Total Marrow and Lymphoid Irradiation and Chemotherapy for Acute Leukemia

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must not be taking: Investigational agents

Disqualifiers: Prior stem cell transplant, 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: 8

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment approach for patients with high-risk acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML) who haven't responded to previous treatments. It combines a targeted radiation type, total marrow and lymphoid irradiation (TMLI), with chemotherapy drugs etoposide and cyclophosphamide, followed by a stem cell transplant (allogeneic bone marrow transplantation). The goal is to prepare the body for the transplant effectively while minimizing side effects. This trial may suit those with ALL or AML who have relapsed or are not in remission after previous therapies and have a matched stem cell donor available.

As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, it does mention that chemotherapy for controlling white blood cell counts is allowed within 14 days of starting the study.

What prior data suggests that this method is safe for treating acute leukemia?

Research has shown that total marrow and lymphoid irradiation (TMLI) is generally well-tolerated. Studies indicate it allows for a higher radiation dose to the bone marrow with fewer side effects compared to standard radiation. This method targets the bone marrow more precisely, helping to protect nearby organs.

Etoposide and cyclophosphamide, the chemotherapy drugs in question, carry some risks. Etoposide has been linked to a rare risk of developing another type of leukemia. Cyclophosphamide can temporarily lower blood cell counts, a condition known as myelosuppression, and may increase the risk of some cancers over time.

In this phase of the trial, TMLI and these drugs have been shown to be safe when used together, but potential side effects exist. Discussing these with a doctor is important to understand what to expect and how they might be managed. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for acute leukemia because it combines Total Marrow and Lymphoid Irradiation (TMLI) with chemotherapy and a stem cell transplant in a potentially more targeted and effective way. Unlike standard treatments that involve more generalized full-body irradiation, TMLI focuses the radiation specifically on the bone marrow and lymphoid tissues, potentially reducing damage to other parts of the body. This targeted approach aims to increase effectiveness while minimizing side effects, offering hope for improved outcomes compared to traditional chemotherapy and radiation regimens.

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

Research has shown that total marrow irradiation (TMI), one of the treatments in this trial, can help prepare patients with acute leukemia for a stem cell transplant. One study found that 88% of patients achieved complete remission after TMI, with a 100% remission rate at a certain radiation dose. In this trial, participants will receive TMI along with Etoposide and Cyclophosphamide. Etoposide, a chemotherapy drug used in the trial, has improved survival rates without the disease when combined with other treatments. Cyclophosphamide, another chemotherapy drug in the trial, has also achieved high remission rates in patients with acute leukemia. These treatments work together to reduce cancer cells and help the body accept the transplant successfully. ^{1 2 3 6 7}

Who Is on the Research Team?

Anthony Stein, MD

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for adults with high-risk acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML) who haven't responded to previous treatments. Participants need a compatible bone marrow donor, good physical function, and normal organ function tests. They must not be pregnant, agree to use contraception, and can't have had certain prior treatments that would conflict with the trial.

Inclusion Criteria

You are able to perform daily activities with a good level of independence and functionality.

Documented (signed) informed consent; the patient, family member and transplant staff physician (physician, nurse, and social worker) meet at least once prior to starting the transplant procedure; during this meeting all pertinent information with respect to risks and benefits to donor and recipient will be presented; alternative treatment modalities will be discussed; the risks are explained in detail in the enclosed consent forms

Agreement of men AND women-of-child-bearing-potential to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately

Exclusion Criteria

Prior radiation therapy that would exclude the use of TMLI

Patients with psychological or medical condition that patient's physician deems unacceptable to proceed to allogeneic hematopoietic stem cell transplantation

Women who are planning to become pregnant or breast feed during the trial

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants undergo image guided total marrow and lymphoid irradiation (TMLI) on days -9 to -5

1 week

5 visits (in-person)

Chemotherapy

Participants receive etoposide IV on day -4 and cyclophosphamide IV on day -2

1 week

2 visits (in-person)

Transplant

Participants undergo allogeneic peripheral blood stem cell or bone marrow transplant on day 0

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Regular visits as per protocol

What Are the Treatments Tested in This Trial?

Interventions

• Allogeneic Bone Marrow Transplantation
• Allogeneic Hematopoietic Stem Cell Transplantation
• Cyclophosphamide
• Etoposide
• Total Marrow Irradiation

Trial Overview The study is testing total marrow and lymphoid irradiation (TMLI) combined with etoposide and cyclophosphamide chemotherapy before receiving a stem cell transplant from a donor. TMLI uses advanced imaging to target radiation at the bone marrow while sparing other organs, aiming to prepare patients better for transplantation.

How Is the Trial Designed?

Group I: Treatment (TMLI, chemotherapy) Experimental Treatment 5 Interventions

Patients undergo image guided TMLI on days -9 to -5, receive etoposide IV on day -4 and cyclophosphamide IV on day -2, and undergo allogeneic peripheral blood stem cell or bone marrow transplant on day 0.

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?

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

In a study of 79 patients undergoing allogeneic bone marrow transplantation, the combination of etoposide, cyclophosphamide, and fractionated total-body irradiation (TBI) showed a 57% overall survival rate at 3 years for patients with early leukemia, indicating its efficacy as a preparative regimen.

Patients with advanced disease experienced significantly lower survival rates (17%) and higher toxicity, highlighting that this regimen is more effective and safer for those with early-stage hematologic malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etoposide, cyclophosphamide, total-body irradiation, and allogeneic bone marrow transplantation for hematologic malignancies. Giralt, SA., LeMaistre, CF., Vriesendorp, HM., et al.[2017]

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 involving 15 patients with relapsed acute leukemia, the combination of total body irradiation (TBI) followed by total marrow irradiation (TMI) was found to be clinically feasible, with all patients achieving complete remission after stem cell transplant.

TMI significantly reduced radiation exposure to surrounding organs by 30% to 65%, while maintaining effective targeting of bone marrow, suggesting it may enhance treatment efficacy with a lower risk of severe side effects compared to conventional TBI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Helical tomotherapy targeting total bone marrow after total body irradiation for patients with relapsed acute leukemia undergoing an allogeneic stem cell transplant. Corvò, R., Zeverino, M., Vagge, S., et al.[2012]

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]

The study established maximum tolerable doses (MTD) for etoposide and cyclophosphamide combined with total body irradiation in 37 patients with advanced hematologic malignancies, finding that the regimen was well tolerated by autologous marrow recipients at 44 mg/kg of VP-16 and 103 mg/kg of CY, and by allogeneic marrow recipients at 36 mg/kg of VP-16 and 67 mg/kg of CY.

Despite achieving complete remission in 31 evaluable patients post-transplant, most experienced disease relapse within a few months, highlighting the need for improved long-term outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etoposide, cyclophosphamide and fractionated total body irradiation as a preparative regimen for marrow transplantation in patients with advanced hematological malignancies: a phase I study. Petersen, FB., Buckner, CD., Appelbaum, FR., et al.[2016]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9176122/

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 ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0006497119328150

Long-Term Outcomes of Patients with Acute Myeloid ... In responding patients (n=76), 5-year relapse-free survival (RFS) and OS were 33% (95% CI 24-46%) and 35% (95% CI 25-47%) respectively. Initial ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6380740/

Cyclophosphamide for the treatment of acute lymphoblastic ... Abstract. Background: Previous clinical trials have reported that cyclophosphamide can be used for the treatment of acute lymphoblastic leukemia (ALL).

4. frontiersin.org frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1193874/full

Venetoclax plus cyclophosphamide and cytarabine as ... Conclusions: This study showed that the 3-day CTX and Ara-C regimen is highly effective in newly diagnosed AML patients, and the addition of VEN ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT01677949?cond=%22Myeloid%20Leukemia%22&intr=%22etoposide%20phosphate%22&viewType=Table&rank=3

Clofarabine, Cyclophosphamide and Etoposide for Minimal ... Types of outcome measures include primary outcome measure and secondary outcome measure. ... A type of intervention model describing a clinical trial in which two ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT00293410

Clofarabine and Cyclophosphamide in Treating Patients ... PURPOSE: This phase I trial is studying the side effects and best dose of clofarabine and cyclophosphamide in treating patients with relapsed or refractory ...

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

cyclophosphamide injection - accessdata.fda.gov Cyclophosphamide is genotoxic [see Nonclinical Toxicology (13.1)]. Secondary malignancies (urinary tract cancer, myelodysplasia, acute leukemias, lymphomas, ...