Beyond JAK2 Inhibitors: A Systematic Review of Management Strategies for Myelofibrosis
Authors: Khan Ali Younas , Iftikhar Nimra , Ijaz Awais , Tariq Muhammad Junaid , Jamil Faiza , Akbar Arshia , Qureshi Anum , Jose Jemin Aby , Kamal Ahmad , Abu Zar Muhammad , Shafqat Madeeha , Selene Insija Ilyas , Aslam Shehroz , Anwer Faiz 
Published: October 2019

Abstract
Introduction
Drugs that target activating mutations of Janus Kinase 2 (JAK2) have been the backbone of myelofibrosis (MF) management. With recent advancements in our understanding of the underlying molecular mechanisms involved in myelofibrosis (MF) pathogenesis, numerous novel agents have been developed in the last decade. We have systematically reviewed the mechanisms of actions, efficacy and safety of these drugs.
Methods
A comprehensive literature research was performed using PubMed, Cochrane, EMBASE, Web of Science and Clinicaltrials.gov. We included all trials that were under development in phase I/II/III trials. Our search identified 1642 full-length manuscripts or abstracts with published results in the last decade were screened for relevant studies. Of these, 212 articles were finalized for our final analyses.
Results
Hedgehog inhibitors (saridegib, glasdegib and sonidegib) targets signaling membrane protein, smoothened. The combination of sonidegib + ruxulotinib (RUX) elicited the best response. Spleen volume reduction (SVR) ≥35% and spleen length reduction (SLR) ≥50% was reported in 15 (55.6%) and 25 (92.6%) patients.
Histone deacetylase inhibitors (panobinostat, pracinostat, vorinostat, givinostat) target JAK2-H3Y41-HP1 pathway involved in hematopoiesis and leukemogenesis. The combination of pracinostat + RUX demonstrated the best response in a phase II trial (n=22), with clinical improvement (IWG-MRT) in splenomegaly, symptoms and both were reported in four (18%), two (9%), and ten (45%) patients that were durable for a median of 7.5 months.
Immunomodulators: Lenalidomide has shown anemia responses in 32% of patients in combination with prednisone, in a phase II trial (n=40). Improvement in bone marrow fibrosis (10/11 patients with G4 reduced to G2 or better) was also seen. Pomalidomide with or without prednisone has shown anemia responses varying from 17-24% across different trials. However, a recent phase III trial (n=32) comparing pomalidomide vs. placebo, found no difference in transfusion independence rates (16% vs. 16%, p=1.00).
Azacytidine (AZA) and decitabine (DCB) are hypomethylating agents. An objective response rate (ORR) of 69% (n=39) with AZA+RUX was noted. DCB+RUX demonstrated an ORR of 57% with a median overall survival of 10.4 months, in a phase I trial (n=21).
Imetelstat is a telomerase inhibitor that has shown an ORR of 21% among 33 MF patients. Responses were characterized by BMF improvement (n=4) and transfusion independence (3/7 responders).
Anti Fibrotics: PRM 151, a recombinant pentraxin-2, has shown an ORR of 35% in a phase II trial (n=27). Anemia response was noted in 6/15 (40%) patients and BMF improvement in two patients, durable up to 72 weeks. Simtuzumab, an antibody lysysl oxidase like-2 (LOXL2) enzyme, failed to show any clinical benefit in a phase II study of 54 patients.
Sotatercept and luspatercept are ligand "traps" that limit the activity of TGF-B superfamily ligands, involved in erythroid differentiation. Sotatercept monotherapy achieved transfusion independence (TI) in six (35%) of 17 evaluable patients. Luspatercept has recently been under investigation in patients with MF (NCT03194542).
LCL-161 is a second mitochondrial activator of caspases (Smac)-mimetic, A phase II clinical trial (n=33) found an ORR of 30% (n=9). Five (56%) of the nine responders achieved anemia responses.
Buparilisib and everolimus targets the PI3K/mTOR pathway. Buparilisib, a PI3K inhibitor, demonstrated a SLR ≥ 50% in 72% patients whereas everolimus, an mTOR inhibitor, showed an ORR of 23%.
Conclusion
The combination of ruxolitinib with some of these novel agents such as hedgehog inhibitors and hypomethylating agents have shown promising efficacy with response rates of more than 40%. LCL-161 and sotatercept has been reassuring with respect to anemia management, achieving response rates of more than 30%. PRM-151 has shown durable responses and will be the first antifibrotic for MF, if approved. Even though initial results with some of these novel agents have been ground breaking, there is a need to further explore pathways that can be targeted to help prolong survival and modify the disease course in MF patients.

Disclosures
No relevant conflicts of interest to declare.