Total Marrow Irradiation + Stem Cell Transplant for Leukemia

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must not be taking: Herbal medications

Disqualifiers: Uncontrolled illness, Active infection, HIV, 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 10

70 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase II trial studies how well total marrow and lymphoid irradiation works as a conditioning regimen before hematopoietic cell transplantation in patients with myelodysplastic syndrome or acute leukemia. Total body irradiation can lower the relapse rate but has some fatal side effects such as irreversible damage to normal internal organs and graft-versus-host disease (a complication after transplantation in which donor's immune cells recognize the host as foreign and attack the recipient's tissues). Total body irradiation is a form of radiotherapy that involves irradiating the patient's entire body in an attempt to suppress the immune system, prevent rejection of the transplanted bone marrow and/or stem cells and to wipe out any remaining cancer cells. Intensity-modulated radiation therapy (IMRT) is a more recently developed method of delivering radiation. Total marrow and lymphoid irradiation is a method of using IMRT to direct radiation to the bone marrow. Total marrow and lymphoid irradiation may allow a greater dose of radiation to be delivered to the bone marrow as a preparative regimen before hematopoietic cell transplant while causing less side effects to normal organs than standard total body irradiation.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, it mentions that patients should be off all previous 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.

Is Total Marrow Irradiation + Stem Cell Transplant safe for humans?

Research shows that Total Marrow and Lymphoid Irradiation (TMLI) can deliver higher doses of radiation without increasing toxicity compared to Total Body Irradiation (TBI), suggesting it is generally safe for humans. Studies indicate low toxicity and good outcomes in patients undergoing stem cell transplantation for certain types of leukemia. ^{1 2 3 4 5}

How is the treatment Total Marrow and Lymphoid Irradiation (TMLI) different from other treatments for leukemia?

Total Marrow and Lymphoid Irradiation (TMLI) is unique because it can deliver higher doses of radiation specifically to the bone marrow and lymphoid tissues without increasing side effects, unlike Total Body Irradiation (TBI) which affects the entire body. This targeted approach may lead to better outcomes and lower toxicity for patients undergoing stem cell transplants for leukemia. ^{1 2 4 5 6}

What data supports the effectiveness of the treatment Total Marrow and Lymphoid Irradiation (TMLI) combined with Stem Cell Transplant for Leukemia?

Research shows that Total Marrow and Lymphoid Irradiation (TMLI) can deliver higher doses of radiation safely, with low toxicity, and is promising for patients with high-risk acute leukemias. It is comparable to other conditioning regimens in preventing relapse and has been associated with good outcomes in stem cell transplantation. ^{1 2 3 5 7}

Who Is on the Research Team?

Monzr M. Al Malki

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for patients with certain types of leukemia or myelodysplastic syndrome who are in remission but at high risk, or have responsive disease. They need good organ function and performance status, no HIV/HBV/HCV, and a related half-matched donor ready. Pregnant women and those with recent intensive treatments or other health issues that could interfere are excluded.

Inclusion Criteria

Karnofsky performance status >= 70

Histologically confirmed diagnosis of one the following:

- Patients with acute myelogenous leukemia

Exclusion Criteria

DONOR: Medical or physical reason which makes the donor unlikely to tolerate or cooperate with growth factor therapy and leukapheresis

DONOR: Factors which place the donor at increased risk for complications from leukapheresis or granulocyte colony-stimulating factor (G-CSF) therapy

DONOR: HIV positive

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Patients receive fludarabine intravenously once daily on days -7 to -5, and undergo total marrow and lymphoid irradiation twice daily on days -4 to 0

7 days

Daily visits for 7 days

Transplant

Patients undergo hematopoietic cell transplantation on day 0

1 day

1 visit (in-person)

GVHD Prophylaxis

Patients receive cyclophosphamide intravenously on days 3-4, followed by granulocyte colony stimulating factor and tacrolimus/mycophenolate mofetil starting on day 5

2 days for cyclophosphamide, ongoing for other medications

Daily visits for 2 days, then as per institutional standard

Follow-up

Participants are monitored for safety and effectiveness after treatment, including twice weekly follow-ups for the first 100 days post-transplant, twice monthly until 6 months post-transplant, monthly until discontinuation of immunosuppressive therapy, and then yearly for 2 years

Up to 2 years

Frequent visits initially, then decreasing over time

What Are the Treatments Tested in This Trial?

Interventions

• Total Marrow and Lymphoid Irradiation

Trial Overview The study tests total marrow and lymphoid irradiation as preparation before hematopoietic cell transplantation. It aims to see if this targeted radiation method can reduce cancer relapse while minimizing damage to healthy organs compared to traditional full-body radiation.

How Is the Trial Designed?

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

CONDITIONING: Patients receive fludarabine IV QD on days -7 to -5, and undergo TMLI BID on days -4 to 0 in the absence of disease progression or unacceptable toxicity. TRANSPLANT: Patients undergo hematopoietic cell transplantation on day 0. GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV QD on days 3-4 in the absence of disease progression or unacceptable toxicity. Beginning on day 5, patients also receive granulocyte colony stimulating factor and tacrolimus/mycophenolate mofetil per institutional standard.

Total Marrow and Lymphoid Irradiation is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Total Body Irradiation for:

• Leukemia
• Lymphoma
• Multiple myeloma

Approved in United States as Total Body Irradiation for:

• Acute lymphoblastic leukemia
• Acute myeloid leukemia
• Chronic lymphocytic leukemia
• Lymphoma
• Multiple myeloma

Approved in Canada as Total Body Irradiation for:

• Leukemia
• Lymphoma
• Multiple myeloma

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 254 patients with refractory or relapsed acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL) treated with Total Marrow and Lymphoid Irradiation (TMLI), radiation therapy (RT) for extramedullary (EM) relapse showed high local control rates, with 86.6% of treated sites achieving durable control.

Patients who received RT with curative intent had significantly better overall survival (OS) and progression-free survival (PFS), with median OS of 50.7 months compared to 1.6 months for those not treated with curative intent, highlighting the potential of RT as an effective salvage treatment for EM relapse after hematopoietic cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of radiotherapy in treatment of extramedullary relapse following total marrow and lymphoid irradiation in high-risk and/or relapsed/refractory acute leukemia. Ladbury, C., Semwal, H., Hong, D., et al.[2022]

Total marrow lymphoid irradiation (TMLI) combined with cyclophosphamide for conditioning in hematopoietic stem cell transplantation (HSCT) showed low toxicity and high engraftment rates (100%) in 20 adult patients with acute lymphoblastic leukemia and chronic myeloid leukemia.

At a median follow-up of 25 months, the overall survival rate was 80% and disease-free survival was 75%, indicating favorable early outcomes with this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total marrow lymphoid irradiation and cyclophosphamide is associated with low toxicity and good outcomes in patients undergoing hematopoietic stem cell transplantation for acute lymphoblastic leukemia and chronic myeloid leukemia in lymphoid blast crises - A phase I study. George, B., Balakrishnan, R., S, P., et al.[2023]

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]

In a study of 326 patients with acute leukemia undergoing bone marrow transplantation (BMT) after total-body irradiation (TBI), the technique of TBI (single dose vs. fractionated) did not significantly affect survival rates or the incidence of complications.

However, the incidence of cataracts was significantly influenced by the instantaneous dose rate of TBI, with higher rates observed in patients receiving higher dose rates, highlighting the importance of dose management in minimizing long-term side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total-body irradiation before bone marrow transplantation for acute leukemia in first or second complete remission. Results and prognostic factors in 326 consecutive patients. Belkacémi, Y., Pène, F., Touboul, E., et al.[2023]

Total Marrow Irradiation (TMI) and Total Marrow and Lymphoid Irradiation (TMLI) are promising alternatives to traditional Total Body Irradiation (TBI) in hematopoietic cell transplantation, allowing for higher doses of targeted radiotherapy while minimizing damage to surrounding organs.

These techniques have been shown to be safely administered with low rates of transplant-related mortality, making them suitable for high-risk patients, including those with multiple myeloma and elderly or frail individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total marrow irradiation in hematopoietic stem cell transplantation for hematologic malignancies. Kerbauy, MN., Arcuri, LJ., Favareto, SL., et al.[2023]

Using 24 MV photons for total-body irradiation (TBI) in bone marrow transplantation helps achieve a more uniform radiation dose distribution, which reduces the risk of organ injury to the lungs, liver, and kidneys in patients with high-risk leukemias.

The study found that while TBI increased bone marrow dose due to interactions with bone, the overall treatment regimen effectively minimized end-organ toxicities, making it a safer option for patients undergoing transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-energy total body irradiation as preparation for bone marrow transplantation in leukemia patients: treatment technique and related complications. Bradley, J., Reft, C., Goldman, S., et al.[2019]

Total body irradiation (TBI) is an effective treatment used to prepare patients for allogeneic stem cell transplantation in leukemia cases, highlighting its importance in myeloablative regimens.

The guidelines emphasize that TBI regimens can differ significantly between institutions regarding dosage, delivery rate, and technique, indicating the need for standardized practices to ensure optimal patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total Body Irradiation: Guidelines from the International Lymphoma Radiation Oncology Group (ILROG). Wong, JYC., Filippi, AR., Dabaja, BS., et al.[2021]

Citations

1. Switzerland pubmed.ncbi.nlm.nih.gov

Role of radiotherapy in treatment of extramedullary relapse following total marrow and lymphoid irradiation in high-risk and/or relapsed/refractory acute leukemia. [2022]

2. Denmark pubmed.ncbi.nlm.nih.gov

Total marrow lymphoid irradiation and cyclophosphamide is associated with low toxicity and good outcomes in patients undergoing hematopoietic stem cell transplantation for acute lymphoblastic leukemia and chronic myeloid leukemia in lymphoid blast crises - A phase I study. [2023]

3. 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]

4. Germany pubmed.ncbi.nlm.nih.gov

Total-body irradiation before bone marrow transplantation for acute leukemia in first or second complete remission. Results and prognostic factors in 326 consecutive patients. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Total marrow irradiation in hematopoietic stem cell transplantation for hematologic malignancies. [2023]

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

High-energy total body irradiation as preparation for bone marrow transplantation in leukemia patients: treatment technique and related complications. [2019]

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

Total Body Irradiation: Guidelines from the International Lymphoma Radiation Oncology Group (ILROG). [2021]