Stem Cell Transplant for Severe Aplastic Anemia

Recruiting at 6 trial locations

Overseen By Jennifer A Farren

Age: Any Age

Sex: Any

Trial Phase: Phase 2

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

Disqualifiers: Organ failure, Pregnancy, Active infection, 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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method for performing stem cell transplants in individuals with severe blood disorders like aplastic anemia. The researchers aim to make the transplant process safer by adjusting how stem cells are collected and used, potentially reducing serious side effects. Individuals with severe blood conditions requiring stem cell treatment, who rely on blood transfusions or frequently experience low blood counts, might be suitable candidates for this trial. Participants will receive a combination of medications and an allogeneic hematopoietic stem cell transplant (a type of donor stem cell transplant) to evaluate the effectiveness of the new method. As a Phase 2 trial, this research focuses on assessing the treatment's efficacy in an initial, smaller group of participants.

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, you will receive specific medications to prepare for the transplant and to prevent rejection, so it's best to discuss your current medications with the trial team.

What prior data suggests that this stem cell transplant method is safe?

Research has shown that using donor stem cells for transplants offers promising safety results for treating severe aplastic anemia. In one study, all patients survived, and only two experienced mild chronic graft-versus-host disease (GVHD). GVHD occurs when the donor's cells attack the patient's body, but the treatment appears generally well-tolerated.

Another study found that survival rates have improved significantly in recent years, ranging from 70% to 90%. Although complications like GVHD can occur, the new method aims to reduce these risks by altering the stem cell donation process. This approach might lower the chance of severe side effects or rejection. Overall, evidence suggests that while risks remain, the treatment has become safer and more effective over time. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using allogeneic hematopoietic stem cell transplantation for severe aplastic anemia because it offers a fresh approach compared to standard treatments like immunosuppressive therapy. Most conventional treatments focus on suppressing the immune system to manage symptoms, but this transplant aims to replace the faulty bone marrow with healthy stem cells from a donor. This has the potential to not only alleviate symptoms but also address the root cause by restoring normal blood cell production. By directly targeting the underlying issue, this method could provide a more lasting and effective solution for patients suffering from this condition.

What evidence suggests that this method of stem cell transplantation could be effective for severe aplastic anemia?

Research has shown that using stem cells from a donor, specifically through Allogeneic Hematopoietic Stem Cell Transplantation, can effectively treat severe aplastic anemia, a condition where the bone marrow doesn't produce enough blood cells. Studies have found that this type of transplant can cure nearly 90% of patients with this condition. In another study, patients who received this transplant had a 3-year survival rate of about 72%. Evidence-based guidelines also support this treatment as a possible cure for severe aplastic anemia. While the treatment can have serious side effects, the trial aims to lower these risks by adjusting the mix of white blood cells used in the transplant. Participants in this trial will receive the experimental treatment with targeted doses of CD34+ and CD3+ cells. ^{1 6 7 8 9}

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 4-80 with severe blood diseases treatable by stem cell transplants, like severe anemia. They must weigh over 18kg and have a related donor or a matched unrelated donor available. It's not suitable for those who could be at high risk from traditional bone marrow transplants.

Inclusion Criteria

Recipient: Patients diagnosed with one of the following hematologic diseases which are associated with reasonable longevity, shown to be curable by allogeneic BMT but where concern for a high procedural mortality with conventional BMT may delay or prevent such treatment: 1) Paroxysmal nocturnal hemoglobinuria (PNH) associated with life-threatening thrombosis, and/or cytopenia, and/or transfusion dependence and/or recurrent and debilitating hemolytic crisis 2) Severe aplastic anemia (SAA) or pure red cell aplasia (PRCA [acquired or congenital]) associated with transfusion dependence and/or neutropenia in patients who are not candidates for, or who have failed immunosuppressive therapy 3) Refractory anemia (RA) or RARS MDS patients who have associated transfusion dependence and/or neutropenia. Ages 4 to 80 (both inclusive), and weight >18kg Availability of HLA identical or single HLA locus mismatched family donor or 10/10 matched unrelated donor at the allelic level (HLA alleles A, B, C, DR, and DQ). 9/10 donors where all the HLA sequences have the same antigen/peptide binding domains in key exons to the patient. This can result in identical protein sequences between patient and donor. Allele mismatches in p and g groups can be considered acceptable due to the exact matching which exists in the binding domains. Telomere Length Testing Germline/Inherited gene panel in patients where a suspicion for a familial bone marrow failure syndrome (BMFS) exists, hTERC and hTERT, GATA2 mutation testing will be performed on protocol 04-H-0012 or performed elsewhere prior to enrolling on 04-H-0012.

Exclusion Criteria

Related Donor: None

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 Conditioning

Participants receive cyclophosphamide, fludarabine, and anti-thymocyte globulin to suppress their immune system and prepare for the transplant

1 week

Inpatient care

Transplantation

Participants receive the donated white blood cells and stem cells as a single infusion

1 day

Inpatient care

Post-transplant Care

Participants receive cyclosporine and methotrexate to prevent rejection of the donor cells

4 months

Regular visits

Follow-up

Participants are monitored for safety and effectiveness after treatment, with regular visits for up to 3 years and periodic visits thereafter

3 years

Regular visits

What Are the Treatments Tested in This Trial?

Interventions

• Allogeneic Hematopoietic Stem Cell Transplantation

Trial Overview The study tests a new stem cell transplant method using G-CSF mobilized CD34+ cells combined with fewer non-mobilized white blood cells to potentially reduce complications. Donors give white blood cells and then stem cells after filgrastim injections; recipients get chemotherapy before the infusion.

How Is the Trial Designed?

Group I: 1 Experimental Treatment 2 Interventions

Target doses: CD34+ cells 8 x 106/kg; CD3+ cells 2 x 107/kg

Group II: 2 Active Control 1 Intervention

Donor

Allogeneic Hematopoietic Stem Cell Transplantation is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Allogeneic Hematopoietic Stem Cell Transplantation for:

• Primary immunodeficiency disorders
• Immune dysregulatory disorders
• Hemophagocytic lymphohistiocytosis
• Bone marrow failure syndromes
• Hemoglobinopathies

Approved in United States as Allogeneic Hematopoietic Stem Cell Transplantation for:

• Primary immunodeficiency disorders
• Immune dysregulatory disorders
• Hemophagocytic lymphohistiocytosis
• Bone marrow failure syndromes
• Hemoglobinopathies

Approved in Canada as Allogeneic Hematopoietic Stem Cell Transplantation for:

• Primary immunodeficiency disorders
• Immune dysregulatory disorders
• Hemophagocytic lymphohistiocytosis
• Bone marrow failure syndromes
• Hemoglobinopathies

Approved in Japan as Allogeneic Hematopoietic Stem Cell Transplantation for:

• Primary immunodeficiency disorders
• Immune dysregulatory disorders
• Hemophagocytic lymphohistiocytosis
• Bone marrow failure syndromes
• Hemoglobinopathies

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

Haploidentical allogeneic hemopoietic stem cell transplantation (allo-HSCT) was found to be safe and effective for treating severe aplastic anemia (SAA) in 8 patients, with successful hematopoietic reconstitution achieved in all cases within an average of 14.8 days for neutrophils and 15.0 days for platelets.

While complications such as acute graft versus host disease (aGVHD) occurred in 7 patients, no severe complications like veno-occlusive disease or hemorrhagic cystitis were reported, and there were no transplantation-related deaths during a median follow-up of 8.5 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical applications of haploidentical hematopoietic stem cell transplantation in severe aplastic anemia. Zhang, P., Feng, K., Xue, Y., et al.[2018]

Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective curative treatment for various hematological and genetic diseases, but it can lead to both early and late complications.

A case study of a 49-year-old patient with acute myeloid leukemia (AML) highlighted the occurrence of acute graft versus host disease (GvHD) and late complications such as chronic GvHD, infections, cataracts, and secondary malignancies, emphasizing the need for awareness and education regarding these risks post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early and Late Complications in Patients with Allogeneic Transplantation of Hematopoietic Stem Cell - Case Report. Trajkovska, I., Georgievski, B., Cevreska, L., et al.[2020]

Allogeneic hematopoietic stem cell transplantation (HSCT) can potentially replace a diseased immune system with healthy donor cells, showing promise in treating conditions like severe aplastic anemia and autoimmune diseases, but results can vary widely with both complete remissions and treatment failures reported.

Despite its potential benefits, allogeneic HSCT is associated with significant risks, including morbidity and mortality, leading to the conclusion that it cannot be generally recommended without further carefully conducted studies to identify the best patient populations and treatment technologies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic stem cell transplantation for severe autoimmune diseases. Gratwohl, A.[2009]

HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a safe and effective treatment for hepatitis-related aplastic anemia (HRAA), with a 2-year overall survival rate of 81.4% based on a study of 28 patients.

While haplo-HSCT showed a higher incidence of cytomegaloviremia compared to matched sibling donor transplants (MSD-HSCT), it did not result in significant differences in overall survival or transplant-related mortality, making it a viable option for patients without HLA-matched donors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of allogeneic hematopoietic stem cell transplantation in the treatment of 28 patients with hepatitis-related aplastic anemia]. Wang, Y., Li, J., Pang, AM., et al.[2023]

Early intervention with bone marrow transplantation can cure up to 80% of patients with severe aplastic anemia, highlighting the importance of timely treatment.

Intensive immunosuppression can also effectively rescue many patients, but both treatment options must be initiated before complications like infection and bleeding arise.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Severe aplastic anemia]. Hinterberger, W.[2021]

In a study involving 15 patients with severe aplastic anemia (SAA), high-dose allogeneic hematopoietic stem cell transplantation (allo-HSCT) using G-CSF mobilized peripheral blood and bone marrow stem cells from HLA-identical siblings resulted in successful bone marrow engraftment for all patients, with only one case of late rejection.

The treatment showed a promising safety profile, with no acute graft-versus-host disease (GVHD) observed and a low incidence of chronic GVHD at 6.67%, alongside a high three-year disease-free survival rate of 79.8%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HLA-matched sibling transplantation with G-CSF mobilized PBSCs and BM decreases GVHD in adult patients with severe aplastic anemia. Sun, ZM., Liu, HL., Geng, LQ., et al.[2021]

HLA-matched sibling donor transplantation for severe aplastic anemia has an approximately 80% survival rate in patients under 20 years old, but lower rates (50-70%) in older patients due to increased transplant-related risks.

Unrelated donor transplantation is an option for patients without a matched sibling donor, with improved survival rates attributed to better donor matching, although it carries higher risks of complications like graft-versus-host disease (GVHD) compared to sibling transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic transplantation for aplastic anemia. Eapen, M.[2012]

In a study of 41 patients undergoing allogeneic peripheral blood stem cell transplantation (PBSCT) for aplastic anemia, the median follow-up was 29 months, showing a 75.6% infection treatment rate and a 39% incidence of acute graft-versus-host disease (GVHD).

The use of a shortened course of antithymocyte globulin (ATGAM) and improved antifungal treatments contributed to a decrease in PBSCT-related mortality, highlighting the importance of early referrals for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Audit of peripheral stem cell transplantation for aplastic anemia in multitransfused infected patients. Seth, T., Kanga, U., Sood, P., et al.[2017]

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was effective in treating aplastic anemia, with 87.5% of patients achieving successful hematopoiesis reconstitution.

While the procedure showed promise, complications such as acute graft-versus-host disease (aGVHD) and graft rejection occurred, suggesting that improving immunosuppressive treatments could enhance outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Allogeneic hematopoietic stem cell transplantation for 16 patients with aplastic anemia]. Zhai, WH., Wang, M., Zhou, Z., et al.[2007]

Allogeneic stem cell transplantation (SCT) from well-matched unrelated donors (WM-URD) shows comparable overall survival rates to matched sibling donors (MSD) in adult patients with severe aplastic anemia (SAA), suggesting it can be considered a first-line treatment option.

However, patients receiving SCT from partially matched unrelated donors (PM-URD) had significantly lower survival rates and higher incidences of complications compared to both MSD and WM-URD groups, indicating that donor matching is crucial for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of HLA-matched sibling and unrelated donor transplantation in adult patients with acquired severe aplastic anemia. Shin, SH., Park, SS., Yoon, JH., et al.[2021]

In a study of 61 patients with aplastic anemia, unrelated allogeneic bone marrow transplantation (alloBMT) showed an overall survival rate of 86%, indicating it as a potentially life-saving option, especially for younger patients under 40 years old.

Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporin A (CsA) had a 71% overall survival rate, but was less effective than alloBMT, suggesting that IST is a suitable alternative when a compatible donor is not available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The use of allogeneic bone marrow transplantation and immunosuppressive therapy in the treatment of patients with acquired aplastic anemia]. Ganapiev, AA., Golubovskaia, IK., Zalialov, IuR., et al.[2021]

In a study involving six young patients (ages 18-26) with severe aplastic anemia, conditioning with alemtuzumab, fludarabine, and melphalan before allogeneic stem cell transplantation resulted in full donor chimerism and no severe complications such as graft failure or graft versus host disease after a median follow-up of 29 months.

The treatment was effective and safe, with only one case of recurrent parvovirus B19 infection, which was successfully managed, indicating that this conditioning regimen could be a viable option for patients with prolonged disease and multiple transfusions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab, fludarabine and melphalan as a conditioning therapy in severe aplastic anemia and hypoplastic myelodysplastic syndrome--single center experience. Rzepecki, P., Sarosiek, T., Szczylik, C.[2017]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9870683/

Allogeneic Hematopoietic Stem Cell Transplantation in ... Hematopoietic stem cell transplantation (HSCT) provides curative therapy in almost 90% of patients with severe aplastic anemia (SAA).

2. astctjournal.org astctjournal.org/article/S2666-6367(24)00682-1/fulltext

Evidence-Based Guidelines From the American Society for ... Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for severe aplastic anemia (SAA).

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11141667/

The outcome of allogeneic hematopoietic stem cell ... In this study, 55 patients undergoing allogeneic HSCT had HID, and their transplants resulted in a 3-year overall survival of 71.8%. Previously, the efficacy of ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2666636724006821

Guideline Allogeneic Hematopoietic Cell Transplantation ... The BMT CTN trial of Haplo-HCT for children and adults with relapsed or refractory SAA showed a 1-year OS of 81% (95% CI 62 to 91) [55]. Meta-analysis by Zhao ...

5. bloodresearch.or.kr bloodresearch.or.kr/journal/view.html?uid=2694&vmd=Full

Incidence and outcomes of subsequent malignancy after ... Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the most effective treatment for severe aplastic anemia (SAA), especially ...

6. ashpublications.org ashpublications.org/bloodadvances/article/9/17/4448/537898/Up-front-alternative-donor-HCT-in-severe-aplastic

Up-front alternative donor HCT in severe aplastic anemia Overall survival was 100%, and only 2 patients developed mild chronic GVHD. A follow-up Blood and Marrow Transplant Clinical Trials Network (BMT ...

7. astctjournal.org astctjournal.org/article/S1083-8791(12)00937-8/pdf

Outcome of Allogeneic Hematopoietic Stem Cell ... Six patients have expired, three of cGVHD complications in remission (3 with FDC) and three patients expired from progressive leukemia (2 with partial chimerism) ...

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1473050208001766

Allogeneic stem cell transplantation for severe aplastic ... We reviewed the outcome in 15 consecutive patients with severe aplastic anemia with a median age of 23 years who received matched sibling peripheral blood ...

9. frontiersin.org frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1378432/full

The state of the art in the treatment of severe aplastic anemia The outcomes of alloHCT in AA improved in the last decade with long-lasting OS reaching 70% to 90% (131). On the other hand, despite the improved response to ...