Study of Combination Ruxolitinib and Decitabine Treatment for Accelerated Phase MPN or Post-MPN AML

At this time, there is no standard medical treatment for MF-BP or MF-AP. The investigators
believe that the combination of ruxolitinib and DEC is a candidate approach to the treatment
of MF-BP/MF-AP that is worthy of exploration based on both the current understanding of the
biology of disease and emerging preclinical data. The molecular pathogenesis of MPN and
progression to blast phase is almost certainly due to a complex combination of gene mutations
(JAK2V617F, MPL) and epigenetic alterations (IDH1/2, IKZF1, EZH2, TET2) that culminate in the
emergence of leukemic clones. Recent evidence indicates that the JAK2V617F protein can
localize in the nucleus and influence global DNA methylation patterns which may lead to
genomic instability and disease progression. The inhibition of JAK-STAT mediated cell
proliferation and survival in conjunction with the reversal of DNA hypermethylation of tumor
suppressor genes would be predicted to have at least an additive if not synergistic effect in
inducing apoptosis of cells belonging to the malignant myeloid clone. Correlative studies
conducted within a trial of Private and Confidential MPD-RC 109 Ruxolitinib + Decitabine
combination JAK2 inhibitor and DMNT1 inhibitor in patients with MPN-BP would explore the
effect on methylation status of various gene promoters as well as the influence on gene
expression of chromatin related proteins and ultimately leukemic cell survival. The
sequential administration of a JAK2 inhibitor followed by a DNMT inhibitor would also
potentially serve to overcome the JAK2-independent effects of epigenetic lesions that lead to
MPN-BP. In addition, a murine model of leukemic transformation has been described. In this
model, bone marrow obtained from Tp53 null mice is retrovirally transduced with Jak2V617F,
and transplanted into donor C56BL/6 mice. The transplanted mice develop an MPN which
progresses to AML. In vitro drug studies utilizing bone marrow from these leukemic mice have
demonstrated that exposure to decitabine or ruxolitinib inhibits colony formation in a
methylcellulose colony-forming assay. Importantly, the combination of decitabine and
ruxolitinib in this assay significantly reduces colony formation when compared to either drug
alone (Rampal et al. ASH 2012 oral abstract 808) thus providing pre-clinical evidence for the
combination study proposed here.

Inclusion Criteria:

- Accelerated phase MPN as defined by 10%-19% blasts in the peripheral blood or bone
marrow and evidence of dysplastic marrow features with a concomitant diagnosis of
essential thrombocythemia (ET), polycythemia vera (PV) or primary myelofibrosis (PMF)
or a diagnosis of acute myelogenous leukemia as defined by 20% blasts in the blood or
bone marrow following a previous diagnosis of ET, PV or PMF.

- >18 years of age

- Eastern Cooperative Oncology Group (ECOG) Performance status of 0-2. Patients with
ECOG performance status of 3 will be eligible if the lower performance status is
deemed by the investigator to be due entirely to accelerated or blastic phase MPN and
not due to another comorbidity.

- Acceptable pre-study organ function during screening as defined as: Total bilirubin <
1.5 times the upper limit of normal (ULN) unless due to Gilbert's disease or
hemolysis, Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5
times ULN, Serum creatinine ≤ 1.5 x ULN

- Women of childbearing potential and males must agree to use adequate contraception
(i.e., hormonal or barrier method of birth control; abstinence) prior to study entry
and for the duration of study participation. Should a female subject become pregnant
or suspect she is pregnant while participating in this study, she should inform the
treating physician immediately.

- Patients who are not candidates for or have declined an allograft.

- Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

- Have had chemotherapy or investigational therapy, with the exception of hydroxyurea,
within 4 weeks of study entry. Previous treatment with either ruxolitinib or
decitabine as single agents will not exclude eligibility. Previous stem cell
transplant will also not exclude eligibility as long as other inclusion/exclusion
criteria have been met.

- Patients with acute myelofibrosis are excluded.

- Uncontrolled intercurrent illness including, but not limited to hepatitis, human
immunodeficiency virus (HIV)-positive subjects receiving combination antiretroviral
therapy, ongoing or active infection, symptomatic congestive heart failure, unstable
angina pectoris, ventricular arrhythmia, or psychiatric illness/social situations that
would limit compliance with study requirements.

- Other medications, severe acute/chronic medical or psychiatric conditions, or
laboratory abnormalities that may increase the risk associated with study
participation or study drug administration, or may interfere with the interpretation
of study results, that in the judgment of the Investigator would make the subject
inappropriate for entry into this study.