Targeted Total Marrow Irradiation for Leukemia

Overseen By Rondelli Damiano, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Illinois at Chicago

Disqualifiers: Cirrhosis, Low ejection fraction, 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: Unknown

27 Participants Needed

Trial Summary

What is the purpose of this trial?

Pre-transplant conditioning will include targeted total marrow irradiation (TMI) at a dose of 6Gy. Graft-versus-host disease prophylaxis will include cyclophosphamide 50 mg/kg on Day +3 and 4 along with tacrolimus and mycophenolate mofetil

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Targeted Total Marrow Irradiation for Leukemia?

Research shows that Total Marrow Irradiation (TMI) can deliver higher doses to the bone marrow while reducing side effects compared to Total Body Irradiation (TBI), making it a promising option for leukemia patients undergoing stem cell transplants. ^{1 2 3 4 5}

Is targeted total marrow irradiation safe for humans?

Total marrow irradiation (TMI) is designed to reduce radiation-related side effects by focusing on the skeleton and sparing other organs, which may make it safer than total body irradiation (TBI). However, TBI, often used in similar treatments, can lead to complications like organ injury, so careful planning is needed to minimize risks. ^{1 6 7 8 9}

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

Total Marrow Irradiation (TMI) is unique because it specifically targets the bone marrow while sparing other organs, unlike Total Body Irradiation (TBI) which affects the entire body. This targeted approach reduces the risk of side effects and toxicity, making it a potentially safer option for patients undergoing stem cell transplantation. ^{1 2 4 6 10}

Research Team

Rondelli Damiano, MD

Principal Investigator

University of Illinois at Chicago

Eligibility Criteria

Adults aged 18-75 with certain types of leukemia or myelodysplastic syndrome, who haven't responded well to other treatments and need frequent transfusions. They must have a related donor that's at least half-matched genetically, or an unrelated donor with specific mismatches. Participants should be in decent health otherwise, without serious liver issues or heart and lung function below half the normal level.

Inclusion Criteria

My vital organs are functioning well.

My cancer has specific genetic features considered high-risk.

Presentation WBC >30 × 109 for B-ALL or >100 109 for T-ALL

Exclusion Criteria

My health is significantly impaired; I need assistance for self-care.

You have other health problems that could interfere with the study.

I have a history of cirrhosis.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-transplant Conditioning

Patients receive a conditioning regimen with fludarabine, cyclophosphamide, and total body irradiation, including targeted total marrow irradiation (TMI) at a dose of 6Gy

2 weeks

Transplantation

Haploidentical hematopoietic stem cell transplant (HSCT) is performed

1 week

Post-transplant Prophylaxis

Graft-versus-host disease prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment, including engraftment rates and donor chimerism at day 30

1 year

Treatment Details

Interventions

• Cyclophosphamide
• Mycophenolate Mofetil
• Tacrolimus
• Total Marrow Irradiation

Trial Overview The trial is testing a pre-transplant conditioning process using targeted total marrow irradiation (TMI) at a dose of 6Gy. After transplant, patients will receive cyclophosphamide along with tacrolimus and mycophenolate mofetil to prevent graft-versus-host disease.

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

Approved in United States as Total Marrow Irradiation for:

• High-risk acute leukemia
• Myelodysplastic syndrome

Approved in European Union as Total Body Irradiation for:

• Acute leukemia
• Myelodysplastic syndrome
• Lymphoma

Approved in Canada as Total Marrow Irradiation for:

• High-risk acute leukemia
• Myelodysplastic syndrome

Who Is Running the Clinical Trial?

University of Illinois at Chicago

Lead Sponsor

Trials

653

Recruited

1,574,000+

Findings from Research

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]

Targeted marrow irradiation (TMI) maintains effective coverage of the clinical target volume (CTV) for patients undergoing bone marrow transplantation, similar to total body irradiation (TBI), but with improved dose distribution.

TMI significantly spares critical organs such as the lungs, brain, kidneys, and liver, reducing their radiation exposure by up to 55%, which may allow for higher doses to the target area or more frequent treatments without increasing tissue complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Organ sparing of linac-based targeted marrow irradiation over total body irradiation. Warrell, GR., Colussi, VC., Swanson, WL., et al.[2023]

Higher biologically effective doses (BEDs) of total-body irradiation (TBI) during hematopoietic stem cell transplantation significantly reduce relapse incidence and improve overall survival, based on a review of multiple studies.

While increasing the dose improves outcomes, it is crucial to manage the BED to minimize damage to vital organs like the lungs, kidneys, and eye lenses, ensuring patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biologically effective dose in total-body irradiation and hematopoietic stem cell transplantation. Kal, HB., Loes van Kempen-Harteveld, M., Heijenbrok-Kal, MH., et al.[2018]

Total body irradiation (TBI) is commonly used in conditioning regimens for hematopoietic stem cell transplantation but carries significant risks of side effects like pulmonary toxicity and second malignancies.

Total marrow irradiation (TMI) is a newer technique that allows for targeted radiation to the bone marrow, potentially delivering higher doses while reducing overall toxicity, paving the way for more personalized treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Status and Perspectives of Irradiation-Based Conditioning Regimens for Patients with Acute Leukemia Undergoing Hematopoietic Stem Cell Transplantation. Potdar, RR., Gupta, S., Giebel, S., et al.[2021]

In a study of 109 pediatric patients treated with total body irradiation (TBI) before stem cell transplantation for leukemia, the overall survival rates were high, with 63% surviving at 10 years, indicating the efficacy of TBI in this context.

Despite the effectiveness of TBI, 43% of patients experienced long-term toxicities, including growth retardation and abnormal liver and kidney function, highlighting the need for improved treatment techniques and long-term follow-up to manage these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total body irradiation as part of conditioning regimens in childhood leukemia-long-term outcome, toxicity, and secondary malignancies. Gruen, A., Exner, S., Kühl, JS., et al.[2022]

Total marrow irradiation (TMI) significantly reduces radiation exposure to critical organs such as the liver, kidneys, and lungs compared to total body irradiation (TBI), achieving up to a 59% reduction in kidney dose while maintaining the necessary dose to the targeted skeletal area.

TMI not only protects organs at risk more effectively but also decreases the treatment time by an average of 217 seconds, making it a potentially safer and more efficient alternative to TBI for patients undergoing hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total marrow irradiation versus total body irradiation using intensity-modulated helical tomotherapy. Köksal, M., Kersting, L., Schoroth, F., 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 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]

Myeloablative Total Body Irradiation (TBI) is primarily used for conditioning in high-risk acute lymphoblastic leukemia (ALL) patients, but it is not recommended for children under 3-4 years old due to higher toxicity risks.

The recommended TBI dose for children is between 12-14.4 Gy, with specific dose reductions for sensitive organs, and advanced techniques like TomoTherapy and VMAT TBI are encouraged to improve safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ESTRO ACROP and SIOPE recommendations for myeloablative Total Body Irradiation in children. Hoeben, BAW., Pazos, M., Seravalli, E., et al.[2022]

In a study of 37 patients receiving total marrow irradiation (TMI) before hematopoietic stem cell transplantation (HSCT), TMI demonstrated a 1-year graft-versus-host disease-free, relapse-free survival (GRFS) rate of 67.5%, which is significantly better than historical data for total body irradiation (TBI).

TMI resulted in faster engraftment of platelets compared to TBI, with a low occurrence of treatment-related toxicities, suggesting that TMI may be a safer and effective alternative to TBI in myeloablative conditioning for HSCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Organ sparing total marrow irradiation compared to total body irradiation prior to allogeneic stem cell transplantation. Haraldsson, A., Wichert, S., Engström, PE., et al.[2022]

References

1. 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]

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

Organ sparing of linac-based targeted marrow irradiation over total body irradiation. [2023]

3. Germany pubmed.ncbi.nlm.nih.gov

Biologically effective dose in total-body irradiation and hematopoietic stem cell transplantation. [2018]

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

Current Status and Perspectives of Irradiation-Based Conditioning Regimens for Patients with Acute Leukemia Undergoing Hematopoietic Stem Cell Transplantation. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Total body irradiation as part of conditioning regimens in childhood leukemia-long-term outcome, toxicity, and secondary malignancies. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

Total marrow irradiation versus total body irradiation using intensity-modulated helical tomotherapy. [2023]

7. 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]

8. 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]

9. Ireland pubmed.ncbi.nlm.nih.gov

ESTRO ACROP and SIOPE recommendations for myeloablative Total Body Irradiation in children. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Organ sparing total marrow irradiation compared to total body irradiation prior to allogeneic stem cell transplantation. [2022]