MF is part of a group of diseases called myeloproliferative neoplasms (MPN), and it is classified as BCR-ABL Philadelphia chromosome negative (Ph-) and characterized by abnormal blood cells which usually harbor mutations that affect the JAK signaling pathway.^7,8

• The JAK2 mutation, JAK2-V617F, is the best characterized mutation seen in these disorders with a prevalence of 40–50% in primary MF.⁷

MPNs are serious and rare bone marrow disorders disrupting the normal production of blood cells.^7,8

• While MF is the least common MPN it is the most aggressive.
• MF is associated with bone marrow fibrosis, characterized by increased deposition of reticulin fibers and in some cases collagen fibers, caused by megakaryocyte-induced overproduction of cytokines.

In MF, megakaryocyte dysplasia/hyperplasia results in the release of inflammatory cytokines that, in turn, stimulate stromal cells and induce bone marrow fibrosis.^7,9

• Aberrant megakaryocytes produce excessive pro-fibrotic growth factors, resulting in bone marrow fibrosis and impaired hematopoiesis.

Pathogenesis of fibrosis: constitutive activation of JAK-STAT pathway in the MPN stem cell cohort leads to cytokine independent growth of megakaryocytes. Emperipolesis of neutrophils occurs that leads to release of TGF-β, PDGF and bFGF from alpha granules present in megakaryocytes. These cytokines cause fibrosis and angiogenesis and also lead to osteosclerosis by causing the stromal cells to release osteoprotegerin.⁷

MPNs, including MF, frequently have an activating mutation in the gene encoding Janus kinase 2 (JAK2).^7,10,11

• The exact etiology of MF is unknown and there are no known risk factors for the disease, although overactive Janus-associated kinase (JAK) pathway signaling is present in all patients.
• Somatic mutations in MF are classified into "driver" and "other" mutations; the former include JAK2 (~65%), CALR (~25%), and MPL (~10%) and the latter ASXL1, SRSF2, and U2AF1, among others.¹¹
• A minority of patients do not have any of the 3 main "driver mutations" and are referred to as Triple Negative disease (10-15%).¹¹
• The pathogenesis of MPNs is poorly understood and even though mutations in JAK2, MPL, and CALR are seen and can lead to constitutive action of the JAK-STAT pathway, it has not been elucidated how these mutations can cause different clinical phenotypes.⁷

About 85% of cases of MF are primary MF (PMF), with the remaining 15% developing from another myeloproliferative disease (i.e. secondary MF, post-ET MF, post-PV MF).^8,12

• Patients with polycythemia vera have about a 10-15% risk of progressing to MF, while essential thrombocythemia (ET) patients have a <4% risk.^13,14

PMF develops spontaneously and is further sub-classified as "overtly fibrotic" or "prefibrotic" based on the degree or presence of bone marrow fibrosis.⁸

• Prefibrotic/early PMF was added in order to distinguish de novo, but not yet fibrotic PMF from essential thrombocythemia, thus allowing for more tailored treatment decisions.⁸

PMF carries the worst prognosis among the MPNs.^7,11,15

• PMF presents with anemia/cytopenias, (hepato)splenomegaly (enlarged spleen and/or liver), and constitutional symptoms, composed of common symptoms of inflammation caused by the overproduction of cytokines such as fatigue, night sweats, fever, bone pain, pruritus, and thrombosis.

• PMF is associated with a median survival of 6.5 years.
• Extramedullary hematopoiesis is seen not only in the liver and spleen but also in the lymph nodes, serosal surfaces, urogenital system and epidural and paraspinal spaces.
• Bone marrow histology shows fibrosis, angiogenesis and osteosclerosis.
• Advanced reticulin or collagen fibrosis is associated with classic stages of PMF, but a diagnosis of MF can be established without obvious fibrosis (prefibrotic/early PMF).
• Bone marrow fibrosis is the most important feature causing increased morbidity and mortality in these patients.

Contemporary prognostic modeling in PMF started with the development of the International Prognostic Scoring System (IPSS) in 2009^.11

• The IPSS for PMF was designed for use at time of initial diagnosis and applies five independent predictors of inferior survival: age > 65 years, hemoglobin <10 g/dL, leukocyte count >25 × 109/L, circulating blasts ≥1% and presence of constitutional symptoms.
• The presence of 0, 1, 2 and ≥3 adverse factors defined low, intermediate-1, intermediate-2 and high risk disease; the corresponding median survivals were reported at 11.3, 7.9, 4 and 2.3 years.

The IWG-MRT subsequently developed a dynamic prognostic model (DIPSS) that utilizes the same prognostic variables used in IPSS but can be applied at any time during the disease course.¹¹

• DIPSS assigned two, instead of one, adverse points for hemoglobin <10 g/dL and risk categorization was accordingly modified: low (0 adverse points), intermediate-1 (1 or 2 points), intermediate-2 (3 or 4 points) and high (5 or 6 points).
• The corresponding median survivals were not reached, 14.2, 4 and 1.5 years.

The DIPSS model continued to evolve with the incorporation of three additional DIPSS-independent risk factors (platelet count <100 × 10⁹/L, red cell transfusion need, and unfavorable karyotype), which is called DIPSS-plus(+).¹¹

• The four DIPSS-plus risk categories are low (no risk factors), intermediate-1 (one risk factor), intermediate-2 (two or three risk factors) and high (four or more risk factors) with median survivals of 15.4, 6.5, 2.9, and 1.3 years, respectively.

Most recently, mutations have also been considered in some prognostic models, including the MIPSS70 (mutation-enhanced international prognostic scoring system for transplant-age patients).¹¹

• MIPSS70+ version 2.0 (the karyotype-enhanced MIPSS70) incorporates mutations, karyotype, and clinical variables.

Disease prognostication in PMF is critical to allow for the identification of patients in whom the risk associated with allogeneic stem cell transplantation or participation in new drug trials may be justified.¹⁶

• For example, the need for stem cell transplantation may be more urgent if the patient is high-risk for leukemic transformation.¹⁶
• Alternatively, in patients at lower risk for leukemic transformation, it is reasonable to pursue investigational drug therapy that targets specific disease complications, such as anemia or splenomegaly.¹⁶

Myelofibrosis treatment is often at least partially based on risk stratification.^11,16

• For example, there is little evidence to support the treatment of asymptomatic patients with "low" or "very low" risk disease.¹¹
• Allogeneic stem cell transplant (ASCT) is the preferred treatment of choice for "high" or "very high" risk disease; clinical trial participation is the most appropriate alternative in nontransplant candidates.¹¹
• Symptom-directed conventional therapy is reasonable to consider in standard- or intermediate-risk disease and in higher risk patients that are not eligible for either ASCT or investigational drug therapy.¹¹

The International Prognostic Scoring System (IPSS), DIPSS, and DIPSS-Plus are the 3 most common prognostic scoring systems used for MF risk stratification^3,17,18

(Adapted from Ishida S, et al. Oncotarget 2018. 9. 10.18632/oncotarget.25515)

JAK-STAT signaling drives proliferation and stimulates expression of pro-survival BCL-family proteins (BCL-X_L and MCL-1).¹⁹

• Therefore, overactive JAK/STAT signaling leads to BCL-X_L overexpression.
• BCL-X_L elevation has been associated with resistance to JAK2 inhibitors.

Inhibiting the JAK2 signaling network at two nodal points, both the initiating stage (JAK2) and the effector stage (BCL-X_L/BCL-2) may reduce tumor burden while minimizing resistance.^19-22

• BCL-X_L/BCL-2 inhibition has shown the ability to overcome JAK2i- resistance.²⁰
• Conversely, aberrant JAK2-STAT signaling has been linked to over-expression of MCL-1, a well-known BCL-X_L/BCL-2 inhibitor resistance factor.¹⁹
• JAK2 inhibitors have been shown to reduce MCL-1 expression.¹⁹

Preclinical hematologic cancer models have shown combined targeting of JAK2 and BCL-2/BCL-X_L may circumvent and overcome acquired resistance to single-agent JAK2 inhibitor treatment.^19-22