PV Treatment Landscape Balancing Effective Regimens With QOL Challenges

Jeanne M. Palmer, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Jeanne M. Palmer, MD

While there is not a large number of treatments for patients with polycythemia vera (PV), there are currently regimens in the first- and second-line setting that work well for this population, says Jeanne M. Palmer, MD.

For example, long-term follow-up data from the phase III RESPONSE study showed that patients who responded to the JAK2 inhibitor ruxolitinib (Jakafi) as a second-line treatment maintained those responses for up to 4 years. At 208 weeks, 41 patients (37%) originally on the ruxolitinib arm remained on treatment compared with no patients on the control arm. Additionally, 70% of patients who had clinicohematologic (CLHM) response maintained that status. There were no new safety signals compared with the previous follow-up at 80 weeks.

OncLive^®: Please provide an overview of your presentation on PV.

What are some of the biggest challenges in diagnosing patients with PV?

What are we looking for when a patient presents with PV-like symptoms?

Are there any other types of molecular abnormalities other than JAK2 that we are in the process of identifying?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Multiple Myeloma, Palmer, an oncologist in the Bone Marrow Transplant Program at Mayo Clinic, discussed the current treatment landscape for patients with PV and highlighted the impact that ruxolitinib has had on the second-line treatment setting.Palmer: I reviewed the treatment for PV and discussed the diagnosis, different prognostic features, as well as the goals of care and treatment. I covered first-line treatment, which includes either phlebotomy, hydroxyurea, or interferon. The second-line therapy is usually ruxolitinib.One of the biggest challenges is since the hemoglobin parameters have been lowered, many patients who have met the hemoglobin criteria do not have the JAK2 mutation and the bone marrow biopsy is nonspecific. That is a challenging factor. If they have a JAK2 mutation and a high hemoglobin, then it is a “slam dunk.” However, if they do not and they have the erythrocytosis, it raises the question of whether there is another diagnosis that we are missing. It is possible they could have JAK2-negative PV.We are primarily looking for elevated hemoglobin. You want to see it in the absence of having another reason for it, such as chronic hypoxia, chronic lung disease, or testosterone use. We also look to see if the patient is JAK2 positive. We mostly look for JAK2 mutations. It is either JAK2 or JAK exon 12; there are also some other mutations that can occur in the JAK protein. In other myeloproliferative diseases, we look for calreticulin mutations and MPL mutations, but those are not often seen in PV.

Can you discuss ruxolitinib and how that agent has had an impact on the treatment landscape?

Finally, we can gather mutation information with next-generation sequencing, which is a way to do a broad overview of mutations that can occur with any myeloid malignancy. The panels run anywhere from a 29-gene panel to a 100-gene panel. There are a few that have been found to potentially carry prognostic value in PV. Many patients with PV are extremely symptomatic, but the symptom control is good with ruxolitinib. That is a good treatment and the best option when you can use it.

Also, if you look at the other therapies, phlebotomy and hydroxyurea have their drawbacks. With hydroxyurea, there are many concerns in the myeloproliferative neoplasm community about its risk for leukemia—even though that has never been validated.

What is the typical amount of time that a patient can undergo phlebotomy before they relapse?

Finally, pegylated interferon is another excellent choice to treat patients, but it is not well tolerated. Hopefully that will be changing with some of the newer formulations of pegylated interferon; currently it is very difficult to tolerate. It is nice to have ruxolitinib as a potential therapeutic option. None of these treatments fix this disease. All of them are primarily designed to reduce the hemoglobin. If you maintain it at a low enough level then you reduce the risk of cardiovascular events, but we also know that by controlling the hemoglobin adequately we can also control the symptom profile very well.

What ongoing clinical trial are you excited about?

A patient can receive phlebotomy for 30 years or however long it takes. However, the patient does have to tolerate iron deficiency, which can be problematic. Some patients who are iron deficient do not feel well; however, once someone becomes iron deficient, their symptoms are well controlled. However, getting them to that point is a challenge.There is a clinical trial investigating TGR-1202, which is a PI3K inhibitor. That trial is for patients whose disease is not controlled with ruxolitinib alone so it uses ruxolitinib plus TGR-1202 for control of their PV. That is going to be a unique case where you cannot control the PV well with just ruxolitinib, but it does provide a potential therapeutic option.

Are researchers looking at pacritinib in PV?

What are the biggest unanswered questions for patients with PV that you would like to tackle in the next couple of years?

Unfortunately, there is not a huge number of therapeutic options for PV but, that is largely related to the fact that the ones we have are quite effective. That is primarily in myelofibrosis right now. Pacritinib could have potential for patients with PV as it is a JAK inhibitor, which works well in this setting. Although, right now, both pacritinib and fedratinib are in such precarious positions with trying to get FDA approval, that they are going to wait for that before they pursue it for patients with PV. I am interested in how to treat patients who do not have a JAK2 mutation and have erythrocytosis. Currently, there is not a good answer for that. These patients have a very substantial symptom burden that is often not addressed, even if the patient has a JAK2 mutation. It is hard to say whether this is something that the PV does to the brain or if this is something that is a cytokine dysregulation feature, which you would expect to be controlled with ruxolitinib.

Addressing the needs of those patients is very important because their quality of life suffers from having that disease. Patients experience severe fatigue and chronic pain. There is also anxiety and distress associated with this disease.

Kiladjian JJ, Verstovsek S, Griesshammer M, et al. Results from the 208-week (4-year) follow-up of RESPONSE trial, a phase 3 study comparing ruxolitinib (rux) with best available therapy (BAT) for the treatment of polycythemia vera (PV). In: Proceedings from the 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, Georgia. Abstract 322.