Total Marrow and Lymphoid Irradiation and Chemotherapy for Acute Leukemia

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

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

108 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the safety and efficacy of total marrow and lymphoid irradiation (TMLI) in combination with two chemotherapy drugs, etoposide and cyclophosphamide, as a preparative regimen before donor stem cell transplant in treating patients with high-risk acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML) who have failed previous therapy. Intensity-modulated radiation therapy (IMRT) uses imaging to provide a three-dimensional view of the area to be irradiated. Doctors can then shape and direct the radiation beams at the area from multiple directions while avoiding, as much as possible, nearby organs. TMLI is a method of using IMRT to direct radiation to the bone marrow. Radiation therapy is given before transplant to suppress the immune system, prevent rejection of the transplanted cells, and wipe out any remaining cancer cells. TMLI may allow a greater radiation dose to be delivered to the bone marrow as a preparative regimen before transplant while causing fewer side effects than standard radiation therapy.

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 data supports the effectiveness of this treatment for acute leukemia?

Research shows that using a combination of high-dose etoposide, cyclophosphamide, and total body irradiation before a bone marrow transplant can improve outcomes for patients with acute leukemia. In children with less advanced disease, this approach resulted in a 68% event-free survival rate over three years, indicating good effectiveness. ^{1 2 3 4 5}

Is the combination of total body irradiation, etoposide, and cyclophosphamide safe for use in humans?

The combination of total body irradiation, etoposide, and cyclophosphamide has been reported to be generally safe for both adults and children undergoing allogeneic bone marrow transplantation, although there is a risk of severe side effects such as fever, rash, nausea, and in rare cases, severe allergic reactions. ^{2 4 6 7 8}

How does the treatment of Total Marrow and Lymphoid Irradiation and Chemotherapy for Acute Leukemia differ from other treatments?

This treatment is unique because it combines total marrow irradiation (TMI) with chemotherapy drugs like cyclophosphamide and etoposide, specifically targeting the bone marrow and lymphoid tissues, which may reduce side effects compared to traditional total body irradiation (TBI). It aims to improve outcomes by focusing radiation on areas most affected by leukemia, potentially offering better disease control and fewer complications. ^{4 9 10 11 12}

Research Team

Anthony Stein, MD

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

References

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

High-dose etoposide (VP-16)-containing preparatory regimens in allogeneic and autologous bone marrow transplantation for hematologic malignancies. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Etoposide in leukemia, lymphoma and bone marrow transplantation. [2019]

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

Improved prognosis with additional medium-dose VP16 to CY/TBI in allogeneic transplantation for high risk ALL in adults. [2018]

4. England 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. [2013]

5. England 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. [2016]

6. Denmark pubmed.ncbi.nlm.nih.gov

Efficacy of etoposide, cyclophosphamide, and total body irradiation in allogeneic bone marrow transplantation for adult patients with hematological malignancies. [2014]

7. Poland pubmed.ncbi.nlm.nih.gov

[Allergic reactions to teniposide (VM-26) in children with neoplasms]. [2013]

8. Germany pubmed.ncbi.nlm.nih.gov

High-dose etoposide in allogeneic stem cell transplantation. [2018]

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

Etoposide, cyclophosphamide, total-body irradiation, and allogeneic bone marrow transplantation for hematologic malignancies. [2017]

10. Italy pubmed.ncbi.nlm.nih.gov

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

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

Cyclophosphamide versus etoposide in combination with total body irradiation as conditioning regimen for adult patients with Ph-negative acute lymphoblastic leukemia undergoing allogeneic stem cell transplant: On behalf of the ALWP of the European Society for Blood and Marrow Transplantation. [2019]

12. Ireland 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. [2012]