Narrator: Identifying Patients Whose Polycythemia Vera Is Uncontrolled With Hydroxyurea
Narrator: Jakafi® (ruxolitinib) is indicated for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.
Dr Erba: Hello, my name is Harry Erba. I'm a professor of internal medicine at the University of Alabama at Birmingham where I serve as the director of the hematologic malignancies program as well as the associate director of the cancer center for clinical research. For the last 20 years I have been a clinical investigator evaluating novel therapies for people with myeloid neoplasms including the myeloproliferative neoplasms.
Narrator: This promotional presentation is being sponsored by Incyte Corporation.
Dr Erba: We're going to speak about the labeled indication for Jakafi® (ruxolitinib) for patients with polycythemia vera who have had either an inadequate response to or are intolerant of hydroxyurea.
Dr Erba: The information that I will present is all consistent with the labeled indication and consistent with FDA regulations. We will also discuss important safety information regarding Jakafi.
Narrator: Clinical Considerations
Dr Erba: Now let’s turn to the clinical management of patients with polycythemia vera. There are important goals in our treatment of patients with polycythemia vera. We have known for some decades now that control of the hematocrit to less than 45% is important in this group of patients.
Dr Erba: Now to that end we've typically used phlebotomy to lower the hematocrit to less than 45% as well as the use of aspirin.
Dr Erba: We should also remember that the goal of phlebotomy therapy is to make the patient deficient in iron, which in and of itself will have separate symptoms including fatigue, memory loss, trouble sleeping, dysgeusia, mouth ulcerations, restless legs and we know of nail and hair changes. And so the quality of life of patients on phlebotomy therapy who've become iron-deficient can be compromised. And that should be considered.
Dr Erba: We also need to recognize that phlebotomy and aspirin may not do anything to control the myeloproliferative symptoms that are associated with the disease including the symptomatic progressive splenomegaly.
Dr Erba: In patients who are undergoing phlebotomy and receiving low-dose aspirin for their disease, why would we then consider the use of cytoreductive therapy? And I believe there are a number of reasons to do so. One is that it’s been difficult to maintain the hematocrit less than 45% in a patient, and this could be for a variety of reasons including the proliferative nature of the disease and the requirement in some patients for very frequent phlebotomies. Or on the other hand poor compliance of patients with phlebotomy and phlebotomy schedules.
Dr Erba: If a patient has a high risk of thrombosis, many experts in this area will recommend cytoreductive therapy as well.
Dr Erba: These are patients over the age of 60 with a prior history of a thrombotic event.
Dr Erba: So for these indications we might consider cytoreductive therapy. In the United States we typically use hydroxyurea but interferon alpha is also used.
Dr Erba: But what do we do for patients that we're giving cytoreductive therapy such as hydroxyurea and they have had an inadequate response in one of those features that led to the use of hydroxyurea or they're intolerant of the use of hydroxyurea?
Dr Erba: The European Leukemia Network has developed a set of criteria for defining patients with uncontrolled polycythemia vera despite hydroxyurea therapy. Now it should be pointed out that in these criteria it is stated that patients should receive at least two grams daily of hydroxyurea for at least three months or the maximally tolerated dose of hydroxyurea before declaring treatment failure.
We can focus on several indicators of resistance. So if patients continue to need phlebotomy to maintain the hematocrit less than 45%. Or if they have leukocytosis with a white count over 10,000 or thrombocytosis with a platelet count over 400,000.
Dr Erba: If they have uncontrolled disease-related symptoms, specifically, for example, splenomegaly.
Dr Erba: And then finally if they are intolerant of the myelosuppressive nature of hydroxyurea. And so in order to control the hematocrit or control the splenomegaly or control those symptoms you need to use a dose that leads to neutropenia or thrombocytopenia or even anemia that would be a reason for considering some alternative therapy and declaring that hydroxyurea is not going to be effective. There are also non-hematologic toxicities with hydroxyurea that we need to consider such as leg ulcerations and gastrointestinal toxicities.
Dr Erba: But how common is it to find patients who have resistance to or intolerance of hydroxyurea?
Narrator: The PV Chart Survey was sponsored by Incyte Corporation.
Dr Erba: There’s been a retrospective analysis done in multiple centers by a variety of physicians looking at 1300 patients with polycythemia vera with a mean age of 62.
And the focus of this was to identify how many patients actually achieved complete hematologic response with hydroxyurea.
Dr Erba: The mean time since diagnosis was about five years and of the 1300 patients, 229 had discontinued hydroxyurea. Let’s look at the most common reasons for discontinuation.
Dr Erba: On this slide you can see that it's because the hematocrit is still too high and uncontrolled and side effects of the therapy itself. We also need to look at how likely it was for patients to achieve complete hematologic remission with hydroxyurea.
Dr Erba: So here you can see that in all patients only 30.6% of patients achieved a complete hematologic remission, which is defined as hematocrit control without phlebotomy, a white count and platelet count that are controlled as well as resolution of splenomegaly and no disease-related symptoms.
Dr Erba: In patients who remain on hydroxyurea only 37.1% had a complete hematologic remission and as many as 20% of patients who are on hydroxyurea actually did not have any response.
Dr Erba: Now we could also look at each of the individual lab parameters that make up complete hematologic remission. We know that from this retrospective review that over half of the patients did have their hematocrit maintained less than 45% but you could see a sizable minority did not.
Dr Erba: Furthermore, more than half of the patients in this retrospective review had persistent thrombocytosis or persistent leukocytosis.
Dr Erba: And when you look at the totality of the data, only about a third of patients had no elevation of the hematocrit, no leukocytosis and no thrombocytosis.
Dr Erba: The retrospective analysis does show that patients with intolerance to or inadequate response to hydroxyurea do exist in our practice.
Narrator: The RESPONSE Trial. A Randomized study of Efficacy and Safety in POlycythemia vera with JAK iNhibitor ruxolitinib verSus bEst available care.
Dr Erba: The RESPONSE trial was a randomized Phase III study that compared Jakafi to best available therapy for patients with polycythemia vera who were either intolerant of or had an inadequate response to hydroxyurea as defined by the European Leukemia Network.
Dr Erba: Patients had to have a persistent phlebotomy requirement and as well they also had to have measurable splenomegaly by MRI.
Dr Erba: There was a pre-randomization phase where all of the patients were kind of brought to the same starting gate.
Dr Erba: The hematocrit had to be controlled to less than 45%. And then they were randomized between Jakafi 10 milligrams twice daily or best available therapy.
Dr Erba: Now what I find interesting about this clinical trial is that the patients who were randomized to best available therapy—and remember they were intolerant of or had an inadequate response to hydroxyurea—almost 60% stayed on or received hydroxyurea.
Dr Erba: The primary analysis was done at 32 weeks. The primary end point was a composite of hematocrit control with freedom from phlebotomy as well as a 35% or more reduction in splenic volume by MRI.
Narrator: More specifically, to achieve the Hematocrit Control end point, patients could not become eligible for phlebotomy between weeks 8 and 32. Phlebotomy eligibility was defined as hematocrit >45% that is ≥3 percentage points higher than baseline or hematocrit >48%, whichever was lower.
Dr Erba: The two groups were well matched for age, gender.
Dr Erba: About half of the patients in both groups had resistance to and the other half intolerance of hydroxyurea.
Dr Erba: Many of these patients had prior thromboembolic events.
Dr Erba: As you can see, patients had a hematocrit less than 45% at the time of randomization. However, the median white blood cell count and platelet count were above normal.
Narrator: RESPONSE: Efficacy data
Dr Erba: Jakafi demonstrated superior results compared to best available therapy at 32 weeks in these patients. Twenty-three percent of patients treated with Jakafi achieved the composite end point versus only less than 1% of patients on best available therapy.
And in fact, at 48 weeks 22 of the 25 patients maintained the composite end point.
Dr Erba: In terms of hematocrit control and freedom from phlebotomy that was achieved in 60% of patients receiving Jakafi versus only 19% of patients on best available therapy. Likewise, for control of splenomegaly with a decrease in splenic volume by 35% or more as measured by MRI, that was achieved in 40% of patients that were receiving Jakafi versus less than 1% of patients on best available therapy.
Dr Erba: Therefore, the RESPONSE trial showed that Jakafi is an effective therapy for people with polycythemia vera who have had an inadequate response to or intolerance to hydroxyurea.
Narrator: Important Safety Information
- Treatment with Jakafi® (ruxolitinib) can cause thrombocytopenia, anemia and neutropenia, which are each dose‐related effects. Perform a pre‐treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated
- Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary
- Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi
- Severe neutropenia (ANC <0.5 × 109/L) was generally reversible by withholding Jakafi until recovery
- Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly
- Tuberculosis (TB) infection has been reported. Observe patients taking Jakafi for signs and symptoms of active TB and manage promptly. Prior to initiating Jakafi, evaluate patients for TB risk factors and test those at higher risk for latent infection. Consult a physician with expertise in the treatment of TB before starting Jakafi in patients with evidence of active or latent TB. Continuation of Jakafi during treatment of active TB should be based on the overall risk‐benefit determination
- Progressive multifocal leukoencephalopathy (PML) has occurred with Jakafi treatment. If PML is suspected, stop Jakafi and evaluate
- Advise patients about early signs and symptoms of herpes zoster and to seek early treatment
- Increases in hepatitis B viral load with or without associated elevations in alanine aminotransferase and aspartate aminotransferase have been reported in patients with chronic hepatitis B virus (HBV) infections. Monitor and treat patients with chronic HBV infection according to clinical guidelines
- When discontinuing Jakafi, myeloproliferative neoplasm-related symptoms may return within one week. After discontinuation, some patients with myelofibrosis have experienced fever, respiratory distress, hypotension, DIC, or multi-organ failure. If any of these occur after discontinuation or while tapering Jakafi, evaluate and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi without consulting their physician. When discontinuing or interrupting Jakafi for reasons other than thrombocytopenia or neutropenia, consider gradual tapering rather than abrupt discontinuation
- Non‐melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred. Perform periodic skin examinations
- Treatment with Jakafi has been associated with increases in total cholesterol, low-density lipoprotein cholesterol, and triglycerides. Assess lipid parameters 8-12 weeks after initiating Jakafi. Monitor and treat according to clinical guidelines for the management of hyperlipidemia
- The three most frequent non‐hematologic adverse reactions (incidence >10%) were bruising, dizziness and headache
- A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or fluconazole or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy
- Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breastfeed during treatment and for two weeks after the final dose
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Dr Erba: Thank you for joining me here today.