Current and future status of JAK inhibitors McLornan, Donal P; Pope, Janet E; Gotlib, Jason ...
The Lancet (British edition),
08/2021, Letnik:
398, Številka:
10302
Journal Article
Recenzirano
An enhanced understanding of the importance of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signalling in multiple disease states has led to an increasing ...applicability of therapeutic intervention with JAK inhibitors. These agents have revolutionised treatments for a heterogeneous group of disorders, such as myeloproliferative neoplasms, rheumatoid arthritis, inflammatory bowel disease, and multiple immune-driven dermatological diseases, exemplifying rapid bench-to-bedside translation. In this Therapeutics paper, we summarise the currently available data concerning the successes and safety of an array of JAK inhibitors and hypothesise on how these fields could develop.
There has been a major revolution in the management of patients with myeloproliferative neoplasms (MPN), and in particular those with myelofibrosis and extensive splenomegaly and symptomatic burden, ...after the introduction of the JAK1 and JAK2 inhibitor ruxolitinib. The drug also has been approved as second-line therapy for polycythemia vera (PV). However, the therapeutic armamentarium for MPN is still largely inadequate for coping with patients' major unmet needs, which include normalization of life span (myelofibrosis and some patients with PV), reduction of cardiovascular complications (mainly PV and essential thrombocythemia), prevention of hematological progression, and improved quality of life (all MPN). In fact, none of the available drugs has shown clear evidence of disease-modifying activity, even if some patients treated with interferon and ruxolitinib showed reduction of mutated allele burden, and ruxolitinib might extend survival of patients with higher-risk myelofibrosis. Raised awareness of the molecular abnormalities and cellular pathways involved in the pathogenesis of MPN is facilitating the development of clinical trials with novel target drugs, either alone or in combination with ruxolitinib. Although for most of these molecules a convincing preclinical rationale was provided, the results of early phase 1 and 2 clinical trials have been quite disappointing to date, and toxicities sometimes have been limiting. In this review, we critically illustrate the current landscape of novel therapies that are under evaluation for patients with MPN on the basis of current guidelines, patient risk stratification criteria, and previous experience, looking ahead to the chance of a cure for these disorders.
Genetic analysis involving 2035 patients with a myeloproliferative disorder identified eight genomic subgroups with distinct clinical phenotypes, risk of leukemic transformation, and event-free ...survival.
Summary
The combined incidence of classical Philadelphia‐negative myeloproliferative neoplasm (MPN) is 6–9/100 000 with a peak frequency between 50 and 70 years. MPN is less frequent in women of ...reproductive age. However, for essential thrombocythaemia (ET) in particular there is a second peak in women of reproductive age and 15% of polycythaemia vera (PV) patients are less than 40 years of age at the time of diagnosis. Thus these diseases are encountered in women of reproductive potential and may be diagnosed in pregnancy or in women being investigated for recurrent pregnancy loss. The incidence of MPN pregnancies is 3·2/100 000 maternities per year in the UK. The majority of data regarding Philadelphia‐negative MPNs relates to patients with ET, for which the literature suggests significant maternal morbidity and poor fetal outcome; specifically maternal thrombosis and haemorrhage, miscarriage, pre‐eclampsia, intrauterine growth restriction (IUGR), stillbirth and premature delivery as summarised in the recent systematic review and meta‐analysis in Blood, 2018, 132, 3046. The literature for PV is more sparse but increasing and is concordant with ET pregnancy outcomes. The literature regarding primary myelofibrosis (PMF) is even more scarce. Treatment options include aspirin, venesection, low molecular weight heparin (LMWH) and cytoreductive therapy. Data and management recommendations are often extrapolated from other pro‐thrombotic conditions or from ET to PV and PMF. Women of reproductive age with a diagnosis of MPN should receive information and assurance regarding management and outcome of future pregnancies. From pre‐conceptual planning to the post‐partum period, women should have access to joint care from an obstetrician with experience of high‐risk pregnancies and a haematologist in a multidisciplinary setting. This paper provides an update with regards to Philadelphia‐negative MPN in pregnancy, details local practise in an internationally recognised centre for patients with MPN and outlines a future research strategy.
Polycythemia vera (PV) was first described by Vaquez in 1892. This is a chronic hematological malignancy which affects both older and young patients. Perhaps due to lack of a curative treatment and ...the perceived toxicities of prior therapies our focus in the past was to intensify treatment only for patients at higher risk of thrombosis. Recent triggers to challenge this approach include: a recognition that low-risk PV is not "no-risk", our ability to better recognize patients who would benefit from more intensive therapy from the perspective of thrombosis, and data showing that some treatments may reduce risk of transformation to myelofibrosis. Furthermore, there is emergent evidence that molecular monitoring may identify an improvement in disease state translating to improved overall survival. Here we describe clinical situations that would trigger the use of cytoreductive treatment for low-risk PV patients as well as our approach to choosing a specific cytoreductive agent and how to effectively monitor treatment.
Myelofibrosis is a BCR-ABL1–negative myeloproliferative neoplasm characterized by anemia, progressive splenomegaly, extramedullary hematopoiesis, bone marrow fibrosis, constitutional symptoms, ...leukemic progression, and shortened survival. Constitutive activation of the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway, and other cellular pathways downstream, leads to myeloproliferation, proinflammatory cytokine expression, and bone marrow remodeling. Transplant is the only curative option for myelofibrosis, but high rates of morbidity and mortality limit eligibility. Several prognostic models have been developed to facilitate treatment decisions. Until the recent approval of fedratinib, a JAK2 inhibitor, ruxolitinib was the only available JAK inhibitor for treatment of intermediate- or high-risk myelofibrosis. Ruxolitinib reduces splenomegaly to some degree in almost all treated patients; however, many patients cannot tolerate ruxolitinib due to dose-dependent drug-related cytopenias, and even patients with a good initial response often develop resistance to ruxolitinib after 2–3 years of therapy. Currently, there is no consensus definition of ruxolitinib
failure
. Until fedratinib approval, strategies to overcome ruxolitinib resistance or intolerance were mainly different approaches to continued ruxolitinib therapy, including dosing modifications and ruxolitinib rechallenge. Fedratinib and two other JAK2 inhibitors in later stages of clinical development, pacritinib and momelotinib, have been shown to induce clinical responses and improve symptoms in patients previously treated with ruxolitinib. Fedratinib induces robust spleen responses, and pacritinib and momelotinib may have preferential activity in patients with severe cytopenias. Reviewed here are strategies to ameliorate ruxolitinib resistance or intolerance, and outcomes of clinical trials in patients with myelofibrosis receiving second-line JAK inhibitors after ruxolitinib treatment.
Ruxolitinib, an oral inhibitor of Janus kinase (JAK) 1 and 2, was associated with hematocrit control and spleen size reduction in 21% of patients with polycythemia vera who had an inadequate response ...to or unacceptable side effects from hydroxyurea.
Polycythemia vera is a chronic clonal myeloproliferative neoplasm characterized by increased red-cell mass; elevated white-cell and platelet counts are also common.
1
Patients have an increased risk of thrombotic and cardiovascular events
2
and a substantial symptom burden that includes pruritus, fatigue, and night sweats.
3
Splenomegaly often develops as the disease progresses.
4
The main goal of therapy is to prevent thrombotic events while avoiding iatrogenic harm and minimizing the risk of transformation to post–polycythemia vera myelofibrosis or acute myeloid leukemia (AML).
5
,
6
Most patients receive low-dose aspirin and undergo phlebotomy,
7
with a goal of maintaining hematocrit values of less than 45%. Aggressive . . .
About 10% of myeloproliferative neoplasms carry mutations in both
TET2
and
JAK2
. Clinical presentation, risk of thrombosis, and rates of tumor progression are affected by which gene mutation is ...acquired first.
Cancers evolve as a consequence of the stepwise accumulation of somatic lesions, with competition between subclones and sequential subclonal evolution.
1
,
2
Darwinian selection of variant subclones results in acquisition of biologic attributes required for tumor formation.
3
Genetic interaction is central to this process, but it is unclear how mutated genes interact to generate the phenotypic hallmarks of cancer, and the influence, if any, of the order in which mutations are acquired is unknown.
4
Cooperation between different genetic lesions has been observed in cell-line models of transformation
5
and in mouse models of several cancers.
6
,
7
Moreover, the consequences of an early . . .
Advances in understanding the pathogenesis and molecular landscape of myelofibrosis have occurred over the last decade. Treating physicians now have access to an ever-evolving armamentarium of novel ...agents to treat patients, although allogeneic hematopoietic stem cell transplantation remains the only curative approach. Improvements in donor selection, conditioning regimens, disease monitoring and supportive care have led to augmented survival after transplantation. Nowadays, there are comprehensive guidelines concerning allogeneic hematopoietic stem cell transplantation for patients with myelofibrosis. However, it commonly remains difficult for both physicians and patients alike to weigh up the risk-benefit ratio of transplantation given the inherent heterogeneity regarding both clinical course and therapeutic response. In this timely review, we provide an up-to-date synopsis of current transplantation recommendations, discuss usage of JAK inhibitors before and after transplantation, examine donor selection and compare conditioning platforms. Moreover, we discuss emerging data concerning the impact of the myelofibrosis mutational landscape on transplantation outcome, peritransplant management of splenomegaly, poor graft function and prevention/management of relapse.
Myelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the long-term survival benefit with ...ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, in patients with intermediate-2 (int-2) or high-risk MF.
This was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy). All continuing patients in the control groups crossed over to ruxolitinib by the 3-year follow-up. Overall survival (OS; a secondary endpoint in both trials) was evaluated using pooled intent-to-treat data from patients randomized to ruxolitinib or the control groups. OS was also evaluated in subgroups stratified by baseline anemia and transfusion status at week 24.
A total of 528 patients were included in this analysis; 301 were originally randomized to ruxolitinib (COMFORT-I, n = 155; COMFORT-II, n = 146) and 227 to control (n = 154 and n = 73, respectively). The risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS, 5.3 vs 3.8 years, respectively; hazard ratio HR, 0.70 95% CI, 0.54-0.91; P = 0.0065). After correcting for crossover using a rank-preserving structural failure time (RPSFT) method, the OS advantage was more pronounced for patients who were originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib (median OS, 5.3 vs 2.3 years; HR ruxolitinib vs RPSFT, 0.35 95% CI, 0.23-0.59). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged OS compared with control (median OS, 5.3 vs 2.4 years; HR ruxolitinib vs censored at crossover, 0.53 95% CI, 0.36-0.78; P = 0.0013). The survival benefit with ruxolitinib was observed irrespective of baseline anemia status or transfusion requirements at week 24.
These findings support ruxolitinib treatment for patients with int-2 or high-risk MF, regardless of anemia or transfusion status. Further analyses will be important for exploring ruxolitinib earlier in the disease course to assess the effect on the natural history of MF.
ClinicalTrials.gov identifiers, NCT00952289 and NCT00934544 .
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