Novel Agents: A Brief Overview

LCL-161 is a novel small molecule therapy that induces cytokine-mediated apoptosis and is being evaluated in patients with post-essential thrombocythemia or post-polycythemia vera myelofibrosis in an ongoing phase 2 study. Preliminary data indicate that when administered as monotherapy, LCL-161 yields a 30% objective response rate. With respect to safety, the most frequently reported cause of dose reductions with the therapy was fatigue.

Notable molecular targets for investigational agents include the bone marrow microenvironment, the TP53 signaling pathway, telomerase inhibition, as well as bromodomain and extraterminal protein inhibition. Some of the agents targeting these pathways include MDM2 inhibitors, TGF-beta inhibitors, telomerase inhibitors, LSD1 inhibitors, and XPO1 inhibitors, and others.

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At the time of the review, all of the agents previously mentioned were undergoing phase 1 or phase 2 trials. Various safety and efficacy measures are being used in these trials, including objective response rate, dose-limiting toxicity, maximum tolerated dose, and anemia and spleen responses.

Expert Opinion: Perspective on Clinical Implementation

“We are seeing a plethora of new agents being evaluated for myelofibrosis. It is [an] exciting time for MPN physicians and patients,” said Srdan Verstovsek, MD, PhD, of the department of leukemia at the University of Texas MD Anderson Cancer Center in Houston.

“Augmenting the benefit of ruxolitinib in the first-line setting is [a] possibility where a new agent, [in combination with] ruxolitinib, would provide more spleen or symptom improvement or, in the best case scenario, anemia improvement,” Dr Verstovsek explained.

He continued, “Having a medication that would improve anemia, whether it is disease-related or therapy-related, would be hugely beneficial. There [are] several areas of unmet need when it comes to myelofibrosis.”

Although many challenges remain, the effective translation of investigational therapies to the clinic is improving. Ultimately, prolonging survival and improving patient quality of life are the key goals of therapy for patients with MPNs.

Disclosures: Some authors have declared affiliations with the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


1.     Economides MP, Verstovsek S, Pemmaraju N. Novel therapies in myeloproliferative neoplasms (MPN): beyond JAK inhibitors [published online August 1, 2019]. Curr Hematol Malig Rep. doi:10.1007/s11899-019-00538-4