Stem Cell Transplant for Immune Deficiency Syndrome

Recruiting at 1 trial location

Overseen By Danielle E Pregent-Arnold, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational agents

Disqualifiers: HIV, Hepatitis B, Psychiatric disorder, 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: 2

144 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, since participants will undergo chemotherapy or radiation before the transplant, it's possible that some medications might need to be adjusted. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment Allogeneic HSCT for Immune Deficiency Syndrome?

Research shows that allogeneic hematopoietic stem cell transplantation (HSCT) can cure many primary immune deficiency disorders, such as Severe Combined Immunodeficiency (SCID), by replacing faulty immune cells with healthy ones from a donor. This treatment has been used successfully for various inherited immune disorders, although challenges like matching donor compatibility remain. ^{1 2 3 4 5}

Is allogeneic hematopoietic stem cell transplantation (HSCT) generally safe for humans?

Allogeneic hematopoietic stem cell transplantation (HSCT) has been used for over 30 years and is generally considered safe, though it does come with risks. The main concerns are related to anesthesia during the procedure and potential complications like graft-versus-host disease (GVHD), which can cause significant health issues. However, serious adverse events are rare, and the procedure is closely monitored to ensure donor and patient safety. ^{1 6 7 8 9}

How is the treatment Allogeneic HSCT different from other treatments for immune deficiency syndrome?

Allogeneic HSCT is unique because it involves transplanting stem cells from a donor to replace the patient's faulty immune system, offering a potential cure for immune deficiency syndromes. Unlike other treatments that may only manage symptoms, this approach aims to reconstitute the immune system, especially when a matched donor is available, although it can be complex due to compatibility issues. ^{2 3 10 11 12}

What is the purpose of this trial?

Background: - GATA2 deficiency is a disease caused by mutations in the GATA2 gene. It can cause different types of leukemia and other diseases. Researchers want to see if a stem cell transplant can be used to treat this condition. A stem cell transplant will give stem cells from a matching donor (related or unrelated) to a recipient. It will allow the donor stem cells to produce healthy bone marrow and blood cells that will attack the recipient s cancer cells. Objectives: - To see if stem cell transplants are successful at treating GATA2 mutations and related conditions. Eligibility: - Recipients who are between 8 and 70 years of age and have GATA2 deficiency. Design: * All participants will be screened with a physical exam and medical history. Blood samples will be collected. Recipients will have imaging studies and other tests. * Recipients will have chemotherapy or radiation to prepare for the transplant. On the day of the transplant, they will receive the donated stem cells. * Recipients will stay in the hospital until their condition is stable after transplant. * Frequent blood tests and scans will be required for the first 6 months after the transplant, followed by less frequent visits over time.

Research Team

Danielle E Pregent-Arnold, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

This trial is for people aged 8-70 with GATA2 deficiency, a genetic condition that can lead to leukemia. Participants need functioning kidneys, liver, heart, and lungs. They must have a matching stem cell donor and agree to use birth control. Excluded are those with active infections or malignancies, pregnant or breastfeeding women, HIV-positive individuals, and anyone allergic to the study drugs.

Inclusion Criteria

Ability to understand and sign a written informed consent document

Left ventricular ejection fraction > 40%

I will have an adult caregiver with me after my transplant.

Exclusion Criteria

History of allergic reactions to specific compounds

History of psychiatric disorder affecting compliance with transplant protocol

Pregnant or lactating

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Pre-transplant Conditioning

Participants receive chemotherapy or radiation to prepare for the transplant

1 week

Daily visits (in-patient)

Transplant

Participants receive the donated stem cells

1 day

1 visit (in-patient)

Post-transplant Monitoring

Frequent blood tests and scans for the first 6 months, followed by less frequent visits

6 months

Frequent visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Periodic visits (in-person)

Treatment Details

Interventions

• Allogeneic HSCT

Trial Overview The trial tests whether an allogeneic hematopoietic stem cell transplant (HSCT) from a matched donor can treat GATA2 mutations effectively. It involves chemotherapy or radiation before the transplant and requires hospitalization until stable post-transplant followed by regular monitoring.

Participant Groups

Group I: Arm A Active Control 6 Interventions

10/10 HLA Matched Related Donor or Unrelated Donor or 9/10 HLA with DQ mismatch Transplant

Group II: Arm B Active Control 7 Interventions

9/10 or 8/10 HLA Match Related Donor or Unrelated Donor or Haploidentical Donor Transplant

Group III: Arm C (combined with Arm B per Amendment N) Active Control 7 Interventions

Haploidentical Related Donor Transplant

Group IV: Arm D (Deleted this arm per amendment I) Active Control 5 Interventions

Umbilical Cord Blood Transplant

Group V: Arm E (Deleted this arm per amendment O) Active Control 1 Intervention

Donor

Allogeneic HSCT is already approved in European Union, United States, Canada, Japan for the following indications:

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

• Acute Myeloid Leukemia
• Acute Lymphoblastic Leukemia
• Chronic Myeloid Leukemia
• Myelodysplastic Syndromes
• Primary Immunodeficiency Diseases
• Severe Combined Immunodeficiency
• Sickle Cell Disease
• Thalassemia

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

• Acute Myeloid Leukemia
• Acute Lymphoblastic Leukemia
• Chronic Myeloid Leukemia
• Myelodysplastic Syndromes
• Primary Immunodeficiency Diseases
• Severe Combined Immunodeficiency
• Sickle Cell Disease
• Thalassemia
• Hodgkin Lymphoma
• Non-Hodgkin Lymphoma

Approved in Canada as Allogeneic Hematopoietic Stem Cell Transplant for:

• Acute Myeloid Leukemia
• Acute Lymphoblastic Leukemia
• Chronic Myeloid Leukemia
• Myelodysplastic Syndromes
• Primary Immunodeficiency Diseases
• Severe Combined Immunodeficiency
• Sickle Cell Disease
• Thalassemia

Approved in Japan as Allogeneic Hematopoietic Stem Cell Transplant for:

• Acute Myeloid Leukemia
• Acute Lymphoblastic Leukemia
• Chronic Myeloid Leukemia
• Myelodysplastic Syndromes
• Primary Immunodeficiency Diseases
• Severe Combined Immunodeficiency
• Sickle Cell Disease
• Thalassemia

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

In a study of 25 patients undergoing allogeneic bone marrow transplantation (alloBMT) with reduced intensity conditioning and post-transplantation cyclophosphamide, the 2-year overall survival rate was an impressive 92%, indicating high efficacy of this treatment approach.

The modified protocol resulted in low rates of graft-versus-host disease (GVHD), with only 17% experiencing grade II acute GVHD and 14% chronic GVHD, suggesting that the removal of low-dose TBI and the use of alternative donor sources can enhance safety and reduce complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced Intensity Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Pediatric Inherited Immune Deficiencies and Bone Marrow Failure Syndromes. Klein, OR., Bapty, S., Lederman, HM., et al.[2022]

Cell therapy began in 1968 with the first successful transplantation of hematopoietic stem cells, which has since helped thousands of patients with immune disorders like Wiskott-Aldrich syndrome and Severe Combined ImmunoDeficiency (SCID).

Despite its success, the effectiveness of hematopoietic stem cell therapy is still limited by immunologic challenges related to HLA compatibility, which poses significant obstacles for broader application in treating various diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cell therapy for inherited diseases of the hematopoietic system]. Cavazzana-Calvo, M., Dal-Cortivo, L., André-Schmutz, I., et al.[2007]

Allogeneic hematopoietic stem cell transplantation is an effective curative treatment for various primary immunodeficiencies, including both well-known and newly identified conditions.

The article highlights the challenges in establishing a universal transplant regimen due to the rarity and diverse pathophysiology of these immunodeficiencies, emphasizing the need for tailored approaches in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell transplantation for primary immunodeficiencies. Kang, E., Gennery, A.[2019]

In a study of 44 patients with severe combined immunodeficiency (SCID) who underwent hematopoietic stem cell transplantation (HSCT), most patients showed normal immune reconstitution, with over 90% achieving normal CD3 counts and 72.7% able to stop intravenous immunoglobulin (IVIG) therapy after HSCT.

Bone marrow transplantation resulted in significantly lower rates of acute graft-versus-host disease (GVHD) compared to peripheral stem cell transplantation, suggesting that bone marrow may be the preferred source for HSCT in SCID patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long Term Follow-Up of the Patients with Severe Combined Immunodeficiency After Hematopoietic Stem Cell Transplantation: A Single-Center Study. Demirtas, D., Cagdas, D., Turul Ozgur, T., et al.[2022]

Allogeneic hematopoietic stem cell transplantation (HSCT) is a critical treatment option for various diseases, but it carries risks of morbidity and mortality, highlighting the importance of donor safety during the stem cell donation process.

Bone marrow donation is a well-established and generally safe procedure, with a low incidence of serious adverse events (only 1 fatal event reported among 27,770 donations), and the most common side effects being pain and fatigue, indicating that careful donor selection is essential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of bone marrow stem cell donation: a review. Bosi, A., Bartolozzi, B.[2010]

Allogeneic hematopoietic stem cell transplantation (HSCT) has the potential to cure severe autoimmune diseases by replacing a diseased immune system with a healthy one, although it carries higher risks compared to autologous HSCT, including complications and mortality.

Despite the risks, allogeneic HSCT may lead to sustained remissions in selected cases, as evidenced by outcomes in conditions like aplastic anemia and chronic myelogenous leukemia, and initial experiences in patients with systemic sclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic HSCT for autoimmune diseases: conventional conditioning regimens. Nash, RA.[2007]

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) with sibling donors experience a complex mix of emotions, feeling both secure in their donor's support and burdened by a sense of responsibility for the donor's safety.

The study highlights the need for healthcare providers to understand the emotional challenges faced by patients and their sibling donors, as this can impact their care and overall experience during the transplantation process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Having a sibling as donor: patients' experiences immediately before allogeneic hematopoietic stem cell transplantation. Kisch, A., Bolmsjö, I., Lenhoff, S., et al.[2022]

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-haplotype disparate T-cell depleted marrow grafts can successfully treat severe combined immunodeficiency (SCID), leading to durable immune function reconstitution without severe graft vs. host disease in many cases.

Despite the success, challenges remain, such as resistance to engraftment and issues with B cell development, but ongoing research is uncovering the cellular mechanisms that influence these outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of HLA-non-identical T-cell-depleted marrow transplants for correction of severe combined immunodeficiency disease. O'Reilly, RJ., Keever, CA., Small, TN., et al.[2008]

In a study involving 25 children with primary immunodeficiencies, haploidentical or mismatched unrelated donor hematopoietic stem cell transplantation (HSCT) after depleting TCRαβ CD3+ cells resulted in an impressive overall survival rate of 83.9% and an event-free survival rate of 80.4% at a median follow-up of 20.8 months.

The approach significantly reduced the incidence of acute graft-versus-host disease (GvHD) to 22%, with no cases of chronic GvHD observed, highlighting the safety and efficacy of this transplantation strategy for treating PIDs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell receptor αβ+ and CD19+ cell-depleted haploidentical and mismatched hematopoietic stem cell transplantation in primary immune deficiency. Shah, RM., Elfeky, R., Nademi, Z., et al.[2022]

Umbilical cord blood is a promising alternative stem-cell source for children with severe primary T-cell immunodeficiencies, showing rapid and reliable recovery of immune function after transplantation in a study of 6 children.

The transplantation resulted in low rates of graft-versus-host disease (GvHD) and effective immune reconstitution, with stable development of T-cells, B-cells, and natural killer cells, indicating its safety and efficacy compared to other donor sources.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinetics of T-cell development of umbilical cord blood transplantation in severe T-cell immunodeficiency disorders. Knutsen, AP., Wall, DA.[2019]

References

1. 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]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Reduced Intensity Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Pediatric Inherited Immune Deficiencies and Bone Marrow Failure Syndromes. [2022]

3. France pubmed.ncbi.nlm.nih.gov

[Cell therapy for inherited diseases of the hematopoietic system]. [2007]

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

Hematopoietic stem cell transplantation for primary immunodeficiencies. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Long Term Follow-Up of the Patients with Severe Combined Immunodeficiency After Hematopoietic Stem Cell Transplantation: A Single-Center Study. [2022]

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

Safety of bone marrow stem cell donation: a review. [2010]

7. England pubmed.ncbi.nlm.nih.gov

Allogeneic HSCT for autoimmune diseases: conventional conditioning regimens. [2007]

8. Scotland pubmed.ncbi.nlm.nih.gov

Having a sibling as donor: patients' experiences immediately before allogeneic hematopoietic stem cell transplantation. [2022]

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

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

10. Switzerland pubmed.ncbi.nlm.nih.gov

The use of HLA-non-identical T-cell-depleted marrow transplants for correction of severe combined immunodeficiency disease. [2008]

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

T-cell receptor αβ+ and CD19+ cell-depleted haploidentical and mismatched hematopoietic stem cell transplantation in primary immune deficiency. [2022]

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

Kinetics of T-cell development of umbilical cord blood transplantation in severe T-cell immunodeficiency disorders. [2019]