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Patients with myelofibrosis (MF), who are intolerant or do no longer respond to the standard of care ruxolitinib, have limited treatment options with challenging management and an approximate median overall survival of 13 months.1 In this setting, one of the alternative regimens under investigation is pacritinib, a Janus kinase 2 (JAK2) and interleukin-1 receptor-associated kinase 1 (IRAK1) inhibitor.1 Pacritinib has shown clinical superiority to best available therapy in two earlier phase III clinical trials (PERSIST-1 and PERSIST-2), when treating JAK inhibitor-naïve patients with primary MF and thrombocytopenia.2
During the 61st American Society of Hematology Annual Meeting & Exposition (ASH 2019), Aaron Gerds presented an oral abstract2 on the results from the phase II part of the PACIFICA trial, PAC203. This study compared the efficacy and safety of different pacritinib dosing schedules in patients with MF, who no longer benefitted or were intolerant to JAK inhibitors. The current article is based on data presented at the ASH and may supersede the data in the published abstract.
Table 1. Baseline characteristics of patients in the PAC203 phase II trial2
|
All doses (N = 161) |
---|---|
Median age (years) |
69 |
Median platelets (/μL) |
55,000 |
Hemoglobin < 10 (g/dL) |
71% |
Peripheral blasts ≥ 1% |
58% |
Median ruxolitinib duration (years) |
1.7 |
Ruxolitinib exposure Treatment failure Intolerance Both |
76% 73% 50% |
Molecular risk (n = 110) High molecular risk TP53 mutation |
41% 7.3% |
Average mutations per patient |
2.5 |
Table 2. Efficacy results reported at week 24 of the PAC203 phase II trial2
IQR, interquartile range; PLT, platelet counts; SVR, spleen volume response; TSS, total symptom score |
|||
Dose group |
Patients with ≥ 35% SVR |
Patients with ≥ 50% TSS reduction |
Median TSS reduction (IQR) |
---|---|---|---|
100 mg once daily (n/N) |
0% (0/52) |
7.7% (4/52) |
−3% (−30% to 29%) |
100 mg twice daily (n/N) |
1.8% (1/55) |
7.3% (4/55) |
−16% (−44% to 1%) |
200 mg twice daily (n/N): All patients Patients with PLT < 50,000/μL |
9.3% (5/54) 17.0% (4/24) |
7.4% (4/54) |
−27% (−39% to 1%) |
Table 3. Most common treatment-related adverse events (> 12%) reported in the PAC203 phase II trial2
TEAEs, treatment-emergent adverse events |
|||
TEAEs > 12% |
100 mg once daily (N = 52) |
100 mg twice daily (N = 55) |
200 mg twice daily (N = 54) |
---|---|---|---|
Diarrhea |
19.2% |
21.8% |
29.6% |
Thrombocytopenia |
21.2% |
21.8% |
40.7% |
Nausea |
23.1% |
20.0% |
27.8% |
Fatigue |
17.3% |
23.6% |
24.1% |
Abdominal pain |
17.3% |
10.9% |
24.1% |
Pyrexia |
15.4% |
16.4% |
13.0% |
Anemia |
9.6% |
10.9% |
24.1% |
Peripheral edema |
13.5% |
9.1% |
16.7% |
Decreased appetite |
11.5% |
7.3% |
18.5% |
Table 4. Key safety results from the PAC203 phase II trial2
TEAEs, treatment-emergent adverse events |
|||
TEAEs |
100 mg once daily (N = 52) |
100 mg twice daily (N = 55) |
200 mg twice daily (N = 54) |
---|---|---|---|
Cardiac TEAEs Grade 3 (n) |
5.8% (3) |
5.5% (3) |
3.7% (2) |
Cardiac TEAEs Grade 4 (n) |
0 (0) |
0 (0) |
0 (0) |
Cardiac TEAEs Grade 5 (n) |
0 (0) |
1.8% (1) |
0 (0) |
Hemorrhagic TEAEs Grade 3 (n) |
7.7% (4) |
0 (0) |
5.6% (3) |
Hemorrhagic TEAEs Grade 4 (n) |
0 (0) |
0 (0) |
0 (0) |
Hemorrhagic TEAEs Grade 5 (n) |
0 (0) |
1.8% (1) |
1.9% (1) |
Patients with ≥ 1 Grade 3–4 TEAEs (n) |
59.6% (31) |
60.0% (33) |
74.1% (40) |
Patients with ≥ 1 serious TEAE (n) |
36.5% (19) |
36.4% (20) |
46.3% (25) |
Patients with ≥ 1 TEAE leading to discontinuation (n) |
13.5% (7) |
21.8% (12) |
16.7% (9) |
Fatal TEAEs (n) |
7.7% (4) |
5.5% (3) |
5.6% (3) |
Pacritinib showed the best efficacy at 200 mg twice daily when treating patients with MF who were ruxolitinib intolerant or did no longer respond to ruxolitinib. At that dosing level, pacritinib led to a clinically meaningful SVR and a reduction in total symptom score in patients with severe thrombocytopenia. Pacritinib was tolerable at all dose levels with only few high-grade cardiac and hemorrhagic TEAEs that were a significant concern in earlier studies. In conclusion, these early results from the PAC203 phase II trial indicate that pacritinib at 200 mg twice daily could be considered as a new treatment option for MF patients who cannot be treated with ruxolitinib. Results from the phase III stage of PAC203 (PACIFICA) that will compare pacritinib (200 mg twice daily) with best available therapy will provide further insights into these preliminary findings.
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