Reduced-Intensity Conditioning for Blood Cancers

Recruiting at 1 trial location

Overseen By Usama Gergis, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Thomas Jefferson University

Disqualifiers: HIV, CNS malignancy, Pregnancy, 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

Compensation: Varies

Number of Visits: Unknown

Duration: Approximately 2 weeks

63 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a less intense treatment plan before a blood stem cell transplant can reduce treatment-related death risk in people with certain blood cancers. It combines radiation and chemotherapy to prepare patients for their transplant. This trial targets individuals with specific blood cancers, such as leukemia or lymphoma, who may have experienced issues with stronger treatments previously. Participants need a matching donor and a life expectancy of at least six months. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group.

Do I need to stop my current medications for this trial?

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

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

Research has shown that fludarabine and total body irradiation (TBI) are generally well tolerated by patients. One study found this combination safe even with imperfect donor matches, reducing risks in transplant procedures. Another study found that this combination improved survival rates without major safety concerns.

For the fludarabine and melphalan combination, research indicates it provides good disease control with manageable side effects. Lower doses of melphalan with fludarabine have been associated with fewer stomach-related issues after transplants.

These findings suggest that both treatment plans, involving radiation and chemotherapy, are relatively safe. They have been tested in various situations and have been well tolerated by patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer a gentler approach for patients with blood cancers, combining chemotherapy and radiation in a way that potentially reduces side effects. Unlike traditional methods that often involve high-intensity conditioning, this protocol uses reduced-intensity conditioning with drugs like fludarabine, cyclophosphamide, and melphalan, along with total-body irradiation. This approach aims to minimize toxicity while still effectively preparing patients for a hematopoietic stem cell transplant (HSCT), which could lead to better outcomes and improved quality of life during treatment. By tailoring the intensity of the treatment, there is hope for fewer complications and a broader range of patients who can benefit from HSCT.

What evidence suggests that this trial's treatments could be effective for reducing treatment-related mortality in blood cancer patients?

In this trial, participants will join different treatment arms to evaluate reduced-intensity conditioning for blood cancers. One arm uses fludarabine with total body irradiation (TBI) before a stem cell transplant. Studies have shown this combination to be effective and safe, often resulting in long-lasting positive outcomes. Another arm tests the combination of fludarabine and melphalan, which research indicates helps control blood cancers, with many patients experiencing good outcomes and manageable side effects. Both combinations aim to make stem cell transplant preparation less intense, potentially reducing the risk of treatment-related death. Overall, early findings suggest these less intense treatments are promising for treating blood cancers while lowering risks. ^{1 2 6 7 8}

Who Is on the Research Team?

Usama Gergis, MD

Principal Investigator

Thomas Jefferson University

Are You a Good Fit for This Trial?

This trial is for patients with various blood cancers or disorders who have adequate lung, liver, heart function, and kidney clearance. They must not be HIV positive, pregnant, breastfeeding, or have another active malignancy or central nervous system involvement. Participants need a specific donor match and should meet certain health scores based on age.

Inclusion Criteria

My liver is functioning well, based on recent blood tests.

Your lung function is at least 50% of what it is expected to be for someone of your age and size.

Patients must have adequate Karnofsky performance status (KPS) and hematopoietic cell transplantation-comorbidity index (HCT-CI) scores: Patients < age 60 years must have a KPS of >= 80% and an HCT-CI score of 5 or less, Patients aged 60 to 65 years must have a KPS of >= 80% and an HCT-CI score of 4 or less, Patients aged 66 to 69 years must have a KPS of 90% and an HCT-CI score of 3 or less, Patients aged 70 years or more must have a KPS of 90% and an HCT-CI score of 2 or less, Patients with greater than the allowable HCT-CI points for age can be enrolled for trial with approval of the principal investigator and at least 1 co-investigator not on the primary care team of the patient. This is an adjustment to account for healthy patients who meet the spirit of this protocol but have histories that result in higher than guideline HCT-CI points. An example is a patient with a solid tumor malignancy in their remote history (adds 3 points to HCT-CI total) where the treatment for the malignancy occurred years to decades before and there has been complete recovery of toxicities, Patients must be willing to use contraception if they have childbearing potential, Patient or patient's guardian is able to give informed consent, Patients should have a life expectancy of >= 6 months for reasons other than their underlying hematologic/oncologic disorder

Exclusion Criteria

I do not have any other cancer besides skin cancer that needs only local treatment.

You have HIV, cancer in the brain, or are pregnant or breastfeeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a reduced-intensity conditioning regimen including fludarabine, total-body irradiation, donor lymphocyte infusion, and cyclophosphamide, followed by hematopoietic stem cell transplant

Approximately 2 weeks

Daily visits for treatment administration

Follow-up

Participants are monitored for safety, effectiveness, and immune recovery after treatment

2 years

Regular visits for monitoring and assessments

Long-term follow-up

Participants are monitored for long-term outcomes such as treatment-related mortality, relapse, and graft versus host disease

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Fludarabine
• Melphalan
• Mycophenolate Mofetil
• Tacrolimus
• Total-Body Irradiation

Trial Overview

The study tests if a less intense conditioning regimen before hematopoietic stem cell transplant can reduce treatment-related mortality in blood cancer patients. It involves lower doses of radiation and chemotherapy drugs like fludarabine and cyclophosphamide to prepare the body for the transplant.

How Is the Trial Designed?

Group I: Arm 3: HLA- Identical cohort (radiation-based or chemotherapy-based conditioning) Experimental Treatment 11 Interventions

This group (HLA- Identical cohort), which is expected to be small, can undergo HSCT with radiation-based or chemotherapy-based conditioning. Due to small numbers of patients with available HLA identical related donors, this third, descriptive arm is included so that this group, too small in number for a free-standing study, are treated on clinical trial. This is also a separate arm of the study and the outcome of patients treated on this arm will be analyzed descriptively without statistical comparison or power analysis.

Group II: Arm 2: Chemotherapy-Based Cohort (fludarabine, melphalan, TBI) Experimental Treatment 11 Interventions

Patients receive fludarabine IV on days -11, -10, -9, and -8 and melphalan IV on days -10 and -9. Patients undergo TBI and DLI once on day -6. Patients receive cyclophosphamide IV on days -3 and -2 and begin tacrolimus and mycophenolate mofetil on day -1. Patients undergo hematopoietic stem cell transplant on day 0. Patients undergo bone marrow biopsy/aspiration, imaging and blood sample collection throughout the study.

Group III: Arm 1: Radiation-Based Cohort (fludarabine, TBI, infusion) Experimental Treatment 10 Interventions

Patients receive fludarabine IV on days -11, -10, -9, and -8, undergo TBI BID on days -10 and -9, undergo DLI on day -6, and receive cyclophosphamide IV on days -3 and -2. Patients begin tacrolimus and mycophenolate mofetil IV on day -1. Patients then undergo HSCT on day 0. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy/aspiration, imaging and blood sample collection throughout the study.

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Thomas Jefferson University

Lead Sponsor

Trials

475

Recruited

189,000+

Published Research Related to This Trial

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 394 acute myeloid leukemia patients undergoing allogeneic stem cell transplantation, the fludarabine plus melphalan (FM) regimen showed a significantly lower relapse incidence compared to fludarabine plus busulfan (FB), indicating better control of the disease.

Despite the differences in relapse rates, both FM and FB regimens resulted in similar overall survival rates, suggesting that while FM may be more effective in preventing relapse, both treatments are comparably effective in terms of long-term survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Baron, F., Labopin, M., Peniket, A., et al.[2015]

In a study of 407 acute lymphoblastic leukemia (ALL) patients undergoing reduced-intensity allogeneic transplantation, overall survival rates were similar across different melphalan doses and TBI conditions, indicating that the intensity of the conditioning regimen may not significantly impact survival outcomes.

Lower-dose melphalan combined with TBI (LDM/TBI+) was associated with fewer central nervous system complications compared to higher-dose melphalan with TBI (HDM/TBI+), suggesting that LDM/TBI+ could be a safer option for vulnerable ALL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of melphalan dose and total body irradiation as reduced-intensity conditioning for acute lymphoblastic leukemia patients undergoing allogeneic stem cell transplantation. Harada, K., Tachibana, T., Ohashi, K., et al.[2020]

In a study of 507 acute myeloid leukemia patients undergoing reduced-intensity allogeneic transplantation, those receiving a higher dose of melphalan (120-140 mg/m2) had a significantly better overall survival rate (48.9%) compared to those on a lower dose (40.3%).

The survival benefit from higher-dose melphalan was linked to reduced tumor-related mortality, particularly in younger patients and those not in complete remission, suggesting that this treatment approach may be especially effective for physically fit individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic impact of melphalan dose and total body irradiation use in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation with reduced-intensity conditioning. Harada, K., Yanada, M., Machida, S., et al.[2020]

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]

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]

The reduced-intensity conditioning regimen of fludarabine and melphalan was found to be feasible and effective in achieving 100% donor chimerism in 22 patients with metastatic breast cancer and renal cell carcinoma after allogeneic stem cell transplantation.

The treatment resulted in a 45% response rate in terms of tumor regression, with some patients experiencing complete or partial responses, suggesting that the graft-versus-host disease may contribute to the graft-versus-tumor effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid induction of complete donor chimerism by the use of a reduced-intensity conditioning regimen composed of fludarabine and melphalan in allogeneic stem cell transplantation for metastatic solid tumors. Ueno, NT., Cheng, YC., Rondón, G., et al.[2021]

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

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12151860/

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Melphalan Dose in Combination With Fludarabine Affects ...

Melphalan 100 versus 140 mg/m2 in combination with fludarabine is associated with lower risk of GI toxicity after allogeneic transplantation.

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Fludarabine Phosphate, Melphalan, Total-Body Irradiation, ...

This clinical trial is studying how well giving fludarabine phosphate and melphalan together with total-body irradiation followed by donor stem cell ...