Alternative Dosing Strategy of Ruxolitinib in Patients With Myelofibrosis

This pilot study was designed to explore an alternative dosing approach with the purpose of
reducing anemia and thrombocytopenia. Subjects began dosing at 10 mg bid and had the
opportunity for dose increases based on assessments of efficacy and overall hematologic
status in a defined prior dosing interval. Dose increases were restricted to those patients
who did not meet criteria for or have a dose hold over the prior 6 weeks, had a platelet
count ≥100 x 10^9/L at week 12 or ≥150 x 10^9/L at week 18, and had a self-reported Patient's
Global Impression of Change (PGIC) score of 3 (minimally improved) to 7 (very much worse) OR
the subject's palpable spleen length below the costal margin had been reduced by less than
40% at that visit relative to Baseline. Dose increases were elective and not required.
Subjects were permitted a dose increase of 5 mg BID to 15 mg BID at Week 12 and to a maximum
of 20 mg BID at Week 18. There were also protocol-required dose decreases for
thrombocytopenia (platelets <100 x 10^9/L) or protocol-defined anemia (decline in hemoglobin
of at least 2 g/dL to a level < 8 g/dL, development of transfusion dependence, or a 50%
increase in transfusion requirements for transfusion dependent subjects).This approach
assumed that beginning at a low dose for initial therapy might have a positive impact on the
rate of the initial hemoglobin decline and the nadir by decreasing the level of JAK-mediated
inhibition of hematopoiesis. Specific dose modifications were described to minimize
excursions of hemoglobin levels into the Grade 3 or Grade 4 range.

Inclusion Criteria:

- Diagnosis of Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis
(PPV-MF), or Post-Essential Thrombocythemia Myelofibrosis (PET-MF) as confirmed by
bone marrow biopsy.

- Must score at least 2 points on the Dynamic International Prognostic Scoring System
(DIPSS) scale for prognostic risk factors.

- Peripheral blast count < 5% at both Screening and Baseline hematology assessments.

- Must discontinue all drugs used to treat underlying myelofibrosis (MF) disease no
later than Day -1 (the day prior to starting ruxolitinib).

- Must have hemoglobin value ≥ 6.5 g/dL and be willing to receive blood transfusions.

- Platelet count ≥ 100*10^9/L.

- Must have a palpable spleen.

Exclusion Criteria:

- Inadequate liver or bone marrow reserves, end stage renal disease on dialysis,
clinically significant concurrent infections requiring therapy, or unstable cardiac
function.

- Invasive malignancies over the previous 5 years (except treated early stage carcinomas
of the skin, completely resected intraepithelial carcinoma of the cervix, and
completely resected papillary thyroid and follicular thyroid cancers).

- Splenic irradiation within 6 months prior to receiving the first dose of study
medication.

- Life expectancy less than 6 months.