Stem Cell Transplant for Severe Aplastic Anemia

Recruiting in Palo Alto (17 mi)

+6 other locations

Overseen by Richard W Childs, M.D.

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

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

Disqualifiers: Organ failure, Pregnancy, Active infection, others

No Placebo Group

Prior Safety Data

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

Background: * Stem cell transplants from related donors (allogenic stem cell transplants) can be used to treat individuals with certain kinds of severe blood diseases or cancers, such as severe anemia. Allogenic stem cell transplants encourage the growth of new bone marrow to replace that of the recipient. Because stem cell transplants can have serious complications, researchers are interested in developing new approaches to stem cell transplants that will reduce the likelihood of these complications. * By reducing the number of white blood cells included in the blood taken during the stem cell collection process, and replacing them with a smaller amount of white blood cells collected prior to stem cell donation, the stem cell transplant may be less likely to cause severe complications for the recipient. Researchers are investigating whether altering the stem cell transplant donation procedure in this manner will improve the likelihood of a successful stem cell transplant with fewer complications. Objectives: - To evaluate a new method of stem cell transplantation that may reduce the possibly of severe side effects or transplant rejection in the recipient. Eligibility: * Recipient: Individuals between 4 and 80 years of age who have been diagnosed with a blood disease that can be treated with allogenic stem cell transplants. * Donor: Individuals between 4 and 80 years of age who are related to the recipient and are eligible to donate blood. OR unrelated donors found through the National Marrow Donor Program. Design: * All participants will be screened with a physical examination and medical history. * DONORS: * Donors will undergo an initial apheresis procedure to donate white blood cells. * After the initial donation, donors will receive injections of filgrastim to release bone marrow cells into the blood. * After 5 days of filgrastim injections, donors will have apheresis again to donate stem cells that are present in the blood. * RECIPIENTS: * Recipients will provide an initial donation of white blood cells to be used for research purposes only. * From 7 days before the stem cell transplant, participants will be admitted to the inpatient unit of the National Institutes of Health Clinical Center and will receive regular doses of cyclophosphamide, fludarabine, and anti-thymocyte globulin to suppress their immune system and prepare for the transplant. * After the initial chemotherapy, participants will receive the donated white blood cells and stem cells as a single infusion. * After the stem cell and white blood cell transplant, participants will have regular doses of cyclosporine and methotrexate to prevent rejection of the donor cells. Participants will have three doses of methotrexate within the week after the transplant, but will continue to take cyclosporine for up to 4 months after the transplant. * Participants will remain in inpatient care for up to 1 month after the transplant, and will be followed with regular visits for up to 3 years with periodic visits thereafter to evaluate the success of the transplant and any side effects.

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 data supports the effectiveness of the treatment Allogeneic Hematopoietic Stem Cell Transplantation for severe aplastic anemia?

Research shows that allogeneic hematopoietic stem cell transplantation is an effective treatment for severe aplastic anemia, especially in young patients. It has been found to improve outcomes, although challenges like graft failure and graft-versus-host disease (when the donor cells attack the recipient's body) can occur. ^{1 2 3 4 5}

Is stem cell transplant safe for severe aplastic anemia?

Stem cell transplants for severe aplastic anemia can be safe, but they come with risks like graft failure and graft-versus-host disease (when the donor cells attack the recipient's body). Some studies show good survival rates, but there are still significant risks, including infections and other complications. ^{5 6 7 8 9}

How is the treatment Allogeneic Hematopoietic Stem Cell Transplantation unique for severe aplastic anemia?

Allogeneic Hematopoietic Stem Cell Transplantation is unique because it can potentially cure severe aplastic anemia by replacing the patient's damaged bone marrow with healthy stem cells from a donor, but it carries risks like graft-versus-host disease (when the donor cells attack the patient's body) and requires a suitable donor match. ^{4 5 10 11 12}

Research Team

Richard W Childs, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Eligibility Criteria

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

Trial Timeline

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

Treatment Details

Interventions

• Allogeneic Hematopoietic Stem Cell Transplantation (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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Dr. Gary H. Gibbons

National Heart, Lung, and Blood Institute (NHLBI)

Chief Executive Officer since 2012

MD from Harvard Medical School

Dr. James P. Kiley

National Heart, Lung, and Blood Institute (NHLBI)

Chief Medical Officer since 2011

MD from University of California, San Francisco

Findings from Research

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]

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]

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]

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]

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-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]

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 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]

References

1. China pubmed.ncbi.nlm.nih.gov

[Allogeneic hematopoietic stem cell transplantation for 16 patients with aplastic anemia]. [2007]

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

Comparison of HLA-matched sibling and unrelated donor transplantation in adult patients with acquired severe aplastic anemia. [2021]

3. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[The use of allogeneic bone marrow transplantation and immunosuppressive therapy in the treatment of patients with acquired aplastic anemia]. [2021]

4. England pubmed.ncbi.nlm.nih.gov

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

5. England 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. [2021]

6. Italy pubmed.ncbi.nlm.nih.gov

Clinical applications of haploidentical hematopoietic stem cell transplantation in severe aplastic anemia. [2018]

7. China 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]. [2023]

8. North Macedonia pubmed.ncbi.nlm.nih.gov

Early and Late Complications in Patients with Allogeneic Transplantation of Hematopoietic Stem Cell - Case Report. [2020]

9. England pubmed.ncbi.nlm.nih.gov

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

10. England pubmed.ncbi.nlm.nih.gov

Allogeneic transplantation for aplastic anemia. [2012]

11. Austria pubmed.ncbi.nlm.nih.gov

[Severe aplastic anemia]. [2021]

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

Audit of peripheral stem cell transplantation for aplastic anemia in multitransfused infected patients. [2017]