Stem Cell Transplant for Aplastic Anemia

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Alemtuzumab, ATG

Disqualifiers: MDS, HIV, Hepatitis B/C, others

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

Compensation: Varies

Number of Visits: 2

6 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach to treat severe aplastic anemia, a condition where the bone marrow doesn't produce enough blood cells. Researchers aim to determine if a combination of drugs—cyclophosphamide, pentostatin, and anti-thymocyte globulin (an immunosuppressive therapy)—administered before a special type of stem cell transplant can be safe and effective. The goal is to create space for new, healthy cells and reduce the risk of complications. Individuals with severe aplastic anemia that hasn't improved with other treatments or has recurred may be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment approach.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, since the trial involves a stem cell transplant and immunosuppressive drugs, it's possible that some medications may need to be adjusted. Please consult with the trial team for specific guidance.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown mixed results for anti-thymocyte globulin (ATG). Some studies report a five-year survival rate of 83.2% for patients using rabbit ATG, but it has not been as effective as horse ATG for treating severe aplastic anemia. Cyclophosphamide, another drug in this trial, demonstrated an overall survival rate of 88% in previous studies, though high doses can be harmful. Moderate doses might reduce these risks. For haploidentical hematopoietic cell transplantation (haplo-HSCT), studies have shown promising results, with survival rates between 67.1% and 89.0%, suggesting the treatment can be safe and effective. Overall, these treatments have potential but also carry some risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment for aplastic anemia?

Unlike the standard of care for aplastic anemia, which often involves immunosuppressive therapy or traditional bone marrow transplants, this new approach involves a haploidentical hematopoietic cell transplantation (haploHCT) that is CD4+ T-cell depleted. This method is unique because it uses a donor whose tissue type is only a half match, which greatly expands the pool of potential donors. Additionally, the process includes a conditioning regimen with cyclophosphamide, pentostatin, and anti-thymocyte globulin to prepare the patient's body to better accept the transplant. Researchers are excited because this combination could improve transplant success rates and reduce the risk of complications, offering new hope for patients who struggle to find fully matched donors.

What evidence suggests that this treatment might be an effective treatment for aplastic anemia?

In this trial, participants will receive a combination of treatments, including cyclophosphamide, anti-thymocyte globulin, and haploidentical hematopoietic cell transplantation (Haplo-HCT). Research has shown that cyclophosphamide effectively treats severe aplastic anemia, with a survival rate of 85% and a response rate of up to 79%. Haplo-HCT also shows promise, offering survival chances similar to fully matched transplants when a perfect donor match isn't available. Anti-thymocyte globulin is effective as well, though its effectiveness varies depending on whether the rabbit or horse version is used. Overall, these treatments aim to create space for new, healthy cells and reduce complications like graft versus host disease, leading to better outcomes for patients with severe aplastic anemia. ^{2 4 5 6 7}

Who Is on the Research Team?

Ryotaro Nakamura, M.D.

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for patients aged 40-75 with severe aplastic anemia that's resistant or has returned after treatment. They must have tried immunosuppressive therapy, have a suitable relative as a donor, and meet specific health criteria like proper kidney function and no HIV or hepatitis infections. Women of childbearing age need a negative pregnancy test.

Inclusion Criteria

My kidney function, measured by creatinine clearance, is adequate.

I have a family member who is a partial genetic match for a transplant.

Potential haplo donor must be willing and able to donate bone marrow

Exclusion Criteria

I have a genetic or acquired condition affecting my bone marrow.

I can follow all the study's required procedures.

I currently have an infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Conditioning

Participants receive a reduced-intensity regimen of cyclophosphamide, pentostatin, and anti-thymocyte globulin prior to CD4+ T-cell depleted haploidentical hematopoietic cell transplant

3 weeks

Multiple visits (in-person)

Transplantation

Participants undergo CD4+ T-cell depleted haploidentical hematopoietic cell transplant

1 day

1 visit (in-patient)

Follow-up

Participants are monitored for safety, effectiveness, and incidence of complications such as GvHD and infections

Up to 3 years

Regular visits (in-person and virtual)

What Are the Treatments Tested in This Trial?

Interventions

• Anti-Thymocyte Globulin
• Cyclophosphamide
• Haploidentical Hematopoietic Cell Transplantation

Trial Overview The study tests if giving cyclophosphamide, pentostatin, and anti-thymocyte globulin before transplanting stem cells from a half-matched donor can be safe and work well for treating severe aplastic anemia. It aims to prepare the body for new cells and reduce disease complications.

How Is the Trial Designed?

Group I: Treatment (conditioning, haploHCT) Experimental Treatment 8 Interventions

Patients receive cyclophosphamide PO and IV, pentostatin IV, anti-thymocyte globulin IV and undergo CD4+ T-cell depleted haploHCT on study. Patients also undergo bone marrow aspirate, bone marrow biopsy, and collection of blood samples at screening and follow-up.

Anti-Thymocyte Globulin is already approved in European Union, United States for the following indications:

Approved in European Union as Thymoglobulin for:

• Prevention and treatment of acute rejection following organ transplantation
• Severe aplastic anemia

Approved in United States as Thymoglobulin for:

• Prevention and treatment of acute rejection following kidney transplantation
• Severe aplastic anemia

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Bone marrow transplantation is typically the first-line treatment for severe aplastic anemia, but this study suggests it may also be beneficial for patients with moderately severe aplastic anemia who do not respond to standard treatments.

The successful use of rabbit anti-human thymocyte globulin in a patient who previously failed treatment with equine anti-human lymphocyte globulin indicates that this approach could expand treatment options for non-severe aplastic anemia patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful bone marrow transplantation with rabbit anti-human thymocyte globulin in aplastic anemia. Report of a case previously treated with equine anti-human lymphocyte globulin. Yoshida, Y., Ichinoe, T., Dodo, M., et al.[2006]

In a randomized trial involving 120 patients with severe acquired aplastic anemia, horse ATG was found to be significantly more effective than rabbit ATG, with a hematologic response rate of 68% compared to 37% at 6 months.

Overall survival rates were also higher in the horse ATG group, with a 3-year survival rate of 96% compared to 76% for the rabbit ATG group, indicating that horse ATG is the preferred treatment option for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. Scheinberg, P., Nunez, O., Weinstein, B., et al.[2022]

Rabbit-derived antithymocyte globulin (ATG) can induce a strong immune response in patients, leading to the production of antibodies against specific rabbit glycoprotein epitopes, which may compromise its effectiveness in treating conditions like type 1 diabetes.

The study found that patients developed significant levels of antibodies against these rabbit-specific epitopes after ATG treatment, suggesting that using IgGs without these xenoantigens could enhance the safety and efficacy of ATG therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-Gal and Anti-Neu5Gc Responses in Nonimmunosuppressed Patients After Treatment With Rabbit Antithymocyte Polyclonal IgGs. Salama, A., Evanno, G., Lim, N., 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 study of 29 patients receiving anti-thymocyte globulin (ATG) and anti-lymphocyte globulin (ALG) for aplastic anemia, 62.1% experienced adverse effects, with fever being the most common.

ATG, which is rabbit-derived, was associated with more frequent adverse effects compared to ALG, and shorter intervals between treatment cycles increased the risk of these reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Adverse effects of anti-thymocyte globulin/anti-lymphocyte globulin therapy]. Kobayashi, R., Kaneda, M., Watanabe, N., et al.[2006]

In a study of 24 patients with aplastic anemia, the survival rates at 6 months varied among different anti-thymocyte globulin (ATG) preparations, with Lymphoglobulin showing the highest survival rate at 77.8%.

None of the patients treated with ATG-Fresenius (ATG-F) responded to the treatment, indicating it is significantly less effective and should not be used for severe aplastic anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of Jurkat cell-reactive anti-T lymphocyte globulin and fetal anti-thymocyte globulin preparations in the treatment of aplastic anemia. Serefhanoglu, S., Buyukasik, Y., Purnak, T., et al.[2011]

In a study of 75 patients with severe aplastic anemia, porcine antithymocyte globulin (ALG) demonstrated a significantly higher overall response rate at 6 months (79.07%) compared to rabbit antithymocyte globulin (ATG) (56.25%).

While porcine ALG showed better hematological response, both treatments had comparable long-term survival rates, indicating that porcine ALG may be a more effective option for initial treatment without compromising safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Therapeutic effects of porcine versus rabbit antithymocyte globulins for treatment of severe aplastic anemia]. Yang, N., Ma, XR., Zhang, H., et al.[2018]

In a study of 30 patients undergoing allogeneic hematopoietic stem cell transplantation, Thymoglobulin and ATG-F showed comparable outcomes in terms of overall survival, disease-free survival, and transplant-related complications after a median follow-up of 3.3 years.

Although adverse events were more frequently reported during Thymoglobulin infusion, the difference was not statistically significant, suggesting that both treatments are similarly safe and effective for preventing graft-versus-host disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing Two Types of Rabbit ATG prior to Reduced Intensity Conditioning Allogeneic Hematopoietic SCT for Hematologic Malignancies. Paiano, S., Roosnek, E., Tirefort, Y., et al.[2020]

Antithymocyte globulin (ATG) is an effective standard treatment for aplastic anemia, improving survival rates and response rates between 40% and 70%.

While mild side effects are common with ATG, recurrent seizures are a rare but serious concern associated with its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antithymocyte globulin induced recurrent seizures in a case of severe aplastic anemia. Sharma, SK., Singh, PK., Seth, T., et al.[2021]

In a study involving five patients with severe aplastic anemia, a conditioning regimen of fludarabine, cyclophosphamide, and thymoglobulin resulted in complete donor type hematologic recovery for all participants, indicating high efficacy for bone marrow transplantation.

The combination treatment showed minimal complications, with only one case of mild acute graft-versus-host disease (GVHD) and no serious complications, suggesting a favorable safety profile for this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen for unrelated bone marrow transplantation in severe aplastic anemia. Kang, HJ., Shin, HY., Choi, HS., et al.[2013]

Antithymocyte immunoglobulin (ATG) is an effective immunosuppressive treatment for severe aplastic anemia (SAA), showing a response rate of 40-70%, especially when combined with cyclosporine.

Bone marrow transplantation (BMT) remains the preferred treatment for eligible patients with SAA, offering a high long-term survival rate of 75-90%, despite initial treatment-related risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antithymocyte immunoglobulin in severe aplastic anemia and bone marrow transplantation. Colby, C., Stoukides, CA., Spitzer, TR.[2017]

In a study comparing two doses of antithymocyte globulin (7.5 mg/kg vs 10 mg/kg) in patients undergoing haploidentical hematopoietic stem cell transplantation, both doses showed similar effectiveness in preventing graft-versus-host disease, with no significant differences in acute or chronic cases.

The lower dose of 7.5 mg/kg was associated with a trend towards a reduced incidence of hemorrhagic cystitis compared to the higher dose, suggesting it may be a safer option without compromising efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of 2 Different Doses of Antithymocyte Globulin in Conditioning Regimens for Haploidentical Hematopoietic Stem Cell Transplantation. Wang, M., Fang, X., Jiang, Y., et al.[2022]

In a study of 352 patients undergoing HLA-mismatched allogeneic hematopoietic stem cell transplantation, low to medium doses of rabbit anti-thymocyte globulin (ATG) (2.5 to 7.5 mg/kg) were associated with higher 5-year overall survival rates compared to other doses.

Patients receiving low to medium doses of ATG also experienced lower rates of extensive chronic graft-versus-host disease (ecGVHD), suggesting that these doses improve patient outcomes without increasing relapse rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical impact of anti-thymocyte globulin on survival and graft-versus-host disease in patients undergoing human leukocyte antigen mismatched allogeneic stem cell transplantation. Kim, T., Choi, Y., Lee, JH., et al.[2021]

Citations

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2. nejm.org nejm.org/doi/full/10.1056/NEJMoa1103975

Horse versus Rabbit Antithymocyte Globulin in Acquired ... In a randomized study, rabbit ATG was inferior to horse ATG as a first treatment for severe aplastic anemia, as indicated by hematologic response and survival.

3. haematologica.org haematologica.org/article/view/6063

Efficacy of rabbit anti-thymocyte globulin in severe aplastic ... Response rates at 3, 6 and 12 months were similar for patients treated with rabbit anti-thymocyte globulin or horse anti-thymocyte globulin: 40% ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0301472X14008133

Rabbit antithymocyte globulin as first-line therapy for ... Five-year overall survival was 83.2%, and the 5-year, event-free survival was 67.2%. Independent prognostic factors for overall survival were neutrophil count ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3971076/

Long-term outcome after immunosuppressive therapy with ... Some prospective studies showed that rabbit antithymocyte globulin was inferior to horse antithymocyte globulin as first-line therapy for patients with severe ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12283839/

Efficacy and safety of rabbit ATLG and ATG in allogeneic ... Without timely treatment, it frequently proves fatal. Rabbit anti-thymocyte globulin (ATG) and anti-human T lymphocyte globulin (ATLG) are ...

7. frontiersin.org frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.889784/full

Retrospective Comparison of Efficacy and Safety of Rabbit ... We compared the efficacy and safety of porcine anti-lymphocyte globulin (pALG) (n=140) and rabbit anti-thymocyte globulin (rATG) (n=86) in patients with ...