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Treatment in Intermediate-High Risk Myelofibrosis Patients

Simoneaux, Richard

doi: 10.1097/01.COT.0000533685.09745.06
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Myelofibrosis is an often-debilitating myeloproliferative disorder that is characterized by symptoms such as enlarged spleen and thrombocytopenia. This presence of thrombocytopenia often serves as an impediment for the use of the dual Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib. To evaluate the efficacy and safety of the JAK2 inhibitor pacritinib against the best available therapy (BAT) for myelofibrosis, the phase III PERSIST-2 clinical trial was undertaken.

This clinical trial was administered by an international team of clinicians, including Aaron T. Gerds, MD, MS, Assistant Professor of Medicine in the Hematology and Medical Oncology Department at the Cleveland Clinic Taussig Cancer Institute. Recently, a report of study results from this panel was published (JAMA Oncol 2018; doi:10.1001/jamaoncol.2017.5818).

Regarding the trial results, Gerds noted, “Study truncation due to the FDA-imposed clinical hold compromised the ability to evaluate the effect of treatment on week 24 endpoints; however, despite these limitations, 200 mg pacritinib BID was more effective than BAT with a benefit-risk profile that compared favorably with 400 mg pacritinib QD and BAT.”


Myelofibrosis is classified as a myeloproliferative neoplasm in which an abnormal clone of hematopoietic stem cells undergoes proliferation in bone marrow and at other locations, resulting in fibrosis. In advanced disease states, the replacement of marrow with scar tissue often necessitates the transfusion of platelets and/or red blood cells, and median survival for patients with this disease is approximately 6 years.

Biochemically, this disease is characterized by dysregulation of Janus kinase signaling, often arising from mutation of JAK2. In November 2011, the FDA approved the use of the JAK1/2 inhibitor ruxolitinib for treating intermediate- or high-risk myelofibrosis patients with baseline platelet counts greater than 50 x 109/L. Despite the advancement that was noted with this drug, there were still patients for whom this therapy did not provide relief, including those with either baseline or treatment-emergent thrombocytopenia or those who relapsed after or had disease refractory to ruxolitinib.

Pacritinib is a macrocyclic compound that primarily inhibits JAK2 and Fms-like tyrosine kinase 3 (FLT3). Notably, this compound showed good activity against the wild-type and V617F mutant of JAK2, with IC50 values of 23 nM and 19 nM, respectively, while showing less affinity for the JAK1 (IC50=1280 nM) and JAK3 (IC50=520 nM) isoforms (J Med Chem 2011;54(13):4638-4658).

The phase III PERSIST-1 clinical trial evaluated the use of once daily pacritinib against BAT, excluding ruxolitinib. “In that study, once daily pacritinib demonstrated both significant and durable SVR and symptom control, irrespective of baseline platelet count,” Gerds noted.

In February 2016, the FDA implemented a full clinical hold on studies for pacritinib. In taking this action, they cited the deaths of patients in the PERSIST-2 trial from cardiac arrest, cardiac failure, and intracranial hemorrhage. “In January 2017, this clinical was hold was lifted,” as Gerd explained, “after a review of mature PERSIST-1 data and complete PERSIST-2 data, as well as submission of a study protocol comparing three doses of pacritinib.”


Myelofibrosis patients were eligible to participate in this study if they exhibited the following:

  • high-risk, intermediate-2, or intermediate-1 stage disease using the Dynamic International Prognostic Scoring System;
  • palpable splenomegaly of 5 cm or greater below the left costal margin;
  • a platelet count of 100 x 109/L or less;
  • absolute neutrophil count of more than 0.5 x 109/L;
  • peripheral blood blast count lower than 10 percent;
  • Total Symptom Score (TSS) of 13 or higher on the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS 2.0);
  • ECOG performance status of 3 or less (this scale ranges from 0 (no symptoms) to 5 (dead));
  • adequate renal and hepatic functioning; and
  • a life expectancy of 6 months or greater.

Prior treatment with one or two other JAK inhibitors was permitted.

Patients were excluded from study participation if they displayed any of the following:

  • active bleeding requiring hospitalization;
  • recent history of myocardial infarction;
  • symptomatic congestive heart failure;
  • severe/unstable angina;
  • ongoing grade 3 or greater dysrhythmias; and/or prolonged QTc.

Central randomization of patients to 400 mg pacritinib QD, 200 mg pacritinib BID, or BAT in roughly a 1:1:1 ratio was accomplished via voice response system or interactive web. In this study, the BAT included any physician-specified treatments for addressing myelofibrosis, its symptoms, or simply watch-and-wait. Stratification was done by geographic region, risk category, and rebound platelet count (defined as the platelet count recovery between informed consent and randomization, indicating likelihood of drug-induced thrombocytopenia rather than myelofibrosis-associated thrombocytopenia).

Patients in all study arms were treated until progressive disease (PD), unacceptable toxic effects, or no treatment-derived benefit was noted. Participants randomized to BAT could cross over to pacritinib therapy for progression of splenomegaly or after 24 weeks of treatment with or without PD.

Regarding the endpoints for this study, Gerds noted, “The primary objective of this study was to compare the efficacy of the pooled pacritinib arms with BAT; efficacy co-primary endpoints were the proportions of patients achieving 35 percent or more spleen volume reduction (SVR), as determined by CT/MRI, and 50 percent or more reduction in TSS (MPN-SAFTSS 2.0) from baseline to week 24.

“One secondary objective was to separately compare efficacy of once daily or twice daily pacritinib versus BAT, while other exploratory endpoints included overall survival, changes in hematologic parameters, and additional patient-reported outcomes,” he added.

The safety and tolerability data were acquired over the interim from the time of informed consent through last day of study participation. Pharmacokinetic data for pacritinib were utilized to assess safety and efficacy as measured by exposure and exposure-response relationships.

Spleen volume was centrally assessed in a blinded fashion using CT/MRI by an independent radiology facility every 12 weeks, starting at baseline and continuing through 48 weeks until PD or treatment withdrawal.

Study Results

Between July 2014 and February 2016, 431 myelofibrosis patients were assessed for inclusion in this study, and of these, 311 were randomized to 400 mg pacritinib QD (n=104), 200 mg pacritinib BID (n=107), or BAT (n=100).

The most commonly employed active single agent therapeutics in the BAT arm were ruxolitinib (n=44), hydroxyurea (n=19), and prednisone and/or prednisolone (n=13). For 19 patients in this study arm, only watchful waiting was utilized as the BAT.

Three randomized participants withdrew prior to receiving their investigational medications, thus they were excluded from the safety data. The intent-to-treat efficacy population consisted of 75, 74, and 72 participants randomized to 400 mg pacritinib QD, 200 mg pacritinib BID, and BAT, respectively. Patient baseline demographics and disease characteristics were considered to be balanced across all study arms.

“Of the patients who had discontinued therapy, 62 of 104 patients treated with 400 mg pacritinib QD, 75 of 106 patients treated with 200 mg pacritinib BID, and 27 of 98 patients treated with BAT were discontinued due to institution of the clinical hold,” Gerds noted.

“The majority of discontinuations for the BAT participants were the result of patient crossover to pacritinib; 50 of 98 patients treated with BAT crossed over primarily (n=43) at or after week 24, and of these patients, 39 were treated with pacritinib until the clinical hold.”

Before implementation of the clinical hold, discontinuations resulting from treatment-related adverse events were highest in the 400 mg pacritinib QD arm (15 patients) followed by the 200 mg pacritinib BID and BAT arms (10 and four patients, respectively). However, discontinuations due to PD were most prevalent in the BAT arm relative to the 400 mg pacritinib QD and 200 mg pacritinib BID arms (five and seven patients, respectively).

Dose interruptions due to adverse events were highest in the 400 mg pacritinib QD arm (39 patients), followed by the 200 mg pacritinib BID (29 patients) and BAT arms (10 patients). Dose reductions due to adverse events followed this trend as well, with the highest number of these events occurring in the 400 mg pacritinib QD arm (21 patients) followed by the 200 mg pacritinib BID (13 patients) and BAT arms (seven patients).

When discussing the SVR efficacy results for this study, Gerds stated, “At week 24, 16 patients in the 200 mg pacritinib BID arm and 11 in the 400 mg pacritinib QD arm had achieved SVR of 35 percent or more; however, only two patients in the BAT arm achieved a similar result. It is of interest to note that only one of 32 BAT patients who received ruxolitinib achieved SVR of 35 percent or more.”


“Myelofibrosis is a chronic progressive hematological malignancy with no proven therapeutic options for patients with thrombocytopenia, which increases in prevalence and severity with disease progression. Patients who are ineligible for or fail ruxolitinib therapy lack therapeutic options and have extremely poor prognoses,” Gerds explained.

Assessing the efficacy data, he observed, “In the primary analysis of the PERSIST-2 study at week 24, the combined pacritinib arms showed significantly more efficacy than BAT, as measured by SVR and trended toward improved TSS reduction in patients with myelofibrosis and thrombocytopenia. The benefit obtained for pacritinib, in terms of SVR and TSS reduction, was in patients with baseline platelet counts of less than 50 × 109/L and those with prior ruxolitinib treatment (more than 40% of patients). The 200 mg pacritinib BID arm met both co-primary SVR and TSS reduction endpoints,” further adding, “the pharmacokinetic profile of 200 mg pacritinib BID also supports the use of this dose schedule.

“Pacritinib was well-tolerated, with the gastrointestinal toxicities being generally low-grade and less frequent with twice daily dosing, rarely leading to treatment discontinuation,” he stated. “There was a potential increased risk of grade 3 or 4 bleeding noted with the 200 mg pacritinib BID arm; however, this appeared to be independent of platelet count. Additionally, the rate of grade 3 or 4 cardiac events was lowest and there were no cardiac failures or deaths due to cardiac events that occurred in the 200 mg pacritinib BID participants.”

When asked to comment on the overall results from the study, Gerds replied, “Without a doubt, study truncation, due to the clinical hold, clearly compromised not only the ability to evaluate the effect of treatment on week 24 co-primary endpoints by reducing the effective sample size, but also the time-to-event endpoints, including OS, by reducing follow-up time for assessment that would enable analyses that follow the intention-to-treat principle.” Patient crossover further confounded time-to-event analyses. Truncation of the study also limited the follow-up of patients for additional safety data.

“Despite all these limitations, 200 mg pacritinib BID was more effective than BAT with a benefit-risk profile that compared favorably to both 400 mg pacritinib QD and BAT,” Gerds concluded.

Richard Simoneaux is a contributing writer.

Wolters Kluwer Health, Inc. All rights reserved.
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