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

Trial Summary

What is the purpose of this trial?

This phase I trial evaluates the safety and feasibility of using a reduced-intensity regimen of cyclophosphamide, pentostatin, and anti-thymocyte globulin prior to a CD4+ T-cell depleted haploidentical hematopoietic cell transplant (haploHCT) for the treatment of patients with severe aplastic anemia that does not respond to treatment (refractory) or that has come back (recurrent). Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's deoxyribonucleic acid. It may also lower the body's immune response. Pentostatin blocks a protein needed for cell growth. Anti-thymocyte globulin is an immunosuppressive drug can destroy immune cells known as T-cells. HaploHCT transfers blood-forming stem cells from a healthy partially-matched donor to a patient. Administering a regimen of cyclophosphamide, pentostatin, and anti-thymocyte globulin before haploHCT may help make room for the new, healthy cells and may reduce the risk of graft versus host disease.

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.

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

Research shows that antithymocyte globulin (ATG), particularly thymoglobulin, is effective in preventing complications like graft-versus-host disease (a condition where the donor cells attack the recipient's body) and ensuring successful engraftment (when donor cells start to grow and make healthy blood cells) in bone marrow transplants for severe aplastic anemia. Studies indicate that ATG improves survival rates, with response rates between 40% and 70%. ^{1 2 3 4 5}

Is stem cell transplant with antithymocyte globulin safe for humans?

Antithymocyte globulin (ATG) is used in stem cell transplants to prevent complications, but it can cause side effects like fever and serum sickness (a reaction to foreign proteins). In some studies, adverse effects occurred in about 62% of patients, and severe reactions led to stopping treatment in about 11% of cases. ^{1 6 7 8 9}

How is the treatment for aplastic anemia using stem cell transplant and anti-thymocyte globulin different from other treatments?

This treatment is unique because it combines a stem cell transplant from a partially matched donor with rabbit anti-thymocyte globulin (ATG), which is more effective in depleting immune cells that attack the bone marrow, potentially leading to better outcomes in patients who do not respond to standard therapies. ^{2 10 11 12 13}

Research Team

Ryotaro Nakamura, M.D.

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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 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 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]

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 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 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]

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]

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]

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]

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]

References

1. Turkey pubmed.ncbi.nlm.nih.gov

Comparison of 2 Different Doses of Antithymocyte Globulin in Conditioning Regimens for Haploidentical Hematopoietic Stem Cell Transplantation. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen for unrelated bone marrow transplantation in severe aplastic anemia. [2013]

3. Switzerland 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. [2011]

4. India pubmed.ncbi.nlm.nih.gov

Antithymocyte globulin induced recurrent seizures in a case of severe aplastic anemia. [2021]

5. China pubmed.ncbi.nlm.nih.gov

[Therapeutic effects of porcine versus rabbit antithymocyte globulins for treatment of severe aplastic anemia]. [2018]

6. Korea (South) 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. [2021]

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

Anti-Gal and Anti-Neu5Gc Responses in Nonimmunosuppressed Patients After Treatment With Rabbit Antithymocyte Polyclonal IgGs. [2022]

8. Japan pubmed.ncbi.nlm.nih.gov

[Adverse effects of anti-thymocyte globulin/anti-lymphocyte globulin therapy]. [2006]

9. Egypt pubmed.ncbi.nlm.nih.gov

Comparing Two Types of Rabbit ATG prior to Reduced Intensity Conditioning Allogeneic Hematopoietic SCT for Hematologic Malignancies. [2020]

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

Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. [2022]

11. Italy pubmed.ncbi.nlm.nih.gov

Efficacy of rabbit anti-thymocyte globulin in severe aplastic anemia. [2021]

12. Japan 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. [2006]

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

Antithymocyte immunoglobulin in severe aplastic anemia and bone marrow transplantation. [2017]