Safety and efficacy of jaktinib in the treatment of Janus kinase inhibitor‐naïve patients with myelofibrosis: Results of a phase II trial

Abstract

Myelofibrosis (MF) is associated with several constitutional symptoms. Currently, there are few therapeutic options for MF. Jaktinib, a novel, small-molecule inhibitor of JAK, is currently being studied for its potential to treat MF. This phase 2 trial investigated efficacy and safety of jaktinib in the treatment of MF patients. The primary end point was the proportion of patients with ≥35% reduction in spleen volume (SVR35, proportion of patients with ≥35% reduction in spleen volume) at week 24. The secondary end points included improvement of anemia, rates of symptom response, and safety profile. Between January 8, 2019 and August 29, 2020, 118 patients were recruited and treated with either jaktinib 100 mg BID or 200 mg QD. At week 24, 54.8% (34/62) of patients in the 100 mg BID group and 31.3% (15/48) in the 200 mg QD group achieved SVR35 (p = .0199). Jaktinib treatment increased hemoglobin level to ≥20 g/L in 35.6% (21/59) of patients with hemoglobin ≤100 g/L at baseline. The proportion of patients who achieved a ≥50% improvement in total symptom score at week 24 was 69.6% (39/56) in the BID group and 57.5% (23/40) in the QD group. The most common ≥ grade 3 hematological treatment-emergent adverse events (TEAEs; ≥ 10%) were anemia (100 mg BID: 24.2%, 200 mg QD: 28.8%), thrombocytopenia (16.7%, 11.5%), and neutropenia (3.0%, 11.5%). All non-hematological TEAEs were mild. These results indicate that jaktinib can shrink the spleen, improve anemia, and other clinical symptoms with good tolerability.

Predictors of anemia response to momelotinib therapy in myelofibrosis and impact on survival

“…Similar results were obtained in an updated analysis from the open‐label phase of the MOMENTUM study, in which all patients received momelotinib, and loss of transfusion independence was documented in 10% and 23% of momelotinib and danazol randomized patients, respectively 22 . Furthermore, a phase 2 study with Jaktinib, a deuterated compound of momelotinib, revealed anemia response rate of 36% in patients with a baseline hemoglobin level ≤10 g/dl, with 2 of 6 transfusion‐dependent patients becoming transfusion‐independent after treatment 23,24 …”

“…22 Furthermore, a phase 2 study with Jaktinib, a deuterated compound of momelotinib, revealed anemia response rate of 36% in patients with a baseline hemoglobin level ≤10 g/dl, with 2 of 6 transfusiondependent patients becoming transfusion-independent after treatment. 23,24 The current study suggests that patients with post-ET MF and those with a lower pre-treatment serum ferritin value were more likely to show an anemia response to momelotinib therapy. In this regard, it is to be noted that transfusion burden was also independently correlated with anemia response in transfusion-dependent patients and in those with hemoglobin <10 g/dl but did not account for the impact of serum ferritin (Table 2).…”

Jaktinib (JAK1/2 inhibitor): A momelotinib derivative with similar activity and optimized dosing schedule

“…In the current issue of AJH , Zhang and colleagues from China present results from a phase‐2 multicenter study of jaktinib, in dynamic international prognostic scoring system (DIPSS)‐plus high/intermediate risk MF (NCT03886415) 9 . The study included 104 patients randomized to jaktinib 100 mg twice‐daily or 200 mg once‐daily, with additional 14 patients enrolled to the 100 twice‐daily cohort.…”

“…Limitations of the above-described study by Zhang et al 9 include lack of laboratory correlative studies, especially in terms of mutation information, underrepresentation of DIPSS-plus high-risk and transfusion-dependent patients at baseline, which is further confounded by regional transfusion practices, and the need for longerterm follow-up to accurately assess treatment-emergent neuropathy, which is known to be prevalent in patients treated with momelotinib. 12 These limitations, however, do not undermine the key observations of more than trivial anemia response and the possible influence of dosing schedule on both rates of response and AEs.…”

“…6,7 Jaktinib and momelotinib are also small-molecule JAK2 inhibitors that are currently under investigation and not FDA approved as yet, but appear poised to address this significant unmet need (i.e., anemia) in MF, at least in some patients. 8,9 In 2009, we reported preclinical observations on momelotinib that included selective activity against JAK1 and JAK2 and less so against JAK3 and in vitro growth inhibition of cell lines harboring JAK2V617F or MPLW515L, as well as erythroid colonies from patients with polycythemia vera. 10 This was followed by the first-in-human phase-1/2 study in MF, serially published in 2013 11 and 2018 (NCT00935987) 8 ; results included responses in anemia (54%), resolution of red cell transfusion need (68%), and clinically vetted reduction in spleen size (40%).…”