Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis

Abstract

Background Myelofibrosis is a Philadelphia chromosome–negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor. Methods We conducted a phase 1–2 trial of INCB018424 in patients with JAK2 V617F–positive or JAK2 V617F–negative primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis. Results A total of 153 patients received INCB018424 for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia. A dose-dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (≥50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis. Conclusions INCB018424 was associated with marked and durable clinical benefits in patients with myelofibrosis for whom no approved therapies existed.

One Thousand Patients With Primary Myelofibrosis: The Mayo Clinic Experience

“…However, most of these patients either belong to higher-risk disease categories, which mandate instead consideration for ASCT, or are the same ones who have anemia or thrombocytopenia, which happen to constitute the main adverse effects of such drugs. 24,25 One interesting aspect of the current study was the significantly higher prevalence of adverse risk factors in patients seen within 1 year of diagnosis compared with those seen at the time of initial diag- …”

“…37,38 The particular information also points out the limitations of drugs that display anemia as an adverse effect, which is a recurrent issue with certain JAK inhibitors. 24,25 The study also suggests that about a third of patients present with marked splenomegaly or constitutional symptoms and might, therefore, benefit from JAK inhibitor therapy. However, most of these patients either belong to higher-risk disease categories, which mandate instead consideration for ASCT, or are the same ones who have anemia or thrombocytopenia, which happen to constitute the main adverse effects of such drugs.…”

“…23 The constitutive activation of janus kinase-signal transducers and activators of transcription (JAK-STAT) in PMF offered hope for targeted therapy, but currently available JAK inhibitor drugs have yet to meet expectations in terms of hematologic, cytogenetic, or molecular remissions. 24,25 This article summarizes our decades of experience with PMF. We considered 1000 consecutive patients who were seen between 1977 and 2011 and in whom clinical and bone marrow pathologic information was available for review.…”

Aquagenic pruritus in polycythemia vera: Characteristics and influence on quality of life in 441 patients

“…Ruxolitinib is the first FDA-and EMA approved JAK2-/JAK1-inhibitor for the treatment of myelofibrosis. In the COMFORT-studies, the response rates for AP were up to 92% [21,22]. This implies that the JAK2/JAK1 pathway is involved in the generation of AP.…”

How to manage children and young adults with myeloproliferative neoplasms

“…The efficacy of novel JAK2 inhibitors seems promising, 63,64 so that I encourage PMF and PV/ET patients with symptomatic refractory splenomegaly and severe constitutional symptoms to participate in clinical trials. However, I underscore that there is no evidence that these novel drugs can eradicate or modify the natural history of disease.…”