Supplements and Featured Publications
Gabriela Hobbs, MD, explains the importance of risk assessment and using disease factors to drive management approaches in myelofibrosis.
When approaching myelofibrosis diagnosis, determining if a patient’s underlying disease is proliferative or cytopenic in nature can help guide prognosis and treatment decision-making, according to Gabriela Hobbs, MD, who added that these classifications can supplement risk score assessments.1
Additionally, Hobbs underscored the importance of consistent monitoring during treatment and the importance of identifying when patients should switch therapies.
“We don’t have to keep those patients on a drug that’s not working. Seek out other treatments for your patients, because there are options that will help patients not just live better, but live longer, and that’s so important for these patients,” Hobbs said in an interview with OncLive®.
In the interview, Hobbs outlined some of the emerging trends and considerations for JAK inhibitor selection and use for patients with myelofibrosis, along with factors she considers during diagnosis and over the course of treatment.
Hobbs is an associate physician in the Department of Medicine-Hematology and Medical Oncology at Massachusetts General Hospital and an associate professor of medicine at Harvard Medical School in Boston.
Hobbs: There are lots of different ways of approaching a newly diagnosed [patient with] myelofibrosis, and I would say the first place to start is to utilize one of the several risk-stratification scores that we have. Clinically speaking, the Dynamic International Prognostic Scoring System [DIPSS] is an easy score to use initially, and then once you have genetic testing back, you can utilize the Mutation-Enhanced International Prognostic Score System score. It’s true that the DIPSS score requires the karyotype, but sometimes you can answer it without that information, as well. Those scores take into account cytopenic or proliferative [status] in a way, because they will give patients points depending on whether they have cytopenia. Therefore, by definition, even if we haven’t always recognized these two [proliferative vs cytopenic] entities as different phenotypes, the risk scorers have always paid attention to the cytopenias to [stratify] patients differently. All the risk scores have recognized that having anemia [or] thrombocytopenia will identify a high-risk patient.
Sometimes, without the risk scores, once you meet a patient, they get their first blood count checked, and immediately you’re able to see [if this] patient has a high white [blood cell] count, if their hemoglobin levels are normal, or if their platelet levels may be elevated. [If so], this is a [patient with] proliferative [disease]. Many times, they have bigger spleens. Maybe they have more constitutional symptoms. [This is] a phenotype that is predictable, and those patients are more likely to have had underlying essential thrombocythemia or polycythemia vera that then turned into myelofibrosis, or what’s called secondary myelofibrosis.
[Conversely], sometimes you’ll meet a patient [who is] going to be maybe higher risk in the risk scores, but you could see them as a cytopenic patient without plugging them into the [risk-stratification systems] because they have low blood counts, maybe don’t have a big spleen, and maybe don’t have a lot of systemic symptoms, [although] fatigue and [some] other symptoms are universal. Then when you do get your molecular diagnostics back, these [cytopenic] patients are more likely to have additional mutations besides the 3 main driver mutations, [JAK2, CALR, and MPL]. There are many different ways of identifying those patients, and I use that information in terms of risk stratification. Before you plug information into a [risk] score, if they have a lot of low blood counts, that’s usually going to be a higher-risk patient.
There are so many different things that impact a patient’s QOL. For the cytopenic patients, if they are transfusion dependent or very anemic, these are patients who oftentimes have an impaired QOL because of the fatigue that is associated with anemia. [This is] not always [the case], but that can sometimes be a consideration. Patients who are very cytopenic [can] have low platelet counts and bleeding as a result of having thrombocytopenia. That’s fortunately not super common.
That being said, some patients with proliferative [myelofibrosis] can also have disease features that impact their QOL, such as splenomegaly, systemic symptoms, fevers, night sweats, and itching. The phenotype informs what’s going to impact the patient’s QOL, [but] not always.
Ruxolitinib [Jakafi] was a standard go-to for a long, long time, and I would say it’s still probably the most utilized JAK inhibitor. It’s the drug that we’ve had available for the longest period of time, but taking the whole patient into account is important in deciding the right treatment for them and [if] a JAK inhibitor is necessary.
Cytopenic vs Proliferative Myelofibrosis1
Sometimes, we have patients who are very cytopenic, and they don’t have splenomegaly or symptoms. Those are not necessarily patients who are going to benefit tremendously from a JAK inhibitor. However, that’s not always true, and that has evolved a little bit with the addition of momelotinib [Ojjaara] and pacritinib [Vonjo] into our armamentarium.
Momelotinib is FDA approved specifically for patients with myelofibrosis with anemia, but remember, it is still a JAK inhibitor, so it can sometimes lower blood counts. However, in addition to helping anemia, it can also help splenomegaly and symptoms, so if you have a patient with anemia but without splenomegaly and symptoms, that’s the patient where you maybe want to try an erythropoietin-stimulating agent first, for example.
For thrombocytopenic patients who oftentimes have anemia as well, I think pacritinib is the right choice. It’s the least myelosuppressive and the one that’s going to impact the other blood counts the least, so that is also a consideration for patients who are cytopenic.
If a patient’s primary concerns are splenomegaly and symptoms, then that’s definitely a [consideration for] ruxolitinib initially, and then you see how those patients do. If they don’t do well with ruxolitinib initially, I think fedratinib [Inrebic] is a good option for those patients in the second line.
Myelofibrosis is not like [most] other diseases where you choose a therapy and a patient is going to be on that forever. [However,] making that first selection is important, as well as dose escalating to the appropriate dose, especially with ruxolitinib. The other [JAK inhibitors] are administered as one flat dose.
We have scores that help us to determine if your patient is doing well on ruxolitinib, or if it is time to change [treatments]. There’s an easy-to-use score in clinic, the RR6 [response to ruxolitinib after 6 months] score; more than anything, it’s a common-sense check-in. For example, your patient has been on [ruxolitinib] for 6 months. Is the drug working? Is it doing what it’s supposed to be doing? Are they on a suboptimal dose? Are they getting less than 20 mg? Are they getting transfusions? Is their spleen still enlarged? If all those things are true, it’s time to switch to something else.
Although there aren’t scores for the other drugs [beyond ruxolitinib], I would say that approach has to apply to all our patients. [Myelofibrosis] is not a static disease; it’s a disease that changes with time. You may have started with ruxolitinib because at the moment, that was the right thing for that patient, but let’s say over time, they end up developing significant anemia. You don’t have to keep that patient on ruxolitinib forever like you did in 2011 because there wasn’t another drug available. We have other drugs available.
[Along with having] other drugs available, [where] you could switch maybe from ruxolitinib to momelotinib, there are multiple clinical trials. Reach out to a friend in an academic center and see if there’s a trial that's right for your patient. There are so many novel agents in development right now that it’s important to not keep your patient on one drug forever because maybe you’re not as familiar with the disease.
Just as importantly, when that patient first came to clinic for that initial evaluation, they [may have] had low-risk disease, and transplantation didn’t seem like it was the right time. Things change. If they’re developing cytopenias, if they’re developing circulating blasts, or if they’re not responding well to their treatment, please send those patients to transplant. That may not have been the right thing at diagnosis, but it [may be at a later point].
This space is going to continue to evolve significantly, and I think that in 5 to 10 years, when I’m answering these questions about how to treat patients, we’re going to have so many more options. I'm excited about the potential, not just with the combinations, but with the truly targeted therapies. I would imagine we will be treated most of our CALR-mutated patients with CALR-directed therapy, whether that’s by [itself] or with a JAK inhibitor. We’ve talked about disease modification in myelofibrosis forever, and we didn’t know what it meant until we saw it happening. If we’re seeing the [frequency of the] CALR mutation going down, the morphology of the marrow getting better, spleen [symptoms] going away, and blood counts getting better, I think that’s disease modification, and [targeted therapies] are the drugs that are going to do that for those patients.
For the patients with JAK2- or MPL-mutant disease, it’s going to be a little bit more complicated. For JAK2-mutant disease, there are lots of different selective JAK2 inhibitors that are being developed, some from which patients with MPL-mutated disease will benefit, and some maybe not.
In the meantime, there are so many combination studies, like the [phase 3] SENTRY [NCT04562389]2 and MANIFEST-2 [NCT04603495]3 studies, demonstrating significant improvements in splenomegaly and symptoms [with combination approaches]. [These approaches are also] probably doing more than that, it’s just difficult to measure in clinical trials. The future looks exciting for our patients.
