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Akriti Jain, MD, discusses treatment selection and sequencing of JAK inhibitors in myelofibrosis, emerging CALR-targeted research, and defining disease modification.
Akriti Jain, MD
As the therapeutic landscape of myelofibrosis continues to evolve, the availability JAK inhibitors has provided clinicians with multiple options to individualize care based on disease biology and patient characteristics, according to Akriti Jain, MD.
In the second part of an interview with OncLive®, Jain discussed the key clinical considerations guiding treatment selection and sequencing for patients with myelofibrosis, the ongoing challenges in defining disease modification, and the next wave of research focused on CALR-mutant disease.
Jain is a hematologist and medical oncologist at Cleveland Clinic in Ohio. In the first part of the interview, she further discussed how JAK inhibition has affected the myelofibrosis and polycythemia vera treatment paradigms.
Out of the 4 JAK inhibitors we have approved—[ruxolitinib (Jakafi), fedratinib (Inrebic), pacritinib (Vonjo), and momelotinib (Ojjaara)]—a harder [decision] is choosing a JAK inhibitor for someone who has cytopenias. Even before that, the question is: does everyone with myelofibrosis need a JAK inhibitor? Not necessarily. If someone has lower-risk disease [per] Molecular International Prognostic Scoring System [MIPSS] 2.0 [criteria], do not have an enlarged spleen, and do not have a heavy symptom burden, they might not need treatment and could potentially be observed.
However, if patients have intermediate- to higher-risk disease [per MIPSS criteria], have an enlarged spleen, or have symptoms, then we have 4 [JAK inhibitor] options in front of us. If their counts look good, I would choose ruxolitinib first because of how well it has performed in terms of responses for both spleen and symptom improvement.
If they have anemia—and I think the threshold for anemia is harder to define, such as whether it is transfusion dependent—then I would probably not go with ruxolitinib, because ruxolitinib can cause anemia initially before it improves. The dosing of ruxolitinib can be challenging in these patients, and if you are unable to give enough of the drug, you won’t get its full benefit. In that case, I would probably choose momelotinib because of its ACVR1 inhibition, which can provide an anemia benefit.
It should be noted that in the [phase 3] Simplify 1 [NCT01969838] and Simplify 2 [NCT02101268] studies, where momelotinib was compared with ruxolitinib for frontline therapy, it was noninferior to ruxolitinib for spleen responses but was inferior for symptom control—ruxolitinib was better at improving symptoms.1,2 That’s why [JAK inhibitor selection] depends on the patient sitting in front of you, whether symptoms are the major problem, the spleen is the major problem, or anemia is the major problem.
For anemia, momelotinib is an option, and another option is pacritinib because it also has that same ACVR1 inhibition and, in addition, has IRAK1/4 inhibition, which can potentially provide anemia benefit by decreasing the anemia of inflammation that occurs in myelofibrosis. The niche for pacritinib right now is for patients with platelets less than 50 × 10⁹/L—that is the FDA- approved [indication]. When platelets are [below that threshold], the dose of ruxolitinib that we can safely give in that situation is much lower, and with a lower dose, we don’t get enough benefit. In that situation, we can dose pacritinib adequately to achieve benefit. Fedratinib is usually used as a second-line drug.
We usually pick one [JAK inhibitor] based on the presentation, whether anemia is a problem, thrombocytopenia is a problem, or blood counts are great, in which case we can choose ruxolitinib. We start off by choosing a JAK inhibitor and then dose modify based on cytopenias and adverse effects. I usually recommend giving at least 12 weeks to get a response because those are the end points we use in clinical trials.
If we’re not seeing a response at 12 weeks, then you move on to the next drug. At that point, you again look at whether anemia or thrombocytopenia are a problem. [If these are problems], there are multiple combination approaches that have been tested. There [are] multiple trials that have combined an experimental drug with ruxolitinib. The big one that we were excited to see results from—but disappointed that it didn’t meet the end point or gain FDA approval—was the combination of ruxolitinib and pelabresib [in the phase 3 MANIFEST-2 trial (NCT04603495)].3 We did see great spleen responses, potential symptom responses, and even some reversal of fibrosis, but it wasn’t able to make it to the finish line. There are other drugs being tested in combination with ruxolitinib. I think the bigger question is: does everyone need a combination?
There is a drug called navtemadlin being studied in [the phase 3] POIESIS trial [NCT03662126], where patients are started on ruxolitinib, and if they do not respond, they are randomly assigned to ruxolitinib alone or [ruxolitinib with navtemadlin added on]. That’s an exciting way of conducting a trial because it shows that not everyone needs a combination up-front. Some patients could potentially benefit from a single drug, but for those not responding to ruxolitinib, the combination could provide additional benefit. These innovative trial designs will hopefully give us answers regarding sequencing and combination strategies in the future.
The big unmet need, which is a point of discussion in most conferences, is how we define disease modification. Is it driving down the JAK2, CALR, or MPL allele burden, based on which mutation is present? In polycythemia vera, over 95% of the time, it’s JAK2 V617F or a JAK2 exon 12 mutation. Whereas in myelofibrosis, we can have JAK2, CALR, or MPL mutations.
Is driving that allele burden down considered disease modification? Is reversal of fibrosis considered disease modification? Is a decrease in some of these cytokine or inflammatory hormone levels considered disease modification? That’s where more work needs to be done.
In addition, do combination therapies help us get there? Right now, the only cure we have for any stem cell or myeloid disorder is a stem cell transplant. Is it possible for us to cure these or modify the natural history of these diseases without a stem cell transplant? That’s a big unmet need.
And how do we get patients to transplant safely? How much do we need to shrink their spleen, and do we keep them on a JAK inhibitor after a stem cell transplant? Those are also important questions that still need to be answered.
We talked a lot about JAK2 and the JAK inhibitors. It’s also interesting to note that sometimes I see patients who say they’ve been told by their local doctor that if you have a CALR mutation, JAK inhibitors won’t work for you. That’s actually not true. We’ve shown that CALR or MPL mutations lead to the same constitutive activation of the JAK-STAT pathway, and these JAK inhibitors don’t need JAK2 mutations [present to be effective]—they just inhibit that pathway. Even if you have a CALR or MPL mutation, you can still use JAK inhibitors.
Specifically for patients with CALR mutations, we have interesting trials using monoclonal antibodies. CALR is present outside the cell and can potentially be targeted by immunotherapy, such as a monoclonal antibody. Exciting results from these trials were presented at the 2025 EHA Congress, and we’re looking forward to learning more about how this approach can benefit our patients with that mutation.
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