Case Study: A Patient with PV and Debilitating Symptoms on HU Srdan Verstovsek, MD, PhD Professor of Medicine Director, Hanns A. Pielenz Clinical Research

Case Study: A Patient with PV and Debilitating

Symptoms on HU

Srdan Verstovsek, MD, PhDProfessor of Medicine

Director, Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms

Department of LeukemiaMD Anderson Cancer Center

Houston, Texas, USA

Co-Presenters

Jeffrey C. Bryan, PharmD, RPhClinical Pharmacy Specialist, Leukemia

Division of Pharmacy, University of TexasMD Anderson Cancer Center

Houston, TX

Otitolola Arterbery, MSN, RN, OCNClinical Nurse

MD Anderson Cancer CenterHouston, TX

Polycythemia Vera

• Polycythemia vera (PV) is a myeloproliferative neoplasm associated with overactivation of the JAK/STAT pathway

• PV is characterized by:– Erythrocytosis

– Debilitating symptoms (eg, pruritus, fatigue)

– Cardiovascular complications due to thrombosis or hemorrhage

Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print].

Risk Classification for Patients with PV

Risk Category Risk Variables

Low • Age < 60 years • No thrombosis history

High• Age ≥ 60 years and/or• Thrombosis history

1. Barbui T et al. Clin Oncol. 2011;29(6):761-770; 2. Vannucchi AM. Blood. 2014 Oct 2. [Epub ahead of print].

Polycythemia Vera Disease Burden

Reprinted with permission from: Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print].

PV Burdens Are Associated with Increased Healthcare Costs

Component Patients with PV Controls P-value

Patients, n 5,752 5,752

Mean (SD) cost, $

Inpatient 4,670 (19,092) 2,019 (11,236) P<0.0001

Outpatient 6,806 (14,072) 3,863 (11,211) P<0.0001

Medication 2,897 (8,376) 1,724 (4,085) P<0.0001

Emergency room 529 (1,602) 306 (1,651) P<0.0001

Total 14,903 (29,018) 7,913 (19,017) P<0.0001

Mehta J et al. Leuk Lymphoma. 2014;55(10):2368-74.

Risk-Adapted Management of Patients with PV 1,2

• Hematocrit (Hct) control is a key therapeutic goal— Maintaining Hct < 45% significantly decreases the risk of cardiovascular

death and major thrombotic events3

• Conventional treatments are unlikely to significantly improvesymptom burden4

Risk Category Risk Variables Therapy

Low • Age < 60 years • No thrombosis history

• Phlebotomy, and• Correction of CV risk factors, and• Aspirin

High• Age ≥ 60 years and/or• Thrombosis history

• Cytoreduction, and• Correction of CV risk factors, and• Aspirin, plus/minus• Phlebotomy

1. Barbui T et al. Clin Oncol. 2011;29(6):761-770; 2. Vannucchi AM. Blood. 2014 Oct 2. [Epub ahead of print]; 3. Marchioli R, et al. N Engl J Med. 2013;368(1):22-33; 4. Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print].

Phlebotomy in PV Management

– Reduces Hct (hyperviscosity); goal is Hct <45%– Does not control systemic symptoms or

progressive symptomatic splenomegaly– Iron deficiency is common with repeated

phlebotomies• Associated with fatigue, cognitive impairment,

increased pulmonary artery pressure

Mascarenhas J et al. Haematologica 2014;99(6):945-49.

Hydroxyurea (HU) in PV Management

• HU, a cytoreductive therapy, is often used as a first-line treatment for patients with PV who are at high risk for vascular complications1,2

• Clinical activities2

– Reduces risk of major thrombosis

– Controls myeloproliferation

– Reduces splenomegaly

• Side effects2

– Myelosuppression, leg ulcers, hyperpigmentation, fever, alopecia, increased risk of squamous cell carcinoma

– Possibly leukemogenic

1. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6; 2. Mascarenhas J et al. Haematologica 2014;99(6):945-49.

Hydroxyurea (HU) Resistance in PV Management

• A subset of patients will develop resistance or intolerance to HU and require treatment with a second-line therapy1,2

Q: What percentage of PV patients on HU therapy will become resistant or intolerant?

A. 2 - 5%

B. 20 – 25%

C. 50 - 60%

D. Almost all1. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6; 2. Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print].

Hydroxyurea (HU) Resistance in PV Management

Q: What percentage of PV patients on HU therapy will become resistant or intolerant?• 2 - 5%• 20 – 25% 1,2 • 50 - 60%• Almost all

1. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6; 2. Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print].

• Resistance and/or intolerance to HU is associated with 1,2 :— Increased symptom burden and complications— Worsening disease transformation — Reduced survival

Case Study: Bruce T.

• 57-year-old man with polycythemia vera (PV)• Disease features at presentation:

– Hemoglobin 18.9 g/dL; Hct 57%; low serum Epo; leukocyte count 10.5 x 109/L; platelet count 419 x 109/L

– JAK2V617F mutation

– Non-palpable spleen

– Symptoms – pruritus, fatigue, night sweats, abdominal discomfort

• Management– Phlebotomies to achieve/maintain Hct < 45%

– Low-dose aspirin

– Unremarkable course, except for fatigue that (at times) interfered with his work and other activities

Most Common Symptoms Reported by Patients with PV

Symptom Incidence

Fatigue 79-92%

Insomnia 68-70%Decreased mood 65-68%Numbness 65-66%Early satiety 62-66%Concentration problems 60-65%

Itching 57-65%Night sweats 52-64%Inactivity 58 – 61%Sexual problems 50-57%Dizziness 51-52%Headache 38-52%Abdominal discomfort 42-51%Bone pains 44-50%


Myeloproliferative Neoplasm Symptom Assessment (MPN SAF) Form Total Symptom Score: An Assessment Tool for the 10 Most

Clinically Important Myeloproliferative Neoplasm Features

Sherber R et al. Blood. 2011; 118(2):401-8; Emanuel RM et al, J Clin Oncol 2012;30:4098-103.Reprinted with permission from: Manea PJ. Clin J Oncol Nursing 2014; 18 (3): 330-7.

15

Systemic Symptoms - Mean MPN-SAF ScoresSymptom Incidence Mean SAF

Score, rangeFatigue 79-92% 3.0 – 4.4Insomnia 68-70% 2.5 – 3.1Decreased mood 65-68% 2.0 - 2.3Numbness 65-66% 2.1 – 2.6Early satiety 62-66% 2.0 - 2.5Concentration problems 60-65% 1.9 – 2.7

Itching 57-65% 1.9 – 2.8Night sweats 52-64% 2.0 – 2.7Inactivity 58 – 61% 1.8 – 2.4Sexual problems 50-57% 2.5 – 2.9Dizziness 51-52% 1.8 – 1.9Headache 38-52% 1.2 – 1.9Abdominal discomfort 42-51% 1.3 – 1.6Bone pains 44-50% 1.5 – 2.1

• Fatigue is the most frequently reported symptom, but is the most challenging to treat

• Many patients turn to lifestyle changes to improve their energy level (eg, exercise, dietary changes, social interactions)


16

Case Study (cont.): Bruce T. • 3 years from diagnosis he had a thromboembolic event

(thrombophlebitis) – he was started on HU, 1 g/day– 7 months later, he had abdominal pain and a palpable

spleen(5 cm below the costal margin) – HU was increased to 2 g/day

– Spleen response

– Symptoms worsened

• At today’s visit (1 year later), he has uncontrolled itching, persistent worsening of fatigue, and abdominal discomfort affecting his ability to eat

17

Case Study (cont.): Bruce T.

Q: Does this patient have resistance/intolerance to HU?

A. Yes

B. No

C. Not sure

Case Study (cont.): Bruce T. • 3 years from diagnosis he had a thromboembolic event

(thrombophlebitis) – he was started on HU, 1 g/day– 7 months later, he had abdominal pain and a palpable spleen

(5 cm below the costal margin) – HU was increased to 2 g/day

– Spleen response

– Symptoms worsened

• At today’s visit (1 year later), he has uncontrolled itching, persistent worsening of fatigue, and abdominal discomfort affecting his ability to eat

Q: Does this patient have resistance/intolerance to HU?

A. Yes

B. No

C. Not sure

European Leukemia Net Criteria for Resistance to, or Intolerance of Hydroxyurea

Barbui T et al, J Clin Oncol 2011;29(6):761–770.

Clinical Perspective

• Why is our patient (Bruce T.) considered HU - resistant/intolerant?

– ELN criteria are useful for clinical studies, but not always practical for everyday decision-making1

– In practice, some patients do not meet ELN criteria but remain symptomatic and, thus, are poorly served by HU therapy2

1. Barbui T et al, J Clin Oncol 2011;29(6):761–770; 2. Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print].


Q: For this PV patient with debilitating fatigue on HU, what would you recommend?

A. Stay on 2 g/day HU, with supportive management of fatigue

B. Increase dose to 2.5 g/day HU, with supportive management of fatigue

C. Hold all therapy except aspirin, phlebotomy until fatigue improves

D. A change in PV therapy and supportive management of fatigue


Q: For this PV patient with debilitating fatigue on HU, what would you recommend?

A. Stay on 2 g/day HU, with supportive management of fatigue

B. Increase dose to 2.5 g/day HU, with supportive management of fatigue

C. Hold all therapy except aspirin, phlebotomy until fatigue improves

D. A change in PV therapy, with supportive management of fatigue


Q: What would you recommend for second-line therapy?

A. Busulfan

B. Pipobroman

C. Pegylated interferon alfa

D. JAK inhibitor (ruxolitinib)

E. Histone deacetylase (HDAC) inhibitor (givinostat, vorinostat)



A. Busulfan

B. Pipobroman


D. Jak inhibitor (ruxolitinib)

E. HDAC inhibitor (givinostat, vorinostat)

Reserved for exceptional cases1-3

1. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6; 2. Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print]; 3. Alvarez-Larran A et al. Ann Hematol. 2014 Jul 2 [Epub ahead of print].



A. Busulfan

B. Pipobroman





1. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6; 2. Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print]; 3. Alvarez-Larran A et al. Ann Hematol. 2014 Jul 2 [Epub ahead of print]; 4. Quintas-Cardama A et al. J Clin Oncol. 2009;27:5418-24; 5. Quintas-Cardama A et al. Blood 2013;122:893-901; 6. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6.

High hematologic response rates in phase 2 4,5; may be alternative for HU-refractory PV 6

Pegylated Interferon Alfa-2a: Efficacy Results from a Phase II Study in

Patients with PV (and ET)

1. Quintas-Cardama A et al. J Clin Oncol. 2009;27:5418-24; 2. Quintas-Cardama A et al. Blood 2013;122:893-901.

Pegylated Interferon Alfa-2a:Phase II Study Safety Results

Overall Grade 3 or 4 Toxicities in Patients with PV (n=40)

1. Quintas-Cardama A et al. J Clin Oncol. 2009;27:5418-24.

Toxicity Grade 3, n (%) Grade 4, n (%)

Neutropenia 3 (8) 0

Elevated LFTs 2 (5) 0

Fatigue 1 (3) 0

Pain 1 (3) 0

Infection 1 (3) 0

Depression 1 (3) 0

Diarrhea 1 (3) 0

Mucositis 0 0

Blurred vision 1 (3) 0

Dizziness 1 (3) 0

Anemia 0 0



A. Busulfan

B. Pipobroman






1. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6; 2. Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print]; 3. Alvarez-Larran A et al. Ann Hematol. 2014 Jul 2 [Epub ahead of print]; 4. Quintas-Cardama A et al. J Clin Oncol. 2009;27:5418-24; 5. Quintas-Cardama A et al. Blood 2013;122:893-901; 6. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6; 7. Jakafi (ruxolitinib) prescribing information; Dec 2014.

Approved for treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea7

Phase II Study of Ruxolitinib (JAK1/JAK2 Inhibitor) in Patients with PV Refractory or

Intolerant to HU• Hematologic response rate: 97%

• 85% maintained Hct >45% for 48 weeks without phlebotomy

• Benefits for PV-related symptoms and splenomegaly

• Most AEs grade 1 or2; ≥grade 3 AEs included: – Anemia, thrombocytopenia (9% each)

– Neutropenia, pyrexia, vomiting, asthenia (3% each)

Verstovsek S, et al. Cancer. 2014;120(4):513-520.

Phase III Study of Ruxolitinib vs BAT (RESPONSE)

• Primary endpoint (composite): % of patients who achieved both Hct control and spleen response at week 32

– Hct control: No phlebotomy eligibility from week 8 to 32, with no more than 1 post-randomization phlebotomy eligibility up to week 8 • Phlebotomy eligibility was defined as Hct > 45% and ≥ 3% higher than baseline or > 48%

– Spleen response : ≥ 35% reduction from baseline in spleen volume by MRI

BAT

Week 32(primary endpoint)

Week 80

n = 110

n = 112

Crossover to ruxolitinib

•Resistance to or intolerance of HU (modified ELN criteria)

•Phlebotomy requirement

•Splenomegaly

Pre-randomization (day −28 to day −1)

Hct 40%-45%

Rand

omiz

ed (1

:1)

Extendedtreatment

phaseRuxolitinib 10 mg BID

Week 208

Week 208

Week 48

Verstovsek S et al. J Clin Oncol 2014;32 (5s): Abstract 7026.

RESPONSE: Baseline Characteristics Parameter

Ruxolitinib (n = 110)

BAT(n = 112)

Age, median (range), years 62 (34-90) 60 (33-84)

Male, % 60 71

HU resistance/intolerance, %

Resistance 46.4 45.5

Intolerance 53.6 54.5

JAK2 V617F mutation positive, % 94.5 95.5

History of prior thromboembolic event, % 35.5 29.5

Hct, mean (SD), %a 43.6 (2.2) 43.9 (2.2)

WBC × 109/L, mean (SD) 17.6 (9.6) 19.0 (12.2)

Platelet count × 109/L, mean (SD) 485 (323) 499 (319)

≥ 3 Phlebotomies in prior 24 weeks, % 30.9 42.0

Palpable spleen length, median (range), cm 7 (0-24) 7 (0-25)

Spleen volume, median (range), cm3 1195 (396-4631) 1322 (254-5147)

a Following Hct control period prior to randomization.

• BAT included HU (n = 66; 59%), IFN/pegylated IFN (n = 13; 12%), anagrelide (n = 8; 7%), pipobroman (n = 2; 2%), IMIDs (n = 5; 4%), and observation (n = 17; 15%)


RESPONSE: Rate of Phlebotomy Procedure Between Week 8 and 32

• The phlebotomy rate between week 8 and 32 was > 3 times higher in the BAT arm compared with the ruxolitinib arm

• Only 2.8% of patients in the ruxolitinib group vs 20.2% in the BAT group required 3 or more phlebotomies during this time


RESPONSE: Percentage Change in Spleen Volume (Week 32)

120

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rom

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e in

Spl

een

Volu

me

at W

eek

32, %

0

100

80

60

40

20

−20

−40

−60

−80

Ruxolitinib120

Chan

ge F

rom

Bas

elin

e in

Spl

een

Volu

me

at W

eek

32, %

0

100

80

60

40

20

−20

−40

−60

−80

BAT

35% reduction 35% reduction


RESPONSE: Primary Analysis (Week 32)

SV, spleen volume.

P < .0001OR, 28.64

(95% CI, 4.50-1206)

Primary Endpoint Individual Components of Primary Endpoint

• Primary endpoint (composite): % of patients who achieved both Hct control and spleen response at week 32

– 77% in the ruxolitinib group met at least 1 component of the primary endpoint

– 91% of patients who met the primary endpoint had a confirmed response at week 48


RESPONSE: Complete Hematologic Remission (Week 32)

a P value, odds ratio, and 95% CI were calculated using stratified exact Cochran-Mantel-Haenszel test.

CHR is defined as Hct control, PLT count ≤ 400 × 109/L, and WBC count ≤ 10 × 109/L.

P = .0034a

OR, 3.19(95% CI, 1.37-7.79)

• 88.5% of patients (23/26) who achieved CHR maintained it at week 48

n = 26

n = 10


RESPONSE: Improvement in SymptomsPercentage of Patients With a ≥ 50% Improvement in

MPN-SAF Symptom Score at Week 32a

a In patients with scores at both baseline and week 32.MPN-SAF, Myeloproliferative Neoplasm Symptom Assessment Form.

MPN-SAFTotal Symptom Score

CytokineSymptom Cluster

HyperviscositySymptom Cluster

SplenomegalySymptom Cluster

TirednessItchingMuscle acheNight sweatsSweating while awake

HeadacheConcentration problemsDizzinessSkin rednessVision problemsRinging in earsNumbness/tingling in hands/feet

Fullness/early satietyAbdominal discomfort

n = 74 81 74 80 71 80 63 71


RESPONSE: Improvement in Individual Symptoms

-49.6

-94.9

-61.1

-99.5 -100

-51.5-44

-80.2-64.1

-41.8

0

-37.1

-93.9

-65.9

-4.2 -2.1

0.4 3.9

-4.4

11.1 16.77.9 5 10.9 17.2 15.7

0 1.4

-120

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-80

-60

-40

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dia

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se

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ee

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Ruxolitinib BAT

Median Percentage Changes From Baseline at Week 32 in Individual Symptom Scores (MPN-SAF)

Patients with assessments at baseline and week 32, with baseline value >0.

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Med

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RESPONSE: Thromboembolic Events to Week 32

Patients, n (%)

Ruxolitinib(n = 110)

BAT(n = 111)

All grade Grade 3/4 All grade Grade 3/4

All thromboembolic events 1 (0.9) 1 (0.9) 6 (5.4)a 2 (1.8)a

Portal vein thrombosis 1 (0.9) 1 (0.9) 0 0

Myocardial infarction 0 0 1 (0.9) 1 (0.9)

Deep vein thrombosis 0 0 2 (1.8) 1 (0.9)

Pulmonary embolism 0 0 1 (0.9) 1 (0.9)

Splenic infarction 0 0 1 (0.9) 0

Thrombophlebitis 0 0 1 (0.9) 0

Thrombosis 0 0 1 (0.9) 0

• A higher proportion of patients in the ruxolitinib arm had a history of prior thromboembolic events at baseline than in the BAT arm (35.5% vs 29.5%)

• There was 1 additional event in the ruxolitinib group over the course of randomized treatment (median exposure 81 weeks)

a 1 patient in the BAT group had both myocardial infarction and pulmonary embolism.


RESPONSE: Nonhematologic Adverse Events to Week 32 (Regardless of Causality)

Patients, %


BAT(n = 111)

All Grades Grade 3/4 All Grades Grade 3/4

Headache 16.4 0.9 18.9 0.9

Diarrhea 14.5 0 7.2 0.9

Fatigue 14.5 0 15.3 2.7

Pruritus 13.6 0.9 22.5 3.6

Dizziness 11.8 0 9.9 0

Muscle spasms 11.8 0.9 4.5 0

Dyspnea 10.0 2.7 1.8 0

Abdominal pain 9.1 0.9 11.7 0

Asthenia 7.3 1.8 10.8 0

Events occurring in at least 10% of patients in either treatment group.

• When adjusted for exposure (per 100 patient-years), the rates of adverse events and grade 3/4 adverse events over the entire course of treatment were lower in patients randomized to ruxolitinib compared with those randomized to BAT (64.7 vs 145.6 and 28.8 vs 44.0)

• Rate of herpes zoster infection was higher in the ruxolitinib group (6.4% vs 0; all grade 1-2)


RESPONSE: New or Worsening Hematology Laboratory Values to Week 32

Patients, %


BAT(n = 111)

All Grades Grade 3/4 All Grades Grade 3/4

Hemoglobin (low) 43.6 1.8 30.6 0.0

Platelets (low) 24.5 5.5 18.9 3.6

Neutrophils (low) 1.8 0.9 8.1 0.9

• No patients discontinued treatment because of anemia or thrombocytopenia


RESPONSE: Conclusions• In patients with PV who had an inadequate response to

or were intolerant of HU, ruxolitinib was superior to BAT in:

– Controlling Hct without phlebotomy

– Normalizing blood cell count

• Most adverse events grade 1/2; a few patients developed grade 3/4 cytopenias

• Ruxolitinib is a valuable new treatment option in this population of patients with PV

– Reducing spleen volume

– Improving symptoms


Case Study (cont.): Bruce T. Q: What would you recommend for second-line therapy?

A. Busulfan

B. Pipobroman






Approved for treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea7

1. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6; 2. Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print]; 3. Alvarez-Larran A et al. Ann Hematol. 2014 Jul 2 [Epub ahead of print]; 4. Quintas-Cardama A et al. J Clin Oncol. 2009;27:5418-24; 5. Quintas-Cardama A et al. Blood 2013;122:893-901; 6. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6; 7. Jakafi (ruxolitinib) prescribing information; Dec 2014; 8. Finazzi G et al. Br J Haematol 2013;161: 688 – 694; 9. Andersen CL et al. Br J Haematol 2013;162:498–508.

Investigational, phase II 8,9


• This case highlights recent advances in second-line treatment for patients with PV

• Bruce T was taking HU for thrombotic and splenic control, but he had persistent symptoms that continued to worsen

• After discussing options, he was enrolled in a clinical trial of ruxolitinib (prior to its PV approval)

• For patients with PV, the approved ruxolitinib starting dose is 10 mg given orally twice daily

Summary• PV is associated with a unique set of burdens

attributed to systemic symptoms, healthcare costs, thrombosis, and disease transformation. – First-line treatment may not be effective for all patients

with PV; a proportion of patients still have symptoms that continue to worsen and require second-line treatment

– With its recent approval, ruxolitinib is a valuable new treatment option for patients with PV who have had an inadequate response to or are intolerant of hydroxyurea1

1. Jakafi (ruxolitinib) prescribing information; Dec 2014.

Documents

Case Study: A Patient with PV and Debilitating Symptoms on HU Srdan Verstovsek, MD, PhD Professor of Medicine Director, Hanns A. Pielenz Clinical Research