Definition

Myelofibrosis (MF) is a clonal proliferative disease of hematopoietic stem cells, leading to an inappropriate cytokines release, fibrosis of the bone marrow, constitutive mobilization of committed progenitor cells into the peripheral blood and extramedullary hematopoiesis. MF is the most symptomatic and has the worst prognosis among the Philadelphia-chromosome-negative chronic myeloproliferative neoplasms (MPNs).

This disease may present either as idiopathic (primary myelofibrosis, PMF) or as transformation of an antecedent polycythemia vera (PV) or essential thrombocythemia (ET). PV and ET are phenotypically overlapping with PMF and manifestations and therapeutic approaches are virtually the same in PMF and PV/ET.

Myleofibrosis is characterized by a progressive clinical course. Established prognostic factors including age, hemoglobin level, and white blood cell count have been used for risk assessment, but these characteristics do not fully explain the risk of death or major clinical events.

Morbidity and mortality of myelofibrosis are usually the result of leukemic transformation, spleno-portal hypertension, and infections, as well as thrombosis and hemorrhage.

Table 1 Poor Prognosis Factors – International Working Group-derived International Prognostic Scoring System (IPSS)

Poor Prognosis Risk Factors
1Age > 65 yrs
2Presence of constitutional Symptoms
3Anemia (Hemoglobin < 10 g/dL)
4Leukocytosis (White blood cell count > 25 x 103/mm3)
5Circulating blast cells of 1% or greater

The presence of the factors in the table above defines risk degree of myelofibrosis:

  • No risk factors – low-risk
  • One risk factor – intermediate-1-risk
  • Two risk factors – intermediate-2-risk
  • Three or more risk factors – high-risk

What must be paied attention is that this system (IPSS) is used for risk evaluating from time of diagnosis. There is another assessment criteria called Dynamic IPSS plus (DIPSS-Plus) which can be used for risk evaluating at any time during the disease course. The DIPSS-Plus has three additional independent risk factors including red cell transfusion need, platelet count < 100 × 109/L, and unfavorable karyotype. The unfavorable karyotype includes complex karyotype or sole or 2 abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23 rearrangement.

Note that leukocytosis can happen in patients after splenectomy due to “myeloproliferative” reaction and it does not necessarily imply disease progression.

Figure 1 The Dynamic International Prognostic Scoring System (DIPSS) plus prognostic model for primary myelofibrosis (PMF).

  • No risk factors – low risk
  • 1 risk factor – intermediate 1
  • 2 or 3 risk factors – intermediate 2
  • ≥ 3 risk factors – high

These four risk groups are with respective median survivals of 15.4, 6.5, 2.9, and 1.3 years. Leukemic transformation was predicted by the presence of unfavorable karyotype or platelet count < 100 × 109/L.

Clinical Manifestations

Symptomatic myelofibrosis can present with anemia, significant splenomegaly, aberrant production of proinflammatory cytokines (which causes constitutional symptoms such as weight loss, night sweats, fever of unknow origin), severe fatigue, cachexia, and pruritis.

These manifestations include anemia (either moderate or transfusion dependent), splenomegaly and/or hepatomegaly, the development of foci of nonhepatosplenic hematopoiesis, myeloproliferation manifesting with marked leukocytosis or thrombocytosis. and increased risk of thrombohemorrhagic complications, and a spectrum of debilitating constitutional symptoms.

Biology

JAK2V617F (Janus kinase 2 mutation V617F) mutation plays an important role in the pathogenesis of myelofibrosis. JAK2V617F has been identified in approxmiately 60% of patients with myelofibrosis (half of patients with PMF and post-ET myelofibrosis and in nearly all of those with a secondary form following a previous PV). Despite its crucial role in pathogenetic role, the clinical relevance of JAK2V617F in myelofibrosis is not completely understood. In a large retrospective survey showed that JAK2V617F mutation plays a significant and independent influence on the disease phenotype and showed that many clinical manifestations are correlated with the expansion of clonal hematopoietic cells harboring the JAK2V617F mutant allele.

Management of Myelofibrosis

The treatment of MF is guided by risk stratification and the patient’s clinical needs. As we mentioned before, the risk stratification are:

  • No risk factors – low risk
  • 1 risk factor – intermediate 1
  • 2 or 3 risk factors – intermediate 2
  • ≥ 3 risk factors – high

For low- or intermediate 1-risk disease, the respective median survival of patients exceeds 15 and 6 years and even longer for patients younger than age 65 years. Therefore, the risk of allo-SCT-associated mortality and morbidity is not justified in such patients, and it is also not prudent to subject them to investigational drug therapy, considering the limited information about long-term safety of new therapeutic agents. Similarly, there is no evidence to support the value of conventional drug therapy in asymptomatic patients with low- or intermediate 1-risk diseases. For this group of patients without symptoms, “watch and wait” is preferred.

For this group of patients with symptoms, they may occasionally experience splenomegaly, nonhepatosplenic extramedullary hematopoiesis, extramedullary hematopoiesis (EMH)-associated pulmonary hypertension, fatigue, bone (extremity) pain, pruritus, or thrombocytosis with a thrombosis history. Intermediate 1-risk patients might in addition display symptomatic anemia, marked leukocytosis, or constitutional symptoms such as drenching night sweats, fever, or weight loss (cachexia). If clinical needed, it is reasonable to start with conventional drug therapy.

However, if the patient is del(5q) present, lenalidomide is the recommended first-line therapy because significant improvement.

Figure 2 Risk-adapted therapy in primary myelofibrosis.

For patients with high- or intermediate 2-risk disease can be managed by conventional drug therapy, splenectomy, radiotherapy, allo-SCT, or experimental drug therapy. With each one of these treatment modalities except allo-SCT, the primary goal is palliation of anemia, symptomatic splenomegaly, constitutional symptoms, or disease complications from EMH (extramedullary hematopoiesis).

(more…)