IST + BMT for Aplastic Anemia

(TransIT Trial)

Not currently recruiting at 55 trial locations

Overseen By Kristi Wilmes, MS

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Boston Children's Hospital

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

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

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine which treatment is more effective for people with severe aplastic anemia (SAA), a condition where the body stops producing enough blood cells. It compares immune suppressive therapy (IST) with a bone marrow transplant from a matched unrelated donor (URD BMT) as the initial treatment option. Participants will provide valuable insights into treatment success, quality of life, and potential effects on fertility. Individuals diagnosed with idiopathic SAA who lack a matched family donor but have unrelated donors available may be suitable for this study. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to potentially groundbreaking treatment advancements.

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.

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

Research has shown that both immunosuppressive therapy (IST) and matched unrelated donor bone marrow transplant (BMT) are generally safe for treating severe aplastic anemia (SAA).

In immunosuppressive therapy, patients typically receive a combination of medications, including horse anti-thymocyte globulin (ATG) and cyclosporine. Studies have found that most people tolerate these well. Some side effects, such as low blood counts or an increased risk of infections, can occur but are usually managed with additional care.

For a matched unrelated donor BMT, a mix of medications—fludarabine, cyclophosphamide, rabbit ATG, and low-dose total body irradiation (TBI)—prepares the body for the transplant. Research suggests that long-term survival rates with this type of transplant are similar to those with a matched sibling donor. Although side effects like graft-versus-host disease (GVHD) can occur, medications such as cyclosporine and methotrexate help prevent it.

Both treatments are standard for SAA and have been safely used in many patients. However, side effects are possible, so ongoing medical support remains important during and after treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for aplastic anemia because they explore innovative approaches beyond standard immunosuppressive therapy. The first treatment arm uses a combination of horse anti-thymocyte globulin (ATG) and cyclosporine, which is a well-established immunosuppressive strategy. The second arm introduces the potential of a matched unrelated donor hematopoietic stem cell transplant, which is prepared using a regimen of fludarabine, cyclophosphamide, rabbit ATG, and low-dose total body irradiation. This approach aims to provide a more robust and potentially curative option by replacing the faulty bone marrow with healthy stem cells. The use of rabbit ATG and low-dose TBI is particularly noteworthy as it may reduce the risk of graft versus host disease, offering a potentially safer and more effective treatment option.

What evidence suggests that this trial's treatments could be effective for severe aplastic anemia?

Research has shown that using stem cells from a matched unrelated donor, one of the treatment options in this trial, has become more successful in treating severe aplastic anemia in recent years. Studies have found that these transplants yield results similar to those from family donors, which are usually preferred. Thus, patients without a family donor still have a good chance of recovery with an unrelated donor. Alternatively, another treatment arm in this trial involves immunosuppressive therapy, which includes drugs like anti-thymocyte globulin and cyclosporine. This treatment has effectively controlled the condition and prevented further problems for many patients. Overall, both treatments offer good options for managing severe aplastic anemia in this trial. ^{1 3 5 6 7}

Who Is on the 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)

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Fludarabine
• Horse Anti-Thymocyte Globulin (ATG)
• Low-dose Total Body Irradiation (TBI)
• Matched Unrelated Donor Hematopoietic Stem Cell Transplant
• Methotrexate
• Rabbit Anti-Thymocyte Globulin (ATG)

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.

How Is the Trial Designed?

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 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?

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+

Published Research Related to This Trial

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 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]

In a study comparing two rabbit anti-thymocyte globulin (ATG) preparations, Thymoglobulin (ATG-G) showed stronger immunosuppressive effects than ATG-Fresenius (ATG-F), as evidenced by delayed recovery of CD4+ and CD8+ T-cells in patients receiving ATG-G.

Despite both preparations preventing graft rejection and acute graft-versus-host disease, ATG-G was associated with higher rates of cytomegalovirus infection, indicating a potential trade-off between immunosuppression and infection risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of different ATG preparations on immune recovery after allogeneic hematopoietic stem cell transplantation for severe aplastic anemia. Terasako, K., Sato, K., Sato, M., et al.[2010]

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 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2791933/

Unrelated donor stem cell transplantation in acquired ... Comparable outcomes of matched-related and alternative donor stem cell transplantation for pediatric severe aplastic anemia. Biol Blood Marrow Transplant.

2. astctjournal.org astctjournal.org/article/S1083-8791(19)30323-4/fulltext

The Case for Upfront HLA-Matched Unrelated Donor ... The improved success of HLA-matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) for severe aplastic anemia (SAA) in recent decades ...

3. ashpublications.org ashpublications.org/blood/article/144/3/323/515801/Alternative-donor-transplantation-for-severe

Alternative donor transplantation for severe aplastic anemia This study aims to compare transplant outcomes across the 3 donor types, MUDs, MMUDs, and Haplo donors, for patients with SAA. Although MUD and ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05600426

NCT05600426 | A Trial Comparing Unrelated Donor BMT ... This study is a multi-center randomized phase III trial to compare the failure free survival between those randomized to IST vs 9-10/10 HLA matched URD BMT.

5. sciencedirect.com sciencedirect.com/science/article/pii/S2666636723016792

Comparison of Stem Cell Transplantation Using Unrelated ... Allogeneic stem cell transplantation (allo-SCT) from HLA-matched sibling donors (MSDs) is the most preferred treatment for severe aplastic anemia (SAA) patients ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11405822/

Long-term survival after unrelated donor marrow ... We aimed to study long-term outcomes after unrelated donor transplantation for severe aplastic anaemia with de-escalation of cyclophosphamide (Cy) dose in ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9533334/

A joint pilot trial of the North American Pediatric Aplastic ... Recent data show survival after matched unrelated donor (MUD) bone marrow transplantation (BMT) is similar to matched sibling procedures for young patients ...