Phenotypes have revealed
another layer of heterogeneity in MF.1,2
Beyond recognizing the mutations that underscore the differences between primary and secondary myelofibrosis (MF), research has shown what else can be discovered about these patients at the phenotypic level (based on several factors, including peripheral blood cell counts).
Phenotypes have revealed
another layer of heterogeneity in MF.1,2
Beyond recognizing the mutations that underscore the differences between primary and secondary myelofibrosis (MF), research has shown what else can be discovered about these patients at the phenotypic level (based on several factors, including peripheral blood cell counts).
Explore phenotypes in MF by focusing on cytopenias.
Patients with primary MF may have 3 or more somatic mutations that can lead to an increase in the frequency and severity of cytopenias.1,3 Although these cytopenias have been shown to be characteristics of primary MF, these patients may also exhibit other clinical manifestations, such as constitutional symptoms (eg, fatigue, pruritus, and night sweats) and splenomegaly.2
Whereas patients with secondary MF more often showcase characteristics from the noncytopenic phenotype, the majority of patients with primary MF often display more attributes of the cytopenic phenotype.2 In patients with primary MF, data suggest that cytopenias may be disease-related, treatment-related, or both.1,2,4 Patients who display the cytopenic phenotype have also been shown to have a worse prognosis.2
As previously discussed, epigenetic mutations may drive disease initiation and progression, while splicing mutations may amplify cytopenias.1 If these mutations are present, your patient may display more attributes that are closer to the cytopenic phenotype.2
Understanding phenotypes can help further classify patients.2
Within these phenotypes, certain characteristics may overlap or change over time, such as the need for transfusions. Thinking of how these characteristics change in each patient can help more specifically inform prognostication and disease management for each patient. Disease progression can often be determined by identifying the rate of phenotypic change over time, which can include the development of cytopenias.
Noncytopenic
Phenotype
(typically associated with
secondary MF)
Intermittent transfusions or transfusion independent
Hypercellular bone marrow
1 somatic mutation1
Cytopenic
Phenotype
(typically associated with
primary MF)
Heavy transfusion burden or transfusion dependent
More fibrotic bone marrow
3 or more somatic mutations1
Cytopenias are an ever-changing challenge.
A main discerning feature between MF phenotypes is peripheral blood cell counts. The noncytopenic phenotype usually exhibits elevated/normal white blood cells and/or platelets, whereas the cytopenic phenotype often mimics a bone marrow failure state and may result in ineffective hematopoiesis.2
In these patients, anemia and thrombocytopenia are common clinical challenges in managing MF.7 These cytopenias are often present at diagnosis and generally increase over time, which further showcases the continued need for monitoring.8-10
In a study measuring anemia and RBC transfusion requirements8*:
‡Based on 807 physicians from 12 countries (60% EU, 25% US, 15% ex-US/EU) who completed surveys, 54% from academic centers and 46% from community-based centers. There were approximately 18,000 patients with MF in the US and 24,000 in the EU.10
As thrombocytopenia and anemia worsened, overall survival (OS) was reduced significantly.9,11
In a retrospective cohort analysis, patients with thrombocytopenia (platelet counts <100 x 109/L) had significantly worse survival than those with normal platelet counts—with a 1.7-fold increased risk of death (26 vs 57 months, P<0.001, HR 1.7 [95% CI 1.37-2]). Among those with even lower platelet counts (<50 x 109/L), patients had a 2x higher incidence of AML (6.9 vs 3.4 cases per 100 person-years), were more anemic and transfusion dependent, and had a higher blast count and unfavorable karyotype compared to patients with platelet counts >100 x 109/L.9
Median OS was 26 months in patients with platelet counts
<100 x 109/L (P<0.001).9
AML=acute myeloid leukemia; mo=months; plt=platelet counts.
Both anemia and RBC transfusion dependence have also been shown to be predictive of shortened survival.11,12
Anemia and thrombocytopenia are independent prognostic risk factors that often occur together.13-15 In one particular study, severe anemia or transfusion-dependence was associated with a more than 1.5-fold increase in risk of death compared to moderate anemia.11 Another study suggests the effect of RBC transfusion-dependency on OS may be due to a deep erythropoietic defect associated with primary MF.12
OS stratified by degree
of anemia11
No anemia defined as Hgb 13.5–17.5 g/dL for men and 12.0–15.5 g/dL for women. Mild anemia defined as Hgb ≥10 g/dL but below sex-adjusted lower limit of normal. Moderate anemia defined as Hgb 8 g/dL to <10 g/dL. Severe anemia defined as Hgb <8 g/dL or transfusion-dependent.11
OS according to RBC
transfusion-dependency12
Transfusion dependent defined as an average transfusion volume of two units of RBC/month.12
Cytopenias are changing
perspectives on survival.
Hear insights from MPN specialist Aaron Gerds, MD, as he discusses the potential impact of cytopenias on disease progression and overall survival—and the challenges that may occur when managing patients with lower platelet counts.
MPN=myeloproliferative neoplasm.
The heterogeneous nature of MF requires a deeper look beyond any one pathway.2
Researchers continue to explore the heterogeneity of MF and the different phenotypes within the disease that may extend beyond the JAK-STAT pathway. These findings could evolve the management for patients with this challenging disease.
For example, the poor prognosis associated with cytopenic MF can be partly characterized by having triple-negative disease or low JAK2V617F allele burden, suggesting that the disease may be driven by complementary JAK-independent mechanisms.
Recent research has shown that pathways beyond JAK-STAT are likely playing a role in the inflammatory pathophysiology of primary MF, which may affect how this disease is managed.7,16
Asking important questions that change
perspectives on MF.
Get more personal insight from Aaron Gerds, MD, as he discusses the impact of interrelated cytopenias, the need to consider various mutations and pathways, and the value of monitoring platelet counts over time.
Explore his story at InsideMF.com
- 1. Vainchenker W and Kralovics R. Blood. 2017;129(6):667-679.
- 2. Marcellino BK, et al. Clin Lymphoma Myeloma Leuk. 2020;20(7):415-421.
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- 15. Modified from Hernandez-Boluda JC, et al. Brit J Haem. 2018;181:397-399.
- 16. Singer JW, et al. Oncotarget. 2018;9(70):33416-33439.