Assessing Risk for JAK Inhibitor Selection in Myelofibrosis

Aaron T. Gerds, MD, MS: How do you use molecular testing, bone marrow results, and clinical features to stratify risk in patients with myelofibrosis?

Prithviraj Bose, MD: At this point, I believe we are all receiving the myeloid mutation panels. We also order JAK2, MPL, and CALR: the 3 drivers. However, most clinicians would order a myeloid mutation panel because we know that many of the mutations are prognostic. This is the whole point of risk stratification, which is now increasingly sophisticated and integrates multiple clinical, molecular, [and] cytogenetic variables to determine who needs a transplant.

These are the first actions I take when speaking with a new patient. I get an idea of their risk in terms of survival and prognosis, and that informs my decision to refer them to transplant. I then counsel the patient appropriately.

I do not believe molecular testing informs treatment because our drugs are, for the most part, mutation agnostic. All we have are JAK inhibitors, which are not mutation specific. However, from a prognostic standpoint, the [role] of molecular testing is key.

Gerds: Regarding mutant allele burden, is it important and how do you use it?

Jeanne Palmer, MD: We do evaluate mutant allele burden. Some [clinicians] suggest that if a patient has a lower allele burden, the prognosis might be slightly worse. We generally tend to associate those with the cytopenic phenotype, but overall, I would say that the allele burden does not impact any decisions, at least not in terms of selecting JAK inhibitors. It may be something that we would monitor, especially if we were going to add an interferon-based therapy to the JAK inhibitor. Aside from that, it does not help me [significantly].

Gerds: With so many advancements in technology, is bone marrow biopsy still relevant today?

Jonathan Asif Abbas, MD: I believe that bone marrow biopsy is still relevant. First and foremost, you need it for assessment of blast percentage, which is involved in any scoring system to help risk stratify a patient properly.

A higher blast percentage suggests a greater risk of the disease progressing to a more severe form, such as leukemic transformation. In addition, assessing the cellularity of the bone marrow helps us understand its state: Is it hypercellular marrow or more fibrotic hypocellular marrow?

These are all variables that not only serve as a good baseline for a pretreatment assessment but also help us predict the direction this [disease] is going, once we pick a treatment. This helps to identify the condition of hypocellular marrow and set an expectation for cytopenia. This is true across the disease, as everything is inter- connected: the molecular factors, the marrow, the clinical picture, and the path forward toward a possible cure with allotransplant for patients who have intermediate-to-high-risk [disease].

Gerds: What other factors or models guide your selection between JAK inhibitor therapy and alternative treatment approaches?

Bose: I do not think the molecular information guides our choice of therapy today, maybe at some point in the future. Right now, all 4 approved agents are JAK inhibitors and mutation agnostic. We know that ruxolitinib [Jakafi] is more effective if the JAK2 allele burden is over 50%. However, that is not to say that you would not use it if the JAK2 allele burden was lower than 50%. I do not believe we are quite there yet with molecular information to guide pharmacotherapy.

It is important to appreciate the [fact that] not all patients need a JAK inhibitor. There are some alternative treatments for when a patient has anemia and does not have increased splenomegaly or other symptoms. For this type of patient, one might choose an erythropoiesis- stimulating agent with danazol [Danocrine] or luspatercept [ Reblozyl] and not necessarily a JAK inhibitor.

Gerds: Do you evaluate other organ functions or models to help understand who would be a good candidate for transplant?

Palmer: When I see a patient, I evaluate their disease to decide on transplant. [One can] evaluate the risk based on whichever scoring system they choose. [From there,] when I deduce that a patient is in a category where transplant is an option, we can assess transplant-specific variables like donor type.

The myelofibrosis transplant scoring system also helps improve risk stratification for patients undergoing transplantation. However, this scoring system does not take into account comorbidity index and performance status. These also weigh into the decision about moving forward with transplant. In a perfect world, we identify these patients prior to needing a transplant so that we can monitor them throughout and avoid organ damage.

Gerds: Are there any other available treatments we use for myelofibrosis?

Abbas: I believe there is still a role for [a] watch-and-wait [approach] for some patients, so not everyone needs therapy. In addition, if you are trying to control cytopenias only, you may have identified a patient for whom something like hydroxyurea is an appropriate frontline treatment.

We do have some ability to go [beyond using] pure JAK inhibition with the 4 FDA-approved drugs for our treatments. There are interferons, although it is becoming harder and harder to find a patient who might be a good candidate for interferon [therapy] and who has not had a JAK inhibitor yet. Thus, I believe we have some options, and it is an amazing place that we are in, having 4 FDA-approved options at this point, whereas recently we only had one and not that long ago we had 0 [options]. As the drugs improve, regarding the JAK inhibitors, and [the] more and more options we gain, it is starting to get harder and harder to find patients who, if they need treatment, are not going to end up on one of those agents.

Gerds: How do you establish and manage treatment expectations across different patient populations?

Bose: It goes back to what we were discussing earlier. I start with prognosis because that must be foremost in patients’ minds. We know from the Myeloproliferative Neoplasm Landmark Survey that at the end of the day, what patients care about most is outcome, disease progression, and… longevity.¹ Thus, I initially discuss that.

I start with prognosis; talk about the possibility of transplant, whether that [should happen] sooner or later; and then I discuss our therapies, which are not curative. However, some have demonstrated survival benefit. I discuss the nuances between the different drugs. They are all JAK inhibitors, but they are all different and have different strengths and weaknesses. Thus, I start with prognosis, discussing an overall big picture with a level-setting approach.

Gerds: What roles do quality-of-life assessments play in your initial treatment planning?

Palmer: I have been fortunate in that I have enabled my entire practice to use the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score [MPN-SAF TSS] on a regular basis and created a flow sheet in the Epic system, which took me 2 years to implement. This has been helpful because sometimes you can look back and say, “Your symptom score is quite a bit better than it was before.” Sometimes this can validate the therapy that has been chosen.

The other aspect that is helpful with the TSS is that if fatigue is the only score that they have on the MPN-SAF TSS, there is a degree of level setting regarding whether JAK inhibitors are going to provide that same degree of benefit. If a patient has night sweats, bone pain, fevers, and weight loss, I can improve this. However, if they only have fatigue, I sometimes hesitate when starting JAK inhibitors especially if there is no splenomegaly or any other symptom that would suggest that they would need one, because I find fatigue is one of the hardest symptoms to reverse. Overall, I do believe that quantifying these, even though it can be difficult for patients, is a helpful process.

Gerds: How do you determine whether bone pain or abdominal discomfort is from the myelofibrosis or something else?

Abbas: I categorize adverse events [AEs] into the 3 arms of JAK inhibition: the cytopenia, the splenomegaly, and the “other,” [which is] all the other symptoms such as night sweats and so on. By separating these AEs into those 3 boxes, I can assess whether, for instance, the fatigue is because of cytopenias or if it is the massive splenomegaly preventing the patient from taking in more than 400 calories a day. In addition, I can assess whether the fatigue is generalized fatigue from the disease state or disease in [older] patients in their 70s, where fatigue and slowing down are a part of the natural aging process.

By separating AEs into those categories as best I can, it helps me determine the treatment direction. For instance, “Am I targeting the cytopenias? Am I targeting the global TSS? Do I want to focus on anemia?” This way, I’m trying to understand the disease well enough to know how to target a symptom while also recognizing that there will be patients for whom fatigue is so prevalent across the whole spectrum that it will be a real challenge.

Gerds: Referring to the case, how do you incorporate this patient’s age and risk category symptom burden when selecting a JAK inhibitor?

Abbas: Clearly, we have identified a patient who is not a candidate for [the] watch-and-wait [approach], having both significant cytopenia and splenomegaly. This is someone who needs treatment first and foremost at 71 years of age. That puts this patient, by my referring transplant center standards, into the category of transplant eligible. Thus, this is the first conversation I would have with this patient, asking the patient if they are interested in allogeneic stem cell transplant [allo-SCT], and this sets that expectation.

Thus, I have to consider whether everything I am doing is a bridge to allo-SCT or if it is definitive multiyear therapy outside of an allo-SCT. My recommendation would be to refer this patient for allo-SCT, but regardless of whether we go to transplant or not, we have a significant disease burden that we have to control with therapy, and this is how I would start that conversation.

Gerds: Is this all you need, or do you think more information is needed to start treatment decisions?

Bose: I believe the information we have been provided is sufficient. We have a significant symptom burden, anemia that is perhaps not severe yet but nearly so, and a significantly enlarged spleen. Clearly, this patient is a candidate for a JAK inhibitor.

Ruxolitinib [Jakafi] is the JAK inhibitor that we have used for the longest amount of time, and is, I believe, most physicians’ go-to drug in the frontline setting. However, this is also a patient where I would be tempted to use momelotinib [Ojjaara] due to the hemoglobin level of 8.2 g/dL, understanding that both these drugs elicit spleen and symptom benefits.

Ruxolitinib does have a demonstrated survival advantage, which I discuss with patients. This is not to say that other [drugs] would not have that advantage, but the others have not had the chance to show it as clearly as ruxolitinib, which was compared with placebo.²

The information we have [for this patient] is fairly straightforward and points to the need for a JAK inhibitor. However, as Dr Abbas mentioned, the patient is 71 years old, and this does not preclude transplant.

Gerds: What are your specific criteria for initiating transplant evaluation in patients with intermediate-2 risk receiving JAK inhibitor therapy?

Palmer: There are a couple of aspects. First, you want to make sure you understand what their other organ function is. If the person has chronic kidney disease and chronic obstructive pulmonary disease where they require oxygen, they are not a good candidate for transplant. Thus, I would focus on how to optimize which to take with the expectation that they would not go to transplant.

In contrast, there are plenty of people who are 70 years of age [or more] and still play tennis every day. For instance, this patient may be discouraged that he can no longer run 5 miles every day. Thus, functional status and overall health play an important role.

The other aspect that I would make sure to discuss with this patient is their qualification for bone marrow transplant. There are several patients who do not want a transplant, and they are somewhat put off by the information we provide them about the procedure.

Sometimes, evaluating a patient’s response to ruxolitinib can help predict whether they will have a more durable response or an unfavorable outcome. The mutations play a role as well in determining the decision for transplant.

Overall, starting this patient on a JAK inhibitor, especially somebody like this prior to transplant, is very appropriate. I would not say that it has to be ruxolitinib, although Dr Bose brings up good points, and then the decision of having the transplant is a very nuanced one and taken carefully.

Gerds: If a patient does not respond to a JAK inhibitor and has an enlarged, painful spleen, would you try other treatments or proceed with a transplant?

Abbas: This is a transplant program–specific question. When I worked in the transplant [department], I did not prefer taking patients with enlarged spleens to transplant [because of] the risks of engraft- ment failure. However, the transplant program that I collaborate with now is very comfortable with taking patients with splenomegaly who have had only modest responses to JAK inhibitors prior to transplant.

Having stepped away from the allotransplant department for 5 years now, I would be interested in Dr Palmer’s perspective on this as someone in that department. I know that there are transplant programs that are hesitant to do a transplant for a patient with an enlarged spleen.

Palmer: It mainly depends on the [level of] urgency. [For instance,] if I have a patient who has a high white blood cell count and blast count and I am unable to reduce spleen size, I’m going to move forward with the transplant.

I generally do not administer splenic radiation. I think there are mounting data about using splenic radiation prior to transplant in terms of safety.³ Whether the approach will impact outcomes, I am not certain. If a patient, for example, has anemia and I am unable to optimize their JAK inhibitor use because of the anemia, then I would probably switch to a second-line treatment such as momelotinib or pacritinib [Vonjo] to see whether I could optimize the JAK inhibition prior to moving forward with transplant. It depends on the patient, the response to treatment, as well as other aspects such as symptom burden, white blood cell count, and other factors that may cause me to move forward with a transplant sooner rather than later.

Bose: Fortunately, becoming refractory to JAK inhibitors is rare. However, in those situations, we would move to novel agents. We have many novel non-JAK approaches to explore: BET, PIM, telomerase, and so on. We also have a new wave of type 2 and mutant-selective JAK inhibitors. Thus, this type of scenario would be ripe for a clinical trial option.

REFERENCES:

1. Mesa R, Miller CB, Thyne M, et al. Myeloproliferative neoplasms (MPNs) have a significant impact on patients’ overall health and productivity: the MPN Landmark Survey. BMC Cancer. 2016;16:167. doi:10.1186/s12885-016-2208-2

2. Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017;10(1):156. doi:10.1186/s13045-017-0527-7

3. Gagelmann N, Hobbs GS, Campodonico E, et al. Splenic irradiation for myelofibrosis prior to hematopoietic cell transplantation: a global collaborative analysis. Am J Hematol. 2024;99(5):844-853. doi:10.1002/ajh.27252