Total Marrow and Lymphoid Irradiation in Combination With Fludarabine and Melphalan as Conditioning for Allogeneic Peripheral Blood Stem Cell Hematopoietic Cell Transplant in Older Patients With Refractory and Relapsed Acute Myeloid Leukemia and High-risk Myelodysplastic Syndrome

NCT07582172 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 3 other identifiers: 25663NCI-2026-03208P30CA033572
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial tests the effect of total marrow and lymphoid irradiation (TMLI) in combination with fludarabine and melphalan as conditioning regimen in older patients with acute myeloid leukemia or high-risk myelodysplastic syndrome that has not responded to previous treatment (refractory) and that has come back after a period of improvement (relapsed) and are undergoing a donor (allogeneic) peripheral blood stem cell (PBSC) hematopoietic cell transplant (HCT) from a matched related or unrelated donor. HCT is the only curative treatment for high-risk patients, but the side effects related to the current conditioning treatments limit the use to younger and more fit patients. TMLI is a targeted form of total body radiation that uses intensity-modulated radiation therapy to target marrow, lymph node chains, and the spleen. It is designed to reduce radiation-associated side effects and maximize the radiation therapeutic effect. Fludarabine blocks cells from making deoxyribonucleic acid (DNA) and may kill cancer cells. It is a type of purine antagonist and a type of ribonucleotide reductase inhibitor. Melphalan is in a class of medications called alkylating agents. It may kill cancer cells by damaging their DNA and stopping them from dividing. Giving chemotherapy, such as fludarabine and melphalan, and TMLI before an allogeneic transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells to grow. When healthy stem cells from a related or unrelated donor, such as PBSC HCT, that closely match the patient's blood, are infused into a patient, they may help the patient's bone marrow make more healthy cells and platelets, an may help destroy any remaining cancer cells. Giving TMLI in combination with fludarabine and melphalan as conditioning treatment for an allogeneic PBSC HCT from a matched related or unrelated donor may be safe, tolerable, and/or effective in treating high-risk older patients with relapsed and refractory acute myeloid leukemia or high-risk myelodysplastic syndrome.

Conditions

Myelodysplastic Chronic Myelomonocytic Leukemia; Myelodysplastic Syndrome; Recurrent Acute Myeloid Leukemia; Recurrent Myelodysplastic Chronic Myelomonocytic Leukemia; Recurrent Myelodysplastic Syndrome; Recurrent Secondary Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Refractory Myelodysplastic Chronic Myelomonocytic Leukemia; Refractory Myelodysplastic Syndrome; Refractory Secondary Acute Myeloid Leukemia; Acute Myeloid Leukemia With Complex Karyotype

Outcome Measures

Primary Outcomes (1)

• Leukemia-free survival

  Will be calculated using the Kaplan-Meier method. Point estimates and 95% confidence intervals will be provided.

  From the date of stem cell infusion to the date of first observation of relapse/progression, or date of death, whichever comes first, assessed at 2 years post-hematopoietic cell transplantation (HCT)

Secondary Outcomes (8)

• Incidence of adverse events (AEs)

  From day 1 of protocol therapy up to day 30 post-HCT

• Incidence of highest grades of AEs

  From day 31 up to day 100 post-HCT

• Overall survival

  From date of stem cell infusion t the date of death, assessed at 1 and 2 years post-HCT

• Relapse

  From date of stem cell infusion to first observation of relapse/progression, assessed at 1 and 2 years post-HCT

• Non-relapse mortality

  From date of stem cell infusion until non-disease related death, assessed at 100 days, and at 1 and 2 years post-HCT

Study Arms (1)

Treatment (TMLI, fludarabine, melphalan, allogeneic PBSC-HCT)

EXPERIMENTAL

Patients receive palifermin IV on days -11, -10, -9, 0, 1 and 2, fludarabine IV on days -4 to -2 and melphalan IV on day -2 and undergo TMLI BID for 8 fractions on days -8 to -5. Patients receive allogeneic PBSC-HCT on day 0. Starting on day -1, patients also receive tacrolimus IV or PO QD and sirolimus QD per standard of care. Additionally, patients undergo echocardiography or MUGA, CT, urine and blood sample collection, and bone marrow biopsy throughout the study.

Procedure: Biospecimen Collection; Procedure: Bone Marrow Biopsy; Procedure: Computed Tomography; Procedure: Echocardiography Test; Drug: Fludarabine Phosphate; Drug: Melphalan; Procedure: Multigated Acquisition Scan; Biological: Palifermin; Procedure: Peripheral Blood Stem Cell Transplantation; Other: Questionnaire Administration; Drug: Sirolimus; Drug: Tacrolimus; Radiation: Total Marrow and Lymphoid Irradiation

Interventions

Biospecimen Collection PROCEDURE

Undergo urine and blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (TMLI, fludarabine, melphalan, allogeneic PBSC-HCT)

Bone Marrow Biopsy PROCEDURE

Undergo bone marrow biopsy

Also known as: Biopsy of Bone Marrow, Biopsy, Bone Marrow

Treatment (TMLI, fludarabine, melphalan, allogeneic PBSC-HCT)

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586

Treatment (TMLI, fludarabine, melphalan, allogeneic PBSC-HCT)

Melphalan DRUG

Given IV

Also known as: Alanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard, L-Sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalan for Injection-Hepatic Delivery System, Melphalanum, Phenylalanine Mustard, Phenylalanine Nitrogen Mustard, Sarcoclorin, Sarkolysin, WR-19813

Treatment (TMLI, fludarabine, melphalan, allogeneic PBSC-HCT)

Palifermin BIOLOGICAL

Given IV

Also known as: Growth Factor, Recombinant Human Keratinocyte, Kepivance, Keratinocyte Growth Factor, Recombinant Human, Recombinant Human Keratinocyte Growth Factor, rhKGF, rhu Keratinocyte Growth Factor

Treatment (TMLI, fludarabine, melphalan, allogeneic PBSC-HCT)

Peripheral Blood Stem Cell Transplantation PROCEDURE

Undergo allogeneic PBSC HCT

Also known as: PBPC transplantation, PBSCT, Peripheral Blood, Peripheral Blood Progenitor Cell Transplantation, PERIPHERAL BLOOD STEM CELL TRANSPLANT, Peripheral Stem Cell Support, Peripheral Stem Cell Transplant, Peripheral Stem Cell Transplantation

Treatment (TMLI, fludarabine, melphalan, allogeneic PBSC-HCT)

Questionnaire Administration OTHER

Ancillary studies

Treatment (TMLI, fludarabine, melphalan, allogeneic PBSC-HCT)

Sirolimus DRUG

Given sirolimus

Also known as: AY 22989, AY-22989, AY22989, RAPA, Rapamune, Rapamycin, SILA 9268A, SILA-9268A, SILA9268A, WY 090217, WY-090217, WY090217

Treatment (TMLI, fludarabine, melphalan, allogeneic PBSC-HCT)

Tacrolimus DRUG

Given IV or PO

Also known as: FK 506, FK-506, FK506, Fujimycin, Hecoria, Prograf, Protopic, Tacforius

Treatment (TMLI, fludarabine, melphalan, allogeneic PBSC-HCT)

Total Marrow and Lymphoid Irradiation RADIATION

Undergo TMLI

Also known as: TMLI

Treatment (TMLI, fludarabine, melphalan, allogeneic PBSC-HCT)

Multigated Acquisition Scan PROCEDURE

Undergo MUGA

Also known as: Blood Pool Scan, Equilibrium Radionuclide Angiography, Gated Blood Pool Imaging, Gated Heart Pool Scan, MUGA, MUGA Scan, Multi-Gated Acquisition Scan, Radionuclide Ventriculogram Scan, Radionuclide Ventriculography, RNV Scan, RNVG, SYMA Scanning, Synchronized Multigated Acquisition Scanning

Treatment (TMLI, fludarabine, melphalan, allogeneic PBSC-HCT)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Treatment (TMLI, fludarabine, melphalan, allogeneic PBSC-HCT)

Echocardiography Test PROCEDURE

Undergo echocardiography

Also known as: EC, Echocardiography

Treatment (TMLI, fludarabine, melphalan, allogeneic PBSC-HCT)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Documented informed consent of the participant and/or legally authorized representative
• Assent, when appropriate, will be obtained per institutional guidelines
• Agreement to allow the use of archival tissue from diagnostic tumor biopsies
• If unavailable, exceptions may be granted with study principal investigator (PI) approval
• Age: ≥ 50 years (no upper age limit)
• Note: Patients ≥ 18 years and \< 50 years are also included if they are not candidates for myeloablative conditioning regimens due to comorbidities or active disease
• Karnofsky or Lansky performance status ≥ 70
• Eligible patients will have a histopathological confirmed diagnosis of hematologic malignancy in one of the following categories:
• Acute myeloid leukemia (AML):
• Patients with de novo or secondary disease in unfavorable risk group including poor risk cytogenetics according to National Comprehensive Cancer Network (NCCN) guidelines for AML i.e., monosomal karyotype, -5,5q-,-7,7q-,11q23-non t(9;11), inv (3), t(3;3), t(6;9), t(9;22) and complex karyotypes (≥ 3 unrelated abnormalities), or all patient in intermediate risk groups
• Patients with active disease:
• Morphologically
• Minimal residual disease (MRD) testing (MRD+ through flow cytometry, cytogenetics, or molecular assays)
• Myelodysplastic syndrome/chronic myelomonocytic leukemia (CMML) (MDS) with ≥ 10% blast
• Patients must have an human leukocyte antigen (HLA) (A, B, C, and DRB1) identical sibling or a 8/8 (A, B, C, and DR) allele matched unrelated donor who is willing to donate primed blood stem cells

You may not qualify if:

• Allogeneic stem cell transplant or autologous HCT within 1 year prior to day 1 of protocol therapy
• Chemotherapy, radiation therapy, biological therapy, immunotherapy within 14 days of day 1 of protocol therapy
• Note: Low dose chemotherapy or maintenance chemotherapy given within 7 days of planned study enrollment is permitted. These include hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors (TKIs). TKIs can also be given up to 3-5 days before conditioning regimen
• More than three previous lines of intensive chemotherapy, where the regimen intent was to induce remission
• Co-enrollment in other clinical trials involving post-HCT maintenance interventions or any study with potential to affect disease-free survival is not allowed
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
• Clinically significant uncontrolled illness
• Active infection not responding to antibiotics
• Other active malignancy. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Females only: Pregnant or breastfeeding
• Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

City of Hope Medical Center

Duarte, California, 91010, United States

Location

MeSH Terms

Conditions

Myelodysplastic Syndromes; Leukemia, Myeloid, Acute

Interventions

Specimen Handling; Biopsy; fludarabine phosphate; Melphalan; Fibroblast Growth Factor 7; Peripheral Blood Stem Cell Transplantation; Sirolimus; Tacrolimus; Lymphatic Irradiation

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Cytodiagnosis; Cytological Techniques; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Fibroblast Growth Factors; Intercellular Signaling Peptides and Proteins; Peptides; Proteins; Biological Factors; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Macrolides; Lactones; Radiotherapy

Study Officials

• Monzr M Al Malki

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 6, 2026
• First Posted: May 12, 2026
• Study Start (Estimated): April 5, 2027
• Primary Completion (Estimated): April 5, 2029
• Study Completion (Estimated): April 5, 2029
• Last Updated: May 12, 2026

Record last verified: 2026-05

Locations

US (1)