Robyn M. Scherber, MD, MPH
Researchers are exploring combination approaches with ruxolitinib (Jakafi) in myelofibrosis as a potential strategy for reinvigorating the drug’s effect in patients who progress, relapse, or become intolerant on single-agent treatment with the JAK inhibitor.
Resistance to ruxolitinib is particularly challenging, as the agents is the only FDA-approved agent for the treatment of patients with myelofibrosis, Robyn M. Scherber, MD, MPH, in a presentation at the 2018 SOHO Annual Meeting. The NCCN guidelines recommend the JAK inhibitor for patients with myelofibrosis who have low-risk symptomatic disease, as well as those who have intermediate- and high-risk disease.
“Since ruxolitinib has been approved 8 years ago, patients with myelofibrosis appear to be living longer,” said Scherber. “However, this advancement is attenuated by the lack of new therapies [that] have undergone FDA approval, despite the robust ongoing research into investigational agents in myelofibrosis.”
Discontinuation of ruxolitinib treatment is most often attributed to loss of response. Additional factors include cytopenia, infections, or disease progression.
“Much heterogeneity exists in both the definition of ruxolitinib failure, as well as in the spectrum in which ruxolitinib failure can manifest,” explained Scherber. “One simple definition is to define this as when individuals stop ruxolitinib treatment, a scenario that does occur at a frequency of approximately 50% by 3 years.”
Mays Cancer Center of UT Health San Antonio and MD Anderson Cancer Center, where Scherber is a physician and researcher, defines ruxolitinib failure as either loss of symptom or spleen response, the need for persistent red blood cell transfusions, the need to adjust ruxolitinib to subtherapeutic dosing due to thrombocytopenia, anemia, or bleeding, or disease progression.
“An important distinction embedded within ruxolitinib failure is broad range of presentations and definitions that are applicable to this setting,” noted Scherber. “A key difference should specifically be made between ruxolitinib refractory/resistant patients and ruxolitinib progressed/relapsed patients.”
Scherber explained how defining these subsets of patients is critical when determining the next step for a patient. Refractory/resistant patients may still derive benefit from continuing single-agent ruxolitinib; however, continuing ruxolitinib monotherapy is often not effective in relapsed patients or those who have progressive disease. Patients who are intolerant to ruxolitinib are included in the relapsed/progressive group.
Combining ruxolitinib and hypomethylating agents has shown promise, said Scherber, and the JAK inhibitor plus azacitidine has demonstrated response rates ≥72%.1
Panobinostat has been considered for use in this population, as well as lenalidomide (Revlimid), which has shown an approximately 20% response rate, with some response in the spleen.2
“There are a lot of different pathways, such as targeting epigenetics, targeting the fibrosis pathways, SMAC inhibition, or CDK4/6 inhibition,” said Scherber. “More than ever, we have kind of a breadth of targeted therapies either in combination with ruxolitinib or alone.”
Scherber noted that if agents are being combined with ruxolitinib, physicians need to be sure that there are not overlapping side effects, such as thrombocytopenia.
Emerging agents being explored in myelofibrosis include fedratinib, which is under a renewed investigation following a previous clinical hold by the FDA in 2013 regarding concerns for thiamine-related Wernicke’s encephalopathy.
Scherber noted that the JAK2/FLT3 inhibitor pacritinib is currently under review to determine an optimal dose for patients with myelofibrosis. In January 2017, the FDA lifted its clinical hold on trials exploring pacritinib, which was put in place in February 2016 based on findings from the PERSIST-1 and 2 trials.
The developer of the pacritinib, CTI BioPharma, provided the FDA with final clinical study reports from PERSIST-1 and 2 to get the hold lifted, and then initiated the new PAC203 trial (NCT03165734). This study is evaluating the safety and efficacy of pacritinib in patients with primary myelofibrosis who previously received ruxolitinib.
Researchers are also examining immunotherapy is being investigated in myelofibrosis. Nivolumab (Opdivo) is being evaluated in patients with primary and secondary myelofibrosis, while pembrolizumab (Keytruda) is being looked at in chronic, accelerated, and blast-phase myelofibrosis.
In her concluding remarks, Scherber stressed that, when treating a patient with myelofibrosis who is becoming refractory or resistant to ruxolitinib, it is important to first maximize the JAK inhibitor. Additionally, she emphasized that it is important to monitor symptoms and keep an eye on the patient’s quality of life.
- Masarova L, Cortes J, Pemmaraju N, Daver N. Phase 2 study of ruxolitinib in combination with 5-azacitidine in patients with myelofibrosis. J Clin Oncol. 2017;35(15):7063.
- Mesa RA, Yao X, Cripe LC, et al. Lenalidomide and prednisone for myelofibrosis: Easten Cooperative Oncology Group (ECOG) phase 2 trial E4903. Blood. 2010;116(22):4436-4438.