Hematopoietic Cell Transplant for Aplastic Anemia

Overseen By Christen Ebens, MD, MPH

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Masonic Cancer Center, University of Minnesota

Disqualifiers: Pregnancy, Uncontrolled infection, Advanced 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

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

Compensation: Varies

Number of Visits: Unknown

60 Participants Needed

Trial Summary

What is the purpose of this trial?

A phase II trial of a reduced intensity conditioned (RIC) allogeneic hematopoietic cell transplant (HCT) with post-transplant cyclophosphamide (PTCy) for idiopathic severe aplastic anemia (SAA), paroxysmal nocturnal hemoglobinuria (PNH), acquired pure red cell aplasia (aPRCA), or acquired amegakaryocytic thrombocytopenia (aAT) utilizing population pharmacokinetic (popPK)-guided individual dosing of pre-transplant conditioning and differential dosing of low dose total body irradiation based on age, presence of myelodysplasia and/or clonal hematopoiesis.

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 study team or your doctor.

What data supports the effectiveness of the treatment Hematopoietic Cell Transplant With Reduced Intensity Conditioning and Post-transplant Cyclophosphamide for Aplastic Anemia?

Research shows that using cyclophosphamide (a chemotherapy drug) with reduced-intensity conditioning in bone marrow transplants can lead to high rates of successful engraftment (when the transplanted cells start to grow and make healthy blood cells) and low risk of graft-versus-host disease (a condition where the donor cells attack the recipient's body) in patients with severe aplastic anemia. ^{1 2 3 4 5}

Is hematopoietic cell transplant generally safe for humans?

Hematopoietic cell transplant, including variations like bone marrow transplantation and stem cell transplantation, has been studied for conditions like aplastic anemia and Fanconi anemia. Safety data shows that using reduced-intensity conditioning regimens and post-transplant cyclophosphamide can lead to high survival rates and low toxicity, with manageable risks of graft-versus-host disease (a condition where the donor cells attack the recipient's body). ^{1 2 3 6 7}

How is the treatment Hematopoietic Cell Transplant With Reduced Intensity Conditioning and Post-transplant Cyclophosphamide different from other treatments for aplastic anemia?

This treatment is unique because it uses a reduced intensity conditioning regimen combined with post-transplant cyclophosphamide to lower the risk of graft-versus-host disease, making it a promising option for patients without a matched sibling donor. ^{2 8 9 10 11}

Eligibility Criteria

This trial is for people with severe bone marrow failure conditions like aplastic anemia or paroxysmal nocturnal hemoglobinuria. Participants must have specific blood and bone marrow characteristics, such as low reticulocyte count or evidence of one to three-lineage aplasia, and adequate organ function. Those who've had a previous transplant that didn't work may also qualify.

Inclusion Criteria

My bone marrow has less than 5% blasts and I've never had MDS/AML.

My bone marrow has less than 5% blasts and I've never had MDS/AML.

My platelet count is below 20,000/uL or I need regular transfusions.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning and Transplantation

Participants undergo reduced intensity conditioning followed by hematopoietic cell transplant and post-transplant cyclophosphamide

Up to 180 days

Multiple visits for conditioning and transplantation procedures

GvHD Prophylaxis

Participants receive GvHD prophylaxis through day +180 post-transplant

180 days

Follow-up

Participants are monitored for safety and effectiveness, including incidence of GvHD and survival outcomes

2 years

Regular follow-up visits

Treatment Details

Interventions

• Hematopoietic Cell Transplant With Reduced Intensity Conditioning and Post-transplant Cyclophosphamide

Trial Overview The study tests a less intense cell transplant method combined with post-transplant cyclophosphamide medication in patients with certain bone marrow failures. It includes individualized dosing based on pharmacokinetics and varying radiation doses by age and disease features.

Participant Groups

Group I: Arm B: Clonal hematopoiesis Experimental Treatment 9 Interventions

Participants 25-75 years old and/or with clonal hematopoiesis. Active study treatment includes the conditioning regimen followed by the stem cell infusion and GvHD prophylaxis through day +180. Supportive care and follow up activities continue through two years post HCT.

Group II: Arm A: No clonal hematopoiesis Experimental Treatment 9 Interventions

Participants 25 years of age and younger with no clonal hematopoiesis. Active study treatment includes the conditioning regimen followed by the stem cell infusion and GvHD prophylaxis through day +180. Supportive care and follow up activities continue through two years post HCT.

Hematopoietic Cell Transplant With Reduced Intensity Conditioning and Post-transplant Cyclophosphamide is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Allogeneic Hematopoietic Cell Transplantation for:

• Severe aplastic anemia
• Paroxysmal nocturnal hemoglobinuria
• Acquired pure red cell aplasia
• Acquired amegakaryocytic thrombocytopenia
• Diamond-Blackfan anemia
• Fanconi's anemia

Approved in United States as Allogeneic Hematopoietic Cell Transplantation for:

• Severe aplastic anemia
• Paroxysmal nocturnal hemoglobinuria
• Acquired pure red cell aplasia
• Acquired amegakaryocytic thrombocytopenia
• Diamond-Blackfan anemia
• Fanconi's anemia

Approved in Canada as Allogeneic Hematopoietic Cell Transplantation for:

• Severe aplastic anemia
• Paroxysmal nocturnal hemoglobinuria
• Acquired pure red cell aplasia
• Acquired amegakaryocytic thrombocytopenia
• Diamond-Blackfan anemia
• Fanconi's anemia

Approved in Japan as Allogeneic Hematopoietic Cell Transplantation for:

• Severe aplastic anemia
• Paroxysmal nocturnal hemoglobinuria
• Acquired pure red cell aplasia
• Acquired amegakaryocytic thrombocytopenia
• Diamond-Blackfan anemia
• Fanconi's anemia

Who Is Running the Clinical Trial?

Masonic Cancer Center, University of Minnesota

Lead Sponsor

Trials

285

Recruited

15,700+

Findings from Research

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]

In a study of 23 patients with severe aplastic anemia, a conditioning regimen of cyclophosphamide and low-dose total body irradiation resulted in only one case of graft rejection, suggesting this approach significantly reduces the risk of rejection compared to traditional methods.

The regimen did not increase the incidence of graft-versus-host disease or interstitial pneumonitis, and the survival rates were 61% at one year and 49% at 2.5 years, indicating it is a safe and effective treatment option for patients lacking predictive tests for graft rejection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention of graft rejection following bone marrow transplantation. Gale, RP., Ho, W., Feig, S., et al.[2021]

In a study of 16 patients with refractory severe aplastic anemia, haploidentical stem cell transplantation (HSCT) using reduced-intensity conditioning and post-transplant cyclophosphamide resulted in a high neutrophil engraftment rate of 94% and a platelet engraftment rate of 75%.

The approach demonstrated a 1-year overall survival rate of 67.1% and a low incidence of acute graft-versus-host disease (GVHD), suggesting it is a promising therapeutic option for patients lacking matched donors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haploidentical BMT and post-transplant Cy for severe aplastic anemia: a multicenter retrospective study. Esteves, I., Bonfim, C., Pasquini, R., et al.[2018]

In a study involving 65 patients with severe aplastic anemia, a new conditioning regimen using Cyclophosphamide and total body irradiation significantly reduced the risk of bone marrow graft rejection compared to previous regimens.

Despite challenges like graft versus host disease and infections, 50% of the patients achieved long-term survival and appeared cured of their disease, highlighting the efficacy of the new treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bone marrow transplantation in 65 patients with severe aplastic anemia. Gluckman, E., Devergie, A., Gerotta, I., et al.[2013]

In a study of 17 patients with severe aplastic anemia who received bone marrow transplants (BMT) after a conditioning regimen of cyclophosphamide and total lymphoid irradiation, the long-term survival rate was 76% with a median follow-up of 11 years.

The conditioning regimen led to sustained engraftment in all patients, with manageable rates of graft-versus-host disease (24% for acute and 35% for chronic), and no patients developed malignancies post-transplant, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bone marrow transplantation for transfused patients with severe aplastic anemia using cyclophosphamide and total lymphoid irradiation as conditioning therapy: long-term follow-up from a single center. Gaziev, D., Giardini, C., Galimberti, M., et al.[2013]

In a study of 43 Fanconi anemia patients undergoing marrow transplantation with a reduced cyclophosphamide (CY) conditioning regimen (15 mg/kg/day for 4 days), 93% of patients are alive after a median follow-up of 3.7 years, indicating high efficacy and safety of this approach.

The study shows that using lower doses of CY results in low incidences of acute and chronic graft-versus-host disease (17% and 28.5%, respectively), confirming that this conditioning method minimizes toxicities while achieving successful engraftment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HLA-matched related donor hematopoietic cell transplantation in 43 patients with Fanconi anemia conditioned with 60 mg/kg of cyclophosphamide. Bonfim, CM., de Medeiros, CR., Bitencourt, MA., et al.[2021]

A reduced-intensity conditioning regimen for severe aplastic anemia patients resulted in a promising 2-year survival rate of 73%, particularly among younger patients (84% survival for those 14 years or younger).

However, there was a notable 18% graft failure rate, especially in patients aged 15 and older, suggesting that the conditioning regimen may need adjustments for older adults to improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, cyclophosphamide and anti-thymocyte globulin for alternative donor transplants in acquired severe aplastic anemia: a report from the EBMT-SAA Working Party. Bacigalupo, A., Locatelli, F., Lanino, E., et al.[2013]

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]

Hematopoietic stem-cell transplantation (BMT) is the preferred treatment for young patients with acquired aplastic anemia who have a matched sibling donor, while immunosuppressive therapies are effective alternatives for older patients or those without suitable donors.

Current advancements in BMT from unrelated and mismatched donors are promising, but this option is mainly for patients who do not respond to or relapse after immunosuppressive therapy, highlighting the need for improved treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical management of aplastic anemia. Dezern, AE., Brodsky, RA.[2022]

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is recommended as the first-line treatment for patients under 40 with stage 3-5 aplastic anemia who have HLA-matched sibling donors, but alternative donor options should be considered for those not responding to immunosuppressive therapy.

The use of a reduced dose of cyclophosphamide combined with fludarabine is becoming the preferred conditioning regimen to minimize cardiotoxicity, while HLA-haploidentical SCT from related donors is gaining attention for its low transplant-related mortality and reduced risk of chronic graft-versus-host disease (GVHD).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Hematopoietic stem cell transplantation for acquired aplastic anemia]. Yamazaki, H.[2015]

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]

References

1. 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]

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

Prevention of graft rejection following bone marrow transplantation. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Haploidentical BMT and post-transplant Cy for severe aplastic anemia: a multicenter retrospective study. [2018]

4. France pubmed.ncbi.nlm.nih.gov

Bone marrow transplantation in 65 patients with severe aplastic anemia. [2013]

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

Bone marrow transplantation for transfused patients with severe aplastic anemia using cyclophosphamide and total lymphoid irradiation as conditioning therapy: long-term follow-up from a single center. [2013]

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

HLA-matched related donor hematopoietic cell transplantation in 43 patients with Fanconi anemia conditioned with 60 mg/kg of cyclophosphamide. [2021]

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

Fludarabine, cyclophosphamide and anti-thymocyte globulin for alternative donor transplants in acquired severe aplastic anemia: a report from the EBMT-SAA Working Party. [2013]

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

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

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

Clinical management of aplastic anemia. [2022]

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

[Hematopoietic stem cell transplantation for acquired aplastic anemia]. [2015]

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

[Severe aplastic anemia]. [2021]