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Combination Chemotherapy (FLAG-Ida) Followed Immediately by Reduced-Intensity Total Body Radiation Therapy and Donor Hematopoietic Cell Transplant for the Treatment of Adults Age 60 and Older With Newly Diagnosed Adverse-Risk Acute Myeloid Leukemia or Other High-Grade Myeloid Cancer

Description

This phase II trial tests the safety, side effects, and how well combination chemotherapy with fludarabine, high-dose cytarabine, granulocyte colony-stimulating factor (G-CSF), and idarubicin (FLAG-Ida) followed immediately by reduced-intensity total body radiation therapy, called total body irradiation (TBI), and donor hematopoietic cell transplant (HCT) works in treating adults age 60 and older with newly diagnosed adverse-risk acute myeloid leukemia (AML) or other high-grade myeloid cancer. Despite advances in supportive care and the approval of more than 10 new drugs since 2017, the outcomes of older adults with adverse-risk acute myeloid leukemia and other high-grade myeloid cancers remains poor. Most patients are expected to die from their cancer or the consequences of treatment-related side effects. Donor HCT is a very important part of any curative-cancer treatment for these patients. However, while accepted as standard care for decades, this treatment exposes patients to long periods of drug-induced low blood cell counts and the problems associated with low blood counts, like infections and bleeding, which are associated with significant risk of chronic side effects and death. This study will use a different approach to the upfront curative-cancer treatment of older adults with an adverse-risk AML or other high-grade myeloid cancer. This study will use intense chemotherapy followed a few days later by lower-dose TBI and donor HCT. Chemotherapy drugs, such as idarubicin, fludarabine, high-dose cytarabine 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. G-CSF helps the bone marrow make more white blood cells in patients with low white blood cell count due to cancer treatment. This approach allows effective treatment of cancer cells and overall reduction of the period of low blood cells counts. This decreases the risk for problems associated with low blood counts, such as infection and chronic side effects. Decreasing these are important for older adults who undergo HCT. This treatment strategy may improve treatment outcomes by allowing more patients to successfully undergo donor HCT and reduce the risk of low blood cell counts and the problems associated with low blood counts. Giving chemotherapy followed immediately by reduced-intensity TBI and donor HCT may be safe, tolerable and/or effective in treating adults age 60 and older with newly diagnosed adverse-risk AML or other high-grade myeloid cancer.

Study Overview

Study Details

Study overview

This phase II trial tests the safety, side effects, and how well combination chemotherapy with fludarabine, high-dose cytarabine, granulocyte colony-stimulating factor (G-CSF), and idarubicin (FLAG-Ida) followed immediately by reduced-intensity total body radiation therapy, called total body irradiation (TBI), and donor hematopoietic cell transplant (HCT) works in treating adults age 60 and older with newly diagnosed adverse-risk acute myeloid leukemia (AML) or other high-grade myeloid cancer. Despite advances in supportive care and the approval of more than 10 new drugs since 2017, the outcomes of older adults with adverse-risk acute myeloid leukemia and other high-grade myeloid cancers remains poor. Most patients are expected to die from their cancer or the consequences of treatment-related side effects. Donor HCT is a very important part of any curative-cancer treatment for these patients. However, while accepted as standard care for decades, this treatment exposes patients to long periods of drug-induced low blood cell counts and the problems associated with low blood counts, like infections and bleeding, which are associated with significant risk of chronic side effects and death. This study will use a different approach to the upfront curative-cancer treatment of older adults with an adverse-risk AML or other high-grade myeloid cancer. This study will use intense chemotherapy followed a few days later by lower-dose TBI and donor HCT. Chemotherapy drugs, such as idarubicin, fludarabine, high-dose cytarabine 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. G-CSF helps the bone marrow make more white blood cells in patients with low white blood cell count due to cancer treatment. This approach allows effective treatment of cancer cells and overall reduction of the period of low blood cells counts. This decreases the risk for problems associated with low blood counts, such as infection and chronic side effects. Decreasing these are important for older adults who undergo HCT. This treatment strategy may improve treatment outcomes by allowing more patients to successfully undergo donor HCT and reduce the risk of low blood cell counts and the problems associated with low blood counts. Giving chemotherapy followed immediately by reduced-intensity TBI and donor HCT may be safe, tolerable and/or effective in treating adults age 60 and older with newly diagnosed adverse-risk AML or other high-grade myeloid cancer.

Pilot Study of FLAG-Ida Followed Immediately by Reduced-Intensity Allogeneic HCT for Adults Age 60 and Older With Newly Diagnosed Adverse-Risk AML or Other High-Grade Myeloid Neoplasm

Combination Chemotherapy (FLAG-Ida) Followed Immediately by Reduced-Intensity Total Body Radiation Therapy and Donor Hematopoietic Cell Transplant for the Treatment of Adults Age 60 and Older With Newly Diagnosed Adverse-Risk Acute Myeloid Leukemia or Other High-Grade Myeloid Cancer

Condition
Acute Leukemia of Ambiguous Lineage
Intervention / Treatment

-

Contacts and Locations

Seattle

Fred Hutch/University of Washington Cancer Consortium, Seattle, Washington, United States, 98109

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

For general information about clinical research, read Learn About Studies.

Eligibility Criteria

  • * PARTICIPANTS: Age ≥ 60 years. Adults age \< 60 years are eligible if they are felt to be unsuitable candidates for myeloablative conditioning as per physician assessment
  • * PARTICIPANTS: Ability to understand and willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of potential study participants
  • * PARTICIPANTS: Newly diagnosed, untreated high-risk myeloid or mixed myeloid/lymphoid neoplasm:
  • * Adverse-risk AML (using 2022 International Consensus Classification for disease categorization and 2022 European LeukemiaNet \[ELN\] criteria for molecular/cytogenetic risk assignment)
  • * Acute leukemia of ambiguous lineage (using 2022 International Consensus Classification for disease categorization)
  • * High-risk myelodysplastic neoplasm (MDS) (Molecular International Prognostic System \[IPSS-M\] moderate high, high, or very high, OR ≥ 10% blasts in blood or marrow)
  • * High-risk chronic myelomonocytic leukemia (CMML) (clinical/molecular CMML-specific prognostic scoring system \[CPSS-Mol\] intermediate-2 or high, OR ≥ 10% blasts in blood or marrow)
  • * Prior treatment of MDS or CMML with lower-intensity therapy (e.g., growth factors, erythropoiesis-stimulating agents, and lenalidomide) is permissible, but patients may not have received prior hypomethylating agents
  • * PARTICIPANTS: Disease not requiring immediate anti-neoplastic therapy (e.g., presenting with leukopenia or pancytopenia)
  • * PARTICIPANTS: Interest in pursuing allogeneic HCT
  • * PARTICIPANTS: Available caregiver
  • * PARTICIPANTS: Karnofsky score ≥ 70; Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • * PARTICIPANTS: Bilirubin ≤ 2.5 x institutional upper limit of normal unless elevation is thought to be due to hepatic infiltration by myeloid neoplasm, Gilbert's syndrome, or hemolysis
  • * PARTICIPANTS: Serum creatinine ≤ 1.5 mg/dL
  • * PARTICIPANTS: Prior autologous HCT is permissible if \> 6 months after planned HCT on this study
  • * PARTICIPANTS: Participants of child-bearing potential must be willing to employ two highly effective and acceptable forms of contraception 7 days before initiation of study treatment and for at least 12 months after HCT. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test during screening (within 2 weeks of treatment initiation, per Fred Hutch Cancer Center \[FHCC\] standard of care \[SOC\]), where WOCBP are defined as all female participants between 18-55 years of age, unless postmenopausal or with hysterectomy
  • * PARTICIPANTS: HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • * PARTICIPANTS: For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load
  • * PARTICIPANTS: 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, as determined by the investigator, are eligible for this trial
  • * DONORS: Patients must have an HLA-matched related donor, an HLA-matched or mismatched unrelated donor, or an HLA- haploidentical donor who meets standard Fred Hutchinson Cancer Center (FHCC) and/or National Marrow Donor Program (NMDP) or other donor center criteria for peripheral blood stem cell (PBSC) donation as follows:
  • * HLA-matched 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
  • * HLA-matched unrelated donor:
  • * 10/10 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. A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion
  • * HLA-mismatched unrelated donor:
  • * HLA-matching must be based on results of high resolution typing at HLA-A, -B, -C, -DRB1, and -DQ
  • * 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
  • * HLA class I HLA-A, -B, -C allele matched donors allowing for any one or two DRB1 and/or DQB1 antigen/allele mismatch
  • * Donor/recipient HLA mismatching at loci for which the patient is homozygous is not allowed (isolated rejection vector)
  • * HLA-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
  • * Donor age ≥ 12 years
  • * Donor 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 than one available haploidentical donor, preference should be given to younger age
  • * 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. Use of donors requiring desensitization treatment of the patient are not permissible
  • * PARTICIPANTS: Active central nervous system (CNS) disease
  • * PARTICIPANTS: Decompensated congestive heart failure and/or uncontrolled arrhythmia and/or significant medical history of cardiac disease precluding allogeneic HCT
  • * PARTICIPANTS: Significant medical history of pulmonary disease and/or symptoms suggestive of pulmonary disease precluding allogeneic HCT
  • * PARTICIPANTS: Treatment with any other approved or investigational anti-leukemia agent(s)
  • * PARTICIPANTS: Concomitant illness associated with a likely survival of \< 1 year
  • * PARTICIPANTS: 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 secondary to myeloid malignancy are eligible
  • * PARTICIPANTS: Known hypersensitivity or contraindication to receiving any of the study drugs used in this trial, including post-transplant cyclophosphamide (PTCy)
  • * PARTICIPANTS: Pregnancy or lactation
  • * PARTICIPANTS: Psychiatric illness/social situations that would limit compliance with study requirements

Ages Eligible for Study

18 Years to

Sexes Eligible for Study

ALL

Accepts Healthy Volunteers

No

Collaborators and Investigators

Fred Hutchinson Cancer Center,

Filippo Milano, MD, PhD, PRINCIPAL_INVESTIGATOR, Fred Hutch/University of Washington Cancer Consortium

Study Record Dates

2029-06-30