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 trial tests a new approach to radiation therapy for individuals with myelodysplastic syndrome or acute leukemia. The researchers aim to determine if targeting the bone marrow with radiation before a stem cell transplant can reduce side effects while effectively treating the cancer. This method, known as total marrow and lymphoid irradiation, could serve as an alternative to traditional total body radiation. Individuals diagnosed with myelodysplastic syndrome or acute leukemia who are in remission or have responsive disease might be suitable candidates. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group.

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 there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Total Marrow and Lymphoid Irradiation (TMLI) is generally well-tolerated by patients undergoing stem cell transplants. One study found that TMLI, administered at a dose of 2000 cGy, was safe for patients with high-risk leukemia and myelodysplastic syndrome, a group of disorders where blood cells are poorly formed or don't function properly. This method targets the bone marrow more precisely, potentially reducing harm to healthy organs compared to traditional total body irradiation.

Another study showed encouraging survival rates for patients with acute conditions who received this treatment. However, intense therapy can lead to side effects. There is also a risk of complications such as graft-versus-host disease, where the donor's immune cells attack the recipient's body. Discuss potential risks with the study team to fully understand what joining a trial could involve. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about this treatment for leukemia because it combines Total Marrow and Lymphoid Irradiation (TMLI) with a stem cell transplant, offering a more targeted approach than traditional full-body irradiation. This precision aims to minimize damage to healthy tissues while effectively targeting cancerous cells. Additionally, the use of cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis, along with granulocyte colony stimulating factor and tacrolimus/mycophenolate mofetil, supports better integration and function of the transplanted stem cells. This combination might improve patient outcomes by reducing side effects and increasing the success rate of the transplant.

What evidence suggests that total marrow and lymphoid irradiation might be an effective treatment for leukemia?

Research has shown that total marrow and lymphoid irradiation (TMLI), which participants in this trial will receive, may benefit patients undergoing stem cell transplants for leukemia. Studies have found that TMLI can increase survival chances compared to traditional whole-body radiation. By focusing more directly on the bone marrow, TMLI allows a higher dose of radiation to target cancer cells while protecting healthy organs. This precision might reduce the risk of harmful side effects. In past cases, patients who received TMLI before transplants experienced positive results. ^{1 2 4 5 6}

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 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]

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]

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]

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]

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]

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 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. astctjournal.org astctjournal.org/article/S2666-6367(24)00725-5/fulltext

Total Marrow and Lymphoid Irradiation (TMLI) Is ... Use of total marrow and lymphoid irradiation (TMLI) is associated with good survival in patients undergoing hematopoietic stem cell transplantation for acute ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10356893/

Total marrow irradiation versus total body irradiation using ... We also compared beam-on times between TBI and TMI. Results. TMI planning achieved significant reductions in the mean, minimum, and maximum ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0167814025001173

Rationale, implementation considerations, delineation and ... Also, more specifically bone-marrow- and/or lymphatics-targeted therapies such as Total Marrow (+ Lymphoid) Irradiation (TMI / TMLI), and Total Lymphoid ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02094794

Total Marrow and Lymphoid Irradiation and Chemotherapy ... This phase II trial studies the safety and efficacy of total marrow and lymphoid irradiation (TMLI) in combination with two chemotherapy drugs, ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7708691/

The safety and efficacy of a novel hypo-fractionated total ... The purpose of this study was to evaluate the clinical outcomes of a novel hypo-fractionation strategy for patients receiving total marrow and ...

6. ashpublications.org ashpublications.org/bloodadvances/article/6/14/4098/485140/Total-marrow-and-lymphoid-irradiation-as

Total marrow and lymphoid irradiation as conditioning in ... TMLI at 2000 cGy for HaploHCT with PTCy was determined to be safe in patients with high-risk leukemia and MDS.