Prognostication in MF: From CBC to cytogenetics to molecular markers

Best Practice & Research Clinical Haematology 27 (2014) 155e164

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Prognostication in MF: From CBC to cytogenetics to molecular markers Amy Zhou, M.D, Fellow a, 1, Stephen T. Oh, M.D, Ph.D, Assistant Professor of Medicine b, * a

Washington University School of Medicine, Division of Hematology, 660 S. Euclid Ave, Campus Box 8056, St. Louis, MO 63110, USA Washington University School of Medicine, Division of Hematology, 660 S. Euclid Ave, Campus Box 8125, St. Louis, MO 63110, USA

b

Keywords: myelofibrosis prognosis survival

Myelofibrosis (MF) is a clonal stem cell disorder characterized by ineffective erythropoiesis and extramedullary hematopoiesis leading to progressive bone marrow failure, severe anemia, constitutional symptoms, hepatosplenomegaly, and thrombosis. MF can arise following a history of polycythemia vera (PV) or essential thrombocythemia (ET), or can present de novo as primary myelofibrosis (PMF). The disease course is variable with median survival ranging from months to years. Clinical and biological features such as advanced age, leukocytosis, anemia, transfusion dependence, and elevated inflammatory markers can impact prognosis in patients with PMF. Cytogenetic abnormalities and molecular markers such as JAK2 V617F, ASXL1, and CALR mutations have also been identified as prognostic variables. Several different scoring systems have been developed based on these prognostic factors. In this review, we will discuss the clinical, biological, molecular, and cytogenetic prognostic factors that have been identified in PMF, and the current prognostic models that have been developed to guide treatment decisions. © 2014 Elsevier Ltd. All rights reserved.

Introduction Myelofibrosis (MF) is a clonal stem cell disorder classified within the category of BCR/ABLnegative myeloproliferative neoplasms (MPNs) that includes polycythemia vera (PV) and essential * Corresponding author. Tel.: þ1 314 362 8846; Fax: þ1 314 362 8826. E-mail addresses: [email protected] (A. Zhou), [email protected] (S.T. Oh). 1 Tel.: þ1 314 508 2634; Fax: þ1 314 362 7086.

http://dx.doi.org/10.1016/j.beha.2014.07.008 1521-6926/© 2014 Elsevier Ltd. All rights reserved.

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thrombocythemia (ET) [1]. It is characterized by ineffective erythropoiesis and extramedullary hematopoiesis leading to progressive bone marrow failure, severe anemia, constitutional symptoms (e.g., night sweats, fever, fatigue), marked hepatosplenomegaly, and thrombosis [2]. MF can arise following a history of PV or ET, or can present de novo as primary myelofibrosis (PMF). Median survival can range from months to years depending on the presence or absence of particular prognostic features [3]. Due to the variability in the disease course, risk stratification models have been developed in recent years to provide prognostic information to patients and to guide treatment decisions for clinicians [3e6]. Most of these prognostic studies have centered on PMF rather than post-ET or post-PV MF, although previous studies found no significant difference in survival between these patient groups [7,8]. Given the paucity of literature in regards to patients with post-ET or post-PV MF, this review will focus primarily on prognostication in PMF. PMF generally affects an older population with the median age at diagnosis around 65 years [2]. It carries a worse prognosis compared to the other BCR/ABL- negative MPNs [9]. Unlike PV or ET, there is a marked reduction in life expectancy in patients with PMF compared to the general population [10]. The main causes of death are due to infection and bleeding as a result of progressive bone marrow failure, thrombosis, and acute leukemia [9]. MF can evolve into acute leukemia in about 10e20% of patients [6,11]. While new therapies have been developed in recent years that can ameliorate symptoms related to PMF [12], the only curative treatment remains allogeneic stem cell transplantation. Decisions on the indication and timing of transplantation relie upon current prognostic scoring systems such as the International Prognostic Scoring System (IPSS) and the dynamic IPSS (DIPSS), which were developed by the International Working Group for Myeloproliferative Neoplasm Research and Treatment (IWG-MRT) and are applicable at the time of diagnosis and during the disease course, respectively. It should be noted, however, that these prognostic scoring systems were developed prior to the availability of JAK inhibitors in the treatment of PMF. In this review, we will discuss the clinical, biological, cytogenetic, and molecular prognostic factors that have been identified in PMF and the current prognostic models that have been developed based on these findings. Clinical and biological prognostic factors Age Age at presentation has been identified as an important prognostic factor, with older patients found to have worse survival compared to younger patients [9,13e16]. In a multivariate analysis of 1054 patients with PMF, age greater than 65 was identified as a predictor of shortened survival [6]. This may be because older patients are less tolerant of the clinical consequences of progressive PMF such as cachexia and severe anemia. Even among younger patients (age <60), more advanced age at presentation was identified as an independent predictor of survival, with patients <50 years displaying a significant survival advantage compared to those aged 51e59 (median survival of approximately 15 vs. 5 years) [17]. White blood cell count (WBC) and circulating blasts Leukocytosis (WBC >25  109/L) and leukopenia (WBC <4  109/L) have both been associated with poor prognosis in patients with PMF [6,14,18e20]. The presence of leukocytosis at diagnosis has been identified as a predictor of shortened survival [6] and is incorporated into current prognostic scoring systems [3,5,6]. The presence of circulating blasts in peripheral blood has also been found to be a poor prognostic indicator, and the presence of 1% or greater circulating blast cells is associated with decreased survival [6,16,18,19,21]. This may be due to the fact that an increased number of CD34þ cells in the blood correlates with longer disease duration and evolution to acute leukemia [21]. Platelet count Thrombocytopenia (platelets <100  109/L) has been found in several studies to be associated with poor prognosis [3,19,20]. However, its value as an independent prognostic factor was initially unclear

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given its frequent association with anemia [6]. In fact, thrombocytopenia was not included as one of the variables in the IPSS or DIPSS based on the observation that platelets <100  109/L did not have prognostic significance in patients with a hemoglobin <10 g/dL [5,6]. A later study, however, identified thrombocytopenia as an IPSS-independent predictor of inferior survival in young patients (age <60) with PMF [17]. Based on this finding, thrombocytopenia was one of the three additional risk factors incorporated into the refined DIPSS scoring system (DIPSS Plus) [3]. Additionally, thrombocytopenia (along with unfavorable karyotype) has been shown to be a predictor of leukemia free survival, with the 10-year risk of developing acute leukemia 31% versus 12% with the presence of either risk factor (HR 3.3; 95% CI 1.9e5.6) [3]. Hemoglobin Anemia is the most consistent adverse prognostic indicator for patients with PMF [14e16,18,19]. It is a surrogate for ineffective erythropoiesis and its presence is likely indicative of a more severe disease state. An initial hemoglobin (Hb) of <10 g/dL at diagnosis has been identified as the variable with the highest impact on survival [6]. Development of anemia during the disease course is also strongly associated with a poor prognosis in patients with PMF [5]. Therefore, anemia is incorporated into all three current risk stratification models [3,5,6]. Red blood cell transfusions Red blood cell transfusion (RBC) dependence at diagnosis or that develops later during the disease course has been associated with poor prognosis in patients with PMF [22e24]. Increased transfusion requirement has been associated with advanced age and lower platelet count, suggesting that a higher degree of ineffective hematopoiesis exists in older patients [22]. The median survival for patients who were transfused at diagnosis, transfused after 1 year from diagnosis, and not transfused were 35 months, 25 months, and 117 months, respectively [23]. RBC need within the first year of diagnosis predicts shortened survival and is independent of the IPSS and DIPSS prognostic scoring systems [22,24]. Based on these findings, RBC transfusion has been incorporated into the DIPSS Plus prognostic scoring system [3]. Constitutional symptoms The presence of constitutional symptoms such as weight loss >10%, fever, and night sweats persisting for >1 month either at presentation or during the disease course have been associated with shorter survival [5,9,16,18]. These clinical symptoms are likely manifestations of an increased inflammatory cytokine response associated with PMF [25]. Increased circulating IL-8 levels, which have been identified as a predictor of poor prognosis, are associated with a higher prevalence of constitutional symptoms and inferior survival [26]. Circulating interleukins Abnormal cytokine expression may reflect the inflammatory state thought to contribute to the clinical phenotype in PMF such as constitutional symptoms, bone marrow fibrosis, and extramedullary hematopoiesis [25]. Recent studies with JAK inhibitors have demonstrated drug-induced downregulation of pro-inflammatory cytokines including interleukin (IL)-6, IL-1RA, and IL-8, which was accompanied by improvement in constitutional symptoms [12]. A recent study by Tefferi et al., of 127 patients with PMF identified several cytokines that were significant for predicting survival: IL-8, IL-2R, IL-12, and IL-15 [26]. IL-8 and IL-2R were found to correlate the most with disease prognostication. Increased plasma levels of either of these two cytokines, for example, were associated with the presence of constitutional symptoms, transfusion need, leukocytosis, and inferior overall and leukemia free survival independent of DIPSS [26]. Based on these findings, a two-cytokine (IL-8/IL-2R) based risk categorization was developed that could delineate ‘short lived’ and ‘long lived’ patients within the specific DIPSS plus risk categories [26]. Of note, the study found no correlation between plasma levels

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of IL-8 and JAK2 V617F mutational status [26]. This study suggests the potential utility of using IL-8 and IL-2R as a laboratory tool for predicting and monitoring treatment response in addition to the currently available prognostic scoring systems. Plasma immunoglobulin free light chains The assumption that the intensity of the host response to tumor in PMF could signify the virulence of the malignant clonal population suggests that markers of immune response can have prognostic value. This led investigators to examine other markers of host immune response such as serum free light chains (FLC) and its prognostic value in PMF. In a study of 240 patients with PMF and 74 patients with MDS, the plasma immunoglobulin FLC concentration was found to be above the upper limit of normal in 33% of patients with PMF [27]. Increased FLC predicted shortened survival in both patients with PMF and MDS, independent of age and other conventional risk factors. There was no correlation, however, seen with leukemia-free survival, karyotype, or JAK2, MPL, or IDH mutations. Interestingly, the prognostic value of an increased FLC was also found to be independent of circulating IL-2R or IL-8 levels [27]. Based on these findings, serum FLC could be another potential tool in identifying PMF patients with worse prognosis. Iron homeostasis Hepcidin is a key regulator of iron homeostasis, affecting iron absorption by duodenal enterocytes and release of body iron stores [28]. Dysregulation of circulating hepcidin levels could have prognostic significance in patients with PMF given the presence of ineffective erythropoiesis, inflammation, and iron overload that characterizes PMF. Pardanani et al., recently observed that hepcidin levels were significantly higher in patients with PMF as compared to normal controls [29]. Hepcidin levels were also strongly correlated with serum ferritin levels. Increased levels of hepcidin and serum ferritin were found in 29% of the study cohort and predicted inferior survival independent of DIPSS Plus or increased levels of inflammatory cytokines (IL-2R and/or IL-8) [29]. Multivariate analysis of the combination of elevated hepcidin and ferritin levels was able to effectively risk stratify patients for overall survival in the overall cohort and in patients classified within the DIPSS Plus intermediate-2 and high risk categories. Analysis of patients within the DIPSS Plus intermediate-1 and low risk categories was not possible given the limited number of patients with elevated levels of both hepcidin and ferritin in these categories [29]. Based on these findings, hepcidin and ferritin levels may be useful additional variables to be incorporated into future prognostic models. Molecular and cytogenetic prognostic factors Karyotypic abnormalities Cytogenetic abnormalities can be detected in approximately 40% of PMF patients at diagnosis are frequently linked to poor prognosis. The abnormalities most frequently observed are 20q-, 13q-, þ8, þ9, 12p-, and abnormalities of chromosome 1 and 7 [6,30,31]. The prognostic significance of these karyotypic abnormalities was identified by Tam et al., in a study of 256 patients with PMF [32]. The study found that patients with isolated 20q-, 13q-, or þ9 had similar survival to that of patients with a normal diploid karyotype, whereas patients with abnormalities involving chromosomes 5, 7, or complex aberrations (defined as 3 chromosomal abnormalities) had shorter survival, and patients with abnormalities of chromosome 17 had the worst prognosis [32]. Another study of 202 patients with newly diagnosed PMF also found that deletion of 13q and 20q had no prognostic significance when compared with normal karyotype, whereas any other cytogenetic abnormality was linked to shorter survival and increased risk of leukemic transformation [30]. A later study on the prognostic value of cytogenetics in PMF was performed by Caramazza et al., in a single center study at the Mayo Clinic of 433 patients [33]. The investigators identified additional karyotypic abnormalities with prognostic potential and defined two risk categories, favorable and unfavorable karyotype. Unfavorable karyotype included patients with complex abnormalities (3) or

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one or two abnormalities that included þ8, 7/7q-, i(17q), 5/5q-, 12p-, inv(3), or 11q23. Favorable karyotype included the normal diploid karyotype and any one or two abnormalities not listed under the unfavorable category [33]. There was a significant difference in 5 year survival between the favorable and unfavorable groups, at 51% and 8%, respectively [33]. Further work by the same group of investigators found that monosomal karyotype was associated with a high risk of leukemic transformation and an extremely poor prognosis, which has also been observed in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) [34]. Median survival was 6 months in patients with a monosomal karyotype compared to 24 months in patients with complex karyotype without monosomies [34]. The 2 year leukemia transformation rates were also significantly increased in patients with monosomal karyotype compared to patients with complex karyotype without monosomies (29.4% vs. 8.3%, P < 0.0001) [34]. Both these studies confirm that specific karyotypic abnormalities have prognostic value independent of the IPSS and DIPSS and, therefore, are now incorporated into the refined DIPSS Plus prognostic model [3]. JAK2 V617F mutation Approximately 50e60% of patients with PMF harbor the JAK2 V617F mutation, an acquired, recurrent mutation located in exon 14 of the JAK2 gene [35]. Since its discovery, several studies have attempted to evaluate the prognostic significance of the JAK2 V617F mutation with inconsistent results. In a longitudinal, prospective study of 174 patients with PMF, Barosi et al., observed that the presence of the JAK2 mutation predicted evolution towards large splenomegaly, need for splenectomy, and leukemic transformation after adjustment for conventional risk factors such as age, sex, hemoglobin level, white blood cell count, and percentage of blasts in the peripheral blood [36]. Additionally, Campbell et al., found that among 152 patients with PMF, those who carried the JAK2 V617F mutation had higher neutrophil and leukocyte counts (P ¼ 0.02) and poorer overall survival compared to those who did not, after correction of confounding factors such as age and hemoglobin (HR 3.3, 95% CI 1.26e8.68, P ¼ 0.01) [37]. In contrast to these studies, the analysis done by the IWG-MRT in the development of the IPSS found that the JAK2 V617F mutation was not associated with a specific IPSS risk group and did not affect survival [5]. In addition, Tefferi et al., noted that the presence of the JAK2 V617F mutation did not impact the incidence of thrombosis, overall survival, or leukemia free survival in 199 patients with PMF; however, interestingly, a low JAK2 V617F allele burden was associated with a worse prognosis [38]. Similarly, Guglielmelli et al., found that among 127 JAK2 V617F-mutated PMF patients, those in the lower quartile of allele burden showed significantly reduced survival compared to patients with a higher allele burden or who were JAK2 wild-type [39]. These studies suggest the presence of an overriding JAK2 V617F negative clone that confers a more aggressive disease phenotype. In another study, Guglielmelli et al., found that JAK2 V617F mutational status and allele burden did not impact prognosis in patients with post-ET and post-PV MF [40]. Other somatic mutations Several more molecular markers have been shown to be useful in the prognostic assessment of patients with PMF (Table 1) [4,43]. In an international collaborative project, Vannuchi et al., studied the

Table 1 Mutations with prognostic significance in PMF. Mutation

Chromosome location

Estimated frequency in PMF

JAK2 CALR ASXL1 EZH2 SRSF2 IDH1/2

9p24 19p13.2 20q11.3 7q36.1 17q25.1 2q33.3/15q26.1

50e60% 30% 13% 7% 17% 4%

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prognostic relevance of mutation in several previously described genes including TET2, CBL, IDH1 or IDH2, ASXL1, EZH2, DNMT3A, MPL, SRSF2, and JAK2, in two independent cohorts of PMF patients, totaling 879 patients [41]. In the first cohort of 483 European patients, mutations in ASXL1, SRSF2, or EZH2 were found to be predictive of shortened overall survival. However, only ASXL1 was found to be independent of IPSS. This was validated in the second cohort of 396 patients from the Mayo Clinic, and again, only ASXL1 retained its prognostic significance independent of DIPSS-plus on multivariate analysis. Leukemia free survival was negatively affected by ASXL1, SRSF2 and IDH1 or IDH2 mutations in the European cohort, but only SRSF2 and IDH mutations were associated with leukemic transformation in the Mayo cohort [41]. Of note, patients with IPSS/DIPSS-plus high risk disease were not affected by the presence of ASXL1 mutations; however, ASXL1 mutations tended to cluster with normal karyotype and predict a worse prognosis in patients classified as intermediate-1 and intermediate-2 risk. Similarly, the presence of SRSF2 or IDH1 mutations appeared to predict leukemic transformation independent of currently known risk factors including thrombocytopenia and unfavorable karyotype [41]. These same researchers also found that the number of these mutations correlated with overall survival (OS) and leukemia free survival (LFS) in patients with PMF. In both the European and Mayo cohorts, patients harboring two or more of the above identified mutations had a worse OS and shortened LFS compared to patients harboring only one mutation which was worse than having no mutations [42]. Based on these findings, mutational profiling for ASXL1, EZH2, SRSF2, and IDH may provide additional information to current prognostic models in regards to identifying patients at risk for decreased survival or leukemic transformation.

CALR mutations Most recently, somatic mutations in calreticulin (CALR), an endoplasmic reticulum chaperone protein, have been found in ET and PMF patients with non-mutated JAK2 or MPL [43,44]. Somatic insertions or deletions in exon 9 of the CALR gene were detected in approximately 85% of PMF patients with PMF who did not have a detectable JAK2 V617F or MPL mutation. Interestingly, patients with the CALR mutation appear to have a more indolent clinical course than patients with the JAK2 V617F mutation as manifested by a lower risk of thrombosis and longer overall survival [43]. In a study by Tefferi et al. on a cohort of 570 patients with PMF, those who were positive for a CALR mutation but negative for ASXL1 had the longest median survival of 10.4 years, while those who did not have a CALR mutation but were positive for an ASXL1 mutation had the shortest median survival of 2.3 years (HR 5.9, 95% CI 3.5e10.0). Patients with both CALR and ASXL1 mutations and patients with neither mutation had similar median survivals of 5.8 years [45]. This study confirms the prognostic significance of CALR as a favorable mutation and ASXL1 as an unfavorable mutation. A CALR/ASXL1 mutationbased prognostic model was shown to be independent of DIPSS Plus (P < 0.0001) and able to differentiate ‘short term’ (median survival 4 years) from ‘long term’ (median survival 20 years) survivors in patients classified as low/intermediate-1 risk by DIPSS Plus [45]. Multivariate analysis also identified CALR-ASXL1þ mutational status as the most significant risk factor for survival compared to age >65 and unfavorable karyotype (HR 3.7 vs. 2.8 vs. 2.7, respectively) [45], signifying the utility of CALR and ASXL1 mutation screening in patients with PMF and incorporation of these molecular markers into DIPSS Plus. Prognostic models Prior to the development of current prognostic scoring systems such as the International Prognostic Scoring System (IPSS), Dynamic International Prognostic Scoring System (DIPSS), and DIPSS-plus, prognostic models such as the Lille score [18] were based on relatively small numbers of patients and did not clearly delineate patients with extremely poor prognosis. In recognition of the need to identify patients with poor prognosis in the setting of allogeneic stem cell transplantation and new investigational drugs as available treatment options, more robust scoring systems have been developed to aid with therapeutic decision making [3,5,6].

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IPSS The International Prognostic Scoring System (IPSS) was developed in 2009 by the IWG-MRT in a multinational study of 1054 patients with PMF from 7 different centers (Table 1). The IPSS is only applicable to patients being evaluated at the time of initial diagnosis and uses 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. The presence of 0, 1, 2, and 3 adverse factors defines low, intermediate-1, intermediate-2, and high-risk disease, respectively, with corresponding median survival rates of 11.3, 7.9, 4, and 2.3 years [6]. Compared to prior prognostic models, the IPSS displayed higher predictive accuracy, replicability, and discriminating power. DIPSS The acquisition of additional risk factors during the disease course may significantly modify a patient's outcome. Because the IPSS was developed for risk assessment at diagnosis, the IWG-MRT subsequently developed a dynamic prognostic model, the Dynamic International Prognostic Scoring System (DIPSS), which utilizes the same prognostic variables as the IPSS, but can be applied at any time during the disease course [5]. The investigators found that the acquisition of anemia over time affected survival with a hazard ratio double that of other parameters. Based on this finding, the DIPSS assigns greater weight to anemia, giving two adverse points instead of one, for hemoglobin <10 g/dL. Risk categorization is divided into low (0 adverse points), intermediate-1 (1 or 2 points), intermediate-2 (3 or 4 points), and high (5 or 6 points) with corresponding median survivals of not reached, 14.2, 4, and 1.5 years, respectively (Table 2). DIPSS has also been shown to predict progression to acute myeloid leukemia in PMF. In an analysis of 525 patients with PMF, DIPSS was shown to be predictive of progression to blast phase (BP) defined as >20% peripheral blasts [46]. Patients stratified into the higher risk categories (intermediate-2 and high) were noted to have a 7.8-fold and 24.9-fold higher risk of developing BP, respectively, compared to those in the low-risk categories [46]. DIPSS plus IPSS- and DIPSS-independent risk factors for survival in PMF have been identified, including unfavorable karyotype [30,33], red cell transfusion [20,24], and platelet count <100  109/L [17]. Subsequently, DIPSS was modified into DIPSS-plus by incorporating these additional DIPSS-independent risk factors. Unfavorable karyotype was specifically defined as complex karyotype (3 chromosomal abnormalities) or sole or two abnormalities that include þ8, 7/7q-, i(17q), 5/5q-, 12p-, inv(3), or 11q23 rearrangement [3]. The four DIPSS-plus risk categories are low (no risk factors), intermediate-1 (one risk factor), intermediate-2 (two or 3 risk factors), and high (four or more risk factors) with

Table 2 IPSS and DIPSS prognostic scoring systems. Risk factors

Age >65 Constitutional symptomsa Hb <10 g/dL WBC count >25  109/L Blood blasts  1% a

Point value

IPSS

IPSS

DIPSS

Risk group

DIPSS

1 1

1 1

Low Intermediate-1

0 1

1 1

2 1

Intermediate-2 High

2 3

1

1

Risk score

Median survival

Risk group

Risk score

Median survival

11.3 years 7.9 years

Low Intermediate-1

0 1 to 2

Not reached 14.2 years

4 years 2.3 years

Intermediate-2 High

3 to 4 5

4 years 1.5 years

Constitutional symptoms defined as weight loss >10% of the baseline value in the year preceding PMF diagnosis and/or unexplained fever or excessive sweats persisting for more than 1 month.

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respective median survivals of 15.4, 6.5, 2.9, and 1.3 years (Table 3). Unfavorable karyotype and platelets <100  109/L were also found to predict inferior leukemia free survival [3].

Predictors of leukemic transformation As discussed previously, several factors have been identified that may lead to increased risk of leukemic transformation in patients with PMF. Excess blasts in the peripheral blood or bone marrow and high levels of circulating CD34þ cells have been associated with a higher risk of leuekmic transformation [47,48]. Morel et al. identified hemoglobin <10 g/dL, leukocytosis >30  109/L, and platelets <150  109/L as the best independent predictors of leukemic transformation [20]. Abnormal and complex karyotype, particularly monosomal karyotype, is also a strong predictor of shortened survival and high risk of leukemic transformation in patients with PMF [3,34]. Incorporation of these risk factors into prognostic scoring systems such as DIPSS and DIPSS Plus have, not surprisingly, been shown to predict risk of acute leukemia [3,46]. In an analysis of 525 patients with PMF, Passamonti et al., observed that those in the DIPSS intermediate-2/high risk group had an increased risk of progression to blast phase (peripheral blasts >20%) compared to patients in the low risk group (HR 7.8, 95% CI 1.8e34.2 in intermediate-2 and HR 24.9, 95% CI 6e102.3 in high) [46]. In DIPSS Plus, platelets <150  109/L and unfavorable karyotype were shown to predict inferior leukemia free survival [3]. The 5- and 10-year risk of leukemic transformation in the absence of either of these two risk factors was 6% and 12% respectively, while the risk in the presence of one or both of these risk factors was 18% and 31%, respectively [3].

Summary The prognosis of patients with PMF is dependent upon the presence or absence of a number of adverse prognostic factors such as age >65 years, white blood cell count >25  109/L or <4  109/L, hemoglobin <10 g/dL, platelets <100  109/L, transfusion dependence, constitutional symptoms, IL8 and IL-2R levels, serum free light chains, hepcidin, karyotypic abnormalities, and molecular markers such as JAK2 V617F, ASXL1, and CALR. The clinical course of patients with PMF is highly variable, with the expected median survival of those with no risk factors exceeding 10 years and those with multiple risk factors being less than one year. Despite the development of new therapeutic drugs such as JAK inhibitors, allogeneic hematopoietic stem cell transplantation remains the only curative treatment for PMF. Incorporation of these previously identified prognostic variables into scoring systems such as the IPSS, DIPSS, and DIPSS Plus can help identify high risk patients who should undergo evaluation for allogeneic stem cell transplant from low risk patients who may do well with minimal treatment. As new insights into the pathogenesis of PMF continue to be revealed, ongoing refinement of these prognostic models will further guide treatment decision making for clinicians and patients.

Table 3 DIPSS plus prognostic scoring system. Risk factors

Points

DIPSS plus Risk group

Risk score

Median survival

DIPSS intermediate-1 DIPSS intermediate-2 High risk Unfavorable karyotypea Platelets <100  109/L RBC transfusion dependent

1 2 3 1 1 1

Low risk Intermediate-1 Intermediate-2 High

0 1 2 to 3 4 to 6

15.4 years 6.5 years 2.9 years 1.3 years

a Unfavorable karyotype ¼ complex karyotype or single or two abnormalities that include þ8, 7/7q-, i(17q), 5/5q, 12p-, inv(3) or 11q23 rearrangement.

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Practice points:  Age >65, WBC >25  109/L or <4  109/L, circulating blast count >1%, platelet count <100  109/L, Hb < 10 g/dL, transfusion dependence, and the presence of constitutional symptoms are predictors of poor prognosis in patients with PMF.  Three main prognostic scoring systems, the International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS Plus have been developed to aid with therapeutic decision making.  Unfavorable karyotype includes patients with complex abnormalities (3) or one or two abnormalities that include þ8, 7/7q-, i(17q), 5/5q-, 12p-, inv(3), or 11q23.  The presence of the JAK2 V617F mutation does not have a clear impact on prognosis, however, a low JAK2 V617F allele burden has been associated with a worse prognosis.  One or more mutations in ASXL1, SRSF2, EZH2, IDH1/2 are predictive of shortened overall survival and an increased risk of leukemic transformation.  CALR is a recently identified mutation found in the majority of patients with PMF who are JAK2 and MPL negative and may be a predictor of good prognosis.

Conflicts of interest statement The authors have no conflict of interest to disclose.

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