Ruxolitinib May Prove Beneficial in Combination for Myelofibrosis

Robyn M. Scherber, MD, MPH

Ruxolitinib (Jakafi) is the only FDA-approved agent for the treatment of patients with myelofibrosis (MF), making resistance to this agent a particularly difficult treatment challenge. Combinations with ruxolitinib may reinvigorate the impact of the JAK inhibitor in relapsed, progressive, or intolerant patients, explained Robyn M. Scherber, MD, MPH, in a presentation at the 2018 SOHO Annual Meeting.

MF is regarded to be the most aggressive myeloproliferative neoplasm (MPN), and therapy for patients is currently focused on prognostic risk, managing cytopenias, toxicities, and spleen size. Ruxolitinib is recommended by the NCCN for patients with MF 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 MF 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 MF.”

Though ruxolitinib has been associated with stabilization or reversal of bone marrow fibrosis, a subset of patients with MF do stop responding to the inhibitor. Ruxolitinib treatment discontinuation is most 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.”

Scherber said that at Mays Cancer Center of UT Health San Antonio MD Anderson Cancer Center, where she is a physician and researcher, they define 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.”

Ruxolitinib can be safely continued and may still have benefit in patients with refractory or resistant disease, but in relapsed or progressive patients, single-agent ruxolitinib is often not adequate, Scherber explained. Patients who are intolerant to ruxolitinib are included in the relapsed/progressive group.

There is promise for combination ruxolitinib and hypomethylating agents, suggested Scherber, and the JAK inhibitor plus azacitidine has demonstrated response rates ≥ 72%.¹Pabinostat 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.

Investigational treatment for patients with MF 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.

Pacritinib is currently under review to determine an optimal dose for patients with MF, noted Scherber. 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. CTI BioPharma, the developer of the JAK2/FLT3 inhibitor, 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 MF who previously received ruxolitinib.

Additionally, immunotherapy is being investigated in MF. Nivolumab (Opdivo) is being evaluated in patients with primary and secondary MF, while pembrolizumab (Keytruda) is being looked at in chronic, accelerated, and blast-phase MF.

References:

1. 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.
2. 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.

When treating a patient with MF that is becoming refractory or resistant to ruxolitinib, Scherber said that it is important to first maximize ruxolitinib. Additionally, Scherber emphasized that it is important to monitor symptoms, and keep an eye on the patient’s quality of life.