John Mascarenhas, MD, discusses the shifts from monotherapy to combination therapies in the evolving field of myelofibrosis care.
John Mascarenhas, MD
Therapies continue to expand for myelofibrosis as anticipated approvals, additional sequencing options, and JAK inhibitors continue to provide new avenues for the treatment of patients, according to John Mascarenhas, MD.
Mascarenhas presented “Updates in Myelofibrosis (MF) Management” at the 40th Annual CFS® detailing the dominant use of ruxolitinib (Jakafi), second-line options after ruxolitinib failure, and recently approved agents that can help fill unmet needs in the treatment paradigm.
“The highlight [of my presentation] was to be aware of the 3 approved JAK inhibitors, the niches that they could fill, and that there’s a fourth JAK inhibitor that will likely be approved,” Mascarenhas said. “Most importantly and most excitingly is the move to combination therapies upfront in the salvage setting and non-JAK inhibitor-based therapies with an overarching goal of improving responses, as well as progression-free survival and overall survival.”
In an interview with OncLive®, Mascarenhas, director of the Center of Excellence for Blood Cancers and Myeloid Disorders at the Icahn School of Medicine at Mount Sinai in New York, New York, discussed the shifts from monotherapy to combination therapies in the evolving field of myelofibrosis care.
Mascarenhas: [As part of the presentation] I provided an update on the management of myelofibrosis geared towards the community provider. It covered that there are 3, soon to be 4, JAK2 inhibitors that will be approved for myelofibrosis. The only drug that was available for over a decade was ruxolitinib, now fedratinib [Inrebic] [has been approved] since 2019, pacritinib [Vonjo] since March of 2022, and [the approval of] momelotinib [is anticipated].
Practitioners must be aware of the different niches perhaps that one could use a JAK inhibitor [for]. There’s a lot of comfort and experience with [ruxolitinib, which] will [most likely] remain the mainstay of JAK inhibitor therapy for myelofibrosis, but there are other options now. Pacritinib fills an [unmet need] as an option for [patients with] low platelet [counts] as a second line JAK inhibitor and fedratinib, which has a broad label and can be used upfront or second line is another option. Fedratinib is a great second-line option in the community if patients have spleen progression or lack of spleen response with ruxolitinib.
Neither ruxolitinib nor fedratinib are great drugs for improving anemia and can be associated with myelosuppression. Drugs such as pacritinib [which has] a clinical improvement rate of approximately 25% in terms of hemoglobin response or momelotinib—MOMENTUM [NCT04173494] study results were presented at [2022 ASCO] and [EHA 2022]—are promising drugs for addressing spleen and other symptoms [and] improving anemia. Momelotinib beat out danazol in the randomized phase 3 study; a primary end point was symptom response, and a secondary end point was spleen response. Importantly, it was noninferior to danazol in terms of maintaining and/or attaining transfusion independence at week 24.
In 2023 [we may have] a level of complexity added to the management of myelofibrosis, as there will be multiple agents that one can use, but that’s not always a bad thing. What you have to plan out is your strategy of how you might sequence these drugs and the reality is that there are multiple options for any given patient and multiple second line options.
The 3 approved drugs are agnostic to line of therapy. You could use pacritinib upfront, the label is but less than 50,000 [platelet count], but there are data from PERSIST-2 (PAC326; NCT02055781) for less than 100,000 [count]. Ruxolitinib and fedratinib can be used up front and any of the 3 drugs can be used as a second-line [option] after the failure of a first line JAK inhibitor.
It starts to become a little bit complicated beyond that to determine which is the optimal drug for any given patient because we don’t have clinical profiles or biomarkers that necessarily tell us which drug may be superior or optimal and which way to sequence them, [but] one can use toxicity profiles. For example, fedratinib and pacritinib are FLT3 inhibitors, they are associated with more [gastrointestinal] GI toxicity than ruxolitinib [and] if I had a patient who had underlying GI complaints—[such as] irritable bowel syndrome or even inflammatory bowel disorder or other comorbidities that might increase diarrhea and risk for complications—that may not be the ideal drug. Patients who [present] with anemia and or thrombocytopenia which would likely be exacerbated by ruxolitinib and fedratinib, would be patients for whom I might be more inclined to [give] pacritinib and momelotinib.
In the absence of mutational profiling that gives us a sense of which way to move or specific clinical features, we are not yet at the point where we can say from a workup of an individual patient this is the ideal JAK inhibitor and this is the next drug to use in sequence. The reality is we probably won’t develop that in the near future as the field is moving toward combination therapy.
The next exciting aspect or question is how do you choose which combination therapies make sense for a patient? I think we will move on from this sequencing monotherapy approach that we have become accustomed to [and] try to get deeper responses up front with combination therapies.
There’s a lot of different examples of trials that are trying to exploit the fact that there are multiple mechanisms that underlie the pathobiology of myelofibrosis and that there’s synergy behind inhibiting different pathways that can be active. A great example of that is ruxolitinib with the pan-BET inhibitor pelabresib (CPI-0610) in the MANIFEST study [NCT02158858] that has now inspired MANIFEST-2 [NCT04603495], which is randomized phase 3 study upfront [of] ruxolitinib and placebo vs ruxolitinib plus pelabresi.
This is a first attempt that I am aware of [to evaluate] efficacy in patients who are JAK inhibitor naïve. There are a lot of different salvage regimens that are under evaluation [such as] navitoclax, the BCL-2 inhibitor, parsaclisib, the PI3K inhibitor, and there are a number of drugs that are monotherapies that are not JAK inhibitor approaches that can be used second line after ruxolitinib failure, which is unfortunately a poor prognostic group of patients. This includes imetelstat, the MDM2 inhibitor, navtemadlin [KRT-232], bomedemstat[IMG-7289], and other drugs. There’s a lot going on in the field and I think we will see a move from a purely JAK inhibitor-based monotherapy approach to JAK inhibitor-based combination therapies early on or salvage and/or non-JAK inhibitor directed therapy as salvage.
It’s important for patients to realize myelofibrosis is a relatively rare disease. It is critical to have a second opinion at a center where there’s a lot of familiarity and experience with myelofibrosis and myeloproliferative neoplasms. For most patients, clinical trials should always be considered if possible whether it’s upfront therapy or salvage therapy; it’s important for patients to realize that the only curative option that exists in 2022 leading into 2023 is still hematopoietic stem cell transplantation. That’s an important consideration early on in the disease course and a consultation when warranted with a transplanter is a good way of understanding whether that makes sense for a given patient and what’s involved because although it offers the potential for cure there are a lot of considerations, and it is an approach that has intrinsic toxicity and risk involved.
You must balance the potential benefits and risks and make sure that’s aligned with the patient’s expectations. Encouraging patients to be very vocal with their hematologists about what they’re looking to accomplish and make sure it’s aligned with what the hematologist is looking to provide is crucial.
One of the best examples that is paradigm shifting in many ways is the IMpactMF study [NCT04576156], which is a randomized phase 3 study in patients who have refractory myelofibrosis to ruxolitinib. Patients are randomly assigned to imetelstat, the telomerase inhibitor, or best available therapy and the primary end point is OS. It is an important study because it moves from spleen and symptom, which are not unimportant, but takes an end point that is the underlying reason why we try to intervene, [which is] to improve spleens and symptoms. Ultimately, we want [and] to extend life with a good quality of life.
It's incumbent upon us as clinical researchers and as people that are passionate about what we do in this field, that we look at those kinds of end points and incorporate them in trials and elevate the goals of what we’re trying to accomplish with our patients.
It’s an exciting time to be involved in this field and it’s a great time to seek a second opinion if that’s a possibility