG), dosing increases to 3 mg/kg every 12 hours for those ≥12 years (6 mg/kg/day total) and 6 mg/kg every 12 hours for those \<12 years (12 mg/kg/day total). Actual body weight is used unless \>125% ideal body weight (IBW), where adjusted IBW applies. CsA is titrated to a trough of 200-400 mcg/L. At 6 months, responders reduce to 2 mg/kg/day through 24 months, with return to full dosing if relapse occurs. h-ATG is given at 40 mg/kg/day for 4 days IV, unless the patient already shows a complete response at the initial NIH visit after remote oral therapy. Eltrombopag (EPAG) starts on Day 1 at 150 mg/day for ages 12-17, 75 mg/day for ages 6-11, and 2.5 mg/kg/day for ages 3-5. For East and Southeast Asian patients, starting doses are reduced to 75 mg/day (ages 12-85), 37.5 mg/day (ages 6-11), and 1.25 mg/kg/day (ages 3-5).

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+

Published Research Related to This Trial

Eltrombopag is an effective treatment for patients with severe aplastic anemia who do not respond to immunosuppressive therapy, showing a hematological response in at least 40% of patients after 12-16 weeks of treatment.

The drug works by stimulating hematopoietic stem cells and increasing platelet, red blood cell, and neutrophil counts, while being generally well tolerated, though it can cause increased liver transaminases and some cytogenetic abnormalities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eltrombopag: a review of its use in patients with severe aplastic anaemia. McCormack, PL.[2018]

Eltrombopag, when used in combination with immunosuppressive therapy, shows a high overall hematologic response rate of 88% in patients with aplastic anemia, indicating its efficacy in this treatment context.

In patients with refractory aplastic anemia treated with eltrombopag alone, the response rate drops to 47%, and there are concerns about karyotype abnormalities, with a 17% rate observed in this group, highlighting potential safety issues associated with the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Eltrombopag for Aplastic Anemia: A Systematic Review and Meta-analysis. Hong, Y., Li, X., Wan, B., et al.[2022]

In a study of 76 treatment-naive patients with transfusion-dependent non-severe aplastic anemia, eltrombopag combined with cyclosporine A significantly improved hematological response and complete response rates compared to cyclosporine A alone over a follow-up period of up to 12 months.

Eltrombopag treatment led to a shorter median time to platelet transfusion independence and a lower volume of platelet transfusions needed, indicating its efficacy in promoting platelet recovery, while adverse events were mild and well tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of Eltrombopag on Response to Immunosuppressive Therapy in Patients with Transfusion-Dependent Non-Severe Aplastic Anemia]. Lin, Y., Zhang, RD., Lin, ZH., et al.[2023]

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 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]

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 study of 13 patients with transfusion-dependent non-severe aplastic anemia, the combination of eltrombopag and cyclosporine A resulted in a high overall hematological response rate of 92% after 3 months, with 2 patients achieving complete response and 9 achieving partial response.

The treatment was generally safe, with only mild and manageable adverse reactions reported in 5 patients, although one patient developed paroxysmal nocturnal hemoglobinuria after 6 months, indicating the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The efficacy of eltrombopag plus cyclosporine A in patients with transfusion-dependent non-severe aplastic anemia: a retrospective study from single center]. Chen, Y., Zha, Q., Huang, F., et al.[2022]

In a study involving 39 healthy adults, the combination of cyclosporine with eltrombopag reduced the drug's plasma exposure by up to 39%, but these changes were not deemed clinically significant due to the ability to adjust eltrombopag doses based on patient needs.

The study found that all treatment combinations were safe and well-tolerated, with no serious adverse events reported, indicating a favorable safety profile for using eltrombopag with cyclosporine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of cyclosporine coadministration on the pharmacokinetics of eltrombopag in healthy volunteers. Aslanis, V., Zhang, J., Lomeli, B., et al.[2019]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8718619/

Long-term outcomes in patients with severe aplastic ...

In 2017, our phase 2 trial reported improved hematologic responses with the addition of eltrombopag (EPAG) to standard IST for SAA when compared with a ...

2.

sciencedirect.com

sciencedirect.com/science/article/pii/S0006497121041306

Efficacy and Safety of Eltrombopag Combined with ...

Data from the SOAR study indicate that ETB + CsA may be bene cial for pts with SAA ineligible for transplant who cannot access or tolerate ATG.

3.

clinicaltrials.gov

clinicaltrials.gov/study/NCT02998645

Study Details | NCT02998645 | Eltrombopag Combined ...

Eligible subjects received eltrombopag and cyclosporine for up to 6 months. Participants who achieved hematologic response any time on or before 6 months were ...

4.

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).

5.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa2109965

Eltrombopag Added to Immunosuppression in Severe ...

Eltrombopag in combination with standard horse ATG plus cyclosporine had efficacy in untreated patients with severe or very severe aplastic anemia.

6.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/38335978/

Activity and safety of eltrombopag in combination with ...

Eltrombopag and cyclosporin was active as front-line treatment of severe aplastic anaemia, with no unexpected safety concerns.

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10428470/

S184: SAFETY AND OUTCOMES FOLLOWING ...

Older SAA patients have a similar tolerance to IST as younger patients. 2.There were no pre-treatment predictors of IST toxicity identified.

8.

thelancet.com

thelancet.com/journals/lanhae/article/PIIS2352-3026(23)00395-2/abstract

Activity and safety of eltrombopag in combination with ...

Eltrombopag in combination with cyclosporin A as first‐line treatment of adults with severe aplastic anaemia (SOAR): a phase 2, single-arm study