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I'm Dr. Raajit Rampal from the Memorial Sloan Kettering Cancer Center in New York. I'm going to be talking about novel agents and therapeutic strategies in myelofibrosis. We'll be covering the current treatment landscape as well as new approaches, including current clinical trials of novel agents and combinatorial approaches. We’ll also talk about preclinical models that may soon be able to be brought in to the clinic.
Ruxolitinib has made a tremendous difference in the treatment of patients with myelofibrosis. We know that it’s very effective at reducing the size of the spleen, reducing symptom burden for patients, and prolonging overall survival. However, we do know that there are limits to the efficacy of ruxolitinib. Over time, patients tend to lose response to the drug. As well, there are limits to the degree of which the JAK2 allele burden can be reduced with the medication.
With these limits in mind, we need to consider ways in which we can improve therapeutic targeting to treat patients with myelofibrosis. There are a number of different strategies that one can consider. This includes: improving targeting of JAK2, which can include the use of novel JAK inhibitors, and the use of other agents that directly target JAK2, such as heat shock protein 90 inhibitors or HDAC inhibitors, which also affect JAK2 expression.
Downstream targets of JAK2, such as the PI3 kinase pathway, are also considerations as potential therapeutic targets. Another pathway to think about are associated genetic and epigenetic targets, of which there are several targets that can be drugable. Finally, we might consider novel mechanisms, such as telomerase inhibitors and anti-fibrosis agents, that don't necessarily directly impact inhibition of the JAK-STAT pathway.
Along those lines, recent data have been put forth regarding the telomerase inhibitor, imetelstat. In a pilot study of 33 patients, many of whom have had prior JAK exposure, 21% of patients had either complete or partial remission. Reversal of bone marrow fibrosis, as demonstrated on this slide, was also observed in a portion of the patients. However, toxicities including grade 4 thrombocytopenia and neutropenia were observed, as well as grade 3 anemia.
This drug is currently under investigation in an ongoing phase 2 study. Another novel agent is PRM-151, which is an anti-fibrotic drug originally developed for idiopathic pulmonary fibrosis. This drug, both alone and in combination with ruxolitinib, has demonstrated the ability to decrease spleen size as well as the total symptom burden of patients with myelofibrosis.
Interestingly, in patients who were on this particular study for 72 weeks or more, increases in platelet counts were observed with a concomitant decrease in platelet transfusion needs. Regarding the JAK-STAT pathway itself, alternative approaches include using heat shock 90 proteins. Heat shock 90 is a chaperon of JAK2 and, therefore, inhibiting HSP 90 will lead to degradation of JAK2.
In a pilot phase 2 study of the AUY922 heat shock 90 inhibitor, several MF patients on the study had stable disease after several months of therapy, with one patient with an anemia response. We did observe decreases in the spleen sizes of patients on this study. This concept is being taken further, with a combination of another HSP 90 inhibitor called PUH 71 in combination with ruxolitinib. This is a phase 1 trial that is currently ongoing and accruing.
Another modality is panobinostat, an HDAC inhibitor that has been combined with ruxolitinib. In an expansion of the phase 1 study, reported at ASH last year, patients were noted to have reductions in spleen volumes, and several patients did in fact have reductions in bone marrow fibrosis. Reductions in the JAK2 allele burden were also noted in this study.
Hypomethylating agents have been previously studied in myelofibrosis, mostly in the study of blast phase disease, with some degree of efficacy. This concept is being taken further in combination with ruxolitinib; a currently ongoing study at MD Anderson, with ruxolitinib in combination with azacitidine for patients with MDS overlap or CMML, is being evaluated.
Thus far, data reported at ASH last year have demonstrated objective responses in 66% of patients as well as spleen size decreases. This concept is also being taken forth with a combination of decitabine and ruxolitinib in patients with blast phase myelofibrosis or post-MPN AML. This is based on preclinical studies that have demonstrated that the combination of decitabine and ruxolitinib in a post-MPN AML model has synergistic efficacy. This is the subject of the NPDRC-109 trial, a phase 2 trial that is currently accruing for patients with more than 10% percent blast and diagnosis of a MPN.
Finally, preclinical studies have brought several new concepts to light. One is the introduction of type II JAK inhibitors, which bind inactive JAK2. These cells are able to overcome persistence whereby JAK-STAT signaling is engaged despite the presence of a JAK inhibitor. When a type II JAK inhibitor is added to these cells, there is reduction in aggregation of JAK-STAT signaling.
Another concept is epigenetic targeting using the lysine specific histone deacetylase one, or LSD-1, inhibitor. In preclinical studies that were presented at ASH last year, this drug is a single agent that was able to reduce the white count and spleen weight in models of polycythemia vera that ultimately progressed to myelofibrosis.
To summarize, we know that ruxolitinib offers important clinical benefits to patients with MF, but there are limits to the efficacy of the drug that may reflect underlying biochemical changes, such as persistence and the impact of other genomic alterations. Other pathways other than JAK-STAT, including epigenetic dysregulation, likely play a role in disease pathogenesis and might in fact be amenable to targeting. General oncologic targets, such as telomerase inhibitors and checkpoint inhibitors, continue to be explored in MF.
Finally, the achievement of remission on a molecular and biologic level will likely require targeting of other pathways aside from JAK-STAT alone. Combinatorial studies utilizing agents with non-overlapping toxicities represent a reasonable and rational approach to ongoing and future investigations.
Thank you for your time and attention.