Chemotherapy (Decitabine in Combination With FLAG-Ida) and Total-Body Irradiation Followed by Donor Stem Cell Transplant for the Treatment of Adults With Myeloid Malignancies at High Risk of Relapse

Sequential Decitabine in Combination With FLAG-Ida Followed Immediately by Reduced-Intensity Conditioning (RIC) Allogeneic Hematopoietic Cell Transplantation (DEC-FLAG-Ida/RIC) for Adults With Myeloid Malignancies at High Risk of Relapse: A Phase 1/2 Study

This phase I/II trial studies the safety, side effects, and best dose of decitabine in combination with fludarabine, cytarabine, filgrastim, and idarubicin (FLAG-Ida) and total body irradiation (TBI) followed by a donor stem cell transplant in treating adult patients with cancers of blood-forming cells of the bone marrow (myeloid malignancies) that are at high risk of coming back after treatment (relapse). Cancers eligible for this trial are acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML). Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. The FLAG-Ida regimen consists of the following drugs: fludarabine, cytarabine, filgrastim, and idarubicin. These are chemotherapy drugs that work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Filgrastim is in a class of medications called colony-stimulating factors. It works by helping the body make more neutrophils, a type of white blood cell. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. TBI is radiation therapy to the entire body. Giving chemotherapy and TBI before a donor peripheral blood stem cell (PBSC) 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 the healthy stem cells from a donor are infused into a patient, they may help the patient's bone marrow make more healthy cells and platelets. Giving decitabine in combination with FLAG-Ida and TBI before donor PBSC transplant may work better than FLAG-Ida and TBI alone in treating adult patients with myeloid malignancies at high risk of relapse.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Recurrent Acute Myeloid Leukemia; Recurrent Chronic Myelomonocytic Leukemia; Recurrent Myelodysplastic Syndrome; Refractory Acute Myeloid Leukemia; Refractory Chronic Myelomonocytic Leukemia; Refractory Myelodysplastic Syndrome; Recurrent Mixed Phenotype Acute Leukemia; Refractory Mixed Phenotype Acute Leukemia; Acute Undifferentiated Leukemia; Mixed Phenotype Acute Leukemia; Recurrent Acute Undifferentiated Leukemia; Refractory Acute Undifferentiated Leukemia
• Intervention / Treatment: Drug: Decitabine; Drug: Cytarabine; Procedure: Biospecimen Collection; Drug: Fludarabine; Biological: Filgrastim; Radiation: Total-Body Irradiation; Procedure: Multigated Acquisition Scan; Drug: Idarubicin; Procedure: Pheresis; Procedure: Echocardiography Test; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Chest Radiography; Procedure: Hematopoietic Cell Transplantation

Detailed Description

OUTLINE: This is a phase I, dose-escalation study of decitabine in combination with FLAG-Ida, TBI, and HCT followed by a phase II study.

DONORS: Participants undergo apheresis for collection of PBSCs on study.

PATIENTS: Patients receive decitabine intravenously (IV) daily over 1 hour on days -12 to -10, -14 to -10, -16 to -10, or -19 to -10, filgrastim subcutaneously (SC) daily on days -9 to -4, idarubicin IV over 60 minutes daily on days -8 to -6, fludarabine IV over 30 minutes daily on days -8 to -4, cytarabine IV over 2 hours daily on days -8 to -4, and undergo TBI twice daily (BID) on day -1 or 0 OR daily on days -1 and 0 in the absence of disease progression or unacceptable toxicity. Patients then undergo HCT (receive donor PBSCs via infusion) on day 0. Patients also undergo multi-gated acquisition (MUGA) scan or echocardiography (ECHO) during screening, chest X-rays and bone marrow aspiration and/or biopsy during screening and as clinically indicated, and collection of blood samples throughout the study.

After completion of study treatment, patients are followed up at 6 months, 1 year, and 2 years.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Naveed Ali, MD; Phone Number: 206-667-5854; Email: nali2@fredhutch.org

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutch/University of Washington Cancer Consortium
      • Contact: Naveed Ali, MD; Phone Number: 206-667-5854; Email: nali2@fredhutch.org
      • Principal Investigator: Naveed Ali, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age ≥ 18 years with an HCT-co-morbidity index (CI) ≤ 5 for patients over 60 years.
• AML (2022 World Health Organization [WHO] criteria) that is either primary refractory (as defined by failure of 2 cycles of 7+3-like chemotherapy, 1 cycle of high-dose cytarabine-based chemotherapy, or at least 2 cycles of venetoclax in combination with other therapies) or is in untreated or unsuccessfully treated first or subsequent relapse. Patients in morphologic remission (i.e. < 5% blasts in the bone marrow) but evidence of minimal residual disease (MRD) by multiparameter flow cytometry, cytogenetics/fluorescence in situ hybridization (FISH), or molecular means will be eligible for trial participation. Patients with relapsed or refractory acute leukemia of ambiguous lineage (acute undifferentiated leukemia or mixed phenotype acute leukemia) that is either primary refractory or is in untreated or unsuccessfully treated first or subsequent relapse are also eligible.
• MDS and CMML: Subjects with previously treated MDS and CMML, defined as prior treatment with at least one hypomethylating agent (hypomethylating agent [HMA]; azacitidine, decitabine and/or decitabine-cedazuridine) whose disease progressed, relapsed, or was refractory to HMA treatment as follows: 1) patients who have failed at least 4 cycles of monotherapy with azacitidine, decitabine or decitabine-cedazuridine, 2) patients who received at least 2 cycles of HMA in combination with another therapeutic agent. Subjects with MDS and CMML who failed at least 1 cycle of induction chemotherapy will be also eligible. Patients with MDS or CMML who progress to secondary AML will be eligible if they received at least 4 cycles of HMA alone or 2 cycles of HMA in combination with another therapeutic agent.
• Patients may have previously received hypomethylating agents or chemotherapy with a mitoxantrone, idarubicin- or cladribine/fludarabine-based regimen for MDS or AML. If the patient has received cladribine-cytarabine-filgrastim-mitoxantrone (CLAG-M) or FLAG-Ida before and has been sensitive to this regimen, defined as MRD negative complete remission (CR) immediately after receiving the treatment and which lasts ≥ 1 year, eligibility will be determined on a case-by-case basis by the study principal investigator (PI).
• The use of hydroxyurea prior to initiation of study treatment is allowed. Patients with symptoms/signs of hyperleukocytosis, white blood cells (WBC) > 100,000/μL or with concern for other complications of high tumor burden of high tumor dynamics (e.g. disseminated intravascular coagulation) can be treated with leukapheresis or may receive up to 2 doses of cytarabine (up to 500 mg/m^2 per dose) prior to start of study treatment.
• Karnofsky score ≥ 70; Eastern Cooperative Oncology Group (ECOG) 0-1.
• Adequate cardiac function defined as absence of decompensated congestive heart failure and/or uncontrolled arrhythmia and left ventricular ejection fraction ≥ 45%.
• Bilirubin ≤ 2.5 x Institutional Upper Limit of Normal unless elevation is thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis
• Adequate pulmonary function defined as absence of oxygen (O2) requirements and either diffusion capacity of the lung for carbon monoxide (DLCO) corrected ≥ 70%mmHg or DLCO corrected 60-69%mmHg and partial pressure of oxygen (pO2) ≥ 70mmHg.
• Creatinine clearance > 60 mL/min.
• Prior autologous HCT is permissible if relapse occurred > 6 months after HCT.
• Prior TBI-containing allogeneic HCT up to 3 Gy is permissible if > 6 months after HCT.
• A human leukocyte antigen (HLA)-matched sibling/unrelated donor, mismatched unrelated donor or haploidentical donor for collection of stimulated peripheral blood stem cells must be identified and readily available.
• Ability to understand and sign a written informed consent document (or legal representative).
• SIBLING DONOR: Related to the patient and genotypically or phenotypically identical for HLA-A, B, C, DRB1 and DQB1. Phenotypic identity must be confirmed by high-resolution typing.
• MATCHED UNRELATED DONOR: Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing; OR mismatched for a single allele without antigen mismatching at HLA-A, B, or C as defined by high resolution typing but otherwise matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing.
• MATCHED UNRELATED DONOR: Donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment. The recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain panel reactive antibody (PRA) screens to class I and class II antigens for all patients before HCT. If the PRA shows > 10% activity, then flow cytometric or B and T cell cytotoxic cross matches should be obtained. The donor should be excluded if any of the cytotoxic cross match assays are positive. For those patients with an HLA Class I allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be obtained regardless of the PRA results. A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion.
• MATCHED UNRELATED DONOR: Patient and donor pairs homozygous at a mismatched allele in the graft rejection vector are considered a two-allele mismatch, i.e., the patient is A*0101 and the donor is A*0102, and this type of mismatch is not allowed.
• MISMATCHED UNRELATED DONOR: HLA-matching must be based on results of high resolution typing at HLA-A, -B, -C, -DRB1, and -DQ.
• MISMATCHED UNRELATED DONOR: Mismatch for one HLA class I antigen with or without an additional mismatch for one HLA-class I allele but matched for HLA-DRB1 and HLA-DQ.
• MISMATCHED UNRELATED DONOR: Mismatched for two HLA class I alleles but matched for HLA-DRB1 and HLA-DQ.
• MISMATCHED UNRELATED DONOR: HLA class I HLA-A, -B, -C allele matched donors allowing for any one or two DRB1 and/or DQB1 antigen/allele mismatch.
• MISMATCHED UNRELATED DONOR: If the patient is homozygous at the mismatch HLA class I locus or II locus, the donor must be heterozygous at that locus and one allele must match the patient (i.e., patient is homozygous A*01:01 and donor is heterozygous A*01:01, A*02:01). This mismatch will be considered a one-antigen mismatch for rejection only.
• HAPLOIDENTICAL DONOR: Donors must be haploidentical relatives of the patients. Donor-recipient compatibility will be tested through HLA typing at high resolution for the HLA loci (-A, -B, -C, -DRB1, -DQB1). Donor and recipient should share at least 5/10 HLA loci.
• HAPLOIDENTICAL DONOR: Age ≥ 18 years.
• HAPLOIDENTICAL DONOR: Weight ≥ 40 kg.
• HAPLOIDENTICAL DONOR: Donor must meet the selection criteria as defined by the Foundation of the Accreditation of Cell Therapy (FACT) and will be screened per the American Association of Blood Banks (AABB) guidelines.

• DONOR: In case of more available donors, selection criteria should include, in this order:

  • For cytomegalovirus (CMV) seronegative recipients, a CMV seronegative donor

  • Red Blood Cell compatibility

    • Red blood cell (RBC) cross match compatible
    • Minor ABO incompatibility
    • Major ABO incompatibility
• DONOR: Donors will undergo diagnostic evaluation (clinical, laboratory test and imaging) as indicated per institutional guidelines.

Exclusion Criteria:

• Active central nervous system (CNS) disease.
• Concomitant illness associated with a likely survival of < 1 year.
• Active systemic fungal, bacterial, viral, or other infection, unless disease is under treatment with antimicrobials and/or controlled or stable. Patients with fever thought to be likely secondary to myeloid malignancy are eligible.
• Known hypersensitivity or contraindication to any study drug used in this trial.
• Pregnancy or lactation.
• Concurrent treatment with any other approved or investigational anti-leukemia agent.
• HAPLOIDENTICAL DONOR: Since detection of anti-donor-specific antibodies (anti-DSA) is associated with higher graft rejection rate, patients will be screened for anti-DSA pre-transplant. Patient with DSA mean fluorescent intensity (MFI) < 5000 after desensitization treatment, will be considered eligible to participate in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (decitabine, FLAG-Ida, HCT); DONORS: Participants undergo apheresis for collection of PBSCs on study. PATIENTS: Patients receive decitabine IV daily over 1 hour on days -12 to -10, -14 to -10, -16 to -10, or -19 to -10, filgrastim SC daily on days -9 to -4, idarubicin IV over 60 minutes daily on days -8 to -6, fludarabine IV over 30 minutes daily on days -8 to -4, cytarabine IV over 2 hours daily on days -8 to -4, and undergo TBI BID on day -1 or 0 OR daily on days -1 and 0 in the absence of disease progression or unacceptable toxicity. Patients then undergo HCT (receive donor PBSCs via infusion) on day 0. Patients also undergo MUGA scan or ECHO during screening, chest X-rays and bone marrow aspiration and/or biopsy during screening and as clinically indicated, and collection of blood samples throughout the study.

Drug: Decitabine; Given IV; Other Names: 5-Aza-2'-deoxycytidine; Dacogen; Decitabine for Injection; Deoxyazacytidine; Dezocitidine; Drug: Cytarabine; Given IV; Other Names: .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-Cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; Procedure: Biospecimen Collection; Undergo collection of blood; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Drug: Fludarabine; Given IV; Other Names: Fluradosa; Biological: Filgrastim; Given SC; Other Names: G-CSF; r-metHuG-CSF; Neupogen; Filgrastim-aafi; Nivestym; Recombinant Methionyl Human Granulocyte Colony Stimulating Factor; rG-CSF; Tevagrastim; Filgrastim Biosimilar Filgrastim-sndz; Zarxio; Filgrastim XM02; Tbo-filgrastim; Granix; Nivestim; XM02; Filgrastim-sndz; Filgrastim Biosimilar Tbo-filgrastim; Filgrastim-ayow; Releuko; Neutroval; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Total Body Irradiation; TBI; SCT_TBI; Whole Body Irradiation; Whole-Body Irradiation; Whole Body; Procedure: Multigated Acquisition Scan; Undergo MUGA; Other Names: Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; MUGA; Radionuclide Ventriculography; RNVG; SYMA Scanning; Synchronized Multigated Acquisition Scanning; MUGA Scan; Multi-Gated Acquisition Scan; Radionuclide Ventriculogram Scan; Gated Heart Pool Scan; RNV Scan; Drug: Idarubicin; Given IV; Other Names: 4-Demethoxydaunomycin; 4-DMDR; 4-Demethoxydaunorubicin; Procedure: Pheresis; Undergo apheresis; Other Names: Apheresis; Apheresed; Blood Component Removal; Collection, Apheresis/Leukapheresis; Hemapheresis; Procedure: Echocardiography Test; Undergo ECHO; Other Names: Echocardiography; EC; Procedure: Bone Marrow Aspiration; Undergo bone marrow aspiration and/or biopsies; Procedure: Bone Marrow Biopsy; Undergo bone marrow aspiration and/or biopsies; Other Names: Biopsy of Bone Marrow; Biopsy, Bone Marrow; Procedure: Chest Radiography; Undergo chest X-rays; Other Names: Chest X-ray; Procedure: Hematopoietic Cell Transplantation; Given via infusion; Other Names: HSCT; HCT; Hematopoietic Stem Cell Transplantation; stem cell transplantation; Hematopoietic Stem Cell Infusion; Stem Cell Transplant; SCT; Stem Cell Transplantation, NOS; HEMATOPOIETIC STEM CELL TRANSPLANT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-relapse mortality (Phase 1)	Will evaluate whether intensification of fludarabine, cytarabine, filgrastim, and idarubicin/reduced intensity conditioning with the potential sequential addition of 4 escalating doses of decitabine prior to allografting with 4 Gy total-body irradiation would be feasible with an acceptable rate of toxicity and non-relapse mortality within the first 100 days following allograft, where day -100 non-relapse mortality is meant to encompass various measures of "toxicity".	At day 100
Disease-free survival (Phase 2)		At 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of stem cell engraftment (Phase 1)	Will use exploratory, descriptive, and observational methods to 1) estimate the rates of stem cell engraftment.	Up to day 80
Rate of donor chimerism (Phase 1)	Will use exploratory, descriptive, and observational methods to estimate donor chimerism.	Up to day 80
Rates of grades II-IV acute graft-versus-host disease (GVHD) (Phase 1)	Will use exploratory, descriptive, and observational methods to estimate the rates of grades II-IV acute GVHD requiring systemic immunosuppressive treatment.	Up to 2 years
Rates of grades II-IV chronic GVHD (Phase 1)	Will use exploratory, descriptive, and observational methods to estimate the rates of grades II-IV chronic GVHD requiring systemic immunosuppressive treatment.	Up to 2 years
Disease response (Phase 1)	Will use exploratory, descriptive, and observational methods to estimate disease response.	Up to 2 years
Duration of remission (Phase 1)	Will use exploratory, descriptive, and observational methods to estimate duration of remission.	Up to 2 years

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Investigators: Principal Investigator: Naveed Ali, MD, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): September 23, 2025
• Primary Completion (Estimated): March 9, 2028
• Study Completion (Estimated): November 29, 2028

Study Registration Dates

• First Submitted: April 8, 2025
• First Submitted That Met QC Criteria: April 8, 2025
• First Posted (Actual): April 15, 2025

Study Record Updates

• Last Update Posted (Actual): May 15, 2026
• Last Update Submitted That Met QC Criteria: May 13, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, Myeloid; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Leukemia, Lymphoid; Leukemia; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Leukemia, Biphenotypic, Acute; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Investigative Techniques; Therapeutics; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Drug Administration Routes; Drug Therapy; Cytological Techniques; Nucleic Acids, Nucleotides, and Nucleosides; Cytodiagnosis; Hydrocarbons; Hydrocarbons, Cyclic; Biological Factors; Carbohydrates; Physical Phenomena; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glycosides; Transplantation; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Diagnostic Techniques, Surgical; Aza Compounds; Nucleosides; Ribonucleosides; Intercellular Signaling Peptides and Proteins; Arabinonucleosides; Anthracyclines; Naphthacenes; Aminoglycosides; Glycoproteins; Glycoconjugates; Electromagnetic Phenomena; Magnetic Phenomena; Radiotherapy; Daunorubicin; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Azacitidine; Electromagnetic Radiation; Radiation; Radiation, Ionizing; Colony-Stimulating Factors; Hematopoietic Cell Growth Factors; Cytokines; Decitabine; Cytarabine; Idarubicin; Injections; Biopsy; Specimen Handling; fludarabine; Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation; X-Rays; Granulocyte Colony-Stimulating Factor; Whole-Body Irradiation; Filgrastim; Blood Component Removal
• Other Study ID Numbers: RG1125142; NCI-2025-01992 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); FHIRB0020797 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No