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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new approach to treat acute myeloid leukemia (AML) by combining targeted bone marrow radiation with the chemotherapy drug cyclophosphamide (also known as Cytoxan, Neosar, or Endoxan). The goal is to evaluate the effectiveness of this method and identify potential side effects. The treatment aims to eliminate cancer cells in the bone marrow while preparing for a donor transplant. This trial may suit patients with AML who are in their first or second complete remission and have a compatible donor ready for a stem cell transplant. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this innovative approach.

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 prior data suggests that total marrow irradiation and cyclophosphamide are safe for treating acute myeloid leukemia?

Research has shown that total marrow and lymphoid irradiation (TMLI) is generally safe up to a dose of 2000 cGy. In a previous study, patients who received TMLI with other medications experienced few serious side effects and had a promising survival rate. This suggests that TMLI might be safer than traditional radiation methods because it targets cancer cells more directly.

Studies have found cyclophosphamide to be well-tolerated, even in high doses, for patients with acute myeloid leukemia (AML). In one study involving 461 patients, including some with heart issues, cyclophosphamide was safe when administered after a transplant. This indicates the drug can be used without causing severe harm to most patients.

Earlier research has shown both TMLI and cyclophosphamide to be reasonably safe. However, it is important to note that this current study is in its early phase, focusing mainly on understanding safety in humans. More information will become available as the trial progresses. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment protocol because it combines total marrow irradiation (TMLI) with cyclophosphamide to create a potentially powerful one-two punch against acute myeloid leukemia (AML). Unlike traditional chemotherapy, which broadly targets dividing cells, TMLI specifically focuses radiation on the bone marrow, aiming to reduce side effects and increase effectiveness. This precise targeting, coupled with cyclophosphamide's ability to kill cancer cells, offers a novel approach that could enhance treatment outcomes and provide new hope for patients battling AML.

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

In this trial, participants will receive a combination of total marrow and lymphoid irradiation (TMLI) and cyclophosphamide. Research has shown that TMLI effectively targets cancer cells in the bone marrow and blood while sparing the rest of the body. One study found that TMLI reduces radiation exposure to non-targeted areas, helping to protect healthy tissues. Cyclophosphamide, a chemotherapy drug, has demonstrated promising results in treating acute myeloid leukemia (AML). Studies report that cyclophosphamide can lead to high remission rates and improve long-term survival. Together, TMLI and cyclophosphamide offer a focused treatment approach that may enhance effectiveness for AML patients. ^{1 4 6 7 8}

Who Is on the Research Team?

Anthony S Stein

Principal Investigator

City of Hope Comprehensive Cancer Center

Are You a Good Fit for This Trial?

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.

Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for six months following duration of study participation

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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 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 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 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 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]

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]

Citations

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Combination of cyclophosphamide and cytarabine as ... In this study, we first time demonstrate that the CA regimen could achieve high CR rate and long‐term survival in newly diagnosed AML, with short chemotherapy ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4734089/

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.

3. 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 ...

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

Long-Term Outcomes of Patients with Acute Myeloid ... VP-Cy is an effective salvage regimen with response rates, long-term survival and rates of early death comparable to reported outcomes using cytarabine-based ...

5. ashpublications.org ashpublications.org/blood/article/122/24/3863/31939/Better-leukemia-free-and-overall-survival-in-AML

Better leukemia-free and overall survival in AML in first ... Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33325761/

High dose cyclophosphamide for cytoreduction in patients ... Here, we report on the efficacy and safety of high dose cyclophosphamide (HDCy; 60 mg/kg). 27 patients with acute myeloid leukemia or blast ...

7. mdpi.com mdpi.com/2072-6694/17/19/3128

Safety of Post-Transplant Cyclophosphamide-Based ... This retrospective study of 461 acute myeloid leukemia patients, including 62 with pre-existing cardiac morbidity, evaluated the safety of post-transplant ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT03417154

Nivolumab and Oral Cyclophosphamide for R/R AML and ... This is a phase II trial of nivolumab and low dose cyclophosphamide (CTX) when given in combination to patients with relapsed/refractory acute myeloid ...