Cord Blood Transplant for Blood Cancers

Recruiting in Palo Alto (17 mi)

Overseen by Maria Cancio, MD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Memorial Sloan Kettering Cancer Center

Disqualifiers: Advanced metabolic disease, CNS leukemic, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This is a single-arm study to investigate 1-year treatment related mortality (TRM) in patients with life threatening non-malignant and malignant hematologic disorders who do not have a matched related donor for allogeneic transplantation.

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 to get specific guidance based on your situation.

What data supports the effectiveness of the treatment for blood cancers?

Research shows that using clofarabine with fludarabine and busulfan as a pretransplant conditioning therapy can improve disease control in patients with blood cancers like acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In one study, 90% of patients achieved complete remission, and the combination was found to be safe and effective, especially in high-risk patients. ^{1 2 3 4 5}

Is cord blood transplant for blood cancers generally safe in humans?

Research shows that using busulfan and fludarabine as part of the preparation for cord blood transplants is generally safe, with studies indicating successful engraftment and minimal toxicity in some cases. However, the effectiveness and safety can vary depending on the specific combination of drugs and patient conditions, as some regimens may not provide sufficient immunosuppression for successful engraftment. ^{1 2 3 4 6}

What makes the Cord Blood Transplant treatment for blood cancers unique?

This treatment uses a combination of drugs, including fludarabine, busulfan, and clofarabine, to prepare patients for a cord blood transplant, which is a novel source of stem cells. The inclusion of clofarabine may enhance antileukemic activity, potentially improving outcomes for patients who are not in complete remission. ^{1 2 4 7 8}

Research Team

Maria Cancio, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for children and young adults up to age 21 with various high-risk blood cancers or non-malignant disorders, who lack a matched donor for transplantation. Participants must have certain types of leukemia or lymphoma in remission, specific metabolic diseases early in their course, adequate heart, lung, liver and kidney function, and no active central nervous system involvement by cancer.

Inclusion Criteria

My leukemia is in remission but at high risk of returning, or it has returned after treatment.

I have a high-risk blood disorder or lymphoma not in remission.

Patients with specific organ function and performance status criteria including Karnofsky or Lansky score ≥ 70%, bilirubin ≤ 1.5 mg/dL, ALT ≤ 3 x upper limit of normal, pulmonary function ≥ 50% predicted, left ventricular ejection fraction ≥ 50%, age-adjusted Hematopoietic Cell Transplantation-Comorbidity Index (aaHCT-CI) ≤ 7, and renal function within specified ranges

Exclusion Criteria

I do not have severe health issues unrelated to my cancer that would prevent me from safely participating.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Transplant Conditioning

Participants receive conditioning regimen including clofarabine, fludarabine, and busulfan, followed by tacrolimus and mycophenolate mofetil

12 days

Transplant

Participants undergo cord blood transplantation (CBT)

1 day

Post-Transplant

Participants receive filgrastim until ANC recovery and undergo blood sample collection, CT, and PET

Until ANC recovery

Follow-up

Participants are monitored for treatment related mortality and other outcomes

1 year

Treatment Details

Interventions

• Busulfan (Alkylating Agent)
• Clofarabine (Antimetabolite)
• Cord Blood Graft (Cell Therapy)
• Cyclosporine-A (Immunosuppressant)
• Fludarabine (Antimetabolite)
• Mycophenolate Mofetil (Immunosuppressant)

Trial Overview The study tests the effectiveness of cord blood transplants combined with chemotherapy drugs (Clofarabine, Fludarabine, Busulfan) and immune suppressants (Cyclosporine-A, Mycophenolate Mofetil) on survival without treatment-related mortality after one year. It's a single-arm study meaning all participants receive the same intervention.

Participant Groups

Group I: Participants with non-malignant hematologic disorders Experimental Treatment 6 Interventions

Patients with non-malignant disorders receive rituximab IV on day -12 and rabbit anti-thymocyte globulin (rATG) over 12 hours on day -12 to -9. Patients then receive clofarabine IV over 2 hours, fludarabine IV over 30 minutes, and busulfan IV over 3 hours on days -5 to -2. Beginning on day -3, patients receive tacrolimus IV or PO and mycophenolate mofetil IV over at least 2 hours. Patients may begin to taper tacrolimus at approximately 6 months post-transplant and mycophenolate mofetil at approximately 60 days post-transplant in the absence of ongoing GVHD requiring systemic immune suppression. TRANSPLANT: Patients undergo CBT on day 0. POST-TRANSPLANT: Beginning on day 7, patients receive filgrastim SC or IV over 15-30 minutes until ANC recovery. Patients also receive rituximab IV on day 30. Additionally, patients undergo blood sample collection, CT and PET on study.

Group II: Participants with malignant hematologic disorders Experimental Treatment 6 Interventions

Patients with malignant disorders receive clofarabine intravenously (IV) over 2 hours, fludarabine phosphate (fludarabine) IV over 30 minutes, and busulfan IV over 3 hours on days -5 to -2. Beginning on day -3, patients receive tacrolimus IV or orally (PO) and mycophenolate mofetil IV over at least 2 hours in the absence of unacceptable toxicity. Patients may begin to taper tacrolimus at approximately 3 months post-transplant and mycophenolate mofetil at approximately 60 days post-transplant in the absence of ongoing graft versus host disease (GVHD) requiring systemic immune suppression. TRANSPLANT: Patients undergo cord blood transplantation (CBT) on day 0.\*\*Subgroup will get rATG (day -12 to -10) POST-TRANSPLANT: Beginning on day 7, patients receive filgrastim subcutaneously (SC) or IV over 15-30 minutes until absolute neutrophil count (ANC) recovery. Additionally, patients undergo blood sample collection, computed tomography (CT) and positron emission tomography (PET) on study.

Busulfan is already approved in Canada, Japan for the following indications:

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?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Lisa M. DeAngelis

Memorial Sloan Kettering Cancer Center

Chief Medical Officer since 2021

MD from Columbia University

Selwyn M. Vickers

Memorial Sloan Kettering Cancer Center

Chief Executive Officer since 2022

MD from Johns Hopkins University

Findings from Research

In a study of 250 patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), the Fludarabine+Clofarabine-Busulfan (FCB) conditioning regimen showed a lower relapse incidence (25%) compared to the Fludarabine-Busulfan (Flu-Bu) regimen (39%), indicating better disease control, especially in non-complete remission (NCR) patients under 60 years old.

While FCB did not overall improve progression-free survival (PFS) compared to Flu-Bu (52% vs. 48%), it demonstrated significant benefits in specific patient groups, particularly younger NCR patients, suggesting that remission status and health condition should guide treatment choices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase III study of pretransplant conditioning for AML/MDS with fludarabine and once daily IV busulfan ± clofarabine in allogeneic stem cell transplantation. Andersson, BS., Thall, PF., Ma, J., et al.[2022]

In a study involving 10 adult patients with myeloid malignancies, the combination of once-daily intravenous busulfan and fludarabine as a preparative regimen for umbilical cord blood transplantation resulted in donor-derived neutrophil recovery in only 2 out of 10 patients, indicating poor engraftment.

The findings suggest that this myeloablative conditioning regimen does not provide adequate immunosuppression for successful engraftment of partially matched dual umbilical cord blood grafts, leading to the premature closure of the study due to graft failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Myeloablative intravenous busulfan/fludarabine conditioning does not facilitate reliable engraftment of dual umbilical cord blood grafts in adult recipients. Horwitz, ME., Morris, A., Gasparetto, C., et al.[2021]

A new conditioning regimen using clofarabine (Clo) combined with busulfan (Bu) has been shown to be safe and effective for patients with high-risk myeloid leukemia undergoing stem cell transplantation, with an encouraging median overall survival of 23 months for this challenging patient group.

In a clinical trial involving 51 patients, 85% achieved complete remission after treatment, indicating that Clo ± Flu with i.v. Bu can effectively support allogeneic stem cell transplantation in patients with active leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clofarabine ± fludarabine with once daily i.v. busulfan as pretransplant conditioning therapy for advanced myeloid leukemia and MDS. Andersson, BS., Valdez, BC., de Lima, M., et al.[2021]

In a study involving three children who were not ideal candidates for standard conditioning protocols, a fludarabine-based regimen combined with total body irradiation (TBI) and melphalan successfully facilitated umbilical cord blood (UCB) transplantation, leading to successful engraftment in all patients.

Two of the three patients are alive with complete chimerism 8 and 20 months post-transplant, suggesting that a fludarabine-based protocol may be a viable option for selected cases of UCB transplants, despite mild extramedullary toxicity observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine-based preparative protocol for unrelated donor cord blood transplantation in children: successful engraftment with minimal toxicity. Chan, KW., Békássy, AN., Ha, CS., et al.[2013]

In a study of 70 patients with high-risk acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS), the combination of clofarabine (Clo) and fludarabine (Flu) with intravenous busulfan (Bu) showed a high efficacy, with 90% of patients achieving complete remission and a low 100-day nonrelapse mortality rate of 4%.

The results indicated that higher doses of Clo and lower doses of Flu were associated with better overall and progression-free survival, particularly in patients with AML and MDS, highlighting the potential for optimizing pretransplant conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Outcomes after Treatment with Clofarabine ± Fludarabine with Once-Daily Intravenous Busulfan as Pretransplant Conditioning Therapy for Advanced Myeloid Leukemia and Myelodysplastic Syndrome. Alatrash, G., Thall, PF., Valdez, BC., et al.[2022]

In a study of 475 patients with acute myeloid leukemia undergoing cord blood transplantation, higher doses of busulfan (12.8 mg/kg) were associated with longer disease-free survival and lower relapse rates compared to intermediate doses (6.4 mg/kg).

The study found no significant difference in non-relapse mortality between the two dosing groups, suggesting that higher busulfan doses are safe and beneficial, especially for patients not in complete remission and those under 60 years old.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advantages of Higher Busulfan Dose Intensity in Fludarabine-Combined Conditioning for Patients with Acute Myeloid Leukemia Undergoing Cord Blood Transplantation. Shibata, S., Arai, Y., Kondo, T., et al.[2023]

Reduced intensity umbilical cord blood transplantation (RI-UCBT) in 21 children and adolescents showed promising results with a 5-year overall survival rate of 59.8%, particularly higher for patients with average-risk malignancies (77.8%) compared to poor-risk malignancies (22.2%).

While RI-UCBT can lead to graft failure in certain high-risk patients, it generally allows for rapid engraftment and may reduce the incidence of severe graft-versus-host disease (28.6%) and transplant-related mortality (14%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced intensity allogeneic umbilical cord blood transplantation in children and adolescent recipients with malignant and non-malignant diseases. Bradley, MB., Satwani, P., Baldinger, L., et al.[2017]

In a study of 2910 patients with acute myeloid leukemia (AML) undergoing transplants, the thiotepa-busulfan-fludarabine (TBF) conditioning regimen showed significantly lower relapse rates compared to the busulfan-fludarabine (BF) regimen, but it also resulted in higher non-relapse mortality (NRM).

Despite the stronger anti-leukemic activity of TBF-MAC, overall survival and leukemia-free survival rates were similar to those of BF-MAC, indicating that while TBF may reduce relapse, it does not necessarily improve long-term survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thiotepa-busulfan-fludarabine compared to busulfan-fludarabine for sibling and unrelated donor transplant in acute myeloid leukemia in first remission. Saraceni, F., Labopin, M., Hamladji, RM., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

A randomized phase III study of pretransplant conditioning for AML/MDS with fludarabine and once daily IV busulfan ± clofarabine in allogeneic stem cell transplantation. [2022]

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

Myeloablative intravenous busulfan/fludarabine conditioning does not facilitate reliable engraftment of dual umbilical cord blood grafts in adult recipients. [2021]

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

Clofarabine ± fludarabine with once daily i.v. busulfan as pretransplant conditioning therapy for advanced myeloid leukemia and MDS. [2021]

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

Fludarabine-based preparative protocol for unrelated donor cord blood transplantation in children: successful engraftment with minimal toxicity. [2013]

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

Long-Term Outcomes after Treatment with Clofarabine ± Fludarabine with Once-Daily Intravenous Busulfan as Pretransplant Conditioning Therapy for Advanced Myeloid Leukemia and Myelodysplastic Syndrome. [2022]

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

Advantages of Higher Busulfan Dose Intensity in Fludarabine-Combined Conditioning for Patients with Acute Myeloid Leukemia Undergoing Cord Blood Transplantation. [2023]

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

Reduced intensity allogeneic umbilical cord blood transplantation in children and adolescent recipients with malignant and non-malignant diseases. [2017]

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

Thiotepa-busulfan-fludarabine compared to busulfan-fludarabine for sibling and unrelated donor transplant in acute myeloid leukemia in first remission. [2022]