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.

OUTLINE:

RE-INDUCTION CHEMOTHERAPY: Patients receive filgrastim subcutaneously (SC) on days 0-5, mitoxantrone hydrochloride intravenously (IV) over 60 minutes on days 1-3, cladribine IV over 2 hours on days 1-5, and cytarabine IV over 2 hours on days 1-5.

CONDITIONING REGIMEN: Beginning 14-60 days after re-induction chemotherapy, patients receive fludarabine phosphate IV over 30 minutes on days -6 to -2, melphalan IV on days -3 to -2, cyclosporine orally (PO) twice daily (BID) starting on day -3. Sirolimus PO BID starting on day -3 will be given to patients who have matched unrelated donors or mismatched unrelated donors. Patients >55 years or with significant co-morbidities will only receive melphalan IV on day -2 and will also receive total body irradiation (TBI) on day -1 or day 0.

EARLY TRANSPLANT: Patients undergo allogeneic HCT after conditioning regimen on day 0.

GVHD PROPHYLAXIS: Patients with matched donors will receive mycophenolate mofetil PO three times daily (TID) on days 0-30, then twice a day (BID) until day 40; and cyclosporine PO BID on days -3 to 96, with a taper until day 150. Patients with matched unrelated donors also receive sirolimus PO BID on days -3 to 150, with a taper until day 180. Patients with mismatched unrelated donors will receive mycophenolate mofetil PO TID on days 0-30, then BID until day 100, with a taper until day 150; cyclosporine PO BID on days -3 to 150, then taper until day 180; and sirolimus BID PO days -3 to 180, then a taper until day 365.

After completion of study treatment, patients are followed up periodically.

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)