Long-Term Treatment with Pacritinib on a Compassionate Use Basis in Patients with Advanced Myelofibrosis
Authors: Harrison Claire N. , Yacoub Abdulraheem , Scott Bart L. , Mead Adam J. , Gerds Aaron T. , Kiladjian Jean-Jacques , Mesa Ruben A. , Egyed Miklos , Scheid Christof , Garcia Gutierrez Valentín , Buckley Sarah A , Kanellopoulos Kris , Mascarenhas John 
Published: November 2021

Abstract

Background
Pacritinib is a JAK2 / IRAK1 inhibitor in development for the treatment of patients with myelofibrosis (MF). The efficacy and safety of pacritinib has been evaluated in multiple clinical trials, including two randomized, controlled phase 3 trials (PERSIST-1 and PERSIST-2) and a Phase 2 dose-finding study (PAC203). These studies are unique in the MF landscape because they enrolled patients with advanced disease and severe cytopenias; all studies included patients with baseline platelet counts &lt;50x10 9/L as well as higher platelet counts. When these studies closed, patients who received pacritinib could apply to continue treatment on a compassionate use basis. This analysis describes pacritinib treatment in this program.
Methods
Patients enrolled in PERSIST-1, PERSIST-2, or PAC203 were eligible for compassionate use if they were benefitting from pacritinib in the opinion of the investigator and had an unmet medical need. Patients were excluded if they had progressed to acute leukemia or experienced high-grade cardiac or bleeding events on study. Dosing regimens of compassionate use pacritinib were 200 mg twice daily (BID), 100 mg BID, and 100 mg daily. For patients treated at lower or intermediate pacritinib doses during the original clinical studies, dose escalation up to 200 mg BID was permitted at the discretion of the medical monitor and treating physician. Blood counts and chemistry were to be evaluated every 3 months, electrocardiogram every 3 months, and left ventricular ejection fraction every 6 months while receiving pacritinib.

Results
A total of 82 patients were approved for compassionate use; 75 received treatment with pacritinib. Of these 75 treated patients, 41 were originally enrolled in the Phase 3 PERSIST-1/PERSIST-2 studies and 34 were originally enrolled in the PAC203 dose-finding study. At the time of this analysis, 20 patients continue to receive compassionate use pacritinib. Patient characteristics were available from the original study for 73 treated patients. Median age at the time of original study enrollment was 69 years (range 37-84). Most patients (70%) had received prior JAK2 inhibitor. Approximately half (51%) had baseline peripheral blast count ≥1%. Baseline platelet count at the time of original study enrollment was &lt;50x10 9/L in 34% of patients and &lt;100x10 9/L in 69%, and baseline hemoglobin level was &lt;10 g/dL in 49%. Prior to compassionate use, 40% had platelet counts &lt;50x10 9/L, 74% had platelet counts &lt;100x10 9/L, and 52% had hemoglobin &lt;10 g/dL.
Among the 69 patients with available dosing data, 67% received compassionate-use pacritinib at a starting dose of 200 mg BID, 28% received 100 mg BID, and 6% received 100 mg daily. Nearly all patients (97%) received the same or a higher dose as they had received on-study.
Median total combined duration of treatment with pacritinib (original study + compassionate use) was 21.1 months (range 0.8-80.9, Table 1). Median treatment duration was 7.8 months (range 0 to 32.9) on the original study and 11.6 months compassionate use (range 0.3 to 61.2). For patients with baseline platelet count &lt;50x10 9/L or with hemoglobin &lt;10 g/dL, the median treatment duration was similar to the overall population. Patients who were JAK inhibitor naïve had longer median treatment durations compared to those who had prior exposure (29.4 vs.18.4 months).
Among the 75 patients treated with compassionate use pacritinib, 44% experienced a serious adverse event (SAE). Most SAEs were considered unlikely related to pacritinib and were those expected in an end-stage MF population, including infection (13%, n=10), bleeding (19%, n=14), cytopenias (4%, n=3), and heart failure (4%, n=3). Among infections, only one was considered atypical or potentially opportunistic: this was a case of actinomyces pneumonia in a patient with baseline neutropenia; pneumonia resolved with administration of IV antibiotics. There was one SAE of skin cancer, which was a case of invasive squamous cell carcinoma on the scalp of a patient with an extensive history of both squamous and basal cell skin cancers.
Conclusions
This analysis demonstrates the feasibility of prolonged treatment with pacritinib in patients with advanced MF, including those with thrombocytopenia and anemia. Reported SAE were consistent with those previously observed with pacritinib and with the end-stage, compassionate use treatment setting.
Figure 1 Figure 1.

Disclosures
Harrison: Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sierra Oncology: Honoraria; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Yacoub: Agios: Membership on an entity's Board of Directors or advisory committees; Acceleron Pharma: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau. Scott: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Mead: Celgene/BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau. Gerds: Constellation: Consultancy; PharmaEssentia Corporation: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Sierra Oncology: Consultancy; CTI BioPharma: Research Funding; Novartis: Consultancy. Kiladjian: Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Mesa: AOP: Consultancy; Pharma: Consultancy; CTI: Research Funding; Abbvie: Research Funding; Gilead: Research Funding; Incyte Corporation: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Novartis: Consultancy; Genentech: Research Funding; Samus: Research Funding; La Jolla Pharma: Consultancy; Constellation Pharmaceuticals: Consultancy, Research Funding; CTI: Research Funding; Celgene: Research Funding; Promedior: Research Funding. Scheid: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria; Roche: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Garcia Gutierrez: BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding. Buckley: CTI Biopharm: Current Employment. Mascarenhas: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merus: Research Funding; Geron: Consultancy; Galecto: Consultancy; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; Prelude: Consultancy; Geron: Consultancy, Research Funding; Forbius: Research Funding; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.