Cord Blood Transplant for Leukemia

Overseen By Claudio Brunstein, MD

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: Masonic Cancer Center, University of Minnesota

Disqualifiers: Pregnant, HIV positive, others

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

Compensation: Varies

Number of Visits: Unknown

200 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a treatment guideline for an unrelated umbilical cord blood transplant (UCBT) using a myeloablative preparative regimen for the treatment of hematological diseases, including, but not limited to acute leukemias. The myeloablative preparative regimen will consist of cyclophosphamide (CY), fludarabine (FLU) and fractionated total body irradiation (TBI).

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, since this is a transplant procedure, it's possible that some medications might need to be adjusted. Please consult with the trial coordinators for specific guidance.

What data supports the effectiveness of the treatment for leukemia?

Research shows that using total body irradiation (TBI) with fludarabine and cyclophosphamide as part of a conditioning regimen for hematopoietic cell transplantation can lead to lower relapse rates in leukemia patients compared to other regimens. However, higher exposures to these drugs can lead to worse outcomes, indicating the need for careful dosing. ^{1 2 3 4 5}

Is cord blood transplant for leukemia safe in humans?

Cord blood transplants using drugs like fludarabine and cyclophosphamide, often combined with total body irradiation, have been studied for safety. While these treatments can be effective, they may cause serious side effects, including severe myelosuppression (a decrease in bone marrow activity) and other toxicities, especially at higher doses. It's important to discuss potential risks with your healthcare provider. ^{1 6 7 8 9}

How is the cord blood transplant treatment for leukemia unique?

The cord blood transplant treatment for leukemia using cyclophosphamide, fludarabine, and total body irradiation is unique because it combines these agents to prepare the body for receiving new stem cells, potentially reducing toxicity compared to other regimens. This approach aims to improve engraftment (the process where new blood cells start to grow) while minimizing side effects, making it a promising alternative for patients with leukemia. ^{1 2 5 10 11}

Research Team

Claudio Brunstein, MD

Principal Investigator

University of Minnesota

Eligibility Criteria

This trial is for people aged 0-55 with certain blood diseases like leukemia, lymphoma, and myeloma. They should be in specific stages of the disease and have responded to initial treatments. Participants must consent to join. It's not for those who've had recent transplants, are pregnant or breastfeeding, HIV positive, or have had extensive prior therapy.

Inclusion Criteria

My initial cancer treatment has been effective.

I am between 0 and 55 years old.

I have a specific type or stage of blood cancer.

Exclusion Criteria

I am HIV positive.

My large cell or high grade NHL cancer did not respond to more than 2 treatments.

I've had extensive cancer treatment, including long-term alkylator therapy or radiation.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preparative Regimen

Participants undergo a myeloablative preparative regimen consisting of cyclophosphamide, fludarabine, and fractionated total body irradiation

1-2 weeks

Umbilical Cord Blood Transplantation

Participants receive an umbilical cord blood transplant followed by administration of immunosuppressive Cyclosporine and Mycophenylate Mofetil

1 week

Follow-up

Participants are monitored for survival, engraftment, and incidence of graft versus host disease

1 year

Treatment Details

Interventions

• Cyclophosphamide
• Fludarabine
• Total Body Irradiation

Trial Overview The study tests an umbilical cord blood transplant using a strong chemotherapy regimen (cyclophosphamide and fludarabine) plus total body irradiation as treatment for various hematological diseases. The goal is to see how well this combination works in patients with these conditions.

Participant Groups

Group I: Umbilical Cord Blood Transplant Experimental Treatment 6 Interventions

The myeloablative preparative regimen will consist of cyclophosphamide (CY), fludarabine (FLU) and fractionated total body irradiation (TBI)followed by umbilical cord blood transplant. Immunosuppressive Cyclosporine and Mycophenylate Mofetil (MMF) will be administered pre- and post UCBT.

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?

Masonic Cancer Center, University of Minnesota

Lead Sponsor

Trials

285

Recruited

15,700+

Findings from Research

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 modified myeloablative regimen using thiotepa, TBI, and fludarabine in 31 adult patients resulted in a high neutrophil engraftment rate of 90% by 60 days, indicating improved engraftment while reducing treatment-related mortality (TRM) to 30% at 3 years.

The study also reported manageable rates of acute and chronic graft-versus-host disease (GVHD), with 45% experiencing grades II to IV acute GVHD by day 100 and 40% developing chronic GVHD by 2 years, suggesting that this regimen is a promising alternative for umbilical cord blood transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adult Umbilical Cord Blood Transplantation Using Myeloablative Thiotepa, Total Body Irradiation, and Fludarabine Conditioning. Anand, S., Thomas, S., Corbet, K., et al.[2018]

In a study of 85 patients with hematological malignancies, adding fludarabine to a 2-Gy total body irradiation (TBI) regimen before stem cell transplantation resulted in better overall survival (65% vs. 54%) and lower relapse rates compared to TBI alone.

The combination of fludarabine and TBI led to significantly higher levels of donor T cell and NK cell chimerism, indicating improved donor engraftment and a stronger graft-versus-tumor effect, which is crucial for successful transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine and 2-Gy TBI is superior to 2 Gy TBI as conditioning for HLA-matched related hematopoietic cell transplantation: a phase III randomized trial. Kornblit, B., Maloney, DG., Storb, R., et al.[2021]

In a study of 2,255 adult patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic cell transplantation, conditioning with total body irradiation (TBI) plus cyclophosphamide (Cy) significantly reduced the risk of relapse compared to TBI plus fludarabine (Flu), with a relapse rate of 18% versus 30% at 2 years.

While TBI/Cy was associated with a higher risk of grade 2-4 acute graft-versus-host disease (GVHD), it did not significantly affect other transplantation outcomes, suggesting that TBI/Cy may be a preferable conditioning regimen for patients in complete remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine or cyclophosphamide in combination with total body irradiation as myeloablative conditioning prior to allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia: an analysis by the Acute Leukemia Working Party of the EBMT. Giebel, S., Labopin, M., Socié, G., et al.[2023]

The addition of 9 Gy of total body irradiation (TBI) to a reduced intensity regimen of fludarabine and melphalan in pediatric patients with advanced hematologic malignancies resulted in successful neutrophil and platelet engraftment, with 27 patients achieving neutrophil engraftment by a median of 16 days.

Despite some toxicities like oral mucositis and diarrhea, the treatment was generally well tolerated, and with a median follow-up of 52 months, 7 out of 22 patients with acute lymphoblastic leukemia (ALL) and 5 out of 6 patients with acute myeloid leukemia (AML) remained alive and in remission, indicating potential efficacy that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies. Petropoulos, D., Worth, LL., Mullen, CA., et al.[2013]

In a meta-analysis of 15 randomized controlled trials involving 10,160 pediatric patients, total body irradiation plus cyclophosphamide (TBI/CY) was found to be more effective than busulfan plus cyclophosphamide (BU/CY) in reducing transplant failure rates and improving long-term disease-free survival rates.

The TBI/CY regimen also demonstrated a lower incidence of adverse reactions compared to the BU/CY regimen, indicating it may be a safer option for pediatric hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two Different Transplant Preconditioning Regimens Combined with Irradiation and Chemotherapy in the Treatment of Childhood Leukemia: Systematic Review and Meta-Analysis. Wang, X., Mu, D., Geng, A., et al.[2023]

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]

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 phase I study involving 9 patients with advanced hematological malignancies, the combination of cytosine arabinoside (Ara-C) and cyclophosphamide (CY) with total body irradiation (TBI) resulted in severe toxicity, with multiple patients experiencing fatal outcomes at higher doses.

The study concluded that the concurrent administration of Ara-C and CY may not be suitable for phase I trials due to the high risk of severe, dose-independent toxicity, highlighting the need for caution in developing such treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simultaneous infusion of high-dose cytosine arabinoside with cyclophosphamide followed by total body irradiation and marrow infusion for the treatment of patients with advanced hematological malignancy. Petersen, FB., Appelbaum, FR., Buckner, CD., et al.[2016]

In a study of 38 patients with hematologic malignancies undergoing single-unit cord blood transplantation, the conditioning regimen of total-body irradiation (TBI) combined with FLAG chemotherapy resulted in a high donor engraftment rate of 97%.

The regimen was well tolerated, with a median follow-up of 46 months showing a 3-year event-free survival rate of 33.5%, significantly higher in the standard-risk group (72.7%) compared to the high-risk group (17.7%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unrelated umbilical cord blood transplantation using a TBI/FLAG conditioning regimen for adults with hematologic malignancies. Okada, M., Fujimori, Y., Misawa, M., et al.[2013]

In a study of 26 pediatric patients with Fanconi anemia undergoing stem cell transplantation, a conditioning regimen of low-dose cyclophosphamide, fludarabine, and antithymocyte globulin was well tolerated, showing low rates of complications like graft-versus-host disease and hemorrhagic cystitis.

All patients receiving HLA-matched related donor transplants successfully engrafted and remained alive and transfusion-independent after a median follow-up of 19 months, highlighting the regimen's effectiveness, especially in matched donor scenarios.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Saudi experience in fludarabine-based conditioning regimens in patients with Fanconi anemia undergoing stem cell transplantation: excellent outcome in recipients of matched related stem cells but not in recipients of unrelated cord blood stem cells. Ayas, M., Al-Seraihi, A., El-Solh, H., et al.[2013]

References

1. 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]

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

Adult Umbilical Cord Blood Transplantation Using Myeloablative Thiotepa, Total Body Irradiation, and Fludarabine Conditioning. [2018]

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

Fludarabine and 2-Gy TBI is superior to 2 Gy TBI as conditioning for HLA-matched related hematopoietic cell transplantation: a phase III randomized trial. [2021]

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

Fludarabine or cyclophosphamide in combination with total body irradiation as myeloablative conditioning prior to allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia: an analysis by the Acute Leukemia Working Party of the EBMT. [2023]

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

Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies. [2013]

6. England pubmed.ncbi.nlm.nih.gov

Two Different Transplant Preconditioning Regimens Combined with Irradiation and Chemotherapy in the Treatment of Childhood Leukemia: Systematic Review and Meta-Analysis. [2023]

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

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

8. England pubmed.ncbi.nlm.nih.gov

Phase I study of fludarabine (2-fluoro-ara-AMP). [2019]

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

Simultaneous infusion of high-dose cytosine arabinoside with cyclophosphamide followed by total body irradiation and marrow infusion for the treatment of patients with advanced hematological malignancy. [2016]

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

Unrelated umbilical cord blood transplantation using a TBI/FLAG conditioning regimen for adults with hematologic malignancies. [2013]

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

The Saudi experience in fludarabine-based conditioning regimens in patients with Fanconi anemia undergoing stem cell transplantation: excellent outcome in recipients of matched related stem cells but not in recipients of unrelated cord blood stem cells. [2013]