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Common “Philadelphia chromosome”-negative myeloproliferative neoplasms (MPN) include essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF), which are a clinically diverse group of diseases. In the last 15 years, there have been rapid advances in understanding the importance and therapeutic potential of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway in MPN. In their recent review,1 Donal McLornan and Claire Harrison, both from the Department of Haematology, Guys and St Thomas’ NHS Foundation Trust, London, UK, aimed to discuss the therapeutic challenges, diagnostic issues, molecular characterization, monitoring and management, novel therapies and treatment failure definition in MPN.
In their discussion of MPN-related issues and challenges, Dr McLornan and Prof Harrison highlighted a study by Grinfield et al. (2018)1 which indicated that MPN outcomes are better predicted by genomic profiling than by traditional clinical criteria. However, they felt that as genomic profiling did not predict outcome with therapy, nor thrombosis, these assessments were unlikely to be adopted at present. Grinfield et al. showed that patients with ET that lack driver mutations (triple negative ET) have the best outcomes amongst ET patients and may therefore benefit from de-escalation of therapy to prevent iatrogenic harm. Further, in an aspirin study by Alvarez-Larran et al. (2016)1, calreticulin (CALR) mutated ET was associated with a bleeding rather than a thrombotic phenotype, suggesting that selected CALR mutated patients may also benefit from de-escalation of therapy.
Studies of novel oral anticoagulants (NOAC) for the prevention of thrombosis suggest that they present a safe and effective treatment, but longer-term studies are needed.
MAJIC-ET, a phase II study of ruxolitinib (a JAK inhibitor; rux) vs best available therapy (BAT) found no difference in efficacy between the treatments but did show that a subgroup of patients with hydroxycarbamide (HC) resistant/intolerant ET have significantly worse outcomes. These were related to the presence of tumor protein p53 (TP53) and splicing factor mutations that led to reduced transformation-free survival [splicing factor 3b subunit 1 (SF3B1), zinc finger CCCH-type RNA binding motif and serine/arginine rich 2 (ZRSR2) and serine and arginine rich splicing factor 2 (SRF2)]. Ten-eleven translocation 2 (TET2) mutations were not associated with decreased survival.
When comparing HC and interferon (IFN) treatment in PV, studies such as the PROUD study have demonstrated that IFNs (specifically pegylated interferon alpha 2b) are considered key players in the treatment of PV. Indeed, the results of the PROUD trial led to the approval of IFN compounds for the treatment of patients with PV without splenomegaly. The RESPONSE phase III trial, which led to the approval of rux for the treatment of hydroxyurea resistant/intolerant PV, suggested that rux may also be effective after IFN treatment. The ongoing phase III study MITHRIDATE will assess rux vs HC or IFN as first line therapy in high-risk PV in terms of thrombosis, hemorrhagic events and disease progression.
Dr McLornan and Prof Harrison go on to discuss how most available MPN studies have not focused on disease progression as an outcome, largely due to the low event rate of progression hence requiring large patient numbers and long term follow-ups. Surrogate markers of disease progression are needed as many studies use markers that have not been shown to correlate with progression (with the exception of hematocrit). Interestingly, the analysis of the MAJIC-PV trial showed that patients achieving a European LeukemiaNET (ELN) partial molecular response by one year (≥50% decrease in JAK2 V617F allelic burden) have improved progression-free survival and no thrombotic events.
Studies of MF include the COMFORT I and II studies, which showed that rux therapy in intermediate-2 or high-risk patients (as defined using the International Prognostic Scoring System [IPSS]) improved overall survival. In addition, the studies found that spleen volume reduction (SVR), and reduction in total symptom score (TSS) may be good surrogate markers of long-term benefit for MF.
Unanswered questions remain regarding the level of SVR and TSS reduction that would be acceptable for adoption of novel therapies, and whether there are other endpoints that may be important indicators of successful treatment. In addition, there are questions around how to define failure and outcomes after rux failure in patients with MF. These are not standardized and vary between trials, and although transplantation remains the best option for a cure, when to transplant patients on JAK inhibitors, the role of these in lower-risk patients and how JAK inhibition may contribute to a reduction in graft-versus-host disease (GvHD) remain largely unknown.
In the MPN Landmark survey,1 fatigue was highlighted as the most common and significant symptom that patients were most keen to address. Fatigue is an elusive side effect that cannot be easily addressed by current treatments and is in fact a side effect of many drugs used for MPN treatment. Patients also reported that interference with family and social life, heavy emotional burden, frequent cancellation of planned activities, reduced productivity, financial hardships and impacts on employment, were significant factors that impacted them, with only a very few of those being assessed in trials. According to the survey, patients also felt that one of the most important treatment outcomes was the prevention of disease progression.
Genomics – classification and prognostics
The Grinfield et al. study (2018), which was mentioned previously, included 2,035 patients (1,321 ET, 356 PV, 309 MF, and 49 other MPN) and by utilizing Bayesian modelling of genomic profiles, revealed eight different MPN genomic subgroups that correlated with clinical phenotype and outcome and may enable treatment stratification once further validated.
Despite studies of hedgehog signaling pathway inhibitors, and phosphatidylinositol 3 (PI3) kinase pathway inhibitors showing initial promise for MPN, these haven’t being investigated further as of yet.
Due to mutations seen in MPN that affect epigenetic processing, the authors highlighted this as an area of growing interest.
The authors discussed how the link between BM fibrosis and clinical outcome is unclear and highlighted how long term rux treatment correlates with a greater odds of fibrosis improvement when compared to BAT.
In their review, Dr McLornan and Prof Harrison highlight the lack of mutation-specific therapies for MPN and pinpoint mutant CALR as a particular area of interest for future targeting. They also refer to JAK inhibition as the main area of focus and mention that combination therapies with rux could increase the benefits of this treatment, but also suggest exploring sequential treatments. There are a number of highly ambitious combination studies ongoing, but the authors point out that they all focus on slightly different cohorts thus potentially impacting the applicability of the results, encouraging careful annotation of patient population in future studies. They also revisit the need to determine appropriate endpoints for studies in the MPN setting and suggest that this is “a pressing clinical need”.
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