Page 155 - 2018_11-Haematologica-web

Safety of obinutuzumab with/without chemotherapy in CLL
continued from previous page.
Second malignancies Second malignancies† TLS
Hemorrhagic events HBV reactivation Cardiac events
PML
6 (4.8) 5 (4.0) 2 (1.6) 1 (0.8) 0
3 (2.4)
9 (4.7) 8 (4.1) 5 (2.6)
7 (6.1) 6 (5.3) 5 (4.4)
39 (7.2) 37 (6.9) 50 (9.3)
0 0 8(1.5)
0 0 1(0.2)‡ 6 (3.1) 3 (2.6) 20 (3.7)
1(0.8) 0 0 0
G: obinutuzumab; mono: monotherapy; FC: fludarabine-cyclophosphamide; Clb: chlorambucil; benda: bendamustine; 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 Regulatory Activities; n: number; h: hour. *Neutropenia and thrombocytopenia selec- tion was via their MedDRA basket dataset subgroups; infection selection was via the MedDRA 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’ starting six months after the first study drug intake; hemorrhagic event selec- tion was via the MedDRA basket dataset subgroup; HBV reactivation was defined as any AE with the preferred term containing ‘hepatitis B’ or ‘hepatitis acute’ that was addi- tionally assessed as HBV reactivation via medical review; and cardiac event selection was via the MedDRA system order class ‘Cardiac Disorders’. †Second malignancy selec- tion: standardized MedDRA query (SMQ),including malignant and unspecified tumors (wide) starting 6 months after the first study drug intake, ‡Three patients had HBV reac- tivation in total, 2 of which were grade <3.
tion were IRRs (65.4%; grade ≥3, 19.9%), neutropenia (61.7%; grade ≥3, 53.7%), infections (53.7%; grade ≥3, 20.1%), thrombocytopenia (32.3%; grade ≥3, 16.8%), car- diac events (11.2%; grade ≥3, 3.3%), second malignancies [(8.4% by MedDRA system organ class, including grade ≥3, 6.3% (listed in full in Online Supplementary Table S2); 7.7% by standardized MedDRA query, including grade ≥3, 5.8%)], hemorrhagic events (7.1%; grade ≥3, 0.9%), TLS (6.4%; all grade ≥3 by definition), hepatitis B virus reactivation (0.3%; grade ≥3, 0.1%) and progressive mul- tifocal leukoencephalopathy (0.1%; grade ≥3, 0.1%). The most commonly reported infections by preferred term were pneumonia (11.9%), bronchitis (6.9%), upper respi- ratory tract infection (6.9%), nasopharyngitis (5.4%) and urinary tract infection (5.4%). Grade ≥3 AESIs/AEPIs were reported at a similar frequency in first-line and R/R patients, and in first-line fit and unfit patients (Table 2); however, grade ≥3 TLS as an AESI was more common in first-line (7.3%) than in R/R patients (4.7%), and in first- line unfit (11.0%) than in first-line fit (4.1%) patients, and grade ≥3 infections as AESIs were more common in R/R patients (26.4%) than in first-line patients (16.7%).
TLS and IRRs
In the 62 patients with TLS events, 32 cases had labora- tory TLS and 30 had clinical TLS. Except for the 2 fatal cases described below, all TLS events resolved, none with sequelae, and there was no recurrence in any patient. In 41 of the 62 patients with TLS, no change in drug dosing was needed; treatment was interrupted or delayed in 17 patients and discontinued in 4 patients. A higher rate of TLS was observed in patients who received G-benda (9.3% overall; 6.6% in first-line fit, 14.4% in first-line unfit, and 6.8% in R/R patients) compared with the other regimens. Of the 2 patients with fatal TLS, one had bulky disease (age 79 years) and the other lymphadenopathy (age 45 years); the older patient also had chronic renal fail- ure at baseline. Both patients died in hospital after cardio- vascular events (sudden cardiac arrest and acute cardiac failure, respectively).
The frequency of IRRs was similar among the three dos- ing cohorts regardless of the IRR mitigation strategy used, although grade ≥3 IRRs, serious IRRs and IRRs leading to obinutuzumab discontinuation were more common in Cohort 3, along with TLS (as a preferred term) (Table 4).
Treatment response
Among first-line patients, the ORR in the ITT popula- tion at the final response assessment was 89.5% with G- FC, 82.4% with G-Clb, 81.8% with G-benda, and 63.5% with G-mono (Table 5); respective CR/CRi rates were 46.4%, 16.2%, 35.7% and 20.6%. In R/R patients, the ORR was 82.5% with G-FC, 54.3% with G-Clb, 72.8% with G-benda and 42.2% with G-mono; CR/CRi rates were 22.5%, 6.5%, 19.9% and 4.7%, respectively. Response rates for the 80 patients with 17p deletion are also shown in Table 5.
Discussion
GREEN evaluated the safety and tolerability of obinu- tuzumab, alone or combined with chemotherapy, in a broad CLL patient population, including first-line (fit and unfit) and R/R patients. The chemotherapy partner options that were available to GREEN investigators mirror those used in standard practice with anti-CD20 antibodies in CLL.11,12 Notably, GREEN represents the first large-scale report of safety data for obinutuzumab in CLL patients following its approval.
While GREEN was subject to certain limitations, the study provides valuable information on the overall safety profile of obinutuzumab, alone or combined with chemotherapy, in a broad CLL population. Importantly, obinutuzumab-based treatment demonstrated a generally manageable toxicity profile. Because of the non-compara- tive/non-randomized study design and potential investigator bias on patient allocation to cohorts/treat- ment, specific treatment regimens could not be compared directly. Furthermore, as treatment allocation was based on investigator’s choice, some subgroups were under-rep- resented [e.g. first-line unfit and fit patients treated with G-mono (n=32 and n=31, respectively), and R/R patients treated with G-FC (n=40) or G-Clb (n=46)], making it dif- ficult to draw conclusions from these small patient cohorts. However, this under-representation was not sur- prising given that most investigators followed current guideline recommendations for treatment.11,12 All patients were also analyzed as treated; for example, the G-mono group included patients who discontinued treatment after their first obinutuzumab administration due to AEs before receiving their planned chemotherapy regimen (n=23), as
haematologica | 2018; 103(11)
1895