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P.M. Barr et al.
robust outcomes were demonstrated in higher-risk groups. No difference in outcome was observed in patients with unmutated IGHV status, a traditional poor prognostic indicator for all chemoimmunotherapy regi- mens. Notably the rate of unmutated IGHV in this study of older patients was somewhat lower than other studies at 48% (vs. 58%-62% in CLL11), consistent with prior reports of higher frequency of unmutated IGHV in younger patients.4,23 For patients with del(11q), another traditionally high-risk subgroup, 100% of the 29 patients responded to treatment with ibrutinib, and there was a 99% reduction in the risk of progression or death, with only 1 del(11q) ibrutinib-treated patient experiencing dis- ease progression after discontinuing therapy for an AE over the extended follow up. While this represents a rela- tively small patient subset (22%), ibrutinib demonstrates a particularly significant benefit in this population, which
historically experiences inferior outcomes with traditional chemotherapy or CD20-based regimens.24-26 Combined analysis of 3 randomized studies not only demonstrated superiority of ibrutinib over traditional chemotherapy and/or anti-CD20 comparators for patients with del(11q), but also equally positive PFS and OS outcomes irrespec- tive of del(11q). These results suggest that current defini- tions of high-risk disease and the impact of prognostic bio- markers may need to be redefined with ibrutinib.27 The mechanism why del(11q) patients may have better out- comes when treated with ibrutinib is of high interest and is the subject of ongoing research.
Safety of therapy administered to older patients over the long term is an area that requires close scrutiny. First- line ibrutinib appears to be well tolerated with extended treatment as evidenced by over 80% of this older popula- tion being able to continue treatment for more than 2
Table 3. Characterization of select AEs of clinical interest in ibrutinib-treated patients observed at any time during follow up.a
AE Grade
Diarrhea
Visual disturbancesb Hypertensionc Arthralgia
Atrial fibrillation Major hemorrhage
Infections (grade ≥3)
Ibrutinib-treated patients
n=135 Resolution, Median time to first event, Median time from onset to
n (%) n (%) days resolution/improvement, days Any 2 3 4 5 Complete Partial Any 2 3 4 5 Any 2 3 4
61(45) 16(12) 5(4) 0 0 30(22) 6(4) 0 0 0
58 (95) 0 17 (57) 0
26 131 219 NA NA 100 201 NA NA NA
27(20) 13(10) 7(5) 0 0 27(20) 9(7) 3(2) 0 0 14(10) 7(5) 6(4) 0 0
12 (44) 21 (78) 8 (57)
1 (4) 1 (4) 1 (7)
187 187 109.5 NA NA
135 55 135 NA NA 249.5 85 773.5 NA NA
9(7) 1 7(5) 1(1) 0 (<1)
31(23) NA 28(21) 4(3) 2(1)
9 (100) 0 28 (90) 0
310 155 446 254 NA 138 NA 119 367.5 422
6 37.5 14 22 3 13.5
9
3 6.5 NA 74.5 NA NA 36 9 NA 22 15 NA 2 7 NA
14.0 11.0 45.0 NA 9 16
AE: adverse event; NA: not applicable. aFrom first dose of study treatment up to 30 days after last dose or initiation of subsequent anti-cancer therapy, whichever occurs earlier bVisual disturbances included the preferred terms blurred vision and reduced visual acuity. cHypertension (standardized MEDRA queries) group of preferred terms.
.
(n=135) (n=123)
(n=112)
Figure 4. Safety and tolera- bility of ibrutinib over time. Rate of grade ≥3 AEs, dis- continuations due to AEs, and dose reductions over dif- ferent periods of time. AE, adverse events.
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haematologica | 2018; 103(9)