Radiation Therapy + Chemotherapy Before Stem Cell Transplant for Leukemia

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Investigational agents

Disqualifiers: Uncontrolled infections, Active malignancies, Prior transplants, others

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

Compensation: Varies

Number of Visits: 101

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks to determine the optimal dose and understand the side effects of combining targeted radiation with chemotherapy before a stem cell transplant for certain blood cancers, such as myelodysplastic syndrome or acute leukemia. The radiation specifically targets the bone marrow and blood, where cancer cells grow, rather than the entire body. The treatment is intended for individuals diagnosed with acute myelogenous leukemia or acute lymphocytic leukemia with specific poor risk factors, or high-risk myelodysplastic syndrome. Participants should have a related donor for the stem cell transplant and lack access to a fully matched donor. This trial may suit those with a confirmed diagnosis seeking new treatment options, especially if previous treatments have not been fully effective. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you should be off any intensive therapy, chemotherapy, or radiotherapy for 3 weeks before starting the study, except for certain low-dose or maintenance chemotherapies, which are allowed up to 7 days before enrollment.

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

Previous studies have shown that total marrow irradiation may be a safer option than traditional total body irradiation. Research suggests it reduces radiation exposure to other organs, potentially lowering the risk of side effects.

Cyclophosphamide, a common cancer treatment, has known side effects, including serious conditions like decreased bone marrow activity, which is expected but usually reversible. Other possible side effects include impacts on the bladder and heart.

Fludarabine phosphate has been used in many clinical trials and is generally well-tolerated in patients with blood cancers. Some side effects might include a drop in blood cell counts, but these are manageable.

Since this trial is in an early phase, it focuses on finding the best dose and understanding side effects. The full safety profile of this treatment is still being explored. However, the treatments involved have been studied before and are generally manageable with close medical supervision. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for leukemia because it combines radiation therapy and chemotherapy before a stem cell transplant, which is not typically standard. Unlike traditional methods that often use full-body radiation, this approach uses Total Marrow Irradiation (TMLI) to precisely target the bone marrow, potentially reducing damage to other tissues. Additionally, the combination of cyclophosphamide and fludarabine phosphate in the conditioning regimen aims to enhance the effectiveness of the bone marrow transplant while managing side effects. This innovative protocol could improve outcomes by focusing treatment intensity where it's needed most, offering hope for better recovery and fewer complications.

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

Research has shown that total marrow and lymphoid irradiation (TMLI), which participants in this trial will undergo, could be promising for treating leukemia. One study found that 88% of patients were in remission 30 days after treatment, and all patients who received a specific dose achieved remission. Cyclophosphamide, a chemotherapy drug used in this trial, has demonstrated high success rates in similar treatments, with some studies reporting a 77.5% complete remission rate. Fludarabine phosphate, another chemotherapy drug in the trial, has also proven effective, with an 80.2% response rate for certain types of leukemia. These treatments work together in this trial to target cancer cells while allowing new, healthy cells to grow after a stem cell transplant. ^{3 6 7 8 9}

Who Is on the Research Team?

Joseph Rosenthal

Principal Investigator

City of Hope Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with myelodysplastic syndrome or acute leukemia who are in remission but at high risk of relapse, have good heart function and overall health, and no severe organ damage. They must be able to use birth control and have a partially matched related donor ready for stem cell donation. People with active infections or unable to tolerate certain therapies cannot participate.

Inclusion Criteria

Patients with the ability to understand and sign a written informed consent

I have been diagnosed with acute myelogenous leukemia or acute lymphocytic leukemia.

My condition is a high-risk type of blood disorder.

Exclusion Criteria

I have a donor who is a complete or partial HLA match.

I currently have an active infection.

I have undergone more than 3 treatments to induce cancer remission.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Patients undergo total marrow and lymphoid irradiation (TMLI) and receive chemotherapy with fludarabine and cyclophosphamide as conditioning for transplantation

1 week

Daily visits for radiation and chemotherapy administration

Transplant

Patients undergo bone marrow or peripheral blood stem cell transplant

1 day

1 visit (in-person)

GVHD Prophylaxis

Patients receive tacrolimus and mycophenolate mofetil to prevent graft-versus-host disease

6 months

Regular visits for monitoring and medication adjustment

Follow-up

Participants are monitored for safety, effectiveness, and long-term outcomes after treatment

5 years

Twice weekly for 100 days, then twice monthly until 6 months, monthly until off immunosuppressive therapy, then yearly

What Are the Treatments Tested in This Trial?

Interventions

• Bone Marrow Transplantation
• Cyclophosphamide
• Fludarabine Phosphate
• Mycophenolate Mofetil
• Peripheral Blood Stem Cell Transplantation
• Tacrolimus
• Total Marrow Irradiation

Trial Overview The study tests the safety and optimal dose of total marrow and lymphoid irradiation combined with chemotherapy before a stem cell transplant from a donor. The goal is to target cancer cells in the bone marrow without harming other parts of the body too much.

How Is the Trial Designed?

Group I: Treatment (TMLI, chemotherapy, transplant, GVHD prophylaxis) Experimental Treatment 8 Interventions

CONDITIONING: Patients undergo TMLI BID on days -7 to -4 or -3 (depending on the dose level). Patients also receive fludarabine phosphate IV on days -7 to -3 and cyclophosphamide IV on days -7, -6, 3, and 4. TRANSPLANT: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0. GHVD PROPHYLAXIS: Patients receive tacrolimus\* IV QD or PO BID on days 5-180. Patients also receive mycophenolate mofetil PO TID or IV on days 5-35. Treatment with tacrolimus and mycophenolate mofetil may continue in the presence of active GVHD. \*NOTE: Patients intolerant of tacrolimus may receive cyclosporine.

Bone Marrow Transplantation is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Bone Marrow Transplant for:

• Leukemia
• Lymphoma
• Multiple Myeloma
• Aplastic Anemia
• Sickle Cell Disease
• Thalassemia
• Immune Deficiency Disorders

Approved in United States as Bone Marrow Transplant for:

• Acute Leukemia
• Chronic Leukemia
• Hodgkin's Lymphoma
• Non-Hodgkin's Lymphoma
• Multiple Myeloma
• Aplastic Anemia
• Sickle Cell Disease
• Thalassemia
• Immune Deficiency Disorders

Approved in Canada as Bone Marrow Transplant for:

• Leukemia
• Lymphoma
• Multiple Myeloma
• Aplastic Anemia
• Sickle Cell Disease
• Thalassemia
• Immune Deficiency Disorders

Approved in Japan as Bone Marrow Transplant for:

• Leukemia
• Lymphoma
• Multiple Myeloma
• Aplastic Anemia
• Sickle Cell Disease
• Thalassemia
• Immune Deficiency Disorders

Approved in China as Bone Marrow Transplant for:

• Leukemia
• Lymphoma
• Multiple Myeloma
• Aplastic Anemia
• Sickle Cell Disease
• Thalassemia
• Immune Deficiency Disorders

Approved in Switzerland as Bone Marrow Transplant for:

• Leukemia
• Lymphoma
• Multiple Myeloma
• Aplastic Anemia
• Sickle Cell Disease
• Thalassemia
• Immune Deficiency Disorders

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Total marrow irradiation (TMI) at doses up to 15 Gy combined with chemotherapy (etoposide and cyclophosphamide) showed acceptable toxicity levels and resulted in complete remission in 11 out of 12 patients in the first trial, indicating its potential efficacy for patients with advanced leukemia.

In contrast, TMI combined with busulfan and etoposide resulted in dose-limiting toxicities at 13.5 Gy, suggesting that this combination may not be safe for further dose escalation, highlighting the importance of selecting appropriate chemotherapy regimens for TMI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose escalation of total marrow irradiation with concurrent chemotherapy in patients with advanced acute leukemia undergoing allogeneic hematopoietic cell transplantation. Wong, JY., Forman, S., Somlo, G., et al.[2021]

MHC-mismatched stem cells can successfully engraft in leukemia treatment after nonmyeloablative conditioning with fludarabine and low-dose total body irradiation, reducing the risk of graft rejection and graft-versus-host disease (GVHD).

The study demonstrated that pretransplantation fludarabine and posttransplantation cyclophosphamide are crucial for successful engraftment and can enhance donor chimerism while minimizing harmful GVHD reactions, allowing for effective adoptive immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. Luznik, L., Jalla, S., Engstrom, LW., et al.[2021]

The study involved 54 patients with acute leukemia and 34 with chronic myeloid leukemia, showing that a conditioning regimen of hyperfractionated total body irradiation (TBI), cyclophosphamide, and thiothepa resulted in a disease-free survival (DFS) of 55.5% for acute leukemia patients at a median follow-up of 40 months.

The addition of thiothepa significantly improved DFS in chronic myeloid leukemia patients, with a 66.6% DFS at a median follow-up of 12 months, while the group without thiothepa had only a 10% DFS at a median follow-up of 60 months, indicating the regimen's efficacy and tolerability despite some patients developing interstitial pneumonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Bone marrow transplantation with T-cell depletion and hyperfractionated whole-body irradiation. The radiobiological and clinical correlations]. Latini, P.[2008]

In a study involving 41 children with high-risk acute leukemia, the combination of total body irradiation (TBI), etoposide (VP-16), and cyclophosphamide (CY) showed a high safety profile, with only one case of fatal regimen-related toxicity reported.

The treatment demonstrated good efficacy, with a 3-year event-free survival rate of 68% for patients with early or intermediate stage disease, while those with advanced disease had a significantly lower survival rate of 17%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic bone marrow transplantation for children with acute leukemia: cytoreduction with fractionated total body irradiation, high-dose etoposide and cyclophosphamide. Duerst, RE., Horan, JT., Liesveld, JL., et al.[2013]

In a study of 146 adults with acute lymphoblastic leukemia undergoing transplantation, both conditioning regimens (Cyclophosphamide/Total Body Irradiation vs. Fludarabine/Busulfan/Low-dose TBI) showed similar overall and progression-free survival rates, indicating comparable efficacy.

However, the Fludarabine/Busulfan/Low-dose TBI regimen resulted in a significantly lower relapse rate (18.5% vs. 31.5% for Cy/TBI), suggesting it may be a safer option, especially for patients with poorer performance status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, busulfan, and low-dose TBI conditioning versus cyclophosphamide and TBI in allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia. Speziali, C., Daly, A., Abuhaleeqa, M., et al.[2020]

In a study of 58 patients with hematologic malignancies, a myeloablative regimen combining high-dose cytosine arabinoside (ara-C), cyclophosphamide, and total body irradiation (TBI) demonstrated a 1-year survival rate of 69% and a 5-year survival rate of 54%.

The regimen showed a low relapse rate of only 7% after a median follow-up of 28 months, suggesting that the combination of these treatments is both safe and effective, potentially due to the additional antileukemic effects of ara-C.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclophosphamide, cytosine arabinoside and TBI as a conditioning regimen for allogeneic bone marrow transplantation in patients with leukemia. Jillella, AP., Doria, R., Khan, K., et al.[2013]

Citations

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Combination of cyclophosphamide and cytarabine as ... With one course of induction chemotherapy, the overall response rate and the complete remission rate (CR) was 82.5% (33/40) and 77.5% (31/40), respectively. The ...

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Cyclophosphamide combined with mitoxantrone and ... The overall survival rate and disease-free survival rate were 72.1 and 59.7% at 1 year, 42.9 and 47.1% at 3 years, and 36.7 and 43.0% at 5 years, respectively.

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Cyclophosphamide therapy in acute leukemia of childhood Cyclo- phosphamide, administered orally, is effective for the treatment of acute leukemia for children in early relapse but is not effective in patients in ...

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Cyclophosphamide RESULTS: After four cycles, complete response (CR) or better in group A (43.6%) was higher than that in group B (12.8%) (P = 0.002). During ...

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cyclophosphamide injection - accessdata.fda.gov Cyclophosphamide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs. 2.

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Cyclophosphamide - StatPearls - NCBI Bookshelf - NIH Cyclophosphamide is a medication primarily used in the management and treatment of neoplasms, including multiple myeloma, sarcoma, and breast cancer.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2025/212501s007lbl.pdf

cyclophosphamide injection - accessdata.fda.gov Serious consequences of overdosage include manifestations of dose dependent toxicities such as myelosuppression, urotoxicity, cardiotoxicity (including cardiac ...

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Cyclophosphamide: Uses, Interactions, Mechanism of Action Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. Modality: Small Molecule; Groups: Approved, Investigational; Structure. 3D.

9. mayoclinic.org mayoclinic.org/drugs-supplements/cyclophosphamide-oral-route-intravenous-route/description/drg-20063307

Cyclophosphamide (oral route, intravenous route) Cyclophosphamide interferes with the growth of cancer cells, which are then destroyed by the body. Since the growth of normal body cells may ...