1. Ruxolitinib + Azacitidine in Newly Diagnosed or R/R, Intermediate- or High-Risk Myelofibrosis
New Findings in Hematology: Independent Conference Coverage of ASH 2016*; December 3-6, 2016; San Diego, California
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
R/R, relapsed/refractory.
This activity is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, and Seattle Genetics.

2. RUX + AZA in Myelofibrosis: Background
RUX, a potent oral JAK1/2 inhibitor, decreases symptoms and splenomegaly in pts with MF[1,2]
AZA, a hypomethylating agent, demonstrates activity in approximately 25% of MF pts[3]
Combination or sequencing of these agents may improve response, decrease toxicity compared with either drug given as monotherapy[4]
Current study evaluates RUX + AZA combination in pts with newly diagnosed or R/R, intermediate- or high-risk MF[5]
AZA, azacitidine; MF, myelofibrosis; R/R, relapsed/refractory; RUX, ruxolitinib.
1. Verstovsek S, et al. N Engl J Med. 2012;366:
2. Harrison C, et al. N Engl J Med. 2012;366:
3. Quintás-Cardama A, et al. Leukemia. 2008;22:
4. Daver N, et al. Haematologica. 2015;100:
5. Daver N, et al. ASH Abstract 1127.
Slide credit: clinicaloptions.com

3. RUX + AZA in Myelofibrosis: Study Design
Open-label, nonrandomized phase II study[1]
Primary endpoint: objective response, defined as CR + PR + CI
Response assessed by IWG-MRT 2013 criteria[2]
Cycles 1-3*
Cycle 4-on*
Pts with newly diagnosed or R/R, intermediate-1–risk, intermediate-2–risk, or high-risk MF, no prior RUX or AZA , platelets ≥ 50 x 109/L, ANC ≥ 1.0 x 109/L
(N = 44)
Ruxolitinib
15-20 mg PO BID
Ruxolitinib
15-20 mg PO BID +
Azacitidine†
25 mg/m² IV QD Days 1-5
*1 cycle lasted 4-6 wks. †Dosage could be increased to 50 or 75 mg/m².
ANC, absolute neutrophil count; AZA, azacitidine; CI, clinical improvement; IWG-MRT, International Working Group-Myeloproliferative Neoplasms Research and Treatment; MF, myelofibrosis; R/R, relapsed/refractory; RUX, ruxolitinib.
1. Daver N, et al. ASH Abstract 1127.
2. Tefferi A, et al. Blood. 2013;122:
Slide credit: clinicaloptions.com

4. RUX + AZA in Myelofibrosis: Baseline Characteristics
RUX + AZA (N = 44)
Median age, yrs (range)
66 (48-87)
Myelofibrosis diagnosis, n
Primary/post ET/post PV
25/11/8
IPSS score, n
Int-1/int-2/high
8/9/27
DIPSS score, n
15/19/10
EUMNET fibrosis grade, n
MF-1/MF-2/MF-3
4/22/18
Prior therapy, % 57
Splenomegaly, % 86
Peripheral blasts ≥ 1%, % 64
Characteristic
RUX + AZA (N = 44)
Median WBC x 109/L (range)
12.1 ( )
Median Hb, g/dL (range)
10.3 ( )
Median platelets x 109/L (range)
271 ( )
Cytogenetics, %
Diploid/abnormal
59/39
JAK2 positive, % 55
Molecular panel, n
TET2
ASXL1
IDH1/2
EZH2
DNMT3/NRAS
(n = 28) 6 4 2
1/2
AZA, azacitidine; DIPSS, Dynamic International Prognostic Scoring System; ET, essential thrombocythemia; EUMNET, European Myelofibrosis Network; Hb, hemoglobin; Int, intermediate; IPSS, International Prognostic Scoring System; MF, myelofibrosis; PV, polycythemia vera; RUX, ruxolitinib; WBC, white blood cell count.
Slide credit: clinicaloptions.com
Daver N, et al. ASH Abstract 1127.

5. RUX + AZA in Myelofibrosis: Response
IWG-MRT 2013 Response, n (%)
RUX + AZA
(n = 39)
Objective response
27 (69) PR
2 (7)
Cl spleen + TSS
8 (30)
CI TSS + hemoglobin
Cl spleen + CR cytogenetic
CI TSS + CR cytogenetic
1 (4)
CI TSS only
CI spleen only
4 (15)
None
12 (31)
Spleen Response
RUX + AZA
Baseline spleen ≥ 5 cm, n
CI in spleen by IWG-MRT criteria, n (%)
Median time to CI in spleen, mos (range)
> 50% reduction in palpable spleen length at Wk 24, n (%)
> 50% reduction in palpable spleen length at any time, n (%) 29
16 (55)
1.8 ( )
14 (48)
23 (79)
5 of 16 pts (31%) demonstrated clinical improvement of splenomegaly after AZA addition to regimen
Median time to spleen improvement: 1.8 mos after AZA (range: )
AZA, azacitidine; CI, clinical improvement; IWG-MRT, International Working Group-Myeloproliferative Neoplasms Research and Treatment; RUX, ruxolitinib; TSS, total symptom score.
6 of 27 pts (22%) had clinical response by IWG-MRT criteria after AZA addition to regimen
Median time to improvement: 4.2 mos after AZA (range: )
Slide credit: clinicaloptions.com
Daver N, et al. ASH Abstract 1127.

6. RUX + AZA in Myelofibrosis: Fibrosis Change
Improvement: 11 pts Stable: 10 pts Worsening: 6 pts
17 of 27 responders were JAK2 positive
15 pts underwent serial JAK2 analysis
Clinical response by IWG-MRT criteria similar
In pts with JAK2 mutations vs those without (18/24 vs 9/20, respectively; P = .31)
In pts with 0-1 mutations vs those with > 1 (19/33 vs 8/19, respectively; P = .67)
n = 4 3 3
n = 4
n = 5
n = 5 2 2
n = 2
Fibrosis Grade
n = 4
Fibrosis Grade
n = 1
JAK2 Response, n
RUX + AZA (n = 15)
0% to 20% reduction 6
20% to 50% reduction 4
> 50% reduction 3
Stable/increase 2
AZA, azacitidine; IWG-MRT, International Working Group-Myeloproliferative Neoplasms Research and Treatment; RUX, ruxolitinib.
n = 1 1 1
n = 1
Baseline
Wk 24
Slide credit: clinicaloptions.com
Daver N, et al. ASH Abstract Reproduced with permission.

7. RUX + AZA in Myelofibrosis: Adverse Events
AE Occurring in ≥ 5% of Pts, n (%)
RUX + AZA (N = 44)
Grade 1/2
Grade 3/4
Thrombocytopenia
20 (45)
10 (23)
Anemia
14 (3)
16 (36)
Constipation
Nausea
4 (9)
1 (2)
Neutropenia
3 (7)
8 (18)
Diarrhea
Pruritis
2 (5)
Insomnia
Fatigue
Time Point
RUX + AZA (N = 44)
Median Hb, g/dL
New Grade 3/4 Anemia, n
Baseline
10.3 NA
Wk 1-12
9.5 13
Wk 13-24
9.4 3
Wk 24-on
9.9
In pts with cytopenias:
New onset cytopenia, n = 16
≥ 2-grade change, n = 4
D/c due to cytopenia, n = 1
AE, adverse event; AML, acute myeloid leukemia; AZA, azacitidine; D/c, discontinued; Hb, hemoglobin; MUD-SCT, matched unrelated donor stem cell transplantation; NA, not applicable; RUX, ruxolitinib.
14 deaths occurred: progression to AML, n = 5; pneumonia, n = 3; other infections, n = 2; meningitis with seizure, cardiac arrest, metastatic melanoma, post MUD-SCT, n = 1 each
Slide credit: clinicaloptions.com
Daver N, et al. ASH Abstract 1127.

8. RUX + AZA in Myelofibrosis: Conclusions
Study investigators suggest that combination ruxolitinib + azacitidine is feasible and promising in pts with newly diagnosed or R/R MF
ORR by IWG-MRT criteria: 69%
CI spleen by IWG-MRT: 55%
Wk 24 splenomegaly reduction by > 50%: 48%
Overall splenomegaly reduction by > 50%: 79%
Acceptable tolerability; rate of cytopenias similar to that of single-agent ruxolitinib
Improvement in bone marrow fibrosis observed but requires confirmation
Analysis of Hb improvement, OS, JAK2 alleles, and fibrosis ongoing
AZA, azacitidine; CI, clinical improvement; Hb, hemoglobin; IWG-MRT, International Working Group-Myeloproliferative Neoplasms Research and Treatment; MF, myelofibrosis; R/R relapsed/refractory; RUX, ruxolitinib.
Slide credit: clinicaloptions.com
Daver N, et al. ASH Abstract 1127.

9. Go Online for More CCO Coverage of ASH 2016!
Short slideset summaries of all the key data
Additional CME-certified analyses with expert faculty commentary on all the key studies in:
Leukemias
Lymphomas/CLL
Myeloma/plasma cell disorders
MDS and myeloproliferative neoplasms
clinicaloptions.com/oncology