The American Society of Hematology (ASH) held its 64th Annual Meeting in December 2022, during which time a variety of medical stakeholders discussed issues, trends, and research in the hematologic sphere. During the Meeting, Dr. Firas El Chaer, MD presented on data from the dose-escalation portion of a Phase 1/2 study evaluating TP-3654 for myelofibrosis. According to OncLive, TP-3654 showed positive preliminary data on safety and tolerability.
Presentation Data
The presented data focused on eight evaluable patients (nine patients overall) with myelofibrosis who were previously treated or not eligible to use a JAK inhibitor. Over the course of the study, patients received varying TP-3654 doses: 480mg once or twice daily, 360mg twice daily, or 720mg once or twice daily. Trial researchers are still working on identifying the ideal dose for future studies.
Findings from the study, which were published in Blood, include:
- Five patients had withdrawn from the study: one personally, two because their physician had requested it, and two because their disease had progressed. The four remaining patients, as of the data cutoff data, were receiving 720mg once daily, 720mg twice daily, and 480mg twice daily (2).
- TP-3654 helped reduce levels of cytokines (inflammatory molecules) related to myelofibrosis.
- Treatment conferred benefits such as symptom reduction, improved quality of life, and reduced spleen volume.
- While relatively safe and well-tolerated, there were some side effects which occurred. These included insomnia, nausea and vomiting, diarrhea, urinary tract infection, shortness of breath, abdominal distention, muscle spasms, fatigue, anemia, decreased platelet counts, leukocytosis, increased bilirubin levels, and abdominal pain.
In mice models of myelofibrosis, treatment with TP-3654 also lowered fibrosis (scarring) in bone marrow, reduced spleen size, and improved overall survival. Researchers hope it will be similarly beneficial in humans; though this trial suggests it may be useful, more research is ultimately needed.
About TP-3654 for Myelofibrosis
TP-3654 is an oral, investigational PIM-1 kinase inhibitor. The National Cancer Institute explains that:
TP-3654 selectively binds to and prevents the activation of the PIM kinases [which] prevents the activation of PIM-mediated signaling pathways and inhibits proliferation in cells that overexpress PIM. PIMs, constitutively active proto-oncogenic serine/threonine kinases, are upregulated in various types of cancers and play key roles in tumor cell proliferation and survival.
What is Myelofibrosis?
Myelofibrosis is a rare bone marrow disorder and blood cancer characterized by scar tissue (fibrosis) formation in the bone marrow. Around 60-70% of people have JAK2 gene mutations, 20% have CALR mutations, and 10% have MPL mutations. These cause a hematopoietic stem cell to continually make copies of itself, proliferating rapidly and pushing healthy blood cells out of the bone marrow. The additional fibrosis prevents the bone marrow from producing healthy cells. Myelofibrosis is more common in people aged 50 or older. If it occurs in children, it typically occurs before age 3, and affects girls nearly 2x more frequently than boys.
Symptoms related to myelofibrosis can, but do not always, include:
- Anemia (low red blood cell count)
- Thrombocytopenia (low platelet count)
- Night sweats
- Bone and joint pain
- Fever
- Enlarged spleen and/or liver
- Fatigue and general weakness
- Shortness of breath
- Lightheadedness
- Excessive bruising and bleeding
- Extremely pale skin
- Headaches
- Irritability
- Frequent infections
Treatment options for myelofibrosis can include stem cell transplantation, radiation, splenectomy, chemotherapy, ruxolitinib, gene therapy, and various therapies to combat anemia.
