All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit the MPN Advocates Network

The MPN Hub uses cookies on this website. They help us give you the best online experience. By continuing to use our website without changing your cookie settings, you agree to our use of cookies in accordance with our updated Cookie Policy

Review | Biology, diagnosis, and treatment of myelofibrosis up to date

Aug 5, 2020
Share:

Recently, the British Journal of Haematology published a review on myelofibrosis by Naseema Gangat and Ayalew Tefferi from Mayo Clinic, Rochester, US.1 This article summarizes the key aspects of biological pathogenesis, their recommendations on the current management of the disease, and new therapies in clinical development.

Classification1

According to the World Health Organization (WHO) in 2016, the disease broadly termed as myelofibrosis, and identified as one of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), can be further classified as

  • prefibrotic myelofibrosis
  • primary myelofibrosis (PMF) or overly fibrotic myelofibrosis
  • secondary myelofibrosis or cases transformed from polycythemia vera (PV) and essential thrombocytopenia (ET; post-PV/ET MF)

Disease biology and pathogenesis1

Like other Philadelphia-negative MPN, the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is constitutively activated in aberrant megakaryocytes by different mechanisms. The most frequently described mutations, reported alone or concomitant, in myelofibrosis are

  • JAK2 V617F mutation: ~ 60%
  • calreticulin (CALR) mutations: 23%
  • thrombopoietin (TPO) receptor, myeloproliferative leukemia virus (MPL) mutations: 7%
  • triple-negative status: 10%
  • All mutations either hinder the inhibition of JAK/STAT signaling or directly increase its activity. The hyperactivation of this proliferative pathway ultimately results in the uncontrolled activation of aberrant megakaryocytes, with release of pro-inflammatory cytokines and the subsequent increase of bone marrow fibrosis. In later stages of the disease, the bone marrow fibrosis progresses to collagen fibrosis and osteosclerosis. Find more specific information on genetic, epigenetic, and cell aberrations in Table 1.

Table 1. Mechanisms of disruption of JAK/STAT signaling and its consequences in aberrant megakaryocytes described in patients with myelofibrosis1 

 

CALR, calreticulin; HSC, hematopoietic stem cell; IDH, isocitrate dehydrogenase; IL, interleukin; IP, induced protein; JAK, Janus kinase; MMP, matrix metalloproteinase; MPL, myeloproliferative leukemia virus; mRNA, messenger RNA; PMF, primary myelofibrosis; PV, polycythemia vera; STAT, signal transducer and activator of transcription; TGF, transforming growth factor; TPO, thrombopoietin

Described driver mutations

JAK2 V617F mutation

  • Gain of function mutation, also described in over 90% of patients with PV

MPL mutations

  • MPLW515K/L described in 7% of patients with PMF, JAK2 wild type

CALR mutations

  • Majority of cases described in JAK2 or MPL wild type
  • Two variants: type 1, a 52-bp deletion (p.L367fs*46); type 2, a 5-bp TTGTC insertion (p.K385fs*47)
  • Mutated CALR binds and activates MPL, which at the same time activates the JAK/STAT pathway signaling
  • See further information on CALR here

Triple-negative

  • Subgroup represented by patients negative for all three mutations previously described
  • Activated JAK/STAT signaling through cytokine secretion of the microenvironment and activation of other downstream pathways, such as MAPK, PI3K/AKT, and NF-

Other cell aberrations

Mutated epigenetic regulators

  • Described in up to 81% of patients with PMF
  • Most frequent mutations observed alone or concomitantly:
  • ASXL1: 36%, also described as an adverse prognostic factor in PMF
  • TET2: 18%, with an increased thrombotic risk (more)
  • SRSF2: 18%
  • U2AF1: 16%
  • DNMT3A: 7%

Splicing factor mutations

  • Mutations have been described, but their role in pathogenesis is not yet fully elucidated
  • SRSF2: 18%, predictor of worse survival outcomes
  • U2AF1: 16%, with two variants:
  •  S34
  • U2AF1Q157, associated with anemia, thrombocytopenia, and shorter survival

GATA1 low expression

  • Transcription factor involved in megakaryocyte development and maturation
  • Deficiency observed irrespective of JAK2 V617F mutational status
  • Impaired mRNA translation of GATA1 mediated by the hyperactivation of the TPO/MPL axis

IDH mutations

  • Only described in 4% of PMF cases
  • Gain of function mutations associated with worse outcomes
  • When concomitant with JAK2 V617F, involvement in the progression to blast phase has been suggested

Megakaryocytic hyperplasia and resulting bone marrow fibrosis

  • Clustering of aberrant immature megakaryocytes
  • Pro-inflammatory cytokines release IL-8, IL-2R, IL-12, IL-15, and IP-10
  • Secretion of TGF-beta and MMP-9

Bone marrow microenvironment

  • Megakaryocytes can be found close to HSC niches, and pro-inflammatory cytokines influence their crosstalk
  • Aberrant megakaryocytes also contribute to the excess of extracellular matrix components, such as fibronectin, laminin, and collagen

Diagnosis and prognostic assessment1

Clinical characteristics and laboratory results at diagnosis

Clinical symptoms frequently observed at myelofibrosis diagnosis:

  • Palpable splenomegaly in 72% of patients
  • Constitutional symptoms in 29% of cases: fatigue, night sweats, weight loss, or cachexia
  • Symptomatic or transfusion-dependent anemia in 33% of patients
  • Pruritus
  • Thrombosis
  • Hemorrhage
  • Recurrent infections

Laboratory findings:

  • Leucoerythroblastic smear with dacrocytosis
  • Nucleated red cells
  • Leukocytosis ±
    • circulating blasts and thrombocytosis, or
    • thrombocytopenia with circulating megakaryocytes
  • Bone marrow sample could be challenging to obtain depending on the fibrotic stage
  • Presence of a driver mutation (JAK2, CALR, or MPL)

Disease prognosis

Several tools for myelofibrosis prognostic assessment have been developed, and the original publication reviews the evolution of the International Prognostic Scoring System (IPSS).1 This article will focus only on the current IPSSs recommended by the authors to identify patients with PMF for allogeneic transplant: the mutation and karyotype-enhanced IPSS for age ≤ 70 years (MIPSS70-plus version 2.0) and the genetically-inspired scoring system for all age groups (GIPSS)(Table 2).

Table 2. MIPSS70-plus version 2.0 and GIPSS1

CALR, calreticulin; GIPSS, genetically-inspired scoring system for all age groups; HMR, high molecular risk; MIPSS 70-Plus, mutation and karyotype-enhanced international prognostic scoring system for age ≤ 70 years; NR, not reached; OS, overall survival; p, points

* Very high risk karyotype includes single/multiple abnormalities of -7, inv(3)/3q21, i(17q), 12p-/12p11.2, or 11q-/11q23, single/multiple autosomal trisomies other than +9 and +8.

Unfavorable karyotype comprises of any abnormal karyotype other than normal karyotype or sole abnormalities of 20q-, 13q-, +9, chromosome 1 translocation/duplication, -Y, or sex chromosome abnormality other than -Y.

HMR mutations include ASXL1, EZH1, SRSF2, IDH1, IDH2, and U2AF1Q157.

MIPSS70-plus version 2.0 (online calculator)

Variables

Identified groups and survival outcomes

Severe (2 p) or moderate (1 p) anemia

0 p = very low risk; median OS, NR

Circulating blasts ≥ 2% (1 p)

1–2 p = low risk; median OS, 16.4 years

Constitutional symptoms (2 p)

3–4 p = intermediate risk; median OS, 7.7 years

Very high risk* (4 p) or unfavorable (3 p) cytogenetics

5–8 p = high risk; median OS, 4.1 years

≥ 2 HMR mutations (3 p)

One HMR mutation (2 p)

Type 1-like CALR absent (2 p)

≥ 9 p = very high risk; median OS, 1.8 years

GIPSS

Variables

Identified groups and survival outcomes

Very high risk (2 p) or unfavorable (1 p) cytogenetics

0 p = very low risk; median OS, 26.4 years

ASXL1 (1 p)

1 p = low risk; median OS, 8 years

SRSF2 (1 p)

2 p = high risk; median OS, 4.2 years

U2AF1Q157 (1 p)

≥ 3 p = very high risk; median OS, 2 years

Type 1-like CALR absent at any time (1 p)

 

 Following transplantation, other prognostic tools can be used to predict disease evolution, such as the recently developed myelofibrosis transplant scoring system (MTSS), which includes clinical and laboratory features to identify four different risk groups and their survival probability at 5 years since diagnosis. This model was developed with data from 361 patients with PMF and secondary myelofibrosis and validated in a cohort of 156 patients (Figure 1).2

Figure 1. Myelofibrosis transplant scoring system (MTSS) to predict outcome after allogeneic transplantation2

CALR, calreticulin; HLA, human leukocyte antigen; MPL, myeloproliferative leukemia virus; OS, overall survival

Additionally, there has been significant progress in formulating a model to predict myelofibrosis conversion from chronic to blast phase. This transformation is infrequent (1020% of patients), but it has a significant impact on survival. The Mayo Clinic recently published a predictive model for blast transformation and found that high-risk karyotype, platelet count, transfusion need, and age were independent predictors of survival after blast transformation. This model identifies high-, intermediate-, and low-risk of blast transformation subgroups with an incidence of 57%, 17%, and 8%, respectively.3

Clinical management

To date, treatment strategies do not distinguish between primary or secondary myelofibrosis and are mostly disease modifying, with the exception of allogeneic stem cell transplantation (allo-SCT), which is the only curative option. So far, however, allo-SCT has been reserved for patients < 70 years old, but this might change with the extended use of MIPSS70-plus helping to identify older patients who are eligible for transplant.

Transplantation, new therapies, and supportive care altogether improve the outcomes of patients with myelofibrosis, but the disease evolution is still very heterogeneous, and thus, median survival ranges from > 10 years to < 2 years.

Several drugs are currently available or in clinical development to palliate determinant symptoms or to slow disease progression. Patients that are asymptomatic and classified as very low or low risk are usually maintained under observation. Therapy is chosen for symptomatic patients according to the predominant symptom at the time of therapy initiation (Figure 2), which predominantly include

  • Symptomatic anemia: Usually managed with recurrent transfusions combined with erythropoietin stimulating agents, androgens (danazol), and immunomodulators (thalidomide or lenalidomide) with prednisone; however, myelofibrosis-related anemia is still an unmet need
  • Splenomegaly: Frequently palliated with hydroxyurea, and if intolerant or refractory, with the approved JAK2 inhibitors (ruxolitinib or fedratinib). When splenomegaly is refractory to drugs, the authors recommend splenectomy or splenic radiation
  • Constitutional symptoms: Effectively and rapidly controlled with ruxolitinib in most patients, although it is essential to consider the higher incidence of significant anemia (33%), thrombocytopenia (26%), opportunistic infections, and withdrawal symptoms (11%) under ruxolitinib therapy

Figure 2. Treatment approach of myelofibrosis according to prognostic risk group1

allo-SCT, allogeneic stem cell transplant; GIPSS, genetically-inspired scoring system for all age groups; MIPSS70-plus v2.0, mutation and karyotype enhanced international prognostic score system for age ≤ 70 years version 2.0; TE, transplant eligible; TNE, transplant non-eligible

The approval of JAK2 inhibitors for patients with myelofibrosis had a considerable impact on the management of disease (see the approval of ruxolitinib in 2011 and, more recently, fedratinib). However, patients still relapse after a median of 23 years on treatment, and outcome after relapse to ruxolitinib is poor. Table 3 summarizes the latest results of the most promising novel JAK2 inhibitors and other targeted therapies being investigated as alternatives, in combination, or as a subsequent treatment to ruxolitinib for patients with myelofibrosis. Find a recent review of these and other selected novel agents for myelofibrosis in clinical development, here.

Table 3. Novel targeted drugs in clinical development for patients with primary and secondary myelofibrosis1 

ACVR1, activin A type 1 receptor; AE, adverse event; ASH, American Society of Hematology; BCL-2, B-cell lymphoma 2; BET, bromodomain and extraterminal domain protein; CLS; capillary leak syndrome; EHA, European Hematology Association; FLT3, fms-like tyrosine kinase 3; IL-3, human interleukin-3; IRAK1, interleukin-1 receptor-associated kinase 1; JAK, Janus kinase; LSD, Lysine-specific demethylase; MF, myelofibrosis; PMF, primary myelofibrosis; TGF, transforming growth factor; TRAE, treatment-related adverse event

Novel JAK2 inhibitors

Momelotinib

  • Inhibitor of JAK1, JAK2, and ACVR1
  • Trials SIMPLIFY-1 and SIMPLIFY-2 demonstrated the continuous benefit of treatment with momelotinib after ≥ 3 years
  • Fast track designation in 2019 for patients with intermediate/high-risk MF who have previously received a JAK inhibitor
  • MOMENTUM, an ongoing trial in symptomatic anemic patients previously treated with ruxolitinib (NCT04173494)

Pacritinib

  • Inhibitor of JAK2, FLT3, IRAK1, and CSF1R
  • The initial studies, PERSIST-1 and PERSIST-2, which studied pacritinib vs best treatment available demonstrated a higher efficacy in symptom control, but could not confirm a survival benefit. In addition, frequent cardiac events were reported
  •  The phase II PAC203 trial identified pacritinib 200 mg twice daily as the best dose to treat patients intolerant or refractory to ruxolitinib (presented at ASH 2019 by Aaron Gerds)
  • Phase III trial PACIFICA (NCT03165734) is currently recruiting patients to compare the identified dose with the best available therapy in patients who cannot receive ruxolitinib

Other novel therapies for myelofibrosis

Metformin

  • Biguanide with antineoplastic activity
  • FIBROMET, ongoing phase II study to evaluate its effect on bone marrow fibrosis in patients with PMF (RBR-52ty66)
  • Preliminary results showed a trend in bone marrow collagen reduction after 3 and 6 months of treatment

Azacitidine

  • Demethylating agent
  • Ongoing phase II trial in combination with ruxolitinib (NCT01787487)
  • After the enrollment of 60 patients, ≥ 70% of patients achieved an objective response and a ≥ 50% spleen reduction

Bomedemstat (IMG-7289)

  • LSD1 inhibitor
  • Fast Track designation in August 2019
  • At EHA 2020, updated results of the ongoing phase II study (NCT03136185) in primary and secondary MF were presented4:
    • 78% demonstrated a reduction in spleen volume, 92% experienced an improvement in symptom scores, and 38% recorded a ≥ 50% reduction in total symptoms scores
    • 94% of patients experienced an AE, but only three serious events were considered related to bomedemstat

Luspatercept

  • Erythroid maturation agent that binds to TGF-ß enabling late-stage erythropoiesis
  • Phase II trial ongoing to study its efficacy in patients with MF-associated anemia (NCT03194542)
  • Last reported results indicate a benefit in patients with and without transfusion dependence, including those receiving concomitant ruxolitinib

Tagraxofusp

  • CD123-directed cytotoxin (IL-3 fused to truncated diphtheria toxin)
  • Ongoing phase I/II trial in relapsed/refractory MF (NCT02268253): the last update was presented at EHA 2020,5 and its clinical development will expand in poor-prognosis subsets of patients
    • 32 patients enrolled; 69% previously treated with a JAK inhibitor
    • Grade 3–4 TRAEs: Anemia (13%), thrombocytopenia (9%), and CLS (6%)
    • 56% showed some grade of spleen reduction; 46% improved symptom burden

CPI-0610

  • BET inhibitor
  • CPI-0610 is well tolerated and showed some clinical activity as a single agent, but a more promising synergistic efficacy is being investigated in combination with ruxolitinib
  • MANIFEST phase II trial is ongoing (NCT02158858), and latest follow-up results were presented at EHA 2020:
    • Find the study design and key results here
    • A subanalysis of the trial is summarized here

Navitoclax

  • Anti-apoptotic agent that binds to BCL2 family proteins
  • Phase II trial to study whether navitoclax + ruxolitinib can overcome resistance to JAK inhibition. Currently recruiting patients with suboptimal response to ruxolitinib (NCT03222609)
  • Latest update presented at EHA 20207:
    • Spleen volume reduction of ≥ 35% was achieved by 26.5% of patients at Week 24; 52.9% had resolved palpable splenomegaly
    • 65% of patients presented some grade of reduction from baseline in total symptoms score
    • Thrombocytopenia, anemia, and pneumonia were the most frequently reported Grade ≥ 3 treatment-emergent AEs

Conclusion

There have been remarkable advances made in the understanding of molecular and pathological processes involved in the development and progression of myelofibrosis. Ongoing research will help to elucidate those mechanisms further and identify future targets for the treatment of primary and secondary myelofibrosis and their disease-related complications.

With the prognostic models used at present, it is possible to stratify patients with myelofibrosis according to their risk of progression and the urgency of treatment initiation. Currently, physicians can offer a curative goal to transplant-eligible patients only, and additional studies are needed to explore early intervention with novel therapies and allo-SCT, especially in high-risk patients.

As the median age of diagnosis of myelofibrosis is 65 years, access to transplantation is limited for most newly-diagnosed patients. Transplant-ineligible patients are treated with symptom control and palliative measures. Due to the limited efficacy of current treatment options, clinical trial enrollment is recommended, particularly for patients with intermediate/high-risk myelofibrosis.


  1. Gangat N, Tefferi A. Myelofibrosis biology and contemporary management. Br J Haematol. 2020. Online ahead of print. DOI:1111/bjh.16576
  2. Gagelmann N, Ditschkowski M, Bogdanov R, et al. Comprehensive clinical-molecular transplant scoring system for myelofibrosis undergoing stem cell transplantation. Blood. 2019;133(20):2233-2242. DOI:1182/blood-2018-12-890889
  3. Vallapureddy RR, Mudireddy M, Penna D, et al. Leukemic transformation among 1306 patients with primary myelofibrosis: risk factors and development of a predictive model. Blood Cancer J. 2019;9(2):12. DOI:1038/s41408-019-0175-y
  4. Pettit K, Yacoub A, Gerds A, et al. A phase 2 study of bomedemstat (IMG-7289), a lysine-specific demethylase-1 (LSD1) inhibitor, for the treatment of later-stage myelofibrosis. Poster #EP1080. 25th EHA Annual Congress. Jun 12, 2020; Virtual.
  5. Pemmaraju N, Gupta V, Ali H, et al. Updated results from a phase 1/2 clinical trial of tagraxofusp, a CD123-targeted therapy, in patients with poor-risk myelofibrosis. Oral abstract #S219. 25th EHA Annual Congress. Jun 12, 2020; Virtual.
  6. Harrison C, Garcia JS, Mesa R, et al. Navitoclax in combination with ruxolitinib in patients with primary or secondary myelofibrosis: a phase II study. Poster #EP1081. 25th EHA Annual Congress. Jun 12, 2020; Virtual.

Share: