Pathogenesis and Clinical

Overview of Myelofibrosis
Chronic Myeloid Malignancies
o A 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.
WHO Classification
of Myeloproliferative Neoplasms
Classic MPN
o Chronic myelogenous
leukemia, BCR-ABL1
positive (CML)
o Polycythemia vera (PV)
o Primary myelofibrosis
(PMF)
o Essential
thrombocythemia (ET)
Nonclassic MPN
o Chronic neutrophilic
leukemia (CNL)
o Chronic eosinophilic
leukemia, not otherwise
specified (CEL-NOS)
o Mastocytosis
o Myeloproliferative
neoplasm, unclassifiable
(MPN-U)

Vardiman et al, 2009.
Myelofibrosis
o A myeloproliferative neoplasm
o Manifested by abnormal blood counts
Anemia
Thrombocytosis or thrombocytopenia
Leukocytosis or leukopenia
o Splenomegaly
o Debilitating symptoms
o The JAK-STAT signal transduction pathway
plays a critical role in the pathogenesis of MF
Tefferi, 2011.
Vardiman et al, 2009.
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.
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
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.
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 (Myeloproliferative
leukemia virus oncogene)
1p34
ET 3%
PMF 10%
Contributes to primarily megakaryocytic
myeloproliferation

Nonmutated JAK2, MPL, and CALR (Triple Negative) implies very
poor prognosis
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.
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
cell
Neutrophils
Basophils
Eosinophils
Monocytes/
macrophages
Platelets
Red blood
cells
J AK 1 AND J AK2
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 Hope www.buildingblocksofhope.com. Adapted with permission.
National Institutes of Health, 2013.
Myelofibrosis: Clinical Presentation
o Physical and Pathological
Findings:
Marrow fibrosis
Osteosclerosis
Angiogenesis
Progressive anemia
Extramedullary
hematopoiesis, 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

Cervantes et al, 2009.
Emmanuel et al, 2012.
The Symptom Burden of Myelofibrosis:
Cytopenias
o 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 is
considered 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.
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.
Dynamic International Prognostic Scoring
System + karyotype + platelet count+
transfusion status (DIPSS-plus)
Risk Factors
1.Red blood cell
transfusion needed
2.Hgb < 10 g/dL
3.Plt < 100 10
9
/L
4.Leukocyte count
>25 10
9
/L
1.Circulating blasts >1%
2.Constitutional symptoms
3.Unfavorable karyotype
4.Age >65 years
793 patients with PMF
Gangat et al, 2010.
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 Observation
Conventional 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.
Current Clinical Management
of Myelofibrosis
Known Causes of Death in a Series of
Consecutive PMF Cases at 7 Centers
Gupta et al, 2012.
Cervantes et al, 2009.
31%
18%
13%
11%
4%
4%
4%
13%
Leukemic
tranformation
PMF progression
Thrombosis/CV
Infections
Bleeding
Portal Hypertension
Second neoplasia
Other
Treatment of
Anemia
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
Androgens
EPO agent
Folate
Thalidomide
Lenalidomide
Limited effective treatment options
Focus on supportive care
Supportive Care
Transfusion support
Nutrition
Tumor lysis prophylaxis
Thromboembolism prophylaxis
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 U 3/wk in 20 patients; response in 9/20 (45%)
Prospective 10,000 U 3/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.
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<10.0 g/dL
o Abgrall (2006): Prospective phase 2
(N = 52)
400 mg/day; No significant
improvement in Hb levels or need
for RBC transfusion
15 of 26 (56%) discontinued by
month 4
o Marchetti (2004): Prospective phase 2
dose escalation (N = 63)
50 mg/day, increased to 400 mg/day
Anemia improved in 22%
Transfusions eliminated in 39% of
transfusion-dependent subjects
51% discontinued at 6 months
o Mesa (2003): Prospective phase 2
(N = 21)
50 mg/day; prednisone taper
Anemia improved in 13/21 (62%)
Improvement in 7/10 (70%) with
transfusion-dependency
o Thapaliya (2011): Pooled analysis
(N = 50)
50 mg/day + prednisone taper +
cyclophosphamide 25 mg/day x 3
mo. or etanercept 25 mg twice/week
Anemia improved in 22%


Gupta et al, 2012.
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
Anemia improved in 30%
o Mesa (2010): Prospective phase 2
(N = 48)
10 mg/day + prednisone taper
Anemia improved in 19%

Pomalidomide
o Tefferi (2009): Prospective phase 2
(N = 84)
0.5 or 2 mg/day prednisone taper
Anemia improved in 24%
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.
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 appetite
o 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
Untreated Patients: Assessment of Patient-
Reported Outcomes in Patients Randomized to
Placebo in the COMFORT-I Study
o 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 myelofibrosis
o Established the role of treatments to reduce symptom burden and
splenomegaly for patients with MF
Mesa et al, 2013.
The MPN Fatigue Project: Stage 1 Results
of the MPN Forum Internet-Based Survey
Among 879 MPN Patients
Emanuel et al, 2013.
Sexuality Age, language, diminished role functioning, insomnia, depression/sad
mood, 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.
Nursing Management of Common
Adverse Events
Myelosuppression 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
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 program
ESA, 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.
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 superficial
vein thrombosis
Disease or Treatment-Related
Factors
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, lenalidomide
o Erythropoietin use
Sullivan et al, 2013.
Cancer Panel Guideline Recommendations
for Outpatient Thromboprophylaxis
Patient
Population
ASCO NCCN ESMO
All
Outpatients
Routine prophylaxis not
recommended
Routine prophylaxis not
recommended
Routine prophylaxis not
recommended
Myeloma,
receiving
IMiD-based
regimens
Aspirin or LMWH for
low-risk and LMWH
for high-risk patients is
recommended
Aspirin for low-risk and
LMWH or warfarin for
high-risk patients is
recommended
Consider LMWH,
aspirin, or adjusted-dose
warfarin
(INR 1.5)
High-risk
outpatients
Consider LMWH
prophylaxis on a case-
by-case basis in highly
select outpatients with
solid tumors on
chemotherapy
Consider patient
conversation about risks
and benefits of
prophylaxis
in Khorana score 3
population
Consider in high-risk
ambulatory cancer
patients. Predictive
model 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.
Case Study 1
58-year-old man presenting to his PCP with extreme
fatigue 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 10
9
/L Hgb
11.5 g/dL
Massive
splenomegaly
(by exam)
Case Study 1 (contd.)
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: Massive
splenomegaly, hepatomegaly
Bone marrow biopsy confirms
PMF
ULN = upper limit of normal
Case Study 1 (contd.)
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

Allogeneic Stem Cell Transplantation
o Allogeneic stem cell transplant (allo-SCT) remains the only potential
cure 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
outcome
o 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.
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 MF
o Other JAK inhibitors are at various stages of
clinical development
Harrison et al, 2012, 2013.
Verstovsek et al, 2012.
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 in
MF-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


Verstovsek et al, 2013.
Cervantes et al, 2013.
COMFORT-I Mean Change in Symptom Scores
Verstovsek et al, 2012.
Ruxolitinib Dosing Considerations
o Dosing should be individualized based on platelet count
to maximize efficacy and minimize toxicities.
5 mg BID for platelet count 50-100 10
9
/L
10 mg BID for platelet count >100-150 10
9
/L and moderate or
severe renal impairment, any hepatic impairment or taking
strong CYP3A4 inhibitor
15 mg BID for platelet count 100-200 10
9
/L
20 mg BID for platelet count >200 10
9
/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.
Case Study 1 (contd.)
Given the patient profile:





What is the appropriate starting dose for ruxolitinib?
1. 20 mg bid
2. 10 mg bid
3. 15 mg bid
4. 5 mg bid

WBC: 75,000/L

Platelets: 680 10
9
/L

Hgb: 11.5 g/dL
Serum creatinine:
1.5 mg/dL (ULN 1.3)
LDH: 980 IU/L (ULN 180)

Case Study 1 (contd.)
o The patient was started on hydroxyurea
1 g bid
o Allopurinol was added at 300 mg qd
o Started on ruxolitinib 10 mg bid
o Allogeneic stem cell transplant was
discussed with the patient
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.
Drugs dont 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
Physician-Patient
Consultation
Informed Consent
Prescription Entered in
the EHR
Individualized
Patient/Caregiver Education
Provided by RN
Activates Prior Authorization
and Financial Assistance
Process
Patient notifies RN when Rx
filled
RN follow-up call within 1 week
of new Rx
Implementation of treatment-specific
standard of care for follow-up,
including toxicity checks and
reinforcement of learning
Reduction in Severity of
Adverse Events,
ED visits, Hospitalizations,
Discontinuation of Therapy
Improved patient satisfaction
Sample Oral
Therapy
Process
Emerging Therapies for the
Management of Myelofibrosis
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 JAK
family members are being explored

Tam and Verstovsek, 2013.
JAK2 Inhibitors: In Trials
Fedratinib and Lestaurtinib
Fedratinib (SAR302503 - formerly
TG101348)
JAK2/FLT3
Phase 3 JAKARTA 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/FLT3 phase 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.
JAK2 Inhibitors: In Trials
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 of
diarrhea was 30 days in the majority of those affected, but
only 2% had drug discontinuation as a consequence
Verstovsek et al, 2013.
JAK2 Inhibitors: In Trials
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 transfusion
independence 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.
PRM-151
o First in class antifibrosis agent
Agonist of monocyte/macrophage
differentiation 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 in
patients with PMF, post-PV MF, or post-ET MF
Orphan drug designation obtained 9/2/14
ET, 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.
Case Study 2
o 69-year-old woman with a long-standing history of essential
thrombocythemia
o Treatment History
Serum EPO level of 25 started 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 10
9
/L Hgb 7.1 g/dL
Serum creatinine: 1.5
mg/dL (ULN 1.3)
LDH: 980 IU/L (ULN 180)

Case Study 2 (contd.)
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

Case Study 2 (contd.)
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
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 burden
associated with MF

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. MPN
Advocacy 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.