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A.R. Mato et al.
Discussion
Table 2. Reasons for Ibrutinib discontinuation.
In the largest reported series of ibrutinib-treated CLL patients so far, we found that the median progression-free survival was 35 months. Interestingly, this outcome was comparable between previously untreated and relapsed/refractory patients. Our observed progression- free survival of 35 months is shorter than that previously described in clinical trials in which the median progres- sion-free survival was 52 months in relapsed/refractory disease.9 These observations suggest that outcomes vary when comparing clinical trial patients and those treated in clinical practice, underscoring the need to better under- stand outcomes and toxicities in a real-world setting.
Patient-specific factors, including molecular prognostic markers, performance status and prior therapies, may par- tially account for these discrepancies. Our front-line cohort of patients had a greater number of molecular abnormalities than typically seen in the treatment-naïve population; 37% of patients had del17p and 40% had a complex karyotype. Both features are associated with an inferior progression-free survival.22 For the relapsed cohort, patients may have received prior idelalisib which could have affected their subsequent response to ibrutinib; notably, this was prohibited in the earliest clinical trials of ibrutinib.11
At a median follow-up of 17 months, overall discontin- uation in our study was high at 41%, suggesting that ibru- tinib discontinuation is an emerging issue in clinical prac- tice. This mirrors the high overall discontinuation patterns seen in longer follow-up studies of clinical trial patients,6-9 particularly the 51% estimated discontinuations seen at a median follow-up of 3.4 years by Woyach et al.8 In addi- tion, 15% of front-line and 20% of relapsed ibrutinib- treated patients required a dose reduction, which is signif- icantly higher than the 4% of patients requiring dose reduction due to adverse events in the RESONATE trial due to adverse events (4%).2
Early ibrutinib trials suggested that progressive disease was the cause of the majority of cases of discontinuation,2 a pattern that has persisted in many,6,8,9 but not all,5,7,10 stud- ies including longer follow-up periods. Surprisingly, our results demonstrate that intolerance (50.2% in the relapsed/refractory setting, 63% in the front-line setting), rather than progressive disease (21% in the relapsed/refractory setting, 16% in the front-line setting), accounts for the majority of cases of discontinuation. Similar findings were previously noted in a smaller series reported by our group.11 With respect to adverse events leading to discontinuation, these values are greater than those reported in a pooled analysis from the phase III relapsed RESONATE and front-line RESONATE-2 studies in which the discontinuation rate was 10%.23 Because at least 50% of discontinuations are due to intolerance rather than progression of disease, it is unlikely that these patients harbor ibrutinib resistance mutations and, there- fore, should likely be sensitive to alternate kinase inhibitors with different side effect profiles. Two clinical trials are being conducted at this time studying umbralisib (NCT02742090) and acalabrutinib (NCT02717611) in kinase inhibitor-intolerant patients.
For the first time we have established a timeline associ- ated with time to discontinuation due to specific ibrutinib- related toxicities. Similar to the experience with idelalisib where specific toxicities appear to occur after different
Reason for ibrutinib discontinuation
Toxicity
Ibrutinib in front-line (n=19)
63.1% (n=12)
15.8% (n=3) 5.3% (n=1) 10.5% (n=2) 5.3% (n=1) 0
0
0
0
Ibrutinib in relapse (n=231)
50.2% (n=116)
20.9% (n=49) 12.1% (n=28) 6.7% (n=15) 4.6% (n=10) 3.3% (n=8) 0.8% (n=2) 0.8% (n=2) 0.4% (n=1)
CLL progression
Other/unrelated death
Physician’s or patient’s preference RT DLBCL
Stem cell transplantation/CAR T-cell Financial concerns
Secondary malignancy
RT Hodgkin lymphoma
878
CLL: chronic lymphocytic leukemia; RT DLBCL: Richter transformation to diffuse large B-cell lymphoma; CAR T-cell: chimeric antigen receptor T-cell); RT: Richter transforma- tion.
periods of time on treatment,24 these data may be of value in developing monitoring strategies for specific toxicities and educational material related to ibrutinib toxicities.
Reasons for discontinuation also varied by line of thera- py. Our analysis revealed a strikingly higher number of discontinuations due to toxicity in the front-line setting; 63% compared to the previously reported 9% in RES- ONATE-2.4 Similar findings, although not as marked, were noted in the relapsed setting; 50% of patients in our analysis discontinued therapy due to intolerance com- pared to 12% discontinuing due to adverse events in the 4-year follow-up of RESONATE data.6 In line with prior reports, we found that atrial fibrillation and pulmonary complications were common reasons for discontinuation. Arthralgias and rash were frequently noted as well, partic- ularly in treatment-naïve patients. The higher discontinu- ation rate for toxicity may reflect lack of physicians’ com- fort in toxicity management, a higher incidence of toxicity in clinical practice, differences in patients’ comorbidities and age, or a lower threshold for discontinuation given an increasing number of available alternative treatment choices. This may be in contrast to the limited number of therapies available to ibrutinib-treated patients in early clinical trials. In a recent series by Lampson et al. of treat- ment-naïve patients treated with idelalisib plus ofatu- mumab adverse events (particularly liver toxicity) were the most common reasons for discontinuation.25 This study suggested that younger patients’ age and intact immunity may lead to autoimmune treatment-related tox- icities in treatment-naïve patients.25
Progression of disease was the second most common indication for ibrutinib discontinuation. Sixteen percent of previously untreated patients experienced progression compared to 10% progressions/deaths at an 18-month fol- low-up in the front-line RESONATE-2 study.4 This differ- ence may be related to the exclusion of patients with del17p from the RESONATE-2 study.4 Rates of discontin- uation due to progression in the relapsed population in our cohort were more comparable with the 27% found in the 4-year follow-up of the RESONATE study.6 Outcomes of patients in our series who discontinued therapy due to toxicity were superior to those of patients who discontin- ued due to progressive disease.
We also considered limitations in the study design. Conducted by physicians and research coordinators from several institutions in a retrospective manner, data collec-
haematologica | 2018; 103(5)