Post-ET and Post-PV Myelofibrosis: Updates on a Distinct Prognosis from Primary Myelofibrosis

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1 Current Hematologic Malignancy Reports MYELOPROLIFERATIVE NEOPLASMS (B STEIN, SECTION EDITOR) Post-ET and Post-PV Myelofibrosis: Updates on a Distinct Prognosis from Primary Myelofibrosis Francesco Passamonti 1,2,3 & Barbara Mora 1 & Daniela Barraco 1 & Margherita Maffioli 1 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Purpose of Review The purpose of this review is to help doctors in the management of patients with post-polycythemia (PPV) and post-essential thrombocythemia (PET) myelofibrosis (MF) facing diagnostic criteria, prognostication, and treatment possibilities. Recent Findings Diagnostic criteria of primary myelofibrosis (PMF) have been recently updated from the WHO classification. A clear-cut distinction between pre-fibrotic and overt PMF has been done. Concerning PPV and PET MF, the criteria come from Prognostication of PMF has been well established on clinical criteria, but recent molecular acquisitions will improve the strategy. For PPV and PET MF, the new MYSEC-PM is helpful for prediction of survival. JAK2-inhibitors and stem cell transplant are the two critical therapeutic approaches in myelofibrosis. Summary Differences between PMF and SMF substantiate the efforts underway to adequately stratify SMF patients with ad hoc prognostic tools and to use such categorization to evaluate available treatment modalities. Keywords Polycythemia. Thrombocythemia. Myelofibrosis. Prognosis. JAK2. Survival Introduction In this review, we will describe the known main differences between primary myelofibrosis (PMF) and post-polycythemia vera (PPV) and post-essential thrombocythemia (PET) myelofibrosis (MF). Criteria for diagnosis of the two conditions are different as well as the expectation of life. All the information collected serve to a better risk stratification of patients and treatment approach to PET MF and PPV MF. This article is part of the Topical Collection on Myeloproliferative Neoplasms * Francesco Passamonti francesco.passamonti@uninsubria.it Barbara Mora b.mora.1988@gmail.com Daniela Barraco barraco.daniela@gmail.com Margherita Maffioli margherita.maffioli@gmail.com Department of Medicine and Surgery, University of Insubria, Varese, Italy Hematology, Department of Specialistic Medicine, Ospedale di Circolo, ASST Sette Laghi, Varese, Italy Hematology, Dipartimento di Medicina e Chirurgia, University of Insubria, Via Guicciardini, Varese, Italy Diagnosis of PMF and SMF MF is a chronic myeloproliferative neoplasm (MPN) characterized by megakaryocytic proliferation and atypia, variable degrees of bone marrow (BM) fibrosis, extramedullary hemopoiesis with splenomegaly, frequent anemia, peripheral blood leukoerythroblastosis, and a high burden of symptomatology. MF can appear as a de novo disease (primary myelofibrosis, PMF) or following a previously known diagnosis of ET or PV [1]. Both PMF and post-et/post-pv MF negatively affect patients life expectancy and can transform into blast phase (BP) [2]. The 2017 World Health Organization (WHO) diagnostic criteria for PMF encompass new evidence collected in the last years, most notably the discovery of CALR mutations, the identification of additional clonal markers with an impact on survival, and the clear distinction between ET and pre-fibrotic/ early PMF (pre-pmf) lacking significant fibrosis [3]. The 2017 WHO diagnostic criteria for ET, pre-pmf, and overt

2 PMF are listed in Table 1. ET and pre-pmf can be indistinguishable with regard to clinical presentation, which is often characterized by prominent thrombocytosis (84.1% of pre- PMF cases present with a platelet count /L at diagnosis) [4]. Furthermore, driver mutations are overlapping [5, 6] and 48% of ET patients present at least one of the minor criteria required to diagnose pre-pmf [4]. The recognition of pre-pmf, which thus rests greatly on histopathologic features, is however compulsory as patients have a higher risk of evolution to overt MF or BP and an inferior survival with respect to ET patients [7, 8]. On the other hand, the presence of grade 2 and 3 reticulin fibrosis seems to imply an inferior survival in PMF [9]. Patients with overt PMF more often belong to higher risk categories and more frequently harbor one or more prognostically detrimental mutation (e.g., mutations in ASXL1 and EZH2) with respect to pre-pmf [8]. While recognizing the essential role of BM morphology, the WHO classification seeks to complement histopathological information with phenotypic and genotypic data, reflecting the complexity of MPNs and possibly limiting the impact of the subjective nature of BM morphology interpretation, often resulting in variable consensus among pathologists [3]. With regard to the diagnosis of post-et/post-pv MF (also referred to as secondary MF, SMF), the criteria remain unchanged since 2008 and are listed in Table 2 [10]. However, since a preceding diagnosis of ET or PV is required, the 2017 WHObased modifications in the diagnostic criteria of these diseases indirectly impact SMF diagnosis. Most notably, the lowering of the hemoglobin threshold for the diagnosis of PV (i.e., > 16.5 g/ dl in men, > 16.0 g/dl in women, or hematocrit > 49% in men, > 48% in women) has brought to the diagnostic reallocation, bearing therapeutic implications, of a proportion of JAK2V617F-positive ET patients [3, 11]. The diagnosis of SMF requires the presence of grade 2 or 3 BM fibrosis and thus mandates a BM histopathological exam [12]. In routine clinical practice BM, biopsies are generally not performed on a regular basis in ET and PV unless clinical features suggest a disease evolution. Such features include, but are not limited to, the minor criteria for SMF diagnosis (i.e., development of constitutional symptoms, increasing splenomegaly, development of anemia or loss phlebotomy/cytoreduction requirement, increased serum LDH, and development of leukoerythroblastosis). Lastly, it is worth mentioning that MPNs can occur as sporadic diseases or have a familial clustering in around 7 11% of cases [13 16]. Phenotype, driver mutations, and disease evolution, comprising a possible evolution to SMF, are shared by both forms. Predictive Factors of SMF Evolution at the Time of PV and ET Fibrotic transformation in PV and ET occurs in a variable rate of 12 21% and 9 10%, respectively [17]. Several clinical parameters have been evaluated to investigate their potential role as predictors of SMF evolution. In PV, the presence of leukocytosis (white blood cell count > 10 or /L) [18], palpable splenomegaly at diagnosis [19] or during follow-up [20, 21], bone marrow reticulin fibrosis equal to or higher than grade 1 [22 24], resistance/intolerance to hydroxyurea, in terms of development of cytopenia and failure to reduce massive splenomegaly [21], and a long disease duration [25] have been associated with a higher risk of evolution into SMF. A large international study highlighted the prognostic relevance of distinguishing diagnosis of pre-fibrotic PMF from ET, in terms of risk to overt MF transformation (higher in pre-fibrotic PMF), identifying advanced age and anemia as risk factors for fibrotic progression to MF [7]. Among genetic risk factors, retrospective studies have identified that patients bearing homozygous JAK2V617F mutations [20, 26] and highest values for mutant allele burden (> 50%) are more likely to progress to post-pv MF [18], while JAK2-mutated ET patients have a lower risk of fibrotic transformation [27]. Concerning MPL mutations, the acquired copy-neutral loss of heterozygosity (CN-LOH) of chromosome1phasbeendemonstratedtorepresentamolecular mechanism of fibrotic transformation in MPL-mutated MPNs [28], whereas CALR mutation and its variants did not appear to influence MF evolution [29]. More recently, a nextgeneration sequencing study identified the prognostic relevance of adverse variants/mutations and in particular of SRSF2 and U2AF1 on MF evolution in PV and ET patients, respectively [6]. A Mayo Clinic study on 196 PV patients has recently highlighted the detrimental effect of abnormal cytogenetic in MF evolution [30]. Clinical Features in PMF and SMF Information on the clinical presentation of PMF and SMF mainly came from the largest datasets of patients as the IPSS (International Prognostic scoring System) for PMF [2, 31] and the MYSEC (myelofibrosis secondary to PVand ET) for SMF [32 ]. Besides, a recent MD Anderson Cancer Center (MDACC) study focused on the different features between the two MF subtypes [33]. As for the IPSS cohort (N =1054PMF)[2, 34], the median age at diagnosis was 64 years; 17% of patients were younger than 50 years and 5% younger than 40. A majority of patients were males. Similar demographics data were obtained from the recent MDACC analysis (755 PMF and 344 SMF) [33] and from the MYSEC study (N = 781 SMF) [32 ]. In the latter, the median age at time of SMF evolution was higher for PPV MF than for PET MF. Males represented 52% of the MYSEC population. In the IPSS dataset, 89% of PMF patients presented with splenomegaly, 27% with constitutional symptoms, and 36%

3 Table 1 The 2017 WHO classification for pre-fibrotic myelofibrosis and overt primary myelofibrosis 2017 WHO criteria for pre-fibrotic/early primary myelofibrosis Diagnosis of pre-pmf requires meeting all three major criteria, and at least one minor criterion Major criteria Criterion 1 (morphologic) Bone marrow morphology Megakaryocytic proliferation and atypia, without reticulin fibrosis > grade 1, accompanied by increased age-adjusted BM cellularity, granulocytic proliferation, and often decreased erythropoiesis Criterion 2 (clinical) WHO criteria for BCR-ABL1+ CML, PV, ET, MDS, or other Not meeting myeloid neoplasms Criterion 3 (genetic) JAK2, CALR, ormpl mutation Clonal marker*, or Reactive BM reticulin fibrosis** Minor criteria Anemia not attributed to a comorbid condition Presence, if absence Presence Absence Presence Leukocyte count > /L Spleen size Palpable Serum LDH Increased to above the upper normal limit of institutional reference range 2017 WHO criteria for overt primary myelofibrosis Diagnosis of overt PMF requires meeting all three major criteria, and at least one minor criterion Major criteria Criterion 1 (morphologic) Bone marrow morphology Presence of megakaryocytic proliferation and atypia, accompanied by either reticulin and/or collagen fibrosis grades 2 or 3 Criterion 2 (morphologic) WHO criteria for ET, PV, BCR-ABL1+ CML, MDS, or other Not meeting myeloid neoplasms Criterion 3 (genetic) JAK2, CALR, ormpl mutation Presence, if absence Clonal marker*, or Presence Reactive BM reticulin fibrosis** Absence Minor criteria Anemia not attributed to a comorbid condition Presence Leukocyte count > /L Spleen size Palpable Serum LDH Increased to above the upper normal limit of institutional reference range Leukoerythroblastosis Presence WHO, World Health Organization; CML, chronic myeloid leukemia; PV, polycythemia vera; ET, essential thrombocythemia; PMF, primary myelofibrosis; MDS,myelodysplastic syndromes *In the absence of any of the 3 major clonal mutations, the search for the most frequent accompanying mutations (e.g., ASXL1, EZH2, TET2, IDH1/ IDH2, SRSF2, SF3B1) are of help in determining the clonal nature of the disease **Minor (grade 1) reticulin fibrosis secondary to infection, autoimmune disorder or other chronic inflammatory conditions, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies with peripheral blood blasts. The incidence of thrombosis in PMF was patients/year at 10 years [35]. As for the MYSEC study [32 ], 44% of SMF patients reported constitutional symptoms, 88% had splenomegaly, and 29% peripheral blood blasts. Subjects with PPV MF had higher values of white blood cells and hemoglobin, larger spleen size, and lower platelet count compared with PET MF cases. Patients with PPV MF had significantly higher frequency of constitutional symptoms and history of prior thrombosis than those with PET MF. Median incidence of thrombosis was patients/year in PET MF and patients/ year in PPV MF. Masarova et al. [33] recentlyshowedalso that PMF patients were more likely RBC transfusion dependent than the SMF counterpart. Causes of death, known in 278 out of 517 PMF patients, in the DIPSS cohort were transformation to BP (31%), PMF

4 Table 2 The International Working Group for Myelofibrosis Research and Treatment (IWG- MRT) criteria for post-essential thrombocythemia and postpolycythemia vera myelofibrosis Criteria for post-essential thrombocythemia myelofibrosis (PET MF) Diagnosis of post-et MF entails meeting both required criteria and at least two additional criteria Required criteria 1. Documentation of a previous diagnosis of essential thrombocythemia as defined by the WHO criteria 2. Bone marrow fibrosis grades 2 3 (on0 3 scale)* or grades 3 4 (on0 4 scale)** Additional criteria 1. Anemia and a 2 g/dl decrease from baseline hemoglobin level 2. A leukoerythroblastic peripheral blood picture 3. Increasing splenomegaly defined as either an increase in palpable splenomegaly of 5 cm (distance of the tip of the spleen from the left costal margin) or the appearance of a newly palpable splenomegaly 4. Increased LDH (above reference level) 5. Development of 1 of three constitutional symptoms: > 10% weight loss in 6 months, night sweats, unexplained fever (> 37.5 C) Criteria for post-polycythemia vera myelofibrosis (PPV MF) Diagnosis of post-pv MF entails meeting both required criteria and at least two additional criteria Required criteria 1. Documentation of a previous diagnosis of polycythemia vera as defined by the WHO criteria 2. Bone marrow fibrosis grades 2 3 (on0 3 scale)* or grades 3 4 (on0 4 scale)** Additional criteria 1. Anemia or sustained loss of requirement of either phlebotomy (in the absence of cytoreductive therapy) or cytoreductive treatment for erythrocytosis 2. A leukoerythroblastic peripheral blood picture 3. Increasing splenomegaly defined as either an increase in palpable splenomegaly of 5 cm (distance of the tip of the spleen from the left costal margin) or the appearance of a newly palpable splenomegaly 4. Development of 1 of three constitutional symptoms: > 10% weight loss in 6 months, night sweats, unexplained fever (> 37.5 C) LDH, lactate dehydrogenase *Grades 2 3 according to the European classification: diffuse, often coarse fiber network with no evidence of collagenization (negative trichrome stain); or diffuse, coarse fiber network with areas of collagenization (positive trichrome stain) **Grades 3 4 according to the standard classification: diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis; or diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis progression (18%), thrombosis and cardiovascular complications (13%), infection (10%) or bleeding (5%) out of the setting of BP, portal hypertension (5%), and other events including secondary cancers (4%) [31]. The MYSEC dataset reported BP in 66 (8.4%) and death in 220 (28%) SMF patients. The most frequent causes of death in SMF patients were nonclonal disease progression (35 40%), BP (20 25%), and infections (6 10%). Other fatal events (included organ failure, complications after SCT, secondary malignancies) happened each in less than 10% of cases. Cytogenetics Relevance in PMF and SMF Information on karyotype and its implications is widely detailed in PMF [36 39], but few studies focused on cytogenetic differences between PMF and SMF [33]. About one third of PMF patients presented chromosomal abnormalities [2, 33, 36]. In the MYSEC study, abnormal karyotype (AK) was present in 34% of SMF patients, with higher frequency in the PPV MF subgroup (40%) (Mora et al., in press). These findings were similar to those of the MDACC SMF dataset [40]. In large cohorts of MF patients, sole abnormalities were the most represented cytogenetic alterations: 68% of PMF [39] and 57% of SMF. In PMF, the most frequent individual abnormalities were 20q (23%), 13q (18%), + 8 (11%), + 9 (10%), chromosome 1q+ (9.5%), and 7q (7%) [39, 41]. Chromosome 17 abnormalities seem specific for PMF, as relatively rare in SMF [33]. The MYSEC study showed that the most prevalent single chromosomal alterations in SMF were, as in PMF, 20q,13q,+8, and + 9 (< 10% each) (Mora et al., in press). Similar results have been reported in PV [30]and even if in a smaller frequency in ET [42]. As suggested by recent sequential data on cytogenetics in PVand PPV MF, chromosomal individual alterations could

5 be a consequence of a pre-existing PV/ET phase rather than being involved in SMF pathogenesis [43]. As for PMF, double abnormalities and complex karyotype (CK) were present in 17 and 11% [39], while in 8 and 5% in another cohort [33]. The MYSEC and the MDACC studies showed a higher rate of double abnormalities (17%) and CK (20%, including 8.5% monosomal MK) in SMF. On the contrary, less than 5% of PV/ET cases showed two or more cytogenetic alterations [23, 43]. Therefore, multiple chromosomal alterations could be more relatedtoevolutioninsmf. Looking for karyotype-phenotype associations in PMF, Wassie et al. [39] showed that AK correlated to leukopenia, anemia, and thrombocytopenia; besides, the CK subgroup was more frequently characterized by younger age and lower platelet count. In the same study, specific phenotypic parameters were associated with single chromosomal abnormalities: leukopenia with 20q, + 8, and 7q ; thrombocytopenia with 20q and 7q. As for SMF, AK clustered with a more advanced phenotype: lower platelets, larger spleen size, higher frequency of symptoms, and more peripheral blood blasts (Mora et al., in press). Preliminary data in SMF showed also an association between CK and more severe bone marrow fibrosis grade [33]. Associations between genotype and karyotype have been detailed in PMF, as the case of 13q and CALR mutation, + 9 and JAK2 mutation, 20q with SRSF2 mutation, ASXL1 and normal karyotype [39]. On the contrary, no definitive associations between driver mutations and karyotype were found in SMF. In the MYSEC study, chromosomal abnormalities did not impact on risk of thrombosis, while CK was a predictor of blast phase evolution (Mora et al., in press). Same prognostic value of CK was suggested in other cohorts, which included also PMF patients [33]. Considering PMF outcome, single or double chromosomal abnormalities including + 8, 7q, i(17q), inv[3], 5q, 12p, rearrangement 11q23, CK, and MK were associated with an unfavorable outcome [36]. Tefferi et al. [44] showed that MK, inv[3], and inv(17)q were very high risk cytogenetic categories, associated with an extremely severe prognosis (median estimate, 9 months). Survival of SMF patients with AK reflected an aggressive disease (median estimate, 6.1 years) and very detrimental impact had CK (median estimate, 2.7 years) or MK (median estimate, 2 years) (Mora et al., in press). Among all the chromosomal aberrations, only MK showed independent prognostic value from the MYSEC-PM stratification. Besides, AK was significantly associated with higher MYSEC-PM risk categories. Distribution and Effects of Genotype in PMF and SMF Overall, 60% of PMF patients in the IPSS cohort carried the JAK2 (V617F) mutation [2]. After the discovery of CALR mutation, other studies clarified driver mutations distribution in PMF: for instance, out of 254 PMF patients, 58% harbored JAK2 (V617F), 25% CALR, 8% MPL mutations, and 9% were negative for all three mutations (TN) [45]. In the MYSEC study, all PPV MF patients carried the JAK2 (V617F) mutation. As for PET MF cases, the driver mutations distribution seems similar to that of PMF: 54% displayed JAK2 (V617F), 30% CALR, 9%MPL, 6% TN. Five PET MF patients had more than one driver clone [46]. Corresponding data were obtained in a recent study on 165 PET MF patients [40], while mutations distribution was different in another smaller cohort (MPL in 0%, CALR in 42%) [47]. Considering CALR mutated cases, CALR type 1 mutations were more frequent (60 70%) than CALR type 2 (15 25%) either in PMF or in SMF [48, 49]. Actually, some studies on ET reported that CALR type 1 mutation is preferentially associated with a higher risk of evolution to PET MF [50]. CALR mutations showed an association with younger age, higher platelet count, lower risk of anemia, or leukocytosis in PMF. JAK2 mutated PMF had higher incidence of thrombosis than CALR [51]. Also in the MYSEC cohort, when compared to JAK2, CALR-mutated patients were younger, with lower white blood cells and smaller spleen size. CALR type 1/type 1-like and CALR type 2/type 2-like were similar in terms of clinical presentation and outcome. In another study, JAK2- positive SMF cases resulted more symptomatic and with a higher risk of thrombosis [40]. In PMF, additional mutation impacting survival (so-called high molecular risk, HMR) was described in 25% of patients: ASXL1 (31%), EZH2 (6%), IDH 1-2 (4%), SRSF2 [52]. On the contrary, HMR mutations had no implication on SMF outcome prediction, with the exception of SRSF2 mutations, which correlated with reduced survival [40]. Looking at PMF outcome, CALR mutations had a favorable impact on survival, while unfavorable factors were CALR( )/ASXL1(+) and TN cases [53] orsrsf2. Inthe MYSEC cohort, JAK2 mutated and TN cases showed a significantly higher incidence of BP compared with CALR-mutated patients, even after adjusting for age and IPSS risk category [46]. To note, in PET MF, CALR type 1-mutated patients had a lower rate of death. This was extensively explored in the MYSEC study: CALR-mutated cases had a significantly superior survival compared with JAK2-mutated PET and PPV MF, even adjusting for age and IPSS category [49]. Survival of PMF and SMF and Prognostication In the last decade, three clinical-derived prognostic models for PMF have been developed and are currently used in the treatment decision-making: (i) the IPSS [2], which is applicable at the time of initial diagnosis and includes five variables that independently impact on survival (age > 65 years, hemoglobin < 10 g/dl, leukocyte count > /L, circulating blasts

6 1%, and constitutional symptoms); (ii) the Dynamic IPSS (DIPSS) score [31], that can be applied at any time of disease course using the same prognostic factors and assigning two points for hemoglobin; (iii) the DIPSS-plus score [54] which considers three additional prognostic factors, as red blood cell transfusion need, platelet count < /L, and unfavorable karyotype. Furthermore, the most comprehensive mutational landscape in PMF and its prognostic relevance allowed the development of scoring systems including both driver and other non-driver mutational status and cytogenetic information for transplant-candidate patients with PMF [55 ]. The MIPSS70 identified the following as significant risk factors for survival: hemoglobin < 10 mg/dl, leukocytes > /L, platelets < /L, circulating blasts 2%, bone marrow fibrosis grade 2, constitutional symptoms, absence of CALR type 1 mutation, presence of high molecular risk mutation (i.e., ASXL1, EZH2, SRSF2, IDH1/2), and presence of two or more high molecular risk mutations. Although, in the clinical practice, the management of PMF and SMF does not differ, there is evidence that the prognostic models IPSS and DIPSS are suboptimal in prognosis stratification of SMF patients [56, 57]. Recent studies have also illustrated a different prognostic molecular profile between PMF and SMF. Vannucchi et al. [52] defined the relevance of HMR in PMF (ASXL1, EZH2, SRSF2, and IDH1/2), whereas in SMF only SRSF2 mutations seem to be associated with reduced survival in PET-MF [40]. Masarova et al. [33] showed that patients with PET-MF have better survival than those with PMF and PPV-MF and that PPV-MF and PMF patients have similar survival. Age > 65 years, hemoglobin < 10 g/dl, and constitutional symptoms are associated with shorter survival for PPV-MF, while hemoglobin < 10 g/dl, platelets < /L, peripheral blasts 1%, and constitutional symptoms were prognostic factors for those with PET-MF. Again, hemoglobin < 10 g/dl, platelet count < /L, and leukocyte count > /L are independent risks of survival in PPV-MF [12]. Hernandez- Boluda et al. [58] identified age > 65, hemoglobin < 10 g/ dl, increased peripheral blood blasts, and treatment with hydroxyurea at the time of transformation as independent factors for predicting worse survival in SMF. Furthermore, the authors demonstrated that the current prognostic scoring systems used in PMF (IPSS/DIPSS) are not effective for an adequate prognostic stratification of SMF. Also, a Mayo Clinic Study on 125 SMF patients provided evidence that IPSS, DIPSS, and DIPSS-plus are ineffective in SMF patients [59]. All these information emphasize the need of new models dedicated to SMF. Ultimately, Passamonti et al. [32 ] developed on a cohort of 781 SMF the MYSEC-PM, in order to address the prediction of survival in patients with SMF. This prognostic model includes age, hemoglobin < 11 g/dl, platelet < /L, circulating blasts 3%, CALR unmutated genotype, and constitutional symptoms (available at prognostic_model/). It allocated SMF patients into four risk categories with different survival: low (median survival NR; 133 patients), intermediate-1 (9.3 years, 95% CI 8.1-NR; 245 patients), intermediate-2 (4.4 years, 95% CI ; 126 patients), and high risk (2 years, 95% CI ; 75 patients). The MYSEC-PM has been recently validated [56, 60]. Treatment of PMF and SMF: Are Differential Strategies Warranted? Treatment avenues for MF patients encompass potentially curative strategies, such as allogeneic stem cell transplant [61, 62 ], and an array of non-disease eradicating options [5, 63, 64, 65 ]. Available prospective and retrospective treatment-centered trials in MF include both PMF and SMF patients without differential approaches according to MF subtype. JAK-inhibitor-based clinical trials comprise a significant proportion (variable between 35 and 55%) of SMF patients [65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75] and the indication of the only currently approved JAK-inhibitor in MF (i.e., ruxolitinib) includes both PMF and SMF. However, as previously mentioned, PMF and SMF differ in clinical features bearing relevance in treatment outcomes. Transfusion-dependence [76 78] more frequent in PMF [33] may impact transplant and JAK-inhibitor treatment outcome, whereas constitutional symptomatology prominent in post-pv MF is a risk factor included in several transplant-specific prognostic scores [33, 79 81]. Furthermore, survival differences between PET MF and PMF may hamper the correct interpretation of clinical trial results [33]. When a risk-based treatment strategy is adopted, both in the transplant and in the non-transplant trial settings [61], patients are currently stratified according to scoring systems geared on PMF, such as the IPSS, DIPSS, or DIPSS-plus [2, 31, 54, 82, 83], regardless of their diagnosis (PMF vs. SMF). Since these models are inadequate for SMF prognostication [32 ], this may lead to the selection of prognostically heterogeneous PMF and SMF patients biasing result assessment. With regard to available JAK-inhibitor trial data, evidence of a differential response according to MF subtype derives from a multivariate analysis of COMFORT-2 suggesting a higher response to ruxolitinib in PET MF with respect to PMF. A pooled analysis of overall survival in COMFORT-1 and COMFORT-2 showed that SMF was associated with a better prognosis than PMF independently of treatment [84].

7 Table 3 Sum of differences between primary and post-pvand post-et myelofibrosis Primary myelofibrosis Secondary myelofibrosis Diagnostic criteria WHO 2016 IWG-MRT (2008) Phenotype Higher transfusion dependence Cytogenetics Higher % of complex karyotype High molecular risk mutations ASXL1, EZH2, IDH1/2, SRSF2 SRSF2 Treatment guidelines ELN 2018 ELN 2018 JAK2 inhibitors Possible higher efficacy Prognostic scores IPSS/DIPSS/DIPSS-plus/MIPSS70 MYSEC-PM Median survival 69 months (IPSS study) 112 months (MYSEC study) Most frequent cause of death Blast phase progression Non-clonal progression Conclusions The aforementioned differences between PMF and SMF (summarized in Table 3) substantiate the efforts underway to adequately stratify SMF patients with ad hoc prognostic tools (such as the MYSEC-PM) [32 ] and to use such categorization to evaluate available treatment modalities according to a SMF-specific risk assessment. In addition, future clinical trials gauging whether a differential clinical approach in PMF and SMF is of value are desirable. In the meanwhile, the most recent ELN guidelines must be adopted [85]. Compliance with Ethical Standards Conflict of Interest interest. The authors declare that they have no conflict of Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. References Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Passamonti F, Maffioli M. Update from the latest WHO classification of MPNs: a user s manual. Hematology Am Soc Hematol Educ Program. 2016;2016(1): Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113(13): Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood. 2016;127: Jeryczynski G, Thiele J, Gisslinger B, Wolfler A, Schalling M, Gleiss A, et al. Pre-fibrotic/early primary myelofibrosis vs. WHOdefined essential thrombocythemia: the impact of minor clinical diagnostic criteria on the outcome of the disease. Am J Hematol. 2017;92(9): Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, Griesshammer M, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011;29(6): Tefferi A, Lasho TL, Guglielmelli P, Finke CM, Rotunno G, Elala Y, et al. Targeted deep sequencing in polycythemia vera and essential thrombocythemia. Blood Adv. 2016;1(1): Barbui T, Thiele J, Passamonti F, Rumi E, Boveri E, Ruggeri M, et al. Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study. J Clin Oncol. 2011;29(23): Guglielmelli P, Pacilli A, Rotunno G, Rumi E, Rosti V, Delaini F, et al. Presentation and outcome of patients with 2016 WHO diagnosis of prefibrotic and overt primary myelofibrosis. Blood. 2017;129: Guglielmelli P, Lasho TL, Rotunno G, Mudireddy M, Mannarelli C, Nicolosi M, et al. MIPSS70: mutation-enhanced international prognostic score system for transplantation-age patients with primary myelofibrosis. J Clin Oncol. 2017; JCO Barosi G, Mesa RA, Thiele J, Cervantes F, Campbell PJ, Verstovsek S, et al. Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment. Leukemia. 2008;22(2): Barbui T, Thiele J, Gisslinger H, Finazzi G, Carobbio A, Rumi E, et al. Masked polycythemia vera (mpv): results of an international study. Am J Hematol. 2014;89(1): Passamonti F, Rumi E, Caramella M, Elena C, Arcaini L, Boveri E, et al. A dynamic prognostic model to predict survival in postpolycythemia vera myelofibrosis. Blood. 2008;111(7): Rumi E, Passamonti F, Della Porta MG, Elena C, Arcaini L, Vanelli L, et al. Familial chronic myeloproliferative disorders: clinical phenotype and evidence of disease anticipation. J Clin Oncol. 2007;25(35): Rumi E, Passamonti F, Pietra D, Della Porta MG, Arcaini L, Boggi S, et al. JAK2 (V617F) as an acquired somatic mutation and a secondary genetic event associated with disease progression in familial myeloproliferative disorders. Cancer. 2006;107(9): Rumi E, Passamonti F, Picone C, Della Porta MG, Pascutto C, Cazzola M, et al. Disease anticipation in familial myeloproliferative neoplasms. Blood. 2008;112(6): author reply 8 9

8 16. Maffioli M, Genoni A, Caramazza D, Mora B, Bussini A, Merli M, et al. Looking for CALR mutations in familial myeloproliferative neoplasms. Leukemia. 2014;28(6): Tefferi A, Guglielmelli P, Larson DR, Finke C, Wassie EA, Pieri L, et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood. 2014;124(16): quiz Passamonti F, Rumi E, Pietra D, Elena C, Boveri E, Arcaini L, et al. A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia. 2010;24(9): Tiribelli M, Barraco D, De Marchi F, Marin L, Medeot M, Damiani D, et al. Clinical factors predictive of myelofibrotic evolution in patients with polycythemia vera. Ann Hematol. 2015;94(5): Alvarez-Larran A, Bellosillo B, Martinez-Aviles L, Saumell S, Salar A, Abella E, et al. Postpolycythaemic myelofibrosis: frequency and risk factors for this complication in 116 patients. Br J Haematol. 2009;146(5): Alvarez-Larran A, Kerguelen A, Hernandez-Boluda JC, Perez- Encinas M, Ferrer-Marin F, Barez A, et al. Frequency and prognostic value of resistance/intolerance to hydroxycarbamide in 890 patients with polycythaemia vera. Br J Haematol. 2016;172(5): Barbui T, Thiele J, Passamonti F, Rumi E, Boveri E, Randi ML, et al. Initial bone marrow reticulin fibrosis in polycythemia vera exerts an impact on clinical outcome. Blood. 2012;119(10): Barraco D, Cerquozzi S, Hanson CA, Ketterling RP, Pardanani A, Gangat N, et al. Prognostic impact of bone marrow fibrosis in polycythemia vera: validation of the IWG-MRT study and additional observations. Blood Cancer J. 2017;7(3):e Abdulkarim K, Ridell B, Johansson P, Kutti J, Safai-Kutti S, Andreasson B. The impact of peripheral blood values and bone marrow findings on prognosis for patients with essential thrombocythemia and polycythemia vera. Eur J Haematol. 2011;86(2): Marchioli R, Finazzi G, Landolfi R, Kutti J, Gisslinger H, Patrono C, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol. 2005;23(10): Vannucchi AM, Antonioli E, Guglielmelli P, Rambaldi A, Barosi G, Marchioli R, et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007;110(3): Passamonti F, Rumi E, Arcaini L, Boveri E, Elena C, Pietra D, et al. Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: a study of 605 patients. Haematologica. 2008;93(11): Rumi E, Pietra D, Guglielmelli P, Bordoni R, Casetti I, Milanesi C, et al. Acquired copy-neutral loss of heterozygosity of chromosome 1p as a molecular event associated with marrow fibrosis in MPLmutated myeloproliferative neoplasms. Blood. 2013;121(21): Elala YC, Lasho TL, Gangat N, Finke C, Barraco D, Haider M, et al. Calreticulin variant stratified driver mutational status and prognosis in essential thrombocythemia. Am J Hematol. 2016;91(5): Barraco D, Cerquozzi S, Hanson CA, Ketterling RP, Pardanani AD, Gangat N, et al. Cytogenetic findings in WHO-defined polycythaemia vera and their prognostic relevance. Br J Haematol Passamonti F, Cervantes F, Vannucchi AM, Morra E, Rumi E, Pereira A, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010;115(9): Passamonti F, Giorgino T, Mora B, Guglielmelli P, Rumi E, Maffioli M, et al. A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis. Leukemia Integrated clinical-molecular prognostic model in SMF.;31: Masarova L, Bose P, Daver N, Pemmaraju N, Newberry KJ, Manshouri T, et al. Patients with post-essential thrombocythemia and post-polycythemia vera differ from patients with primary myelofibrosis. Leuk Res. 2017;59: Cervantes F, Passamonti F, Barosi G. Life expectancy and prognostic factors in the classic BCR/ABL-negative myeloproliferative disorders. Leukemia. 2008;22(5): Barbui T, Carobbio A, Cervantes F, Vannucchi AM, Guglielmelli P, Antonioli E, et al. Thrombosis in primary myelofibrosis: incidence and risk factors. Blood. 2010;115(4): Caramazza D, Begna KH, Gangat N, Vaidya R, Siragusa S, Van Dyke DL, et al. Refined cytogenetic-risk categorization for overall and leukemia-free survival in primary myelofibrosis: a single center study of 433 patients. Leukemia. 2011;25(1): Caramazza D, Hussein K, Siragusa S, Pardanani A, Knudson RA, Ketterling RP, et al. Chromosome 1 abnormalities in myeloid malignancies: a literature survey and karyotype-phenotype associations. Eur J Haematol. 2010;84(3): Caramazza D, Ketterling RP, Knudson RA, Hanson CA, Siragusa S, Pardanani A, et al. Trisomy 11: prevalence among 22,403 unique patient cytogenetic studies and clinical correlates. Leukemia. 2010;24(5): Wassie E, Finke C, Gangat N, Lasho TL, Pardanani A, Hanson CA, et al. A compendium of cytogenetic abnormalities in myelofibrosis: molecular and phenotypic correlates in 826 patients. Br J Haematol. 2015;169(1): Rotunno G, Pacilli A, Artusi V, Rumi E, Maffioli M, Delaini F, et al. Epidemiology and clinical relevance of mutations in postpolycythemia vera and post-essential thrombocythemia myelofibrosis. A study on 359 patients of the AGIMM group. Am J Hematol. 2016;91: Li B, Xu J, Li C, Gale RP, Xu Z, Qin T, et al. Cytogenetic studies and their prognostic contribution in 565 Chinese patients with primary myelofibrosis. Am J Hematol. 2014;89(11): Gangat N, Tefferi A, Thanarajasingam G, Patnaik M, Schwager S, Ketterling R, et al. Cytogenetic abnormalities in essential thrombocythemia: prevalence and prognostic significance. Eur J Haematol. 2009;83: Tang G, Hidalgo Lopez JE, Wang SA, Hu S, Ma J, Pierce S, et al. Characteristics and clinical significance of cytogenetic abnormalities in polycythemia vera. Haematologica. 2017;102: Vaidya R, Caramazza D, Begna KH, Gangat N, Van Dyke DL, Hanson CA, et al. Monosomal karyotype in primary myelofibrosis is detrimental to both overall and leukemia-free survival. Blood. 2011;117(21): Tefferi A, Lasho TL, Finke CM, Knudson RA, Ketterling R, Hanson CH, et al. CALR vs JAK2 vs MPL-mutated or triplenegative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. 2014;28(7): Passamonti F, Mora B, Giorgino T, Guglielmelli P, Cazzola M, Maffioli M, et al. Driver mutations effect in secondary myelofibrosis: an international multicenter study based on 781 patients. Leukemia Beauverd Y, Alimam S, McLornan DP, Radia DH, Harrison CN. Disease characteristics and outcomes in younger adults with primary and secondary myelofibrosis. Br J Haematol. 2016;175: Rumi E, Pietra D, Pascutto C, Guglielmelli P, Martinez-Trillos A, Casetti I, et al. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood. 2014;124(7): Passamonti F, Mora B, Giorgino T, Guglielmelli P, Cazzola M, Maffioli M, et al. Driver mutations effect in secondary

9 myelofibrosis: an international multicenter study based on 781 patients. Leukemia. 2017;31(4): Pietra D, Rumi E, Ferretti VV, Buduo CA, Milanesi C, Cavalloni C, et al. Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms. Leukemia. 2016;30(2): Finazzi G, Carobbio A, Guglielmelli P, Cavalloni C, Salmoiraghi S, Vannucchi AM, et al. Calreticulin mutation does not modify the IPSET score for predicting the risk of thrombosis among 1150 patients with essential thrombocythemia. Blood. 2014;124(16): Vannucchi AM, Lasho TL, Guglielmelli P, Biamonte F, Pardanani A, Pereira A, et al. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013;27(9): Tefferi A, Guglielmelli P, Lasho TL, Rotunno G, Finke C, Mannarelli C, et al. CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. Leukemia. 2014;28(7): Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29(4): Guglielmelli P, Lasho TL, Rotunno G, Mudireddy M, Mannarelli C, Nicolosi M, et al. MIPSS70: mutation-enhanced international prognostic score system for transplantation-age patients with primary myelofibrosis. J Clin Oncol. 2018;36(4): Integrated clinical-molecular prognostic model in PMF. 56. Hernandez-Boluda JC, Pereira A, Correa JG, Alvarez-Larran A, Ferrer-Marin F, Raya JM, et al. Performance of the myelofibrosis secondary to PV and ET-prognostic model (MYSEC-PM) in a series of 262 patients from the Spanish registry of myelofibrosis. Leukemia Gowin K, Coakley M, Kosiorek H, Mesa R. Discrepancies of applying primary myelofibrosis prognostic scores for patients with post polycythemia vera/essential thrombocytosis myelofibrosis. Haematologica. 2016;101:e Hernandez-Boluda JC, Pereira A, Gomez M, Boque C, Ferrer- Marin F, Raya JM, et al. The International Prognostic Scoring System does not accurately discriminate different risk categories in patients with post-essential thrombocythemia and postpolycythemia vera myelofibrosis. Haematologica. 2014;99(4): e Tefferi A, Saeed L, Hanson CA, Ketterling RP, Pardanani A, Gangat N. Application of current prognostic models for primary myelofibrosis in the setting of post-polycythemia vera or postessential thrombocythemia myelofibrosis. Leukemia. 2017;31: Masarova L, Bose P, Pemmaraju N, Daver N, Cortes JE, Estrov Z, et al. Validation of the myelofibrosis secondary to PV and ETprognostic model in patients with post-polycythemia vera and post-essential thrombocythemia myelofibrosis: MD Anderson Cancer Center. Blood. 2017;130(Suppl 1): Kroger N, Giorgino T, Scott BL, Ditschkowski M, Alchalby H, Cervantes F, et al. Impact of allogeneic stem cell transplantation on survival of patients less than 65 years with primary myelofibrosis. Blood. 2015;125: Kroger NM, Deeg JH, Olavarria E, Niederwieser D, Bacigalupo A, Barbui T, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group. Leukemia Indication and management of allogeneic stem cell transplantation in PMF.;29: Passamonti F, Maffioli M, Caramazza D. New generation smallmolecule inhibitors in myeloproliferative neoplasms. Curr Opin Hematol. 2012;19(2): Verstovsek S, Kantarjian HM, Estrov Z, Cortes JE, Thomas DA, Kadia T, et al. Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood. 2012;120(6): Passamonti F, Maffioli M, Cervantes F, Vannucchi A, Morra E, Barbui T, et al. Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT-2 cohorts. Blood Impact on MF natural history of ruxoltinib.;123: Cervantes F, Vannucchi AM, Kiladjian JJ, Al-Ali HK, Sirulnik A, Stalbovskaya V, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood. 2013;122: Harrison CN, Vannucchi AM, Platzbecker U, Cervantes F, Gupta V, Lavie D, et al. Phase 3 randomized trial of momelotinib (MMB) versus best available therapy (BAT) in patients with myelofibrosis (MF) previously treated with ruxolitinib (RUX). J Clin Oncol. 2017;35(15_suppl): Mesa RA, Kiladjian JJ, Catalano JV, Devos T, Egyed M, Hellmann A, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor-naive patients with myelofibrosis. J Clin Oncol. 2017;35(34): Randomized trial with momelotinib in MF. 69. Mesa RA, Passamonti F. Individualizing care for patients with myeloproliferative neoplasms: integrating genetics, evolving therapies, and patient-specific disease burden. Am Soc Clin Oncol Educ Book. 2016;35:e Harrison CN, Schaap N, Vannucchi AM, Kiladjian JJ, Tiu RV, Zachee P, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017;4(7):e317 e24. Randomized trial with fedratinib in ruxolitinib-treated MF. 71. Pardanani A, Harrison C, Cortes JE, Cervantes F, Mesa RA, Milligan D, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1(5): Randomized trial with fedratinib in MF. 72. Mesa RA, Vannucchi AM, Mead A, Egyed M, Szoke A, Suvorov A, et al. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. Lancet Haematol. 2017;4(5):e225 e Talpaz M, Mascarenhas J, Hoffman R, Gerds AT, Stein B, Gupta V, et al. Pacritinib (Pac) vs best available therapy (Bat), including ruxolitinib, in patients (Pts) with myelofibrosis (Mf) and baseline thrombocytopenia: focus on anemia in the phase 3 PERSIST-2 Trial. Haematologica. 2017;102: Randomized trial with pacritinib in MF. 74. Tefferi A, Al-Ali HK, Barosi G, Devos T, Gisslinger H, Jiang Q, et al. A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence. Leukemia. 2017;31(5):1252. Randomized trial with pomalidomide in MF. 75. Tefferi A, Verstovsek S, Barosi G, Passamonti F, Roboz GJ, Gisslinger H, et al. Pomalidomide is active in the treatment of anemia associated with myelofibrosis. J Clin Oncol. 2009;27(27): Elena C, Passamonti F, Rumi E, Malcovati L, Arcaini L, Boveri E, et al. Red blood cell transfusion-dependency implies a poor survival in primary myelofibrosis irrespective of IPSS and DIPSS. Haematologica. 2011;96(1): Gale RP, Barosi G, Barbui T, Cervantes F, Dohner K, Dupriez B, et al. What are RBC-transfusion-dependence and -independence? Leuk Res. 2011;35(1):8 11.

10 78. Gale RP, Barosi G, Barbui T, Cervantes F, Dohner K, Dupriez B, et al. RBC-transfusion guidelines update. Leuk Res. 2012;36(5): Bacigalupo A, Soraru M, Dominietto A, Pozzi S, Geroldi S, Van Lint MT, et al. Allogeneic hemopoietic SCT for patients with primary myelofibrosis: a predictive transplant score based on transfusion requirement, spleen size and donor type. Bone Marrow Transplant. 2010;45(3): Shanavas M, Popat U, Michaelis LC, Fauble V, McLornan D, Klisovic R, et al. Outcomes of allogeneic hematopoietic cell transplantation in patients with myelofibrosis with prior exposure to Janus kinase 1/2 inhibitors. Biol Blood Marrow Transplant. 2016;22(3): Alchalby H, Yunus DR, Zabelina T, Kobbe G, Holler E, Bornhauser M, et al. Risk models predicting survival after reduced-intensity transplantation for myelofibrosis. Br J Haematol. 2012;157(1): Cervantes F, Dupriez B, Passamonti F, Vannucchi AM, Morra E, Reilly JT, et al. Improving survival trends in primary myelofibrosis: an international study. J Clin Oncol. 2012;30(24): Passamonti F, Cervantes F, Vannucchi AM, Morra E, Rumi E, Cazzola M, et al. Dynamic International Prognostic Scoring System (DIPSS) predicts progression to acute myeloid leukemia in primary myelofibrosis. Blood. 2010;116(15): Vannucchi AM, Kantarjian HM, Kiladjian JJ, Gotlib J, Cervantes F, Mesa RA, et al. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica. 2015;100(9): Barbui T, Tefferi A, Vannucchi AM, Passamonti F, Silver RT, Hoffman R, et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia. 2018; /s

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