Myelofibrosis is a rare and serious blood cancer that originates in the bone marrow, the tissue responsible for producing blood cells. This chronic condition leads to the formation of scar tissue, disrupting the normal production of healthy blood cells. As a result, patients often experience a range of debilitating symptoms and complications.
Understanding Myelofibrosis
Myelofibrosis is classified as a myeloproliferative neoplasm, a blood cancer characterized by the overproduction of abnormal blood cells. The bone marrow’s scarring hinders its ability to create new blood cells, leading to issues like anemia (low red blood cells), thrombocytopenia (low platelets), or leukopenia (low white blood cells). To compensate, other organs like the spleen and liver may attempt to produce blood cells, often becoming enlarged.
The disease manifests through various symptoms, including severe fatigue due to anemia, an enlarged spleen causing discomfort or pain in the upper left abdomen, and bone pain. Other common symptoms include night sweats, fever, weight loss, and easy bruising or bleeding due to low platelet counts. Myelofibrosis often involves dysregulation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, a signaling route for cell growth and blood cell production. This pathway’s overactivity contributes to uncontrolled cell proliferation and inflammation.
Pacritinib: A Targeted Treatment
Pacritinib is an oral kinase inhibitor. It works by targeting several key enzymes involved in the disease’s progression, primarily Janus kinase 2 (JAK2) and interleukin-1 receptor-associated kinase 1 (IRAK1). The drug also shows inhibitory activity against Fms-like tyrosine kinase 3 (FLT3). By inhibiting JAK2, pacritinib helps normalize the overactive JAK-STAT pathway, reducing uncontrolled production of abnormal blood cells and the associated inflammatory response.
Its unique mechanism of action, including IRAK1 inhibition, distinguishes pacritinib from other treatments. IRAK1 plays a role in inflammatory signaling, and its inhibition helps reduce chronic inflammation in myelofibrosis. Pacritinib is effective in patients with very low platelet counts, a challenging aspect of myelofibrosis where other JAK inhibitors might require dose adjustments or be unsuitable due to potential myelosuppression. The U.S. Food and Drug Administration (FDA) granted accelerated approval to pacritinib for adults with intermediate or high-risk primary or secondary myelofibrosis who have severe thrombocytopenia, defined as platelet counts less than 50 × 10⁹/L.
Clinical Experience with Pacritinib
The accelerated FDA approval was largely supported by findings from the PERSIST-2 trial. In this study, pacritinib showed a significant reduction in spleen volume. Specifically, 29% of patients with platelet counts below 50,000/µL treated with pacritinib experienced a spleen volume reduction of at least 35%, compared to 3% in the best available therapy group.
Beyond spleen reduction, pacritinib also led to improvements in myelofibrosis-related symptoms such as fatigue, night sweats, and bone pain. In the PERSIST-2 trial, 25% of patients treated with pacritinib achieved a 50% or more reduction in total symptom score by week 24, compared to 14% in the best available therapy group.
The safety profile of pacritinib indicates that common side effects are generally manageable. These include gastrointestinal disturbances like diarrhea and nausea, as well as anemia and thrombocytopenia. Bleeding events, including hemorrhage, have also been observed. While these side effects can occur, they are typically mild to moderate and can often be managed with supportive care.