Jamile M. Shammo, MD, FASCP, FACP, discusses the current treatment paradigm of myelofibrosis, criteria for ruxolitinib resistance and intolerance, and promising agents on the horizon.
Jamile M. Shammo, MD, FASCP, FACP
Ongoing clinical trials are paving the way for a potential rush of alternative agents to be added to the therapeutic armamentarium of myelofibrosis, explained Jamile M. Shammo, MD, FASCP, FACP.
In November 2011, ruxolitinib (Jakafi) was approved to treat patients with intermediate- or high-risk myelofibrosis. The drug remained the only targeted therapy for the disease until the approval of fedratinib (Inrebic) in August 2019, which has an indication for adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis.
The approval of fedratinib comes with an FDA Boxed Warning for serious and fatal encephalopathy, including Wernicke's encephalopathy; however, it has become an alternative for patients who were previously exposed to ruxolitinib.
Other agents and combination strategies are poised to infiltrate the paradigm pending further data, but have shown intriguing potential thus far, explained Shammo, citing imetelstat and MDM2 inhibitors.
"Obviously, having more available therapies is important,” said Shammo. “Ultimately, we need something that controls this disease in a chronic fashion and develop alternatives should this disease progress. Those therapeutic options should have a small impact on somebody's quality of life."
In an interview during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies, Shammo, a professor of medicine and pathology in the Department of Internal Medicine at Rush University Medical Center, discussed the current treatment paradigm of myelofibrosis, criteria for ruxolitinib resistance and intolerance, and promising agents on the horizon.
OncLive: What therapeutic developments are we seeing in myelofibrosis?
Shammo: Myelofibrosis is a malignant hematologic disorder that has a heterogeneous clinical presentation. The initial approval of ruxolitinib in 2011, based on the COMFORT-1 and COMFORT-2 studies [were revolutionary]. Then in August 2019, fedratinib was approved from the JAKARTA-1 and JAKARTA-2 trials.
There are other agents that may be close to being available. Momelotinib is being considered for second-line in comparison with danazol. It will be interesting to see where momelotinib will fit in because it may have the potential to reduce transfusion-dependency for patients. Pacritinib is also interesting, as thrombocytopenia has always been an area of need in myelofibrosis. Many clinical trials exclude patients who have a platelet count <50,000, so pacritinib may fit in for that niche. The PERSIST-1 trial is looking at that agent.
Imetelstat and MDM2 inhibitors are also potentially interesting approaches for treating a disease that originates from hematopoietic stem cells. In essence, MDM2 is the mast regulator of TP53. Utilizing MDM2 inhibitors may control the malignant stem cell rather than treat the consequences of malignant growth. This could demonstrate a need to focus on the etiology of myelofibrosis rather than just reduce spleen volume and improve symptoms.
What benefit did we see in the COMFORT-1 and -2 trials?
COMFORT-1 was a randomized phase III study that randomized patients with intermediate 2- or high-risk myelofibrosis to either ruxolitinib versus placebo. Primary endpoints were spleen volume reduction of ≥35% evaluated by imaging study, and also ≥50% reduction in TSS from baseline.
The study evaluated patients at 6 months of either assigned treatment, and crossover was allowed either at 6 months or earlier, if they met certain criteria for progression.
At 24 weeks, the results demonstrated that about 41% of patients achieved ≥35% reduction in spleen volume and almost half of them had improvement in TSS.
Those numbers account for the patients who met the primary endpoint, but most patients did have some degree of spleen volume reduction and improvement in their TSS. The rate of patients who came off study strictly because of toxicity was in the range of 11% to 12%.
How is resistance and intolerance to ruxolitinib being addressed?
Resistance and intolerance to ruxolitinib was not well-defined [in the beginning of studies looking at JAK inhibitors]. Later on, those definitions became clearer.
It is fair to say that if a patient attained an initial response, followed by spleen regrowth and their spleen volume reduction is now ≤10%, or ≤30% by exam, then that patient meets the criteria for relapsed disease.
A patient is also considered intolerant if they become transfusion-dependent with a JAK2 inhibitor and require 2 units per month for at least 2 months, or if they develop significant thrombocytopenia with hemorrhagic complications. A patient who never attained a response, despite minimum treatment of 3 months without meaningful reduction in spleen size, has resistant disease.
Is that where fedratinib could come in?
That is when consideration for alternative treatments should come in. That could be with fedratinib or a clinical trial [of another agent].
What impact has fedratinib had on this paradigm?
It is good to have another option. The degree of utilization remains to be seen due to the Boxed Warning and the concern about Wernicke's encephalopathy. There is an ongoing phase IIIb trial called FREEDOM, which is evaluating the long-term toxicity with fedratinib for patients who are resistant or intolerant of ruxolitinib. We are going to learn a lot from that trial because Wernicke's encephalopathy was not something that was prospectively monitored. Perhaps this is not something we need to worry about moving forward, but at least we will know [the risks and safety concerns].
What can you share about the potential with imetelstat and MDM2 inhibitors?
Imetelstat has already gained fast track designation by the FDA in myelofibrosis and myelodysplastic syndrome. It appears to have the ability to reduce the need for transfusions. For the patient who is dealing with anemia and transfusion-dependency rather than spleen-related symptoms, imetelstat may be the drug for them. Again, long-term follow-up is important because liver function abnormalities and other toxicities need more definition.