Narrator: Jakafi (ruxolitinib) in Intermediate-2 or High-Risk Myelofibrosis (MF): Spleen Volume, Symptom, and Overall Survival Data
Jakafi is indicated for treatment of intermediate or high-risk myelofibrosis (MF), including primary MF, post–polycythemia vera MF and post–essential thrombocythemia MF in adults.
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 intermediate-2 or high-risk myelofibrosis, including spleen volume, symptom, and overall survival data.
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: Similar to other malignancies, MF is a serious disease that may require active management at diagnosis.
In myelofibrosis, we use risk level to assess the severity of patient’s disease and also for assessment of prognosis.
Interestingly, the presence of any of the risk factors shown on the screen, which are derived from the Dynamic International Prognostic Scoring System Plus tool, or DIPSS Plus, indicates that the patient has already reached intermediate risk and may be appropriate for therapeutic intervention. Constitutional symptoms are weight loss greater than 10% of the baseline value in the year preceding primary MF diagnosis and/or unexplained fever or excessive sweats persisting for more than 1 month.
In fact, in a study of patients with primary MF, approximately 90% of evaluable patients, 375 of 428, were considered to be intermediate or high risk within 1 year of diagnosis.
It’s helpful to think about the implications of risk level on the prognosis in patients with MF.
For example, the International Prognostic Scoring System, or IPSS, which is used to assess patients at the time of diagnosis of MF, provides projected life expectancy for patients with low-, intermediate-1, intermediate-2, and high-risk disease.
As you can see from the graph, each step up in risk level has implications for diminished life expectancy, with a fairly significant drop from low-risk to high-risk.
These data help underscore that MF is a serious hematologic malignancy.
Let’s switch focus now and discuss Jakafi, a potential therapy for patients with MF.
Narrator: Jakafi is indicated for treatment of intermediate or high-risk myelofibrosis (MF), including primary MF, post–polycythemia vera MF and post–essential thrombocythemia MF in adults.
Dr Grad: Treatment with Jakafi 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, then as clinically indicated.
Now let’s take a look at the clinical trial data that provided support for the FDA's approval of Jakafi in these patients.There were two large clinical trials with Jakafi that provided support for the FDA's approval of Jakafi in patients with intermediate- or high-risk myelofibrosis.
The COMFORT-I clinical trial compared Jakafi with placebo and the COMFORT-II clinical trial compared Jakafi with best available therapy, or BAT. In the COMFORT-II trial, BAT included hydroxyurea in 46.6% of patients and glucocorticoids in 16.4% of patients, as well as a variety of other therapies.
The primary endpoint for both trials was spleen volume reduction of at least 35%, as shown by imaging. Both trials also had a prespecified secondary endpoint of overall survival.
The COMFORT-I clinical trial also had a secondary endpoint of at least ≥50% reduction in Total Symptom Score, or TSS. As you probably know, the TSS measures core symptoms of MF.
In both trials, significantly more patients receiving Jakafi achieved the primary endpoint compared with those who received placebo or best available therapy.
In the COMFORT-I trial, significantly more patients receiving Jakafi achieved a greater than or equal to 50% improvement in TSS compared with placebo, which was a secondary endpoint.
In both COMFORT trials, overall survival was a prespecified secondary endpoint. However, neither trial was designed to compare survival probabilities between Jakafi and the comparator at 3 or 5 years.
In both trials, patients randomized to either placebo or best available therapy were eligible to cross over to receive Jakafi because of progression-driven events or at their physician’s discretion.
In fact, in the trials, all patients in the comparator arms crossed over to Jakafi or discontinued.
However, for purposes of analysis of survival probability, patients were grouped based on their original randomized assignment.
Let’s look at the results for overall survival probabilities from the COMFORT-I study. The treatment arms were Jakafi and placebo. As noted previously, all patients crossed over to Jakafi or discontinued. Median time to crossover was 9 months.
At 3 years, survival probability was 70% for patients originally randomized to Jakafi and 61% for those originally randomized to placebo.
At 5 years, survival probability was 51.4% for patients originally randomized to Jakafi and 40.1% for those originally randomized to placebo.
I should note that the 5-year overall survival analysis is not included in the Full Prescribing Information for Jakafi. Although the 3-year overall survival analysis is presented in the Full Prescribing Information, P values and hazard ratios are omitted from the overall survival Kaplan-Meier curves. The COMFORT-I trial was not designed to compare survival probabilities between Jakafi and placebo at 3 or 5 years.
Now let’s look at the results for overall survival probabilities from the COMFORT-II study. The treatment arms were Jakafi and best available therapy. As noted previously, all patients crossed over to Jakafi or discontinued. Median time to crossover was 17 months.
At 3 years, survival probability was 79% for patients originally randomized to Jakafi and 59% for those originally randomized to best available therapy.
At 5 years, survival probability was 56% for patients originally randomized to Jakafi and 44% for those originally randomized to best available therapy.
I should note that, as with the data we reviewed from the COMFORT-I trial, the 5-year overall survival analysis is not included in the Full Prescribing Information for Jakafi. Although the 3-year overall survival analysis is presented in the Full Prescribing Information, P values and hazard ratios are omitted from the overall survival Kaplan-Meier curves. The COMFORT-II study was not designed to compare survival probabilities between Jakafi and best available therapy at 3 or 5 years.
It is important to realize MF is a serious malignancy that may require active therapeutic intervention at diagnosis. The COMFORT trials, conducted in patients with intermediate-2 or high-risk myelofibrosis both had a primary endpoint of spleen volume reduction and a secondary endpoint of overall survival. The COMFORT-I trial also had a secondary endpoint of reduction in total symptom score measured at week 24.
In these trials, significant reductions in spleen volume were observed in the Jakafi arm. The trials also produced data concerning overall survival probability for patients treated with Jakafi and either placebo or best available therapy but were not designed to compare survival probabilities between Jakafi and either placebo or best available therapy.
We’ll turn now to safety information about 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 (NMSC) 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
- Another JAK-inhibitor has increased the risk of major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and stroke (compared to those treated with tumor TNF blockers) in patients with rheumatoid arthritis, a condition for which Jakafi is not indicated. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Jakafi particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur
- Another JAK-inhibitor has increased the risk of thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which Jakafi is not indicated. In patients with myelofibrosis (MF) and polycythemia vera (PV) treated with Jakafi in clinical trials, the rates of thromboembolic events were similar in Jakafi and control treated patients. Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately
- Another JAK-inhibitor has increased the risk of lymphoma and other malignancies excluding NMSC (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which Jakafi is not indicated. Patients who are current or past smokers are at additional increased risk. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Jakafi, particularly in patients with a known secondary malignancy (other than a successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers
- 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 (pathogen not specified) and edema. In chronic graft-versus-host disease, the most common nonhematologic adverse reactions (incidence ≥20%) were infections (pathogen not specified) and viral infections
- Avoid concomitant use with fluconazole doses greater than 200 mg. Dose modifications may be required when administering Jakafi with fluconazole doses of 200 mg or less, or with strong CYP3A4 inhibitors, 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 MF Clinical Trials on the MF Efficacy page on the Jakafi website.