Bone Marrow Irradiation + Cyclophosphamide for Acute Myeloid Leukemia

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Investigational agents

Disqualifiers: Uncontrolled illness, Prior transplant, others

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

Compensation: Varies

Number of Visits: 3

18 Participants Needed

Trial Summary

What is the purpose of this trial?

This pilot phase I trial studies the side effects of total bone marrow and lymphoid irradiation and how well it works with cyclophosphamide in treating patients with acute myeloid leukemia. Total marrow and lymphoid irradiation targets cancer in bone marrow and blood, instead of applying radiation to the whole body. Giving total bone marrow and lymphoid irradiation before a donor transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving total bone marrow and lymphoid irradiation before donor transplant and cyclophosphamide after transplant may work better at treating acute myeloid leukemia.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot be on other investigational agents or concurrent biological, chemotherapy, or radiation therapy. Maintenance therapy with certain FDA-approved targeted therapies is allowed after day 60.

What data supports the effectiveness of the treatment Bone Marrow Irradiation + Cyclophosphamide for Acute Myeloid Leukemia?

Research shows that using cyclophosphamide with total body irradiation (TBI) as part of a treatment plan for leukemia can be effective, with a 5-year survival rate of 54% and a low relapse rate of 7% in one study. This suggests that the combination of these therapies can help control the disease and improve survival outcomes. ^{1 2 3 4 5}

Is the combination of bone marrow irradiation and cyclophosphamide generally safe for humans?

The combination of bone marrow irradiation and cyclophosphamide has been studied in various settings, including for leukemia treatment. While it can be effective, there are risks of severe side effects, such as cardiac (heart) toxicity and gastrointestinal issues. However, many patients have successfully undergone treatment with careful monitoring and supportive care. ^{1 4 6 7 8}

How does the treatment of Bone Marrow Irradiation + Cyclophosphamide for Acute Myeloid Leukemia differ from other treatments?

This treatment is unique because it combines bone marrow irradiation with cyclophosphamide, focusing the radiation specifically on the bone marrow rather than the whole body, which may reduce side effects compared to total body irradiation. This approach aims to effectively target leukemia cells while potentially minimizing damage to other tissues. ^{1 2 4 6 9}

Research Team

Anthony S Stein

Principal Investigator

City of Hope Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults with acute myeloid leukemia in first or second complete remission. Participants must have a matched sibling or unrelated donor for stem cell transplant, good heart and kidney function, and no recent chemotherapy or radiation. They should not be pregnant, agree to use contraception, and be able to give informed consent.

Inclusion Criteria

My AML is in the first or second complete remission.

It has been at least 14 days since my last cancer treatment session.

Pulmonary function tests including DLCO and FEV 1 greater than 50% of predicted normal value

Exclusion Criteria

I am not currently on any experimental treatments or undergoing chemotherapy or radiation.

I have a health or mental condition that makes stem cell transplant unsafe for me.

Abnormal EKG, echocardiogram, or MUGA scan results

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Patients undergo total marrow and lymphoid irradiation (TMLI) twice daily on days -4 to 0

1 week

Daily visits for radiation

Transplantation

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

1 day

1 visit (in-person)

Chemotherapy

Patients receive cyclophosphamide intravenously over 2 hours on days 3 and 4

2 days

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of GvHD and quality of life

24 months

Regular follow-up visits

Treatment Details

Interventions

• Cyclophosphamide
• Total Marrow Irradiation

Trial Overview The trial tests total marrow and lymphoid irradiation followed by a stem cell transplant from a donor, along with cyclophosphamide treatment. It aims to see how well this approach works compared to traditional whole-body radiation therapy in treating leukemia without harming other organs.

Participant Groups

Group I: Treatment (TMLI, cyclophosphamide) Experimental Treatment 8 Interventions

Patients undergo TMLI BID on days -4 to 0, then undergo bone marrow or peripheral blood stem cell transplant on day 0. Patients receive cyclophosphamide IV over 2 hours on days 3 and 4, tacrolimus given by CIV on days 5-90, and filgrastim beginning on day 5 until ANC is at least 1,500/mm\^3 for 3 consecutive days.

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 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]

In a study of 852 patients with refractory acute myeloid leukaemia, the conditioning regimen of intravenous busulfan plus cyclophosphamide showed similar overall survival (31.2%) and leukaemia-free survival (25.0%) at 2 years compared to cyclophosphamide plus total body irradiation (TBI) (33.4% and 28.4%, respectively), indicating that busulfan is a viable alternative.

The study suggests that intravenous busulfan plus cyclophosphamide may be a practical option for patients, particularly in transplant centers lacking radiation facilities, without compromising survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes after use of two standard ablative regimens in patients with refractory acute myeloid leukaemia: a retrospective, multicentre, registry analysis. Nagler, A., Savani, BN., Labopin, M., et al.[2018]

In a study of 1,659 patients with acute myelogenous leukemia undergoing allogeneic stem-cell transplantation, the use of intravenous busulfan combined with cyclophosphamide (IV Bu/Cy) resulted in significantly lower rates of acute and chronic graft-versus-host disease (GVHD) compared to cyclophosphamide with total-body irradiation (Cy/TBI).

While the engraftment rates and leukemia-free survival were similar between the two conditioning regimens, IV Bu/Cy showed a trend towards lower nonrelapse mortality, indicating a potentially safer profile for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia in remission: comparison of intravenous busulfan plus cyclophosphamide (Cy) versus total-body irradiation plus Cy as conditioning regimen--a report from the acute leukemia working party of the European group for blood and marrow transplantation. Nagler, A., Rocha, V., Labopin, M., et al.[2022]

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 50 patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) undergoing allogeneic bone marrow transplantation, the conditioning regimen of busulfan, cyclophosphamide, and total body irradiation resulted in a 5-year leukemia-free survival rate of 85% for patients in first remission (group I) compared to 50% for those with advanced disease (group II).

Severe regimen-related toxicities occurred in 16% of patients, primarily affecting the lungs, liver, and heart, indicating that while the treatment is effective, there are significant risks associated with the conditioning regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Busulfan, cyclophosphamide and total body irradiation as conditioning for allogeneic bone marrow transplantation for acute and chronic myeloid leukemia. Hirabayashi, N., Goto, S., Ishii, M., et al.[2013]

In a meta-analysis of 15 randomized controlled trials involving 10,160 pediatric patients, total body irradiation plus cyclophosphamide (TBI/CY) was found to be more effective than busulfan plus cyclophosphamide (BU/CY) in reducing transplant failure rates and improving long-term disease-free survival rates.

The TBI/CY regimen also demonstrated a lower incidence of adverse reactions compared to the BU/CY regimen, indicating it may be a safer option for pediatric hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two Different Transplant Preconditioning Regimens Combined with Irradiation and Chemotherapy in the Treatment of Childhood Leukemia: Systematic Review and Meta-Analysis. Wang, X., Mu, D., Geng, A., et al.[2023]

High doses of cyclophosphamide (CY) can be toxic to bone marrow, but when combined with autologous marrow transplantation, it allows for recovery from severe side effects, as shown in dog studies where 100 mg/kg was lethal without support but manageable with marrow infusion.

In human patients, conditioning with CY (50 mg/kg) before allogeneic marrow transplantation for severe aplastic anemia has resulted in an 80% long-term survival rate, demonstrating the efficacy of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose therapy and bone marrow transplantation. Thomas, ED.[2018]

In a study of 30 adult patients undergoing haematopoietic stem cell transplantation, conditioning with fractionated total body irradiation and high-dose cyclophosphamide showed no evidence of cardiotoxicity, as indicated by stable cardiac troponin T levels and echocardiographic parameters over a median follow-up of 5 months.

The findings suggest that TBI/CY is safe for patients without pre-existing cardiac dysfunction, indicating that any cardiotoxic effects of cyclophosphamide may arise from interactions with other chemotherapy drugs rather than from cyclophosphamide alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring of cardiac function by serum cardiac troponin T levels, ventricular repolarisation indices, and echocardiography after conditioning with fractionated total body irradiation and high-dose cyclophosphamide. Auner, HW., Tinchon, C., Brezinschek, RI., et al.[2019]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Cyclophosphamide, cytosine arabinoside and TBI as a conditioning regimen for allogeneic bone marrow transplantation in patients with leukemia. [2013]

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

Outcomes after use of two standard ablative regimens in patients with refractory acute myeloid leukaemia: a retrospective, multicentre, registry analysis. [2018]

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

Allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia in remission: comparison of intravenous busulfan plus cyclophosphamide (Cy) versus total-body irradiation plus Cy as conditioning regimen--a report from the acute leukemia working party of the European group for blood and marrow transplantation. [2022]

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

Busulfan, cyclophosphamide and total body irradiation as conditioning for allogeneic bone marrow transplantation for acute and chronic myeloid leukemia. [2013]

6. England pubmed.ncbi.nlm.nih.gov

Two Different Transplant Preconditioning Regimens Combined with Irradiation and Chemotherapy in the Treatment of Childhood Leukemia: Systematic Review and Meta-Analysis. [2023]

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

High-dose therapy and bone marrow transplantation. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Monitoring of cardiac function by serum cardiac troponin T levels, ventricular repolarisation indices, and echocardiography after conditioning with fractionated total body irradiation and high-dose cyclophosphamide. [2019]

9. Italy pubmed.ncbi.nlm.nih.gov

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