by Dr. C.H. Weaver M.D. updated 1/2020
A phase III pivotal clinical trial has determined that Jakafi® (ruxolitinib) is more effective than other available therapies in for reducing symptoms and improving clinical outcomes for patients with polycythemia vera (PV). These findings were published in the New England Journal of Medicine.
About Polycythemia Vera
Polycythemia vera is a slow-growing type of blood cancer that belongs to a group of blood disorders called myeloproliferative neoplasms (MPN). In these disorders, the bone marrow cells that produce blood cells develop and function abnormally. In PV the bone marrow makes too many blood cells, particularly red blood cells. These excess cells thicken the blood and can cause complications, such as a risk of blood clots or bleeding. Without treatment, PV can be life threatening and can eventually progress to more serious blood cancers, such as myelofibrosis or acute leukemia. Effective treatment, however, can significantly decrease risks and complications.
About Jakafi® (ruxolitinib)
Jakafi is a first-in-class JAK1/JAK2 inhibitor approved by the U.S. Food and Drug Administration for treatment of people with PV who have had an inadequate response to or are intolerant of hydroxyurea. Jakafi is also indicated for treatment of people with intermediate or high-risk myelofibrosis (MF), including primary MF, post–polycythemia vera MF, and post–essential thrombocythemia MF.
The goal of therapy for PV is to reduce the thickness of the blood and prevent bleeding and clotting. Jakafi has proven effective in the therapy of PV, including patients with intolerance or resistance to Hydrea® (hydroxyurea), the most common first-line therapy for patients with high-risk PV. Jakafi works by inhibiting proteins that may play a role in the development of MPNs by causing the body to make the wrong number of blood cells (JAK1/JAK2 proteins).
Researchers conducted a Phase III study to compare Jakafi with standard therapies in patients who did not respond well to Hydrea. Patients included in the study were being treated with phlebotomy (a procedure to draw blood that is used to manage PV) and had an enlarged spleen (splenomegaly). They were divided into two study groups: one received Jakafi, and the other received standard therapy (which is often Hydrea). The researchers monitored hematocrit levels among the patients. Hematocrit is a measure of the proportion of total blood volume that is composed of red blood cells; because PV results in excessive levels of red blood cells, hematocrit is used to measure disease control. They also monitored spleen size.
At eight months, patients receiving Jakafi had significantly better disease control than those on standard therapy: 21% of Jakafi patients had disease control versus only 1% for standard therapy. Patients on Jakafi also had better hematocrit control (60% versus 20%) and had greater reduction in spleen size: 38% of Jakafi patients had at least a 35% reduction in spleen volume compared with only 1% on standard therapy. Furthermore, more patients on Jakafi experienced remission: 24% versus 9% of those in the standard-therapy group. More patients on Jakafi also experienced at least a 50% reduction in symptoms (49% versus 5%).
Side effects were similar between patients who received Jakafi and standard therapy. They included moderate anemia and thrombocytopenia (low platelet count).
These findings suggest that for patients with PV who don’t respond to or can’t tolerate Hydrea, Jakafi is more effective than standard treatment. Patients on Jakafi had better outcomes in three important areas: hematocrit control, reduction of spleen volume, and improved symptoms.
The RESPONSE trial, is comparing outcomes between Jakafi and best available therapy in patients with PV who can’t tolerate Hydrea or are resistant to it. Participants have been assigned to either best available treatment or Jakafi. Best available therapy includes Hydrea, several other drugs, or no medication. In a primary analysis of RESPONSE outcomes, Jakafi more effectively improved clinical signs of disease (hematocrit control and at least a 35% reduction in spleen size) and symptoms in patients with PV. After eights months of study, patients on best available therapy who had not reached desired disease control were allowed to switch to treatment with Jakafi.(2,3)
In this particular analysis, researchers used hematocrit control to measure the effectiveness of Jakafi as treatment for PV. Hematocrit is a measure of the proportion of total blood volume that is composed of red blood cells. Because PV results in excessive levels of red blood cells, hematocrit is used to measure disease control. Specifically, with this analysis researchers assessed whether even patients who didn’t reach the trial’s defined level for hematocrit control after eight months of treatment could still reach hematocrit control with Jakafi.
The 222 patients included in the RESPONSE trial all had PV and were resistant or intolerant to Hydrea. They were divided into two treatment groups: 110 received Jakafi and 112 received best available therapy. The researchers measured hematocrit regularly throughout the first eight months and continued after the eight-month screening. The researchers also monitored the number of phlebotomy procedures (procedure to draw blood that is used to manage PV) needed to treat PV in both groups.
Jakafi appeared to more effectively help manage hematocrit levels than best available treatment, even among patients who at eight months had not reached the study’s defined levels for hematocrit control. At 12 months, 97% of patients receiving Jakafi were likely to have maintained hematocrit control; at 20 months, 87% of these patients were likely to have maintained hematocrit control. Patients receiving Jakafi also had a longer period before becoming eligible for phlebotomy: Jakafi patients weren’t eligible for a median of one year versus a median of just over five months for those on best available therapy. Patients who received Jakafi also had better control of symptoms overall that those on best available therapy, with greater improvements in tiredness, itching, and night sweats.
In January 2020 doctors reported the long term results of the RESPONSE study after 5-years of follow-up. (3)
- At 5 years, the probability of maintaining a complete hematologic remission was 55% and the probability of maintaining overall clinical-hematological responses was 67%.
- The probability of survival at 5 years was 92% with Jakafi therapy.
- Of the 112 patients initially assigned to best available therapy all patients crossed over to receive Jakafi treatment by 80 weeks.
- Anemia was the most common side effect in patients receiving Jakafi.
What About Symptom Control?
Symptoms from PV are a major burden and negatively impact quality fo life. Doctors reported the results of symptom control in patients treated with Jakafi verses BAT at eight months. Overall more patients on Jakafi experienced an at least 50% reduction in symptoms (49% versus 5%) compared to those receiving BAT. The control rates for specific symptoms with Jakafi were as follows:
- Tiredness: reduced by 50% (compared to 4% with standard therapy)
- Itching: reduced by 95% (compared to 2% with standard therapy)
- Muscle ache: reduced by 61% (compared with a minor increase with standard therapy)
- Night sweats: reduced by 100% (compared with a 4% increase with standard therapy)
- Sweating while awake: reduced by 100% (compared to 4% with standard therapy)
- Headache: reduced by 52% (compared to 11% with standard therapy)
- Concentration problems: reduced by 44% (compared to 17% with standard therapy)
- Dizziness: reduced by 80% (compared to 8% with standard therapy)
- Skin redness: reduced by 64% (compared with a 5% increase with standard therapy)
- Vision problems: reduced by 42% (compared with an 11% increase with standard therapy)
- Numbness and tingling in hands or feet: reduced by 37% (compared to 16% with standard therapy)
- Feeling full quickly when eating: reduced by 94% (compared to no change with standard therapy)
- Stomach discomfort: reduced by 66% (compared to a 1% increase with standard therapy)
These findings suggest that patients with PV experience more effective symptom control with Jakafi compared with standard treatment. Because there is no cure for PV, symptom control is critical for the health and well-being of patients. (4)
The researchers concluded that “Jakafi is a safe and effective long-term treatment option for patients with polycythemia vera who are resistant to or intolerant of hydroxyurea. Jakafi treatment offers the first widely approved therapeutic alternative for this post-hydroxyurea patient population.”
This analysis of findings from the RESPONSE trial indicates that Jakafi more effectively helps patients with PV maintain long-term hematocrit control than best available therapy. As more study data is released, Jakafi appears increasingly promising in the treatment of PV.
- Verstovse S, Kiladjian J-J, Mesa R, et al. Ruxolitinib. Efficacy By Hematocrit Control in Patients with Polycythemia Vera: An Analysis of the RESPONSE Trial. Program and Abstracts of 56th American Hematological Society Annual Meeting and Exposition; December 6–9, 2014; San Francisco, California. Abstract 3201.
- Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care: (The RESPONSE Trial) ((RESPONSE)). ClinicalTrials.gov website. Available at: . Accessed December 6, 2014.
- Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus Standard Therapy for the Treatment of Polycythemia Vera. New England Journal of Medicine. 2015 Jan 29;372(5):426-35.
Response - 2 Study
Researchers have also reported data from a phase 3 trial referred to as the RESPONSE-2 study, further evaluating the effectiveness of Jakafi in the treatment of PV.
The trial included 149 patients with PV who either did not achieve a response to hydroxyurea, or who were intolerant to hydroxyurea. Patients were dependent on phlebotomy to control their hematocrit levels, but did not have an enlarged spleen.
Patients were treated with either Jakafi or best available therapy (BAT), and were directly compared. The data presented at the 2016 EHA meeting consisted of 28 weeks of follow-up of these patients.
- Hematocrit levels were maintained in 62.2% of patients treated with Jakafi, compared with only 18.7% of patients treated with BAT.
- Complete remission was achieved in 23% of patients treated with Jakafi, compared with 5.3% of patients treated with BAT.
- Improvement in PV symptoms was achieved in 50% of patients treated with Jakafi, compared with 7.7% of patients treated with BAT.
- Overall, Jakafi was well tolerated by patients.
The researchers concluded that Jakafi provides superior results compared to BAT among patients with PV who have stopped responding to, or are intolerant to hydroxyurea. These results are promising, and provide an effective and well-tolerated treatment option among patients with uncontrolled PV.
- Passamonti F, Griesshammer M, Palandri F, et al. Ruxolitinib Proves Superior to Best Available Therapy in Patients with Polycythemia Vera (PV) and a Nonpalpable Spleen: Results from the Phase IIIb RESPONSE-2 Study. Abstract ##S112. 21st Congress of the European Hematology Association (EHA) Copenhagen, Denmark, 2016