Chemotherapy + Stem Cell Transplant for Fanconi Anemia

(RAFA Trial)

Recruiting at 1 trial location

Overseen By Sara Loveless, RN

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Hospital Medical Center, Cincinnati

Disqualifiers: Active CNS leukemia, HIV, 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

70 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The trial aims to improve stem cell transplant outcomes for individuals with Fanconi Anemia by testing lower doses of the chemotherapy drug busulfan and removing cyclosporine to reduce side effects. Participants are divided into groups based on risk level, testing the combination of busulfan, cyclophosphamide (another chemotherapy drug), and other supportive treatments. The trial seeks participants with Fanconi Anemia and conditions such as severe aplastic anemia, myelodysplastic syndrome, or acute myelogenous leukemia. Participants must function well in daily life and meet specific blood and organ health criteria.

As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in treatment.

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

The trial does not specify if you need to stop taking your current medications. However, since the study involves chemotherapy and a stem cell transplant, it's possible that some medications might need to be adjusted. Please consult with the trial coordinators for specific guidance.

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

Research has shown that both busulfan and cyclophosphamide have been studied in people with Fanconi Anemia, providing some information about their safety. Patients who received busulfan experienced few side effects and no serious cases of graft-versus-host disease (GVHD), where donor cells attack the patient's body. Studies have also found that lowering the busulfan dose remains effective, suggesting that the treatment is generally well-tolerated.

Cyclophosphamide supports the growth of new cells without causing serious genetic damage in animal studies, indicating good safety potential. It has also been used safely after transplants in similar situations.

These findings are promising, as they show that both treatments can be managed well by patients, even those with a sensitive condition like Fanconi Anemia. However, it's important to remember that individual reactions can vary, and these studies provide a general idea of safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the chemotherapy plus stem cell transplant approach for Fanconi Anemia because it optimizes the use of existing chemotherapy drugs like busulfan and cyclophosphamide in combination with stem cell transplants. Unlike standard treatments that often rely heavily on cyclosporine for GVHD prophylaxis, this protocol skips cyclosporine and focuses on enhancing engraftment using granulocyte-colony stimulating factor (G-CSF) and T-cell depletion through the Miltenyi system. This method not only aims to maintain high survival rates but also introduces a slightly reduced busulfan dose to improve outcomes while ensuring successful engraftment. By refining these aspects, the treatment holds promise for better efficacy and safety profiles compared to traditional options.

What evidence suggests that this trial's treatments could be effective for Fanconi Anemia?

Studies have shown that using busulfan in stem cell transplants has produced positive results for patients with Fanconi Anemia. Specifically, research found that patients did not experience severe cases of GVHD (graft-versus-host disease) and saw improvements in blood cell health without needing radiation. In this trial, participants in different arms will receive busulfan, with doses carefully adjusted for each patient to reduce the risk of harmful side effects, a major concern for those with Fanconi Anemia.

Cyclophosphamide also plays a crucial role in this trial's treatment regimen. It has effectively prevented GVHD and is associated with good survival rates in patients. The combination of busulfan and cyclophosphamide in transplants appears promising, offering a potentially successful treatment option for people with this condition. ^{1 2 4 5 6}

Who Is on the Research Team?

Parinda Mehta, MD

Principal Investigator

CCHMC

Are You a Good Fit for This Trial?

This trial is for patients with Fanconi Anemia who need a stem cell transplant. They should have specific blood conditions like severe aplastic anemia or leukemia, and be in good physical shape with a performance status over 70%. Pregnant or breastfeeding women can't join, nor can those with HIV, active CNS leukemia, or uncontrolled infections.

Inclusion Criteria

I have been diagnosed with Fanconi anemia.

My heart, liver, kidneys, and lungs are functioning well.

I am not pregnant or breastfeeding and agree to pregnancy tests and avoiding pregnancy while in the study.

Exclusion Criteria

You have tested positive for HIV or HTLV infection.

I do not have any ongoing serious infections.

I have leukemia that has spread to my brain.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy

Participants receive a risk-adjusted chemotherapy-based cytoreductive regimen including busulfan, cyclophosphamide, fludarabine, and rabbit ATG prior to stem cell transplant.

2 weeks

Stem Cell Transplant

Participants undergo a CD34+ selected T-cell depleted peripheral blood stem cell transplant.

1 week

Follow-up

Participants are monitored for safety and effectiveness, including observation for graft versus host disease and other post-transplant complications.

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Busulfan
• Cyclophosphamide

Trial Overview

The study tests if lower doses of busulfan without cyclosporine reduce side effects in FA patients getting transplants from mismatched related or unrelated donors. The regimen includes busulfan, fludarabine, anti-thymocyte globulin (ATG), and cyclophosphamide.

How Is the Trial Designed?

Group I: Arm C: High Risk Patients Experimental Treatment 6 Interventions

Patients 19 years old or older with marrow aplasia or MDS or AML will receive intravenous busulfan (4 doses x 2 days), cyclophosphamide (4 doses x 4 days) and fludarabine (4 doses x 4 days). In this study, we will test whether outcomes can be improved, yet engraftment maintained, with a slightly reduced dose of busulfan. Patients will receive rabbit ATG (4 doses x 4 days) prior to and G-CSF post transplant to promote engraftment. Cyclosporine will not be used for GVHD prophylaxis. The source of the stem cells will be peripheral blood stem cells collected from donors treated with G-CSF. T-cell depletion will be performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device). The maximum number of patients enrolled will be 10.

Group II: Arm B: Intermediate Risk Patients Experimental Treatment 6 Interventions

Patients 18 years old or younger with MDS or AML will receive intravenous busulfan (4 doses x 2 days), cyclophosphamide (4 doses x 4 days) and fludarabine (4 doses x 4 days). Busulfan pharmacokinetics will be used in this arm, as the dose of busulfan is higher. All patients will receive rabbit ATG (thymoglobulin) (4 doses x 4 days) prior to and G-CSF post transplant to promote engraftment. Cyclosporine will not be used for prophylaxis against GVHD. The source of the stem cells for all patients will be peripheral blood stem cells induced and mobilized by treatment of the donor. T-cell will be performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device). The maximum number of patients enrolled in this arm will be 10.

Group III: Arm A: Good Risk Patients Experimental Treatment 6 Interventions

Patients 18 years old or younger with marrow aplasia or single lineage cytopenias will be receive intravenous busulfan (4 doses x 2 days), cyclophosphamide (4 doses x 4 days) and fludarabine (4 doses x 4 days), as used in our most current study that led to \> 90% survival rates . Busulfan pharmacokinetics will not be used. All patients will receive rabbit ATG (4 doses x 4 days) prior to and granulocyte-colony stimulating factor (G-CSF) after transplant to promote engraftment. Cyclosporine will not be used for GVHD prophylaxis. The source of the stem cells for all patients will be peripheral blood stem cells mobilized by treatment of the donor with G-CSF. T-cell depletion will be performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device). Enrollment on this arm will include up to 50 patients.

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

Approved in United States as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Malignant lymphoma
• Bone marrow transplantation conditioning

Approved in European Union as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Canada as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Japan as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

Memorial Sloan Kettering Cancer Center

Collaborator

Trials

1,998

Recruited

602,000+

Fred Hutchinson Cancer Center

Collaborator

Trials

583

Recruited

1,341,000+

Published Research Related to This Trial

An 11-year-old girl with myelodysplastic syndrome due to Fanconi anemia successfully underwent allogeneic bone marrow transplantation after failing initial chemotherapy, showing promising results.

17 months post-transplant, she achieved full hematological recovery with no signs of myelodysplastic syndrome, indicating the efficacy of the treatment and a favorable post-transplant course.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermediate-dose busulfan and cyclophosphamide as a conditioning regimen for bone marrow transplantation in a case of Fanconi anemia in myelodysplastic transformation. Maschan, AA., Kryzanovskii, OI., Yourlova, MI., et al.[2013]

A novel conditioning regimen for allogeneic hematopoietic stem cell transplantation (SCT) in Fanconi anemia patients showed rapid engraftment and stable donor hemopoiesis with minimal short-term toxic complications, indicating its safety and efficacy.

The conditioning regimen, which avoided irradiation and cyclophosphamide, resulted in low organ toxicity and effective immunosuppression, although some patients experienced mild acute graft-versus-host disease (GVHD).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, low-dose busulfan and antithymocyte globulin as conditioning for Fanconi anemia patients receiving bone marrow transplantation from HLA-compatible related donors. Maschan, AA., Trakhtman, PE., Balashov, DN., et al.[2013]

A radiation-free conditioning regimen for hematopoietic cell transplantation (HCT) in 45 patients with Fanconi anemia resulted in an overall survival rate of 80% and disease-free survival of 77.7% after one year, demonstrating the efficacy of this approach.

The study showed that no patients developed severe acute graft-versus-host disease (GVHD), and all young children under 10 years old survived, indicating a safer profile for this transplantation method.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation-free, alternative-donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Mehta, PA., Davies, SM., Leemhuis, T., et al.[2021]

In a pilot study of 20 patients with acute myeloid leukemia (AML), a new preparative regimen combining high-dose busulfan (120 mg/kg) and reduced cyclophosphamide (200 mg/kg) resulted in significant non-life-threatening toxic effects, including skin reactions, nausea, and oral mucositis, but showed a manageable safety profile overall.

The regimen demonstrated promising outcomes with a 3-year event-free survival rate of 55% and a leukemic recurrence probability of 38%, suggesting its potential effectiveness compared to traditional preparative regimens for marrow transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute toxicity and first clinical results of intensive postinduction therapy using a modified busulfan and cyclophosphamide regimen with autologous bone marrow rescue in first remission of acute myeloid leukemia. Beelen, DW., Quabeck, K., Graeven, U., et al.[2021]

The BUCY regimen, combining busulfan and cyclophosphamide, was found to be safe for autologous hematopoietic stem cell transplantation in 20 patients with multiple myeloma, with no treatment-related mortality within 100 days post-transplant.

Hematopoietic recovery was prompt, with neutrophil and platelet counts returning to normal within 8 to 18 days, and all patients survived the treatment, although the partial remission rate dropped significantly after transplantation, indicating the need for further long-term monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Busulfan Combined with Cyclophosphamide as the Conditioning Regimen in Patients with Multiple Myeloma Treated by Autolo-gous Hematopoietic Stem Cell Transplantation]. Jin, S., Xu, Y., Wang, PF., et al.[2018]

In a study of 69 patients undergoing allogeneic hematopoietic stem cell transplantation with busulfan and cyclophosphamide (Bu/Cy), the three-year overall survival rate was 62%, indicating that this treatment regimen is relatively safe and effective over the long term.

The study found that using body size measures like ideal body weight for dosing busulfan resulted in adequate drug exposure in 73% of patients, suggesting that these measures are important for optimizing treatment, especially in patients with extreme body weights.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluating the Efficacy, Toxicity and Pharmacokinetic Profile of Oral Busulfan in Allogeneic Stem Cell Transplant Patients. Salvaris, R., Salman, S., O'Halloran, S., et al.[2023]

In a study of 17 patients with Fanconi anemia who underwent allogeneic bone marrow transplantation, a low-dose conditioning regimen of cyclophosphamide and busulfan resulted in successful engraftment in all patients, with a median engraftment time of 12 days.

The overall survival rate was 72% after a median follow-up of 16 months, indicating that this treatment approach is effective with relatively low toxicity, although early graft failure remains a concern that may need further adjustments to the regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bone marrow transplantation from matched related donors for patients with Fanconi anemia using low-dose busulfan and cyclophosphamide as conditioning. Torjemane, L., Ladeb, S., Ben Othman, T., et al.[2013]

All five patients aged 7-14 with Fanconi anemia successfully underwent allogeneic bone marrow transplantation (BMT) and are alive 18-67 months post-transplant, demonstrating the treatment's efficacy.

The modified conditioning regimen used in this study, which included low-dose cyclophosphamide and fractionated total body irradiation, resulted in normal blood cell production and a reduced risk of severe complications, supporting BMT as a first-choice treatment for FA when an HLA-identical donor is available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic bone marrow transplantation for Fanconi anemia. Di Bartolomeo, P., Di Girolamo, G., Olioso, P., et al.[2006]

A non-radiation preparative regimen using cyclophosphamide and busulfan was evaluated in 23 adults with advanced multiple myeloma, resulting in 3 complete responses and 13 partial responses, indicating its efficacy as a conditioning treatment before bone marrow or blood cell transplants.

The study found a 1-year survival rate of 63% post-transplant, with better outcomes for patients who were responsive to chemotherapy before the transplant (78% survival) compared to those with resistant disease (38% survival), highlighting the importance of pre-transplant disease status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I-II study of busulfan and cyclophosphamide conditioning for transplantation in advanced multiple myeloma. Schiller, G., Nimer, S., Vescio, R., et al.[2013]

In a phase I study involving 12 adult patients with intermediate-risk acute myeloid leukemia (AML), targeted intravenous busulfan combined with etoposide was found to be safe, with mucositis being the most significant side effect observed.

The study indicated a trend towards improved two-year relapse-free survival in patients receiving the higher dose of busulfan (AUC 1400 μmol/min) compared to the lower dose (AUC 1250 μmol/min), suggesting potential efficacy that warrants further investigation in a phase II study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of targeted, dose-escalated intravenous busulfan in combination with etoposide as myeloablative therapy for autologous stem cell transplantation in acute myeloid leukemia. Mannis, GN., Andreadis, C., Logan, AC., et al.[2015]

In a study of 122 patients with Fanconi anemia who underwent hematopoietic stem cell transplantation (HSCT) using a radiation-free, busulfan-based conditioning regimen, the 1- and 5-year overall survival rates were 84.14% and 82.16%, respectively, indicating promising outcomes for this treatment approach.

Graft rejection was rare, occurring in only one patient, suggesting that this conditioning regimen is effective and safe for patients with Fanconi anemia, particularly when considering the risks associated with radiation exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation-free reduced-intensity hematopoietic stem cell transplantation with in vivo T-cell depletion from matched related and unrelated donors for Fanconi anemia: prognostic factor analysis. Rostami, T., Mousavi, SA., Kiumarsi, A., et al.[2022]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12443608/

Irradiation- and busulfan-free stem cell transplantation in ...

All patients are alive and well with resolution of earlier chromosomal breakage abnormalities in peripheral blood lymphocytes post treatment.

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC7219959/

Busulfan Pharmacokinetics and Precision Dosing

Fanconi anemia (FA) patients are at risk for excessive toxicity during transplant · This is the first report of Busulfan (BU) pharmacokinetics in patients with ...

3.

sciencedirect.com

sciencedirect.com/science/article/pii/S2666636725000855

36 Hematopoietic Recovery in Fanconi Anemia Patients ...

Our results highlight the successful development of a busulfan and TBI-free protocol for FA patients using anti-CD117 mAb-containing conditioning and ...

4.

ashpublications.org

ashpublications.org/blood/article/129/16/2308/35914/Radiation-free-alternative-donor-HCT-for-Fanconi

Radiation-free, alternative-donor HCT for Fanconi anemia ...

No patients developed acute grade 3-4 GVHD. Sequential reduction of busulfan dose was successfully achieved per study design. Our results show ...

5.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03600909?term=AREA%5BConditionSearch%5D(%22Fanconi%20Syndrome%22)%20AND%20AREA%5BInterventionSearch%5D(%22Busulfan%22)&rank=1

A Study of the Effect of Blood Stem Cell Transplant After ...

A standard dose of busulfan , associated with excellent outcomes in our previous trial will be used for young patients with marrow aplasia (arm A). A higher ...

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT02143830

HSCT for Patients With Fanconi Anemia Using Risk ...

A standard dose of busulfan, associated with excellent outcomes in our previous trial will be used for young patients with marrow aplasia (arm A). A higher dose ...