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V. Leblond et al.
Table 4. Summary of infusion-related reactions according to the approach used to prevent or mitigate these events in first-line patients.
N (%)*
Any IRR
Chills
Pyrexia
Nausea
Vomiting
TLS
Hypertension Hypotension Thrombocytopenia Dyspnea Hypersensitivity Chest discomfort Flushing
Hot flush
Anemia
Oxygen saturation decreased Hyperhidrosis
Headache
Tremor
Rash
AST increased
ALT increased
Feeling hot
Dizziness
Cohort 1 (n=237)†
141 (59.5)
49 (20.7) 45 (19.0) 24 (10.1) 16 (6.8) 14 (5.9) 12 (5.1) 12 (5.1) 8 (3.4)
7 (3.0) 7 (3.0) 6 (2.5) 5 (2.1) 5 (2.1) 5 (2.1) 5 (2.1) 5 (2.1) 3 (1.3) 3 (1.3) 2 (0.8) 2 (0.8) 2 (0.8) 2 (0.8) 1 (0.4)
Cohort 2 (n=228)‡
153 (67.1)
41 (18.0) 24 (10.5) 5 (2.2)
26 (11.4) 42 (18.4) 34 (14.9) 14 (6.1) 6 (2.6) 10 (4.4) 31 (13.6) 16 (7.0) 17 (7.5) 1 (0.4) 10 (4.4) 8 (3.5)
1 (0.4) 3 (1.3) 3 (1.3) 7 (3.1) 12 (5.3) 5 (2.2) 6 (2.6) 8 (3.5) 6 (2.6) 5 (2.2) 5 (2.2)
Cohort 3 (n=151)§
96 (63.6)
37 (24.5) 23 (15.2) 12 (7.9)
13 (8.6) 28 (18.5) 7 (4.6) 4 (2.6) 15 (9.9) 5 (3.3) 4 (2.6) 9 (6.0) 9 (6.0) 1 (0.7) 3 (2.0) 2 (1.3) 1 (0.7) 5 (3.3) N/R
1 (0.7) 5 (3.3) N/R
4 (2.6) 6 (4.0) 6 (4.0) 1 (0.7) N/R
Grade ≥3 IRRs
Serious IRRs
IRRs leading to any obinutuzumab discontinuation
IRRs (reported by ≥2% patients in any cohort, any grade by preferred term)
45 (19.0) 26 (11) 4 (1.7)
IRR: infusion-related reaction; TLS: tumor lysis syndrome; N/R: not reported; AST: aspartate aminotransferase; ALT: alanine aminotransferase; G: obinutuzumab; mono: monother- apy; FC: fludarabine-cyclophosphamide; Clb: chlorambucil; benda: bendamustine; n: number; h: hour. Patients within each cohort could have received any of the permitted immunochemotherapy regimens: G-mono (Cohort 1, n=15; Cohort 2, n=25; Cohort 3, n=20), G-FC (Cohort 1, n=61; Cohort 2, n=57; Cohort 3, n=33), G-Clb (Cohort 1, n=12; Cohort 2, n=40; Cohort 3, n=16) or G-benda (Cohort 1, n=149; Cohort 2, n=106; Cohort 3, n=82). *Sixteen previously untreated patients from the safety population were excluded from the cohort analysis as they did not receive treatment as planned (n=15) or were not assigned to any cohort (n=1). †Cycle 1 day 1 dose of obinutuzumab over two days: 25 mg (12.5 mg/h) + 975 mg (50-400 mg/h). ‡Cycle 1 day 1 dose of obinutuzumab over two 2 days: 100 mg (25 mg/h) + 900 mg (50-400 mg/h) with oral dexamethasone 20 mg (or equivalent) 12 h pre-dose. §Cycle 1 day 1 dose of obinutuzumab over two days: doses and infusion rates as in Cohort 1 with pre-medication scheme as in Cohort 2.
well as patients who were only ever planned to receive single-agent obinutuzumab. As such, patients in this sub- group had a higher rate of AEs and discontinuations due to AEs than would be expected for patients treated with G-mono, based on previous single-agent studies.4,5
The safety data from GREEN were generally in line with the safety profile for obinutuzumab-based immunochemotherapy previously observed in patients treated for CLL1-7 and non-Hodgkin lymphoma.13-18 Common AEs included IRRs (typically mild or moderate events observed almost exclusively during the first obinu- tuzumab infusion), infections and hematologic toxicities. The higher frequency of grade ≥3 AEs (including infec- tions) and SAEs compared with the pivotal CLL11 study (which enrolled first-line patients with co-existing condi- tions2,3) likely reflects the broader patient population, and inclusion of more heavily pre-treated R/R patients. As expected, R/R patients in GREEN experienced more AEs and more deaths due to AEs or disease progression com-
pared with first-line patients. While the rate of deaths due to AEs, particularly infections/sepsis, in first-line patients was higher than expected, it is reflective of that seen in clinical practice (rather than in classical clinical trials), where a broad range of patients and difficult-to-treat infections are also encountered. Predictably, there was a higher rate of SAEs and fatal AEs in first-line unfit versus fit patients; an observation that may have been due to the general health of the patients rather than the treatment regimen(s) received.
The high reported rates of AESIs/AEPIs, including neu- tropenia, thrombocytopenia, IRRs, infections and TLS, may have resulted from the inclusion of R/R and unfit patients who may be more vulnerable to the adverse effects of treatment, although this did not appear to markedly affect grade ≥3 AESI/AEPI rates. Furthermore, despite the additional risk minimization measures, the rate of IRRs, including TLS, remained relatively high, par- ticularly in Cohort 3. During the initial stages of recruit-
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haematologica | 2018; 103(11)