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

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of total bone marrow and lymphoid irradiation when given together with chemotherapy before donor stem cell transplant in treating patients with myelodysplastic syndrome or acute leukemia. Total marrow and lymphoid irradiation is a type of radiation therapy that targets bone marrow and blood, where the cancer is, instead of applying radiation to the whole body. Stem cell transplants use high doses of chemotherapy and radiation therapy, such as total marrow and lymphoid irradiation, to kill cancer cells, but these treatments kill normal cells as well. After chemotherapy, healthy cells from a donor are given to the patient to help the patient grow new blood cells.

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.

What data supports the effectiveness of the treatment Radiation Therapy + Chemotherapy Before Stem Cell Transplant for Leukemia?

Research shows that using high-dose cyclophosphamide and total body irradiation (TBI) as part of the preparation for stem cell transplants can improve outcomes for leukemia patients, especially those with less advanced disease. In children with acute leukemia, this approach has shown a 68% event-free survival rate for early or intermediate stage disease, indicating its effectiveness in improving survival rates. ^{1 2 3 4 5}

Is the combination of radiation therapy and chemotherapy before stem cell transplant generally safe for humans?

Studies show that using radiation therapy and chemotherapy before stem cell transplants can be safe, but there are risks of side effects. In children with leukemia, severe side effects were rare, and in adults, serious side effects were uncommon. However, long-term side effects can be a concern, and the safety can vary depending on the specific drugs and radiation doses used. ^{1 6 7 8 9}

How is the treatment of radiation therapy and chemotherapy before stem cell transplant for leukemia different from other treatments?

This treatment is unique because it combines total marrow irradiation (TMI) with chemotherapy drugs like cyclophosphamide and fludarabine phosphate before a stem cell transplant, aiming to target the bone marrow more precisely and reduce damage to other organs compared to traditional total body irradiation (TBI). ^{1 8 10 11 12}

Research Team

Joseph Rosenthal

Principal Investigator

City of Hope Comprehensive Cancer Center

Eligibility Criteria

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

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

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

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

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

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

Treatment Details

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.

Participant Groups

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+

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]

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]

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]

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]

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]

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]

References

1. 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]

2. United States 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. [2020]

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

Efficacy and toxicity of radiation in preparative regimens for pediatric stem cell transplantation. I: Clinical applications and therapeutic effects. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Allogeneic bone marrow transplantation with matched unrelated donors for patients with hematologic malignancies using a preparative regimen of high-dose cyclophosphamide and fractionated total body irradiation. [2020]

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

Allogeneic bone marrow transplantation for leukemia following piperazinedione and fractionated total body irradiation. [2019]

6. United States 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. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Regimen-related toxicity in patients undergoing BMT with total body irradiation using a sweeping beam technique. [2013]

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

Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study. [2022]

9. 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]

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

Dose escalation of total marrow irradiation with concurrent chemotherapy in patients with advanced acute leukemia undergoing allogeneic hematopoietic cell transplantation. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Additional myeloablation with 52Fe before bone marrow transplantation. [2006]