NP - Myelofibrosis

8/10/2019 NP - Myelofibrosis

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Pathogenesis and Clinical

Overview of Myelofibrosis


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Chronic Myeloid Malignancies

oA group of clonal myeloid malignancies with

unique clinicopathologic characteristics

o Two primary subtypes:

Myelodysplastic syndromes (MDS): significant dysmyelopoiesis, dysplastic bone marrow

hyperplasia, associated with variable degrees of peripheral

blood cytopenia

Myeloproliferative neoplasms (MPN): do not display significant dysmyelopoiesis, usually exhibit

terminal myeloid cell expansion in the peripheral blood

Subdivided into Classical and Non-classical MPNs

Tefferi, 2001.


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WHO Classification

of Myeloproliferative Neoplasms

Classic MPN

o Chronic myelogenous

leukemia, BCR-ABL1

positive (CML)o Polycythemia vera (PV)

o Primary myelofibrosis

(PMF)

o Essentialthrombocythemia (ET)

Nonclassic MPN

o Chronic neutrophilic

leukemia (CNL)

o Chronic eosinophilicleukemia, not otherwise

specified (CEL-NOS)

o Mastocytosis

o Myeloproliferativeneoplasm, unclassifiable

(MPN-U)

Vardiman et al, 2009.


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Myelofibrosis

oA myeloproliferative neoplasm

o Manifested by abnormal blood counts

Anemia

Thrombocytosis or thrombocytopenia

Leukocytosis or leukopenia

o Splenomegaly

o Debilitating symptomso The JAK-STAT signal transduction pathway

plays a critical role in the pathogenesis of MF

Tefferi, 2011.

Vardiman et al, 2009.


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Myeloproliferative Neoplasms

Classical Myeloproliferative Neoplasms

CML PV ET

Ph+

BCR-ABL

Ph

Primary MF Post-PV MF Post-ET MF

Myelofibrosis encompasses three distinct entities:

Primary myelofibrosis (1 per 100,000 /year)

Post-PV myelofibrosis - ~ 10% transformation rate per 10 years (0.3-0.7 per 100,000)

Post-ET myelofibrosis ~ 4% transformation rate per 10 years (0.5-1.1 per 100,000)

Estimated prevalence: 16,000-18,500 cases in the United States

Median age at diagnosis: 67 years (range 42-84)

PV, polycythemia vera; ET, essential thrombocythemia.

Mehta et al, 2013.CancerCare, 2012.

Osca-Gelis et al, 2013.


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The JAK-STAT Pathway

o Intracellular signaling pathway

o Transduction of extracellular signals

to the nucleus to control gene

expression

o Necessary for growth and

differentiation:

normal hematopoiesis, fertility,lactation, growth and

embryogenesis

o Involved in inflammatory cytokine

signaling and immune-regulation

o Janus Kinases (JAKs)

a family of four cytoplasmic

tyrosine kinases:

JAK1, JAK2, JAK3, and TYK2

Adapted from Macmillan Publishers Ltd: Nature Reviews Drug Discovery 2004;3:555-64, copyright 2004.

*Janus associated kinase-signal transducer and activator of transcription pathway


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Janus Kinases

o When dysregulated, the JAK signaling pathways can

lead to ineffective hematopoiesis and increased

inflammatory cytokines

o In 2005, the JAK2 V617F mutation was identified as the

most common molecular abnormality in

myeloproliferative neoplasms

o Other mutations that activate the JAK pathway have

been identified

o Thus, dysregulation of the JAK signaling pathway is

frequently noted in patients who have myelofibrosis, with

or without the V617F mutation

Furqan et al, 2013.James, 2008.

Quints-Cardama et al, 2010.


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Key Molecular Mutations in MF

ET, essential thrombocytopenia; PMF, primary myelofibrosis; PV, polycythemia vera.Cazzola M, et al. Blood. 2014;123(24):3714-3719.

Tefferi A.Am J Hematol. 2014;89(9):915-925.

Molecular abnormality/

Chromosome location

Frequency Clinical Significance

JAK2 (Janus kinase 2)

9p24

PV 96%

ET 55%

PMF 65%

Most common molecular mutation in MF

Contributes to abnormal myeloproliferation

and progenitor cell growth factor

hypersensitivity

CALR (Calreticulin)

19p13.2

PMF 25%

ET 20%

PV 0%

Second most common mutation in MF

Patients who are CALR+ with ET have a

reduced risk of thrombosis

Mutation carries more favorable survival

MPL (Myeloproliferativeleukemia virus oncogene)

1p34

ET 3%PMF 10%

Contributes to primarily megakaryocyticmyeloproliferation

Nonmutated JAK2, MPL, and CALR (Triple Negative)implies very

poor prognosis


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Myelofibrosis: Clinical

Presentation

o Presenting signs and symptoms of MF related to:

Myeloid proliferation/clonal expansion

Release of inflammatory cytokines

Janus kinasemediated symptoms

Cervantes et al, 2009.

Emmanuel et al, 2012.


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Abnormal JAK1 and JAK2 Signaling Drives the

Clinical Manifestations in Myelofibrosis

Multipotential

stem cell

Myeloid

progenitor cell

Natural killer

(NK) cells

T lymphocytes

B lymphocytes

Lymphoid

progenitor

cellNeutrophils

Basophils

Eosinophils

Monocytes/

macrophages

Platelets

Red blood

cellsJAK 1 AND JAK2

OVERACTIVITY

Hematopoietic

stem cell

Bone Marrow Fibrosis

Erythrocytosis followed by progressive anemia

Thrombocytosis

Extramedullary hematopoiesis with splenomegaly

Abnormal levels of inflammatory cytokines

Copyright 2012 - Building Blocks of Hopewww.buildingblocksofhope.com. Adapted with permission.

National Institutes of Health, 2013.


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Myelofibrosis: Clinical Presentation

o Physical and Pathological

Findings: Marrow fibrosis

Osteosclerosis

Angiogenesis

Progressive anemia

Extramedullaryhematopoiesis, manifested

primarily as splenomegaly

o Signs and Symptoms:

Severe constitutional

symptoms (night sweats and

weight loss)

Pruritus

Fatigue

Splenomegaly (abdominal or

rib pain, early satiety)

o Potential complications of

disease: Clonal evolution and disease

transformation to MDS or AML

~ 20%-30% of patients (differs

among subgroups)

Thrombosis

Bleeding


Emmanuel et al, 2012.


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The Symptom Burden of Myelofibrosis:

Cytopeniaso Anemia

Present in 66% of patients 20% of individuals being red

blood cell transfusion-

dependent

Secondary symptoms:

Fatigue, dyspnea

Organ dysfunction

Transfusion dependence/Iron

overload

o Thrombocytopenia

Present in 37% of patients

Severe thrombocytopenia isconsidered an adverse

prognostic finding and

increases the risk of

hemorrhage

o Leukopenia

Present in 7%-22% Neutropenia is also rare in the

absence of transformation to

blast phase or treatment-

related myelosuppression

Increased risk of infections

Greer et al, 2013.Degos et al, 2004.

Elena et al, 2011.


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The Symptom Burden of Myelofibrosis:

Splenomegaly and Cytokine-Mediated Symptoms

o Splenomegaly Early satiety, abdominal discomfort, and

abdominal pain

o Cytokine-mediated symptoms in 40% of

patients

Significant fatigue Night sweats

Pruritus

Bone pain

Other symptoms due to end-organ dysfunction:

Problems with sexual desire and function

Portal hypertension with secondary

variceal bleeding or ascites

Inactivity

Insomnia

Dizziness

Headache

Cachexia

Decreased concentration

Issues of mood

Degos et al, 2004.

Elena et al, 2011.


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Dynamic International Prognostic Scoring

System + karyotype + platelet count+

transfusion status (DIPSS-plus)

Risk Factors1.Red blood cell

transfusion needed

2.Hgb < 10 g/dL

3.Plt < 100109/L

4.Leukocyte count

>25109/L

1.Circulating blasts >1%

2.Constitutional symptoms

3.Unfavorable karyotype

4.Age >65 years

793 patients with PMF

Gangat et al, 2010.


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Risk Stratification and Risk-Adapted

Therapy in Primary Myelofibrosis

DIPSS-plus risk groups

PMF

Median survival Management

Low risk

(No risk factors)

11.3 years Observation

Conventional drugs

Intermediate-1 risk(1 risk factor) 7.9 years ObservationConventional drugs

Clinical Trial

Intermediate-2 risk

(2 or 3 risk factors)

4.0 years JAK Inhibitor

Allo-SCT

Clinical Trial

High risk

(4 risk factors)

2.3 years JAK Inhibitor

Allo-SCT

Clinical Trial

Approximately 80% of patients have intermediate- or high-risk disease

Gangat et al, 2010.


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Current Clinical Management

of Myelofibrosis


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Treatment ofAnemia

Treatment to

Reduce

Splenomegaly

Treatment of

MF-Associated

Symptoms

Treatment Strategies Prior to JAK Inhibitors:

Reduction of Symptom Burden

Gowin et al, 2013.

MedlinePlus, 2013.

Hydroxyurea

Busulfan

Cladribine

Splenectomy

Splenic radiation

Lenalidomide

AndrogensEPO agent

Folate

ThalidomideLenalidomide

Limited effective treatment options

Focus on supportive care

Supportive Care

Transfusion support

Nutrition

Tumor lysis prophylaxis

Thromboembolism prophylaxis


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Conventional Agents for

Treatment of Myelofibrosis

o Hydroxyurea: 500 mg/day

Retrospective study of 40 MF patients

Clinical improvement in 16/40 (40%)

Median duration of response 13.2 months

Worsening of anemia/pancytopenia in 18/40 (45%)o Androgens: Danazol 600 mg/day

Retrospective study of 30 patients

Response in 11/30 (37%); 4 stopped responding at 6-24 months

o Erythropoietin (requires REMS program for prescribing)

Prospective 10,000 U3/wk in 20 patients; response in 9/20 (45%) Prospective 10,000 U3/wk in 20 patients; response in 12/20 (60%)

o Darbepoetin alfa (requires REMS program for prescribing)

Prospective 150-300 mcg/wk in 20 patients; response in 8/20 (40%)

Gupta et al, 2012.


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Conventional Agents for Treatment

of MF: Thalidomide

o Barosi (2002): Pooled analysis of 62 MF

patients

100 mg/day starting dose

Increase in Hb, reduced transfusion

requirement in 29%

o Thomas (2006): Prospective phase 2

(N = 44)

200 mg/day, increased to max. 800

mg/day

Anemia improved in 7/35 (20%) with

Hb


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Conventional Agents for Treatment of

MF: Lenalidomide/Pomalidomide

Lenalidomide

o Tefferi (2006): Combined analysis of

two

prospective phase 2 trials (N = 68)

5-10 mg/day

Anemia improved in 22%

o Quintas-Cardama (2009): Prospective

phase 2 (N = 40)

5-10 mg/day + prednisone


o Mesa (2010): Prospective phase 2

(N = 48)

10 mg/day + prednisone taper


Pomalidomide

o Tefferi (2009): Prospective phase 2

(N = 84)

0.5 or 2 mg/dayprednisone taper


o Begna (2011): Prospective phase 2 (

N = 58)

0.5 mg/day

Anemia improved in 24%; response

only in JAK2V617F-positive patients

o Begna (2012): Combined analysis of

two trials (N = 94)

Anemia response of 27%

53% in the absence of marked

splenomegaly, presence of < 5%

circulating blasts, or presence of

JAK2V617F

Gupta et al, 2012.


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The MPN QOL International Study Group

(MPN-QOL-ISG)

o Inflammatory deregulation may be a major factor

in MF-related symptoms:

pruritus, fatigue, sexuality, night sweats, insomnia,

weight loss, and lack of appetiteo Myelofibrosis (MF) patients treated with

ruxolitinib, a JAK1/JAK2 inhibitor

have been shown to have normalization of selected

cytokines and improvement in symptom burden

Dueck et al, 2013.

Progressive Burden of Myelofibrosis in


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Progressive Burden of Myelofibrosis in

Untreated Patients: Assessment of Patient-

Reported Outcomes in Patients Randomized to

Placebo in the COMFORT-I Studyo COMFORT-I study: double-blind study of the JAK1/JAK2 inhibitor

ruxolitinib compared to placebo in patients with intermediate-2 or

high-risk myelofibrosis

154 MF patients randomized to the placebo group in a randomized,Patient-reported outcomes (PROs) and spleen size were evaluated

Baseline PROs indicated considerable disease burden

o Symptom burden, fatigue, and HRQOL worsened from baseline

through week 24 in the placebo arm

o

Progressive and debilitating effects of myelofibrosiso Established the role of treatments to reduce symptom burden and

splenomegaly for patients with MF

Mesa et al, 2013.


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The MPN Fatigue Project: Stage 1 Results

of the MPN Forum Internet-Based Survey

Among 879 MPN Patients

Emanuel et al, 2013.
https://ash.confex.com/data/abstract/ash/2013/8/2/Paper_59028_abstract_96802_0.png


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Sexuality Age, language, diminished role functioning, insomnia, depression/sadmood, night sweats, and QOL have been correlated with challenges

with intimacy and sexuality

Insomnia Insomnia is highly prevalent and severe in MPN patients

Correlates with most other MPN-related symptoms

Headaches, extremity tingling, depression, sexual problems, night sweats,

pruritus, fever, and QOL have been correlated with insomnia

Pruritus Pruritus is common and disabling in patients with MPNs

The most effective strategies for management observed in 88 patients with

MF (N = 566) reporting pruritus:

JAK inhibitors (92%), thalidomide (83%), or pain relievers (83%);

hydroxyzine (43%), antihistamine (37%), and antidepressants (32%)

The average time to pruritus alleviation in the entire cohort was 2 months

(range, 1 day to 25 months)

The MPN QOL International Study

Group (MPN-QOL-ISG)

Geyer et al, 2013a, 2013b.

Vaa et al, 2013.


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Nursing Management of Common

Adverse EventsMyelosuppression Establish baseline bone marrow function

Monitor CBC with differential every 1-2 weeks for the first

12 weeks and monthly or as clinically indicated thereafter

Hold drug or reduce dose based on symptomatic

cytopenias, bone marrow capacity to recover

Transfusions and growth factors as clinically indicated

Monitor closely for signs of infection

Infections Evaluate patients for risk of developing infections (atypical,

fungal, viral)

Monitor closely for symptoms of pneumonia

Prophylaxis as indicated for atypical infections

Educate patient on reportable signs and symptoms

Renal Impairment Dose modification is required for ruxolitinib

Thromboembolic

Events (Immuno-

modulatory

agents)

Evaluate risk factors:

Daily aspirin for patients at lower risk

Anticoagulation recommended for > 2 risk factors

Monitor coagulation assays


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Management of Anemia in MF

o Risk assessment for complications

o Establish underlying cause: bleeding, nutritional,

inherited, renal insufficiency, therapy

o Consider risks/benefits of treatment approach Transfusion risks: viral transmission, TRALI, TACO,

fatal hemolysis, febrile nonhemolytic reactions

ESA risks: thrombotic events, potential decreased

survival, potential reduced TTP If Hgb increases > 1 g/dL in any 2-week period, dose

reductions are required

REMS programESA, erythropoiesis-stimulating agent; TACO, transfusion-associated circulatory overload;

TRALI, transfusion-related acute lung injury; TTP, time to progression.Kurtin, 2012.

ESA APPRISE Oncology Program, 2013.


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Risk Factors for Thromboembolism

(Immunomodulatory Agents)

Risk Factors: Individual

o Older age

o Obesity or diabetes

o Cardiovascular or renal

disease

o Acute infection

o Elevated homocysteine levels

o Central venous catheter

o Prior DVT, PE, or superficialvein thrombosis

Disease or Treatment-RelatedFactors

o Diagnosis of ET, PV, MF

o Anesthesia, surgery, trauma,

or hospitalization

o Immobilization, sedentary

lifestyle, extremity paresis

o Other malignant neoplasm

o Hyperviscosity

o Thalidomide, lenalidomideo Erythropoietin use

Sullivan et al, 2013.


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Cancer Panel Guideline Recommendations

for Outpatient ThromboprophylaxisPatient

Population

ASCO NCCN ESMO

All

Outpatients

Routine prophylaxis not

recommended


recommended


recommended

Myeloma,

receivingIMiD-based

regimens

Aspirin or LMWH for

low-risk and LMWHfor high-risk patients is

recommended

Aspirin for low-risk and

LMWH or warfarin forhigh-risk patients is

recommended

Consider LMWH,

aspirin, or adjusted-dosewarfarin

(INR 1.5)

High-risk

outpatients

Consider LMWH

prophylaxis on a case-

by-case basis in highlyselect outpatients with

solid tumors on

chemotherapy

Consider patient

conversation about risks

and benefits ofprophylaxis

in Khorana score 3

population

Consider in high-risk

ambulatory cancer

patients. Predictivemodel may be used to

identify patients clinically

at high risk for VTE

IMiD, immunomodulatory drugs; INR, international normalized ratio; LMWH, low-molecular-weight heparin.Khorana, 2013.


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Case Study 1

58-year-old man presenting to his PCP with extremefatigue and abdominal bloating, headaches, and pruritus.

He gets full very fast and has been losing weight over the

previous 3 months.

Key lab findings:

The patient is referred to hematology/oncology.

WBC: 75,000/L Platelets: 680 x 109/L Hgb

11.5 g/dL

Massivesplenomegaly

(by exam)


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Case Study 1 (cont

d.)

Normal iron, B12, folate

Serum erythropoietin: 830

mU/mL

Serum creatinine: 1.5 mg/dL

LDH : 980 IU/L (ULN, 180)

Increase in the size of his spleen

(24.5 cm) on ultrasound

Abdominal CT: Massivesplenomegaly, hepatomegaly

Bone marrow biopsy confirms

PMF

ULN = upper limit of normal


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Case Study 1 (cont

d.)

All of the following treatment options would

be appropriate EXCEPT

1) Hydroxyurea 1 g bid

2) Ruxolitinib

3) Evaluate for allogeneic stem cell transplant

4) Evaluate for autologous stem cell transplant


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Allogeneic Stem Cell Transplantation

o

Allogeneic stem cell transplant (allo-SCT) remains the only potentialcure for MF

o Very few patients with MF meet the stringent allo-SCT transplant

eligibility criteria

Age (median age at diagnosis for MF is 67 years)

Comorbidity index Performance status

Massive splenomegaly

Unexpected rapid progression of disease

o Adequate leukemic clearance prior to allo-SCT offers an optimal

outcomeo The prognosis of MPN-blast phase is poor, with reported median

survivals of 2-5 months

o High rates of treatment-related mortality have been reported in trials

for patients undergoing allo-SCT for MF

Cherington et al. 2012.


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JAK2 Inhibitors

o One of the most important developments in MF

in recent years

o The first-in-class JAK1/2 inhibitor, ruxolitinib,

was approved in 2011 for patients with MFo Other JAK inhibitors are at various stages of

clinical development

Harrison et al, 2012, 2013.

Verstovsek et al, 2012.


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JAK2 Inhibitors: Ruxolitinib

Ruxolitinib: JAK1/2 inhibitor

FDA approved, November

2011, based on 2 phase 3

trials, COMFORT-I and

COMFORT-II)

Currently in phase 3b

o Non-hematological toxicities

No significant difference from

placebo

o Hematological toxicities

Compared with placebo (45%vs 19%)

Thrombocytopenia (13% vs

1%)

o Clinical Benefits

Reduction in splenomegaly

seen in almost all patients,

29%-42% (35% reduction in

spleen volume)

Significant improvement inMF-associated symptoms, and

improvement in self-reported

QOL, marginal survival benefit

in COMFORT-1, no survival

benefit in COMFORT-II,

Equally effective in unmutated

JAK2 patents




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COMFORT-I Mean Change in Symptom Scores



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Ruxolitinib Dosing Considerations

o Dosing should be individualized based on platelet countto maximize efficacy and minimize toxicities.

5 mg BID for platelet count 50-100109/L

10 mg BID for platelet count >100-150109/L and moderate or

severe renal impairment, any hepatic impairment or taking

strong CYP3A4 inhibitor

15 mg BID for platelet count 100-200109/L

20 mg BID for platelet count >200109/L

o Ruxolitinib should be tapered slowly if treatment needs

to be discontinued MF-related symptoms can return rapidly if drug is discontinued

abruptly

Treatment should continue until disease progression, allo-HST,

or unacceptable toxicity

PDR Network, 2013.


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Case Study 1 (cont

d.)

Given the patient profile:

What is the appropriate starting dose for ruxolitinib?

1. 20 mg bid2. 10 mg bid

3. 15 mg bid

4. 5 mg bid

WBC: 75,000/L Platelets: 680 109/L Hgb: 11.5 g/dL

Serum creatinine:

1.5 mg/dL (ULN 1.3)

LDH: 980 IU/L (ULN 180)


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Case Study 1 (cont

d.)

o The patient was started on hydroxyurea

1 g bid

oAllopurinol was added at 300 mg qd

o Started on ruxolitinib 10 mg bid

oAllogeneic stem cell transplant was

discussed with the patient


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Patient Education Tips on the Use

of Ruxolitinib for MF

o May be taken with or without food

o May be given via nasogastric tube (8 French or greater)

o Should not be taken before dialysis

o

Inform patient to report any: Bleeding

Signs and symptoms of infection

Changes in medications (Rx or OTC)

o Discuss need for frequent monitoring of blood counts,

renal and hepatic function during the early days of

treatment

Dose adjustments may be needed based on cytopenias, or renal

or hepatic function

PDR Network, 2013.

D d t k i ti t h d t t k th


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Drugs don

t work in patients who dont take them.

~ C. Everett Koop, MD

To be adherent, the patient must:1. Fill the prescription

2. Consume it in a manner

consistent with the prescription

3. Continue to take it unless directed

otherwise by the HCP

4. Keep follow-up appointments

Nonadherence is:

1. A multifaceted process

2. Linked to both intentional and

unintentional factors

3. Not linked to any one type of

disease

4. There is no typical patient profile

for adherence

Osterberg et al, 2005; Bazeos et al, 2009; Boyle et al, 2007.

Provider

Health Care

System

Patient


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Physician-PatientConsultation

Informed Consent

Prescription Entered inthe EHR

IndividualizedPatient/Caregiver Education

Provided by RN

Activates Prior Authorizationand Financial Assistance

Process

Patient notifies RN when Rxfilled

RN follow-up call within 1 weekof new Rx

Implementation of treatment-specificstandard of care for follow-up,including toxicity checks and

reinforcement of learning

Reduction in Severity ofAdverse Events,

ED visits, Hospitalizations,Discontinuation of Therapy

Improved patient satisfactionSample Oral

Therapy

Process


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Emerging Therapies for the

Management of Myelofibrosis


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JAK2 Inhibitors in Trials

o Dysregulation of JAK-STAT pathway

central to pathophysiology of MPN

o Small molecule inhibitors of JAK family

currently under investigation for the

treatment of MPN

o Novel resistance mechanisms including

heterodimerization of JAK2 with other JAKfamily members are being explored

Tam and Verstovsek, 2013.


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JAK2 Inhibitors: In Trials

Fedratinib and Lestaurtinib

Fedratinib (SAR302503 - formerly

TG101348)

JAK2/FLT3

Phase 3JAKARTA trial

(N = 289)

o Nonhematological toxicities:

Grade 3/4 diarrhea 5%;

thrombocytopenia 9%

(placebo), 17% (400 mg), and

27% (500 mg); and increased

ALT 0%/3%/3%

o Halted due to Wernickes

encephalopathy in clinical trials

Lestaurtinib (formerly CEP-701)

JAK2/FLT3phase 2 (N = 22)

o Non-hematological toxicities:

Diarrhea 9%

o Hematological toxicities: Anemia 14%,

thrombocytopenia 23%

o Clinical benefits:

18% of patients had 50%

reduction in spleen size,tested only in JAK2 mutation-

positive patients

Harrison et al, 2013.

Santos et al, 2010.


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Pacritinib

o Oral JAK1/2 Inhibitor

Data from 2 phase 1/2 clinical trials of advanced

myeloid malignancies (65 MF pts)

400 mg orally once daily in 2 phase 2 studies 35% reduction in spleen volume from baseline

37% in all evaluable patients

43% in patients with platelets 100,000/L

Most common AEs Diarrhea (grade 1, 43%; grade 2, 26%), time to onset ofdiarrhea was 30 days in the majority of those affected, but

only 2% had drug discontinuation as a consequence


JAK2 I hibi I T i l


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Momelotinib

o Oral JAK1/2 Inhibitor

Final data from the phase 1/2 core study and updated data from the

extension study presented at 2013 ASH annual meeting (120 MF pts)

Following a dose escalation phase, 150 mg or 300 mg once-daily, or

150 mg twice-daily for 9 months

Median time to onset of Spleen Response, 12-week transfusionindependence and median duration of anemia response were not yet

reached at time of reporting

Constitutional symptoms assessment at 3 months: 50% improvement

in 72%, 46%, 77%, 100%, and 74% of subjects with pruritus, cough,

bone pain, fever, and night sweats, respectively Most common AEs

Thrombocytopenia (29%), neutropenia (5%), and elevated lipase (4%)

without clinical pancreatitis, and peripheral neuropathy (38%)

Pardanani et al, 2013.


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PRM-151

o First in class antifibrosis agent

Agonist of monocyte/macrophagedifferentiation factor

Aimed at preventing or reversing fibrosis

Phase 2 clinical trial (NCT01981850) Multicenter, 2 stage, adaptive design

PRM-151 given as an infusion weekly

Every 4 weeks

Either alone or in combination with ruxolitinib is inpatients with PMF, post-PV MF, or post-ET MF

Orphan drug designation obtained 9/2/14ET, essential thrombocytopenia; MF, myelofibrosis; PMF, primary myelofibrosis; PV, polycythemia vera.

Mascarenhas J. Best Pract Res Clin Haematol. 2014;27(2):197-208.

Promedior Press Release, 2014.

Cliincaltrials.gov, 2014.

C S d 2


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Case Study 2

o 69-year-old woman with a long-standing history of essential

thrombocythemia

o Treatment History

Serum EPO level of 25started on erythropoietin

Initial improvement in anemia, then loss of response

Hydroxyurea dose counts Transfusions support for anemia

Patient declined allogeneic bone marrow transplant

o Patient now presents with progressive fatigue and progressive

cytopenias

WBC: 12,000/L Platelets 75 109/L Hgb 7.1 g/dL

Serum creatinine: 1.5

mg/dL (ULN 1.3)

LDH: 980 IU/L (ULN180)


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Case Study 2 (cont

d.)

o Bone marrow biopsy: Reticulin (MF-2/3)

and collagen Cellularity variable: 0%-60%

Clustered megakaryocytes, up to 10/hpf JAK2 negative

o Diagnosis: Postessential

thrombocythemia myelofibrosis


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Case Study 2 (cont

d.)

Given this information, which treatment

would be the best option for this patient?

1) Ruxolitinib 10 mg po bid

2) Proceed with evaluation for autologous bone

marrow transplant

3) Ruxolitinib 5 mg po bid

4) Continue hydroxyurea at an increased dose


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Summary

o Myelofibrosis is a debilitating myeloproliferative

neoplasm

o Dysregulation of the JAK-STAT pathway is

central to the pathophysiology of MPNs JAK-negative MF may respond to the currently

available JAK inhibitor, ruxolitinib

o Treatment of the underlying disease is the best

strategy to manage the symptom burdenassociated with MF


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MPN Advocacy and Education International is dedicated to providing the

knowledge, support, and resources patients will need as they adjust to

living with an MPN through educational symposia in several cities each

year, website access, free webcasts of each program, collateral materials,

and direction to people, resources and other organizations that can help.

MPN Advocacy and Education International visits cancer centers and

hematology groups and associations to grow awareness and engage

physicians in smaller communities who may only see one or two patients with

MPN, and who may not have the information available to them that their

colleagues in larger cities and academic institutions can access. MPNAdvocacy and Education International is dedicated to finding all portals to

reach the entire MPN community to grow awareness, understanding, and a

better quality of life while living with an MPN.

To learn more about MPN A&EI, visit www.mpnadvocacy.com.
http://www.mpnadvocacy.com/http://www.mpnadvocacy.com/


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