Haploidentical Bone Marrow Transplant for Aplastic Anemia

Recruiting at 1 trial location

Overseen By Melhem Solh, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Northside Hospital, Inc.

Disqualifiers: Poor cardiac, pulmonary, liver, renal, 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

20 Participants Needed

Trial Summary

What is the purpose of this trial?

Severe aplastic anemia is a rare and serious form of bone marrow failure related to an immune-mediated mechanism that results in severe pancytopenia and high risk for infections and bleeding. Patients with matched sibling donors for transplantation have a 80-90% chance of survival; however, a response rate with just immunosuppression for those patients lacking suitable HLA-matched related siblings is only 60%. With immunosuppression, only 1/3 of patients are cured, 1/3 are dependent on long term immunosuppression, and the other 1/3 relapse or develop a clonal disorder. Recent studies have shown that using a haploidentical donor for transplantation has good response rates and significantly lower rates of acute and chronic GVHD.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Haploidentical Bone Marrow Transplant for Aplastic Anemia?

Research shows that using a combination of fludarabine, cyclophosphamide, and anti-thymocyte globulin (ATG) as part of the conditioning regimen for bone marrow transplants in patients with severe aplastic anemia can lead to successful engraftment and survival. Studies have demonstrated that these drugs help prevent graft rejection and improve survival rates, making them effective components of the treatment. ^{1 2 3 4 5}

Is the Haploidentical Bone Marrow Transplant for Aplastic Anemia safe?

Research shows that using fludarabine, cyclophosphamide, and antithymocyte globulin in bone marrow transplants for severe aplastic anemia can be safe, with some studies reporting good survival rates and manageable side effects. However, higher doses of these drugs can lead to increased risks, so careful monitoring and dose adjustments are important to minimize potential harm. ^{1 2 4 6 7}

How does the treatment for aplastic anemia using Cyclophosphamide, Fludarabine, Rabbit ATG, and Total Body Irradiation differ from other treatments?

This treatment is unique because it uses a combination of drugs and total body irradiation to prepare the body for a bone marrow transplant from a partially matched donor, which is an option when a fully matched donor is not available. The use of high-dose post-transplant cyclophosphamide helps reduce the risk of graft-versus-host disease, a common complication in such transplants. ^{1 3 8 9 10}

Research Team

Melhem Solh, MD

Principal Investigator

Blood and Marrow Transplant Group of Georgia

Eligibility Criteria

This trial is for people under 75 with severe aplastic anemia who haven't found a perfect bone marrow match but have a related donor partially matched. They should be in relatively good health, with their heart, lungs, liver, and kidneys functioning well.

Inclusion Criteria

I have a family donor who matches 3/6 to 5/6 of my HLA markers and we are compatible.

I am 65 or younger if untreated, and 75 or younger if previously treated.

I am mostly able to care for myself.

Exclusion Criteria

My lung function is significantly reduced.

My liver is not functioning well (bilirubin >= 2mg/dL).

I have had a transplant from a donor.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preparative Regimen

Participants undergo a preparative regimen of Fludarabine, Cyclophosphamide, and Total Body Irradiation (TBI) followed by haploidentical bone marrow transplantation

1 week

Post-Transplant Treatment

Post-transplant Cyclophosphamide is administered on Days 3 & 4. Immunosuppression with Tacrolimus and MMF begins on Day +5; MMF is discontinued on Day +35 while Tacrolimus continues until Day +180

6 months

Follow-up

Participants are monitored for sustained engraftment and safety, with chimerism tests collected monthly following transplant

2 years

Treatment Details

Interventions

• Cyclophosphamide
• Fludarabine
• Rabbit ATG
• Total Body Irradiation

Trial Overview The study tests if bone marrow transplants from half-matched donors followed by Cyclophosphamide can help patients with severe aplastic anemia. It includes Fludarabine and Rabbit ATG treatment plus low-dose Total Body Irradiation.

Participant Groups

Group I: Flu/Cy/TBI Experimental Treatment 4 Interventions

Fludarabine, Cyclophosphamide, TBI followed by bone marrow transplantation. Post-transplant Cyclophosphamide will be on Days 3 \& 4.

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?

Northside Hospital, Inc.

Lead Sponsor

Trials

26

Recruited

1,100+

Findings from Research

In a study involving three children with refractory severe aplastic anemia (SAA), a radiotherapy-free conditioning regimen using fludarabine and other agents was effective in preparing them for hemopoietic cell transplantation (HCT) without the development of graft-versus-host disease (GVHD).

All patients achieved normal blood counts and complete donor chimerism after the transplant, demonstrating that fludarabine-based conditioning can be a safe and effective option for children undergoing HCT from alternative donors, even after previous transplant failures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. Urban, C., Benesch, M., Sykora, KW., et al.[2013]

In a multicenter phase 1-2 study involving 96 patients with severe aplastic anemia, using cyclophosphamide at reduced doses of 50 mg/kg and 100 mg/kg, along with fludarabine, anti-thymocyte globulin, and total body irradiation, resulted in high engraftment rates of 92% and 85% respectively, demonstrating effective conditioning for unrelated donor transplantation.

The study found that lower doses of cyclophosphamide were associated with significantly reduced major regimen-related toxicity, with only 11% experiencing severe side effects at 50 mg/kg compared to 22% at 100 mg/kg, suggesting a safer approach to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study. Anderlini, P., Wu, J., Gersten, I., et al.[2021]

In a study involving 34 adult patients with severe aplastic anemia undergoing haplo-identical stem cell transplantation, a conditioning regimen using 600 cGy total body irradiation, fludarabine, and intermediate-dose rabbit ATG resulted in successful primary engraftment for all patients.

The group receiving the lower dose of total body irradiation (600 cGy) showed a trend towards better overall survival (91.7%) and graft-versus-host disease (GVHD)-free survival (78.4%) compared to those receiving higher doses, indicating a potentially safer and more effective approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimal conditioning regimen for haplo-identical stem cell transplantation in adult patients with acquired severe aplastic anemia: Prospective de-escalation study of TBI and ATG dose. Lee, SE., Park, SS., Jeon, YW., et al.[2019]

A conditioning regimen using fludarabine, cyclophosphamide, and anti-thymocyte globulin was well tolerated in five patients with severe aplastic anemia, showing only mild toxicity (grade I).

All patients achieved complete donor chimerism and remained alive after a median follow-up of 9 months, suggesting that this regimen could effectively replace irradiation in alternative donor transplants for children with SAA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A fludarabine-based conditioning regimen for severe aplastic anemia. Chan, KW., Li, CK., Worth, LL., et al.[2013]

The new pretransplant immunosuppressive regimen (CY-TBI-2) using cyclophosphamide and low-dose total body irradiation resulted in a 62% disease-free survival rate over two years for 46 patients with severe aplastic anemia, indicating its efficacy in preventing graft rejection.

The regimen showed a low incidence of graft-versus-host disease (GVHD) and interstitial pneumonia (IPn), with only one case of graft rejection, suggesting it is a safe option for patients, particularly those under 25 years old who had an impressive 82% survival rate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved survival following bone marrow transplantation for aplastic anaemia. Feig, SA., Champlin, R., Arenson, E., et al.[2019]

In a study of 89 hematopoietic cell transplantation recipients, higher levels of the active metabolite of cyclophosphamide (PM AUC0-8 hr) were linked to worse nonrelapse mortality and overall survival, indicating that careful monitoring of this metabolite is crucial for patient outcomes.

Patients with low levels of the active metabolite of fludarabine (F-ara-ADay-4) and low PM AUC0-8 hr had significantly lower nonrelapse mortality, suggesting that optimizing drug exposure could improve safety and efficacy in reduced-intensity conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher Fludarabine and Cyclophosphamide Exposures Lead to Worse Outcomes in Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Adult Hematologic Malignancy. Takahashi, T., Scheibner, A., Cao, Q., et al.[2021]

A new phase II study with a reduced-toxicity conditioning regimen for hematopoietic stem cell transplantation (HSCT) in severe aplastic anemia (SAA) patients showed significantly improved overall survival (96.7%) and event-free survival (93.3%) compared to a previous regimen (67.9% OS and 64.3% EFS).

The new regimen, which included lower doses of cyclophosphamide (Cy) and a modified schedule for fludarabine (FLU) and antithymocyte globulin (ATG), achieved successful hematologic recovery in all patients, indicating it may be a safer and more effective option for HSCT with unrelated donors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved Outcome of a Reduced Toxicity-Fludarabine, Cyclophosphamide, plus Antithymocyte Globulin Conditioning Regimen for Unrelated Donor Transplantation in Severe Aplastic Anemia: Comparison of 2 Multicenter Prospective Studies. Kang, HJ., Hong, KT., Lee, JW., et al.[2018]

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 47 adult patients with severe aplastic anemia, the combination of rabbit antithymocyte globulin (ATG), fractionated total body irradiation (fTBI), and fludarabine (Flu) as a conditioning regimen for haploidentical stem cell transplantation (haplo-SCT) resulted in a high overall survival rate of 91% and failure-free survival of 88.6% after 3 years.

The study demonstrated that haplo-SCT can be a viable alternative for patients needing urgent transplantation when a fully matched donor is unavailable, with manageable rates of acute and chronic graft-versus-host disease (GVHD) at 27.7% and 13.5%, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of Haploidentical Stem Cell Transplantation using Total Body Irradiation (600 cGy) and Fludarabine with Antithymocyte Globulin in Adult Patients with Severe Aplastic Anemia: A Prospective Phase II Study. Lee, SE., Min, GJ., Park, SS., et al.[2021]

In a study of 203 patients with aplastic anemia undergoing allogeneic stem cell transplantation, a low-dose cyclophosphamide (less than 100 mg/kg) regimen showed a trend towards higher five-year overall survival (93.0%) compared to high-dose (84.2%) and reduced-dose (83.8%) regimens.

The findings suggest that reducing the dose of cyclophosphamide does not compromise engraftment success and may improve survival outcomes, indicating a safer approach when combined with fludarabine in HLA-identical sibling transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of cyclophosphamide dose of conditioning on the outcome of allogeneic hematopoietic stem cell transplantation for aplastic anemia from human leukocyte antigen-identical sibling. Mori, T., Koh, H., Onishi, Y., et al.[2022]

References

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

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. [2013]

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

Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study. [2021]

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

Optimal conditioning regimen for haplo-identical stem cell transplantation in adult patients with acquired severe aplastic anemia: Prospective de-escalation study of TBI and ATG dose. [2019]

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

A fludarabine-based conditioning regimen for severe aplastic anemia. [2013]

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

Improved survival following bone marrow transplantation for aplastic anaemia. [2019]

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

Higher Fludarabine and Cyclophosphamide Exposures Lead to Worse Outcomes in Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Adult Hematologic Malignancy. [2021]

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

Improved Outcome of a Reduced Toxicity-Fludarabine, Cyclophosphamide, plus Antithymocyte Globulin Conditioning Regimen for Unrelated Donor Transplantation in Severe Aplastic Anemia: Comparison of 2 Multicenter Prospective Studies. [2018]

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

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

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

Outcomes of Haploidentical Stem Cell Transplantation using Total Body Irradiation (600 cGy) and Fludarabine with Antithymocyte Globulin in Adult Patients with Severe Aplastic Anemia: A Prospective Phase II Study. [2021]

10. Japan pubmed.ncbi.nlm.nih.gov

Impact of cyclophosphamide dose of conditioning on the outcome of allogeneic hematopoietic stem cell transplantation for aplastic anemia from human leukocyte antigen-identical sibling. [2022]