Novel targets in myelofibrosis: overview of emergent therapies

Several late-stage clinical trials have shown encouraging results for novel therapies for myelofibrosis in at least a subset of patient populations. The novel agents, including pacritinib, momelotinib, parsaclisib, KRT-232, and tagraxofusp, are directed at a variety of targets.

Prof. Francesco Passamonti (University of Insubria, Italy) gave an overview of the evolving therapeutic landscape of myelofibrosis, which is moving beyond ruxolitinib alone [1]. Different pathways can be used to modify myelofibrosis: signal transduction inhibitors such as JAK inhibitors, apoptotic pathway enhancers, epigenetic modifiers, agents harnessing host immunity, and agents affecting DNA replication [2].

The JAK2 inhibitor pacritinib was tested in phase 3 clinical studies (PERSIST-1 [NCT01773187]; PERSIST-2 [NCT02055781]) and found to be effective in spleen volume response (SVR35; P≤0.001) but not in total symptom score (TSS50; P≤0.24) [3,4]. In a phase 2 study (NCT04884191), pacritinib was assessed as a monotherapy in patients (n=161) with ruxolitinib intolerance or resistance. Overall efficacy was poor, but SVR35 was 17% in a subpopulation with severe thrombocytopaenia [5].

Momelotinib is another JAK inhibitor developed in phase 3 trials (SIMPLIFY-1 [NCT01969838]; SIMPLIFY-2 [NCT02101268]). Its efficacy was compared with ruxolitinib. SIMPLIFY-1 (n=432) demonstrated robust overall survival (OS) for JAK inhibitor-naïve patients (median OS ≥53.1 months), met the non-inferiority endpoint SVR35 (P=0.011) but not TSS50 (P=0.98). SIMPLIFY-2 (n=156) also showed robust OS with a median of 34.3–37.5 months. Momelotinib failed to meet the primary endpoint for SVR35 (P=0.90) but achieved the TSS50 endpoint (P=0.0006). Both studies showed a good safety profile [6,7].

A third signal transduction inhibitor is the PI3K inhibitor parsaclisib. In a phase 2 trial (NCT02718300), parsaclisib plus ruxolitinib was effective in SVR in patients (n=33) with a suboptimal response to ruxolitinib. At 24 weeks, haemoglobin level and platelet count were stable [8].

Prof. Passamonti further presented results for KRT-232, an MDM2 inhibitor (i.e. apoptotic pathway enhancer), which was evaluated in the BOREAS phase 2 trial (NCT03662126) in patients with refractory or relapsing myelofibrosis. The most effective dose (240 mg once daily) showed SVR35 of 16% (n=25) and a TSS50 of 30% (n=27). However, results may be confounded by a lack of ruxolitinib washout [9].

CD123 could also be a useful target in myelofibrosis patients with ruxolitinib failure. Tagraxofusp is a novel CD123-directed cytotoxin therapy developed in a phase 2 trial (NCT02268253). Results from 36 patients showed 56% with a spleen (by palpation at week 24), 46% had symptom burden reduction, and 56% of patients were classified as having stable disease. The safety profile was good [10].

To conclude, the therapeutic landscape of myelofibrosis is evolving. Many non-JAK inhibitor-based therapies are being investigated in pre-clinical and early clinical studies and several novel therapies are in late-stage clinical development. The future treatment landscape aiming to improve the lives of patients with myelofibrosis is emerging.

1. 
   
   1. Passamonti F. Novel targets in myelofibrosis – Emergent therapies. 2SS16-SL3, EHA 2021 Virtual Congress, 9–17 June.
   2. Venugopal S & Mascarenhas J. J Hematol Oncol 2020;13:162.
   3. Mesa RA, et al. Lancet Haematol 2017;4(5):e225–36.
   4. Mascarenhas J, et al. JAMA Oncol 2018;4(5):652–9.
   5. Gerds AT, et al. Abstract 667, ASH 2019, 7–10 December.
   6. Mesa RA, et al. J Clin Oncol 2017;35:3844–50.
   7. Harrison CN, et al. Lancet Haematol 2018;5:e73–e81.
   8. Yacoub A, et al. S216, EHA 2020, 11-21 June.
   9. Al-Ali HK, et al. S215, EHA 2020, 11-21 June.
   10. Pemmaraju N, et al. P2986, ASH 2020, 5-8 December.

 

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Posted on 5 August, 202116 February, 2024