CLAG-M or FLAG-Ida Chemotherapy and Reduced-Intensity Conditioning Donor Stem Cell Transplant for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Chronic Myelomonocytic Leukemia

CLAG-M or FLAG-Ida Chemotherapy Followed Immediately by Related/Unrelated Reduced-Intensity Conditioning (RIC) Allogeneic Hematopoietic Cell Transplantation for Adults With Myeloid Malignancies at High Risk of Relapse: A Phase 1 Study

This phase I trial studies the best dose of total body irradiation when given with cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M) or idarubicin, fludarabine, cytarabine and filgrastim (FLAG-Ida) chemotherapy reduced-intensity conditioning regimen before stem cell transplant in treating patients with acute myeloid leukemia, myelodysplastic syndrome, or chronic myelomonocytic leukemia that has come back (relapsed) or does not respond to treatment (refractory). Giving chemotherapy and total body irradiation before a donor peripheral blood stem cell 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 and may help destroy any remaining cancer cells. Sometimes the transplanted cells from a donor can attack the body's normal cells called graft versus host disease. Giving cyclophosphamide, cyclosporine, and mycophenolate mofetil after the transplant may stop this from happening.

Study Overview

• Status: Recruiting
• Conditions: Recurrent Acute Myeloid Leukemia; Recurrent Chronic Myelomonocytic Leukemia; Recurrent Myelodysplastic Syndrome; Refractory Acute Myeloid Leukemia; Refractory Chronic Myelomonocytic Leukemia; Refractory Myelodysplastic Syndrome; Refractory Mixed Phenotype Acute Leukemia; Refractory Acute Leukemia of Ambiguous Lineage; Refractory Acute Undifferentiated Leukemia
• Intervention / Treatment: Drug: Cytarabine; Procedure: Biospecimen Collection; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Mitoxantrone; Biological: Filgrastim; Radiation: Total-Body Irradiation; Procedure: Hematopoietic Cell Transplantation; Procedure: Multigated Acquisition Scan; Drug: Cladribine; Procedure: X-Ray Imaging; Drug: Mycophenolate Mofetil; Drug: Idarubicin; Drug: Mycophenolate Sodium; Drug: Cyclosporine; Procedure: Bone Marrow Biopsy; Procedure: Bone Marrow Aspiration; Procedure: Echocardiography Test

Detailed Description

OUTLINE: This a dose-escalation study of TBI. Patients are assigned to 1 of 2 arms.

ARM I: Patients receive filgrastim (G-CSF) subcutaneously (SC) daily on days -9 to -4, cladribine intravenously (IV) over 2 hours daily on days -8 to -4, cytarabine IV over 2 hours daily on days -8 to -4, and mitoxantrone IV over 60 minutes daily on days -8 to -6. If white blood cell (WBC) > 20,000/uL, filgrastim on days -9 and -8 may be omitted at physician discretion. Patients undergo TBI on either day -1 or 0 and HCT on day 0.

GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours daily on days 3-4, cyclosporine IV over 1-2 hours twice daily (BID) on days 5-60, and mycophenolate mofetil IV or orally (PO) BID on days 5-28 (transplant with related donors) or three times daily (TID) on days 5-35 (transplant with unrelated donors). After day 60, patients continue to receive cyclosporine tapered through day 180 at the discretion of the treating physician in the absence of GVHD.

ARM II: Patients receive G-CSF SC daily on days -9 to -4, fludarabine IV over 30 minutes daily on days -8 to -4, cytarabine IV over 2 hours daily on days -8 to -4, and idarubicin IV over 60 minutes daily on days -8 to -6. If white blood cell (WBC) > 20,000/uL, filgrastim on days -9 and -8 may be omitted at physician discretion. Patients undergo TBI on either day -1 or 0 and HCT on day 0. Patients receiving an unrelated cord blood (UCB) transplant also receive cyclophosphamide IV on day -2.

GVHD PROPHYLAXIS: Patients who received peripheral blood stem cell transplant receive cyclophosphamide IV over 1-2 hours daily on days 3-4, cyclosporine IV over 1-2 hours BID on days 5-60, and mycophenolate mofetil IV or PO BID on days 5-28 (transplant with related donors) or TID on days 5-35 (transplant with unrelated donors). After day 60, patients continue to receive cyclosporine tapered through day 180 at the discretion of the treating physician in the absence of GVHD. Patients who received an UCB transplant receive cyclosporine IV, over 1 hour, every 8 hours (Q8H) from day -3 until day +100 and mycophenolate mofetil IV or PO TID on days 5-35. After day 100 patients continue to receive cyclosporine tapered up to at least 6 months post-transplant.

Patients in both arms undergo multigated acquisition scan (MUGA) or echocardiography, and x-ray imaging during screening and as clinically indicated or per standard practice. Patients also undergo bone marrow biopsy and aspirate during screening, day 28, day 80 and at 1 year. Additionally, patients undergo blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 100 days, at 6, 12, and 24 months post-transplant.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Filippo Milano; Phone Number: 206.667.5925; Email: fmilano@fredhutch.org

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutch/University of Washington Cancer Consortium
      • Contact: Filippo Milano; Phone Number: 206-667-5925; Email: fmilano@fredhutch.org
      • Principal Investigator: Filippo Milano

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age >= 18 years with an Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) =< 5 for patients over 60 years -(Enrollment of patients >= 75 years of age will require case presentation at the transplant Patient Care Conference (PCC) and approval by consensus)
• Acute myeloid leukemia (AML) (2016 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 morphological 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, mixed phenotype acute leukemia) that is either primary refractory or is in untreated or unsuccessfully treated first or subsequent relapse are also eligible
• Subjects with previously treated myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML), defined as prior treatment with at least one hypomethylating agent (HMA; azacitidine and/or decitabine) 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 or decitabine, 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
• The use of hydroxyurea prior to initiation of study treatment is allowed. Patients with symptoms/signs of hyperleukocytosis, WBC > 100,000/uL or with concern for other complications of high tumor burden (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 carbon monoxide diffusing capability test (DLCO) correct >= 70% mmHg or DLCO corrected 60-69% mmHg and partial pressure of oxygen (pO2) >= 70 mmHg
• Serum creatinine =< 1.5 mg/dL
• Prior autologous HCT is permissible if relapse occurred > 3 months but =< 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 or near-matched related, unrelated or haploidentical donor for collection of stimulated peripheral blood stem cells or HLA-matched or near-matched cord blood unit must be identified and readily available
• Women of childbearing potential and men must agree to use adequate contraception beginning at the signing of the consent until at least 12 months post-transplant
• Patients may have previously received chemotherapy with a mitoxantrone, idarubicin- or cladribine/fludarabine-based regimen for MDS or AML. If the patient has received CLAG-M or FLAG-Ida before and has been sensitive to this regimen, eligibility will be determined on a case-by-case basis by the study principal investigator (PI)
• Ability to understand and sign a written informed consent document (or legal representative)

• DONOR: Patients must have an HLA-matched related donor or an HLA-matched unrelated donor, or haploidentical donor who meets standard FHCC and/or National Marrow Donor Program (NMDP) or other donor center criteria for peripheral blood stem cell (PBSC) donation as follows:

  • Related 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

  • 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
    • 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
    • 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

• 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.
  • Age ≥ 12 years
  • Weight ≥ 40 kg.
  • Ability of donors younger than 18 years of age to undergo apheresis without use of a vascular access device. Vein check must be performed and verified by an apheresis nurse prior to arrival.
  • 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.

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

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

    • Red Blood Cell compatibility

      • i. RBC cross match compatible
      • ii. Minor ABO incompatibility
      • iii. Major ABO incompatibility

Exclusion Criteria:

• Patients >= 18 years being treated at Seattle Children's Hospital
• 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 anti-microbials 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 exclusion criteria:

  • 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: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis); See detailed description.	Drug: Cytarabine; Given IV; Other Names: U-19920; Udicil; WR-28453; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Drug: Mitoxantrone; Given IV; Other Names: Dihydroxyanthracenedione; Mitozantrone; 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-ayow; Releuko; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Total Body Irradiation; TBI; SCT_TBI; Whole Body Irradiation; Whole-Body Irradiation; Procedure: Hematopoietic Cell Transplantation; Undergo HCT; Other Names: HSCT; HCT; Hematopoietic Stem Cell Transplantation; stem cell transplantation; Hematopoietic Stem Cell Infusion; Stem Cell Transplant; Procedure: Multigated Acquisition Scan; Undergo MUGA; Other Names: Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; MUGA; Multi-Gated Acquisition Scan; Radionuclide Ventriculogram Scan; Gated Heart Pool Scan; Drug: Cladribine; Given IV; Other Names: 2-CdA; CdA; 2CDA; Cladribina; Leustat; Leustatin; Leustatine; RWJ-26251; Procedure: X-Ray Imaging; Undergo x-ray; Other Names: Conventional X-Ray; Diagnostic Radiology; Medical Imaging; Drug: Mycophenolate Mofetil; Given IV or PO; Other Names: Cellcept; MMF; Drug: Mycophenolate Sodium; Given PO; Other Names: ERL 080; ERL 080A; Socium Mycophenolate; Drug: Cyclosporine; Given IV then PO; Other Names: 27-400; Sandimmune; Ciclosporin; CsA; Neoral; Gengraf; Cyclosporin; Cyclosporin A; OL 27-400; SangCya; Cyclosporine Modified; Procedure: Bone Marrow Biopsy; Undergo bone marrow biopsy and aspirate; Procedure: Bone Marrow Aspiration; Undergo bone marrow biopsy and aspirate; Procedure: Echocardiography Test; Undergo ECHO; Other Names: EC
Experimental: Arm II (FLAG-Ida, TBI, HCT, GVHD prophylaxis); See detailed description.	Drug: Cytarabine; Given IV; Other Names: U-19920; Udicil; WR-28453; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Drug: Fludarabine; Given IV; Other Names: Fluradosa; 9-Beta-D-arabinofuranosyl-2-fluoroadenine; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Total Body Irradiation; TBI; SCT_TBI; Whole Body Irradiation; Whole-Body Irradiation; Procedure: Hematopoietic Cell Transplantation; Undergo HCT; Other Names: HSCT; HCT; Hematopoietic Stem Cell Transplantation; stem cell transplantation; Hematopoietic Stem Cell Infusion; Stem Cell Transplant; Procedure: Multigated Acquisition Scan; Undergo MUGA; Other Names: Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; MUGA; Multi-Gated Acquisition Scan; Radionuclide Ventriculogram Scan; Gated Heart Pool Scan; Procedure: X-Ray Imaging; Undergo x-ray; Other Names: Conventional X-Ray; Diagnostic Radiology; Medical Imaging; Drug: Mycophenolate Mofetil; Given IV or PO; Other Names: Cellcept; MMF; Drug: Idarubicin; Given IV; Other Names: 4-DMDR; Drug: Mycophenolate Sodium; Given PO; Other Names: ERL 080; ERL 080A; Socium Mycophenolate; Drug: Cyclosporine; Given IV then PO; Other Names: 27-400; Sandimmune; Ciclosporin; CsA; Neoral; Gengraf; Cyclosporin; Cyclosporin A; OL 27-400; SangCya; Cyclosporine Modified; Procedure: Bone Marrow Biopsy; Undergo bone marrow biopsy and aspirate; Procedure: Bone Marrow Aspiration; Undergo bone marrow biopsy and aspirate; Procedure: Echocardiography Test; Undergo ECHO; Other Names: EC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of hematopoietic cell transplantation (HCT) failure	Defined as graft rejection (< 5% donor T-cell chimerism).	Within 200 days post-transplant
Rate of disease progression	Defined by European LeukemiaNet (ELN) 2017 criteria and International Working Group (IWG).	Within 200 days post-transplant

Secondary Outcome Measures

Outcome Measure	Time Frame
Duration of remission	Up to 2 years
Incidence of adverse events	Up to 100 days post-transplant
Rates of stem cell engraftment and donor chimerism	At 80 days (+/- 7 days)
Rates of grades II-IV acute graft versus host disease (GVHD) and chronic GVHD requiring systemic immunosuppressive treatment	Up to 2 years
Disease response	Up to 2 years

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Filippo Milano, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): December 3, 2020
• Primary Completion (Estimated): February 28, 2027
• Study Completion (Estimated): March 17, 2027

Study Registration Dates

• First Submitted: May 1, 2020
• First Submitted That Met QC Criteria: May 1, 2020
• First Posted (Actual): May 5, 2020

Study Record Updates

• Last Update Posted (Actual): March 5, 2026
• Last Update Submitted That Met QC Criteria: March 3, 2026
• Last Verified: March 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; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Therapeutics; Fatty Acids; Lipids; Surgical Procedures, Operative; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons; Hydrocarbons, Cyclic; Biological Factors; Carbohydrates; Physical Phenomena; Acids, Acyclic; Carboxylic Acids; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glycosides; Transplantation; Purines; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Nucleosides; Ribonucleosides; Intercellular Signaling Peptides and Proteins; Arabinonucleosides; Anthracyclines; Naphthacenes; Aminoglycosides; Glycoproteins; Glycoconjugates; Electromagnetic Phenomena; Magnetic Phenomena; Radiotherapy; Macrocyclic Compounds; Daunorubicin; Anthraquinones; Anthrones; Anthracenes; Quinones; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Deoxyribonucleosides; Peptides, Cyclic; Electromagnetic Radiation; Radiation; Radiation, Ionizing; Colony-Stimulating Factors; Hematopoietic Cell Growth Factors; Cytokines; Caproates; 2-Chloroadenosine; Adenosine; Purine Nucleosides; Deoxyadenosines; Cyclophosphamide; Cytarabine; Mycophenolic Acid; Cyclosporine; Cyclosporins; Mitoxantrone; Cladribine; Idarubicin; fludarabine; Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation; X-Rays; Granulocyte Colony-Stimulating Factor; Whole-Body Irradiation; Filgrastim
• Other Study ID Numbers: RG1006914 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); NCI-2020-02616 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 10457 (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