Abdulraheem Yacoub, MD, an associate professor of medicine at the University of Kansas Medical Center, discusses next steps with the combination of parsaclisib and ruxolitinib (Jakafi) in myelofibrosis.

During week 1 of the 2021 AACR Annual Meeting, findings from a phase 2 trial (NCT02718300) were presented as a virtual poster. At 24 weeks, the all-daily regimen of the PI3Kδ inhibitor parsaclisib plus the JAK inhibitor ruxolitinib led to a median percentage change of –25.4% in spleen volume from baseline. The median percentage change in the Myelofibrosis Symptom Assessment Form-Total Symptom Score was –39.6% at 12 weeks.

As such, two international, phase 3 studies are open to further evaluate parsaclisib in combination with ruxolitinib, says Yacoub. The LIMBER-313 trial (NCT04551066) is randomizing patients with previously untreated myelofibrosis to the combination regimen vs ruxolitinib plus placebo, Yacoub says. The goal of the study is to determine whether the up-front use of the combination provides additional benefit to patients vs the standard of care, Yacoub says. 

The LIMBER-304 trial (NCT04551053) is evaluating parsaclisib plus ruxolitinib vs ruxolitinib plus placebo in patients who achieved a suboptimal response with a stable dose of ruxolitinib, Yacoub concludes.

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Abdulraheem Yacoub, MD, discusses next steps with the combination of parsaclisib and ruxolitinib in myelofibrosis.  



Dr. Yacoub on Next Steps With Parsaclisib Plus Ruxolitinib in Myelofibrosis 

Abdulraheem Yacoub, MD, an associate professor of medicine at the University of Kansas Medical Center, discusses efficacy and safety results with parsaclisib in myelofibrosis.

During the 2021 AACR Annual Meeting, findings from a phase 2 study (NCT02718300) demonstrated an improvement in spleen volume reduction (SVR) and symptom burden with the combination of ruxolitinib (Jakafi) and the PI3K inhibitor parsaclisib in patients with myelofibrosis who have previously experienced a suboptimal response to a standard dose of single-agent ruxolitinib.

The combination resulted in rapid and durable improvements in quality of life for patients, says Yacoub. Moreover, patients who received continuous daily dosing with parsaclisib had higher SVR compared with patients who switched from daily to weekly dosing with the agent, Yacoub says. Patients on the daily dosing regimen had continued SVR reduction at 24 weeks, Yacoub adds.

Regarding safety, the combination of ruxolitinib and parsaclisib elicited minimal non-hematologic adverse effects (AE) and no significant decrement in hemoglobin levels, Yacoub says. Thrombocytopenia was the most commonly observed dose-limiting AE, but cases of thrombocytopenia were reversible, concludes Yacoub.

Abdulraheem Yacoub, MD, discusses efficacy and safety results with parsaclisib in myelofibrosis.  



Dr. Yacoub on Efficacy and Safety Results With Parsaclisib in Myelofibrosis 

Abdulraheem Yacoub, MD, an associate professor of medicine at the University of Kansas Medical Center, discusses the rationale behind examining parsaclisib following suboptimal response to ruxolitinib (Jakafi) in patients with myelofibrosis.

Ruxolitinib is an agent that has demonstrated notable activity in patients with myelofibrosis and has existed in the myeloproliferative neoplasm arsenal for several years, according to Yacoub. The agent has demonstrated splenic and clinical responses in this population; however, responses have not proven to be durable and it is rare that the responses are complete, Yacoub explains. The median time to loss of response is approximately 3 years with the agent, Yacoub says.

Some of the partial responses observed in patients who have been treated with ruxolitinib may be due, in part, to the PI3K delta pathway, which allows cancer cells to escape inhibition by JAK2 inhibitors, Yacoub explains. It was hypothesized that the combination of a JAK inhibitor and a PI3K inhibitor would provide a double hit to the pathway, yielding a deeper, more durable response, Yacoub concludes.

Abdulraheem Yacoub, MD, discusses the rationale behind examining parsaclisib following suboptimal response to ruxolitinib in patients with myelofibrosis.

Dr. Yacoub on the Rationale For Parsaclisib After Suboptimal Response to Ruxolitinib in Myelofibrosis

Abdulraheem Yacoub, MD, associate professor of medicine, University of Kansas Medical Center, discusses the potential of pegylated interferon treatment in patients with polycythemia vera (PV).

For patients who failed on hydroxyurea (Hydrea) therapy, ruxolitinib (Jakafi) has shown promise. It is a very convenient oral tyrosine kinase inhibitor that results in rapid response. Yacoub says these responses have been durable. However, ruxolitinib is not disease-modifying in the sense that it prevents disease progression. Interferons are a class of drugs that can produce synthetic hormones to fight the cancer cells and enhance immune response. Researchers have yet to prove that these agents effectively change the natural history of the disease, Yacoub says.

Ongoing clinical trials seem to suggest that interferons are very active, with deep responses and some complete molecular responses. Yacoub adds that the toxicities associated with this class of drugs can be controlled.

Abdulraheem Yacoub, MD, associate professor of medicine, University of Kansas Medical Center, discusses the potential of pegylated interferon treatment in patients with polycythemia vera.

Abdulraheem Yacoub, MD

Articles

Dr. Yacoub on Next Steps With Parsaclisib Plus Ruxolitinib in Myelofibrosis

Dr. Yacoub on Efficacy and Safety Results With Parsaclisib in Myelofibrosis

Dr. Yacoub on the Rationale For Parsaclisib After Suboptimal Response to Ruxolitinib in Myelofibrosis

Dr. Yacoub on Pegylated Interferon Treatment for PV