Stem Cell Transplant for Severe Aplastic Anemia

Recruiting in Palo Alto (17 mi)

Overseen by Richard W Childs, M.D.

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

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

Disqualifiers: HIV, Pregnancy, Fanconi anemia, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

Background: Severe aplastic anemia (SAA), and myelodysplastic syndrome (MDS), and paroxysmal nocturnal hemoglobinuria (PNH) cause serious blood problems. Stem cell transplants using bone marrow or blood plus chemotherapy can help. Researchers want to see if using peripheral blood stem cells (PBSCs) rather than bone marrow cells works too. PBSCs are easier to collect and have more cells that help transplants. Objectives: To see how safely and effectively SAA, MDS and PNH are treated using peripheral blood hematopoietic stem cells from a family member plus chemotherapy. Eligibility: Recipients ages 4-60 with SAA, MDS or PNH and their relative donors ages 4-75 Design: Recipients will have: * Blood, urine, heart, and lung tests * Scans * Bone marrow sample Recipients will need a caregiver for several months. They may make fertility plans and a power of attorney. Donors will have blood and tissue tests, then injections to boost stem cells for 5-7 days. Donors will have blood collected from a tube in an arm or leg vein. A machine will separate stem cells and maybe white blood cells. The rest of the blood will be returned into the other arm or leg. In the hospital for about 1 month, recipients will have: * Central line inserted in the neck or chest * Medicines for side effects * Chemotherapy over 8 days and radiation 1 time * Stem cell transplant over 4 hours Up to 6 months after transplant, recipients will stay near NIH for weekly physical exams and blood tests. At day 180, recipients will go home. They will have tests at their doctor s office and NIH several times over 5 years.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment for severe aplastic anemia?

Research shows that using cyclophosphamide (a drug that suppresses the immune system) after a stem cell transplant can be effective for severe aplastic anemia, with studies reporting high survival rates and successful engraftment (when the new stem cells start to grow in the bone marrow). ^{1 2 3 4 5}

Is stem cell transplant using cyclophosphamide safe for humans?

Cyclophosphamide, used in stem cell transplants, has been studied for safety in humans and animals. It can cause serious side effects like bone marrow and heart toxicity, but with proper care, many patients recover well. Long-term studies show high survival rates in patients with severe aplastic anemia treated with high-dose cyclophosphamide. ^{3 6 7 8 9}

How is the stem cell transplant treatment with cyclophosphamide unique for severe aplastic anemia?

This treatment is unique because it combines high-dose cyclophosphamide, a powerful drug that suppresses the immune system, with peripheral blood stem cells to help restore bone marrow function. Unlike traditional bone marrow transplants, this approach can be used even if a perfect donor match is not available, and it may offer a higher chance of complete remission without the need for additional immunosuppressive therapy. ^{1 3 4 5 6}

Research Team

Richard W Childs, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Eligibility Criteria

This trial is for people aged 4-55 with severe aplastic anemia, myelodysplastic syndrome (MDS), or paroxysmal nocturnal hemoglobinuria (PNH) who haven't responded to standard treatments. They need a family member donor aged 4-75. Participants must understand the study and consent; minors will need guardian consent. Exclusions include certain heart, liver, kidney issues, active infections not responding to treatment, HIV positive individuals, pregnant women or those not using birth control.

Inclusion Criteria

I have been diagnosed with severe aplastic anemia.

I don't have antibodies against the donor's tissue markers.

My PNH does not respond to eculizumab/ravulizumab or I can't access this treatment.

Exclusion Criteria

Your direct bilirubin level is higher than 3 mg/dl.

I have an infection that isn't getting better with treatment.

I have a family member who is a near-perfect match for a stem cell donation.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Pre-transplant Preparation

Recipients undergo blood, urine, heart, and lung tests, scans, and bone marrow sampling. Donors receive injections to boost stem cells for 5-7 days.

1-2 weeks

Multiple visits (in-person)

Transplantation

Recipients receive chemotherapy over 8 days and radiation 1 time, followed by a stem cell transplant over 4 hours.

1 month

Inpatient stay

Post-transplant Monitoring

Recipients stay near NIH for weekly physical exams and blood tests for up to 6 months after transplant.

6 months

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with tests at their doctor's office and NIH several times over 5 years.

5 years

Several visits (in-person)

Treatment Details

Interventions

• Cyclophosphamide (Alkylating agents)
• Peripheral Blood Stem Cells (Procedure)

Trial Overview The trial tests if peripheral blood stem cells from a relative plus chemotherapy can treat SAA, MDS and PNH effectively and safely. Patients undergo extensive testing before receiving chemo and radiation followed by the stem cell transplant in hospital for about a month with follow-up visits over five years.

Participant Groups

Group I: Treatment Arm Experimental Treatment 2 Interventions

G-CSF mobilized peripheral stem cells and post haplo-identical transplantation cyclophosphamide

Cyclophosphamide is already approved in Canada, Japan for the following indications:

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

Dr. Gary H. Gibbons

National Heart, Lung, and Blood Institute (NHLBI)

Chief Executive Officer since 2012

MD from Harvard Medical School

Dr. James P. Kiley

National Heart, Lung, and Blood Institute (NHLBI)

Chief Medical Officer since 2011

MD from University of California, San Francisco

Findings from Research

Hematopoietic stem cell transplantation (HSCT) using a post-transplantation cyclophosphamide (PTCy) approach showed an 85% overall survival rate at 2 years for patients with severe aplastic anemia (SAA) who failed immunosuppressive therapy, indicating its efficacy as a treatment option.

All patients in the study engrafted successfully, with 9 out of 11 survivors achieving complete donor chimerism, and most patients became transfusion-independent, highlighting the potential of PTCy in improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Case Series of Post-Transplantation Cyclophosphamide in Unrelated Donor Hematopoietic Cell Transplantation for Aplastic Anemia. Arcuri, LJ., Nabhan, SK., Loth, G., et al.[2021]

In a study of 28 pediatric patients with severe aplastic anemia treated with high-dose cyclophosphamide, the overall survival rate was 85%, with a hematologic response rate of 79% and a complete response rate of 66%.

Despite high rates of bacterial (86%) and fungal (62%) infections, the treatment was associated with rare deaths due to infection and manageable toxicity, suggesting that high-dose cyclophosphamide can be an effective and safer option for children compared to traditional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose Cyclophosphamide is Effective Therapy for Pediatric Severe Aplastic Anemia. Gamper, CJ., Takemoto, CM., Chen, AR., et al.[2019]

In a long-term follow-up study of 67 patients with severe aplastic anemia treated with high-dose cyclophosphamide, the overall survival rate at 10 years was 88% for treatment-naive patients, indicating its effectiveness as a therapy.

For patients with refractory severe aplastic anemia, the outcomes were less favorable, with a 10-year survival rate of 62%, highlighting the need for further research to compare high-dose cyclophosphamide with other treatment options like bone marrow transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose cyclophosphamide for severe aplastic anemia: long-term follow-up. Brodsky, RA., Chen, AR., Dorr, D., et al.[2021]

In a study of 10 patients with severe aplastic anemia (SAA) who lacked an HLA-identical sibling, high-dose cyclophosphamide (45 mg/kg/d for 4 days) led to a complete response in 7 patients, with 6 remaining in continuous remission for a median of 10.8 years.

The results suggest that high-dose cyclophosphamide may be more effective than conventional immunosuppressive therapies in restoring normal blood cell production and preventing relapse or secondary diseases, indicating a need for further research on this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete remission in severe aplastic anemia after high-dose cyclophosphamide without bone marrow transplantation. Brodsky, RA., Sensenbrenner, LL., Jones, RJ.[2021]

A novel hematopoietic cell transplantation (HCT) protocol using post-transplantation cyclophosphamide (PTCy) was found to be effective and safe for treating severe aplastic anemia (SAA) in young patients, with a 93.9% survival rate after 12 months.

The study showed that treatment-naive patients had better overall survival (100%) compared to relapsed or refractory patients (84.8%), indicating that early intervention may lead to improved outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alternative Transplantation With Post-Transplantation Cyclophosphamide in Aplastic Anemia: A Retrospective Report From the BMF-WG of Hunan Province, China. Gong, S., Chen, C., Chen, K., et al.[2023]

High doses of cyclophosphamide (CY) can be toxic to bone marrow, but when combined with autologous marrow transplantation, it allows for recovery from severe side effects, as shown in dog studies where 100 mg/kg was lethal without support but manageable with marrow infusion.

In human patients, conditioning with CY (50 mg/kg) before allogeneic marrow transplantation for severe aplastic anemia has resulted in an 80% long-term survival rate, demonstrating the efficacy of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose therapy and bone marrow transplantation. Thomas, ED.[2018]

Granulocyte colony-stimulating factor (G-CSF) is the gold standard for mobilizing hematopoietic stem cells (HSCs) from the bone marrow to the peripheral blood for autologous stem cell transplantation, but some patients do not respond adequately to this treatment.

Plerixafor (AMD3100) has been recently approved to enhance the mobilization of peripheral blood stem cells when used in combination with G-CSF, providing a new option for patients who struggle to mobilize sufficient stem cells for transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in mobilization for the optimization of autologous stem cell transplantation. Vose, JM., Ho, AD., Coiffier, B., et al.[2021]

In a phase II study involving 14 women with stage II-IV breast cancer, the combination of cyclophosphamide and PIXY321 was well tolerated, with manageable side effects like injection site reactions and fever.

Patients treated with PIXY321 showed promising results in mobilizing peripheral blood progenitor cells, with enhanced platelet recovery compared to traditional methods using GM-CSF, suggesting a potential benefit in supporting high-dose chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of cyclophosphamide followed by PIXY321 as a means of mobilizing peripheral blood hematopoietic progenitor cells. Roman-Unfer, S., Bitran, JD., Garrison, L., et al.[2013]

Hematopoietic progenitor cells, such as CFU-Mix, BFU-E, and CFU-GM, are highly sensitive to the cytotoxic effects of 4-hydroperoxycyclophosphamide (4-HC), with varying degrees of sensitivity observed at different doses.

Despite the depletion of certain hematopoietic progenitors at high doses of 4-HC, the most primitive hematopoietic stem cells appear to be spared, as evidenced by the ability of treated marrow to generate CFU-GM in long-term culture, indicating that standard colony assays may not accurately predict the survival of pluripotent stem cells after 4-HC exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of in vitro purging with 4-hydroperoxycyclophosphamide on the hematopoietic and microenvironmental elements of human bone marrow. Siena, S., Castro-Malaspina, H., Gulati, SC., et al.[2021]

References

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

A Case Series of Post-Transplantation Cyclophosphamide in Unrelated Donor Hematopoietic Cell Transplantation for Aplastic Anemia. [2021]

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

High-dose Cyclophosphamide is Effective Therapy for Pediatric Severe Aplastic Anemia. [2019]

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

High-dose cyclophosphamide for severe aplastic anemia: long-term follow-up. [2021]

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

Complete remission in severe aplastic anemia after high-dose cyclophosphamide without bone marrow transplantation. [2021]

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

Alternative Transplantation With Post-Transplantation Cyclophosphamide in Aplastic Anemia: A Retrospective Report From the BMF-WG of Hunan Province, China. [2023]

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

High-dose therapy and bone marrow transplantation. [2018]

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

Advances in mobilization for the optimization of autologous stem cell transplantation. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

A phase II study of cyclophosphamide followed by PIXY321 as a means of mobilizing peripheral blood hematopoietic progenitor cells. [2013]

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

Effects of in vitro purging with 4-hydroperoxycyclophosphamide on the hematopoietic and microenvironmental elements of human bone marrow. [2021]