Expert Discusses the Management of Polycythemia Vera After Hydroxyurea Failure

Abdulraheem Yacoub, MD

Abdulraheem Yacoub, MD

For decades, hydroxyurea (Hydrea) has been used to treat patients with polycythemia vera (PV). While hydroxyurea is highly-effective for the majority of patients, some still do not benefit from this agent.

Patients with PV who fail hydroxyurea make up a small percent of the population, but there are other treatment options available. For example, ruxolitinib (Jakafi) has been shown to be an effective option in a number of randomized phase III clinical trials.

Interferons are another class of drugs that can be used in this patient population. While these treatments can be associated with toxicity, evidence has shown that these drugs are active with some deep responses, according to Abdulraheem Yacoub, MD.

In an interview withTargeted Oncologyduring the2018 Society of Hematologic Oncology Annual Meeting,Yacoub, associate professor of hematology, University of Kansas Medical Center, discussed how to manage patients with PV after failure on hydroxyurea and some of the upcoming treatment options for this patient population on the horizon.

TARGETED ONCOLOGY:You gave a presentation on managing patients with PV after hydroxyurea failure. Can you start by providing a brief overview of your talk?

Yacoub:Hydroxyurea has been our first-line therapy for PV for decades. It’s a very effective therapy when it works. It is still very successful in the majority of patients who receive it, but there is a fraction of the patient population that still does not do well with hydroxyurea. They experience either early or late failure. It’s an unmet need. Those patients have poor outcomes with significant morbidity, but it’s great to live in a world where we can offer them better options.

I discussed some of the approved and upcoming options, [as well as] future research that can help move this forward.

TARGETED ONCOLOGY:What other agents are available for patients with PV?

Yacoub:Of the options that we have already, [there] is ruxolitinib, which is a JAK1/JAK2 inhibitor. The use of ruxolitinib in PV makes perfect sense because this is a JAK2-driven malignancy, and therapy with ruxolitinib has proven to be effective in multiple randomized phase III clinical trials. The response rate in the hematocrit control is about 60% in both studies. In addition to this, ruxolitinib was associated with other benefits including splenic reduction, splenic symptom improvement, improvement in the general symptoms of the patient, and quality of life, as well as more favorable iron metabolism and [avoidance of] iron deficiency and phlebotomy.

TARGETED ONCOLOGY:Is there an advantage to ruxolitinib compared to interferons?

Yacoub:Ruxolitinib, being an oral agent, is definitely more convenient and does result in a very rapid, very effective, and, as far as we know, durable response. [However,] it is not modifying in the sense that it does not necessarily prevent disease progression or transformation that we can prove at this time.

Interferons are a class of drugs that are the synthetic equivalent of a naturally produced hormone that can result in direct toxicity to the cancer and can also harvest the immune system to try to achieve any immediate responses in those patients. We have not yet proven that this actually does change the paradigm or change the natural course of those cancers; [however] the body of evidence is very convincing that these drugs are very active with some deep responses and some complete molecular responses, which is very intriguing and definitely worth further thought.

The long-acting interferons are being used and, in the hands of experts, [patients] are well-managed and the toxicities associated with it can be controlled to allow patients to receive benefit of the therapy.

TARGETED ONCOLOGY:How do you choose the right treatment for these patients?

Yacoub:So far, hydroxyurea remains our first line of therapy. However, interferons are also making themselves a very legitimate first-line option, especially in young patients who are going to live with the therapy for longer and might wish to avoid some of the long-term side effects of hydroxyurea. It also is important for younger patients who wish to preserve fertility and to have a chance at achieving a deep molecular response and potentially [to look] at an effective therapy where they can be on a low-dose maintenance or off of therapy for a while.

TARGETED ONCOLOGY:Do you see any upcoming changes on the horizon that will shake up the current management of PV?

Yacoub:Absolutely. There is a lot of research going on in PV to raise the bar higher and achieve better results for our patients, including harvesting some of the knowledge that we know about the PV physiology. Among these very promising molecules are the MDM2 inhibitors, which are drugs that suppress the MDM2 binding to P53, which is also an activation of P53 and results in rapid apoptosis in PV.

The clinical experience has been that these drugs are very effective and if we could tweak their doses correctly, they can be paradigm-shifting in terms of PV treatment. Some of the early studies show correction of the blood counts, as well as correction of the immune burdens, and significant improvements in the bone marrow findings. This is in phase II trials, and we are all looking forward to hearing more about the final results of those studies once they are made available. We have high expectations for this molecule.

Additional therapeutic options that are on the horizon are hepcidin agonists, which are synthetic equivalents of a naturally made hormone called hepcidin that separates iron from blood-making. This way, you can cause a synthetic iron deficiency and result in controlling of the PV without having to undergo therapeutic phlebotomy.

TARGETED ONCOLOGY:What is the takehome message from your presentation?

Yacoub:I think all physicians who treat PV should be aware of all the available therapeutic options and the upcoming therapeutic options. Different patients respond differently to the same therapy, and some patients might have great benefit in alternative therapeutic options if they are offered that. I think it’s great to have multiple options to treat those patients and try to find the best option for each patient that is also the most important clinical benefit in them. In addition, as those therapeutic options are resulting in more novel outcomes and molecular responses, I think this will be a factor in future decision making where we can treat patients with different therapeutic options based on the unique responses and deep responses that can be achieved.

TARGETED ONCOLOGY:What is your final advice for physicians treating PV?

Yacoub:Interferons have been a therapeutic option for several decades. However, the more novel formulations are a lot more tolerable and in the hands of experts and the experienced physicians using them, they can result in very good responses that are deep and sustainable.

Against the common belief that this is restricted to a certain category of patients, clinical trials have included elderly patients and younger patients, as well as patients with wide-range of general health, provided none of the contrary indications are present. To highlight the contrary indications are usually the act of autoimmune disorders, patients with uncontrolled depression or mood disorders. It’s important to avoid using interferons in the patients that are not fit for it. However, without those contrary indications, almost any patient with PV or thrombocytosis can be a candidate for this very effective therapy which has a deep and effective responses.