Shortened Chemotherapy Before Stem Cell Transplant for Blood Cancers

Overseen By Roni Tamari, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Disqualifiers: Active infection, CNS malignancy, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a shortened chemotherapy regimen can reduce severe side effects for individuals with various blood cancers following a stem cell transplant. It will test a combination of drugs, including antithymocyte globulin (ATG), busulfan, melphalan, and fludarabine, to assess their effectiveness when administered over a shorter duration. Suitable candidates for this trial have blood cancers, such as multiple myeloma or certain types of leukemia, and have not previously undergone a donor stem cell transplant. As a Phase 1 trial, the research focuses on understanding the treatment's effects in participants, offering them a chance to be among the first to receive this potentially groundbreaking therapy.

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.

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

Research has shown that the chemotherapy drugs busulfan, melphalan, and fludarabine, used before stem cell transplants, can cause serious side effects. Some studies found a high rate of non-relapse mortality, indicating serious risks unrelated to cancer recurrence. This suggests that this drug combination can be particularly taxing on the body, especially for older adults.

Antithymocyte globulin (ATG) helps prevent graft-versus-host disease, where transplanted cells attack the body. While ATG reduces some risks, it can also slow immune system recovery and delay new blood cell growth.

The current study is in its early testing phase, so specific safety information for this shorter chemotherapy treatment remains limited. Early trial phases generally focus on safety, and the results will help determine how well participants can tolerate this new approach. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this trial because it explores a shortened chemotherapy regimen before stem cell transplants for blood cancers, aiming to make the process less taxing on patients. Unlike traditional, prolonged chemotherapy protocols, this approach uses a combination of Busulfan, Melphalan, and Fludarabine over a compressed timeframe, potentially reducing side effects and improving recovery times. Additionally, the use of Antithymocyte globulin (ATG) is intended to enhance engraftment and provide extra protection against graft-versus-host disease. This innovative approach could offer a more effective and patient-friendly alternative to existing treatment options.

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

Research has shown that the combination of chemotherapy drugs busulfan, melphalan, and fludarabine can effectively treat blood cancers. In this trial, one group of patients with multiple myeloma will receive a specific regimen of these drugs, while another group with other hematologic malignancies will receive a slightly different regimen. Specifically, using busulfan and melphalan together has been linked to longer periods without cancer progression and longer overall survival. Fludarabine has demonstrated positive results in patients with blood cancers, improving their outcomes. Additionally, all patients receiving matched related or unrelated donor allografts in this trial will receive antithymocyte globulin (ATG) to reduce the risk of graft-versus-host disease (GVHD) after a stem cell transplant. Overall, these drugs work together to target cancer cells and support the success of a stem cell transplant. ^{3 6 7 8 9}

Who Is on the Research Team?

Michael Scordo, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

Adults with various blood cancers eligible for stem cell transplantation may join this trial. They should have specific types of leukemia, myeloma, or lymphoma responding to therapy, adequate organ function, and not be pregnant or breastfeeding. Those with active brain cancer, uncontrolled infections, recent autologous transplants (except certain myeloma cases), HIV/HTLV, or unwillingness to use contraception are excluded.

Inclusion Criteria

My AML is in the first complete remission and is not low risk.

My condition is chronic myeloid leukemia (CML).

I am recommended for a stem cell transplant due to my blood cancer.

Exclusion Criteria

I had a stem cell transplant using my own cells less than 6 months ago, except if I have high-risk multiple myeloma.

Patient or guardian unable to give informed consent or unable to comply with the treatment protocol.

My cancer has spread outside the bone marrow.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy

Participants receive a condensed chemotherapy regimen of busulfan, melphalan, and fludarabine, along with antithymocyte globulin (ATG) for GVHD prophylaxis

7 days

Transplantation

Participants undergo allogeneic hematopoietic cell transplantation

1 day

Follow-up

Participants are monitored for safety and effectiveness, focusing on grade 4 toxicities, for 30 days post-transplantation

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Allogeneic hematopoietic cell transplantation (Allo-HCT)
• Antithymocyte globulin (ATG)
• Busulfan
• Fludarabine
• Melphalan

Trial Overview The study is testing a shortened chemotherapy regimen before allogeneic hematopoietic cell transplantation (Allo-HCT). It involves lower doses of busulfan combined with melphalan and fludarabine plus antithymocyte globulin (ATG) to see if it reduces severe side effects within 30 days post-transplant.

How Is the Trial Designed?

Group I: patients with multiple myeloma Experimental Treatment 5 Interventions

A. Busulfan 0.8 mg/kg every 6 hours x 10 doses, with dose adjustments made according to PK levels. B. Melphalan (70 mg/m2/day) administered on days -6 and -5. C. Fludarabine (25 mg/m2/day) administered on days -6, -5, -4, -3, -2. All patients receiving matched related or unrelated donor allografts receive anti-thymocyte globulin (ATG) 2.5 mg/kg/day on days -3 and -2 to deplete chemotherapy resistant host T-cells that could hinder engraftment, and it may provide additional GVHD prophylaxis.

Group II: patients hematologic malignancies other than multiple myeloma Experimental Treatment 5 Interventions

A. Busulfan 3.2 mg/kg/day, with dose adjustments made according to pharmacokinetic (PK) levels. B. Melphalan (70mg/m2/day) administered on days -6 and -5. C. Fludarabine (25mg/m2/ day) administered on days -6, -5, -4, -3, and -2. All patients receiving matched related or unrelated donor allografts receive anti-thymocyte globulin (ATG) 2.5 mg/kg/day on days -3 and -2 to deplete chemotherapy resistant host T-cells that could hinder engraftment, and it may provide additional GVHD prophylaxis.

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 of 32 patients with acute myeloid leukemia in first complete remission, the busulfan/fludarabine (Bu/Flu) conditioning regimen resulted in significantly lower transplant-related toxicity compared to the busulfan/cyclophosphamide (Bu/Cy) regimen, with a lower incidence of severe side effects (68.8% vs. 25.0%).

Both regimens showed similar efficacy in terms of overall survival and event-free survival rates, indicating that Bu/Flu is a safer option without compromising treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A comparison of toxicity and efficacy between busulfan plus fludarabine and busulfan plus cyclophosphamide for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia]. Liu, H., Fan, ZP., Jiang, QL., et al.[2014]

In a study comparing two treatment regimens for children undergoing hematopoietic cell transplantation, the combination of fludarabine and busulfan (FluBu) showed similar survival rates to busulfan and cyclophosphamide (BuCy), with 2-year survival rates of 82% for FluBu and 78% for BuCy.

The FluBu regimen was associated with significantly lower toxicity, including reduced rates of lung injury, veno-occlusive disease, and infections, as well as a shorter duration of neutropenia, indicating it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine and exposure-targeted busulfan compares favorably with busulfan/cyclophosphamide-based regimens in pediatric hematopoietic cell transplantation: maintaining efficacy with less toxicity. Bartelink, IH., van Reij, EM., Gerhardt, CE., et al.[2014]

The FLU/BU4/MEL conditioning regimen, which includes fludarabine, busulfan, and melphalan, demonstrated curative potential in patients with advanced myeloid malignancies, achieving complete chimerism within one month after transplantation.

In a study of 42 patients, the 4-year overall survival rate was 66.0% and the disease-free survival rate was 59.5%, indicating that this regimen is effective even for those who were not in complete remission at the time of transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of melphalan to fludarabine/busulfan (FLU/BU4/MEL) provides survival benefit for patients with myeloid malignancy following allogeneic bone-marrow transplantation/peripheral blood stem-cell transplantation. Ueda, T., Maeda, T., Kusakabe, S., et al.[2020]

The study compared outcomes of 67 patients treated with intravenous busulfan-cyclophosphamide to 148 patients treated with busulfan-fludarabine before allogeneic stem cell transplantation, finding that the busulfan-fludarabine regimen resulted in significantly improved safety and recovery from side effects.

Patients receiving the busulfan-fludarabine treatment had extremely low one-year treatment-related mortality and high overall and event-free survival rates, suggesting that this regimen may be a better option than conventional chemotherapy for those in first complete remission of acute myeloid leukemia or myelodysplastic syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-toxicity conditioning therapy with allogeneic stem cell transplantation for acute leukemia. Andersson, BS., de Lima, M., Thall, PF., et al.[2021]

In a study of 54 adults undergoing matched related donor blood cell transplantation, pretransplantation anti-thymocyte globulin (ATG) significantly reduced the incidence of chronic graft-versus-host disease (cGVHD) from 96% in the control group to 55% in the ATG group, indicating improved safety and potential quality of life for survivors.

Patients receiving ATG also experienced lower non-relapse mortality rates at 100 days (4% vs. 17%) and at 4 years (9% vs. 34%), suggesting that ATG may enhance overall survival despite a trend towards higher relapse rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adult recipients of matched related donor blood cell transplants given myeloablative regimens including pretransplant antithymocyte globulin have lower mortality related to graft-versus-host disease: a matched pair analysis. Russell, JA., Turner, AR., Larratt, L., et al.[2013]

In a study of 95 patients undergoing allogeneic stem cell transplantation, replacing cyclophosphamide with fludarabine in the conditioning regimen (busulfan+fludarabine) led to faster engraftment and significantly lower rates of acute and chronic graft-versus-host disease (GVHD).

The fludarabine regimen also resulted in better event-free survival and overall survival rates compared to the standard busulfan and cyclophosphamide regimen, indicating it may be a more effective option for myeloablative conditioning in allogeneic SCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. Chae, YS., Sohn, SK., Kim, JG., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12031750/

Comparison of ATG-thymoglobulin with atg-fresenius in ... We retrospectively compared the outcomes of 166 patients with hematological malignancies who underwent allogeneic hematopoietic stem cell ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/23383989/

Long-term outcomes of antithymocyte globulin in patients ... We conclude prophylactic use of ATG exerts a favorable effect in reducing cGVHD without survival impairment in a long term, although a higher relapse rate is a ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S1465324925007194

Adjustment of low-dose ATG exposure improves outcomes ... This study aimed to explore the relationship between ATG exposure and transplant outcomes, with a focus on immune reconstitution and GVHD prevention.

4. nature.com nature.com/articles/s41598-023-34442-y

Impact of anti-thymocyte globulin on survival outcomes in ... The use of ATG in female-to-male allo-HCT resulted in survival outcomes that were almost equivalent to those in the male-to-male allo-HCT group.

5. link.springer.com link.springer.com/article/10.1007/s00277-025-06608-3

Cytogenetic risk–associated outcomes of antithymocyte ... After a median follow-up of 91 months, ATG use (n = 96) reduced the incidence of cGvHD (HR 0.43; 95% CI 0.26–0.72; p = 0.001) and improved cGvHD ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26973125/

Antithymocyte globulin in allogeneic hematopoietic cell ... Antithymocyte globulin (ATG) is an important in vivo T-cell depletion strategy, which reduces the risk of graft-versus-host disease in HLA-matched or - ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2473952925001247

Improved survival with model-based dosing of ... Model-based dosing of ATG leads to improved survival and reduced morbidity compared with conventional fixed dosing.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12370499/

Optimizing anti-thymocyte globulin dosing in allogeneic ... This review summarizes the advances and the challenges of individualized ATG dosing in allo-HSCT. Keywords: antithymocyte globulin, graft-versus-host disease, ...

9. ashpublications.org ashpublications.org/bloodadvances/article/1/9/573/15605/ATG-in-allogeneic-stem-cell-transplantation

ATG in allogeneic stem cell transplantation: standard of care ... Antithymocyte globulin clearly impairs immune reconstitution after HSCT and may also lead to delayed engraftment.10,16 In the Canadian ...