1. Myelofibrosis and Polycythemia Vera: Current and Emerging Treatment Options
Srdan Verstovsek, MD, PhD
Professor
Division of Cancer Medicine Department of Leukemia The University of Texas M. D. Anderson Cancer Center Houston, Texas
This activity is supported by an educational grant from Incyte.

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3. Faculty Disclosures
Srdan Verstovsek, MD, PhD, has disclosed that his institution has received funds for the conduct of clinical studies that he participated in from AstraZeneca, Blueprint Medicines, Bristol-Myers Squibb, Celgene, CTI BioPharma, Galena BioPharma, Genentech, Geron, Gilead Sciences, Incyte, Lilly Oncology, NS Pharma, Pfizer, Promedior, Roche, and Seattle Genetics.
This slide lists disclosures for the faculty who was involved in the production of these slides.

4. Polycythemia Vera

5. Case 1: Pt With PV Requiring First-line Cytoreductive Therapy
A 51-yr-old postmenopausal woman with PV
Good control of hematocrit; no need for phlebotomy for last 2 yrs
Hematocrit: 42%; platelets: 945 x 109/L; WBC: 12 x 109/L; chemistry normal; iron deficiency
History of hypertension and depression
She complains about significant itching that affects quality of life, no relief from antihistamines or increased dose of aspirin, increasing fatigue
On physical exam, you feel spleen 3 cm below left costal margin
PV, polycythemia vera; WBC, white blood cell.
Slide credit: clinicaloptions.com

6. Case 1: Expert Recommendations
51-yr-old woman with PV; hematocrit controlled; PMH of HTN and depression; complains about significant itching, increasing fatigue
HTN, hypertension; PMH, past medical history; PV, polycythemia vera.
Available at: clinicaloptions.com/MPNTool

7. Thrombosis Risk-Adapted Management of PV
Category
Characteristics
Treatment
Low risk
Age ≤ 60 yrs AND no history of thrombosis
Therapeutic phlebotomy (goal Hct < 45%)
ASA 81 mg daily
Address CV modifiable risk factors
High risk
Age > 60 yrs OR history of thrombosis
All the above, AND
Cytoreductive therapy
First line
Hydroxyurea
IFN-α
Busulfan*
Second line
Ruxolitinib
CV, cardiovascular; Hct, hematocrit; IFN, interferon; PV, polycythemia vera.
*For pts > 70 yrs of age.
Indications for cytoreduction in low-risk pts with:
Frequent phlebotomy requirement – Platelets > 1500 x 109/L (risk of bleeding)
Progressive leukocytosis – Severe disease-related symptoms
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Barbui T, et al. J Clin Oncol. 2011;29: Tefferi A, et al. Am J Hematol. 2015;90:

8. European LeukemiaNet Clinicohematologic Response in PV
Response Grade
Response in PV CR
Hematocrit < 45% without phlebotomy and
Platelet count ≤ 400 x 109/L and
WBC count ≤ 10 x 109/L and
Normal spleen size on imaging and
No disease-related symptoms PR
Hematocrit < 45% without phlebotomy or
Response in ≥ 3 of the other criteria
No response
Any response that does not satisfy PR
PV, polycythemia vera; WBC, white blood cell.
*Disease-related symptoms include microvascular disturbances, pruritus, and headache.
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Barbui T, et al. J Clin Oncol. 2011;29:

9. CYTO-PV: Intensity of Treatment and Cardiovascular Events in PV
Multicenter, randomized, open-label phase III trial in 26 Italian centers
Primary endpoint: time to major thrombotic events or death from CV causes
Low hematocrit target (Hct < 45%)
ASA + more intensive phlebotomy and/or cytoreductive drugs* per investigator decision
(n = 182)
Pts with JAK2-positive PV being treated with phlebotomy, hydroxyurea, or both; no substantially shortened life expectancy
(N = 365)
High hematocrit target (Hct 45% to 50%)
ASA + less intensive phlebotomy and/or cytoreductive drugs* per investigator decision
(n = 183)
ASA, aspirin; CV, cardiovascular; Hct, hematocrit; PV, polycythemia vera.
*Hydroxyurea recommended for pts with progressive thrombocytosis, splenomegaly, or high risk of thrombosis.
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Marchioli R, et al. N Engl J Med. 2013;368:22-33.

10. CYTO-PV: Total CV Events by Hematocrit Target
1.0
0.8
Low Hct
High Hct
P = .01
0.6
Probability of Remaining Event Free
0.4
Events, n/N (%) HR (95% CI)
Low Hct 8/182 (4.4)
High Hct /183 (10.9) ( )
CV, cardiovascular; Hct, hematocrit.
0.2 6 12 18 24 30 36 42 48
Mos
Mean follow-up: 28.9 mos
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Marchioli R, et al. N Engl J Med. 2013;368:22-33.

11. Time to Thrombosis in PV Pts Treated With HU Requiring Ongoing Therapeutic Phlebotomy
Retrospective analysis of observational data from first 5 yrs of hydroxyurea + phlebotomy in pts with PV (N = 533)
100 80 60
Thrombosis (%) 40
HU, hydroxyurea; PV, polycythemia vera.
≥ 3 phlebotomies/yr
P = .0001 20
< 3 phlebotomies/yr 12 24 36 48 60
Mos on Therapy
Slide credit: clinicaloptions.com
Alvarez-Larrán A, et al. Haematologica. 2017;102:

12. Characteristics and Treatment of PV Pts With HU in Clinical Practice
Retrospective chart review at 34 German centers (N = 1476)
HU Doses Used
Response Rates to HU
Reasons for HU Resistance (n = 306)
6.3%
Constitutional Symptoms
20%
32.2%
Splenomegaly 8%
43.4%
50.3%
67.8%
WBC/PLT Elevation
41%
HU, hydroxyurea; PLT, platelet; PV, polycythemia vera; WBC, white blood cell.
Phlebotomy
77%
< 1 g/day
1-2 g/day
> 2 g/day
Sensitive
Resistant 20 40 60 80
100
Pts (%)
Slide credit: clinicaloptions.com
Jentsch-Ullrich K, et al. J Cancer Res Clin Oncol. 2016;142:

13. PVN1: PegIFN as Initial Cytoreductive Therapy for PV
Multicenter, single-arm phase II trial: pts with PV with no prior treatment or < 2 yrs phlebotomy/cytoreductive therapy treated with ASA QD + pegIFN SC QW (N = 37)[1]
78% still on pegIFN alone after median follow-up of 31 mos
12-mo hematologic CR rate: 95%
12-mo AE rate: 89%; treatment discontinued in 35% (24% for toxicity)
AEs mostly grade 1/2, decreased over time
JAK2 V617F allele burden CR in 7/29 (24%) of pts treated with pegIFN alone
PR in 14/29 (48%)
Targets JAK2 V617F clones without affecting TET2-mutant cells[2]
100 6 12 18 24 30 36 80 60
JAK2 V617F Circulating Alleles (%) 40 20
AE, adverse event; ASA, aspirin; pegIFN, peginterferon; PV, polycythemia vera.
Mos
Slide credit: clinicaloptions.com
1. Kiladjian JJ, et al. Blood. 2008;112: Kiladjian JJ, et al. Leukemia. 2010;24:

14. Planned interim analysis conducted when 75 pts treated for 1 yr
MPD-RC 112: First-line PegIFN vs HU for High-Risk PV and Essential Thrombocythemia
Multicenter, randomized, open-label phase III study[1]
Primary endpoint: CR by ELN criteria at 12 mos[2]
Mo 12
Hydroxyurea 500 mg BID PO
(n = 86)
Pts with high-risk* PV/ET diagnosed < 5 yrs prior and no prior treatment†
(N = 168)
Planned interim analysis conducted when 75 pts treated for 1 yr
PegIFN α-2a 180 mcg QW SC‡
(n = 82)
ET, essential thrombocythemia; ELN, European LeukemiaNet; HU, hydroxyurea; pegIFN, peginterferon; PV, polycythemia vera.
*Defined as age ≥ 60 yrs; prior thrombosis, erythromelalgia, or migraine (or hemorrhage for ET); splenomegaly > 5 cm or symptomatic; platelets > 1000 x 109/L for PV or > 1500 x 109/L for ET; or diabetes or hypertension requiring treatment.
†Hydroxyurea for < 3 mos permitted.
‡Starting dose of 45 mcg QW gradually increased to maximum dose of 180 mcg QW.
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1. Mascarenhas JO, et al. ASH Abstract Barosi G, et al. Blood. 2009;113:

15. MPD-RC 112: Key Findings Mo 12 Response Hydroxyurea (n = 39)
PegIFN α-2a (n = 36)
P Value* PR CR
ORR
All pts, n (%)
14 (36)
13 (33)
27 (69)
19 (53)
10 (28)
29 (81) .6
ET subset, n/N (%)
4/16 (25)
7/16 (44)
11/16 (69)
6/15 (40)
12/15 (80) .8
PV subset, n/N (%)
10/23 (44)
6/23 (26)
16/23 (70)
13/21 (62)
4/21 (19)
17/21 (81)
AE,† n (%)
Hydroxyurea (n = 36)
PegIFN α-2a (n = 36)
P Value
Any AE
32 (89)
36 (100)
.04
AE grade ≥ 3
5 (14)
17 (47)
.002
Depression
10 (28)
< .001
Dyspnea
1 (3)
7 (19)
.02
Fatigue
18 (50)
.05
Flulike symptoms
12 (33)
Injection-site reaction
9 (25)
.001
Pruritus
3 (8)
.03
AE, adverse event; ET, essential thrombocythemia; pegIFN, peginterferon; PV, polycythemia vera.
*P value for comparison of CR across arms. †Showing AEs that occurred in ≥ 15% of pts in either arm and for which there was a significant difference in rates between study arms.
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Mascarenhas JO, et al. ASH Abstract 479.

16. Use of PegIFN to Treat PV: Expert Recommendations
Pt with high-risk PV for whom first-line cytoreductive therapy is required; no factors that would preclude pegIFN use
PegIFN, peginterferon; PV, polycythemia vera
Available at: clinicaloptions.com/MPNTool

17. Case 2: Pt With Inadequate Response to HU
68-yr-old man diagnosed with PV 3 yrs ago
Characteristic
Finding
Past treatments
Has been managed successfully with low-dose ASA, phlebotomy, and HU (500 mg BID; higher dose caused mouth ulcers)
Past medical history
Diabetes, depression
Current visit
Presents with complaints of fatigue, pruritus, and occasional night sweats
Hb: 13.7 g/dL
Hct: 43%
WBC count: 16.4 x 109/L
Platelets: 640 x 109/L
Peripheral smear: leukocytosis, thrombocytosis, no nucleated RBCs, no blasts
Ferritin decreased, TIBC increased, MCV low; chemistry WNL
Physical exam reveals splenomegaly of 5 cm below left costal margin
Bone marrow biopsy: 1+ out of 3+ fibrosis, normal cytogenetics
ASA, aspirin; Hb, hemoglobin; Hct, hematocrit; HU, hydroxyurea; MCV, mean corpuscular volume; PV, polycythemia vera; RBC, red blood cell; TIBC, total iron binding capacity; WBC, white blood cell; WNL, within normal limits.
Slide credit: clinicaloptions.com

18. Case 2: Expert Recommendations
68-yr-old man with fatigue, pruritus, and night sweats despite hydroxyurea therapy; splenomegaly of 5 cm below left costal margin; history of depression
Available at: clinicaloptions.com/MPNTool

19. ELN Criteria for Hydroxyurea Resistance and Intolerance in PV
Need for phlebotomy (Hct <45%)
Platelets > 400 x 109/L and WBC > 10 x 109/L
No reduction of spleen by 50%
No reduction of spleen symptoms
After > 3 mos at MTD or 2 g/day
Cytopenias (any)
ANC < 1.0 x 109/L
Hemoglobin x 109/L
Platelets < 100 x 109/L
At lowest dose to achieve either a PR or CR
Intolerance/Resistance
ANC, absolute neutrophil count; ELN, European LeukemiaNet; GI, gastrointestinal; Hct, hematocrit; MTD, maximum tolerated dose; PV, polycythemia vera; WBC, white blood cell.
GI toxicity
Fevers
Mucocutaneous toxicity
Skin cancers
At any dose
Barosi G et al. Br J Haematol. 2010;148:

20. Mean MPN-10 Symptom Scores by Known HU Use
Symptom Profiles of PV Pts by HU Use: Implications for Inadequately Controlled Disease
Prospective analysis of symptom burden in pts with PV (N = 1334)
Mean MPN-10 Symptom Scores by Known HU Use
Abdominal discomfort *
Bone pain *
Known HU use
No known HU use
Concentration *
Early satiety *
Fatigue *
Symptom
Fever
HU, hydroxyurea; MPN-10, Myeloproliferative Neoplasm Symptom Assessment Form; PV, polycythemia vera.
Inactivity *
Itching †
*P < .001 †P < .05
Night sweats *
Weight Loss 1 2 3 4 5 6 7 8 9 10
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Geyer H, et al. J Clin Oncol. 2016;34:

21. Time to Transformation to MF or AML in PV Pts Treated With Hydroxyurea
Retrospective analysis of time to myelofibrotic transformation and cytopenia for median follow-up of 4.6 yrs in pts with PV (N = 890)
Myelofibrosis
Acute Myeloid Leukemia
100
100
HU intolerance/resistance
No HU intolerance/resistance
Cytopenia
No cytopenia 80 80 60 60
Pts (%)
Pts (%)
P = .03 40 40
AML, acute myeloid leukemia; HU, hydroxyurea; MF, myelofibrosis; PV, polycythemia vera. 20 20
P < .001 5 10 15 20 25 30 5 10 15 20 25 30
Yrs
Yrs
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Alvarez-Larrán A, et al. Br J Haematol. 2016;172:

22. Recommendations for Second-line PV Therapy
Pt Characteristics
Options
Inadequate response or intolerance to HU
Ruxolitinib, IFN-α[1,2]
Inadequate response or intolerance to IFN-α
HU[1]
Short life expectancy
Busulfan, pipobroman, or 32P[1]
HU, hydroxyurea; IFN, interferon; PV, polycythemia vera.
1. Barbui T, et al. J Clin Oncol. 2011;29:
2. Ruxolitinib [package insert].
Slide credit: clinicaloptions.com

23. PegIFN for Pts With Advanced PV
Open-label, single-arm phase II trial in which pts with PV treated with pegIFN (n = 43)
Baseline characteristics: median age, 54 yrs; PV duration, 50 mos; previous cytoreductive therapy, 49%; median prior therapies, 1 (range: 0-4)
Median follow-up, entire cohort*: 42 mos
100 80
Outcome
Pts (n = 43)
Overall hematologic response, % 79
Complete hematologic response, % 76
Median time to CR, days (range)
40 (3-1478)
Complete molecular response,† % 18
Partial molecular response,‡ % 35
Drug-related tx discontinuation, % 20 64 60 53
JAK2 V617F Circulating Alleles (%) 41 40
ET, essential thrombocythemia; pegIFN, peginterferon; PV, polycythemia vera; tx, treatment. 29 20 19 16 17 13 9 8
4.5
*Included an additional 40 pts with ET.
†Undetectable JAK2V617F allele burden. ‡> 50% decrease. 6 12 18 24 30 36 42 48 54 60
Mos
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Quintás-Cardama A, et al. Blood. 2013;122:

24. PegIFN for Pts With Advanced PV: Long-term Follow-up
Post hoc analysis of open-label, single-arm phase II trial in which pts with PV treated with pegIFN (n = 43)
Median follow-up: 83 mos
Response
Median hematologic response duration: 65 mos
Median molecular response duration: 58 mos
Therapy failures occur (vascular events and progression)
Safety*
Toxicity continued over time (new grade 3/4 events in 10% to 17% of pts/yr)
Discontinuations in overall study population: 61% (22% for overt toxicity)
PegIFN, peginterferon; PV, polycythemia vera.
Slide credit: clinicaloptions.com
Masarova L, et al. Lancet Haematol. 2017;4:e165-e175.

25. RESPONSE: Ruxolitinib vs Standard Therapy in Pts With HU Resistance/Intolerance
Ruxolitinib: Janus kinase (JAK) 1 and 2 inhibitor
International, multicenter, randomized, open-label phase III study
Primary endpoint: proportion with Hct control + spleen volume reduction ≥ 35% (Wk 32)
Stratified by HU status (resistance vs intolerance)
Wk 32
Ruxolitinib Initial 10 mg BID; dose titrated to maintain Hct
(n = 110)
Pts with PV requiring phlebotomy; HU resistance/intolerance; spleen volume ≥ 450 cm3, no JAK inhibitor experience, Hct 40% to 45% before randomization*
(N = 222)
Primary analysis data cutoff at Wk 48 or treatment discontinuation
ASA, aspirin; Hct, hematocrit; HU, hydroxyurea; IFN, interferon; PD, progressive disease; PV, polycythemia vera.
Crossover at PD or Wk 32 if primary endpoint not met
Standard Therapy selected by investigator†
(n = 112)
All pts received low-dose ASA. *Pts with Hct < 40% or > 50% entered Hct control period prior to randomization. †Excluding 32P, busulfan, and chlorambucil.
Slide credit: clinicaloptions.com
Vannucchi AM, et al. N Engl J Med. 2015;372:

26. RESPONSE: Key Efficacy Findings at Wk 32
Study design adopted form Rux figures 70
Ruxolitinib
Standard therapy
60.0 60
P < .001
Odds ratio: 28.6
(95% CI: ) 50 40
38.2
Pts (%) 30
20.9
19.6 20 10
0.9
0.9
Composite Primary Endpoint
≥ 35% Reduction in Spleen Volume
Hematocrit Control
Complete hematologic response also significantly improved with ruxolitinib vs standard therapy (23.6% vs 8.9%; P = .003)
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Vannucchi AM, et al. N Engl J Med. 2015;372:

27. Mean Change From Baseline at Wk 32 GHS/QoL and Functional Subscales
RESPONSE: Mean Change From Baseline in QoL and Disease‐Related Symptoms at Wk 32
Ruxolitinib*
Standard therapy* 15
Improvement 10 5
Mean Change From Baseline at Wk 32
Improvement -5
-10
-15
Social
Role
Pain
GHS, global health status; QoL, quality of life.
Fatigue
GHS/QoL
Physical
Emotional
Cognitive
Insomnia
Dyspnea
Diarrhea
Appetite loss
Financial difficulties
Constipation
Nausea and vomiting
GHS/QoL and Functional Subscales
Individual Symptoms
*Pts with available data at both time points: ruxolitinib, n = 86-90; standard therapy, n =
Slide credit: clinicaloptions.com
Mesa R, et al. Eur J Haematol. 2016;97:

28. RESPONSE: Durability of Hematocrit Control With Ruxolitinib
Graph adopted from RUX RUX3011_figs2ab-3
Preplanned analysis after all pts discontinued or completed Wk 80 study visit
1.0
0.8
0.6
Probability of Remaining Event Free
Probability of maintaining Hct control in ruxolitinib arm for ≥ 80 wks from time of response was 0.89
0.4
Hct, hematocrit.
0.2 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
102
108
114
120
126
132
138
144
Wks
Pts at risk, n
Events, n 25 25 25 25 25 25 24 1 22 2 21 2 20 2 20 2 16 2 16 2
152
152
152
142
102
102 7 2 6 2 5 2 1 2 1 2 2
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Verstovsek S, et al. Haematologica. 2016;101:

29. RESPONSE: Thromboembolic AEs at Wk 80
Longer exposure in ruxolitinib arm vs standard therapy arm (227.7 vs 73.6 pt-yrs)
Event Rate per 100 Pt-Yrs of Exposure
Ruxolitinib (n = 110)
Standard Therapy (n = 111*)
All Grades
Grade 3/4
All thromboembolic events
1.8
0.9
8.2
2.7
Portal vein thrombosis
0.4
Cerebral infarction
Ischemic stroke
Retinal vascular thrombosis
Myocardial infarction
1.4
Deep vein thrombosis
Pulmonary embolism
Splenic infarction
Thrombophlebitis
Thrombosis
AE, adverse event.
*1 pt did not receive study treatment.
Slide credit: clinicaloptions.com
Verstovsek S, et al. Haematologica. 2016;101:

30. RESPONSE: Ruxolitinib Dose at Wk 32
Starting dose was 10 mg BID
At Wk 32, 55 of 98 assessed pts (56%) in ruxolitinib arm were receiving doses of mg BID
Most dose adjustments occurred within first 8 wks of treatment
Dose adjustments based on CBC monitoring, particularly Hct, white cells, and platelets
CBC, complete blood count; Hct, hematocrit.
< 10 mg BID
10 mg BID
15 mg BID
20 mg BID
25 mg BID
Dose at Wk 32*
*Maximum dose within 2-week window of Wk 32 study visit.
Slide credit: clinicaloptions.com
Vannucchi AM, et al. N Engl J Med. 2015;372:

31. RESPONSE-2: Ruxolitinib vs Best Available Therapy in Pts Without Splenomegaly
International, multicenter, randomized, open-label phase IIIb study in which pts with HU-resistant/intolerant PV who required phlebotomy and had no splenomegaly were treated with ruxolitinib or best available therapy (N = 149)
Outcome, Wk 28
Ruxolitinib (n = 74)
BAT (n = 75)
P Value
Hct control,* n (%)
46 (62)
14 (19)
< .0001
Complete hematologic response, n (%)
17 (23)
4 (5)
.0019
Complete resolution in symptoms, n/N† (%)
17/34 (50)
2/26 (8) NR
≥ 50% reduction in MPN-SAF TSS, n/N (%)
29/64 (45)
5/22 (23)
BAT, best available therapy; Hct, hematocrit; HU, hydroxyurea; MPN-SAF TSS, Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score; NR, not reported; PV, polycythemia vera.
*Primary endpoint. †Pts with baseline MPN-SAF TSS of ≥ 20.
Slide credit: clinicaloptions.com
Passamonti F, et al. Lancet Oncol. 2017;18:88-99. 31

32. Myelofibrosis

33. Case 3: Pt With MF Who Is a Potential Transplantation Candidate
A 58-yr-old man living with JAK2 V617F-negative primary MF for a number of yrs
Characteristic
Finding
Past treatments
Erythropoietin, androgens, HU, thalidomide plus prednisone
Anemic, transfused PRBC every 4 mos
Current laboratory values
Anemic
Platelets: 126 x 109/L
WBC 17 x 109/L
2% blood blasts
Physical examination and interview
ECOG PS: 2
Has lost 15 kg in past yr and is very fatigued
Experiencing night sweats, low grade fever, bone aches
Splenomegaly of 15 cm below costal margin
ECOG, Eastern Cooperative Oncology Group; HU, hydroxyurea; MF, myelofibrosis; PRBC, packed red blood cell; PS, performance status; WBC, white blood cell.
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34. MF Treatment Is Based on Risk and MF-Related Symptoms/Signs
Minimally symptomatic observation or interferon
Low Risk
Many symptoms ruxolitinib
Intermediate-1 Risk
Ruxolitinib or anemia treatment and/or allogeneic HSCT
Intermediate-2 Risk
Allogeneic HSCT or ruxolitinib and/or anemia treatment
HSCT, hematopoietic stem cell transplantation; MF, myelofibrosis.
High Risk
Allogeneic HSCT or ruxolitinib and/or anemia treatment
Mesa RA. Leuk Lymphoma. 2013;54:
Geyer HL, et al. Hematology Am Soc Hematol Educ Program. 2014;2014:
Slide credit: clinicaloptions.com

35. International Prognostic Scoring System: Risk Classification of MF at Presentation
Risk factors
Older than 65 yrs of age
Constitutional symptoms
Hb < 10 g/dL
WBC count > 25 x 109/L
Peripheral blood blasts ≥ 1%
No. Risk Factors
Risk Group
Median Survival, Yrs
Low
11.3 1
Intermediate-1
7.9 2
Intermediate-2
4.0
≥ 3
High
2.3
Hb, hemoglobin; MF, myelofibrosis, WBC, white blood cell.
Slide credit: clinicaloptions.com
Cervantes F, et al. Blood. 2009;113:

36. Prognostic Impact of Driver and High Molecular Risk Nondriver Mutations in Primary MF
Analysis of association between driver mutations and survival in pts with primary MF (N = 617)[1]
Analysis of association between set of nondriver mutations (IDH, EZH2, ASXL1, SRSF2) and survival in pts with PMF (N = 797)[2]
Presence of mutations predicted decreased survival; ≥ 2 mutations predicted worst survival
Driver Mutation
Pts, %
Median OS, Yrs
CALR mutated
22.7
17.7
JAK2 mutated
64.7
9.2
MPL mutated
4.0
9.1
Triple negative
8.6
3.2
MF, myelofibrosis.
Slide credit: clinicaloptions.com
1. Rumi E, et al. Blood. 2014;124: Guglielmelli P, et al. Leukemia. 2014;28:

37. Allogeneic HSCT: Why We Prognosticate
Consider HSCT in younger, higher- risk pts whose survival is expected to be < 5 yrs
Very few MF pts undergo HSCT
Traditionally limited to pts younger than 60 yrs of age and those with HLA-identical sibling match; now possible up to age 75
High transplant-related mortality and morbidity associated with transplantation due to acute and chronic graft vs host disease[2]
1-yr nonrelapse mortality rate: 12% (completely matched donors) to 38% (mismatched)
5-yr survival rate: 56% (matched sibling donors) to 34% (partially matched/mismatched)
Risk Group[1]
Median Survival, Yrs
Low
11.3
Intermediate-1
7.9
Intermediate-2
4.0
High
2.3
HSCT, hematopoietic stem cell transplantation; MF, myelofibrosis.
1. Cervantes F, et al. Blood. 2009;113:
2. Kröger NM, et al. Leukemia. 2015;29:
Slide credit: clinicaloptions.com

38. Case 4: Transplant-Ineligible Pt With High-Risk MF
You are taking over care from a retiring doctor of a 76-yr-old man with MPL mutation–positive primary MF
Transplantation is not being considered
Characteristic
Finding
Past treatments
Hydroxyurea, prednisone, danazol, and thalidomide
Current visit
Significant constitutional symptoms and weight loss
Hb: 8.6 g/dL without transfusions
WBC count: 19 x 109/L
Platelets: 189 x 109/L
EPO level: 125 mU/mL
2% blood blasts
Liver is enlarged 4 cm and spleen 9 cm by palpation
EPO, erythropoietin; Hb, hemoglobin; MF, myelofibrosis; WBC, white blood cell.
Slide credit: clinicaloptions.com

39. Case 4: Expert Recommendations
76-yr-old man with several previous treatments, anemia, 2% blood blasts, EPO mU/mL, platelets 189 x 109/L, splenomegaly, and MF symptoms
EPO, erythropoietin; MF, myelofibrosis.
Available at: clinicaloptions.com/MPNTool

40. Main Clinical Complications in MF
Pts (%)
Anemia (Hb < 10 g/dL) 36
Leukocytosis (> 25 x 109/L) 10 16
Thrombocytopenia (< 100 x 109/L)
Splenomegaly 83
Hepatomegaly 65
Thrombosis 7
Hb, hemoglobin; MF, myelofibrosis.
Constitutional symptoms 27
Leukemia transformation 13
Passamonti F, et al. Blood. 2010;115: Barbui T, et al. Blood. 2010;115: Passamonti F, et al. Blood. 2010;116:
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41. Symptomatic Burden in MF
Mean MPN-SAF Results From Surveys of Pts With MF (N = 96)
Symptoms related to:
Insomnia 74
Role/
functioning
Inactivity 77
Fatigue 99
Itching 54
Myeloproliferation
Bone pain 55
Symptom
Cough 55
Abd discomfort 72
Splenomegaly
Early satiety 76
Abd, abdominal; MF, myelofibrosis; MPN-SAF, Myeloproliferative Neoplasm Symptom Assessment Form.
Fever 29
Constitutional
symptoms
Weight loss 49
Night sweats 63 10 20 30 40 50 60 70 80 90
100
Pts (%)
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Scherber R, et al. Blood. 2011;118:

42. Needs-Oriented Therapy for MF
Clinical Issue
Treatments
Anemia
ESAs
Corticosteroids
Danazol
Thalidomide, lenalidomide (IMIDs)
Symptomatic splenomegaly
Ruxolitinib
Hydroxyurea
Cladribine, IMIDs
Splenectomy
Constitutional symptoms/QoL
Extramedullary hematopoiesis
Radiation therapy
Hyperproliferative (early) disease
Interferon
Risk of thrombosis
Low-dose aspirin
Accelerated/blastic phase
Hypomethylating agents
Improved survival
Allogeneic HSCT
ASA, acetylsalicylic acid; ESA, erythropoiesis-stimulating agents; HSCT, hematopoietic stem cell transplantation; IMID, immunomodulatory drug; MF, myelofibrosis.
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43. COMFORT-I and -II: Ruxolitinib for Pts With Intermediate-2–Risk/High-Risk MF
Randomized phase III studies in which pts with intermediate-2–risk/high-risk MF were treated with ruxolitinib (15 or 20 mg BID) vs placebo (COMFORT-I, N = 309) or best available therapy (COMFORT-II, N = 149)
Outcome
COMFORT-I, Wk 24[1]
P Value
COMFORT-II, Wk 48[2]
Ruxolitinib (n = 155)
Placebo (n = 154)
Ruxolitinib (n = 144)
BAT (n = 73)
Spleen volume reduction ≥ 35%,* %
41.9
0.7
< .001 28
≥ 50% reduction in MF-SAF TSS, %
45.9
5.3 NR
D/c for AEs
11.0
10.6 8 5
AE, adverse event; BAT, best available therapy; D/c, discontinued; MF, myelofibrosis; NR, not reported.
*Primary endpoint. †n = 151.
Grade 3/4 anemia/thrombocytopenia/neutropenia in COMFORT-I, %
Ruxolitinib, 45/13/7 ; placebo 19/1/2†
1. Verstovsek S, et al. N Engl J Med. 2012;366:
2. Harrison C, et al. N Engl J Med. 2012;366:
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44. COMFORT-I: 5-Yr OS With Ruxolitinib vs Placebo
Deaths,
n/N (%)
Censored,
n/N (%)
Median OS,
Wks
Median F/U,
Wks
RUX
PBO
69/155 (44.5)
82/154 (53.2)
86/155 (55.5)
72/154 (46.8) NR
200
268.4
269.0
1.00
0.75
Probability of OS
0.50
Median time to crossover from PBO to RUX: 39.9 wks
0.25
F/U, follow-up; NR, not reached; PBO, placebo; RUX, ruxolitinib.
HR: 0.69 (95% CI: ; P = .025 [nominal]) 24 48 72 96
120
144
168
192
216
240
264
Wks
Pts at Risk, n
RUX
PBO
155
154
148
144
137
119
124
105
112 95
108 85
100 78 86 72 80 59 75 51 69 46 57 38
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Verstovsek S, et al. J Hematol Oncol. 2017;10:55.

45. COMFORT-II: 5-Yr OS With Ruxolitinib vs BAT
Median OS,
Yrs
1.0
RUX NR
BAT (ITT)
BAT (RPSFT*) 2.7
0.8
0.6
Probability of OS
0.4
0.2
HR: 0.67 (95% CI: ; P = .06)
BAT, best available therapy; ITT, intent to treat; NR, not reached; RPSFT, rank-preserving structural failure time; RUX, ruxolitinib. 1 2 3 4 5 6
Pts at Risk, n
RUX
BAT (ITT)
BAT (RPSFT*)
Yrs
0 0 0
*PRSFT modeling estimates treatment effect corrected for crossover.
Median follow-up: 4.3 yrs; majority crossover from best available therapy to ruxolitinib
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Harrison CN, et al. Leukemia. 2016;30:

46. COMFORT-I and -II Exploratory Analysis: Impact of Anemia on OS
Anemia at BL associated with decreased OS in both arms
New or worsening anemia (after initiating ruxolitinib) did not affect OS (HR: 1.030)
OS improved with ruxolitinib vs control regardless of anemia status at BL
HR: (95% CI: ; P = .0102)
1.0
0.8
0.6
0.4
0.2 12 23 35 48 60 72 84 96
108
120
132
144
156
Wks
168
Ctl: anemic at BL
Ctl: not anemic at BL
Control
Probability of OS
RUX: anemic at BL
RUX: not anemic at BL
Ruxolitinib
1.0
0.8
0.6
0.4
0.2 12 23 35 48 60 72 84 96
108
120
132
144
156
Wks
168
Probability of OS
No Anemia at BL
1.0
0.8
0.6
0.4
0.2 12 23 35 48 60 72 84 96
108
120
132
144
156
RUX: not anemic at BL
Ctl: not anemic at BL
Wks
168
Anemia at BL
1.0
0.8
0.6
0.4
0.2 12 23 35 48 60 72 84 96
108
120
132
144
156
Wks
168
RUX: anemic at BL
Ctl: anemic at BL
BL, baseline; Ctl, control; RUX, ruxolitinib.
After Wk 144, curve interpretation affected by low pt n.
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Gupta V, et al. Haematologica. 2016;101:e482-e484.

47. OS by Degree of Spleen Length Reduction in Pts Receiving Ruxolitinib
Open-label, single-arm phase I/II study (N = 107)
1.0
0.8
0.6
Probability of OS
0.4
< 25% spleen length reduction (n = 23)
≥ 25% but < 50% spleen length reduction (n = 13)
≥ 50% spleen length reduction (n = 61)
0.2
For < 25% vs ≥ 50% spleen length reduction: HR: 0.22 (95% CI: ; P = .0001) 6 12 18 24 30 36 42 48
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Verstovsek S, et al. Blood. 2012;120:
Mos

48. Tips for Using Ruxolitinib to Treat Pts With MF
Starting dose selected based on platelet number; anemia is NOT contraindication for use
Development of anemia DOES NOT affect benefits
Decision to stop ruxolitinib will depend on a combination of different factors, including benefit and presence/absence of toxicity
Avoid abrupt interruption of ruxolitinib in pts responding well to therapy
MF, myelofibrosis.
Mesa RA, et al. Int J Hematol. 2016;104: Ruxolitinib [package insert].
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49. Initial Approach to the Treatment of Anemia in Myelofibrosis
EPO levels
ADEQUATE ≥ 500 mU/mL
INADEQUATE < 500 mU/mL
ESA
x 3 mos
EPO, erythropoietin; ESA, erythropoiesis-stimulating agent.
Danazol,
others
No response
Response
Mesa RA. Leuk Lymphoma. 2013;54: Cervantes F, et al. Br J Haematol ;127: Kröger N, et al. Leukemia. 2008;22:
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50. Splenectomy and Splenic Irradiation for MF
Treatment
Indications
Contraindications
Risks
Splenectomy
Symptomatic splenomegaly unresponsive to treatment
Severe refractory anemia and thrombocytopenia
Unresponsive constitutional symptoms
Uncontrollable hemolysis
Portal hypertension
Thrombocytosis
Up to 31% operative morbidity
Up to 9% perioperative mortality
Liver enlargement and failure
Higher acute transformation rate
Median survival post splenectomy: 27 mos
Splenic irradiation
Symptomatic splenomegaly in poor candidates for surgery
Severe pain from splenic infarction
As preparation for splenectomy
Long-lasting cytopenias (44%)
MF, myelofibrosis.
Tefferi A, et al. Blood. 2000;95: Li Z, et al. Leukemia. 2001;15: Elliott MA, et al. Blood Rev. 1999;13:
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51. JAK Inhibitors Under Investigation for MF
Agent
MoA
Key Studies
Pacritinib
JAK2 and FLT3 kinase inhibitor
Phase III PERSIST-1[1,2]: no JAK2 inhibitors in BAT
Spleen volume reduction ≥ 35% at Wk 24: pacritinib 19% vs BAT 5% (P = .0003)
Improved responses durable out to Wk 72 without cumulative toxicity
Phase III PERSIST-2[3]: platelets < 100 x 109/L; JAK2 inhibitors allowed in BAT
Spleen volume reduction ≥ 35% at Wk 24: pacritinib (BID or QD) 18% vs BAT 3% (P = .0001)
≥ 50% reduction in MF-SAF TSS at Wk 24: pacritinib (BID or QD) 25% vs BAT 14% (P = .079)
No significant differences in OS between groups
Clinical trials placed on hold in December 2016 due to concerns about excess pt deaths related to intracranial hemorrhage, cardiac failure, and cardiac arrest; hold has since been removed
NS-018
JAK2 inhibitor
Ongoing phase I/II study: phase II focus on pts with MPN previously treated with other JAK2 inhibitors[4]
BAT, best available therapy; MF, myelofibrosis; MoA, mechanism of action; MPN, myeloproliferative neoplasm.
1. Mesa RA, et al. Lancet Haematol. 2017;[Epub ahead of print]. 2. Mesa RA, et al. ASCO Abstract Mascarenhas J, et al. ASH Abstract LBA ClinicalTrials.gov. NCT
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52. Other Agents Under Investigation for MF
MoA
Key Studies
Imetelstat
Telomerase inhibitor
Phase II study[1]
Imetelstat for JAK inhibitor-treated pts with int-2–risk to high-risk MF suspended due to lack of response
LCL 161
SMAC mimetic/inhibitor of apoptosis antagonists
Ongoing phase II study[2,3]
In preplanned efficacy analysis, 6 of 16 (38%) evaluable pts with MPNs showed objective responses
PRM-151
Recombinant PTX-2; antifibrotic
Phase II study[4,5]
Reductions in bone marrow fibrosis observed in 11 of 26 (43%) evaluable pts at Wk 24; sustained reductions in responders through Wk 72
Many pts had reductions in symptoms and spleen size, improvements in anemia at Wk 24
MF, myelofibrosis; MoA, mechanism of action; MPN, myeloproliferative neoplasm; PBO, placebo; RBC, red blood cell; SMAC, second mitochondria-derived activator of caspases.
1. ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT Pemmaraju N, et al. ASH Abstract Verstovsek S, et al. 2014;124: Verstovsek S, et al. Blood. 2015;126:56.
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53. Summary Treatment for MF and PV should be individualized
PV: assess for thrombotic risk; low-risk pts: aim to control Hct < 45% and eliminate disease-related symptoms; high-risk pts: institute cytoreductive therapy and aim to control Hct, WBCs, platelets, splenomegaly and disease-related symptoms
First-line cytoreductive treatment: HU, pegIFN
For pts with HU resistance/intolerance: ruxolitinib, pegIFN
MF: assess potential for transplant; aim to control clinically relevant symptoms and signs
Allogeneic HSCT considered for pts with intermediate-2–risk or high-risk MF and life expectancy < 5 yrs
Manage splenomegaly and disease-related symptoms (ruxolitinib), and anemia (ESA, danazol)
ESA, erythropoiesis-stimulating agents; Hct, hematocrit; HSCT, hematopoietic stem cell transplantation; HU, hydroxyurea; MF, myelofibrosis; pegIFN, peginterferon; PV, polycythemia vera; WBC, white blood cell.
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54. Go Online for More CCO Coverage of MF and PV!
CME-certified online text module on the treatment of MF and PV to accompany these slides with expert faculty commentary on all key studies Interactive Treatment Decision Support Tool for MF and PV— see treatment choices of 5 experts for your patient scenarios
clinicaloptions.com/oncology