Fludarabine RIC for Bone Marrow Failure Syndrome

Overseen By Timothy S Olson, MD, PhD

Age: < 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Children's Hospital of Philadelphia

Disqualifiers: Uncontrolled infections, Myelodysplastic syndrome, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment approach for individuals with specific bone marrow issues, including severe aplastic anemia and inherited bone marrow failure syndromes. Researchers aim to determine if a combination of fludarabine (a type of chemotherapy) and a bone marrow transplant from a matched donor can benefit these patients. The trial includes different groups for conditions like Fanconi Anemia and Diamond-Blackfan Anemia. Suitable candidates are those under 22 who rely on regular blood transfusions due to their condition and have a fully matched family member willing to donate bone marrow. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking medical discoveries.

Do I need to stop my current medications for the trial?

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 shows that fludarabine is often used to treat bone marrow failure conditions like aplastic anemia. Studies have found that treatments using fludarabine are generally well-tolerated by patients with these conditions. Fludarabine helps prepare the body for a bone marrow transplant by slightly suppressing the immune system, allowing new, healthy bone marrow to grow with minimal side effects.

When considering bone marrow transplants from a matched related donor (MRD-BMT), this method has been safely used for both inherited and acquired bone marrow failure conditions. While all treatments have risks, the use of fludarabine and MRD-BMT in clinical settings suggests they are reasonably safe. However, since this trial is in its early stages, the researchers are still gathering information to fully understand all potential risks and side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer a tailored approach to bone marrow failure syndromes. While traditional treatments often involve intensive chemotherapy or immunosuppressive therapies, these investigational treatments utilize reduced intensity conditioning (RIC) with fludarabine, thymoglobulin, and other agents to prepare patients for a matched related donor bone marrow transplant. This approach is potentially less toxic and more tolerable, especially for patients with inherited conditions like Fanconi Anemia or acquired aplastic anemia. By using RIC, the treatments aim to reduce the risk of complications and improve outcomes, giving hope to patients who traditionally have had limited options.

What evidence suggests that this trial's treatments could be effective for bone marrow failure syndrome?

Research has shown that fludarabine can help prepare patients for bone marrow transplants. In previous studies, using fludarabine in the preparation process led to positive outcomes, such as patients remaining disease-free and experiencing a low risk of graft failure. In this trial, some participants with severe aplastic anemia will receive a matched related donor bone marrow transplant (MRD-BMT) following reduced intensity conditioning with fludarabine. For patients with severe aplastic anemia, fludarabine treatments have been well-tolerated, even in older adults, with high survival rates. Bone marrow transplants from a matched related donor have also succeeded, with fewer cases of graft failure compared to other transplant methods. This trial studies these treatments together to determine if they can improve outcomes for people with bone marrow failure syndromes. ^{2 6 7 8 9}

Who Is on the Research Team?

Timothy S Olson, MD, PhD

Principal Investigator

Children's Hospital of Philadelphia

Are You a Good Fit for This Trial?

This trial is for young people (ages 0-22) with bone marrow failure syndromes like aplastic anemia or inherited conditions causing low blood counts. They need a fully matched related bone marrow donor, good organ function, and no uncontrolled infections. Pregnant females or those without a suitable donor are excluded.

Inclusion Criteria

I am 22 or younger with a rare disorder affecting my bone marrow.

I have a relative who is a perfect match for my transplant needs.

I have severe aplastic anemia confirmed by specific tests and blood counts.

Exclusion Criteria

I do not have any untreated serious infections.

I have been diagnosed with Myelodysplastic syndrome.

I do not have a fully matched family donor for a transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants receive fludarabine-based reduced intensity conditioning (RIC) regimens to facilitate donor engraftment

1-2 weeks

Transplantation

Participants undergo matched related donor bone marrow transplantation

1 day

Post-Transplant Monitoring

Participants are monitored for neutrophil engraftment and graft failure

Up to 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Fludarabine
• MRD-BMT

Trial Overview The study tests if fludarabine-based reduced intensity conditioning helps patients with acquired aplastic anemia or inherited bone marrow failures successfully accept transplants from matched donors.

How Is the Trial Designed?

Group I: Inherited Bone Marrow Failure Syndrome no Trilineage Aplasia Experimental Treatment 1 Intervention

Patients with inherited bone marrow failure (iBMF) syndromes without trilineage aplasia includes those with diagnoses of Severe Congenital Neutropenia, Diamond-Blackfan Anemia, and related conditions. Patients will receive a matched related donor bone marrow transplant following conditioning with thymoglobulin, busulfan and fludarabine.

Group II: Inherited Bone Marrow Failure Syndrome + Trilineage Aplasia Experimental Treatment 1 Intervention

Patients with inherited bone marrow failure (iBMF) syndromes with trilineage aplasia includes those with diagnoses of Fanconi Anemia, Dyskeratosis Congenita, and related conditions. Patients will receive a matched related donor bone marrow transplant following conditioning with fludarabine, cyclophosphamide, thymoglobulin.

Group III: Acquired Aplastic Anemia (AA) Experimental Treatment 1 Intervention

Patients with severe or very severe acquired aplastic anemia (AA). Patients will receive a matched related donor bone marrow transplant following reduced intensity conditioning (RIC) including thymoglobulin (ATG), fludarabine and dose-reduced cyclophosphamide.

Fludarabine is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Fludara for:

• Chronic lymphocytic leukemia
• Mantle-cell lymphoma
• Non-Hodgkin's lymphoma

Approved in United States as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma
• Stem Cell Transplant Conditioning

Approved in Canada as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Recruited

11,400,000+

Published Research Related to This Trial

A child with Fanconi's anemia and leukemic transformation successfully underwent allogeneic bone marrow transplantation (BMT) using a conditioning regimen of fludarabine, ATG, and cyclophosphamide, which was well tolerated with no transplant-related complications.

Ten months post-transplant, the child showed excellent clinical outcomes, including normal blood counts, 100% chimerism, and no signs of graft-versus-host disease (GVHD), suggesting that fludarabine-based conditioning may be a safe and effective option for BMT in patients with Fanconi's anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A fludarabine-based protocol for bone marrow transplantation in Fanconi's anemia. Kapelushnik, J., Or, R., Slavin, S., et al.[2013]

Fludarabine phosphate, an antimetabolite derived from adenosine arabinoside, has been found to be safe at a dose of 20 mg/m2 administered every 12 hours for 6 doses in good-risk patients during a phase I trial.

The main side effect of fludarabine phosphate is myelosuppression, which can become severe at higher doses, highlighting the need for careful dose management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of fludarabine (2-fluoro-ara-AMP). Kavanagh, JJ., Krakoff, IH., Bodey, GP.[2019]

In a study involving four children with Fanconi's anemia, a fludarabine-based conditioning regimen for bone marrow transplantation (BMT) resulted in successful engraftment in 75% of patients, with a median follow-up of 13 months.

The addition of fludarabine provided effective immunosuppression to reduce rejection during BMT without increasing toxicity, suggesting it is a beneficial component of the treatment protocol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine-based conditioning for allogeneic stem cell transplantation for multiply transfused patients with Fanconi's anemia. George, B., Mathews, V., Shaji, RV., et al.[2005]

In a study of 102 patients undergoing hematopoietic cell transplantation (HCT) with fludarabine and low-dose total body irradiation, significant variability was observed in pharmacological biomarkers related to fludarabine metabolism, indicating that individual responses to the drug can differ widely.

Despite the variability in biomarkers such as F-ara-A area under the curve and F-ara-ATP accumulation, no significant associations were found between these biomarkers and clinical outcomes like acute graft-versus-host disease or overall mortality, suggesting that these pharmacological measures may not predict treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients. McCune, JS., Mager, DE., Bemer, MJ., et al.[2018]

Fludarabine phosphate (F-ara-AMP) is highly effective in treating chronic lymphocytic leukemia, but high doses can lead to severe neurotoxicity, as shown in mice with leukemia L1210.

Co-administering NBMPR-P, a nucleoside transport inhibitor, significantly reduces the neurotoxic effects of F-ara-AMP and improves treatment outcomes, resulting in a higher cure rate in the experimental model.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protection against fludarabine neurotoxicity in leukemic mice by the nucleoside transport inhibitor nitrobenzylthioinosine. Adjei, AA., Dagnino, L., Wong, MM., et al.[2019]

In a study of 394 acute myeloid leukemia patients undergoing allogeneic stem cell transplantation, the fludarabine plus melphalan (FM) regimen showed a significantly lower relapse incidence compared to fludarabine plus busulfan (FB), indicating better control of the disease.

Despite the differences in relapse rates, both FM and FB regimens resulted in similar overall survival rates, suggesting that while FM may be more effective in preventing relapse, both treatments are comparably effective in terms of long-term survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Baron, F., Labopin, M., Peniket, A., et al.[2015]

The study of 137 patients undergoing allogeneic hematopoietic stem cell transplantation found that the fludarabine-total body irradiation (FB-TBI) regimen showed trends toward improved progression-free survival (PFS) and overall survival (OS) compared to the fludarabine (FB) regimen, with 5-year PFS rates of 50% versus 34%.

FB-TBI was associated with a significantly lower incidence of chronic graft-versus-host disease (cGVHD) at 29% compared to 52% in the FB group, indicating it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of Busulfan, Fludarabine, and 400 cGy Total Body Irradiation Compared With Busulfan and Fludarabine Reduced-Intensity Conditioning Regimens for Allogeneic Stem Cell Transplantation in Adult Patients With Hematologic Diseases: A Single-Center Experience. Alkhaldi, H., Goloubeva, O., Rapoport, AP., et al.[2023]

Fludarabine, while used to reduce toxicity in bone marrow transplantation, can actually damage human endothelial and epithelial cells and provoke a proinflammatory response, which may complicate transplantation outcomes.

Defibrotide has been identified as a protective agent against the harmful effects of fludarabine, potentially allowing for safer pretransplant conditioning without compromising its antileukemic properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide. Eissner, G., Multhoff, G., Gerbitz, A., et al.[2021]

A conditioning regimen using fludarabine for haploidentical hematopoietic stem cell transplantation (HSCT) in 35 patients was found to be safe and feasible, with all patients achieving full donor-type engraftment.

The regimen resulted in a low incidence of severe acute graft-versus-host disease (GVHD) at 12.1% and a disease-free survival probability of 79.7% over an 8-25 month follow-up, indicating effective outcomes without increasing relapse or infection rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Conditioning regimen containing fludarabine instead of cyclophosphamide for haploidentical hematopoietic stem cell transplantation]. Chen, HR., He, XP., Si, YJ., et al.[2013]

Citations

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Early Results of a Cyclophosphamide Dose Deescalation ... Optimization of conditioning for marrow transplantation from unrelated donors for patients with aplastic anemia after failure of immunosuppressive therapy.

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Study Results | NCT00474747 | Fludarabine-based ... Outcome Measures · 1. Disease-free Survival (DFS). Type: Primary | Time Frame: Day 100 · 2. Cumulative Incidence of Graft Failure. Type: Secondary | Time Frame: ...

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Fludarabine Based RIC for Bone Marrow Failure Syndromes This is a pilot study to determine whether fludarabine-based reduced intensity conditioning (RIC) regimens facilitate successful donor engraftment.

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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.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02928991

Fludarabine Based RIC for Bone Marrow Failure Syndromes Patients 0-22 years with acquired aplastic anemia or a diagnosed inherited bone marrow failure syndrome, and a fully Human leukocyte antigen (HLA)-matched (10/ ...

7. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK459249/

Bone Marrow Failure - StatPearls - NCBI Bookshelf Common symptoms of inherited bone marrow failure syndromes are related to aplastic anemia. ... Nonmyeloablative regimens including fludarabine are preferred, ...

8. ashpublications.org ashpublications.org/blood/article/129/11/1428/35931/How-I-treat-acquired-aplastic-anemia

How I treat acquired aplastic anemia | Blood - ASH Publications Acquired aplastic anemia remains a difficult disease, with problems of ... bone marrow failure syndromes using fludarabine-based ...

9. ashpublications.org ashpublications.org/blood/article/140/6/556/485319/Inherited-bone-marrow-failure-in-the-pediatric

Inherited bone marrow failure in the pediatric patient | Blood ... aplastic anemia or myelodysplasia represent cryptic cases of inherited BM failure. Significant advances in the genetics of these syndromes ...