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

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 

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

 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 (10–20% 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 2–3 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 

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.