Sirolimus 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

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Myelodysplastic syndrome, Pregnancy, Cancer, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 3 months

83 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: People with severe aplastic anemia (SAA) do not make enough red and white blood cells, and/or platelets. Their body's immune system stops the bone marrow from making these cells. The treatment cyclosporine leads to better blood counts. But when this treatment is stopped, the disease may return in 1 in 3 people. The drug sirolimus may help by suppressing the immune system. Objective: To evaluate and compare the usefulness of sirolimus in preventing aplastic anemia from returning after cyclosporine is stopped, compared with stopping cyclosporine alone. Eligibility: People ages 2 and older with SAA who: Have responded to immunosuppressive therapy that includes cyclosporine, and continue to take cyclosporine Are not taking drugs with hematologic effects Design: Participants will be screened with: Medical history Physical exam Blood and urine tests Bone marrow biopsy: The area above the hipbone will be numbed. A thin needle will remove some bone marrow. Participants will be randomly assigned to a group. All will stop cyclosporine. Group 1 will take sirolimus by mouth at the same time each day for 3 months with close monitoring. Group 2 will not receive the study drug but will be monitored closely. Participants will have clinical tests for the first 3 months: Weekly blood test Monthly fasting blood test For group 1, measurements of sirolimus in the blood every 1 2 weeks Participants will have clinic visits at 3 months, 12 months, and annually for 5 years after the study starts. They may have another visit if their SAA returns. These will include: Blood and urine tests Bone marrow biopsy

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

The trial requires you to stop taking cyclosporine. You cannot participate if you are taking drugs with hematologic effects or certain CYP3A4 inhibitors unless you can replace them with equivalent medications. The protocol does not specify other medication restrictions, but you should discuss your current medications with the study team.

Will I have to stop taking my current medications?

The trial requires participants to stop taking cyclosporine, but it does not specify if you need to stop other medications. However, you cannot participate if you are taking certain drugs like CYP3A4 inhibitors and cannot switch to alternatives.

What data supports the idea that Sirolimus for Aplastic Anemia (also known as: Sirolimus, Rapamune) is an effective drug?

The available research shows that Sirolimus can be effective for treating Aplastic Anemia, especially in cases where other treatments like cyclosporine and anti-thymocyte globulin have failed. For example, one study reported two patients who became independent of blood transfusions after being treated with Sirolimus combined with cyclosporine. Another study highlighted that Sirolimus has lower kidney toxicity, making it a safer option for patients with both Aplastic Anemia and chronic kidney disease. In mouse models, Sirolimus improved blood cell counts and bone marrow health, similar to cyclosporine, but worked through different mechanisms, suggesting it could be a valuable alternative treatment. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Sirolimus for treating aplastic anemia?

Sirolimus has shown effectiveness in treating aplastic anemia, especially in patients who relapse after standard treatments, by helping them become independent of blood transfusions. Additionally, in mouse models, Sirolimus improved bone marrow function and survival, suggesting its potential as an alternative treatment for aplastic anemia. ^{1 2 3 4 5}

What safety data is available for Sirolimus in treating aplastic anemia?

Sirolimus, also known as Rapamune, is associated with anemia as a known adverse effect, potentially due to its antiproliferative effects or impact on kidney function and iron utilization. It has lower nephrotoxicity compared to cyclosporine, making it a viable option for patients with chronic kidney disease. However, it may impair hematopoiesis, as observed in heart transplant patients. Despite these concerns, Sirolimus has been effective in treating relapsed aplastic anemia when combined with cyclosporine, achieving transfusion independence in some cases. Overall, Sirolimus has a lower risk of renal, neurologic, and lymphoproliferative complications compared to other immunosuppressants. ^{1 2 4 6 7}

Is sirolimus safe for humans?

Sirolimus, also known as Rapamune, is generally considered safe for humans, but it can cause anemia (a condition where you don't have enough healthy red blood cells) and may affect bone marrow function. It has a lower risk of kidney and nerve problems compared to some other drugs, but it can still have side effects, especially related to blood cell production. ^{1 2 4 6 7}

Is the drug Sirolimus a promising treatment for Aplastic Anemia?

Yes, Sirolimus is a promising treatment for Aplastic Anemia. It helps patients who don't respond to other treatments and has lower toxicity, making it safer for those with kidney issues. It also works well with other drugs to improve treatment outcomes. ^{1 2 7 8 9}

How is the drug sirolimus different from other treatments for aplastic anemia?

Sirolimus is unique because it targets a specific pathway in the immune system (mTOR) that other treatments like cyclosporine do not, making it effective for patients who do not respond to standard immunosuppressive therapy. Additionally, it has lower kidney toxicity, which is beneficial for patients with chronic kidney disease. ^{1 2 7 8 9}

Research Team

Bhavisha A Patel, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Eligibility Criteria

This trial is for people aged 2 and older who weigh more than 12 kg, have severe aplastic anemia (SAA) previously treated with immunosuppressive therapy including cyclosporine, and show a positive response to treatment. They must not be pregnant or breastfeeding, should agree to use birth control if of childbearing potential, haven't used sirolimus or similar drugs recently, aren't on certain medications that affect the study drug's action, don't have other blood disorders like leukemia or myelodysplastic syndrome, and are generally healthy enough to participate.

Inclusion Criteria

I am at least 2 years old.

Weight greater than 12 kg

I have been on cyclosporine consistently for the last 6 months.

Exclusion Criteria

I am taking medications that affect liver enzyme levels and cannot switch them.

My infection is not improving despite treatment.

Anaphylactic or hypersensitivity reaction to sirolimus

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants in Group 1 take sirolimus daily for 3 months with close monitoring; Group 2 is monitored without sirolimus

3 months

Weekly blood tests, monthly fasting blood tests, sirolimus measurements every 1-2 weeks for Group 1

Follow-up

Participants are monitored for safety and effectiveness after treatment, with clinic visits at 3 months, 12 months, and annually for 5 years

5 years

Clinic visits at 3 months, 12 months, and annually

Treatment Details

Interventions

• Sirolimus

Trial Overview The trial tests whether taking Sirolimus orally can prevent SAA from returning after stopping cyclosporine treatment. Participants will either receive Sirolimus daily for three months while being closely monitored (Group 1), or they'll stop cyclosporine without receiving Sirolimus but still under close observation (Group 2). The effectiveness will be measured through regular blood tests and bone marrow biopsies over five years.

Participant Groups

Group I: Sirolimus Experimental Treatment 1 Intervention

sirolimus

Group II: Standard of Care Active Control 1 Intervention

no intervention

Who Is Running the Clinical Trial?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

Findings from Research

In two cases of aplastic anemia (AA) that relapsed after standard immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and cyclosporine (CsA), patients achieved transfusion independence after being treated with sirolimus combined with CsA.

Sirolimus works by inhibiting the mTOR pathway, which may provide an effective alternative treatment for patients who do not respond to traditional IST, highlighting its potential role in managing refractory AA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relapse of aplastic anemia responsive to sirolimus combined with cyclosporine. He, G., Zhang, X., Wu, D., et al.[2013]

Sirolimus was successfully used to treat a 55-year-old patient with severe aplastic anemia and chronic kidney disease, leading to a gradual increase in blood cell counts and achieving transfusion independence.

The treatment was well-tolerated and demonstrated lower nephrotoxicity compared to traditional therapies like cyclosporine, making sirolimus a promising option for patients with similar conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful sirolimus therapy of an aplastic anemia patient with chronic kidney disease: A case report. Niu, H., Qi, W., Wang, Y., et al.[2022]

In a study of 77 patients with severe aplastic anemia, the addition of sirolimus to standard treatment (h-ATG and cyclosporine) did not improve the hematologic response rate at 3 or 6 months compared to the standard treatment alone.

The overall response rates were 37% for the h-ATG/CsA/sirolimus group and 50% for the h-ATG/CsA group at 3 months, indicating that sirolimus did not provide the expected benefits despite its theoretical advantages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of severe aplastic anemia with a combination of horse antithymocyte globulin and cyclosporine, with or without sirolimus: a prospective randomized study. Scheinberg, P., Wu, CO., Nunez, O., et al.[2021]

In a study of 84 heart transplant patients treated with sirolimus, the prevalence of anemia increased from 71% to 75% after starting the medication, indicating a significant impact on hemoglobin levels.

A quarter of the patients experienced a drop in hemoglobin of 20 g/L or more, and the hematologic profile suggested that the anemia was related to chronic disease and functional iron deficiency, highlighting the need for monitoring and management in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus is associated with impaired hematopoiesis in heart transplant patients? A retrospective analysis. McDonald, MA., Gustafsson, F., Almasood, A., et al.[2013]

In mouse models of acquired aplastic anemia, rapamycin effectively improved blood cell counts and bone marrow health, showing comparable efficacy to cyclosporine, a standard treatment.

Rapamycin works through unique mechanisms, such as increasing regulatory T cells and reducing harmful CD8+ T cells, suggesting it could be a promising alternative therapy for patients with aplastic anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin is highly effective in murine models of immune-mediated bone marrow failure. Feng, X., Lin, Z., Sun, W., et al.[2019]

In a study of 25 stable renal transplant patients, switching from sirolimus to enteric coated mycophenolate sodium resulted in an increase in hemoglobin levels in 86% of patients, indicating improved anemia management.

The conversion also led to a significant decrease in endogenous erythropoietin levels and reduced erythropoietin resistance, suggesting that sirolimus may contribute to anemia by making the body less responsive to erythropoietin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduction in erythropoietin resistance after conversion from sirolimus to enteric coated mycophenolate sodium. Augustine, JJ., Rodriguez, V., Padiyar, A., et al.[2013]

Sirolimus (rapamycin) is an effective immunosuppressant approved for preventing graft rejection in kidney transplants, with a lower risk of complications compared to other immunosuppressants.

Recent findings suggest that sirolimus may also have potential in treating skin disorders and extending lifespan, making it a promising candidate for addressing age-related diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. Peters, T., Traboulsi, D., Tibbles, LA., et al.[2014]

Sirolimus is a powerful immunosuppressant used in kidney transplantation that works by inhibiting the mTOR pathway, which is crucial for cell growth and proliferation, leading to reduced rates of acute rejection episodes to less than 10% when combined with cyclosporin A (CsA).

In clinical trials, using sirolimus at doses of 2 or 5 mg/day alongside CsA and steroids resulted in acute rejection rates of only 19% and 14% within 12 months, while also potentially reducing the need for nephrotoxic calcineurin inhibitors, although it may cause side effects like myelosuppression and increased lipid levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a comprehensive review. Kahan, BD.[2019]

Sirolimus (RAPA) treatment in renal transplant patients significantly increases plasma triglyceride levels and VLDL-apoB100 concentrations due to a reduced catabolic rate of these lipoproteins, rather than increased production.

The study found that RAPA-induced hyperlipidemia is linked to decreased clearance of apoB100-containing lipoproteins, highlighting a metabolic pathway that could be targeted to manage lipid levels in patients undergoing immunosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. Hoogeveen, RC., Ballantyne, CM., Pownall, HJ., et al.[2019]

References

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

Relapse of aplastic anemia responsive to sirolimus combined with cyclosporine. [2013]

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

Successful sirolimus therapy of an aplastic anemia patient with chronic kidney disease: A case report. [2022]

3. Italy pubmed.ncbi.nlm.nih.gov

Treatment of severe aplastic anemia with a combination of horse antithymocyte globulin and cyclosporine, with or without sirolimus: a prospective randomized study. [2021]

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

Sirolimus is associated with impaired hematopoiesis in heart transplant patients? A retrospective analysis. [2013]

5. Italy pubmed.ncbi.nlm.nih.gov

Rapamycin is highly effective in murine models of immune-mediated bone marrow failure. [2019]

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

Reduction in erythropoietin resistance after conversion from sirolimus to enteric coated mycophenolate sodium. [2013]

7. Canada pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. [2014]

8. England pubmed.ncbi.nlm.nih.gov

Sirolimus: a comprehensive review. [2019]

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

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. [2019]