Early Allogeneic Hematopoietic Cell Transplantation in Treating Patients With Relapsed or Refractory High-Grade Myeloid Neoplasms
Condition: Blasts 10 Percent or More of Bone Marrow Nucleated Cells; Chronic Myelomonocytic Leukemia-2; High Grade Malignant Neoplasm; Myelodysplastic Syndrome; Myelodysplastic Syndrome With Excess Blasts-2; Myeloid Neoplasm; Previously Treated Myelodysplastic Syndrome; Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia
MeSH terms: Leukemia; Neoplasms; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Anemia, Refractory, with Excess of Blasts; Syndrome
Intervention: Cladribine; Cyclosporine; Cytarabine; Filgrastim; Fludarabine Phosphate; Allogeneic Hematopoietic Stem Cell Transplantation; Laboratory Biomarker Analysis; Melphalan; Mitoxantrone Hydrochloride; Mycophenolate Mofetil; Questionnaire Administration; Sirolimus; Total-Body Irradiation; Melphalan Hydrochloride
Intervention description: Given IV; Given PO; Given IV; Given SC; Undergo allogeneic hematopoietic stem cell transplantation; Correlative studies; Given IV; Given IV; Given PO; Ancillary studies; Given PO; Undergo TBI; Given IV
Intervention MeSH terms: Cytarabine; Cyclosporine; Mycophenolic Acid; Sirolimus; Fludarabine; Fludarabine phosphate; Melphalan; Mechlorethamine; Mitoxantrone; Nitrogen Mustard Compounds; Cladribine; 2-chloro-3'-deoxyadenosine; Cyclosporins; Lenograstim
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 30.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      This clinical trial studies how well early stem cell transplantation works in treating
      patients with high-grade myeloid neoplasms that has come back after a period of improvement
      or does not respond to treatment. Drugs used in chemotherapy, such as filgrastim, cladribine,
      cytarabine and mitoxantrone hydrochloride, 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. Giving chemotherapy before a donor peripheral blood cell transplant
      helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem
      cells) and cancer cells. When the healthy stem cells from a donor are infused into the
      patient they may help the patient's bone marrow make stem cells, red blood cells, white blood
      cells, and platelets. The donated stem cells may also replace the patient's immune cells and
      help destroy any remaining cancer cells. Early stem cell transplantation may result in more
      successful treatment for patients with high-grade myeloid neoplasms.
    

Eligibility criteria:

        Inclusion Criteria:

        INCLUSION CRITERIA (ENROLLMENT)

          -  Relapsed or refractory high-grade myeloid neoplasms, defined as having a blast count
             of >= 10% blasts at initial diagnosis; examples include excess blasts (EB)-2, with >=
             10% blasts at initial diagnosis, acute myeloid leukemia (AML) or chronic
             myelomonocytic leukemia (CMML-2); standard definitions of relapse will apply (i.e.,
             characterized by >= 5% abnormal blasts or blast equivalents as assessed by
             multiparameter flow cytometry or morphologic examination; peripheral blood blasts or
             blast equivalents; or extramedullary granulocytic sarcoma, per European LeukemiaNet
             [ELN] 2017 guidelines); bone marrow aspirate/biopsy will be accepted if performed
             outside University of Washington/Fred Hutchinson Cancer Research Center (UW/FHCRC);
             determination of disease status should occur within 30 days of signing informed
             consent

               -  R/R high-grade myeloid neoplasm following intensive induction chemotherapy;
                  relapsed high-grade myeloid neoplasm: patients will be classified as relapsed if
                  they have >= 5% blasts after being in a complete remission (CR) following
                  treatment for high-grade myeloid neoplasm; refractory high-grade myeloid
                  neoplasm: patients may be classified as refractory if they have received at least
                  one prior cycle of induction chemotherapy, whether with cladribine cytarabine
                  mitoxantrone (GCLAM) or another regimen

                  ** Patients may have received up to two courses of intensive induction
                  chemotherapy during initial treatment prior to enrollment on this protocol; for
                  example, patients who have received two courses of granulocyte colony stimulating
                  factor (G-CSF) GCLAM (or similar) chemotherapy, with most recent high-dose
                  cytarabine-containing chemotherapy > 6 months ago and CR lasting > 6 months, will
                  be eligible for this protocol; regimens "similar to GCLAM" would include
                  cytarabine at doses of 1g/m^2 for at least 5 doses; examples of regimens "similar
                  to GCLAM" would be GCLA, fludarabine cytarabine granulocyte (FLAG), and
                  FLAG-idarubicin (ida); however, patients who received more than two courses of
                  GCLAM (or similar) chemotherapy, or patients who received two courses of GCLAM
                  and had CR lasting < 6 months, would not be eligible

               -  R/R high-grade myeloid neoplasm following less intensive induction chemotherapy.
                  Patients who have received at least three cycles of treatment with a
                  hypomethylating agent (HMA; such as azacitidine or decitabine) and still have >=
                  10% blasts will be eligible for the study (they will be considered refractory);
                  similarly, patients who have received three or more cycles of HMA therapy who
                  have had a response (e.g., achieving CR with < 5% blasts), but who then progress
                  using standard definitions of relapse, will also be eligible (they will be
                  considered relapsed)

          -  Potentially eligible for reduced intensity conditioning based on known organ function
             (formal organ function testing may occur after consent)

          -  Caregiver capable of providing post-HCT care

          -  Written informed consent

        INCLUSION CRITERIA (TRANSPLANT)

          -  Identified donor (see DONOR SELECTION below for further details)

               -  Matched related or unrelated (one allele mismatch in HLA-A, B, or C OK) donor
                  according to institutional standards

               -  Unrelated volunteer donor who is mismatched with the recipient (i.e. 9/10 match)

          -  Caregiver capable of providing post-HCT care, who will be present once induction
             therapy with filgrastim, cladribine, cytarabine, mitoxantrone hydrochloride (GCLAM)
             begins

          -  Written informed consent for transplant

          -  Either bone marrow or peripheral blood is allowed

        Exclusion Criteria:

        EXCLUSION CRITERIA (ENROLLMENT)

          -  Prior allogeneic HCT

          -  More than two prior courses of induction chemotherapy

          -  Relapse after minimal residual disease (MRD)-negative CR within 3 months of most
             recent GCLAM chemotherapy

          -  Low likelihood of being eligible for reduced intensity conditioning HCT based on known
             information

               -  Cardiac ejection fraction < 40% or symptomatic coronary artery disease or
                  uncontrolled arrhythmia, as assessed by multigated acquisition (MUGA) or
                  transthoracic echocardiography (TTE) within previous 3 months and since the most
                  recent anthracycline exposure

               -  Corrected diffusing capacity of the lungs for carbon monoxide (DLCOc) < 40% or
                  forced expiratory volume in 1 second (FEV1) < 50%

               -  Estimated glomerular filtration rate (GFR) < 40 ml/min

               -  Need for supplemental oxygen

               -  Direct bilirubin or alanine aminotransferase (ALT) > 2 x upper limit of normal,
                  unless these abnormalities are thought to be related to Gilbert's disease or
                  leukemic infiltration of hepatic parenchyma

          -  Known human immunodeficiency virus (HIV) positivity

          -  Pregnant or nursing (to be confirmed with quantitative human chorionic gonadotropin
             [HCG] testing)

          -  Invasive solid tumor within 5 years; non-melanoma skin cancer or in situ malignancies
             are allowed

          -  Evidence of serious uncontrolled infection

          -  Eastern Cooperative Oncology Group (ECOG) of 3 or 4

          -  EXCLUSION CRITERIA (TRANSPLANT)

          -  Donor specific antibodies against donor HLA-DQ or -DP

          -  Active bacterial, fungal or viral infections unresponsive to medical therapy

          -  Active leukemia in the central nervous system (CNS)

          -  HIV positive

          -  Cardiac ejection fraction < 40% or symptomatic coronary artery disease or uncontrolled
             arrhythmia

          -  DLCOc < 40% or FEV1 < 50%

          -  Estimated GFR < 40 ml/min

          -  Need for supplemental oxygen

          -  Direct bilirubin or ALT > 2 x upper limit of normal, unless these abnormalities are
             thought to be related to Gilbert's disease or leukemic infiltration of hepatic
             parenchyma

        DONOR SELECTION:

        Identification of an appropriate donor will follow the general guidelines listed below.

          -  HLA-matched related or unrelated donor. Donors must be:

               -  Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing

               -  Only a single allele disparity will be allowed for HLA-A, B, or C as defined by
                  high resolution typing

          -  HLA-mismatched unrelated donor. Unrelated volunteer donors who are mismatched with the
             recipient within one of the following limitations will be permitted:

               -  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, OR

               -  Mismatched for two HLA class I alleles, but matched for HLA-DRB1 and HLA-DQ

               -  HLA class I HLA-A, -B, -C allele matched donors allowing for any one or two DRB1
                  and/or DQB1 antigen/allele mismatch

        HLA-matching must be based on results of high resolution typing at HLA-A, -B, -C, -DRB1,
        and -DQ. 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)