Overview of Myelofibrosis and Risk Stratification
An expert on myeloproliferative neoplasms gives an overview of myelofibrosis and assessing patient risk.
Case: A 68-Year-Old Woman with Myelofibrosis
- A 68-year-old woman presented to her physician with symptoms of mild fatigue, moderate night sweats, and abdominal pain/fullness lasting 4 months; she also reported increased bruising and unexplained weight loss
- Spleen was palpable 8 cm below the left costal margin
- Genetic testing shows a JAK2 V617F mutation; CALR negative; Karyotype: 46XX
- Bone marrow biopsy: megakaryocyte proliferation and atypia with evidence of reticulin fibrosis
- Blood smear reveals leukoerythroblastosis
- Diagnosis: Primary myelofibrosis
- Risk: DIPSS: Intermediate-2; MIPSS70: Intermediate risk
- Labs demonstrate:
- RBC 3.40 x 1012/L
- HGB 13.2 g/dL
- HCT 36%
- MCV 94 fL
- WBC 23.0 x 109/L
- PLT 450 x 109/L
- PB Blasts 1%
Transcript:
Abdulraheem Yacoub, MD: Myelofibrosis, as a myeloproliferative neoplasm, is defined and characterized by JAK-STAT activation. Myeloproliferative neoplasms—particularly myelofibrosis—are dependent on JAK-STAT activation in the pathogenesis and clinical features, including proliferation, constitutional symptoms, and risk of transformation to higher-risk myeloid neoplasms. JAK-STAT activation can be the result of an acquired somatic JAK2 mutation, an acquired MPL mutation, an acquired CALR [calreticulin] mutation, or other unknown mutations that continue to be discovered as we go on.
[Regardless of] the driver mutation, it will result in the downstream STAT activation and uncontrolled proliferation and constitutional symptoms. Although the common pathway of pathogenesis is the same in the majority of patients with myelofibrosis, patients present with different clinical vignettes or subtypes. Classically, we’ve recognized the proliferative vs the cytopenic myelofibrosis, especially as the treatment pathways have diverged for these clinical subtypes. Cytopenic myelofibrosis has recently been recognized, particularly in patients who present with a uniquely low white blood cell count, severe-to-moderate thrombocytopenia, and severe-to-moderate anemia, including transfusion requirements.
Most patients who are cytopenic meet many of those cytopenic features, and this relates to the pathogens of these diseases. Because those patients are often primary vs secondary myelofibrosis, they’re often JAK2 mutated or triple negative. And they often have higher-risk karyotype, higher-risk mutations, and generally worse prognosis and high-risk transformation. Cytopenic myelofibrosis has been recognized because it carries a worse clinical presentation, more restrictions to the standard therapies for myelofibrosis, and worse prognosis in general. We’re fortunate that we have dedicated therapeutic options available commercially for those patients. That’s why we try to recognize them early, so we can address their diseases differently and more effectively.
Because many oncologists are very familiar with the staging of cancers, we often [give] a solid tumor a stage so we can describe it to patients, prescribe therapy, and provide prognosis for patients. In myelofibrosis, we use a calculator for risk assessment to define the prognostic risk for those patients, which serves the same purposes. One is for providing prognostic information for our patients. A second is for choosing the appropriate therapy. And third is also for clinical trial enrollment, to better define inclusion and exclusion criteria for those studies.
Prognostic models have evolved over time, from simple clinical prognostic models to more sophisticated, integrated models that include clinical, cytogenetic, and molecular data. We often use multiple prognostic calculators in each patient to serve different purposes. For example, our patient has an advanced age, which by all prognostic models adds a relatively negative prognostic value to these patients. She has circulating blasts. On the other hand, she’s not anemic or thrombocytopenic, which is favorable. She has symptoms that seem to be adverse in all prognostic models. She has a favorable cytogenic and molecular profile. By integrating all these variables, she has an intermediate-2 prognostic risk on the clinical features and an intermediate risk on the molecular-inspired prognostic scores. These prognostic scores provide a relative estimate of life expectancy of under 5 years on a clinical prognostic model without therapy. Of course, with modern therapy, patients do much better than they did in historical reports.
This creates a different therapeutic approach to these patients. Patients with relatively higher-risk disease, such as this patient, will advance into a more immediate intervention path. They should be advancing into earlier evaluation for curative-intent therapy. This will put heightened clinical attention on immediate intervention rather than a watch-and-wait approach, where you would implement that in patients with relatively lower-risk disease. This is an integrated and very essential step in every new case of myelofibrosis as we make that diagnosis and provide staging and prognostic value for our patients. In addition, these are dynamic scores, meaning that as patients live longer with their disease, they can potentially be reassessed for their prognosis. At different time intervals, they probably will transform, or advance into a high-risk category. Then we have to adapt to their new score and treat them differently. This is a dynamic tool that we need to apply every time the patient has a disease event or worsening of their clinical features.
Transcript edited for clarity.
