Co-Chairs Srdan Verstovsek, MD, PhD, and Ruben A. Mesa, MD, FACP, prepared useful Practice Aids pertaining to myelofibrosis for this CME activity titled “Understanding the Clinical Spectrum of Myelofibrosis: Expert Perspectives on Molecular Biology, JAK Inhibitors, and Emerging Therapeutics.” For the full presentation, downloadable Practice Aids, and complete CME information, and to apply for credit, please visit us at https://bit.ly/3wzK6zG. CME credit will be available until October 9, 2022.

1. Pathophysiology and Primary Mutations in Myelofibrosis1
Pathophysiology Inflammation Inefficient hematopoiesis EMH
Clinical Manifestations Constitutional systems Cytopenia(s) and/or cytosis Splenomegaly
Complications Thromboembolism Infection Portal hypertension
!
Myeloproliferation
Neoangiogenesis
Stem Cell
Mobilization
Osteosclerosis
Fibrosis
Cytogenetic
Abnormalities
+8, -7/7q-, i(17q), -5/5q-,
12p-, inv(3),
11q23 rearrangement
!
!
! #)%"3'(.
CALR
CALR
Endoplasmic
reticulum
JAK2
515
exon 9
mutation
MPL
STAT
ON
exon 12
mutation
or
V617F
HSC
Other Genetic
Mutations
LNK, CBL, TET2, U2AF1,
ASXL1, IDH1, IDH2,
IKZF1, EZH2, DNMT3A,
TP53, SF3B1, SFSR2
Primary Myelofibrosis: Molecular Biology, Clinical Features,
Diagnosis, and Useful Resources
Full abbreviations, accreditation, and disclosure information available at PeerView.com/ZZW40

2. Clinical Manifestations in Patients With Myelofibrosis2
Splenomegaly
• Abdominal pain
• A feeling of early fullness
• Bloating
• High pressure in the liver vasculature
Impaired Blood Cell Production
• Thrombocytopenia
• Anemia
• Leukopenia
Constitutional Systems
• Fatigue, tiredness
• Night sweats
• Itching
• Bone pain
• Inactivity
• Concentration problems
• Fever
• Weight loss
Primary Myelofibrosis: Molecular Biology, Clinical Features,
Diagnosis, and Useful Resources
Full abbreviations, accreditation, and disclosure information available at PeerView.com/ZZW40

3. WHO Criteria for Diagnosis of Primary Myelofibrosis3
Major Criteria Minor Criteria
•
Proliferation and atypia of megakaryocytes
accompanied by either reticulin and/or collagen
fibrosis grades 2 or 3 on a scale of 0 to 3
•
Not meeting WHO criteria for ET, PV, BCR-
ABL1+ CML, MDS, or other myeloid neoplasm
• Presence of JAK2, CALR, or MPL mutation
or in the absence of these mutations, presence
of another clonal marker, or absence of
reactive MF
•
Anemia not attributed to a comorbid condition
•
Leukocytosis ≥11 × 109
/L
• Palpable splenomegaly
•
LDH increased to above upper normal limit of
institutional reference range
• Leukoerythroblastosis
Diagnosis requires meeting all three major criteria, and at least
two minor criteria confirmed in two consecutive determinations
Primary Myelofibrosis: Molecular Biology, Clinical Features,
Diagnosis, and Useful Resources
Full abbreviations, accreditation, and disclosure information available at PeerView.com/ZZW40

4. 1. Garmezy B. Blood Rev. 2020;100691. 2. Tefferi A. Am J Hematol. 2021;96:145-162. 3. Arber DA et al. Blood. 2016;127:2391-2324.
Resources for Your Patients With Myelofibrosis
The Leukemia Lymphoma Society
https://www.lls.org/patient-support
NCCN Guidelines for Patients®: Myeloproliferative Neoplasms
https://www.nccn.org/patients/guidelines/content/PDF/mpn-patient.pdf
MPN Education Foundation
https://mpninfo.org/
MPN Cancer Connection
https://mpncancerconnection.org/
National Cancer Institute
https://www.cancer.gov/types/myeloproliferative
MPN Research Foundation
https://www.mpnresearchfoundation.org/
Clinical Resources for Prognosis and Risk Stratification
DIPSS Plus Score for Prognosis in Myelofibrosis
https://qxmd.com/calculate/calculator_315/dipss-plus-score-for-prognosis-in-myelofibrosis
DIPSS (Dynamic International Prognostic Scoring System)
for Myelofibrosis
https://www.mdcalc.com/dipss-dynamic-international-prognostic-scoring-system-myelofibrosis
MIPSS70 score
http://www.mipss70score.it/
Estimating Prognosis in Myelofibrosis (MF)
https://www.mpnconnect.com/estimate-myelofibrosis-prognosis-tool.aspx
Primary Myelofibrosis: Molecular Biology, Clinical Features,
Diagnosis, and Useful Resources
Full abbreviations, accreditation, and disclosure information available at PeerView.com/ZZW40

5. Ruxolitinib1,2,a
FDA approval: November 16, 2011
Indication
•
Intermediate or high-risk myelofibrosis, including primary myelofibrosis,
post-polycythemia vera myelofibrosis, and post-essential
thrombocythemia myelofibrosis in adults
Dosing
Myelofibrosis
•
The starting dose is based on patient’s baseline platelet count:
–
200 × 109
/L: 20 mg orally twice daily
– 100 × 109
/L to 200 × 109
/L: 15 mg orally twice daily
–
50 × 109
/L to 100 × 109
/L: 5 mg orally twice daily
•
Monitor complete blood counts every 2 to 4 weeks until doses are
stabilized and then as clinically indicated. Modify or interrupt dosing
for thrombocytopenia
WARNING
• Thrombocytopenia, anemia, and neutropenia
• Risk of infection
• Symptom exacerbation following interruption or discontinuation
• Risk of non-melanoma skin cancer
• Lipid elevations
Adverse Events
•
Thrombocytopenia and anemia (incidence 20%)
• Bruising, dizziness, headache, and diarrhea (incidence ≥10%)
Fedratinib capsules3,4,b
FDA approval: August 16, 2019
Indication
•
Intermediate-2 or high-risk primary or secondary (post-polycythemia vera
or post-essential thrombocythemia) myelofibrosis in adults
Dosing
•
Recommended dosage: 400 mg orally once daily with or without food
for patients with a baseline platelet count of ≥50 × 109
/L
•
Reduce dose for patients taking strong CYP3A inhibitors or with severe
renal impairment
WARNING
• Anemia and thrombocytopenia
• Gastrointestinal toxicity
• Hepatic toxicity
• Amylase and lipase elevation
Adverse Events
•
The most common adverse reactions (≥20%) are diarrhea, nausea,
anemia, and vomiting
Currently Approved JAK Inhibitors for Myelofibrosis
BOXED WARNING: ENCEPHALOPATHY, INCLUDING WERNICKEb
Serious and fatal encephalopathy, including Wernicke, has occurred in
patients treated with fedratinib. Assess thiamine levels in all patients before
starting fedratinib, periodically during treatment and as clinically indicated.
Primary Myelofibrosis: Current and Emerging
Treatment Options
Full abbreviations, accreditation, and disclosure information available at PeerView.com/ZZW40
a
ONLY myelofibrosis-specific indications, doses, and adverse events are included here. See full prescribing information for complete list (https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202192Orig1s019Rpllbl.pdf).
b
See full prescribing information for complete information, including assessment and management of warning/boxed warning (https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212327s000lbl.pdf).

6. Selected Clinical Trials for Emerging JAK-Based Combinations for Myelofibrosis5
Primary Myelofibrosis: Current and Emerging
Treatment Options
Full abbreviations, accreditation, and disclosure information available at PeerView.com/ZZW40
NCT Number Phase Status
Study Title
Agent
(Therapeutic Target)
NCT02158858
Phase 1
Phase 2
Recruiting
Recruititng
Recruiting
Recruiting
A Phase 2 Study of CPI-0610 With and Without
Ruxolitinib in Patients With Myelofibrosis
CPI-0610 (small-molecule inhibitor of BET protein)
Ruxolitinib (JAKi)
NCT04603495 Phase 3
Study of CPI-0610 in Myelofibrosis (MF) (MANIFEST-2) CPI-0610 (small-molecule inhibitor of BET protein)
NCT03136185 Phase 2
Active,
not
recruiting
IMG-7289 in Patients With Myelofibrosis IMG-7289 (LSD1 inhibitor)
NCT04576156 Phase 3
A Study Comparing Imetelstat Versus Best Available
Therapy for the Treatment of Intermediate-2
or High-risk Myelofibrosis (MF) Who Have Not
Responded to Janus Kinase (JAK)-Inhibitor Treatment
Imetelstat (telomerase inhibitor )
NCT03069326 Phase 2
A Clinical Study to Test the Effects of Ruxolitinib and
Thalidomide Combination
for Patients With Myelofibrosis
Ruxolitinib (JAKi)
Thalidomide (IMiD)

7. Primary Myelofibrosis: Current and Emerging
Treatment Options
Full abbreviations, accreditation, and disclosure information available at PeerView.com/ZZW40
Selected Clinical Trials for Emerging JAK-Based Combinations for Myelofibrosis5
(Cont’d)
1. Jakafi (ruxolitinib) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202192Orig1s019Rpllbl.pdf. 2. https://www.drugs.com/newdrugs/fda-approves-jakafi-myelofibrosis-2949.html. 3. Inrebic (fedratinib) Prescribing
Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212327s000lbl.pdf. 4. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fedratinib-myelofibrosis#:~:text=On%20August%2016%2C%202019%2C%
20 the,thrombocythemia)%20myelofibrosis%20(MF). 5. https://clinicaltrials.gov/.
NCT Number Phase Status
Study Title
Agent
(Therapeutic Target)
NCT04097821
Phase 1
Phase 2
Recruiting
Recruititng
Recruiting
Recruiting
Platform Study of Novel Ruxolitinib Combinations
in Myelofibrosis Patients
Ruxolitinib (JAKi)
Siremadlin (p53-MDM2 inhibitor)
Crizanlizumab (anti–P-selectin antibody)
Sabatolimab (anti–TIM-3 antibody)
LTT462 (ERK1/2 inhibitor)
NIS793 (anti–TGF-β antibody)
NCT03878199
Phase 1
Phase 2
Testing the Effect of Taking Ruxolitinib and CPX-351
in Combination for the Treatment of Advanced Phase
Myeloproliferative Neoplasms
Ruxolitinib (JAKi)
CPX-351 (cytarabine and daunorubicin)
NCT04468984 Phase 3 Recruiting
Study of Oral Navitoclax Tablet in Combination With
Oral Ruxolitinib Tablet to Assess Change in Spleen
Volume in Adult Participants With Relapsed/Refractory
Myelofibrosis
Navitoclax (Bcl-2 inhibitor)
Ruxolitinib (JAKi)
NCT03222609 Phase 2
A Study Evaluating Tolerability and Efficacy
of Navitoclax Alone or in Combination With
Ruxolitinib in Participants With Myelofibrosis
Navitoclax (Bcl-2 inhibitor)
Ruxolitinib (JAKi)
NCT04472598 Phase 3
Study of Oral Navitoclax Tablet in Combination
With Oral Ruxolitinib Tablet When Compared With
Oral Ruxolitinib Tablet to Assess Change in Spleen
Volume in Adult Participants With Myelofibrosis
Navitoclax (Bcl-2 inhibitor)
Ruxolitinib (JAKi)