Srdan Verstovsek, MD, PhD, discusses the second-line use of ruxolitinib in patients with in PV and additional benefits with the agent as more data become available.
Srdan Verstovsek, MD, PhD
Since the FDA approval of ruxolitinib (Jakafi), new data continue to provide additional evidence to support the benefits and durability of the JAK1/2 inhibitor for patients with polycythemia vera (PV).
Ruxolitinib was approved in 2014 as a second-line option for patients who are resistant or intolerant to hydroxyurea, based on findings from the phase III RESPONSE trial.
Findings from that trial showed that 60% of patients treated with ruxolitinib achieved hematocrit control without phlebotomy, compared with 20% of patients who received best available therapy. The primary endpoint of the trial looked specifically at patients who achieved hematocrit control without phlebotomy from week 8 to 32 and experienced greater than a 35% reduction in spleen volume by week 32. Overall, 21% of patients in the ruxolitinib arm met this criteria compared with 1% for best available therapy.
According to Srdan Verstovsek, MD, PhD, investigators have since realized that while nearly 80% of patients were considered non-responders by the study restraints, many still had clinical benefit with ruxolitinib.
During a presentation at the36thAnnualCFS, Srdan Verstovsek, MD, PhD, highlighted some of the additional quality of life benefits with the agent.
“One emphasis of the talk was not only to emphasize the utility of the drug in the second-line setting, which should be very well known by now, but to say that the benefit of the drug is much greater than what the clinical study suggests,” Verstovsek said.
In an interview withTargeted Oncology, Verstovsek, director of the Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms at The University of Texas MD Anderson Cancer Center, discussed the second-line use of ruxolitinib in patients with in PV.
TARGETED ONCOLOGY:What are the key points to understand about ruxolitinib in patients with PV?
Verstovsek: PV is 1 of the MPNs of the bone marrow. That is the chronic condition where cells grow without control and in PV, the main problem is control of the red blood cells. In many patients, the white cell platelets and spleen, as well as symptoms, are affected as well. The standard practice is to treat people who are at high risk of thrombosis with hydroxyurea. That’s a chemotherapy that they give very mild, but it doesn’t work with everybody. About 20% of the patients have intolerance or resistance to it that develops over time, then you need something else. Recently, relatively speaking, a new medication called ruxolitinib was approved for these patients in the second-line setting after hydroxyurea therapy. Ruxolitinib is a JAK1/2 inhibitor. It inhibits the JAK pathway which is an underlying biological problem in PV and other MPNs that make cells grow.
The activity of ruxolitinib in the second-line setting has been very well regarded in clinical studies, where it controlscompared to standard therapy in these randomized studies—the red blood cells and white cell platelets, decreases the spleen, and improves the overall quality of life. There were 2 studies actually. One in patients that had a big spleen and another in patients that did not have a big spleen. The presence or absence of the spleen as a decision maker for utility of ruxolitinib in the second-line setting did not matter. [Ruxolitinib] is very effective in controlling blood cell count and symptoms in the majority of patients.
What we realized since then was that the study’s definition of response was very vigorous and while many more patients, by the study design, were non-responders, they actually had clinical benefit. We use this term, clinical benefit, to say that there is significant improvement in the blood cell count and a decrease in phlebotomy, which is a bloodletting that you do in addition to pills. There is improvement in the quality of life, despite these people being labeled as non-responders. One emphasis of the talk was not only to emphasize the utility of the drug in the second-line setting, which should be very well known by now, but to say that the benefit of the drug is much greater than what the clinical study suggests.
We also show the data that improves the iron levels. Iron levels, the hallmark of PV, are very low because iron is basically food for red blood cells, so everybody is iron deficient and may have some symptoms. On ruxolitinib, it appears that everyone is improving and normalizing iron levels without even being given iron to the patients. We don’t know how that is possible, but it happens.
We also now have long-term evidence that the drug works [for a] very long time. After 40 years of follow-up, 3-quarters of patients who were responders are still responding. The ability of the benefit is much longer than in myelofibrosis (MF). In MF, this is usually about 3 years. That was the first indication, and it appears to be much, much longer. We also show that the thrombotic eventsthis is the ultimate goal of the therapy, to decrease the blood cell count and decrease the thrombotic events—seen in the safety analysis appear to be much, much lower than in the control arm. Some new data that has not been published yet but presented at different meetings over the last year show that when you compare these findings from the clinical study to historical matched patients on different registries, there actually is significant decrease in thrombosis and possibly, also an effect on overall survival in the second-line setting.
For the second-line setting in PV, these people do usually have a shorter survival than otherwise normal PV patients. They have more aggressive disease and need a second-line, so there are benefits beyond just control of the red blood cells: control of the white blood cells, the spleen, and symptoms, iron improves, thrombotic events appear to be decreasing as expected, and perhaps some effect on the overall survival. This is all ongoing and I will present where we are going and what’s happening now.
TARGETED ONCOLOGY:What are the unanswered questions that remain?
Verstovsek: One of the unanswered questions is the safety of ruxolitinib in PV. In MF, the average duration of exposure is about 3 years in clinical studies, perhaps even in practice not that much. We identify some events that are of concern, and that is some immunosuppression. People are at a high risk of having opportunistic infections, viral infections in particular, so it is very well known that in 5% to 6% of the patients have hepatic infections. Other opportunistic infections include fungal infections and are more sporadic that don’t come even in the percentages, but everybody needs to know about it.
The last part is the non-melanoma skin cancer issue. Now, ruxolitinib is approved for the second-line setting after hydroxyurea. Hydroxyurea is very well known to increase risk of squamous cell carcinoma. That’s a skin cancer that can be aggressive, and the patients who have a history of squamous cell carcinoma on hydroxyurea or cancerous lesions on the skin are switched over to ruxolitinib, where that side effect of skin cancer can actually be visible in higher degree on ruxolitinib. Non-melanoma skin cancers, in patients with a history of it, when they are on ruxolitinib, need to be taken seriously, and these people need to have a skin exam by their dermatologist.