Haploidentical Transplant for Severe Aplastic Anemia

Overseen By Amr Qudeimat, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: St. Jude Children's Research Hospital

Must not be taking: Alemtuzumab, ATG

Disqualifiers: Fanconi anemia, Dyskeratosis congenita, MDS, 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

Compensation: Varies

Number of Visits: Unknown

21 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is a prospective, single center phase II clinical trial in which patients with Severe Aplastic Anemia (SAA) ) will receive a haploidentical transplantation. The purpose of this study is to learn more about newer methods of transplanting blood forming cells donated by a family member that is not fully matched to the patient. This includes studying the effects of the chemotherapy, radiation, the transplanted cell product and additional white blood cell (lymphocyte) infusions on the patient's body, disease and overall survival. The primary objective is to assess the rate of engraftment at 30 days and overall survival (OS) and event free survival (EFS) at 1 year post-hematopoietic cell transplantation (HCT). Primary Objectives * To estimate the rate of engraftment at 30 days after TCR αβ+ T-cell-depleted graft infusion in patients receiving a single dose of post graft infusion cyclophosphamide. * To estimate the overall survival and event free survival at 1-year post transplantation. Secondary Objectives * To calculate the incidence of acute and chronic GVHD after HCT. * To calculate the rate of secondary graft rejection at 1-year post transplantation * To calculate the cumulative incidence of viral reactivation (CMV, EBV and adenovirus). * To describe the immune reconstitution after TCR αβ+ T-cell-depleted graft infusion at 1 month, 3 months, 6 months, 9 months, and 1 year. Exploratory Objectives * To longitudinally assess the phenotype and epigenetic profile of T-cells in SAA patients receiving HCT for SAA. * To assess the phenotype and epigenetic profile of T-cells in DLI administered to SAA patients post HCT. * To longitudinally assess CD8 T cell differentiation status in SAA patients using an epigenetic atlas of human CD8 T cell differentiation. * To examine the effector functions and proliferative capacity of CD8 T cells isolated from SAA patients before and after DLI. * Quantify donor derived Treg cells at different time points in patients received HCT. * Determine Treg activation status at different stages after HCT. * Are specific features of the DLI product associated with particular immune repertoire profiles post-transplant? * How does the diversity and functional profile of the DLI product alter the response to pathogens in the recipient? * Do baseline features of the recipient's innate and adaptive immune cells correlate with post-transplant immune repertoires and response profiles?

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

The trial protocol does not specify whether you need to stop taking your current medications. However, since the trial involves a complex medical procedure like a haploidentical transplant, it's important to discuss your current medications with the trial team to ensure safety and compatibility.

What data supports the effectiveness of the treatment Haploidentical HCT for severe aplastic anemia?

Research shows that haploidentical transplantation for severe aplastic anemia can lead to similar survival outcomes as other donor types, with a 5-year survival rate of over 90% in some studies. It also results in faster recovery of blood cells, making it a promising option for patients without a matched sibling donor. ^{1 2 3 4 5}

Is haploidentical transplant generally safe for severe aplastic anemia?

Haploidentical transplants for severe aplastic anemia have shown promising safety results, with most patients achieving successful engraftment and manageable complications. However, some patients experienced severe complications like graft-versus-host disease (a condition where the donor's immune cells attack the recipient's body) and cardiac issues, which require careful monitoring. ^{6 7 8 9 10}

How is the treatment Haploidentical HCT different from other treatments for severe aplastic anemia?

Haploidentical HCT is unique because it allows for stem cell transplantation from a partially matched family member, expanding donor options for patients who do not have a fully matched donor. This treatment has shown promising survival outcomes and can be a valid alternative for patients, especially those under 40, who lack a matched sibling donor. ^{1 2 3 7 11}

Research Team

Amr Qudeimat, MD

Principal Investigator

St. Jude Children's Research Hospital

Akshay Sharma, MBBS

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for patients under 21 with Severe Aplastic Anemia who have failed at least one immunosuppressive therapy, lack a fully matched donor, and have good organ function. Donors must be family members partially matching the patient (≥3 of 6 HLA types), willing to donate stem cells, and HIV negative. Pregnant or breastfeeding women can't participate.

Inclusion Criteria

I don't have a matching family or unrelated donor for a cell transplant.

My potential donor is ready and can donate stem cells.

I am 18 years old or older.

Exclusion Criteria

You had a life-threatening reaction (like anaphylaxis) to ATG in the past, which means you cannot use it again.

I do not have an ongoing infection that isn't getting better with treatment.

I have been diagnosed with dyskeratosis congenita.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants receive chemotherapy, antibodies, and radiation to prepare the body for donor cell infusion

2-3 weeks

Transplantation

Participants receive a progenitor blood cell infusion followed by a donor lymphocyte infusion

1 week

Engraftment

Monitoring of engraftment and initial immune reconstitution

4 weeks

Follow-up

Participants are monitored for safety, effectiveness, and immune reconstitution post-transplant

1 year

Treatment Details

Interventions

• Haploidentical HCT

Trial Overview The study tests haploidentical hematopoietic cell transplantation (HCT) in SAA patients using chemotherapy, radiation, transplanted cells from half-matched family donors, and additional white blood cell infusions. It aims to assess engraftment success at 30 days post-transplantation and survival rates after one year.

Participant Groups

Group I: Haploidentical HCT Experimental Treatment 9 Interventions

To assess the safety and efficacy of haploidentical donor transplantation for patients with severe aplastic anemia who lack an available HLA-matched donor. The goal of this study is to develop a novel, reduced-toxicity, post-transplant pharmacologic immunosuppression (GVHD prophylaxis)- free, highly tolerogenic haploidentical transplant regimen that is associated with few post- transplant complications or late toxicities and is available promptly to all patients, irrespective of matched donor availability. Cells for infusion are prepared using the CliniMACS System.

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Findings from Research

In a study of 189 patients with severe aplastic anemia (SAA) who underwent either HLA-haploidentical or HLA-identical hematopoietic stem cell transplantation (HSCT), the 5-year overall survival rate was 72.0% for the HLA-haploidentical group, which is slightly lower than the 76.5% for the HLA-identical group.

The study suggests that HLA-haploidentical HSCT is a viable option for SAA patients under 40 years old who do not have a matched sibling donor, as older patients showed poorer outcomes in this group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimal donor for severe aplastic anemia patient requiring allogeneic hematopoietic stem cell transplantation: A large-sample study from China. Zeng, Y., Wang, S., Wang, J., et al.[2018]

A multicenter study involving 392 patients with severe aplastic anemia (SAA) found that haploidentical transplantation from various family members (fathers, mothers, siblings, and children) resulted in high engraftment rates (99.5%) and similar overall survival rates, indicating that all these donor types are effective options.

The study revealed that patients with a shorter history of SAA (less than 12 months) and better performance status had significantly better overall survival and failure-free survival, suggesting that these factors are important for optimizing transplant outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Who is the best haploidentical donor for acquired severe aplastic anemia? Experience from a multicenter study. Xu, LP., Wang, SQ., Ma, YR., et al.[2020]

HLA-haploidentical donor hematopoietic transplantation (Haplo-HSCT) for severe aplastic anemia (SAA) showed a high overall survival rate of 91.3% in a study of 50 patients, with no significant difference in outcomes compared to unrelated donor transplantation (UD-HSCT).

However, Haplo-HSCT was associated with a significantly higher incidence of acute and chronic graft-versus-host disease (aGVHD and cGVHD) and viral infections (CMV and EBV viremia) compared to UD-HSCT, indicating potential safety concerns despite its comparable efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[HLA- haploidentical donor hematopoietic transplantation for severe aplastic anemia achieved comparable outcomes with HLA- unrelated donor transplantation]. Lu, Y., Wu, T., Cao, X., et al.[2020]

Hematopoietic stem cell transplantation (BMT) is the only curative treatment for severe aplastic anemia, with HLA-matched sibling donor transplants being the standard care for younger patients.

The use of high-dose post-transplant cyclophosphamide has significantly improved outcomes in haploidentical BMT by reducing the risks of graft rejection and graft-versus-host disease, making it a viable option for patients with refractory or relapsed disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haploidentical Donor Bone Marrow Transplantation for Severe Aplastic Anemia. DeZern, AE., Brodsky, RA.[2023]

In a study of 67 pediatric patients with severe aplastic anemia, haploidentical family donor transplants led to significantly faster neutrophil engraftment (10 days) compared to matched sibling (14 days) and unrelated donor transplants (12 days).

The 5-year overall survival rate was high at 93.8%, with no significant differences in survival outcomes based on donor type, indicating that haploidentical transplantation is a viable and effective option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparable Outcome with a Faster Engraftment of Optimized Haploidentical Hematopoietic Stem Cell Transplantation Compared with Transplantations from Other Donor Types in Pediatric Acquired Aplastic Anemia. Kim, H., Im, HJ., Koh, KN., et al.[2020]

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]

Haploidentical stem cell transplantation (haplo-HSCT) has emerged as a promising treatment for severe aplastic anemia (SAA), providing a viable option when matched donors are not available, with improved survival outcomes due to advancements in treatment regimens.

The most successful regimen involves granulocyte colony-stimulating factor (G-CSF) combined with antithymocyte globulin (ATG), which has been widely adopted in China, while other regimens like posttransplantation cyclophosphamide (PT-Cy) and T-cell depletion (TCD) are also effective but have smaller sample sizes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haploidentical stem cell transplantation for aplastic anemia: the current advances and future challenges. Xu, ZL., Huang, XJ.[2021]

Haploidentical allogeneic hemopoietic stem cell transplantation (allo-HSCT) showed a survival rate of 71.4% in 21 patients with severe aplastic anemia (SAA) over a follow-up period of 16 months, indicating its therapeutic efficacy.

While the treatment was effective, 66.7% of patients experienced graft versus host disease (GVHD), with some cases being severe, highlighting the need for careful monitoring and management of complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Retrospective analysis of therapeutic efficacy of haploidentical allogeneic hematopoietic stem cell transplantation for severe aplastic anemia]. Zhang, Y., Liu, XD., He, XP., et al.[2018]

In a study of 26 adult patients with severe aplastic anemia (SAA) who underwent HLA-haploidentical hematopoietic stem cell transplantation (HSCT), the engraftment rate was high at 92.3%, with most patients achieving engraftment within 13 days after the procedure.

The overall survival rate was 84.6% over an average follow-up of about 1313 days, indicating that HLA-haploidentical HSCT is a promising treatment option for adults with SAA when a fully matched donor is not available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcome of HLA-haploidentical hematopoietic SCT without in vitro T-cell depletion for adult severe aplastic anemia after modified conditioning and supportive therapy. Gao, L., Li, Y., Zhang, Y., et al.[2022]

In a study of 216 severe aplastic anemia patients undergoing haploidentical transplantation, 5.6% experienced severe cardiac toxicity, which significantly worsened their overall survival rates (12.5% vs. 89.6% for those without toxicity).

Four key predictors of severe cardiotoxicity were identified: a pre-transplant ECOG score of 2 or higher, abnormal ST-T waves on ECG, hyperlipaemia, and a high dose of cyclophosphamide (≥1.8 g/m2/d), indicating that patients with more risk factors had much poorer outcomes and should be monitored closely.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and predictors of severe cardiotoxicity in patients with severe aplastic anaemia after haploidentical haematopoietic stem cell transplantation. Xu, ZL., Xu, LP., Zhang, YY., et al.[2020]

Haploidentical stem cell transplantation (HSCT) is a feasible and effective upfront treatment for severe aplastic anemia (SAA) patients, showing similar overall and failure-free survival rates compared to matched related donor transplants, with 86.1% and 91.3% survival rates respectively over three years.

While haploidentical HSCT was associated with a higher incidence of acute and chronic graft-versus-host disease (GVHD), the overall safety profile remains acceptable, indicating that this method can be a viable alternative for patients without suitable donors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Upfront haploidentical transplant for acquired severe aplastic anemia: registry-based comparison with matched related transplant. Xu, LP., Jin, S., Wang, SQ., et al.[2022]

References

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

Optimal donor for severe aplastic anemia patient requiring allogeneic hematopoietic stem cell transplantation: A large-sample study from China. [2018]

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

Who is the best haploidentical donor for acquired severe aplastic anemia? Experience from a multicenter study. [2020]

3. China pubmed.ncbi.nlm.nih.gov

[HLA- haploidentical donor hematopoietic transplantation for severe aplastic anemia achieved comparable outcomes with HLA- unrelated donor transplantation]. [2020]

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

Haploidentical Donor Bone Marrow Transplantation for Severe Aplastic Anemia. [2023]

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

Comparable Outcome with a Faster Engraftment of Optimized Haploidentical Hematopoietic Stem Cell Transplantation Compared with Transplantations from Other Donor Types in Pediatric Acquired Aplastic Anemia. [2020]

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

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

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

Haploidentical stem cell transplantation for aplastic anemia: the current advances and future challenges. [2021]

8. China pubmed.ncbi.nlm.nih.gov

[Retrospective analysis of therapeutic efficacy of haploidentical allogeneic hematopoietic stem cell transplantation for severe aplastic anemia]. [2018]

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

Long-term outcome of HLA-haploidentical hematopoietic SCT without in vitro T-cell depletion for adult severe aplastic anemia after modified conditioning and supportive therapy. [2022]

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

Incidence and predictors of severe cardiotoxicity in patients with severe aplastic anaemia after haploidentical haematopoietic stem cell transplantation. [2020]

11. England pubmed.ncbi.nlm.nih.gov

Upfront haploidentical transplant for acquired severe aplastic anemia: registry-based comparison with matched related transplant. [2022]