Long-Term Effect of Ruxolitinib (RUX) in Inadequately Controlled Polycythemia Vera (PV) without Splenomegaly: 5-Year Results from the Phase 3 Response-2 Study
Authors: Passamonti Francesco , Palandri Francesca , Saydam Guray , Egyed Miklos , Callum Jeannie , Devos Timothy , Sivgin Serdar , Guglielmelli Paola , Vannucchi Alessandro M. , Zor Evren , Gilotti Geralyn , Zhang Yifan , Griesshammer Martin 
Published: February 2021

BACKGROUND
RUX, a JAK 1/2 inhibitor, is a second-line treatment for symptom management and control of trilineage expansion in patients (pts) with PV who are resistant or intolerant to hydroxyurea (HU). In the RESPONSE study, RUX showed a superior and durable response in controlling hematocrit (HCT) and improving splenomegaly in PV pts resistant or intolerant to HU. RESPONSE-2 (NCT02038036) is a multicenter, open-label, Phase 3 trial comparing RUX with best available therapy (BAT) in HU-resistant/intolerant PV pts without splenomegaly. The primary analysis at Week (Wk) 28 and follow-ups at Wks 80 and 156 proved superiority of RUX over BAT. Here we present the final study results of the 5-year follow-up (Wk 260).
METHODS
Pts were randomized (1:1) to RUX 10 mg twice daily or BAT; crossover from BAT to RUX was allowed from Wk 28. The final analysis at Wk 260 evaluated durability of HCT control, complete hematologic response (CHR), and safety. Durability of HCT control was defined as absence of phlebotomy eligibility from Wk 8 to Wk 260 with ≤1 phlebotomy eligibility post-randomization to Wk 8. CHR was defined as HCT control with a white blood cell count &lt;10×109/L, platelet count ≤400×109/L. Safety is reported as exposure-adjusted rates per 100 pt-years. Other evaluated endpoints were changes in pt-reported outcomes (PRO) and JAK2 V617F allele burden over time.
RESULTS
Pts were randomized to RUX (n=74) or BAT (n=75). A total of 59/74 RUX pts and 61/75 BAT pts completed the treatment duration. Among the 75 BAT pts, 58 pts crossed over to RUX, with 38 of them completing the study, allowing for long-term follow-up of 97 pts treated with RUX. Median (range) exposure was 260.0 (0.1 - 273.1) wks in RUX, 28.4 (6.7 - 83.0) wks in BAT, and 224.7 (2.7 - 236.1) wks in crossover arms.
At Wk 260, 21.6% of RUX pts (16/74) achieved durable HCT control. The Kaplan-Meier (KM) -estimated median duration of HCT control was not reached (Fig. A). Durable CHR was achieved in 24.3% of RUX pts (18/74; estimated median duration, 34.0 wks). Crossover pts derived RUX benefit by achieving HCT control with HCT levels decreasing over time (median HCT was 46.2% at the crossover baseline and 38.9% at the end of treatment). JAK2 V617F allele burden reduced over time for pts treated with RUX from baseline with a median decrease of 14.8% in RUX (59 evaluable pts) and 13.5% in crossover arms (42 evaluable pts).
RUX showed durable improvement in PV-associated symptoms; about 45% of RUX pts continued to achieve ≥50% reduction in MPN-SAF TSS at Wk 260. RUX pts also continued to experience improvements in all 5 dimensions of the EQ-5D-5L assessment. Total number of phlebotomies was 60 in the RUX arm (at Wk 260) vs 106 for BAT (Wk 80). At Wk 260, RUX- (vs BAT-) treated pts required &gt;0 − ≤2 phlebotomies in 16.2% (vs 38.7%), &gt;2 − ≤4 in 9.5% (vs 21.3%), &gt;4 − ≤6 in 5.4% vs (2.7%), and &gt;6 − ≤8 in none (vs 1.3%).
The most common AEs (&gt;5%, exposure-adjusted rate) were anemia, arthralgia, and increased weight in the RUX arm and anemia, and hypertension in pts after crossover. Of note, exposure-adjusted rates of herpes zoster were 3.9 in both RUX (Grade 3/4, 0.9) and crossover pts (no Grade 3/4) and none in the BAT arm. The exposure-adjusted rate of thromboembolic events was higher with BAT than RUX (3.7 vs 1.5). As expected given prior HU exposure, non-melanoma skin cancer was the most common secondary malignancy in RUX (exposure-adjusted rates: randomized, 2.7; crossover, 2.9) and BAT-treated pts (1.9). No RUX pts developed AML, whereas myelofibrosis was reported in 2 pts (exposure-adjusted rate, 0.6%). On-treatment death was reported in 5 pts: 1 each in the RUX arm (metastatic melanoma) and BAT arm (septic shock), and 3 in crossover (1 pt each - cardiac disorder, general health deterioration, and PV progression).
The KM-estimated median overall survival was not reached in both RUX (95.8%; 95% CI: 87.4, 98.6) and BAT arms (90.7%; 95% CI: 80.3, 95.7; Fig. B) at ≥260 wks. Transformation-free survival (KM-estimated, 95% CI) in the RUX arm was 94.18% (85.23, 97.78) at ≥260 wks.
CONCLUSIONS
In line with the RESPONSE study outcomes, final analysis from the 5-yr follow-up of RESPONSE 2 proved superiority of RUX over BAT with a safety profile that remained consistent with previous reports. RUX provided durable HCT control with a decrease in the need for phlebotomies, CHR, improved PV-associated symptoms and PRO scores, with fewer thromboembolic events in PV pts without splenomegaly, who are HU resistant or intolerant.

Disclosures
Palandri: Novartis: Consultancy, Honoraria. Callum:Canadian Blood Services: Research Funding; Octapharma Canada: Research Funding. Devos:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vannucchi:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zor:Novartis: Current Employment. Gilotti:Novartis: Current Employment. Zhang:Novartis: Current Employment. Griesshammer:Celgene: Honoraria, Speakers Bureau; AOP Orphan: Honoraria, Speakers Bureau; CTI: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.