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P.M. Barr et al.
Survival outcomes
Ibrutinib resulted in significantly longer PFS compared with chlorambucil (median, PFS not reached vs. 15.0 months; Figure 1A). There was an 88% reduction in risk of PFS events (progression or death; hazard ratio [HR], 0.12; 95% CI, 0.07-0.20; P<0.0001) for patients random- ized to ibrutinib. PFS at 24 months was 89% with ibruti- nib versus 34% with chlorambucil. This rate was relatively stable with ibrutinib with an 18-month PFS of 94%. Ibrutinib consistently demonstrated significant improve- ments in PFS for patients in all subgroups including those considered high risk (Figure 2). In patients treated with ibrutinib, only 1 patient with del(11q) has had disease pro- gression, and the rates of 24-month PFS were 97% and 86% for those with or without del(11q), respectively (Figure 1B). No significant difference was observed in the PFS of patients with unmutated versus mutated IGHV (24- month PFS, 90% and 89%, respectively; Figure 1C). PFS benefits were consistent across additional subgroups of patients, including those with advanced disease (Rai stage 3 or 4) or bulky disease (Figure 2). PFS and OS rates were also similar regardless of age (24-month PFS, <75 years [88%], ≥75 years [89%]; OS, <75 years [94%], ≥75 years [96%]; Figure S2). With longer follow up and despite patient crossover, ibrutinib continues to demonstrate an OS benefit compared with chlorambucil (HR, 0.43; 95% CI, 0.21-0.86; P=0.0145; Online Supplementary Figure S3 and Table S1), with a 24-month OS of 95% for ibrutinib vs. 84% for chlorambucil (Online Supplementary Figure S3).
Responses for ibrutinib-treated patients
With a maximum of 36 months of follow up, the ORR with ibrutinib treatment was 92% (Table 2). Eighteen per- cent of patients achieved CR, which improved from 7% at 12 months and 15% at 24 months (Figure 3). Comparable ORR and CR rates were also observed in high-risk sub- groups, including those with del(11q) (ORR, 100%; CR rate, 14%) or unmutated IGHV (ORR, 95%; CR rate, 21%).
Disease burden and symptoms
The vast majority of ibrutinib-treated patients experi- enced substantial reduction in lymphadenopathy and splenomegaly at the time of the primary analysis which was much greater than observed with chlorambucil. A ≥50% reduction in the lymph node sum of the product of longest diameter (SPD) occurred in 95% of patients treat- ed with ibrutinib versus 40% of those treated with chlo- rambucil, with complete resolution in lymphadenopathy in 42% versus 7%, respectively (Online Supplementary Figure S4A,B). Reduction in splenomegaly by ≥50% occurred in 95% with ibrutinib versus 52% with chloram- bucil, with complete resolution in splenomegaly in 56% versus 22%, respectively (Online Supplementary Figure S4C,D). Ibrutinib also resulted in higher rates of improve- ments in disease symptoms including weight loss, fatigue, and night sweats, which were indications for therapy in many patients.
Patient-reported QOL
Greater improvements in QOL occurred with ibrutinib versus chlorambucil in FACIT-Fatigue (P=0.0013) by repeated measure analyses (Online Supplementary Figure S5). Clinically meaningful improvements occurred more frequently with ibrutinib versus chlorambucil in FACIT-
Table 1. RESONATE-2 reasons for initiation of treatment and baseline patient characteristics.1
Baseline Characteristic
0 1 2
Rai stage III or IV, n (%)
Bulky disease ≥ 5 cm, n (%) Hierarchical Classificationa, n (%)
Del(11q) Trisomy 12 Del(13q) None of above
IGHV statusb, n/N (%) Mutated
Unmutated Unclassifiablec
Ibrutinib (n=136)
73 (65-89)
46 (34) 88 (65)
60 (44) 65 (48)
Chlorambucil (n=133)
72 (65-90)
47 (35) 81 (61)
54 (41)
67 (50)
Median age (range), y
≥75y,(%)
Male, n (%)
ECOG performance status, n (%)
11(8) 12(9)
60 (44) 54 (40)
29/130 (22) 20/117 (17) 25/112 (22) 38/112 (34)
40/121 (33) 58/121 (48) 23/121 (19)
62 (47) 40 (30)
25/121 (21) 23/108 (21) 32/108 (30) 28/108 (26)
42/127 (33) 60/127 (47) 25/127 (20)
49 (37) 44 (33) 44 (33) 28 (21) 5 (4)
56 (42)
16 (12)
29 (22) 3 (2) 35 (26)
Patients meeting criteria for active disease, n (%)
Progressive marrow failure Lymphadenopathy Splenomegaly
Progressive lymphocytosis Autoimmune anemia and/or thrombocytopenia
Any documented constitutional
symptoms
Unintentional weight loss (>10% within 6 months) Significant fatigue
Fever
Night sweats
54 (40) 55 (40) 36 (26) 23 (17) 3 (2)
64 (47)
14 (10)
44 (32) 4 (3) 32 (24)
ECOG: Eastern Cooperative Oncology Group; FISH: fluorescence in situ hybridization; a
IGHV: immunoglobulin heavy-chain variable-region gene. Patients with missing results were excluded (Del(11): n=6 for ibrutinib, n=12 for chlorambucil; Trisomy 12: n=19 for ibrutinib, n=25 for chlorambucil; Del(13q): n=24 for ibrutinib, n=25 for chlo- rambucil; None of the above: n=24 for ibrutinib, n=25 for chlorambucil). bPatients with missing results were excluded (n=15 for ibrutinib, n=6 for chlorambucil). cUnclassifiable includes patients with polyclonal IGHV status if no specific IGHV sub- family member was dominant (>50% of all reads) and samples with no amplification.
Fatigue, although this was not statistically significant (86/136 [63%] vs. 71/133 [53%]; odds ratio, 1.50; 95% CI, 0.92-2.45; P=0.1013).
Safety and tolerability of ibrutinib
Median treatment duration with ibrutinib was 28.5 months (range, 0.7-35.9 months). Most patients continue ibrutinib treatment, with 83% (112/135) receiving ibruti- nib continuously for durations exceeding 2 years. The most frequent AEs with ibrutinib with extended follow up were similar to the primary report13: diarrhea, fatigue,
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