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Safety of obinutuzumab with/without chemotherapy in CLL
continued from previous page.
Thrombocytopenia TLS
Second malignancies Second malignancies† Hemorrhagic events HBV reactivation Cardiac events
47 (13.9) 14 (4.1) 12 (3.5) 12 (3.5) 2 (0.6) 0
9 (2.7)
48 (16.5) 32 (11.0) 23 (7.9) 20 (6.9) 2 (0.7) 1 (0.3) 14 (4.8)
95 (15.1) 46 (7.3) 35 (5.6) 32 (5.1) 4 (0.6) 1 (0.2) 23 (3.7)
68 (19.9) 16 (4.7) 26 (7.6) 24 (7.0) 5 (1.5) 0
9 (2.6)
163 (16.8) 62 (6.4) 61 (6.3) 56 (5.8) 9 (0.9)
1 (0.1)
32 (3.3)
PML 0 0 0 1(0.3) 1(0.1)
R/R: relapsed/refractory; AE: adverse event; TLS: tumor lysis syndrome; AML: acute myeloid leukemia; SAE: serious adverse event; AESI: adverse event of special interest; AEPI: adverse event of particular interest; IRR: infusion-related reaction; HBV: hepatitis B virus; PML: progressive multifocal leukoencephalopathy; MedDRA: Medical Dictionary for RegulatoryActivities;n:number;h:hour.*NeutropeniaandthrombocytopeniaselectionwasviatheirMedDRAbasketdatasetsubgroups;infectionselectionwasviatheMedDRA system order class ‘Infections and Infestations’; IRRs were defined as any AE occurring during or within 24 h of obinutuzumab infusion and considered related to obinutuzumab; TLS and PML were defined by their preferred terms; second malignancy selection was via the MedDRA system organ class ‘Neoplasms Benign, Malignant, and Unspecified’ start- ing six months after the first study drug intake; hemorrhagic event selection was via the MedDRA basket dataset subgroup; HBV reactivation was defined as any AE with the pre- ferred term containing ‘hepatitis B’ or ‘hepatitis acute’ that was additionally assessed as HBV reactivation via medical review; and cardiac event selection was via the MedDRA system order class ‘Cardiac Disorders’. †Second malignancy selection [standardized MedDRA query (SMQ)], including malignant and unspecified tumors (wide) starting six months after the first study drug intake.
≥5 cm but <10 cm with lymphocytes ≥25x109/L) and were classified as being at increased risk of TLS. Other criteria also used to determine TLS risk are specified in the Online Supplementary Appendix. Median number of prior lines of therapy received by R/R patients was 1.0 (range 1.0-3.0) (Online Supplementary Table S1).
Treatment exposure
Treatment received was [G-mono; n=126 (12.9%); first- line n=62, R/R n=64), G-FC (n=193 (19.9%); first-line n=153, R/R n=40), G-Clb (n=114 (11.7%); first-line n=68, R/R n=46) and G-benda (n=538 (55.3%); first-line n=347, R/R n=191]. Seven hundred and eighty-nine (81.2%) patients completed all six cycles of protocol-specified treatment and 182 (18.7%) discontinued treatment prema- turely. For all chemotherapy regimens, most patients received all six treatment cycles, i.e. 79.0% for benda, 84.5% for fludarabine, 85.0% for cyclophosphamide, and 76.3% for Clb. The main reasons for not completing study treatment were tolerability [including AEs; n=146 (15.0%)] and withdrawal of consent [n=15 (1.5%)].
Patients received a median of 9 (range 1-13) administra- tions of obinutuzumab, with 94.5% of patients receiving ≥90% of the planned dose. Median exposure time to obin- utuzumab was 20.4 (range 0.1-30.1) weeks.
Safety
Median observation time was 24.5 (range 0.3-37.8) months. In the safety analysis, the most frequent treat- ment-emergent AEs (any grade, by preferred term), occur- ring in ≥20% patients, were neutropenia (58.4%), pyrexia (32.0%), thrombocytopenia (31.2%), nausea (27.8%), and anemia (23.7%), with no notable differences between the first-line and R/R, or fit and unfit subgroups (Table 2). Overall, 23.4% of patients (n=227) had at least one prolonged cytopenia (any grade, occurring during the treatment period and still present >24 days after end of treatment) and 2.4% (n=23) had at least one late-onset cytopenia (any grade, occurring during the post-treatment follow-up period, ≥24 days after end of treatment). AEs were considered related to obinutuzumab in 85.8% of patients, most commonly neutropenia (40.2%), thrombo- cytopenia (22.6%), nausea (16.8%), pyrexia (23.2%) and anemia (11.1%). AEs leading to discontinuation of obinu-
tuzumab occurred in 14.6% of patients (first-line, 14.4%; R/R, 15.0%), with 5.4% discontinuing obinutuzumab due to IRRs, 3.9% due to neutropenia and 1.8% due to throm- bocytopenia. Treatment-emergent AEs by treatment are shown in Table 3.
Severe and serious AEs
Grade ≥3 AEs (the primary safety outcome of interest) occurred in 79.2% (95% CI: 75.8-82.3%) of first-line patients 78.5% (95% CI: 73.7-82.7%) in fit and 80.1% (95% CI:75.0-84.5%) in unfit patients and 82.4% (95% CI:77.9-86.3%) of R/R patients (Table 2). Among the 80.3% of patients overall who experienced grade ≥3 AEs (Table 2), the most frequent events were neutropenia (49.9%), thrombocytopenia (16.4%), anemia (9.6%) and pneumonia (9.0%). The most common SAEs were neutropenia (10.8%), pneumonia (9.5%) and febrile neutropenia (7.0%); the overall rate of SAEs in the safety population was 53.1% (Table 2). Grade ≥3 AEs and SAEs generally occurred at a similar frequency in first-line and R/R patients, and in first-line fit and unfit patients (Table 2), although the overall rate of SAEs was higher in first- line unfit (58.8%) than first-line fit (43.7%) patients.
Deaths
A total of 112 (11.5%) patients died during the study (12 within 28 days of their last dose of study treatment and 100 during the post-treatment follow-up period), primari- ly due to AEs [n=71 (7.3%)]. AEs leading to death were numerically more common in R/R patients [n=40 (11.7%)] than in first-line patients [n=31 (4.9%)]; fit n=13, unfit n=18). Pneumonia [n=12 (1.2%)]) and sepsis [n=5 (0.5%)]) were the most common AEs leading to death (Table 2). By treatment received, the lowest rate of death due to AEs was observed in the G-FC group [4.7% (9/193)] vs. 7.9% (9/114) in the G-Clb group, 7.8% (42/538) in the G-benda group and 8.7% (11/126) in the G-mono group)] (Table 3). Two patients died due to TLS (both in the first-line G-benda subgroup). Disease progression was listed as the primary cause of death in 43 (4.4%) patients.
Adverse events of special or particular interest
AESIs/AEPIs (any grade, as defined in the footnote to Table 2 and Table 3) reported in the overall safety popula-
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