Phase 2/3 randomized trials of pegylated IFNs and RUX in PV
| . | PEG-IFN-α-2a . | roPEG-IFN-α-2b . | Ruxolitinib . | |||
|---|---|---|---|---|---|---|
| Phase 3 MPD-RC 1121 PV (n = 87) . | Phase 3 PROUD-PV (n = 254) / CONTINOUS-PV27,28 (n = 171) . | Phase 2, randomized low-PV study30 (n = 127) . | Phase 3 RESPONSE43,46 (n = 212) . | Phase 3 RESPONSE-247 (n = 127) . | Phase 3b RELIEF48 (n = 110) . | |
| Comparator; 1° endpoint | HU; CR at 12 mo | HU; CHR with normal spleen size at 12 mo (PROUD-PV) | Phlebotomy; maintenance of Hct <45% | Standard therapy; Hct control and ≥35% reduction in spleen volume at week 32 | BAT; Hct control at week 28 | HU; ≥50% improvement in MPN SAF TSS at week 16 |
| Hematologic responses | 12-mo CR: 30% (HU) vs 28% (PEG-IFN) in patients with PV; Hct control: 43% (HU) and 65% (PEG-IFN) (P = .04) in patients with PV | 60-mo CHR: 44% (HU) vs roPEG-IFN (56%) (P = .0974); 5-y rates of freedom from phlebotomy: 63.2% (HU) vs 81.8% (roPEG-IFN) | Hct <45%: 84% (roPEG-IFN) vs 60% (phlebotomy) (P = .0075); early trial cessation due to superiority of roPEG-IFN | 1° endpoint: 21% (RUX) vs 1% (standard therapy); Hct control: 60% (RUX) vs 20% (standard therapy) ≥35% spleen volume decrease: 38% (RUX) vs 1% (standard therapy) | Hct control: 62% (RUX) vs 19% (BAT) (P <.0001); requirement for phlebotomy: 19% (RUX) vs 60% (BAT); CHR: 23% (RUX) vs 5% (BAT) | 1° endpoint: 43.4% (RUX) vs 29.6% (HU) (P = .139); post hoc analysis of 1° endpoint in patients with stable screening to baseline scores: 47.4% (RUX) vs 24.0% (HU) (P = .0346) |
| Molecular responses | JAK2 V617F VAF decreased through month 48 with PEG-IFN, increased with HU after 12 mo; median best VAF change: −5.3% (HU) vs −10.7% (PEG-IFN) | 60-mo molecular response per ELN criteria: 21.6% (HU) vs 69.1% (roPEG-IFN) | JAK2 V617F VAF: −10.43% (roPEG-IFN) vs +1.03% (phlebotomy); molecular response per ELN criteria: 22% (roPEG-IFN) vs 0% (phlebotomy) | JAK2 V617F VAF: −12.2% (RUX) vs +1.2% (standard therapy) at week 32; week 112: −34.7% maximal mean change on RUX | Not assessed | Not assessed |
| Symptoms | At 12 mo: in CR/PR patients, ≥50% improvement in MPN-SAF TSS score: 49% (HU) vs 37% (PEG-IFN) (combined PV & ET patients)97 | No difference in QOL data at 36 mo using the EQ-5D-3L* questionnaire at month 36 | RoPEG-IFN: increase in fatigue and fevers; all other symptoms improved; pruritis decreased by 60% vs 30%, and night sweats 40% vs 18% in roPEG-IFN vs phlebotomy arms, respectively | ≥50% reduction in TSS: 49% (RUX) vs 5% (standard therapy) | ≥50% reduction in TSS: in 45% (RUX) vs 23% (BAT); mean % change in TSS: −45.3% (RUX) vs +2.4% (BAT) | See primary endpoint above; significant difference from baseline to week 16 in itching (P = .027) between the 2 arms |
| AEs | ≥Grade 3 AEs: 28% (HU) vs 46% (PEG-IFN); grade 1-2 depression: 3% (HU) vs 15% (PEG-IFN) | 60-mo period: serious AEs: 25.2% (HU) vs 23.6% (roPEG-IFN) | All AEs: 78% (roPEG-IFN) vs 42% (phlebotomy) (P <.0001); grade 3 AEs: 6% (roPEG-IFN) vs 5% (phlebotomy) | Rate of ≥ grade 3 AEs per 100 patient years: 28.8 (RUX) vs 44.0 (standard therapy); herpes zoster in 7 (6.4%) of RUX; none in standard therapy | Rate of ≥ grade 3 AEs: 17% (RUX) vs 27% (BAT); rate of ≥ grade 3 AEs per 100 patient years: 25.6 (RUX) vs 45.4 (BAT) | Serious AEs: 5 vs 4 events (RUX vs HU); most events grade 1 or 2; herpes zoster and squamous cell carcinoma (n = 1 each) with RUX, none with HU |
| TEs | Cumulative incidence of 2% at 24 mo for both HU and PEG-IFN (combined PV and ET patients) | 1.2%–patient year in both HU and ro-PEG-IFN arms | 1 (splenic vein) thrombosis in the phlebotomy arm vs none in the roPEG-IFN arm | 1 TE event (RUX) vs 6 (standard therapy); 5-y follow-up: 1.2 (RUX) vs 8.2 (standard therapy) per 100 patient-years | 1 TE event in the RUX arm vs 3 in the BAT arm | 2 TE events in each arm |
| . | PEG-IFN-α-2a . | roPEG-IFN-α-2b . | Ruxolitinib . | |||
|---|---|---|---|---|---|---|
| Phase 3 MPD-RC 1121 PV (n = 87) . | Phase 3 PROUD-PV (n = 254) / CONTINOUS-PV27,28 (n = 171) . | Phase 2, randomized low-PV study30 (n = 127) . | Phase 3 RESPONSE43,46 (n = 212) . | Phase 3 RESPONSE-247 (n = 127) . | Phase 3b RELIEF48 (n = 110) . | |
| Comparator; 1° endpoint | HU; CR at 12 mo | HU; CHR with normal spleen size at 12 mo (PROUD-PV) | Phlebotomy; maintenance of Hct <45% | Standard therapy; Hct control and ≥35% reduction in spleen volume at week 32 | BAT; Hct control at week 28 | HU; ≥50% improvement in MPN SAF TSS at week 16 |
| Hematologic responses | 12-mo CR: 30% (HU) vs 28% (PEG-IFN) in patients with PV; Hct control: 43% (HU) and 65% (PEG-IFN) (P = .04) in patients with PV | 60-mo CHR: 44% (HU) vs roPEG-IFN (56%) (P = .0974); 5-y rates of freedom from phlebotomy: 63.2% (HU) vs 81.8% (roPEG-IFN) | Hct <45%: 84% (roPEG-IFN) vs 60% (phlebotomy) (P = .0075); early trial cessation due to superiority of roPEG-IFN | 1° endpoint: 21% (RUX) vs 1% (standard therapy); Hct control: 60% (RUX) vs 20% (standard therapy) ≥35% spleen volume decrease: 38% (RUX) vs 1% (standard therapy) | Hct control: 62% (RUX) vs 19% (BAT) (P <.0001); requirement for phlebotomy: 19% (RUX) vs 60% (BAT); CHR: 23% (RUX) vs 5% (BAT) | 1° endpoint: 43.4% (RUX) vs 29.6% (HU) (P = .139); post hoc analysis of 1° endpoint in patients with stable screening to baseline scores: 47.4% (RUX) vs 24.0% (HU) (P = .0346) |
| Molecular responses | JAK2 V617F VAF decreased through month 48 with PEG-IFN, increased with HU after 12 mo; median best VAF change: −5.3% (HU) vs −10.7% (PEG-IFN) | 60-mo molecular response per ELN criteria: 21.6% (HU) vs 69.1% (roPEG-IFN) | JAK2 V617F VAF: −10.43% (roPEG-IFN) vs +1.03% (phlebotomy); molecular response per ELN criteria: 22% (roPEG-IFN) vs 0% (phlebotomy) | JAK2 V617F VAF: −12.2% (RUX) vs +1.2% (standard therapy) at week 32; week 112: −34.7% maximal mean change on RUX | Not assessed | Not assessed |
| Symptoms | At 12 mo: in CR/PR patients, ≥50% improvement in MPN-SAF TSS score: 49% (HU) vs 37% (PEG-IFN) (combined PV & ET patients)97 | No difference in QOL data at 36 mo using the EQ-5D-3L* questionnaire at month 36 | RoPEG-IFN: increase in fatigue and fevers; all other symptoms improved; pruritis decreased by 60% vs 30%, and night sweats 40% vs 18% in roPEG-IFN vs phlebotomy arms, respectively | ≥50% reduction in TSS: 49% (RUX) vs 5% (standard therapy) | ≥50% reduction in TSS: in 45% (RUX) vs 23% (BAT); mean % change in TSS: −45.3% (RUX) vs +2.4% (BAT) | See primary endpoint above; significant difference from baseline to week 16 in itching (P = .027) between the 2 arms |
| AEs | ≥Grade 3 AEs: 28% (HU) vs 46% (PEG-IFN); grade 1-2 depression: 3% (HU) vs 15% (PEG-IFN) | 60-mo period: serious AEs: 25.2% (HU) vs 23.6% (roPEG-IFN) | All AEs: 78% (roPEG-IFN) vs 42% (phlebotomy) (P <.0001); grade 3 AEs: 6% (roPEG-IFN) vs 5% (phlebotomy) | Rate of ≥ grade 3 AEs per 100 patient years: 28.8 (RUX) vs 44.0 (standard therapy); herpes zoster in 7 (6.4%) of RUX; none in standard therapy | Rate of ≥ grade 3 AEs: 17% (RUX) vs 27% (BAT); rate of ≥ grade 3 AEs per 100 patient years: 25.6 (RUX) vs 45.4 (BAT) | Serious AEs: 5 vs 4 events (RUX vs HU); most events grade 1 or 2; herpes zoster and squamous cell carcinoma (n = 1 each) with RUX, none with HU |
| TEs | Cumulative incidence of 2% at 24 mo for both HU and PEG-IFN (combined PV and ET patients) | 1.2%–patient year in both HU and ro-PEG-IFN arms | 1 (splenic vein) thrombosis in the phlebotomy arm vs none in the roPEG-IFN arm | 1 TE event (RUX) vs 6 (standard therapy); 5-y follow-up: 1.2 (RUX) vs 8.2 (standard therapy) per 100 patient-years | 1 TE event in the RUX arm vs 3 in the BAT arm | 2 TE events in each arm |
AE, adverse event; BAT, best available therapy; Hct: hematocrit; MPN-SAF TSS: myeloproliferative neoplasm symptom assessment form total symptom score; PR, partial response; TE, thromboembolic event.
EQ-5D-3L: European Quality of Life, 5 dimensions, 3 levels.