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  • The combination therapy was exceedingly well tolerated witho

    2019-06-26

    The combination therapy was exceedingly well tolerated without any side effects to either drug. Remarkably, despite an advanced PV-stage the JAK2V617F allele burden was rapidly lowered from 90% mutated Dyphylline at referral to 59% at 6 months, 28% at 10 months and 12% at 16 months of therapy (Fig. 2).
    Discussion This case report – being the first on combination therapy with IFN and a JAK1-2 inhibitor – has convincingly shown that this combinatorial approach is highly efficacious in a PV-patient with advanced disease and a large tumor burden, as evidenced by pronounced splenomegaly and a high JAK2V617F-allele burden. Most importantly, the treatment was associated with a rapid decline in the JAK2V617F-allele burden within a few months, which has been argued not to be possible due to inhibition of IFN-signaling during JAK-inhibitor treatment. Of note, serial ultrasound examinations of the carotid arteries showed an improvement of the blood-flow. Whether this improvement was attributed to normalization of the hematocrit, leukocyte and platelet-counts or might be due to the anti-inflammatory potential of Rux within the carotid artery wall diminishing inflammation (atherosclerosis being a chronic inflammatory disease) is elusive but certainly warrants further investigation. The potent efficacy of this combination therapy in our patient may be explained by several mechanisms [1]. Firstly, using Rux with a half-life of approximately 3h may leave a time-window of a several hours daily in which efficient IFN-signaling is possible. Also the possibility exists that – at a certain level of JAK-inhibition by Rux – the IFN-signaling is merely modulated rather than totally abolished. Secondly, the potent anti-inflammatory effect of JAK1-2 inhibition may have reduced or eliminated the (transient) systemic inflammation response, mediated by the release of inflammatory cytokines in the context of the IFN- mediated tumor killing. Thirdly, by reducing the release of TNF-alpha – a cytokine, which has been shown to facilitate clonal evolution – concomitant JAK1-2 inhibition with Rux might have improved the tumor-reducing effect of IFN. Fourthly, the possibility exists that IFN might actually have augmented the effects of JAK1-2 inhibition, as IFN blocks the intramedullary release of cytokines from bone marrow stroma. These cytokines have been shown to protect JAK2V617F-positive tumor cells from the JAK1-2 inhibitor-induced tumor killing [2]. Fifthly, most recently, chronic inflammation with oxidative stress and generation of reactive oxygen species (ROS) has been argued to be of major importance for clonal evolution and disease progression in MPNs [1–3]. Indeed, MPNs have been shown most recently to be associated with pronounced oxidative stress and ROS accumulation and most lately the JAK2V617F mutation per se has been demonstrated to generate ROS [4]. Since IFN-signaling is impaired by oxidative stress it is most intriguing to consider, if a combinatorial approach with a JAK1-2 inhibitor indeed might improve IFN-signaling – otherwise potentially impaired by oxidative stress mediated by the MPN-clone itself [2,4]. Accordingly, considering all the above anti-inflammatory actions, a combinatorial approach with IFN and a JAK1-2 inhibitor may prove to be more efficacious than single-agent therapy [5]. Furthermore, IFN-a2 also activates dormant stem cells [6] and mobilizes them to be targets for potent JAK1-2 inhibition. Thus, by concurrently depleting dormant JAK2V617F MPN propagating stem cells with IFN-alpha [7] and targeting the proliferating downstream progeny with JAK1-2 inhibitors [6,8], a combination of IFN and a JAK1-2 inhibitor may be a highly efficacious treatment modality in MPNs with superior tumor control and less IFN side-effects [1,2]. Our patient tolerated the combination therapy exceedingly well without side effects or myelosuppression, which otherwise might be a concern, taking into consideration that both JAK inhibition and IFN may be associated with myelosuppression. However, in the context of treating MPN patients with elevated cell counts (the pancytopenic myelofibrosis patient with severe myelofibrosis is not a candidate for IFN and accordingly neither for combination therapy) myelosuppression is not likely to occur provided that low-dose IFN (e.g., Pegasys 45µg subcutaneously once weekly) and low-dose Rux (e.g., ruxolitinib 10mg twice daily) are being used. Otherwise, combination therapy with IFN+Rux is not expected to be associated with any particular risk or side effects. In fact, the flue-like symptoms during the initial phase of IFN treatment, being likely associated with “a systemic inflammation response”, may actually vanish, when IFN-a2 is combined with a potent anti-inflammatory agent such as Rux.