Persistence of myelofibrosis treated with ruxolitinib: biology and clinical implications

Abstract

Activation of JAK-STAT signaling is one of the hallmarks of myelofibrosis, a myeloproliferative neoplasm that leads to inflammation, progressive bone marrow failure, and a risk of leukemic transformation. Around 90% of patients with myelofibrosis have a mutation in JAK2, MPL, or CALR: so-called ‘driver’ mutations that lead to activation of JAK2. Ruxolitinib, and other JAK2 inhibitors in clinical use, provide clinical benefit but do not have a major impact on the abnormal hematopoietic clone. This phenomenon is termed ‘persistence’, in contrast to usual patterns of resistance. Multiple groups have shown that type 1 inhibitors of JAK2, which bind the active conformation of the enzyme, lead to JAK2 becoming resistant to degradation with consequent accumulation of phospho-JAK2. In turn, this can lead to exacerbation of inflammatory manifestations when the JAK inhibitor is discontinued, and it may also contribute to disease persistence. The ways in which JAK2 V617F and CALR mutations lead to activation of JAK-STAT signaling are incompletely understood. We summarize what is known about pathological JAK-STAT activation in myelofibrosis and how this might lead to future novel therapies for myelofibrosis with greater disease-modifying potential.

Targeting human CALR‐mutated MPN progenitors with a neoepitope‐directed monoclonal antibody

“…Ongoing follow‐up of COMFORT‐1 and COMFORT‐2 studies (Harrison et al , 2012; Verstovsek et al , 2012) suggests patients with CALR mutations are less responsive to the JAK inhibitor ruxolitinib than patients with JAK2 mutations, but cytopenia limits the use of higher treatment doses (Ross et al , 2021). We therefore tested whether an immunotherapeutic approach would have efficacy in cells with ruxolitinib “persistence/resistance” (Meyer et al , 2015).…”

“…CALR mutations appear to be an early event in MPN ontogeny (perhaps only preceded by TET2 in some cases). This results in it being present in all of the cells of the clone, unlike JAK2 V617F which can be either an initiating or a secondary lesion, and found in only around half of patients with AML arising from an antecedent JAK2 V617F MPN (Ross et al , 2021).…”

“…Mutations within CALR , the second most common genetic aberration associated with PMF, are observed in 70% of non‐JAK2 V617F and non‐MPL cases (Klampfl et al , 2013; Nangalia et al , 2013) and are found in 20–30% of ET (Tefferi et al , 2014). Importantly, patients with CALR mutations do not effectively respond to JAK inhibitor therapy and no CALR ‐specific therapy has been developed (Ross et al , 2021).…”

Turner syndrome with primary myelofibrosis, cirrhosis and ovarian cystic mass: A case report

“…In essential thrombocythemia patients, mutation in SH2B3 was found to be an additional negative prognostic factor[ 18 ], which has not been clearly demonstrated in PMF. Though it is recognized that MPL is associated with higher risk of fibrotic progression in essential thrombocythemia[ 19 ], definitive conclusions regarding the impact of MPL and SH2B3 mutations on prognosis or other pathological changes are difficult due to the fact that less than 10% of patients with PMF harbor alternations in the MPL gene[ 20 ] and the rarity of SH2B3 mutations in PMF patients.…”

Understanding Aberrant Signaling to Elude Therapy Escape Mechanisms in Myeloproliferative Neoplasms

“…The reactivation of the JAK2/STAT pathway and the concomitant activation of alternative pathways have been highlighted in response to prolonged treatment with ruxolitinib. Indeed, the compensatory stimulation of the MAPK pathway clearly reduces the efficacy of JAK2 inhibitors both in vitro and in MPN mouse models [ 81 , 82 ]. The use of inhibitors of these additional pathways attracted interest in the field [ 83 , 84 ] that is now translating into the clinic ( Table 2 ).…”