Page 25 - 2020_08-Haematologica-web

Future research projects in PV and ET
MDM2/p53 interaction and restores p53 activity, pro- duced clinical responses in PV both as monotherapy and in combination with interferon.24 HDAC inhibitors like givinostat are equally non-genotoxic and active drugs in PV and ET.25
As regards the therapeutic approach to post-myelopro- liferative neoplasms-acute myeloid leukemia (MPN- AML), prognosis is largely dismal except for the few patients who undergo allogeneic hematopoietic stem cell transplantation (alloHSCT), preferably after debulking with induction chemotherapy. However, new drugs are particularly appealing in this setting, including enasi- denib and ivosidenib for patients with IDH2 or IDH1 mutated AML, possibly in combination with azaciti- dine26 or ruxolitinib (in case of enasidenib).27 In addition, BCL2 inhibitors, like venetoclax or navitoclax, (alone or in combination with hypomethylating agents) and CPX- 351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin, are also under investigation. At the moment, however, results from rigorously designed clin- ical trials in this category of high-risk patients are still lacking and the little interest, if any, of pharma compa- nies to promote studies in this setting represents a major problem. It is, therefore, a clear duty of the scientific community to promote academic trials for this unmet clinical need. Since alloHSCT remains the only potential- ly curative treatment option for these patients,28 inten- sive treatment capable of achieving remission with a full or even incomplete hematologic reconstitution has to be made available. Apart from some new forthcoming pro- tocols, registry collection of the outcomes of these patients is strongly recommended, particularly with the intent to identify biologic subgroups.
Are the current prevention methods for thrombosis adequate?
The current annual incidence of arterial and venous thrombosis in patients with PV and ET is 2.62% and 1.77%, respectively, a figure 1.5-fold and 3.2-fold higher than that in the general population.12,15-20 The antithrom- botic role of cytoreductive drugs is uncertain. Hydroxyurea (HU) has demonstrated significant efficacy in preventing arterial thromboses, but doubts remain as to its ability to prevent recurrent venous thromboem- bolism (VTE),29-31 particularly in patients with splanchnic venous thrombosis.32,33 The antithrombotic efficacy of interferon-a has not yet been convincingly demonstrat- ed, and the performance of ruxolitinib in PV patients resistant/intolerant to HU is largely uncertain.34 Although there is no direct evidence that thrombocytosis per se is a risk factor for thrombosis, the favorable effect of ana- grelide versus HU in preventing the occurrence of venous thromboembolism in ET, as shown in the PT1 random- ized clinical trial,35 is of interest. However, the interpreta- tion of that study is complicated by the heterogeneity of the patient population that was diagnosed according to WHO 2008 criteria. Of note, the ANAHYDRET study, that included patients with a diagnosis of ET that strictly followed WHO 2016 criteria, showed non-inferiority in terms of arterial and venous events.36 As a whole, there is still no convincing evidence of a clear antithrombotic action of cytoreductive drugs in ET and PV, and new ran- domized clinical trials with thrombosis as the primary end point are warranted.
The indication of low-dose aspirin (LDA) is mainly based on a phase III trial in PV37 and on retrospective studies in ET, but the quality of evidence is low.38 However, new hypotheses are now being tested to improve the antithrombotic efficacy of aspirin in ET. These are based on the notion that accelerated release of new platelets in ET may accelerate the recovery of thromboxane (TX)A2-dependent platelet function during the once-daily (od) LDA dosing interval. Accordingly, inhibition of the surrogate biomarker platelet TXA2 by o.d. LDA is incomplete in ≥80% of ET patients, but it was seen to be improved by a twice-daily regimen.39,40 In the phase II ARES randomized trial,41 most of the 245 ET patients treated with LDA displayed incomplete platelet inhibition, which was improved by shortening the dos- ing interval to 12 hours.42 The long-term superiority, compliance, and tolerability of an optimized LDA regi- men is now being investigated in a clinical trial.
The prevention of recurrent venous thromboembolism by vitamin K-antagonists (VKA) was estimated in several retrospective studies showing an annual incidence of VTE recurrences as high as 5.6-6.5,31,43-46 that rose to as high as 12.8 after discontinuation.45 In addition, the inci- dence of major bleeding on VKA of 1.7-1.8 per 100 patients/years44,45 is unsatisfactory when compared with non-MPN patients. As mentioned above, the addition of hydroxyurea to VKA has a weak effect,31 and the com- bined treatment with LDA significantly increases the risk of bleeding with no substantial benefit on antithrombot- ic prevention.43,47 Thus, the prevention of recurrences after VTE is a crucial unmet clinical need in MPN, and innovative strategies are needed. Direct oral anticoagu- lants (DOAC) can represent a suitable alternative, but before embarking on a formal randomized comparative trial assessing DOAC versus warfarin, a retrospective analysis of treated cases may guide its design. In this regard, some preliminary evidence has been presented in the prospective multicenter observational REVEAL study.47
Conclusion
We have highlighted some clinical topics about which the available evidence is limited. We believe these areas represent priorities for future research projects. Since both PV and ET are relatively rare diseases, and the out- comes of interest occur after long periods of observation, the methodology to conduct these studies cannot be rea- sonably based on conventional phase II/III design. Therefore, well organized observational and registry- based studies will play a key role in analyzing the clinical outcomes, hopefully with the help of a data mining approach and artificial intelligence techniques, as sug- gested by preliminary experiences in patients with PV treated with ruxolitinib.48
Acknowledgments
This study was supported by Fondazione per la Ricerca Ospedale (FROM), Papa Giovanni XXIII Hospital, Bergamo, Italy; and by Associazione Italiana per la Ricerca sul Cancro, Grant 5 per Mille, Progetto MYNERVA (P.G. and A.M.V.) and Progetto ISM (AR)
haematologica | 2020; 105(8)
2001