Myeloproliferative neoplasms (MPNs) are characterized by clonal myeloproliferation in 1 or more of the hematopoietic stem cell lineages. Primary myelofibrosis (MF), post–polycythemia vera MF, and post–essential thrombocythemia MF have the worst prognosis and are characterized by the presence of cytokine-mediated symptom complex, splenomegaly, progressive marrow failure, and clonal instability, leading to leukemic transformation. The key therapeutic aims encompass the management of symptoms, splenomegaly, and anemia and the improvement of survivals. These therapeutic aims have evolved with the availability of Jak inhibitors and novel agents, making disease modification potentially achievable. Novel agents may potentially target MPN stem cells, epigenetic alterations, signaling pathways, and apoptotic pathways. In this case-based review, we outline our approach to the management of MF and discuss the therapeutic landscape of MF, highlighting the utility of Jak inhibitors and novel Jak inhibitor–based combinations.

1.
Pemmaraju
N
,
Verstovsek
S
,
Mesa
R
, et al.
Defining disease modification in myelofibrosis in the era of targeted therapy
.
Cancer
.
2022
;
128
(
13
):
2420
-
2432
.
doi:10.1002/cncr.34205.
Google Scholar
Crossref
Search ADS
PubMed
 
2.
Verstovsek
S
,
Gotlib
J
,
Mesa
RA
, et al.
Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses
.
J Hematol Oncol
.
2017
;
10
(
1
):
156
.
doi:10.1186/s13045-017-0527-7
.
Google Scholar
Crossref
Search ADS
PubMed
 
3.
Guglielmelli
P
,
Ghirardi
A
,
Carobbio
A
, et al.
Impact of ruxolitinib on survival of patients with myelofibrosis in the real world: update of the ERNEST study
.
Blood Adv
.
2022
;
6
(
2
):
373
-
375
.
doi:10.1182/bloodadvances.2021006006
.
Google Scholar
Crossref
Search ADS
PubMed
 
4.
Mascarenhas
J
,
Hoffman
R
,
Talpaz
M
, et al.
Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial
.
JAMA Oncol
.
2018
;
4
(
5
):
652
.
doi:10.1001/jamaoncol.2017.5818
.
Google Scholar
Crossref
Search ADS
PubMed
 
5.
Gerds
AT
,
Savona
MR
,
Scott
BL
, et al.
Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis
.
Blood Adv
.
2020
;
4
(
22
):
5825
-
5835
.
doi:10.1182/bloodadvances.2020003314
.
Google Scholar
Crossref
Search ADS
PubMed
 
6.
Maffioli
M
,
Mora
B
,
Ball
S
, et al.
A prognostic model to predict survival after 6 months of ruxolitinib in patients with myelofibrosis
.
Blood Adv
.
2022
;
6
(
6
):
1855
-
1864
.
doi:10.1182/bloodadvances.2021006889
.
Google Scholar
Crossref
Search ADS
PubMed
 
7.
Harrison
CN
,
Schaap
N
,
Vannucchi
AM
, et al.
Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: an updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure
.
Am J Hematol
.
2020
;
95
(
6
):
594
-
603
.
doi:10.1002/ajh.25777
.
Google Scholar
Crossref
Search ADS
PubMed
 
8.
Pardanani
A
,
Tefferi
A
,
Masszi
T
, et al.
Updated results of the placebo- controlled, phase III JAKARTA trial of fedratinib in patients with intermediate-2 or high-risk myelofibrosis
.
Br J Haematol
.
2021
;
195
(
2
):
244
-
248
.
doi:10.1111/bjh.17727
.
Google Scholar
Crossref
Search ADS
PubMed
 
9.
Harrison
CN
,
Schaap
N
,
Vannucchi
AM
, et al.
Fedratinib improves myelofibrosis- related symptoms and health-related quality of life in patients with myelofibrosis previously treated with ruxolitinib: patient-reported outcomes from the phase II JAKARTA2 trial
.
Hemasphere
.
2021
;
5
(
5
):
e562
.
doi:10.1097/HS9.0000000000000562
.
Google Scholar
Crossref
Search ADS
PubMed
 
10.
Tefferi
A
,
Pardanani
A
,
Gangat
N.
Momelotinib (JAK1/JAK2/ACVR1 inhibitor): mechanism of action, clinical trial reports, and therapeutic prospects beyond myelofibrosis [published online ahead of print 2 March 2023]
.
Haematologica
.
doi:10.3324/haematol.2022.282612
.
11.
Mesa
RA
,
Kiladjian
JJ
,
Catalano
JV
, et al.
SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in janus kinase inhibitor-naïve patients with myelofibrosis
.
J Clin Oncol
.
2017
;
35
(
34
):
3844
-
3850
.
doi:10.1200/JCO.2017.73.4418
.
Google Scholar
Crossref
Search ADS
PubMed
 
12.
Mesa
R
,
Harrison
C
,
Oh
ST
, et al.
Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis
.
Leukemia
.
2022
;
36
(
9
):
2261
-
2268
.
doi:10.1038/s41375-022-01637-7
.
Google Scholar
Crossref
Search ADS
PubMed
 
13.
Harrison
CN
,
Vannucchi
AM
,
Platzbecker
U
, et al.
Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial
.
Lancet Haematol
.
2018
;
5
(
2
):
e73
-
e81
.
doi:10.1016/S2352-3026(17)30237-5
.
Google Scholar
Crossref
Search ADS
PubMed
 
14.
Verstovsek
S
,
Gerds
AT
,
Vannucchi
AM
, et al;
MOMENTUM Study Investigators
.
Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study
.
Lancet
.
2023
;
401
(
10373
):
269
-
280
.
doi:10.1016/S0140-6736(22)02036-0
.
Google Scholar
Crossref
Search ADS
PubMed
 
15.
Kiladjian
JJ
,
Ianotto
JC
,
Soret
J
, et al.
Final results of ruxopeg, a phase 1/2 adaptive randomized trial of ruxolitinib (rux) and pegylated interferon alpha (IFNa) 2a in patients with myelofibrosis (MF)
.
Blood
.
2022
;
140
(
suppl 1
):
577
-
578
.
doi:10.1182/blood-2022-156389
.
Google Scholar
 
16.
Gill
H
,
Au
L
,
Yim
R
, et al.
Efficacy and safety of ropeginterferon alfa-2b for pre-fibrotic primary myelofibrosis and DIPSS low/intermediate-1 risk myelofibrosis
.
Blood
.
2022
;
140
(
suppl 1
):
1522
.
doi:10.1182/blood-2022-169613
.
Google Scholar
PubMed
 
17.
Mascarenhas
J
,
Komrokji
RS
,
Palandri
F
, et al.
Randomized, single-blind, multicenter phase II study of two doses of imetelstat in relapsed or refractory myelofibrosis
.
J Clin Oncol
.
2021
;
39
(
26
):
2881
-
2892
.
doi:10.1200/JCO.20.02864
.
Google Scholar
Crossref
Search ADS
PubMed
 
18.
Masarova
L
,
Verstovsek
S
,
Hidalgo-Lopez
JE
, et al.
A phase 2 study of ruxolitinib in combination with azacitidine in patients with myelofibrosis
.
Blood
.
2018
;
132
(
16
):
1664
-
1674
.
doi:10.1182/blood-2018-04-846626
.
Google Scholar
Crossref
Search ADS
PubMed
 
19.
Rampal
RK
,
Mascarenhas
JO
,
Kosiorek
HE
, et al.
Safety and efficacy of combined ruxolitinib and decitabine in accelerated and blast-phase myeloproliferative neoplasms
.
Blood Adv
.
2018
;
2
(
24
):
3572
-
3580
.
doi:10.1182/bloodadvances.2018019661
.
Google Scholar
Crossref
Search ADS
PubMed
 
20.
Kleppe
M
,
Koche
R
,
Zou
L
, et al.
Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms
.
Cancer Cell
.
2018
;
33
(
4
):
785
-
787
.
doi:10.1016/j.ccell.2017.11.009
.
Google Scholar
Crossref
Search ADS
PubMed
 
21.
Mascarenhas
J
,
Kremyanskaya
M
,
Patriarca
A
, et al.
MANIFEST: pelabresib in combination with ruxolitinib for janus kinase inhibitor treatment-naive myelofibrosis [published online ahead of print 7 March 2023]
.
J Clin Oncol
.
2023
:JCO2201972.
doi:10.1200/JCO.22.01972
.
22.
Harrison
C
,
Kremyanskaya
M
,
Bose
P
, et al.
Pelabresib (CPI-0610) as add-on to ruxolitinib in myelofibrosis: durability of response and safety beyond week 24 in the phase 2 MANIFEST study
.
Blood
.
2022
;
140
(
suppl 1
):
9659
-
9662
.
doi:10.1182/blood-2022-157735
.
Google Scholar
 
23.
Pettit
KM
,
Gill
H
,
Yacoub
A
, et al.
A phase 2 study of the LSD1 inhibitor bomedemstat (IMG-7289) for the treatment of advanced myelofibrosis (MF): updated results and genomic analyses
.
Blood
.
2022
;
140
(
suppl 1
):
9717
-
9720
.
doi:10.1182/blood-2022-167122
.
Google Scholar
 
24.
Harrison
CN
,
Garcia
JS
,
Somervaille
TCP
, et al.
Addition of navitoclax to ongoing ruxolitinib therapy for patients with myelofibrosis with progression or suboptimal response: phase II safety and efficacy
.
J Clin Oncol
.
2022
;
40
(
15
):
1671
-
1680
.
doi:10.1200/JCO.21.02188
.
Google Scholar
Crossref
Search ADS
PubMed
 
25.
Passamonti
F
,
Foran
J
,
Tandra
A
, et al.
S197: navitoclax plus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis: preliminary safety and efficacy in a multicenter, open-label phase 2 study
.
HemaSphere
.
2022
;
6
(
June
):
98
-
99
.
doi:10.1097/01.HS9.0000843680.94912.c5
.
Google Scholar
 
26.
Marcellino
BK
,
Farnoud
N
,
Cassinat
B
, et al.
Transient expansion of TP53 mutated clones in polycythemia vera patients treated with idasanutlin
.
Blood Adv
.
2020
;
4
(
22
):
5735
-
5744
.
doi:10.1182/bloodadvances.2020002379
.
Google Scholar
Crossref
Search ADS
PubMed
 
27.
Vachani
P
,
Lange
A
,
Delgado
RG
, et al.
Potential disease-modifying activity of navtemadlin (KRT-232), a first-in-class MDM2 inhibitor, correlates with clinical benefits in relapsed/refractory myelofibrosis (MF)
.
Blood
.
2021
;
138
(
suppl 1
):
3581
.
doi:10.1182/blood-2021-147543
.
Google Scholar
 
28.
Yan
D
,
Pomicter
AD
,
Tantravahi
S
, et al.
Nuclear-cytoplasmic transport is a therapeutic target in myelofibrosis
.
Clin Cancer Res
.
2019
;
25
(
7
):
2323
-
2335
.
doi:10.1158/1078-0432.CCR-18-0959
.
Google Scholar
Crossref
Search ADS
PubMed
 
29.
Ali
H
,
Kishtagari
A
,
Maher
KR
, et al.
Selinexor (SEL) plus ruxolitinib (RUX) in JAK inhibitor (JAKi) treatment-naïve patients with myelofibrosis: updated results from XPORT-MF-034
.
J Clin Oncol
.
2023
;
41
(
suppl 16
):
7063
. 10.1200/JCO.2023.41.16_suppl.7063.
Google Scholar
 
30.
Mesa
RA
,
Barosi
G
,
Harrison
CN
, et al.
A phase 2, multicenter, open-label study of the safety and efficacy of luspatercept in subjects with myeloproliferative neoplasm (MPN)-associated myelofibrosis and anemia with or without RBC transfusion dependence
.
J Clin Oncol
.
2018
;
36
(
suppl 15
):
TPS7083
.
doi:10.1200/JCO.2018.36.15_suppl.TPS7083
.
Google Scholar
 
31.
Gerds
AT
,
Harrison
C
,
Kiladjian
JJ
, et al.
Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis: results from the ACE-536-MF-001 study
.
J Clin Oncol
.
2023
;
41
(
suppl 16
):
7016
.
doi:10.1200/JCO.2023.41.16_suppl.7016
.
Google Scholar
 
32.
Zhang
Y
,
Zhou
H
,
Jiang
Z
, et al.
Safety and efficacy of jaktinib in the treatment of Janus kinase inhibitor-naïve patients with myelofibrosis: results of a phase II trial
.
Am J Hematol
.
2022
;
97
(
12
):
1510
-
1519
.
doi:10.1002/ajh.26709
.
Google Scholar
Crossref
Search ADS
PubMed
 
33.
Harrison
CN
,
Garcia
JS
,
Somervaille
TCP
, et al.
Addition of navitoclax to ongoing ruxolitinib therapy for patients with myelofibrosis with progression or suboptimal response: phase II safety and efficacy
.
J Clin Oncol
.
2022
;
40
(
15
):
1671
-
1680
.
doi:10.1200/JCO.21.02188
.
Google Scholar
Crossref
Search ADS
PubMed
 
34.
Passamonti
F
,
Foran
JM
,
Tandra
A
, et al.
Navitoclax plus ruxolitinib in JAK inhibitor-naive patients with myelofibrosis: preliminary safety and efficacy in a multicenter, open-label phase 2 study
.
J Clin Oncol
.
2022
;
40
(
suppl 16
):
7015
.
doi:10.1200/jco.2022.40.16_suppl.7015
.
Google Scholar
 
35.
Passamonti
F
,
Foran
JM
,
Tandra
A
, et al.
The combination of navitoclax and ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis mediates responses suggestive of disease modification
.
Blood
.
2022
;
140
(
suppl 1
):
583
-
585
.
doi:10.1182/blood-2022-157949
.
Google Scholar
 
36.
Pemmaraju
N
,
Garcia
JS
,
Potluri
J
, et al.
Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study
.
Lancet Haematol
.
2022
;
9
(
6
):
e434
-
e444
.
doi:10.1016/S2352-3026(22)00116-8
.
Google Scholar
Crossref
Search ADS
PubMed
 
Copyright © 2023 by The American Society of Hematology
2023
You do not currently have access to this content.