Case Study: A Young Patient with PV has a Major Thrombotic

Event and Worsening Leukocytosis - Is she Progressing to Post-PV MF?

Ruben A. Mesa, MD, FACPChair, Division of Hematology & Medical Oncology

Deputy Director, Mayo Clinic Cancer CenterProfessor of Medicine

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

Case Study: Trisha K. • Diagnosed with PV at the age of 32 years • Disease features at diagnosis

– Hb: 17.4 g/dL– Hematocrit: 56%– Leukocyte count: 9.2 x 109/L– Platelet count: 520 x 109/L– Suboptimal serum EPO– 0% circulating blasts on smear– Spleen not palpable; asymptomatic– JAK2V617F mutation

• No history of thrombosis or major bleeding events• Mild hypertension

Case Study (cont.): Trisha K.

Conventional risk stratification in PV is based on:

A. Risk of progression to myelofibrosis

B. Risk of leukemic transformation

C. Risk of death

D. Risk of thrombosis

E. Risk of major hemorrhage

Case Study (cont.): Trisha K.

Conventional risk stratification in PV is based on:

A. Risk of progression to myelofibrosis

B. Risk of leukemic transformation

C. Risk of death

D. Risk of thrombosis

E. Risk of major hemorrhage

Risk Stratification in PV Based on Thrombotic Risk

Risk Category Risk Variables

Low• Age < 60 years • No thrombosis history

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

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

• Novel biomarkers of increased thrombosis risk include leukocytosis and JAK2V617F allele burden.

Rates of Thrombotic Events During The Clinical Course of PV

All patients3

(n=1543)Age >61 years(n = 743)

Age ≤ 61 years(n=802)

P-value

Median follow-up, years (range)

6.9 (0-39) 5.8 (0-22) 8 (0-39)

Arterial thrombosis 184 (12%) 86 (12%) 98 (12%) NS

Venous thrombosis 137 (9%) 63 (8%) 74 (9%) NS

Major hemorrhage 24/572 (4%) 13/281 (5%) 11/291 (4%) NS

Aspirin therapy 1281/1535 (84%) 599/739 (81%) 682/796 (85%) 0.02

• Rate estimates for thrombosis in patients with PV range from 2.7 to 3.8 per 100 patients/year1-3

1. Marchioli R, et al. J Clin Oncol. 2005;23(10):2224-32; 2. Marchioli R, et al. N Engl J Med. 2013;368(1):22-33;3. Tefferi A et al. Leukemia 2013;27:1874-81.

Low-Dose Aspirin in Management of PV

• Persistently enhanced platelet activation contributes to the higher risk of thrombosis in patients with PV1,2

• Placebo-controlled ECLAP trial (N= 518) demonstrated that low-dose aspirin can safely prevent thrombotic complications in patients with PV who have no contraindications to aspirin2

1. Patrono C, et al. Blood. 2013;121(10):1701-11; 2. Landolfi R, et al. N Engl J Med 2004;350: 114-24.

European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) Trial

Landolfi R, et al. N Engl J Med 2004;350: 114-24.

• Incidence of major bleeding episodes was not significantly increased in the aspirin group (relative risk, 1.62; 95% CI, 0.27 to 9.71).

Low-dose aspirin (100 mg) reduced the risk of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes (relative risk, 0.40; 95% CI, 0.18 to 0.91; P = 0.03)

Estimated Rates of Upper GI Complications in Men Receiving Regular Treatment with Low-Dose Aspirin

1. Patrono C, et al. Blood. 2013;121(10):1701-11.

Low-Dose Aspirin in Management of PV

• Primary prevention with low-dose aspirin (81-100 mg) is currently recommended for almost all patients with PV1,2

• Risks may include increased risk of bleeding, especially GI bleeds

• Benefit/risk balance depends on the level of thrombotic and hemorrhagic risks for the individual patient

1. Patrono C, et al. Blood. 2013;121(10):1701-11; 2. Barbui T et al. J Clin Oncol. 2011;29(6):761-770.

Hematocrit (Hct) Control is a Key Therapeutic Goal

• Maintaining Hct <45% significantly decreases the risk of cardiovascular death and major thrombotic events

Marchioli R, et al. N Engl J Med. 2013;368(1):22-33. .

Death from cardiovascular causes or thrombotic events Total cardiovascular events

Low Hct – target <45%High Hct – target 45 – 50%

Reducing the Risk of Vascular Complications: Lifestyle Interventions

• Weight control• Physical exercise• Adherence to antihypertension, antidiabetes,

and/or antihypercholestrolemia/hyperlipidemia medications

• Avoidance of oral contraceptives• Smoking cessation• Avoidance of situations that carry a risk of

bleedingVannucchi AM. Blood. 2014 Oct 2. [Epub ahead of print]. .

Risk-Adapted Management of Patients with PV 1,2

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. J 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].

Case Study (cont.): Trisha K.

• Classified as ‘Low-Risk’ at diagnosis (age <65 years; no history of thrombosis)

• Control of hypertension, reduction of CV risk factors

• Phlebotomies to maintain Hct < 45% plus low-dose aspirin– 9 phlebotomies over the first 3 months, every 1.5 -2 months thereafter

– Fatigue related to iron deficiency (repeated phlebotomies)

• 6 years later, she experienced venous thromboembolism (DVT) in her right leg – Anticoagulation with low-molecular weight heparin (LMWH) was

instituted at time of thrombosis followed by vitamin K antagonists

– She had a good outcome

Case Study (cont.): Trisha K. • Due to her DVT event and underlying PV, she is at high-risk

for re-thrombosis.

Q: Despite her younger age (38 years), Trisha is now at high risk for thrombosis (high-risk PV). What would you suggest for management?

A. Continue with phlebotomy plus low-dose aspirin

B. Maintain on oral anticoagulation instead of aspirin

C. Combine oral anticoagulation and aspirin

D. Institute oral anticoagulation plus cytotreductive therapy (hydroxyurea or interferon)

E. Other strategy

Case Study (cont.): Trisha K. • Due to her DVT event and underlying PV, she is at high-risk

for re-thrombosis.

Q: Despite her younger age (38 years), Trisha is now at high risk for thrombosis (high-risk PV). What would you suggest for management?

A. Continue with phlebotomy plus low-dose aspirin

B. Maintain on oral anticoagulation instead of aspirin

C. Combine oral anticoagulation and aspirin

D. Institute oral anticoagulation plus cytotreductive therapy (hydroxyurea or interferon)

E. Other strategy

Risk-Adapted Treatment for Patients with High-Risk PV

High risk

If prior thrombosis or age >60 years or poor compliance to phlebotomy

Or progressive myeloproliferation (splenomegaly, leukocytosis, thrombocytosis)

First-line cytoreductive therapy is hydroxyurea or interferon alfa. Busulfan in age >75 years

Barbui T et al. J Clin Oncol. 2011;29(6):761-70;

• Trisha K. managed with oral anticoagulation plus interferon alfa therapy

PV is a Progressive Disease• Estimated probability of evolution to post-PV MF (N=116): 16% at 10 years

and 34% at 15 years1 • Events During the Clinical Course (N=1543)2

1. Alvarez-Larran A, et al. Br J Haematol. 2009;146(5):504-509; 2. Tefferi A et al. Leukemia 2013;27:1874-81.

All patients(n=1543)

Age >61 years(n = 743)

Age ≤ 61 years(n=802)

P-value

Median follow-up, years (range) 6.9 (0-39) 5.8 (0-22) 8 (0-39)

Progression to myelofibrosis 138 (9%) 50 (7%) 88 (11%) 0.004

Leukemic transformation 50 (5%) 25 (3%) 25 (3%) NS

Deaths 347 (23%) 237 (32%) 110 (14%) < 0.0001

• Most common causes of death (>10 pts) 2 ─ Acute leukemia - 36 ─ Second malignancy - 36 ─ Thrombotic complications – 32─ Heart failure – 13─ Non-leukemic progressive disease – 12

Adverse Prognostic Factors in Patients with PV

Tefferi A et al. Leukemia 2013;27:1874-81.

Adverse Prognostic Factors

• Age > 67 yrs (5 points)

• Age 57-66 yrs (2 points)

• Leukocyte count >15 x 109/L (1 point)

• Venous thrombosis (1 point)

Low risk – 0 points

Intermediate risk - 1 or 2 points

High risk - >3 points

• Based on this prognostic model, Trisha K is ‘Intermediate Risk’• Leukocyte count >15 x 109/L (1 point)• Venous thrombosis (1 point)

Case Study (cont.): Trisha K.

• Managed with oral anticoagulation plus interferon alfa therapy. Two years later: – Increasing constitutional symptoms (esp. pruritus) – Unintentional weight loss of 5% in past 4 months;

full on smaller meals – Worsening leukocytosis (22 x 109/L) and

thrombocytosis – Newly palpable spleen (3 cm)

Case Study (cont.): Trisha K.

Q: How can we tell if the patient has progressed to post-PV MF?

A. Re-evaluate PV risk status B. Assess JAK2 allele burdenC. Perform bone marrow biopsyD. Obtain cytogenetic profile

Case Study (cont.): Trisha K. • Managed with oral anticoagulation plus interferon alfa

therapy. Two years later: – Increasing constitutional symptoms (esp. pruritus) – Unintentional weight loss of 5% in past 4 months; full on smaller meals – Worsening leukocytosis (22 x 109/L) and thrombocytosis – Newly palpable spleen (3 cm)

Q: How can we tell if the patient has progressed to post-PV MF? A. Re-evaluate PV risk status B. Assess JAK2 allele burdenC. Perform bone marrow biopsyD. Obtain cytogenetic profile

IWG-MRT Criteria for the Diagnosis ofPost-PV-MF

3 of 4 additional criteria

1 of 2 required criteria

Diagnosis of PPV-MF requires at least two additional criteria beyond the two main criteria.• According to the European classification (scale 0-3) or standard classification (scale 0-4) ** Below the reference range for appropriate age, sex, gender, and altitude considerations.

European Classification (scale 0-3) on Grading of Bone Marrow Fibrosis in MF*

O 1

2 3

Grade Description

MF - 0 Scattered linear reticulin with no intersections consistent with normal bone marrow

MF - 1 Loose meshwork of thin reticulin fibers with many intersections

MF - 2 Diffuse and dense increase in reticulin with extensive intersection, occasionally with only focal bundles of collagen and/or focal osteosclerosis

MF - 3 Diffuse and dense increase in reticulin with extensive interaction with coarse bundles of collagen, often associated with significant osteosclerosis

Silver impregnation after Gomori ; x180

Thiele J et al. Haematologica 2005; 90:1128-1132.

*Grade 2 or 3 required for post PV-MF criteria

Standard Classification (scale 0-4) on Grading of Bone Marrow Fibrosis in MF*

0-4: Reticulin silver stain; x200.

*Grade 3 or 4 required for post PV-MF criteria

O 1

2 3

Kuter DJ et al. Br J Haematol. 2007; 139: 351–362.

4Collagen fibers (blue) – Mason’s trichrome stain

Grade Description

0 Staining of small vessel walls (confirms stain was successful); no staining in the surrounding bone marrow.

1 Short, thin reticulin fibers, but these do not intersect to form a network.

2 Network of thin reticulin fibers with numerous intersections.

3 Network of reticulin fibers, including thick and reduplicated fibers.

4 Dense network of thick reticulin fibers throughout the bone marrow.

Case Study (cont.): Trisha K. • Clinical findings (review)

– Increasing constitutional symptoms (esp. pruritus and night sweats)

– Spleen is now palpable (3 cm)

– Worsening leukocytosis (32 x 109/L); reduced need for phlebotomy

– No peripheral blasts

• Bone marrow biopsy findings: • Grade 1 fibrosis (0-3 scale) (ie, loose meshwork of thin reticulin fibers

with many intersections)

• Megakaryocyte proliferation, atypia

• Increased JAK2 allele burden vs baseline assessment (at diagnosis)

Case Study (cont.): Trisha K.

Q: Which of the below best describes this patient’s clinical picture?

A. Adequately controlled PV

B. Uncontrolled/advancing PV

C. Progression to post-PV myelofibrosis

D. Transformation to leukemia

Case Study (cont.): Trisha K.

Q: Which of the below best describes this patient’s clinical picture?

A. Adequately controlled PV

B. Uncontrolled/advancing PV – Grade 1 BM fibrosis is not sufficient for post-PV MF diagnosis

C. Progression to post-PV myelofibrosis

D. Transformation to leukemia

Case Study (cont.): Trisha K.

Diagnosis of PPV-MF requires at least two additional criteria beyond the two main criteria.• According to the European classification (scale 0-3) or standard classification (scale 0-4) ** Below the reference range for appropriate age, sex, gender, and altitude considerations.

IWG-MRT Criteria for the diagnosis of Post-PV-MF

3 of 4 additional criteria

1 of 2 required criteria

Case Study (cont.): Trisha K. • Interferon therapy was stopped and she was started on

hydroxyurea (HU) to manage cytopenias and splenomegaly (with continued oral anticoagulation)

6

Phlebotomy + low-dose aspirin

8

IFN-alfa + oral anticoagulation

HU + oral anticoagulation

0

Years from PV diagnosis

• To date, no therapeutic used to treat PV has been proven to prevent transformation to post-PV MF

HU Resistance and/or Intolerance in PV• 20-25% of patients will become resistant and/or intolerant to HU 1,2

– Increased complications and symptom burden– Worsening disease transformation – Reduced survival

Criteria3

• HU Resistance - After 12 weeks of HU, at a total dose ≥2 g/day:– Need for phlebotomy to maintain Hct at <45%– Elevated platelet and WBC counts or – <50% reduction in splenomegaly or failure to completely relieve

splenomegaly symptoms

• HU Intolerance– Leg ulcers or other unacceptable HU-related toxicity– ANC <1 x 109/L or Hgb <10 g/dL

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. Barbui T et al, J Clin Oncol 2011;29(6):761–70.

Ruxolitinib (JAK1/JAK2 Inhibitor) in the Treatment of MPNs

Indication US Approval DatePatients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis

2011

Patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea *

Dec 2014

* For PV, the approved starting dose is 10 mg orally twice daily.

Jakafi (ruxolitinib) prescribing information, 2014.

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 (Primary Response at Week 32)• Phase 3 study of ruxolitinib in PV patients resistant to or intolerant of HU (N = 222)

SV, spleen volume.

P < .0001OR, 28.64

(95% CI, 4.50-1206)

Primary Endpoint Individual Components of Primary Endpoint

• To achieve Hct control, patients could not be eligible for phlebotomy based on protocol-defined Hct values

– Phlebotomy eligibility defined as Hct > 45% and ≥ 3% higher than baseline or a Hct > 48%

• 91% of patients who achieved the primary endpoint had a confirmed response at week 48

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

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 Hyperviscosity

Symptom 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

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

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.

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

RESPONSE: Nonhematologic Adverse Eventsto Week 32 (Regardless of Causality)

Patients, %

Ruxolitinib(n = 110)

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)

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

RESPONSE: New or Worsening Hematology Laboratory Values to Week 32

Patients, %

Ruxolitinib(n = 110)

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

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

Case Study (conclusion): Trisha K.

• Trisha’s case illustrates a clinical course for a typical PV patient (i.e., high thrombotic risk as well as progressing underlying PV disease)

• She has taken JAK inhibitor therapy (ruxolitinib) for 2 months – Good spleen response and symptom improvement

– We monitor CBC every 2-4 weeks

– Treatment-related cytopenias managed with dose modifications

Conclusions

• Contemporary treatment for patients with PV combines:– Modification of CV risk factors

– Antiplatelet therapy

– Phlebotomy

– Cytoreduction (HU, IFN-alfa, busulfan)

• Recently, ruxolitinib demonstrated benefit in PV patients resistant or intolerant to HU (RESPONSE trial)