IST + BMT for Aplastic Anemia

(TransIT Trial)

Recruiting at 50 trial locations

Overseen by Bronwen Shaw, MD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Boston Children's Hospital

Must not be taking: Androgens, Eltrombopag, Romiplostim, others

Disqualifiers: Inherited bone marrow syndromes, MDS, HIV, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

Severe Aplastic Anemia (SAA) is a rare condition in which the body stops producing enough new blood cells. SAA can be cured with immune suppressive therapy or a bone marrow transplant. Regular treatment for patients with aplastic anemia who have a matched sibling (brother or sister), or family donor is a bone marrow transplant. Patients without a matched family donor normally are treated with immune suppressive therapy (IST). Match unrelated donor (URD) bone marrow transplant (BMT) is used as a secondary treatment in patients who did not get better with IST, had their disease come back, or a new worse disease replaced it (like leukemia). This trial will compare time from randomization to failure of treatment or death from any cause of IST versus URD BMT when used as initial therapy to treat SAA. The trial will also assess whether health-related quality of life and early markers of fertility differ between those randomized to URD BMT or IST, as well as assess the presence of marrow failure-related genes and presence of gene mutations associated with MDS or leukemia and the change in gene signatures after treatment in both study arms. This study treatment does not include any investigational drugs. The medicines and procedures in this study are standard for treatment of SAA.

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

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have had disease-modifying treatments like androgens, eltrombopag, romiplostim, or immune suppression before enrolling. Supportive care like G-CSF, blood transfusions, and antibiotics are allowed.

What data supports the idea that IST + BMT for Aplastic Anemia is an effective treatment?

The available research shows that the combination of IST (immunosuppressive therapy) and BMT (bone marrow transplant) for Aplastic Anemia is effective. In one study, five patients who received this treatment had complete recovery of blood cell production from the donor's bone marrow, and four out of five patients were still alive after a median of 566 days. Another study with 28 patients showed a survival rate of about 68%, indicating that the treatment can be successful, although there were some treatment-related complications. These studies suggest that IST + BMT can lead to good outcomes for patients with Aplastic Anemia. ^{1 2 3 4 5}

What safety data is available for IST + BMT treatment in aplastic anemia?

The safety data for IST + BMT treatment in aplastic anemia includes studies showing that the combination of fludarabine, cyclophosphamide, and thymoglobulin in conditioning regimens is effective in achieving good engraftment with tolerable toxicity and minimal GVHD. In one study, five patients underwent BMT with this regimen, and all achieved complete donor-type hematologic recovery with no serious complications. Another study compared different ATG preparations, finding that Thymoglobulin had stronger immunosuppressive activity but was associated with delayed T-cell recovery and higher cytomegalovirus antigenemia. Overall, the use of Thymoglobulin and ATG-F in conditioning regimens showed comparable outcomes in terms of survival, relapse, and transplant-related mortality, although adverse events were more frequent with Thymoglobulin. These findings suggest that the treatment is generally safe with manageable side effects. ^{1 2 3 5 6}

Is the drug combination of Cyclophosphamide, Fludarabine, and Anti-Thymocyte Globulin (ATG) a promising treatment for Aplastic Anemia?

Yes, the combination of Cyclophosphamide, Fludarabine, and Anti-Thymocyte Globulin (ATG) is promising for treating Aplastic Anemia. It has shown good results in helping patients recover blood cell production and has a low risk of serious complications. Many patients have successfully recovered and remained disease-free for years after treatment. ^{1 4 7 8 9}

Research Team

David Williams, MD

Principal Investigator

Boston Children's Hospital

Michael Pulsipher, MD

Principal Investigator

University of Utah

Bronwen Shaw, MD

Principal Investigator

CIBMTR/Medical College of Wisconsin (MCW)

Eligibility Criteria

This trial is for young patients (25 years or younger) with severe aplastic anemia without a matched family bone marrow donor. They must have specific blood cell counts, at least two potential unrelated donors, and no contraindications to bone marrow transplant or immune suppressive therapy. Exclusions include inherited syndromes, prior transplants, certain infections like HIV, pregnancy, breastfeeding, and previous disease-modifying treatments.

Inclusion Criteria

I am 25 years old or younger.

I have severe aplastic anemia with specific blood counts, no matched family donor, but potential unrelated donors.

Provision of signed and dated informed consent form for the randomized trial by patient and/or legal guardian

Exclusion Criteria

Presence of Inherited bone marrow failure syndromes (IBMFS); Clonal cytogenetic abnormalities or Fluorescence In-Situ Hybridization (FISH) pattern consistent with pre- myelodysplastic syndrome (pre-MDS) or MDS on marrow examination; Known severe allergy to ATG; Prior allogeneic or autologous stem cell transplant; Prior solid organ transplant; Infection with human immunodeficiency virus (HIV); Active Hepatitis B or C; Female patients who are pregnant or breast-feeding; Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ; Disease modifying treatment prior to study enrollment, including but not limited to use of androgens, eltrombopag, romiplostim, or immune suppression

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to receive either immune suppressive therapy (IST) or matched unrelated donor bone marrow transplantation (BMT) as initial therapy for severe aplastic anemia.

Up to 2 years

Follow-up

Participants are monitored for safety, effectiveness, and long-term outcomes, including survival and quality of life.

3-5 years

Treatment Details

Interventions

• Cyclophosphamide (Alkylating Agent)
• Fludarabine (Anti-metabolite)
• Horse Anti-Thymocyte Globulin (ATG) (Antibody)
• Low-dose Total Body Irradiation (TBI) (Radiation Therapy)
• Matched Unrelated Donor Hematopoietic Stem Cell Transplant (Hematopoietic Stem Cell Transplant)
• Methotrexate (Immunosuppressant)
• Rabbit Anti-Thymocyte Globulin (ATG) (Antibody)

Trial Overview The study compares initial treatment of severe aplastic anemia using either immune suppressive therapy (IST) or a bone marrow transplant from an unrelated donor (URD BMT). It will measure the time until treatment failure or death and examine quality of life, fertility markers, genetic factors related to marrow failure and changes after treatment.

Participant Groups

Group I: Immunosuppressive Therapy Active Control 3 Interventions

Patient will receive standard immunosuppressive therapy combination of drugs: horse anti-thymocyte globulin (ATG) and cyclosporine.

Group II: Matched Unrelated Stem Cell Transplant Active Control 7 Interventions

Patient will under go matched unrelated donor transplant of hematopoietic stem cells as their therapy using fludarabine, cyclophosphamide, rabbit anti-thymocyte globulin (ATG), and low-dose total body irradiation (TBI) as preparative regimen and cyclosporine and methotrexate for graft versus host disease (GVHD) prevention.

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?

Boston Children's Hospital

Lead Sponsor

Trials

801

Recruited

5,584,000+

Pediatric Transplantation and Cellular Therapy Consortium

Collaborator

Trials

1

Recruited

230+

Pediatric Transplantation and Cellular Therapy Consortium

Collaborator

Trials

1

Recruited

230+

Center for International Blood and Marrow Transplant Research

Collaborator

Trials

40

Recruited

200,190,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

North American Pediatric Aplastic Anemia Consortium

Collaborator

Trials

1

Recruited

230+

Blood and Marrow Transplant Clinical Trials Network

Collaborator

Trials

51

Recruited

14,600+

Findings from Research

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 phase II study involving 16 patients with hematologic malignancies, the addition of rabbit antithymocyte globulin (rATG) to the fludarabine and busulfan conditioning regimen showed low rates of acute and chronic graft versus host disease (GvHD), which is a positive safety outcome.

The study found significant interpatient variability in pharmacologic biomarkers related to busulfan and fludarabine, suggesting that further research is needed to optimize the conditioning regimen for better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients. McCune, JS., Woodahl, EL., Furlong, T., et al.[2021]

In a phase II clinical trial involving 28 patients with severe aplastic anemia, a conditioning regimen of fludarabine, cyclophosphamide, and thymoglobulin led to successful donor-type hematologic recovery in all participants, indicating effective engraftment.

Despite the promising engraftment results, the study reported a high treatment-related mortality rate of 67.9%, with complications such as thrombotic microangiopathy and chronic GVHD, highlighting the need for further research to reduce these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful engraftment with fludarabine, cyclophosphamide, and thymoglobulin conditioning regimen in unrelated transplantation for severe aplastic anemia: A phase II prospective multicenter study. Kang, HJ., Shin, HY., Park, JE., et al.[2017]

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 study of 1170 adult patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia undergoing allogeneic stem cell transplantation, the use of anti-thymocyte globulin (ATG) significantly reduced the incidence of chronic graft-versus-host disease (GVHD) from 52% to 35%.

While ATG treatment improved outcomes related to GVHD and overall survival free from GVHD and relapse, it was associated with an increased risk of relapse, indicating the need for careful monitoring of patients post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of anti-thymocyte globulin on results of allogeneic peripheral blood stem cell transplantation for patients with Philadelphia-positive acute lymphoblastic leukaemia: An analysis by the Acute Leukemia Working Party of the EBMT. Giebel, S., Labopin, M., Czerw, T., et al.[2020]

This case study provides the first pharmacokinetic analysis of anti-thymocyte globulin (ATG) in a 38-year-old woman with severe aplastic anemia undergoing bone marrow transplantation, showing effective engraftment and lymphocyte recovery without complications.

The patient achieved successful long-term outcomes, remaining disease-free for 6 years post-transplant, suggesting that a reduced-dose ATG regimen can be safely administered in conjunction with a fludarabine-based conditioning regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of anti-thymocyte globulin in a patient with severe aplastic anemia treated with allogeneic bone marrow transplantation from a matched unrelated donor. Kawano, N., Matsumoto, K., Takami, A., et al.[2023]

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 of 78 patients with severe aplastic anemia, the combination of anti-human thymocyte immunoglobulin (ATG-F) and cyclosporin A (CsA) achieved a 100% effective rate, demonstrating its efficacy in treating the condition.

The combination therapy also significantly shortened the time for patients to show improvement compared to ATG-F alone, indicating a faster response to treatment while maintaining a reliable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of Rabbit Anti-human Thymocyte Immunoglobulin Combined with Cyclosporin A on Severe Aplastic Anemia]. Luo, W., Ji, LH., Geng, H., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

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

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

The effect of different ATG preparations on immune recovery after allogeneic hematopoietic stem cell transplantation for severe aplastic anemia. [2010]

3. Germany pubmed.ncbi.nlm.nih.gov

A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients. [2021]

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

Successful engraftment with fludarabine, cyclophosphamide, and thymoglobulin conditioning regimen in unrelated transplantation for severe aplastic anemia: A phase II prospective multicenter study. [2017]

5. Egypt pubmed.ncbi.nlm.nih.gov

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

6. England pubmed.ncbi.nlm.nih.gov

Impact of anti-thymocyte globulin on results of allogeneic peripheral blood stem cell transplantation for patients with Philadelphia-positive acute lymphoblastic leukaemia: An analysis by the Acute Leukemia Working Party of the EBMT. [2020]

7. Japan pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of anti-thymocyte globulin in a patient with severe aplastic anemia treated with allogeneic bone marrow transplantation from a matched unrelated donor. [2023]

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

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

9. China pubmed.ncbi.nlm.nih.gov

[Effect of Rabbit Anti-human Thymocyte Immunoglobulin Combined with Cyclosporin A on Severe Aplastic Anemia]. [2018]