Ruxolitinib (RUX), a potent Janus kinase (JAK)1/JAK2 inhibitor, is approved for hydroxyurea (HU)-resistant/-intolerant patients (pts) with polycythemia vera (PV) based on findings from the RESPONSE study (NCT01243944). RUX proved superior to best available therapy (BAT) in maintaining hematocrit (Hct) control without phlebotomy eligibility, normalizing blood cell count, reducing spleen volume, and improving symptoms in pts with PV with splenomegaly who are resistant to or intolerant of HU. RESPONSE-2 (NCT02038036) is a global, multicenter, open-label, phase 3 trial comparing RUX with BAT in HU-resistant or -intolerant pts with PV without splenomegaly. In the primary analysis at wk 28, RUX proved superior to BAT in controlling Hct without phlebotomy eligibility, normalizing blood cell count, and improving symptoms. Responses were durable at 80 wk of follow-up. Here we evaluate the long-term safety and efficacy of RUX after a follow-up of 156 wk.


Patients were randomized 1:1 to RUX 10 mg twice daily or BAT; BAT patients could cross over to RUX starting at wk 28. The primary endpoint was Hct control at wk 28 (absence of phlebotomy eligibility [Hct >45% and ≥3% higher than baseline, or >48%] from wk 8 to 28, with ≤1 phlebotomy eligibility up to wk 8). The key secondary endpoint was complete hematologic remission (CHR; Hct control, white blood cell count <10×109/L, platelet count ≤400×109/L) at wk 28. Other endpoints included changes in patient-reported outcomes and in JAK2 V617F allele burden over time. Durability of Hct control (ie, primary response), CHR, and safety were evaluated at wk 156.


At data cutoff (April 6, 2018), 65/74 RUX pts were still on treatment. Primary reasons for discontinuation were adverse events (AEs; 5.4%), consent withdrawal (2.7%), death, disease progression, and physician decision (1.4% each). All 75 BAT pts had discontinued; 58 pts had crossed over to RUX; 46 were ongoing. Reasons for early discontinuation in crossover pts were AEs (13.8%), consent withdrawal (3.4%), death (1.7%), and disease progression (1.7%). Median exposure was 168.5 wk for RUX, 28.4 wk for BAT, and, in crossover pts, 137.0 wk for RUX.

At wk 156, durable Hct control was achieved in 41.9% of RUX pts (31/74). The Kaplan-Meier estimated median duration of Hct control had not been reached (Figure A). Durable CHR was achieved in 24.3% of RUX pts (18/74; estimated median duration, 35.9 weeks; Figure B). RUX also led to durable improvements in PV-associated symptoms, with approximately half of RUX pts (48%) continuing to achieve a ≥50% reduction in MPN-SAF TSS at wk 156. Pts in the RUX arm also continued to experience improvements in all 5 dimensions of the EQ-5D-5L assessment. Pts who crossed over to RUX derived benefits from RUX therapy as well, achieving Hct control following crossover, with Hct decreasing over time. As seen in RUX pts, crossover pts experienced a reduction in JAK2 V617F allele burden over time from the time of crossover.

The safety profile of RUX was consistent with previous reports. The most common AEs were anemia (exposure-adjusted rate per 100 pt-years, 10.7), increased weight (8.5), arthralgia (6.8), and hypertension (6.0) in the RUX arm and anemia (12.8), nasopharyngitis (7.1), and increased weight (6.4) in pts after crossover. Of interest, exposure-adjusted rates of herpes zoster were 3.8 with RUX and 5.0 in crossover pts. Overall, exposure-adjusted rates of AEs with RUX were lower than those reported at 80 wk of follow-up. The exposure-adjusted rate of thromboembolic events was higher in the BAT arm (3.7; RUX, 2.6). As expected given prior HU exposure, nonmelanoma skin cancer was the most common second malignancy in RUX-treated pts (randomized, 3.4; crossover, 2.8). No RUX-treated pts developed AML; 1 pt (RUX arm; 0.4) developed myelofibrosis. Three pts died on study: 1 in the RUX arm (metastatic melanoma), 1 in the BAT arm (septic shock), and 1 after crossover (general health deterioration).


In this 156-wk follow-up, RUX provided durable Hct control and CHR in pts with PV without splenomegaly. RUX was well tolerated, with 88% of randomized pts and 79% of crossover pts still receiving RUX at the time of this analysis. AEs were consistent with previous reports, and no new safety signals were observed. Overall, findings are consistent with those from RESPONSE and support RUX as the standard of care for second-line therapy in pts with inadequately controlled PV.


Passamonti:Novartis: Consultancy, Honoraria, Speakers Bureau. Palandri:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Saydam:Gilead: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria. Devos:Novartis: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Vannucchi:Celgene: Membership on an entity's Board of Directors or advisory committees; ITALFARMACO: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Bensasson:Novartis: Employment. Kandra:Novartis: Employment, Research Funding. Morando:Novartis: Employment, Equity Ownership. Griesshammer:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Author notes


Asterisk with author names denotes non-ASH members.

Sign in via your Institution