Early Allogeneic Hematopoietic Cell Transplantation in Treating Patients With Relapsed or Refractory 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)