Patients who develop post–essential thrombocythemia myelofibrosis or post–polycythemia vera myelofibrosis, which are associated with significant symptom burden and bone marrow failure, have limited therapies available for effective treatment.
Ruben A. Mesa, MD
Patients who develop post–essential thrombocythemia myelofibrosis (PET-MF) or post–polycythemia vera myelofibrosis (PPV-MF), which are associated with significant symptom burden and bone marrow failure, have limited therapies available for effective treatment. Unlike primary myelofibrosis, the biology of these 2 presents a challenge for investigators at the time of diagnosis and initiation of treatment.1 However, progress in prognostic scoring systems and a deeper understanding of associated cytogenetics of the disease have led investigators to develop novel agents for the treatment of patients with PET-MF and PPV-MF.1
The JAK2/IRAK1 inhibitor pacritinib (Vonjo) was granted accelerated approval by the FDA for the treatment of adult patients with intermediate or high-risk primary or secondary PET-MF or PPV-MF and with a platelet count below 50 × 109/L. The approval was based on findings from PERSIST-2 (NCT02055781), a phase 3 trial in which the primary end points were a reduction in spleen volume of at least 35% and a total symptom score (TSS) reduction of at least 50% at 24 weeks.
The approval marks the first treatment specifically for patients with cytopenic myelofibrosis, according to Ruben A. Mesa, MD, director of the Mays Cancer Center at The University of Texas Health San Antonio MD Anderson Cancer Center.
“[Pacritinib] is an important additional JAK2 inhibitor with a unique lane for patients with marked thrombocytopenia or even the broader cytopenic myelofibrosis,” Mesa said in an interview with OncologyLive®. “[This] is a disease where multiple therapies are needed.”
In PERSIST-2, patients with PET-MF and PPV-MF with enlarged spleens and platelet counts of 100 × 109/L or less were randomly assigned to received 200-mg pacritinib at a twice-daily dose (n = 107), 400-mg once-daily dose (n = 104), or best available therapy (BAT; n = 100), which included agents such as ruxolitinib (Jakafi), watch-and-wait approaches, or symptom-directed treatment.2 The recommended dosage of pacritinib is 200 mg orally twice daily.2 During the course of the trial, the toxicity profile of the 400-mg dose was deemed unsafe.
Investigators evaluated efficacy among those participants with platelet count of less than 50 × 109/L. Of those who received pacritinib at the 200-mg twice-daily dose (n = 31), 29.0% (95% CI, 14.2%-48.0%) experienced a reduction in spleen volume of at least 35% vs 3.1% (95% CI, 0.1%-16.2%) of those who received BAT (n = 32).2
Additionally, 26% of patients who received the twice-daily dose experienced a reduction in TSS of at least 50% using the Modified Myelofibrosis Symptom Assessment Form compared with 9% of those who received BAT.2
“Pacritinib is somewhat distinct in that it is able to improve splenomegaly, a very important area of burden in myelofibrosis that has not been able to be safely used in patients with severe thrombocytopenia or a platelet count of [below 50 × 109/L with other agents],” Mesa said. “And, [pacritinib] can be given at full dose.”
Pacritinib had a predictable and manageable safety profile. In an analysis of the safety population, the most common all-grade adverse effects (AEs) among those who received pacritinib twice daily (n = 106) were diarrhea (48%), thrombocytopenia (34%), nausea (32%), anemia (24%), and peripheral edema (20%). For the 98 patients in the safety population who received BAT, the most common all-grade AEs were thrombocytopenia (23%), diarrhea (15%), nausea (15%), and peripheral edema (15%).2
Ruxolitinib and fedratinib (Inrebic), both included as BAT options, have been used off label for patients with myelofibrosis whose platelet counts are below 50 × 109/L, but they are typically given at a significantly reduced dose.
“[Ruxolitinib and fedratinib] can improve splenomegaly but have the [adverse] effect of potentially causing anemia; thrombocytopenia is the dose-limiting toxicity,” Mesa said. Pacritinib can be given at full dose for this patient population, Mesa explained.
Treatment with pacritinib also favorably affected transfusion burden among these patients. Specifically, among patients who were not transfusion independent at baseline, treatment with pacritinib reduced red blood cell (RBC) transfusion burden at week 24 on study.3 Eight of 36 patients who received the twice-daily dose and were not transfusion independent vs 3 of 35 patients who received BAT experienced a reduction in burden.
Further, at week 24, among 44 patients who had hemoglobin (Hb) at least 10 g/dL at baseline who received pacritinib, 25% had an Hb increase of at least 2 g/dL or RBC transfusion independence for at least 8 weeks. Among the 41 patients who received BAT, only 12% achieved a clinical benefit.
Although these data were not included in the approval, Mesa noted that it marks an important clinical factor for this treatment. “There has been, for some patients, improvement in anemia or even turning patients from transfusion dependent to transfusion independent,” Mesa said.
The approval of pacritinib for patients with PET-MF or PPV-MF is not tied to a specific line of therapy. “In particular, [for] patients with a platelet count [below 50 × 109/L],” Mesa said, “it will be the most unique for any amount of thrombocytopenia under [below 100 × 109/L]. There clearly is activity in the PERSIST-1 study [NCT01773187] where it was not limited only to patients with thrombocytopenia; it is active for patients [who] have a normal platelet count. In those settings, it will be more in the second-line setting or potentially in combinations.”
Considering the significance of JAK inhibitors in myelofibrosis, breakthroughs will be needed in terms of monitoring. Moreover, when looking at progression-free and overall survival, it is important to further examine how the data correlate with the exact degree of splenomegaly shrinkage or symptom improvement, as well as the overall effect on the biology of the disease. Overall, the realm of correlative studies will be important to further understand the utility of these agents in myelofibrosis, Mesa said.
Future investigative efforts include those monitoring molecular markers, as well as inflammatory markers that may change rapidly, Mesa said. “There is a range of different phenotypes within the disease and many new mechanisms of action are being identified, [such as] IRAK1, as an additional, important new target.” As these breakthroughs continue to reshape the treatment of patients with myelof ibrosis, it will be important to note that if there are multiple therapies, it will be necessary to have more evidence-based ways of sequencing them, Mesa said.