br Discussion The natural history

Discussion The natural history of PMF is characterized by the possibility of blastic transformation in approximately 20% of all the cases [9]. Several factors might predict leukemic transformation, including percentage of circulating blasts, low platelets count and the presence of an unfavorable karyotype. At a molecular level, it is well known that PMF patients harboring type-1 CALR mutation have a more indolent clinical course compared to other mutational profiles, especially considering those cases without known driver mutations (i.e. triple-negative patients). Furthermore, patients carrying high risk mutations, namely ASXL1, IDH1-2, EZH2 and SRSF2 show a reduced leukemia-free survival [10–12]. Only few cases of MS have been reported in the literature so far [4,5], and even fewer cases developed synchronous or metachronous PMF. Regarding MS pathogenesis, aberrant tropism of leukemic blasts for extramedullary tissues is poorly understood. It is clear that homing of tumor SYBR Safe DNA Gel Stain is a complex phenomenon determined by several factors, including the expression of chemokine receptors and adhesion molecules that is already under control of many genetic and epigenetic mechanisms [13]. To address the hypothesis that MS is genetically similar to AML, in 2015 Li et al. performed next-generation sequencing analysis in six cases of isolated MS [11], and confirmed the frequent occurrence of FLT3 and NPM1 mutations. Furthermore, they identified other mutations in a broad spectrum of AML associated genes, including tumor suppressors (WT1), epigenetic modifiers (TET2, ASXL1, EZH2), spliceosome proteins (SF3B1) and tyrosine kinase (FLT3 and KIT). With regard to KIT mutation, interestingly, Li et al. showed the presence of somatically acquired mutation KITM541L in four of the six analyzed patients, being the latter previously associated with a variety of neoplasms including hematologic malignancies such as CML or Chronic Eosinophilic Leukemia [11, 14, 15]. Concerning MS prognosis, it varies according to the different background of MS formation. In particular, it seems clear that isolated MS presents a more favorable clinical course than cases with either concomitant AML or at AML relapse. In addition, Lan et al. and Kawamoto et al. showed a more aggressive clinical course in MS following MDS or MPN [5,16]. Furthermore, the authors showed that immunohistochemical expression of CXCR4, that could be implicated in MS pathogenesis, was a poor prognostic factor for overall survival (OS) [5]. CXCR4 over-expression in cancer is thought to be associated with chemotaxis, invasion, angiogenesis and proliferation. It has also been demonstrated that in hematological malignancies, the over-expression of CXCR4 is related to a shortened progression-free and overall survival, in particular in AML patients [13,17]. This genomic complexity of MS implies that this malignancy presents a poor response to therapy. In fact, as recently reported by Lazzarotto et al., the complete remission rate of a cohort of 48 MS treated with various intensive induction chemotherapy regimens (including fludarabine-based, anthracicline and cytarabine containing treatments) was about 45%, and the median (OS) of the entire population was 16.7 months, with a 5-year OS of 33%. This outcome was favorably influenced by response to first induction chemotherapy and was better in patients receiving allogeneic stem cell transplantation [18]. Demethylating agents may have a role in the therapeutic scenario of MS patients, in particular for those who are ineligible for intensive treatments, although the number of cases treated is still low, due to the rarity of this disease. Recently, Gornicec et al. described three MS cases treated with decitabine achieving a good response [19]. Two other cases with durable remission were previously described [20,21]. Radiotherapy may also be useful in the treatment of MS. In fact, this therapeutic approach provides timely symptom palliation with modest radiation doses and minimal toxicity [22]. Some case-series reported that RT for consolidation in addition to systemic chemotherapy was associated with a better outcome in patients with MS [23]. Consolidation with RT has also been suggested in patients with incomplete response to chemotherapy [24].