Transcript



Narrator: Jakafi (ruxolitinib) Efficacy and Safety: The COMFORT trials
Narrator: Jakafi (ruxolitinib) is indicated for treatment of patients with intermediate or high-risk myelofibrosis (MF), including primary MF, post–polycythemia vera MF and post–essential thrombocythemia MF.
Dr Fazal: My name is Salman Fazal. I’m the Interim Director of Cell Transplantation Program at the Allegheny Health Network Cancer Institute in Pittsburgh. I'm also Assistant Professor at Temple University School of Medicine. And over the last seven years, I have been the investigator for clinical trials involving myeloid-malignancies and with myelofibrosis.
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 Fazal: In this presentation, we are going to discuss patients with intermediate or high-risk myelofibrosis.
Dr Fazal: The information that I will present is all consistent with labeled indication and consistent with FDA regulations. We will also discuss important safety information regarding Jakafi.
Dr Fazal: Treatment of ruxolitinib in intermediate-2 and high-risk myelofibrosis has been evaluated in… two large randomized Phase III study. COMFORT-I which was a double-blind placebo controlled study and COMFORT-II where patients were randomized between the ruxolitinib and best available therapy. COMFORT-I had one to one randomization and COMFORT-II had two to one randomization.
Dr Fazal: In terms of the patient enrollment, patients who were 18 or above and had intermediate-2 or high-risk myelofibrosis, who had good ECOG performance status, were able to be enrolled. In terms of the baseline characteristic of the patients, 40% of patients had intermediate-2-risk disease, and 60% of patients had high-risk disease.
In terms of the actual enrollment, 309 patients were enrolled in the COMFORT-I study, and 219 patients were enrolled in the COMFORT-II study.
Dr Fazal: The criteria for the crossover differed between the COMFORT-I and COMFORT-II study. For the COMFORT-I study, it was worsening in the spleen volume by 25% or more from the baseline and development of splenic symptoms, which was defined as worsening satiety with weight loss or if the patients had more splenic pain and required narcotics.
For the COMFORT-II study, the criteria for this crossover was worsening in the spleen volume by 25% or more from the nadir or if the patients underwent splenectomy.
Dr Fazal: The COMFORT-I study was mainly conducted in US; the COMFORT-II study was mainly conducted in Europe. The primary end point of the study was looking at the spleen volume reduction by 35% or more. For COMFORT-I study, that end point was assessed at week 24; for COMFORT-II study, that end point was assessed at week 48. Both of the studies allowed the spleen volume assessments to be done by CT scan or MRI.
Dr Fazal: The COMFORT-I study also included patient-reported outcome in the pre-specified secondary end point and that was 50% or more reduction in the total symptom score by the patients. These patients were able to report their symptoms by electronic diary. In terms of the COMFORT-II study, it also had the pre-specified secondary end point of looking at the spleen volume reduction by 35% or more at week 24.
Dr Fazal: In terms of the pre-specified secondary end point, both of them included overall survival assessment at three years.
Narrator: Results of the COMFORT-I and COMFORT-II trials
Dr Fazal: The primary end point of the study was greater than 35% reduction in the spleen volume by CT scan or MRI at week 24. In patients who were treated with ruxolitinib, 42% of patients met that end point. In patients who were getting placebo, less than 1% of patients achieved reduction in the spleen volume. The difference between the ruxolitinib and placebo was significant.
Dr Fazal: In terms of the secondary end point of the study which was to assess the total symptom score, 46% of patients achieved improvement in the total symptom score by 50% on the ruxolitinib arm versus 5% on the placebo.
Dr Fazal: Because these patients had electronic diaries and they were able to report their symptoms on daily basis, we were able to determine that the median time to symptom improvement was less than four weeks.
Dr Fazal: In terms of the results of the COMFORT-I study, ruxolitinib met both the primary and the secondary end point of the study...
Dr Fazal: The COMFORT-II study was a randomized study between ruxolitinib and best available therapy. The best available therapy in the COMFORT-II study was at the investigator’s discretion and would include any commercially available agent alone or in combination or the investigator could decide to choose no therapy at all. However, that could change at any time during the trial.
In the trial, 46% of patients received hydroxyurea and 16% of patients received glucocorticoid.
Dr Fazal: In terms of the primary end point which was to look at the spleen volume reduction by 35% or more, by CT scan or MRI at week 48, 29% of patients treated with ruxolitinib met the end point. In the best available therapy which included patients who received hydroxyurea or glucocorticoids, 0% of patients achieved the end point. The difference between the two arm was statistically significant.
Dr Fazal: One of the pre-specified secondary end point of the study was to look at the overall survival and as a treating hematologist/bone marrow transplant physician, we always wanted to look at the outcome of the patients who were treated with ruxolitinib on the COMFORT-I study. Fortunately, Incyte was able to discuss with FDA and incorporate this information in the prescribing information.
As a result, I’m able to share this information with you.
Dr Fazal: This shows the Kaplan-Meier curve of all survival of patients who were treated with ruxolitinib. It also shows the survival curve of patients who initially received placebo and later on, was able to be switched to ruxolitinib.
Dr Fazal: The three-year survival probability of patients who initially received ruxolitinib was 70%. For patients who initially received placebo and subsequently were able to be crossed over to ruxolitinib, their three-year survival probability was 61%.
Dr Fazal: The crossover was based on the progression-driven events or investigator’s choice. The median time to crossover was nine months.
Dr Fazal: Similarly, one of the pre-specified secondary end point of the COMFORT-II study was to look at the overall survival at three years. This shows the Kaplan-Meier curve of overall survival of patients who received ruxolitinib and also shows the Kaplan-Meier curve of overall survival of patients who initially received best available therapy and were able to be switched over to ruxolitinib.
The three-year survival probability of patients who initially received ruxolitinib was 79%. The three-year survival probability of patients who initially received best available therapy and subsequently, went on to receive ruxolitinib was 59%.
Patients were able to be crossed over at the physician’s discretion or if these patients had progressed. The median time to cross over was 17 months.

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

Please view Full Prescribing Information.
Dr Fazal: Thank you for joining me here today.

Jakafi® (ruxolitinib) Efficacy and Safety: The COMFORT* trials

In this video, Salman Fazal, MD, discusses the COMFORT I and COMFORT II trials. In addition to reviewing the study design for each, Dr Fazal highlights important efficacy and safety data in these trials. The data show efficacy and safety results of Jakafi® (ruxolitinib) in patients with intermediate-2 risk and high-risk myelofibrosis.

*COMFORT=COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment



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Image of Dr. Salman Fazal

Salman Fazal, MD
Allegheny Health Network Cancer Institute

Salman Fazal, MD
Allegheny Health Network Cancer Institute

Salman Fazal, MD
Allegheny Health Network Cancer Institute

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Indications and Usage

Jakafi is indicated for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.

Jakafi is indicated for treatment of patients with intermediate or high‐risk myelofibrosis (MF), including primary MF, post–polycythemia vera MF and post–essential thrombocythemia MF.

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

Please see Full Prescribing Information for Jakafi.