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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if using a partially matched family member for a bone marrow transplant can benefit individuals with severe aplastic anemia, a condition where the bone marrow produces insufficient blood cells. The treatment combines drugs such as Cyclophosphamide (also known as Cytoxan, Neosar, or Endoxan), Fludarabine, and Rabbit ATG (Rabbit Antithymocyte Globulin), along with Total Body Irradiation (TBI), to prepare the body for the transplant. This approach might lead to better outcomes than current options. Suitable candidates have severe aplastic anemia and a related donor who is a partial match. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using a partially matched family donor for bone marrow transplants in severe aplastic anemia appears promising. This method has demonstrated good success rates and significantly reduces the risk of graft-versus-host disease (GVHD), where the donor's cells attack the recipient's body.

The treatment involves fludarabine, cyclophosphamide, and total body irradiation (TBI). Studies have found these components work well in similar transplants. Fludarabine has proven effective in both acquired and inherited types of aplastic anemia. These treatments are generally well-tolerated, though side effects such as infections or bleeding can occur.

The trial is in its second phase, indicating that the treatment has shown some safety in earlier trials, but more information is needed. It is important to discuss with a doctor to determine if this trial might be suitable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using a haploidentical bone marrow transplant for treating aplastic anemia because it opens up the possibility of more donor options. Unlike traditional bone marrow transplants that require a perfect match, this approach allows for partial matches, significantly expanding the donor pool. Additionally, the treatment regimen combines fludarabine, cyclophosphamide, and total body irradiation, with post-transplant cyclophosphamide to reduce the risk of graft-versus-host disease, a common complication in transplants. By improving donor availability and potentially reducing complications, this treatment could offer a new lifeline for patients who cannot find a perfect donor match.

What evidence suggests that this trial's treatments could be effective for aplastic anemia?

Research has shown that using a partially matched family member as a donor for bone marrow transplants in patients with severe aplastic anemia can lead to good results. In this trial, participants will receive a treatment plan combining the drugs fludarabine and cyclophosphamide with total body irradiation (TBI), followed by bone marrow transplantation. This approach has resulted in high rates of patients living without the disease and low rates of graft-versus-host disease (GVHD), a condition where the body rejects the transplant. Patients receiving this treatment have experienced significant improvements, making it a promising option for those without a fully matched sibling donor. Overall, this method offers hope for better outcomes in managing severe aplastic anemia. ^{1 2 6 7 8}

Who Is on the Research Team?

Melhem Solh, MD

Principal Investigator

Blood and Marrow Transplant Group of Georgia

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2878797/

Fludarabine, cyclophosphamide, antithymocyte globulin ... This study confirms positive results of alternative donor transplants in patients with severe aplastic anemia, the best outcomes being achieved in patients ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11368812/

Efficacy and safety of outpatient fludarabine ... The FCR regimen in SAA was well tolerated, even in older adults, with 100% disease-free survival with low GVHD and infection rates.

3. haematologica.org haematologica.org/article/view/5636

Fludarabine, cyclophosphamide, antithymocyte globulin ... This study confirms positive results of alternative donor transplants in patients with severe aplastic anemia, the best outcomes being achieved in patients ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02828592

NCT02828592 | Haploidentical Bone Marrow Transplant ... Recent studies have shown that using a haploidentical donor for transplantation has good response rates and significantly lower rates of acute and chronic GVHD.

5. astctjournal.org astctjournal.org/article/S1083-8791(12)00176-0/fulltext

Early Results of a Cyclophosphamide Dose Deescalation ... All patients received fixed doses of antithymocyte globulin, fludarabine, and low-dose total body irradiation. The starting CY dose was 150 mg/kg, with ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03333486?cond=PNH&locStr=USA&country=United+States&aggFilters=phase%3A0+1+2+3+4

Study Details | Fludarabine Phosphate, Cyclophosphamide ... This phase II trial studies how well fludarabine phosphate, cyclophosphamide, total body irradiation, and donor stem cell transplant work in treating ...

7. astctjournal.org astctjournal.org/article/S1083-8791(20)30400-6/fulltext

Outcomes of Haploidentical Stem Cell ... A regimen of fractionated total body irradiation 600 cGy/fludarabine/intermediate-dose antithymocyte globulin (5 mg/kg) results in feasible outcomes.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6063510/

Haploidentical Donor Bone Marrow Transplantation for ... Fludarabine has been used in conditioning for patients with both acquired and constitutional aplastic anemia with good results. We favor the use of a ...