Narrator: The Phase 3 RESPONSE trial in Polycythemia Vera: Count Control and Spleen Volume Reduction in Patients With an Inadequate Response to or Intolerance of Hydroxyurea
Jakafi (ruxolitinib) is indicated for treatment of polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea.
Dr Grad: Hi. I’m Dr Gary Grad, a hematologist-oncologist in private practice in the Chicago area. Patients with myeloproliferative neoplasms, or MPNs, form an important part of my practice, and I’m happy to be able to talk to you today about clinical trial results with Jakafi in patients with polycythemia vera, or PV, who have had an inadequate response to or are intolerant of hydroxyurea, or HU.
Narrator: This promotional presentation is being sponsored by Incyte Corporation.
The speaker is presenting on behalf of, and is being compensated by, Incyte Corporation.
Dr Grad: This Phase 3 trial of Jakafi versus an active control in the form of best available therapy was conducted in patients who were resistant to or intolerant of hydroxyurea.
Eligible patients required phlebotomy for hematocrit control and had splenomegaly.
The primary endpoint of the RESPONSE trial was actually a composite endpoint of two measures: hematocrit control and a greater than or equal to 35% reduction in spleen volume.
This composite endpoint was a stringent standard for evaluation of therapy that required both components to be met.
To achieve the component of “Hematocrit control,” patients could not become eligible for phlebotomy between weeks 8 and 32.
Phlebotomy eligibility was defined as hematocrit >45% that was greater than or equal to 3 percentage points higher than the baseline or hematocrit >48%, whichever value was lower.
Let’s look at the results of the RESPONSE trial with regard to the composite primary endpoint.
As you can see on the screen, Jakafi demonstrated superior results to best available therapy for this measure. Best available therapy included hydroxyurea, interferon/pegylated interferon, anagrelide, pipobroman, lenalidomide/thalidomide, and observation. At week 32, twenty-three percent of patients receiving Jakafi achieved the composite primary endpoint, compared with <1% of patients receiving best available therapy. This difference was statistically significant.
It’s important to recall that Jakafi was used as a second-line agent in this trial in patients who had already failed first-line therapy with hydroxyurea because of resistance or intolerance.
One question that might arise is how durable the responses were to Jakafi past Week 32.
76% of patients, or 19 of 25, who initially achieved the composite primary endpoint at 32 weeks maintained their response through at least week 80.
Narrator: 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.
Dr Grad: We know that PV is a trilineage disorder and that patients may have elevated white blood cell counts and/or platelet counts.
Because of this, we monitor not only hematocrit, but these other counts as well.
Failure to control these other counts, as well as hematocrit, is part of resistance to hydroxyurea, as defined by European LeukemiaNet, or (ELN) guidelines, and other criteria.
To examine the effect of therapy on counts other than hematocrit, the RESPONSE trial had a secondary endpoint of complete hematologic remission, or CHR. This included the hematocrit control portion of the composite primary endpoint as well as white blood cell count of less than or equal to 10 thousand and a platelet count of less than or equal to 400 thousand.
As you can see on the screen, in the RESPONSE trial, Jakafi demonstrated significantly higher rates of complete hematologic remission versus best available therapy.
In fact, 3 times more patients receiving Jakafi achieved complete hematologic remission at Week 32 compared with best available therapy.
The RESPONSE trial also explored the durability of the response to Jakafi for this secondary endpoint of complete hematologic remission.
We can see that, in the RESPONSE trial, 58% of patients, or 15 of 26, treated with Jakafi who achieved complete hematologic remission at Week 32 maintained that response through Week 80.
Let’s dive a little deeper into two of the blood counts, specifically hematocrit and white blood cell count.
Given the importance of hematocrit control in patients with PV, it might be helpful to be able to separate out that piece of the composite primary endpoint to see how patients responded in both arms.
This analysis demonstrated that patients treated with Jakafi achieved a higher rate of hematocrit control versus best available therapy.
Looking at the best available therapy treatment arm, 4 out of 5 patients failed to achieve hematocrit control at Week 32.
As for the durability of the hematocrit control component of the primary endpoint for patients on Jakafi, we see that 77% of patients, or 51 of 66 who achieved the hematocrit control at Week 32 maintained their response through Week 80.
Now let’s look at the results for white blood cell counts, which were part of the secondary endpoint of complete hematologic remission.
Exploratory analyses from the RESPONSE trial examined trends in mean white blood cell counts over time.
An analysis was also performed to examine mean change from baseline in white blood cell counts, and this was done by analyzing subgroups based on therapy.
This graph shows not only Jakafi and best available therapy, but the subgroup of patients who specifically received hydroxyurea. Data for patients treated with hydroxyurea were also included in the group of patients receiving best available therapy.
Of note, at baseline, 75.5% of patients receiving Jakafi and 71.4% of patients receiving best available therapy had white blood cell counts of greater than or equal to 11 thousand.
Now, let’s turn our attention to safety information that you should be aware of when prescribing Jakafi.
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. Use active surveillance and prophylactic antibiotics according to clinical guidelines
- 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
- In myelofibrosis and polycythemia vera, the most common nonhematologic adverse reactions (incidence ≥15%) were bruising, dizziness, headache, and diarrhea. In acute graft-versus-host disease, the most common nonhematologic adverse reactions (incidence >50%) were infections and edema
- Dose modifications may be required 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 2 weeks after the final dose
Please see Full Prescribing Information.
Dr Grad: Thank you for your time.
You can learn more about PV Clinical Trials on the PV Efficacy page on the Jakafi website.