Optimizing JAK Inhibitor Use for Hemoglobin and Platelet Regulation in Myelofibrosis (Part 2)

Case 2

Part 1 previously appeared in the April issue.

Aaron T. Gerds, MD, MS: How do you interpret and apply COMFORT-I [NCT00952289] and COMFORT-II [NCT00934544] trial data across different patient subgroups when making treatment decisions?

Prithviraj Bose, MD: It is easy to forget that in the COMFORT trials investigators evaluated patients who had a platelet [count] of 109/L and higher.^1,2 We have been used to ruxolitinib [Jakafi] for so long that it has become our default agent and sometimes we lose sight of that fact.

Patients in the COMFORT [trials] received 15 mg or 20 mg of ruxolitinib twice daily, and ruxolitinib is a very dose-dependent drug. It works best at higher doses, so we cannot expect the same results when we are using 5 mg or 10 mg twice a day. This is important to remember, and this is also where the new drugs come into play. For example, in patients with cytopenic adverse events [AEs] who are not able to maintain this dose intensity for ruxolitinib because [it is known to] cause cytopenia, perhaps in this situation it would be better to use a drug [for which] we can maintain dose intensity.

Gerds: Do you find the results from these studies still useful today?

Jonathan Asif Abbas, MD: Yes, these data have established the standard of care [SOC] on how to perform trials evaluating myelofibrosis, setting the parameters for spleen volume reduction and what that success looks like.

Overall survival [OS] is important, and oral chemotherapy is a scary concept for patients. It is a bonus that not only is this [treatment] going to make a patient feel better, but by feeling better, needing [fewer] transfusions, and by improving nutrition, activity, and fatigue, the patient is going to live longer. It was not one of the primary end points of the study, but it showed a huge benefit that resonates for patients. Thus, I use that OS advantage to help patients get over the discomfort regarding the concept of [receiving] oral chemotherapy.

Optimizing JAK Inhibitor Use for Hemoglobin and Platelet Regulation in Myelofibrosis (Part 2)

Gerds: Do you think a 35% reduction in spleen volume is a valuable end point for patients, or should we be focusing on other outcomes?

Jeanne Palmer, MD: I do not believe that a patient needs a 35% spleen volume reduction to benefit. Thus, the 35% reduction and 50% total symptom score reduction were chosen as meaningful response rates for these initial studies, but now we know more. For instance, we know that much smaller differences can be clinically meaningful to patients. I try to avoid questions such as, “What was the response rate, and what does that response rate mean?” I focus more on completing the therapy to make the patient feel better from the standpoint of their spleen shrinking and symptoms improving.

When it comes down to using these response criteria, they worked great for these trials, and it was novel to use a patient- reported outcome as an end point in a clinical trial. We have to acknowledge that this was a very new approach. However, the limitations are that they do not work well for second-line therapy, and with some of the newer agents, they are lacking in their ability to demonstrate whether a drug is beneficial. I focus more on the simplicity of it and less on the response rates, but whenever I talk with providers or patients, and they ask about the response rates, we know that at the end of the day patients can get a lot of benefit from this even without a clinical response.

Gerds: Regarding case 2, when would you consider the anemia to be drug related vs disease related in this setting?

Bose: Perhaps this patient has had their hemoglobin [level] decrease to 7.2 g/dL. That said, how much of this [decrease] is caused by ruxolitinib, and how much is caused by the disease progressing? This question comes up in practice, and in this case, the spleen grew. Thus, I would imagine there is some degree of resistance to the therapy, and in that sense, I would say that it is disease progression. However, our JAK inhibitors do differ in their myelosuppressive potential, and some of the anemia we are seeing is probably drug-induced, which might have been less with another agent.

Gerds: When you see platelet counts of 98 [µL], do you think it is more related to the disease or the drug? Does it influence your choice of the next treatment?

Abbas: A dose of ruxolitinib at 20 mg twice daily with platelet count less than 100 [µL] is an aggressive dose. Thus, if cytopenia were present, I would be concerned [about] a possible treatment-related AE. However, I believe this patient has progressive splenomegaly, which in this case translates to a clinically significant progression on the maximum dose of ruxolitinib. Thus, I think this is clearly progression and time to move on to a different treatment. A platelet count of 98 [µL] is an interesting threshold because if it was 48 [µL] or 58 [µL], I think we would all be leaning a certain way. [However,] at a platelet count of 98 [µL,] there is a little bit of leeway to determine [whether to use] pacritinib [Vonjo] vs momelotinib [Ojjaara] as the next line of therapy.

Gerds: For case 2, do we go to transplant now, or do we try something else first?

Palmer: This depends on whether I have met this patient before because if I have met her and did human leukocyte antigen typing, then I [am] more [able] to quickly get her to transplant. That said, she is clearly experiencing progressive disease due to her loss of response to ruxolitinib and is someone who would need a transplant.

I still would try to use another JAK inhibitor, such as momelotinib, to see if I could optimize getting her to transplant. I have a lot of experience with conducting transplants with several patients who are on momelotinib up to the time of their transplant, whether in the first line or second line. Now, I would not predicate her transplant on having an adequate spleen response. I still would try to get her to transplant as soon as I could, but I would see if I could do [a treatment] such as momelotinib in the interim.

Gerds: What considerations guide your approach to dose optimization when initiating fedratinib [Inrebic] therapy?

Bose: I do administer fedratinib frequently; however, I have not used it in the frontline setting. This is because I do not believe there is a reason to use it over ruxolitinib. There is some risk with the gastrointestinal toxicity and the fear of Wernicke encephalopathy, causing me to not use it in the front line.

However, I would absolutely use fedratinib in the second line. I might hesitate in this case because the hemoglobin [level] was 7.2 g/dL, which is very low. I would use momelotinib for this patient. Otherwise, I often use fedratinib in the second line when patients still have a proliferative phenotype, the laboratory values are still reasonably good, and the spleen is large.

Gerds: Do you notice any difference in the efficacy of fedratinib in patients with a platelet count above 100 [µL] vs those with moderate thrombocytopenia in the 50 [µL] to 100 [µL] range?

Palmer: Similarly to Dr Bose, I typically use fedratinib in the second-line setting. One of the areas where it can be beneficial is that it does not have the same weight gain effect that ruxolitinib does. The diarrhea and gastrointestinal [GI] AEs can be somewhat worse with fedratinib, and the other reason I use it in the second line vs the first line is because we have data using fedratinib as second-line therapy after patients progressed on ruxolitinib. According to the data, 30% of patients can have a response [after ruxolitinib with fedratinib].

Gerds: Based on the JAKARTA data [NCT01437787] evaluating fedratinib vs placebo, in your experience, is a 20% reduction in spleen volume a meaningful benefit?

Abbas: Absolutely. This is a disease that is not black and white, and you can tell if 30% or 40% of patients are going to respond. The clinical benefit to patients far exceeds that, because it could take only a small reduction in spleen size to reduce pressure on the stomach, increase caloric intake, and ease the uncomfortable distension to make them feel better. I have seen 10% reductions [in spleen volume] have a clinical benefit.

In the JAKARTA data, we saw how many patients had spleen reduction and did not meet the study end point.³ Thus, it is important not to say to a patient that only 1 in 3 patients are going to respond. [In addition,] it is a pretty depressing thing to say to a patient. The clinical benefit is much more than just the study end point.

Gerds: For case 3, what specific monitoring strategies and dose modifications have proven most effective when treating patients with severe cytopenia on JAK inhibitor therapy?

Bose: I would use pacritinib because their platelets are less than 50 × 109/L, signifying that they are very anemic.⁴

However, when we monitor patients on ruxolitinib we tend to adjust the dose, although we also know that ruxolitinib is less effective at lower doses. We can also try luspatercept [-aamt; Reblozyl] and erythropoiesis-stimulating agents.

Gerds: What other treatment options do we have?

Bose: It is nice that we now have these options, although it does make the field more complex. We have many more treatment choices to switch to, and we also have models to guide us, such as the response to ruxolitinib after 6 months (RR6) model.

The RR6 model indicates that if we are unable to deliver a sufficient dose, there is inadequate spleen shrinkage, and continued transfusion needs, it is a strong indication that the patient may not respond well to the current treatment.

Gerds: Is this someone [for whom] you might consider an anemia-supportive agent straight away, or do you think this person needs a JAK inhibitor?

Abbas: In the pre-pacritinib era, this would have been a very challenging patient to [treat], and I would attribute that degree of cytopenia to splenomegaly.

When you look at the whole picture of the aggressive mutation and 3% blast, I would conclude that this is an extremely high-risk myelofibrosis that is trying to move very quickly toward leukemia.

This is a patient who would need a fasttrack allogeneic transplant, and we may be limited to only cytopenia-supportive care in that bridge to allogeneic transplant. This is because none of our other JAK inhibitors, prior to pacritinib, would have allowed for that.

You may have been able to give a 5-mg twice-daily dose of ruxolitinib, but the chances of that working would be very low to provide meaningful clinical benefit.

This is why we are fortunate we have an agent with an alternate target pathway. This patient would be a perfect candidate for pacritinib with a fast track to allogeneic transplant.

Gerds: Regarding pacritinib, fedratinib, and ruxolitinib, how do you balance symptom improvement, spleen response, and quality of life measures when assessing treatment success?

Abbas: The answer to this is assessing how the patient feels. I try my best to tease out and form an opinion on the aspect of what I think needs the most improvement to get a patient’s quality of life where we need it, whether that is focusing on the spleen, cytopenia, or constitutional symptoms.

Once you have given the treatment enough time and you should be seeing a response, the patient lets you know. For instance, their pants fit looser, they’re gaining healthy weight back, and the split temporal wasting is resolving from the malnutrition. In this way, you can tell you are on the right track, which is based on an individualized patient experience. We do the best we can to choose a treatment that is going to match what we think the patient’s need is and hope we achieve the results ideal for quality of life.

Gerds: What specific cytopenia thresholds do you use to select JAK inhibitors?

Bose: I have always used pacritinib per the label, and that is how I will continue to use it. This is because it has been studied in patients with platelets up to 100 [µL], but I feel that it [is appropriate for] patients [who] have a platelet count less than 50 [µL]. Other JAK inhibitors either do not have any data or have too little data on this. In the situation where platelets are 50 [µL] to 100 [µL] is where it gets interesting because all 4 drugs have data for this population.⁵

Regarding pacritinib, the initial story was that it keeps the platelet count stable, and we have since learned that it can give an anemia benefit. However, with the advent of momelotinib, when anemia is a major factor in the decision-making, I now lean toward momelotinib.

Regarding fedratinib and the JAKARTA data,³ this past American Society of Hematology meeting, we heard from Haifa Kathrin Al-Ali, MD, on the FREEDOM2 study [NCT03952039].⁶

These were robust data, showing that fedratinib works well in patients with a platelet count between 50 [µL] to 100 [µL] or 100 [µL] and higher.

This is reassuring data [about] fedratinib because my perception had been that fedratinib was as myelosuppressive as ruxolitinib. Perhaps this is evidence to rethink that.

Thus, we have a lot of choices for when platelets are 50 [µL] to 100 [µL], but I tend to reserve pacritinib for patients with a platelet count less than 50 [µL].

REFERENCES:

1. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. doi:10.1056/nejmoa1110557

2. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798. doi:10.1056/nejmoa1110556

3. Pardanani A, Tefferi A, Masszi T, et al. Updated results of the placebo-controlled, phase III JAKARTA trial of fedratinib in patients with intermediate-2 or high-risk myelofibrosis. Br J Haematol. 2021;195(2):244-248. doi:10.1111/bjh.17727

4. Oh ST, Mesa RA, Harrison CN, et al. Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis. Blood Adv. 2023;7(19):5835-5842. doi:10.1182/ bloodadvances.2023010151

5. Reynolds SB, Pettit K. New approaches to tackle cytopenic myelofibrosis. Hematology Am Soc Hematol Educ Program. 2022;2022(1):235-244. doi:10.1182/hematology.2022000340

6. Harrison CN, Mesa R, Talpaz M, et al. Efficacy and safety of fedratinib in patients with myelofibrosis previously treated with ruxolitinib (FREEDOM2): results from a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Haematol. 2024;11(10):e729-e740. doi:10.1016/S2352-3026(24)00212-6