Sertraline and Cytosine Arabinoside in Adults With Relapsed and Refractory AML

Relapsed and refractory acute myeloid leukemias are characterized by net drug resistance. At
the root of this drug resistance is an enhanced survival that relates to intrinsic cell cycle
dysregulation and aberrations in the overall process of the repair of DNA damage. These
malignancies represent a continuing therapeutic challenge, since currently no "standard
treatments" for these diseases exist. Approximately 30% of adults with newly diagnosed AML
are primary refractory to chemotherapy and at least 50% of those who achieve remission will
relapse. For patients with relapsed or refractory AML, the expected CR/CRi rates with
traditional multi-agent chemotherapies range from < 10% for primary refractory AML to 25-30%
for relapsed AML and cure rates < 20%, even with allogeneic stem cell transplantation. Thus,
novel treatment approaches are needed.

Inclusion Criteria:

- Pathologically-confirmed diagnoses of relapsed AML: Patients with AML that have
relapsed at least once or are primary induction failure will be eligible

- Age ≥ 18 and ≤ 70 years

- Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - 2

- ≥ 2 weeks off cytotoxic chemotherapy

- ≥ 2 weeks off radiation therapy

- Off biologic therapies including hematopoietic growth factors ≥ 1 week

- If using tyrosine kinase inhibitors (TKIs)/src inhibitors, other non-cytotoxics, or
leukopheresis for blast count control, the patient must be off these therapies for >
24 hrs before starting sertraline. Hydroxyurea will be allowed with sertraline but
should be stopped ≥24 hours before starting cytarabine.

- Adequate organ function as defined below:

- Renal function: Serum creatinine <2.0 mg/dL or creatinine clearance ≥ 50
mL/minute

- Hepatic function: aspartate aminotransferase (AST), alanine aminotransferase
(ALT) and Alkaline Phosphatase ≤ 5x Upper Limit normal (ULN), bilirubin ≤ 2.0
mg/dl, unless due to Gilbert's, hemolysis or leukemic infiltration

- Left Ventricular Ejection Fraction ≥ 45% by multigated acquisition (MUGA) scan or
Echocardiogram

- Patients who have undergone stem cell transplantation (SCT), autologous or allogeneic,
are eligible provided that they are ≥ 8 weeks from stem cell infusion, have no active
graft versus host disease (GVHD), are off immune suppression for at least 2 weeks, and
do not have a history of veno-occlusive disease (VOD)

- Female patients of childbearing age must have negative pregnancy test and women of
child-bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for 30 days
after study participation

- Patients must be able to give informed consent

Exclusion Criteria:

- Concomitant chemotherapy, radiation therapy, or immunotherapy

- Patients who are receiving any other investigational agents concurrently

- Hyperleukocytosis with ≥ 30,000 blasts/microliter (uL). If using tyrosine kinase/src
inhibitors (FLT-3 inhibitors), other non-cytotoxics, or leukopheresis for blast count
control, the patient must be off these therapies for ≥ 24 hours prior to beginning
sertraline. If using hydroxyurea for blast count control, this may be continued until
up to 24 hours before starting cytarabine

- Acute Progranulocytic Leukemia (APL)

- Active central nervous system (CNS) leukemia

- Active, uncontrolled infection. Patients with infection under active treatment and
controlled with antibiotics are eligible

- Presence of other life-threatening illness

- Patients with mental deficits and/or psychiatric history that preclude them from
giving informed consent or from following protocol

- Pregnant women are excluded from this study due to potential teratogenic and/or
abortifacient effect of this combination chemotherapy. Nursing mother should stop
breastfeeding to be eligible due to potential risk for adverse events in nursing
infant

- Subjects with the following cardiac risk factors must be excluded: transmural
myocardial infarction (MI) within prior 6 months, severe/unstable angina pectoris,
coronary/peripheral artery bypass graft, cerebrovascular accident or transient
ischemic attack (TIA) or seizure disorder within 6 months prior to study drug
administration. In addition, patients with New York Heart Association (NYHA) class III
or IV heart failure will be excluded

- Patients requiring treatment with other anti-depressive medications including the
selective and non-selective monoamine oxidase (MAO) inhibitors (including linezolid),
5-hydroxytryptamine (5-HT) receptor agonists (triptans), tryptophan or
antidopaminergic agents (anti-psychotics, metoclopramide, promethazine, haloperidol)

- Patients requiring prolonged treatment with fluconazole, voriconazole, or
posaconazole. Use of isavuconazonium sulfate, liposomal amphotericin, are
echinocandins are permitted

- Prior treatment with clofarabine within 6 months or history of clofarabine-induced
liver dysfunction

- History of hypersensitivity to sertraline

- Patients taking sertraline at the time of study entry will not be eligible for the
study