Reduced-Intensity Conditioning for Blood Cancers

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

Trial Summary

What is the purpose of this trial?

This phase II clinical trial evaluates whether a modified modality of conditioning reduces treatment-related mortality (TRM) in patients who undergo a hematopoietic stem cell transplant (HSCT) for a hematological malignancy. HSCT is a curative therapy for many hematopoietic malignancies, however this regimen results in higher rates of TRM than other forms of treatment. In recent years, less intense conditioning regimens with radiation and chemotherapy prior to HSCT have been developed. Radiation therapy uses high energy sources to kill cancer cells and shrink tumors while chemotherapy drugs like fludarabine and cyclophosphamide work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. This study evaluates whether a two-step approach with lower-intensity regimens of these treatments prior to HSCT reduces the rate of TRM.

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.

What data supports the idea that Reduced-Intensity Conditioning for Blood Cancers is an effective treatment?

The available research shows that Reduced-Intensity Conditioning (RIC) using a combination of drugs like fludarabine and melphalan, along with total body irradiation (TBI), can be effective for treating blood cancers. For example, one study found that a specific RIC regimen (FluMelTBI-75) improved survival and disease control compared to another regimen without TBI. Another study indicated that adding TBI to the regimen did not significantly improve outcomes but still provided durable disease control. However, the treatment can have significant side effects, such as mucositis and cardiac toxicity. Overall, RIC with TBI can be a viable option, especially for patients who cannot undergo more intense treatments. ^{1 2 3 4 5}

What safety data is available for reduced-intensity conditioning in blood cancer treatment?

Safety data for reduced-intensity conditioning regimens, such as those involving fludarabine and melphalan, indicate several potential toxicities. Cardiotoxicity, including severe left ventricular failure, has been observed in some patients. Other regimen-related toxicities include mucositis, renal, hepatic, and mucosal toxicity, with some cases leading to regimen-related deaths. The addition of total body irradiation (TBI) did not significantly improve outcomes and was associated with considerable non-relapse mortality, especially in older patients or those with prior transplants. Despite these risks, the regimens have shown consistent engraftment and durable disease control in some patients. ^{2 4 6 7 8}

Is the treatment Cyclophosphamide, Fludarabine, Melphalan, Total-Body Irradiation a promising treatment for blood cancers?

Yes, the treatment using Cyclophosphamide, Fludarabine, Melphalan, and Total-Body Irradiation shows promise for blood cancers. It has been found to improve survival and disease control, especially when using a specific combination of these drugs and therapies. This approach is better tolerated and can lead to better outcomes for patients. ^{1 2 3 6 9}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

Group I: 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.

Group II: 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.

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+

Findings from Research

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]

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 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 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]

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 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 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 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]

References

1. United States 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. [2022]

2. United States 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. [2021]

3. United States 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. [2020]

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

Regimen-related toxicity after fludarabine-melphalan conditioning: a prospective study of 31 patients with hematologic malignancies. [2013]

5. United States 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. [2020]

6. United States 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. [2015]

7. England pubmed.ncbi.nlm.nih.gov

Acute left ventricular failure following melphalan and fludarabine conditioning. [2013]

8. England 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. [2013]

9. United States 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. [2021]