Stem Cell Transplant for Severe Aplastic Anemia

Overseen By Jennifer A Farren

Age: Any Age

Sex: Any

Trial Phase: Phase 2

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

Disqualifiers: HIV, Pregnancy, Fanconi anemia, 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: 1

56 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if using peripheral blood stem cells (PBSCs) from a family member, combined with chemotherapy, can safely and effectively treat severe blood conditions such as severe aplastic anemia (SAA), myelodysplastic syndrome (MDS), and paroxysmal nocturnal hemoglobinuria (PNH). PBSCs are easier to collect and may improve transplant outcomes compared to traditional bone marrow cells. Individuals with SAA, MDS, or PNH who rely on blood transfusions or have had limited success with standard treatments may be suitable candidates. Participants will receive chemotherapy, including cyclophosphamide, and a stem cell transplant, with a family member donating the stem cells. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research has shown that peripheral blood stem cells (PBSCs) can safely treat severe aplastic anemia (SAA). One study found that PBSCs can be used in transplants with potential benefits in transplant efficacy and in reducing the risk of graft-versus-host disease (GVHD), where donor cells attack the recipient's body.

For cyclophosphamide, a common chemotherapy drug, studies have shown mixed results regarding its safety. While effective for SAA, high doses can cause serious side effects, such as toxicity and increased infection risk. However, moderate doses have been associated with good survival rates, suggesting that dose adjustment can help manage these risks.

Overall, these findings indicate that both PBSCs and cyclophosphamide require careful monitoring of their safety profiles, but they can be well-tolerated with the right approach. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike standard treatments for severe aplastic anemia, which often involve immunosuppressive therapy or bone marrow transplants, this new approach uses a combination of cyclophosphamide and peripheral blood stem cells. What's unique here is the use of G-CSF mobilized peripheral stem cells alongside post-transplant cyclophosphamide, which helps reduce the risk of graft-versus-host disease, a common complication with traditional transplants. Researchers are excited because this method might offer a safer and potentially more effective treatment option, paving the way for better outcomes for patients who don't respond well to existing therapies.

What evidence suggests that using peripheral blood stem cells might be an effective treatment for severe aplastic anemia?

In this trial, participants will receive a combination of G-CSF mobilized peripheral stem cells and post haplo-identical transplantation cyclophosphamide. Research has shown that stem cells from the bloodstream can effectively treat severe aplastic anemia (SAA), improving blood counts and increasing patient survival rates. One study found that these stem cells resulted in high survival rates without serious side effects. Cyclophosphamide, a chemotherapy drug included in this trial, has also proven effective for SAA, with studies showing up to an 88% survival rate and good recovery of blood cells. Together, these treatments offer a strong chance of improving SAA symptoms. ^{1 3 6 7 8}

Who Is on the Research Team?

Richard W Childs, 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 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.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Peripheral Blood Stem Cells

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.

How Is the Trial Designed?

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 United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

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

Approved in European Union as Endoxan for:

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

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

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 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]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC2844020/

High-dose cyclophosphamide for severe aplastic anemia

High-dose cyclophosphamide is highly effective therapy for severe aplastic anemia. Large randomized controlled trials will be necessary.

2.

ashpublications.org

ashpublications.org/blood/article/124/18/2758/33348/Cyclophosphamide-in-severe-aplastic-anemia

Cyclophosphamide in severe aplastic anemia? | Blood

The reported high-level range results were of an overall actuarial survival rate of 88% (response rate of 71%) and an actuarial event-free ...

3.

pure.johnshopkins.edu

pure.johnshopkins.edu/en/publications/high-dose-cyclophosphamide-is-effective-therapy-for-pediatric-sev

High-dose Cyclophosphamide is Effective Therapy for ...

Results: Overall survival was 85%, with hematologic response of 79% and complete response of 66%. Cumulative incidences of bacterial infection ( ...

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT01193283

Cyclophosphamide Plus Cyclosporine in Treatment-Naive ...

The efficacy endpoint is complete response rate at 6 months, with complete response defined as blood counts no longer meeting the standard criteria for severe ...

5.

healio.com

healio.com/news/hematology-oncology/20120325/high-dose-cyclophosphamide-effective-treatment-for-severe-aplastic-anemia

High-dose cyclophosphamide effective treatment for ...

At 10-year follow-up, OS was 88% (95% CI, 75%-95%), hematologic response rate was 70.5% and event-free survival was 58% among treatment-naive ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC4215312/

Moderate-dose cyclophosphamide for severe aplastic ...

First-line therapy of severe aplastic anemia (SAA) with high-dose cyclophosphamide causes toxicity and increased short-term mortality.

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC3096466/

High Dose Cyclophosphamide without Stem Cell Rescue in ...

Overall and event-free survival are less in patients with refractory severe aplastic anemia and the risk of fungal infections is increased; however, durable ...

8.

sciencedirect.com

sciencedirect.com/science/article/pii/S0006497119750198

High Dose Cyclophosphamide (CY) for Severe Aplastic ...

With a median follow-up of 41 (range, 6 – 111) months, 33/38 patients survive (actuarial survival of 86%, 95% CI 72–95%) with 28 (74%, 95% CI 58 ...