Rossetti Reviews Myelofibrosis Risk Stratification and Outcome Data for Pacritinib

James M. Rossetti, DO

Hematologist/Oncologist

UPMC Hillman Cancer Center

Pittsburgh, PA

CASE SUMMARY

• The patient is a 62-year-old man in Florida.
• He presented to his primary care physician (PCP) with symptoms of fatigue, night sweats, and increased bruising.
• His past medical history includes type 2 diabetes, hypercholesterolemia, and hypertension.
• Normal physical and blood work 1 year ago
• His PCP noticed lower hemoglobin (11-9.5 g/dL) and platelet count (350,000/μL-195,000/μL) from the previous year’s physical.
• He was referred to hematology/oncology; first available appointment in 2 months
• At the appointment, exam findings include spleen 5 cm below left costal margin, worsening fatigue and night sweats, and bone pain.
• He has a history of squamous cell carcinoma of the skin.
• Blood: 1% blasts by manual count/flow cytometry
• White blood cells: 19 × 10⁹/L; hemoglobin: 9.1 g/dL; platelets: 135,000/μL; lactate dehydrogenase: 330 U/L
• Bone marrow biopsy showed blasts less than 5% and grade 2/3 fibrosis
• Karyotype was 46,XY[20], and next-generation sequencing panel showed a JAK2 V617F mutation with variable allele frequency of 53%
• ECOG performance status: 2
• Diagnosis: primary myelofibrosis

Peers & Perspectives in Oncology: Which tools can be used to assess risk status for a patient such as this?

Rossetti: The PASS tool looks at the prognosis, anemia and thrombocytopenia, systemic symptoms, and splenomegaly and related symptoms.

Looking at the MIPSS70+ [Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis], certain [prognostic variables] stand out.¹ The absence of the CALR type 1 mutation [is a risk factor. This means] if you have [the mutation], it’s a very good thing. If you don’t, [you are at higher risk]. High-risk molecular mutations [also increase risk]. If we compare the MIPSS70+ with some of the older models we had, the [overall survival (OS)] curves were a lot closer together previously. With the newer models, the curves are spreading out pretty nicely, similar to the models for myelodysplastic syndrome. It’s not just that they are cytopenic, but the degree of cytopenia, how many mutations they have, [the] karyotype, [the] molecular [status], and the number of circulating blasts by flow cytometry [are all factors]. I use the MIPSS70+ all the time. For patients with secondary myelofibrosis, we have other models that capture similar factors. Dividing these patients up the best we can is important.

What are the challenges of using these scoring systems?

[This patient has] moderate anemia, constitutional symptoms, and absence of the CALR mutation. The constitutional symptoms are a tough [challenge]. Are they related to something else? The reality is you are seeing a lot of patients in clinic with a variety of different illnesses, so when you start to talk about symptom scores, it’s very difficult. I know several of my colleagues have very simple tools that we might be able to use to capture this. It’s difficult when you’re doing retrospective review on these patients to capture constitutional symptoms accurately if risk scores aren’t done as they are published, which, to be honest, is exceedingly difficult for anyone who is in the practice as busy as all of us have.

It’s a big [question] that we have to tease out to discern: Are they feeling poorly from their disease [or other reasons]? [Should we suspect] fatigue is from anemia if the anemia is not that bad? Is it fatigue from the proinflammatory state that they have? There’s a lot of overlap within this PASS criteria.

Night sweats, bone pain, and fever are very common, in my experience. Often, these patients will have fevers associated with their disease, and sometimes they’ll end up in the hospital for long periods of time because we want to rule out infections and the like, especially if they’re on therapies that might increase the risk of infection. There is abdominal discomfort and early satiety [that is] typically spleen related but not always. Some patients whose spleens are improving [in size experience worsening] pain because they have a splenic infarct or something else. Conversation is important as we decide what to use and how well something might be working, which predicts outcomes for some agents.

How do trial data support the use of pacritinib (Vonjo) in patients with thrombocytopenic myelofibrosis?

I [focus on] the PERSIST-2 [NCT02055781] data on first- and second-line therapy for patients with thrombocytopenia. Even though the [approval] is for those with a platelet count under 50,000/μL, the trial that led to that approval was for patients [whose platelet count was] under 100,000/μL.² The dose that we all use, as it relates to safety and efficacy, is pacritinib 200 mg twice daily. The primary end points were splenic volume reduction [SVR] and total symptom score [TSS] at [more than] 50% improvement at the 24-week mark against best available therapy [BAT].

These are patients who were on a variety of therapies, which even included thalidomide…. Lenalidomide [Revlimid] is used more now in some of these patients, but the reality is immunomodulatory imide drugs have a role here, albeit increasingly limited with the development of these newer agents. These patients generally had intermediate-1 and higher-risk disease. A good number had intermediate-2 and high risk, approaching 80% of the patients with those higher-risk categories. A significant number had hemoglobin under 10 g/dL, [59% in the experimental arm and 57% in the BAT arm]. We think about this trial as one for patients with thrombocytopenia, but anemia was demonstrated there.

What were the outcomes for the primary end points?

Looking at the 200-mg twice-daily dosing for those patients with platelet count under 50,000/μL, you saw a 30% improvement in SVR with [patients who were] severely thrombocytopenic.² That’s a very good number considering the fact that a good number of these patients would not have been able to dose escalate on alternative therapy. One thing I always remind people of is that these data are excellent as it relates to SVR, [but] it…takes a little more time to achieve the same response. Though we don’t see a great degree of thrombocytopenia associated with treatment, we might not see a rise, though we do in some patients. It doesn’t necessarily mean we’re not helping if the spleen is regressing. In these patients, you can see SVR at the baseline dose of 200 mg without dose modification.

TSS was clearly favoring pacritinib at the 200-mg twice-daily dosing. Interestingly, there was a [nearly] 50% change in the pruritus, which is tough [to manage]. Ruxolitinib [Jakafi] has always had a good track record there, and I think it’s on par with pacritinib. There was marked reduction in the night sweats, discomfort in the spleen, and the early satiety associated with it. Across the board, there are improvements.

What other data from the trials of pacritinib are relevant to this patient population?

I want to draw attention to the anemia response rates. Sixty percent [of those] enrolled in the PERSIST-2 trial at a standard dosing of 200 mg twice daily were anemic. The patients who were anemic at baseline had a substantially lower rate of transfusion need as treatment continued [Figure²]. That continued to improve throughout the 24-week treatment course, where it was under 1 red blood cell unit per month, approaching only one-half of a unit per month across the group. There was some improvement over time in the platelet count, though sometimes there was a bit of a dip.

I have dose adjusted, but it is not standard for everyone. I have a lot of colleagues who will push through, but if it’s severe enough, I will push down. I have a handful of patients who do well on 100 mg twice daily. There are those few patients who require that, but overall, most of my patients are dose intensified on pacritinib. We either see stability of the platelet count or some rise over the course of time, but it works more slowly.

Achievement of transfusion independence is an important [end point]. Some 24% of patients treated with pacritinib in PERSIST-2 achieved transfusion independence [vs 5% with BAT; P = .013].³ The group who [received] BAT included patients who were on erythropoietics. It speaks to the fact that the erythropoietin-stimulating agents don’t work that well for our patients, as is evidenced in PERSIST-2. [However], approximately one-quarter of patients on pacritinib will [achieve] transfusion independence as a conversion rate.

What toxicity concerns are there with pacritinib?

The [rate of] cytopenias was less than what we saw with ruxolitinib.^2,4,5 These are patients who are generally thrombocytopenic to begin with, but it is something we have to be paying attention to. These patients are already in a state of marrow failure. We recognize these cytopenic patients with myelofibrosis. For any of the drugs, I start with weekly laboratory tests across the board for the first 8 weeks of therapy. It’s my standard routine, and then I start to space it out thereafter. Diarrhea of grade 3 or higher is very uncommon [4%]. I have had a lot of ruxolitinib and pacritinib use, and I don’t see a ton of diarrhea. I see mild diarrhea not infrequently. Within the first 2 weeks, most of these patients start to improve. The other gastrointestinal adverse events are fairly uncommon. For me, pacritinib has been a very well-tolerated agent.

If you look at ruxolitinib and the risk of viral infections, I tend to use acyclovir for prophylaxis. [The risk of] shingles is not small. Not all my colleagues do it but several do. Infections tend not to be a big problem with pacritinib, presumably because of the lack of JAK1 inhibition.⁶ Similarly, we start thinking about the secondary malignancies, nonmelanoma skin cancers being one of the more common, which favored pacritinib in this adverse event of interest compared with those who had BAT consisting of ruxolitinib [5 events with pacritinib vs 11 with ruxolitinib]. This was very intriguing when we looked at the very early pacritinib data, as they relate to the infection and secondary cancers. We’re having all these patients see a dermatologist regularly—6 months to 1 year—being evaluated for nonmelanoma skin cancers. It’s something we have to think about with most JAK inhibitors. Pacritinib seems to be one where it’s less of a concern.

What did the landmark survival analysis of PERSIST-2 show?

Looking at symptom responses and how it can predict for OS, those patients who had improvement in TSS—even 10% to 20%—had improvement in OS.⁷ These were newer data that are encouraging as we learn, especially in the nontransplant patient. With transplant, we’re thinking about OS [and] cure, but in the patient who’s not a transplant candidate, which is the overwhelming majority of patients, [we don’t have much] data to suggest that OS might be improved in patients who are on the other agents.

As long as they’re improving by symptom score, that’s one of the predictors. The other thing is SVR. We know that suboptimal spleen management across the board for all agents and suboptimal white blood cell count management predicts for worse outcome.

REFERENCES:

1. Tefferi A, Guglielmelli P, Lasho TL, et al. MIPSS70+ Version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis. J Clin Oncol. 2018;36(17):1769-1770. doi:10.1200/JCO.2018.78.9867

2. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652-659. doi:10.1001/jamaoncol.2017.5818

3. 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.202301015

4. 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

5. 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

6. Pemmaraju N, Harrison C, Gupta V, et al. Risk-adjusted safety analysis of the oral JAK2/IRAK1 inhibitor pacritinib in patients with myelofibrosis. EJHaem. 2022;3(4):1346-1351. doi:10.1002/jha2.591

7. Ajufo H, Bewersdorf JP, Harrison CN, et al. Impact of symptom benefit and transfusion response on survival in myelofibrosis patients treated with pacritinib: PERSIST-2 landmark survival analysis. Blood. 2023;142(suppl 1):3207. doi:10.1182/blood-2023-177643