Cord Blood Transplant + Chemo for Blood Cancers

Overseen By Ann E. Dahlberg

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Fred Hutchinson Cancer Center

Must not be taking: Checkpoint inhibitors

Disqualifiers: Myelofibrosis, CNS involvement, 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: 181

54 Participants Needed

Trial Summary

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 trial involves chemotherapy and a cord blood transplant, it's possible that some medications might need to be adjusted or stopped. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment involving Cord Blood Transplant and Chemo for Blood Cancers?

Research shows that using fludarabine and cyclophosphamide in combination with total body irradiation can lead to successful engraftment and survival in patients undergoing stem cell transplantation. In one study, patients had a 73% overall survival rate at 180 days, indicating the potential effectiveness of this treatment approach. ^{1 2 3 4 5}

Is the combination of cord blood transplant, chemotherapy, and total body irradiation safe for treating blood cancers?

The combination of cord blood transplant, chemotherapy (including drugs like fludarabine and cyclophosphamide), and total body irradiation has been studied for safety. Some studies show that high doses can lead to severe side effects, including fatal toxicity, while others suggest that modified regimens can reduce these risks. Overall, treatment-related mortality and severe side effects are concerns, but adjustments in treatment plans may improve safety. ^{1 2 6 7 8}

How is the Cord Blood Transplant + Chemo treatment for blood cancers different from other treatments?

This treatment is unique because it uses umbilical cord blood transplantation combined with a reduced-intensity conditioning regimen of cyclophosphamide, fludarabine, and total-body irradiation, which can be an alternative for patients without a matched donor and who have not responded to other therapies. It offers a practical option for those who cannot undergo traditional stem cell transplants due to donor availability or previous treatment failures. ^{2 9 10 11 12}

What is the purpose of this trial?

This phase II trial studies how well giving an umbilical cord blood transplant together with cyclophosphamide, fludarabine, and total-body irradiation (TBI) works in treating patients with hematologic diseases. Giving chemotherapy, such as cyclophosphamide, fludarabine and thiotepa, and TBI before a donor cord blood transplant (CBT) helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after transplant may stop this from happening in patients with high-risk hematologic diseases.

Research Team

Ann E. Dahlberg

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

This trial is for patients aged 6 months to 65 years with high-risk blood cancers like leukemia, who haven't responded well to initial treatments or have specific genetic abnormalities. They must be in remission but can have some remaining cancer signs. Good organ function and performance status are required, and they shouldn't be pregnant, breastfeeding, or have had certain other recent treatments.

Inclusion Criteria

My overall health, organ function, and lab results meet specific criteria.

I am between 6 months and 65 years old.

My AML is in remission but still shows abnormal test results.

Exclusion Criteria

Inability to give informed consent or comply with treatment protocol

I've had radiation that makes it unsafe to receive more at 400cGy.

I do not have an active, uncontrolled infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Conditioning and Transplantation

Patients receive myeloablative conditioning with fludarabine, cyclophosphamide, thiotepa, and total-body irradiation followed by umbilical cord blood transplant

9 days

Daily visits for conditioning and transplantation

GVHD Prophylaxis

Patients receive GVHD prophylaxis with cyclosporine and mycophenolate mofetil

Up to 100 days

Regular monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Follow-up visits at day 180, 1 year, and 2 years

Treatment Details

Interventions

• Cyclophosphamide
• Fludarabine
• Total-Body Irradiation
• Umbilical Cord Blood Transplantation

Trial Overview The study tests if a cord blood transplant (CBT) combined with chemotherapy drugs cyclophosphamide, fludarabine, thiotepa and total-body irradiation (TBI) is effective for high-risk hematologic diseases. It aims to destroy cancer cells and prevent immune rejection of the donor stem cells which help rebuild the patient's bone marrow.

Participant Groups

Group I: Arm II (myeloablative UCBT) Experimental Treatment 13 Interventions

See detailed description.

Group II: Arm I (myeloablative UCBT) Experimental Treatment 12 Interventions

See detailed description.

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?

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

National Cord Blood Network

Collaborator

Trials

1

Recruited

50+

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 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]

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 47 adults undergoing double umbilical cord blood allogeneic stem cell transplantation, early recovery of immune cells (monocytes and lymphocytes) was linked to better overall survival rates, highlighting the importance of hematopoietic recovery in patient outcomes.

The study found that higher counts of monocytes and lymphocytes at specific recovery days (day +30 and day +42) were significant predictors of survival, suggesting that enhancing these immune responses could improve transplant success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher Early Monocyte and Total Lymphocyte Counts Are Associated with Better Overall Survival after Standard Total Body Irradiation, Cyclophosphamide, and Fludarabine Reduced-Intensity Conditioning Double Umbilical Cord Blood Allogeneic Stem Cell Transplantation in Adults. Le Bourgeois, A., Peterlin, P., Guillaume, T., et al.[2018]

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]

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 of 219 patients treated with fludarabine and cytosine arabinoside for acute leukemia or myelodysplasia, neurological toxicity occurred in 8 patients, with severe cases leading to fatal outcomes primarily in older patients with kidney issues.

The combination of fludarabine and cytosine arabinoside was linked to a low incidence of neurotoxicity, especially compared to high-dose Ara-C therapy, suggesting that careful monitoring and dose adjustments could mitigate risks in vulnerable populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurotoxicity associated with fludarabine and cytosine arabinoside chemotherapy for acute leukemia and myelodysplasia. Kornblau, SM., Cortes-Franco, J., Estey, E.[2013]

Umbilical cord blood transplantation from unrelated donors can be a viable treatment option for patients with severe aplastic anemia who lack an HLA-identical donor and have not responded to immunosuppressive therapy.

In a study involving two Japanese patients, the use of a reduced-intensity conditioning regimen (fludarabine, cyclophosphamide, and low-dose total-body irradiation) allowed for successful engraftment of all three blood lineages after cord blood transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Umbilical-cord blood cell transplantation conditioned with a reduced intensity-regimen is a practical salvage therapy for severe aplastic anemia refractory to immunosuppressive therapy with antithymocyte globulin/ciclosporin. Tajika, K., Mizuki, T., Nakayama, K., et al.[2021]

The pilot study involving 17 adult patients with advanced hematologic malignancies demonstrated the feasibility of reduced-intensity cord blood transplantation (RI-CBT) using a non-total body irradiation (TBI) regimen, with 9 out of 13 evaluable patients achieving successful engraftment.

Among the patients who achieved engraftment, 6 were alive in remission at a median follow-up of 13.1 months, suggesting that RI-CBT can provide a clinically significant graft-vs-tumor effect when disease progression is managed effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful engraftment of mismatched unrelated cord blood transplantation following reduced intensity preparative regimen using fludarabine and busulfan. Komatsu, T., Narimatsu, H., Yoshimi, A., et al.[2013]

The combination of granulocyte colony-stimulating factor (G-CSF) with cytarabine (Ara-C) showed enhanced cytotoxic effects on myeloid leukemic cells, suggesting a potentially more effective treatment approach for acute myelogenous leukemia during cord blood transplantation (CBT).

In a small study of five patients, a conditioning regimen using G-CSF, Ara-C, fludarabine, and total body irradiation led to successful engraftment and survival without leukemia relapse for up to 15 months, although some patients experienced mild to moderate side effects like gastrointestinal issues and acute graft-versus-host disease (GVHD).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cord blood transplantation for acute myelogenous leukemia using a conditioning regimen consisting of granulocyte colony-stimulating factor-combined high-dose cytarabine, fludarabine, and total body irradiation. Tomonari, A., Takahashi, S., Ooi, J., 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. England pubmed.ncbi.nlm.nih.gov

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

4. 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]

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

Higher Early Monocyte and Total Lymphocyte Counts Are Associated with Better Overall Survival after Standard Total Body Irradiation, Cyclophosphamide, and Fludarabine Reduced-Intensity Conditioning Double Umbilical Cord Blood Allogeneic Stem Cell Transplantation in Adults. [2018]

6. 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]

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

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

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

Neurotoxicity associated with fludarabine and cytosine arabinoside chemotherapy for acute leukemia and myelodysplasia. [2013]

9. Japan pubmed.ncbi.nlm.nih.gov

Umbilical-cord blood cell transplantation conditioned with a reduced intensity-regimen is a practical salvage therapy for severe aplastic anemia refractory to immunosuppressive therapy with antithymocyte globulin/ciclosporin. [2021]

10. Germany pubmed.ncbi.nlm.nih.gov

Successful engraftment of mismatched unrelated cord blood transplantation following reduced intensity preparative regimen using fludarabine and busulfan. [2013]

11. England pubmed.ncbi.nlm.nih.gov

Cord blood transplantation for acute myelogenous leukemia using a conditioning regimen consisting of granulocyte colony-stimulating factor-combined high-dose cytarabine, fludarabine, and total body irradiation. [2013]

12. 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]