Newer JAK Inhibitors Aid in Cytopenia Management for High-Risk Myelofibrosis

Kristen M. Pettit, MD (Moderator)

Clinical Associate Professor

Rogel Cancer Center

University of Michigan Health

Ann Arbor, MI

DISCUSSION QUESTIONS

• When do you usually refer for allogeneic stem cell transplant (SCT) evaluation? ​
• How coordinated is communication between you/your institution and the transplant team?​
• Do you coordinate with the transplant center regarding the choice and duration of bridging therapy?

KRISTEN PETTIT, MD: When do you refer a patient for allogeneic SCT, and how does it work with your institution? I'm always interested in bridging, too. How do you coordinate that with the transplant center? I know some transplant centers are a little bit more hands-on with their involvement pretransplant, and some are more hands-off.

TAREQ AL BAGHDADI, MD: I tend to make those decisions and not leave them to the transplanters. If the patient needs treatment, I start treatment, and then they can weigh in on transplant. A small minority of my patients get transplanted, so I start treatment and do not leave it [to them]. If there's a trial, that would be my go-to option. If there's no trial, in the case [of an anemic patient] I would probably start ruxolitinib [Jakafi] with a weekly complete blood count to see what's happening with the hemoglobin. We can talk about titrating ruxolitinib [based on the new data,¹ starting at 10 mg twice daily vs the classic start, but either is fine.

PALLAVI JASTI, MD: When I see a patient and I feel like they’re transplant eligible, we usually have a leukemia/lymphoma tumor board where our transplant team is part of the discussion. If they also agree that this patient looks transplant eligible, I start them with initial therapy, but I do refer them early on while I'm initiating treatment, because it takes time to get to the point of allogeneic SCT. I work at 30 minutes away from the transplant center but patients can travel and get the allogeneic SCT if the patient is deemed eligible after being evaluated by them. Typically, the transplanters send the patient back to us after the initial 90 days if they're stable, but they also comanage with us in the first year posttransplant.

DISCUSSION QUESTIONS

• What are your reactions to the efficacy and safety data from COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544), PERSIST-2 (NCT02055781), and MOMENTUM (NCT04173494)? ​
• For a patient with a low platelet count at baseline, what is your preferred Janus kinase (JAK) inhibitor, based on the data presented?

PALLAVI JASTI, MD: Myelofibrosis has been a tough disease before the advent of JAK inhibitors. For several years, all we had was ruxolitinib, which comes with significant cytopenias, requiring dose interruptions or dose reductions. I'm excited to see 2 different JAK inhibitors with different targets which potentially can be useful, especially when there is either severe thrombocytopenia or severe anemia, and still showing a favorable toxicity profile. Both have their own unique space in these patients with high-risk myelofibrosis.

PETTIT: I agree; I'm happy to have the tools out there to use. Which tool to use in which situation is tricky, and it's a good problem to have. But when we have patients with anemia, and [a degree of] thrombocytopenia, I don't know whether pacritinib [Vonjo] or momelotinib [Ojjaara] is going to be better for the patient, and I don't have great guidance on how to choose one or the other. If anemia is the main driver, I tend to choose momelotinib more commonly. If thrombocytopenia is more of an issue, especially a platelet count of less than 50,000/μL, then I tend to choose pacritinib, although they're both good options in both situations.

ADRIANA ALVAREZ, MD: Do you see the degree of improvement of splenomegaly being the same with all of them? It seems like with ruxolitinib…even though the other ones seem to be better in terms of preventing low platelets and anemia…[in terms of] overall survival, with the decrease of the spleen [size] the patients did better.² If I have a patient who potentially could use any of the 3, could I still remain with the ruxolitinib because of the improved survival?

PETTIT: There's a lot of debate and differences in practice there. We have so much long-term data from ruxolitinib. The dose of ruxolitinib matters in terms of response and response duration. If we're running into issues where we can't get ruxolitinib doses of at least 10 mg twice daily into the patient, if we're having to drop below 10 mg twice daily, we see the response rates and their response duration drop off dramatically from real-world studies and from long-term outcomes.^3,4

If we're having to lower doses or start at that low of a dose because of cytopenias, then I do get concerned about ruxolitinib. But I agree that for patients with platelet counts between 50,000/μL and 100,000/μL, [particularly] closer to 100,000/μL, ruxolitinib is still on the table. Anemia can be a challenge, too.

AL BAGHDADI: Ruxolitinib and momelotinib were compared head-to-head in a negative study in the sense that momelotinib was not seen to be non-inferior in the first line to ruxolitinib.⁵ The main difference was in symptom control, as opposed to spleen shrinkage. If I have a patient with significant symptoms, I can't tell them that momelotinib and ruxolitinib are equivalent in terms of dealing with the symptoms.

PETTIT: That's correct. But the patient population we're talking about with lower blood counts, who aren't going to be able to get a full dose of ruxolitinib, was not the population that was included in the SIMPLIFY-1 trial [NCT01969838]. That’s where it gets [challenging]. If you're dealing with a patient with normal blood counts, where you're going to be able to use a full dose of ruxolitinib, I would use a full dose of ruxolitinib and not use something like momelotinib or pacritinib. But if you're going to have to be getting down to low doses of ruxolitinib, then that's where those agents have their efficacy and their role.

REFERENCES:

1. Cervantes F, Ross DM, Radinoff A, et al. Efficacy and safety of a novel dosing strategy for ruxolitinib in the treatment of patients with myelofibrosis and anemia: the REALISE phase 2 study. Leukemia. 2021;35(12):3455-3465. doi:10.1038/s41375-021-01261-x

2. Palandri F, Palumbo GA, Bonifacio M, et al. Durability of spleen response affects the outcome of ruxolitinib-treated patients with myelofibrosis: Results from a multicentre study on 284 patients. Leuk Res. 2018;74:86-88. doi:10.1016/j.leukres.2018.10.001

3. Verstovsek S, Gotlib J, Gupta V, et al. Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. Onco Targets Ther. 2013;7:13-21. Published 2013 Dec 17. doi:10.2147/OTT.S53348

4. Palandri F, Palumbo GA, Bonifacio M, et al. Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis. Oncotarget. 2017;8(45):79073-79086. Published 2017 Jun 27. doi:10.18632/oncotarget.18674

5. Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: A phase III randomized trial of momelotinib versus ruxolitinib in janus kinase inhibitor-naïve patients with myelofibrosis. J Clin Oncol. 2017;35(34):3844-3850. doi:10.1200/JCO.2017.73.4418