Cord Blood Transplant for Blood Cancers

Overseen By Jaap Jan Boelens, MD, PhD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Disqualifiers: Advanced metabolic disease, CNS leukemic, 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

31 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method for treating blood cancers and severe blood disorders when patients lack a matching donor for a typical transplant. The study uses cord blood, rich in stem cells, to determine if it can safely replace diseased blood cells. Patients with certain types of leukemia or other life-threatening blood conditions might qualify. The trial will monitor patient outcomes one year after treatment. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, giving patients an opportunity to contribute to significant medical advancements.

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.

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

Research has shown that treatments used in cord blood transplants vary in safety levels. Clofarabine is generally well-tolerated by patients undergoing a second transplant for certain blood cancers, with acceptable side effects. However, risks include delayed engraftment, where transplanted cells take longer to function, and increased chances of graft rejection, where the body rejects the transplanted cells.

Fludarabine, another drug used in treatment, has been linked to high rates of treatment-related deaths and graft failure, indicating that some patients may not respond well and could face complications.

Busulfan, used to prepare the body for the transplant, has a 1-year graft failure rate of 11% and carries the risk of severe graft-versus-host disease (GVHD), where transplanted cells attack the patient's body.

Cord blood grafts are generally considered safe and effective but share similar risks, including graft rejection and GVHD. Despite these risks, umbilical cord blood is often used for high-risk leukemia cases.

As this trial is in an early phase, the researchers are still gathering safety evidence. However, previous studies provide some insight into potential risks and patient tolerance of the treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the cord blood transplant approach because it offers a unique mechanism to treat both malignant and non-malignant blood disorders. Unlike traditional bone marrow transplants or chemotherapy, this method utilizes cord blood, which is rich in stem cells that can regenerate healthy blood cells. Additionally, the combination of drugs like clofarabine, fludarabine, and busulfan before the transplant helps prepare the body more effectively, potentially reducing the risk of rejection and complications. This treatment could offer a promising alternative for patients who have not responded well to conventional therapies.

What evidence suggests that this trial's treatments could be effective for blood cancers?

Research has shown that using cord blood for transplants, especially with strong pre-treatment, leads to excellent results for patients with blood cancers. In this trial, participants with malignant hematologic disorders will receive clofarabine, fludarabine, and busulfan as part of their pre-transplant regimen. One study found that the survival rate one year after a double cord-blood transplant ranged from 65% to 73%. Clofarabine and fludarabine, used in preparation for the transplant, have proven effective, with patients experiencing good survival rates and fewer side effects compared to other methods. Additionally, busulfan in these transplants has improved long-term survival. These treatments aim to increase survival chances and reduce complications for patients without a matching donor. ^{1 4 6 7 8}

Who Is on the Research Team?

Maria Cancio, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Busulfan
• Clofarabine
• Cord Blood Graft
• Cyclosporine-A
• Fludarabine
• Mycophenolate Mofetil

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.

How Is the Trial Designed?

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 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?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Published Research Related to This Trial

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]

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]

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]

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 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]

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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32961374/

Outcome After Cord Blood Transplantation Using Busulfan ... We report the outcomes of cord blood transplantation (CBT) with a busulfan (Bu) pharmacokinetics-targeted myeloablative conditioning regimen in 97 children ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S1083879120305826

Outcome After Cord Blood Transplantation Using Busulfan ... We report the outcomes of cord blood transplantation (CBT) with a busulfan (Bu) pharmacokinetics-targeted myeloablative conditioning regimen in 97 children ...

3. astctjournal.org astctjournal.org/article/S1083-8791(20)30582-6/pdf

Outcome After Cord Blood Transplantation Using Busulfan ... In this cohort, the 5-year. OS of CBT has improved to 88% compared with previous results on CBT for children with HS [9,10] Compared with unrelated donor ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT00436761?tab=table

Busulfan, Melphalan, and Antithymocyte Globulin Followed By ... Types of outcome measures include primary outcome measure and secondary outcome measure. ... A type of intervention model describing a clinical trial in which two ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3163510/

Effect of Graft Source on Unrelated Donor Haemopoietic ... Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukemia: a retrospective analysis.

6. astctjournal.org astctjournal.org/article/S1083-8791(20)30582-6/fulltext?elqTrackId=4b9e3b95e9d242719f44492eba0cc00b

Outcome After Cord Blood Transplantation Using Busulfan ... The 1-year cumulative incidence of graft failure was 11% (95% confidence interval, 6% to 21%). Five patients (5%) had grade III-IV acute GVHD, 5 patients had ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0145212624000833

Single vs double umbilical cord blood transplantation in ... The Research found double umbilical cord blood transplant (UCBT) increases risk of severe acute graft-versus-host disease (GVHD. •. The study revealed a ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT01247701

Umbilical Cord Blood Transplant for Children With Myeloid ... In this study, the investigators will use busulfan and cyclophosphamide (BuCy) backbone with the addition of fludarabine as the preparative Stem Cell ...