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T. Barbui et al.
information definitely represents the most compelling unmet need in pre-PMF. A prospective registry collecting all new cases may be of significant help in finding an answer, but it may take several years. An alternative option may be a study enrolling not only all incident cases, but also retrospective ones, provided all the diag- noses are validated by a centralized panel of expert histopathologists and clinicians. Moreover, a compre- hensive clinical and biologic database (with a tissue bank collecting samples at diagnosis and during follow up) should be made available. This approach may help to identify the causes of death in patients with pre-PMF, the rate of transformation to overt PMF and acute leukemia, and possibly allow predictive variables to be identified.
Should patients with essential thrombocythemia or polycythemia vera be stratified in genomic subgroups? Recent publications have highlighted the prognostic contribution of genetic information in both ET and PV, which includes driver mutational status, karyotype abnormalities, and presence or absence of mutations in other myeloid genes. Next-generation sequencing (NGS) analysis identified the prognostic relevance of “adverse variants” in terms of inferior overall and shorter leukemia-free or fibrosis-free survival, including ASXL1, SRSF2 and IDH2 in PV and SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2 in ET.10 Although these studies have cer- tainly contributed to advance our knowledge of the potential prognostic value of mutational genotyping in PV and ET, and provided informative tools to identify patients at higher risk of disease progression and leukemia transformation, this approach is still far from being considered relevant in clinical practice. In ET, CALR mutations have been shown to correlate with lower risk of thrombosis compared to JAK2V617F muta- tion and, indeed, the latter is included in the IPSET thrombosis score.11,12 In PV, there is some evidence that patients with higher JAK2V617F allele burden may be at increased risk of thrombosis;13 however, lack of prospec- tive data weakens the value of this information. Future research should evaluate prospectively whether genetic data may add clinically relevant information on top of a conventional score for PV and the IPSET for ET; not an easy task, when considering that the rate of cardiovascu- lar event is around 2% patient-years in ET and 2-3% in PV. Large, international registries may represent the most productive approach using series of patients carefully
annotated according to the 2016 WHO classification.
Should cytoreduction be prescribed to all patients with polycythemia vera regardless of risk?
The first step in approaching a patient with PV is to identify the potential risk of developing major thrombot- ic or hemorrhagic complications. Patients are considered to be low-risk by age <60 years and absence of previous thrombosis,14 but this distinction is weakening. In fact, low-risk patients optimally treated with phlebotomy and low-dose aspirin still exhibit an annual rate of major thrombotic episodes of 2% patients/year; an estimate 2- and 3-fold higher than in the general population with, or without, multiple risk-factors, respectively.15 Thus, one may argue whether, in the presence of such residual risk of thrombosis, the conservative approach based on phle- botomy and aspirin is still appropriate. The greater added benefit of cytoreductive drugs over phlebotomy in
PV is based on the results of the Polycythemia Vera Study Group 01-PVSG study,16 a propensity score analy- sis of the European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP)17 prospective study and one recent retrospective cohort analysis.18 Nonetheless, experts discourage the use of cytoreductive drugs in clin- ical practice for young patients without previous throm- bosis since the supposed leukemogenic risk associated with the currently available drugs, such as hydroxyurea, although largely uncertain, might outweigh the possible antithrombotic benefits.
However, although the prognostic and predictive role of leukocytosis is still debated, it may be worthwhile up- grading low-risk patients presenting with leukocyte counts greater than 11x109/L to the high-risk category and, indeed, these have been included in randomized clinical trials testing hydroxyurea, and ruxolitinib (Mithridate trial; clinicaltrials.gov identifier: NCT4116502). Such a claim could be criticized since there has still been no formal demonstration of a clear advantage of cytore- ductive therapy over a well-conducted phlebotomy poli- cy. Therefore, we believe that young patients with no history of previous thrombosis could be exposed to cytoreductive treatment as long as they only receive drugs for which there is no evidence of promoting sec- ondary leukemias or solid tumors. One such a drug is interferon, either in conventional or novel retard formu- lation, such as Ropeginterferon a-2ba which has recently been approved by the European Medicines Agency (EMA) for PV based on phase II and III studies.19 In these studies, an overall hematologic response in more than 80% of patients, good tolerability and evidence of molecular responses were found.20 The ongoing random- ized clinical trial (Low-PV), testing Ropeginterferon a- 2ba in addition to conventional treatment, may hopeful- ly provide a convincing answer to one of the clinical needs of patients with low-risk PV.
Can we improve the prevention and treatment of post- myeloproliferative neoplasms-acute myeloid leukemia? Leukemia transformation of PV and ET is part of the natural history of these diseases.21 The risk of leukemic transformation is highest in PMF, but a sizeable propor- tion of PV and ET patients are involved, with an estimat-
ed risk of 3% and 1% at 10 years, respectively.22 It is like- ly that, in these patients, the unrestricted proliferation of bone marrow progenitors lasting for many years may itself favor the leukemic transformation, and, not surpris- ingly, older age, leukocytosis, and massive thrombocyto- sis represent significant risk factors in both PV and ET. Most importantly, biologic characteristics such as abnor- mal karyotype, presence of SRSF2 or IDH2 mutations are emerging risk factors in PV. In ET, anemia, older age, leukocytosis, and presence of TP53 or EZH2 mutations have been reported as risk factors.22 Therefore, NGS- based molecular profile performed at diagnosis and dur- ing the course of the disease may provide important information to identify patients at higher risk of disease progression and leukemia transformation.10
There is no evidence that hydroxyurea, interferon, anagrelide or ruxolitinib can slow down the intrinsic ten- dency of these diseases to transform into AML.23 On the other hand, there are expectations that some new, target- ed drugs may reduce the risk of leukemic transformation. Idasanutlin, an MDM2 inhibitor which modulates
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haematologica | 2020; 105(8)