Marrow Irradiation + Chemotherapy for Leukemia

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Investigational agents

Disqualifiers: Uncontrolled illness, Other malignancies, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 100

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of combining marrow irradiation and chemotherapy for individuals with certain high-risk blood cancers. The treatment aims to halt the growth of cancer and normal blood-forming cells in the bone marrow before a donor stem cell transplant, which aids in producing healthy blood cells. The trial seeks participants with acute leukemia or myelodysplastic syndrome who have active or chemosensitive disease. Participants should not have had more than three prior intensive chemotherapy treatments or previous transplants. As a Phase 1 trial, this research focuses on understanding the treatment's effects in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but you should stop any intensive chemotherapy or radiotherapy at least 2 weeks before starting the trial. Some low-dose or maintenance chemotherapy drugs are allowed within 7 days of enrollment.

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

Research has shown that combining total marrow and lymphoid irradiation with fludarabine and melphalan is generally well-tolerated by patients. One study found this treatment feasible, recommending an irradiation dose of 12 Gy, which suggests manageable side effects at this level.

Another study reported that this combination had acceptable side effects and a low risk of non-cancer-related death. Most patients in these studies had high-risk leukemia, similar to those who might consider joining this trial. Overall, this combination appears promising and has a safety profile comparable to other treatments for similar conditions.

Please note, this trial is in an early phase, focusing on determining the best dose and gaining a better understanding of the side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the combination of total marrow irradiation (TMLI), fludarabine, and melphalan for treating leukemia because it offers a unique approach compared to standard treatments like traditional chemotherapy and radiation. Unlike conventional full-body radiation, TMLI targets the marrow directly, potentially reducing damage to other tissues and minimizing side effects. This targeted approach, combined with the potent effects of fludarabine and melphalan, aims to enhance the effectiveness of bone marrow transplants by better preparing the body to accept healthy donor cells. This innovative combination could lead to improved outcomes for patients with leukemia.

What evidence suggests that this trial's treatments could be effective for high-risk acute leukemia or myelodysplastic syndrome?

In this trial, participants will receive a combination of total marrow and lymphoid irradiation (TMLI), fludarabine, and melphalan. Research has shown that TMLI may effectively treat acute leukemia, with one study reporting complete remission in 88% of patients and 100% remission at a higher dose. Fludarabine has helped patients with various types of leukemia achieve remission, with some studies reporting up to a 51% complete remission rate. Melphalan prepares the body for stem cell transplants, enhancing results when combined with other treatments. Together, these treatments aim to halt cancer growth and support healthy cell development. ^{6 7 8 9 10}

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 people with high-risk acute leukemia or myelodysplastic syndrome who haven't had more than three intensive chemotherapy treatments and no previous transplants. Participants should be between 12-55 years old, have a certain level of physical fitness, and proper organ function. Women and men must use birth control during the study.

Inclusion Criteria

My cancer diagnosis is a type of blood cancer.

My AML is classified as high or intermediate risk, excluding FLT3-NPM1+.

My condition is acute lymphocytic leukemia.

Exclusion Criteria

I can understand and am willing to sign the consent form for the study.

I do not have any uncontrolled illnesses or infections.

I am on low dose or maintenance chemotherapy like hydroxyurea or TKIs.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation and Chemotherapy

Participants undergo total marrow and lymphoid irradiation (TMLI) twice daily on days -8 to -5, receive fludarabine intravenously on days -4 to -2, and melphalan on day -2.

8 days

Transplantation

Participants undergo allogeneic hematopoietic stem cell transplantation (alloHCT) on day 0.

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments for graft versus host disease, infection, and immune reconstitution.

Up to 2 years

Twice weekly for 100 days, twice monthly for 6 months, then monthly or yearly

What Are the Treatments Tested in This Trial?

Interventions

• Fludarabine
• Melphalan
• Total Marrow Irradiation

Trial Overview The trial tests how safe and effective it is to give total marrow and lymphoid irradiation with fludarabine and melphalan before a stem cell transplant from a donor. The goal is to see if this combination can help stop cancer growth in bone marrow before the transplant.

How Is the Trial Designed?

Group I: Treatment (TMLI, fludarabine, melphalan) Experimental Treatment 4 Interventions

Participants undergo TMLI BID on days -8 to -5, and receive fludarabine IV on days -4 to -2 and melphalan on day -2. Participants then undergo alloHCT on day 0.

Fludarabine is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Fludara for:

• Chronic lymphocytic leukemia
• Mantle-cell lymphoma
• Non-Hodgkin's lymphoma

Approved in United States as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma
• Stem Cell Transplant Conditioning

Approved in Canada as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's 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 addition of 9 Gy of total body irradiation (TBI) to a reduced intensity regimen of fludarabine and melphalan in pediatric patients with advanced hematologic malignancies resulted in successful neutrophil and platelet engraftment, with 27 patients achieving neutrophil engraftment by a median of 16 days.

Despite some toxicities like oral mucositis and diarrhea, the treatment was generally well tolerated, and with a median follow-up of 52 months, 7 out of 22 patients with acute lymphoblastic leukemia (ALL) and 5 out of 6 patients with acute myeloid leukemia (AML) remained alive and in remission, indicating potential efficacy that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies. Petropoulos, D., Worth, LL., Mullen, CA., et al.[2013]

In a study of 30 adult patients undergoing allogeneic hematopoietic stem cell transplant, fludarabine combined with full-dose busulfan (FluBu) and fludarabine with melphalan (FluMel) showed similar levels of hematological toxicity, indicating that both regimens are comparably safe.

The timing and duration of severe neutropenia were similar between the two groups, with both regimens resulting in a comparable recovery time for neutrophils and platelets post-transplant, suggesting that FluBu can be an effective alternative to standard reduced intensity conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparable kinetics of myeloablation between fludarabine/full-dose busulfan and fludarabine/melphalan conditioning regimens in allogeneic peripheral blood stem cell transplantation. Chunduri, S., Dobogai, LC., Peace, D., et al.[2013]

The combination of fludarabine and melphalan with total body irradiation (Flu-Mel140-TBI) in 81 patients undergoing allogeneic stem cell transplantation showed a 3-year overall survival rate of 39.81%, indicating that this regimen is feasible and can provide durable disease control.

Despite the addition of TBI, there was no significant improvement in outcomes compared to previous reports of Flu-Mel140 alone, and the study highlighted considerable non-relapse mortality (29.9%) particularly in older patients and those with prior transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of Fludarabine, Melphalan and Total Body Irradiation as a Reduced Intensity Conditioning Regimen in Matched Donor Allogeneic Peripheral Blood Stem Cell Transplantation. Modi, D., Chi, J., Kim, S., et al.[2021]

In a study of 85 patients with hematological malignancies, adding fludarabine to a 2-Gy total body irradiation (TBI) regimen before stem cell transplantation resulted in better overall survival (65% vs. 54%) and lower relapse rates compared to TBI alone.

The combination of fludarabine and TBI led to significantly higher levels of donor T cell and NK cell chimerism, indicating improved donor engraftment and a stronger graft-versus-tumor effect, which is crucial for successful transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine and 2-Gy TBI is superior to 2 Gy TBI as conditioning for HLA-matched related hematopoietic cell transplantation: a phase III randomized trial. Kornblit, B., Maloney, DG., Storb, R., et al.[2021]

The addition of total body irradiation (TBI) and a reduction in melphalan dosage in the FluMelTBI-75 regimen led to improved overall survival (OS) and progression-free survival (PFS) compared to the standard FluMel regimen, based on a phase II trial involving 94 patients.

FluMelTBI-75 was better tolerated, showing a significant reduction in stomatitis and improved disease control for patients not in complete remission at the time of transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-Intensity Conditioning with Fludarabine, Melphalan, and Total Body Irradiation for Allogeneic Hematopoietic Cell Transplantation: The Effect of Increasing Melphalan Dose on Underlying Disease and Toxicity. Chen, GL., Hahn, T., Wilding, GE., et al.[2022]

In a study of 21 patients undergoing non-myeloablative conditioning chemotherapy with melphalan and fludarabine before allogeneic stem cell transplantation, three patients developed severe left ventricular failure, indicating a potential risk of cardiotoxicity with this treatment combination.

This finding is significant as cardiotoxicity from melphalan and fludarabine has not been previously reported, highlighting the need for careful assessment and monitoring of cardiac health in patients receiving this pre-transplant regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute left ventricular failure following melphalan and fludarabine conditioning. Ritchie, DS., Seymour, JF., Roberts, AW., et al.[2013]

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]

A study involving 21 patients undergoing a second or greater allogeneic stem cell transplantation (allo-SCT) found that combining intensity-modulated total marrow irradiation (IM-TMI) with fludarabine and melphalan is feasible, with a recommended dose of 12 Gy for effective treatment.

The 2-year cumulative incidence of relapse was 35%, with a 50% overall survival rate, indicating that while the relapse rate remains a concern, this combination therapy shows promise for improving outcomes in patients with relapsed hematologic diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 trial utilizing TMI with fludarabine-melphalan in patients with hematologic malignancies undergoing second allo-SCT. Tran, MC., Hasan, Y., Wang, A., et al.[2023]

In a study of 31 patients with hematologic malignancies who were poor candidates for total body irradiation (TBI), the fludarabine-melphalan regimen resulted in successful engraftment for all patients, indicating its efficacy in stem cell transplantation.

However, the treatment was associated with significant regimen-related toxicities, including renal, hepatic, and mucosal issues, leading to seven regimen-related deaths, highlighting the need for careful patient selection and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regimen-related toxicity after fludarabine-melphalan conditioning: a prospective study of 31 patients with hematologic malignancies. Van Besien, K., Devine, S., Wickrema, A., et al.[2013]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/15051774/

Efficacy and safety of oral fludarabine phosphate in ... The response rate using National Cancer Institute criteria was 80.2% (complete remission, 12.3%; partial remission, 67.9%). Median time to progression was 841 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3952498/

Long-term results of the fludarabine, cyclophosphamide, ... In this report, we present the final results of all 300 study patients at a median follow up of 6 years.

3. sciencedirect.com sciencedirect.com/science/article/pii/S2213048921000029?via%3Dihub

Fludarabine-based salvage therapy for refractory/relapsed ... This retrospective study found the 30-day mortality rate for Fludarabine-based regimens for adult acute leukemias to be 8%, complete remission in 51% of the ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT00049075

Fludarabine in Treating Patients With Chronic Lymphocytic ... PURPOSE: Phase II trial to study the effectiveness of fludarabine in treating patients who have chronic lymphocytic leukemia that has not been previously ...

5. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.2001.19.5.1414

Results of the Fludarabine and Cyclophosphamide ... RESULTS: Fludarabine and cyclophosphamide produced ≥ 80% response rates in all patients not refractory to fludarabine at the start of therapy as well as a 38% ...

6. astctjournal.org astctjournal.org/article/S1083-8791(17)30761-9/fulltext

Total Marrow Lymphoid Irradiation/Fludarabine/ Melphalan ... The median follow-up was 7.4 years. The majority of patients had acute leukemia (72%); 49% had high/very high-risk disease. The median patient age was 55 years ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9898602/

A phase 1 trial utilizing TMI with fludarabine-melphalan in ... TMI combined with fludarabine-melphalan is a feasible conditioning regimen for second or greater SCT. The recommended tolerable dose of TMI is 12 Gy; ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT03494569?term=CB-3025&rank=9

Total Marrow and Lymphoid Irradiation, Fludarabine, and ... This phase I studies the side effects and best dose of total marrow and lymphoid irradiation when given together with fludarabine and melphalan before donor ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S2666636723012460

Total Marrow Irradiation for Second Allogeneic ... The overall cumulative incidence of TRM, relapse rate, and disease free-survival were 27%, 7%, and 67%, respectively. This retrospective study demonstrates the ...

10. clinicalkey.com clinicalkey.com/#!/content/journal/1-s2.0-S1083879117307619#refInSitubib0160

Total Marrow Lymphoid Irradiation/Fludarabine/ Melphalan ... Treatment was well tolerated, with acceptable toxicity and nonrelapse mortality. •. Outcomes compare favorably with those associated with reduced-intensity ...