Myelofibrosis: Disease and treatment overview

Myelofibrosis (MF) is the most aggressive myeloproliferative neoplasm (MPN) disease subtype, characterized by abnormal megakaryocyte proliferation and bone marrow granulocytes.^1,2 MF can be divided into pre-fibrotic and fibrotic variants, each presenting at different stages of increased reticulin fibrosis, which ultimately progresses to collagen fibrosis and osteosclerosis.² The aggressive clinical nature of MF is linked to a propensity for transformation to acute myeloid leukemia (AML), which accounts for approximately 20% of deaths.³ Here, we provide a disease overview of MF.

Etiology

• Approximately 65% of patients harbor a mutation in Janus kinase 2 (JAK2), specifically the JAK2^V617F mutation³;
• a further 25% harbor a mutation in the calreticulin gene³; and
• around 10% of patients harbor a mutation in the myeloproliferative leukemia gene or are triple negative (negative for JAK, calreticulin, and myeloproliferative leukemia mutations).²

In a healthy individual, JAK2 is responsible for the activation of an intracellular signaling pathway involved in the control of cell proliferation, DNA damage repair, and cellular apoptosis.⁴ The presence of a mutation leads to loss of the normal inhibitory function of JAK2 and results in the constitutive activation of the JAK/signal transducer and activator of transcription and phosphatidylinositol 3-kinase/mitogen-activated protein kinase signaling pathways.⁴

Epidemiology

*Data from Gangat and Tefferi.²; McMullin and Anderson.⁵; Li, et al.⁶; Tremblay, Yacoub, and Hoffman.⁷

 Pathophysiology

• The main characteristic of MF is clonal proliferation of myeloid cells in the bone marrow.²
• Specifically, monoclonal increases in the myeloid, lymphoid, and erythroid lineages originating from a mutant clone with a stem cell origin (Figure 2).
• It has been proposed that clustering of megakaryocytes and altered expression of the adhesion molecule P-selectin stimulates the release of pro-fibrotic cytokines, such as transforming growth factor beta, platelet-derived growth factor, and fibroblast growth factor.⁸
• Increased cytokine levels, especially transforming growth factor-beta, increase the deposition of reticulin fibers, collagen types I, III, IV, and V, laminin, and glycoproteins; all of which are known to mediate fibrosis.⁸
• Transforming growth factor beta also decreases extracellular matrix degradation, which results in a reduction in the proteolysis of collagen and other extracellular matrix components.⁸
• The result is significant scar tissue buildup within the bone marrow and the development of severe anemia, neutropenia, and leukopenia.⁸

ASK1, Apoptosis signal-regulating kinase 1; CALR, calreticulin; DNMT3A, DNA methyltransferase 3 alpha; EZH2, enhancer of zeste homolog 2; GATA1, GATA-binding factor 1; IDH1/2, isocitrate dehydrogenases types 1 and 2; IL-18, interleukin 18; JAK, Janus kinase; LOX, lysyl oxidase; MMP, matrix metalloproteinase; PDGF, platelet derived growth factor; PI3K, phosphoinositide 3-kinase; NF-κB, nuclear factor kappa light chain enhancer of activated B cells; SRSF2, serine and arginine rich splicing factor 2; STAT, signal transducers and activators of transcription; TGF-β, transforming growth factor beta; TIMP, tissue inhibitor of metalloproteinases; U2AF1, U2 small nuclear RNA auxiliary factor 1;VEGF, vascular endothelial growth factor.
*Adapted from Gangat and Tefferi.²

 Signs and symptoms

*Adapted from Garmezy, et al. ⁸
Created with BioRender.com.

 Diagnosis

A review of a bone marrow biopsy is critical to the diagnosis of MF.⁹ A comprehensive histopathological report, together with a cytogenetic analysis, must also be completed to maximize the diagnostic information given by the biopsy.⁹

• Identifiable clinical features essential for diagnostic confirmation include,
  • patchy hematopoietic cellularity and reticular fibrosis;
  • possible megakaryocytes present in clusters and dysplasia;
  • distended marrow sinusoids; and
  • leukoerythroblastosis with teardrop poikilocytosis.⁹

The diagnosis of MF historically has been defined by the World Health Organization (WHO) classification of MPN; however, the most recent revision has resulted in a new scheme, the International Consensus Classification of MPN, with an emphasis on criteria refinement for easier distinction between subtypes (Figure 4).¹⁰

For a confirmed subtype diagnosis, a patient must meet all major criteria defined in the International Consensus Classification, or most of the major criteria together with a minor criterion. Diagnosis should attempt to distinguish MF from other closely related myeloid neoplasms.¹⁰

BCR::ABL1, breakpoint cluster region::Abelson murine leukemia viral oncogene homolog 1; BM, bone marrow; CALR, calreticulin; CML, chronic myeloid leukemia; ET, essential thrombocythemia; Hb, hemoglobin; ICC, International Consensus Classification; JAK, Janus kinase; LDH, lactate dehydrogenase; MDS, myelodysplastic syndrome; MF, myelofibrosis; MPL, myeloproliferative leukemia virus; PV, polycythemia vera; RBC, red blood cell; WBC, white blood cell.
*Adapted from Arber, et al.¹⁰

 Prognostic analysis for MF employs several risk stratification models³

The International Prognostic Scoring System:

• 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; and
  • presence of 0, 1, 2, and ≥3 adverse factors define low, intermediate-1, intermediate-2 and high-risk disease categories, respectively.

The Dynamic International Prognostic Scoring System:

• Uses the same variables as the International Prognostic Scoring System; however, two points instead of one are assigned to hemoglobin <10 g/dl.
• Risk categorization was modified to low (0 adverse points), intermediate-1 (1/2 points), intermediate-2 (3/4 points), and high (5/6 points).

The Dynamic International Prognostic Scoring System plus:

• Incorporates three additional risk factors:

• • Platelet count <100 × 10⁹/L, red cell transfusion needs, and unfavorable karyotype
  • Risk categorization is set as low (no risk factors), intermediate-1 (1 risk factor), intermediate-2 (2/3 risk factors), and high (≥4 risk factors)

Three further prognostic models were recently developed:

• Mutation-Enhanced International Prognostic Scoring System for transplant-age patients
• Karyotype-enhanced MIPSS70
• The genetically inspired prognostic scoring system

Newer models incorporate factors associated with driver mutations among others, karyotype, and sex-adjusted hemoglobin levels.

Management

Despite the aggressive clinical nature of MF, research surrounding the JAK/signal transducer and activator of transcription pathway has yielded positive results in the form of JAK inhibitor (JAKi) therapy (Figure 5).

• The first U.S. Food and Drug Administration (FDA) approved JAKi treatment was ruxolitinib, which inhibits JAK1/2 and is considered the standard of care for patients with symptomatic, intermediate, or high-risk disease; further analysis has shown clinical benefit in patients with symptomatic low-risk disease.⁸

• Fedratinib was the second approved JAKi, with clinically selective activity against JAK2, and was approved for use in patients with intermediate-2 and high-risk disease and in the second-line treatment setting for patients who have become refractory or intolerant to ruxolitinib.⁸
• The third JAKi approved was pacritinib, a multikinase inhibitor with clinical activity against JAK2, FLT3 (fms-like tyrosine kinase 3), IRAK1 (interleukin-1 receptor-associated kinase 1), and CSF1R (colony-stimulating factor 1 receptor); treatment is specifically used in thrombocytopenic patients with a platelet count <50 × 10⁹/L.¹¹
• Momelotinib is another JAKi with clinical activity against JAK1, JAK2, and activin A receptor type 1, used as a second-line therapeutic option for patients refractory or intolerant to ruxolitinib and treatment induced anemia; it was recently approved by the U.S. FDA in September 2023.¹²
• Newer approaches include the addition of navitoclax, a B-cell lymphoma 2 inhibitor, to ruxolitinib for patients who have developed resistance to other JAKi and are diagnosed with persistent or progressive MF.¹¹
• Pelabresib, a bromodomain and extraterminal domain inhibitor, both as a single agent and in combination with ruxolitinib is another option considered for both first-line and refractory settings in MF.¹¹
• Currently, the only form of therapy that has shown measurable disease modification and curative ability is allogeneic hematopoietic stem cell transplantation.¹¹

ACVR1, activin receptor type 1; BCL2, B-cell lymphoma 2; BET, bromodomain and extra-terminal; FLT3, FMS-like tyrosine kinase 3; JAK, Janus kinase.
*Adapted from Venugopal and Mascarenhas. ¹¹

•  Key complications associated with JAKi treatment include,
• • anemia;
  • neutropenia;
  • leukopenia; and
  • increased risk of infection.³

B-cell lymphoma 2 inhibitors, such as navitoclax, are associated with dose-dependent thrombocytopenia and neutropenia.¹² The hematologic adverse events of pelabresib include thrombocytopenia, anemia, and neutropenia.² Other common non-hematologic adverse events include diarrhea, nausea, and fatigue.²

Key Guidelines and organizations

• European LeukemiaNet
• Leukemia & Lymphoma Society
• World Health Organization
• MPN Research Foundation
• MPN Hub key updates to the 5th WHO Classification of MPN
• MPN Hub International Consensus Classification 2022