Early Allogeneic Hematopoietic Cell Transplantation in Treating Patients With Relapsed or Refractory High-Grade Myeloid Neoplasms

PRIMARY OBJECTIVES:

I. To evaluate the feasibility of "early" allogeneic hematopoietic cell transplant (HCT) for
patients with relapsed or refractory (R/R) high-grade myeloid neoplasms.

SECONDARY OBJECTIVES:

I. Estimate relapse-free survival (RFS), acute graft versus host disease (GVHD), treatment
related mortality (TRM), event-free survival (EFS), overall survival (OS), and complete
remission (with or without measurable disease) among patients who receive early HCT.

II. Assess factors that distinguish patients who receive early HCT from those who do not.

III. Compare RFS, EFS, OS, acute GVHD, and TRM between patients in the feasibility study and
matched patients who were transplanted with standard scheduling.

IV. Demonstrate the feasibility of collecting patient-reported outcomes and resource
utilization data for trial participants.

V. Describe the outcomes of patients enrolled who went on to allogeneic HCT off-study.

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. Treatment continues for a
maximum of 2 courses in the absence of disease progression or unacceptable toxicity.

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) on day -3, and sirlolimus PO BID on day -3.
Patients > 55 years or with significant co-morbidities 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 receive mycophenolate mofetil PO three times daily (TID) on days
0-30, then 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 on days -3 to 150, with
a taper until day 180.

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 as assessed by multiparameter flow cytometry or
morphologic examination; peripheral blood blasts; 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)

- Matched related or unrelated (8/8 matched at human leukocyte antigen [HLA]-A, -B, -C,
-DRB1) donor according to institutional standards

- 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

- 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

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