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Safety of obinutuzumab with/without chemotherapy in CLL
Table 5. Summary of response at the final response assessment according to treatment (intent-to-treat population).
All patients (N=972) First-line, % (95% CI)
ORR
CR (including CRi) R/R, % (95% CI)
ORR
CR (including CRi)
Patients with 17p deletion* (n=80)
First-line, n/N (%) ORR
CR (including CRi) R/R, n/N (%)
ORR
CR (including CRi)
G-mono (n=127)
63.5 (50.4-75.3) 20.6
42.2 (29.9-55.2) 4.7
1/2 (50.0) 0/2
2/6 (33.3)
0/6
G-FC (n=193)
89.5 (83.6-93.9) 46.4
82.5 (67.2-92.7) 22.5
1/5 (20.0) 1/5 (20.0)
5/6 (83.3)
0/6
G-Clb (n=114)
82.4 (71.2-90.5) 16.2
54.3 (39.0-69.1) 6.5
5/7 (71.4) 1/7 (14.3)
5/7 (71.4)
0/7
G-benda (n=538)
81.8 (77.4-85.8) 35.7
72.8 (65.9-79.0) 19.9
12/20 (60.0) 5/20 (25.0)
12/27 (44.4)
3/27 (11.1)
n/N: number; G: obinutuzumab; mono: monotherapy; FC: fludarabine-cyclophosphamide; Clb: chlorambucil; benda: bendamustine; CI: confidence interval; ORR: overall response rate; CR: complete response; CRi: complete response with incomplete marrow recovery; R/R: relapsed refractory. *17p deletion status was determined by fluorescence in situ hybridization.
ment into Cohort 3, up-dated and expanded definitions of patients at risk of TLS and additional TLS risk mitigation measures (for patients treated with G-benda) were implemented. Nonetheless, the TLS rate in GREEN, including 2 fatal cases, highlights the need for careful risk assessment, prophylaxis and monitoring, particularly in unfit patients [with a CIRS score of >6 and/or reduced renal function (CrCl <70 mL/min)] treated with the G- benda regimen, in whom a high incidence of TLS (14.4%) was observed. It should be noted that, because of the non- randomized study design, it is impossible to conclude whether the increase in TLS seen in G-benda-treated patients in this trial was due to the chemotherapy partner or to differences in patients’ characteristics compared with the other treatment cohorts. The current labeling states that any patients with a high tumor burden, high circulat- ing lymphocyte count (>25x109/L) or renal impairment, who are considered at greater risk for TLS, should receive appropriate TLS prophylaxis with anti-hyperuricemics (e.g. allopurinol or rasburicase) and hydration prior to obinutuzumab infusion.8,9 Pre-treatment should then be followed by intensive monitoring of clinical signs/symp- toms and laboratory parameters during the first few days of treatment. For IRRs, it is recommended that patients are pre-medicated with an intravenous corticosteroid, acetaminophen and antihistamine, and then monitored closely during obinutuzumab infusion.8,9 Antimicrobial prophylaxis is advised for patients with prolonged severe neutropenia to prevent infection; granulocyte colony- stimulating factors should be considered in case of grade ≥3 neutropenia.
All four obinutuzumab-based immunochemotherapy regimens appeared manageable in both first-line (fit or unfit) and R/R patients with CLL. G-FC, which was the most intensive regimen, was associated with a high rate of grade ≥3 neutropenia, but this did not translate into an ele- vated incidence of infection; an observation that may be explained by the underlying fitness of patients who received G-FC. Fitness may also explain the low rate of
deaths due to AEs in G-FC-treated patients.
Investigation of strategies to prevent or mitigate IRRs
during the first infusion of obinutuzumab was inconclu- sive, with rates comparable to those reported for G-Clb in CLL11 (grade ≥3, 21%).2 Despite efforts to minimize IRRs using approaches whereby the dosage of obinutuzumab was modified, the infusion rate slowed and/or additional corticosteroid was given as pre-medication, no one strategy appeared better than another. A recent nursing review of all IRR data from GREEN and CLL11 concluded that IRRs observed with obinutuzumab during the first infusion are generally manageable in CLL patients through treatment interruptions, but management could be improved considerably with extra vigilance during the first infusion.19
Analysis of anti-leukemic activity revealed high response rates across all settings and regimens, thus sup- porting findings from previous studies, including CLL11 and phase I/II trials, which have evaluated the G-Clb, G-FC, G-benda and G-mono regimens.1-7 Response rates tended to be higher in first-line versus R/R patients, and in patients who received combination versus single-agent obinutuzumab therapy. The response rates also compared favorably with those reported for rituximab-containing immunochemotherapy (rituximab plus Clb, benda or FC) in CLL.2,3,20-24 While longer-term data are required to con- firm the efficacy of obinutuzumab-based therapy in GREEN, they do suggest that these regimens are clinically active and associated with a generally manageable toxicity profile.
In conclusion, in the largest obinutuzumab patient cohort analyzed to date, the GREEN primary safety data were in line with the safety and tolerability profile previ- ously observed in patients receiving obinutuzumab-based treatment for CLL. Toxicities were generally manageable and response rates were encouraging in this broad popu- lation of CLL patients, including previously untreated, fit and unfit patients and those with R/R disease. Based on these data, future trials are warranted.
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