Understanding the Deep Response to Pacritinib in Myelofibrosis


During a Case-Based Roundtable® event, John Mascarenhas, MD, discussed the deep response with pacritinib and its adverse event profile for patients with myelofibrosis in the second article of a 2-part series.

Targeted Oncology: In the PERSIST-2 trial (NCT02055781) how did the achievement of transfusion independence impact patients?

JOHN MASCARENHAS, MD​: The anemia benefit was seen with pacritinib [Vonjo], specifically looking at transfusion independence with 200 mg [of pacritinib] given twice daily [compared with the best available therapy (BAT)] at 24% vs 5%, which was statistically significant [P = .013].1 No matter how you looked at the data, the anemia benefit from the transfusion independence rate was superior with pacritinib at 200 mg twice daily...including [the patient’s] platelet count and excluding [patients who had] prior...ruxolitinib [Jakafi] treatment.1

Were there any toxicities of note with pacritinib?

John Mascarenhas, MD​

Director, Center of Excellence for Blood Cancers and Myeloid Disorders

Professor of Medicine

Icahn School of Medicine at Mount Sinai​

New York, NY

John Mascarenhas, MD​

Director, Center of Excellence for Blood Cancers and Myeloid Disorders

Professor of Medicine

Icahn School of Medicine at Mount Sinai​

New York, N

If you treat [patients with] acute myeloid leukemia you know that FLT3 inhibitors are associated with gastrointestinal [GI] toxicity, and this is no different.... [The GI toxicity is] mild, it's usually grade 1 or 2, and in the first 2 months they're easy to manage,2 and it's easy to manage with an antiemetic given about 30 minutes before dosing [is given] twice a day. Usually, patients don’t even need it after the first month, or it’s barely needed during the first month. Otherwise, there was no real signal of toxicity in terms of neuropathy or infectious risk.2 I noticed with bleeding, particularly in patients who had epistaxis previously were more likely to have epistaxis when using pacritinib. We maintained the dose intensity of pacritinib, meaning it didn’t require dose reductions in most patients that were treated, and remember these are patients with low platelets.

How did adjusting for risk impact the adverse event profile seen in PERSIST-2?

Researchers used time as a variable so [we] can have a better sense of the actual risk of pacritinib.... They pooled treated patients from the PERSIST-2 trial and PAC 203 dose-finding study [NCT03165734] compared with the BAT- and ruxolitinib-treated patients.3 At least numerically, there was less incidence of malignancy, nonmelanoma skin cancer, viral infections, and shingles with pacritinib, but fungal infections [occurred at] the same rate. Fungal infections are not that common, and I was surprised that even 6 patients [with fungal infections] were seen here, but that is a consideration [when using this drug]. I'm not sure why with pacritinib we saw fungal infections, but viral, bacterial, and second primary malignancies seem to be less common with pacritinib.3

What was the correlation between survival and the use of pacritinib?

Even if you have a symptom response of at least 10% or better, those patients who had that response with pacritinib appear to have an improved survival compared with patients who did not.4 With the patients who got BAT, including ruxolitinib, that relationship didn’t seem to happen. So, having the symptom response didn’t seem to correlate with survival benefit [for these patients], and if you did [see a total symptom score increase of] 20% you saw similar phenomena that were maybe not as statistically significant. We did a similar analysis with spleen response, and we saw the same phenomena that you get spleen and symptom benefit correlated with survival with pacritinib but not with BAT including ruxolitinib in these patients with low platelets, so it appeared like pacritinib was perhaps doing something a little bit deeper than we had anticipated.4


1. 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

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. 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

4. 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

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