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S. Rule et al.
Table 1. Patient and disease characteristics at the start of Maintenance II.
Table 2. Summary of adverse events occurring during extended main- tenance.
Number of patients (%)
Patients with ≥1 event, n (%) ≥1 AE
Grade ≥3 AE affecting ≥1% patients in either arm
Neutropenia
Pneumonia
Hypertension
Neutrophil count decreased Acute kidney injury
Febrile neutropenia
Leukopenia
Myelodysplastic syndrome Upper respiratory tract infection Sepsis
Thrombocytopenia Vomiting
Serious AE affecting ≥1% patients in either arm
Pneumonia
Acute kidney injury
Appendicitis
Bronchitis
Fall
Febrile neutropenia Myelodysplastic syndrome Neutropenia
Sepsis
Squamous cell carcinoma of skin
Grade 5 (fatal) AE
AE leading to treatment discontinuation
R-SC: subcutaneous rituximab; AE: adverse event.
R-SC n=138
111 (80.4) 48 (34.8)
12 (8.7) 7 (5.1) 3 (2.2) 3 (2.2) 0
2 (1.4) 0
1 (0.7) 0
2 (1.4) 1 (0.7) 2 (1.4)
31 (22.5)
8 (5.8) 0
2 (1.4) 0
0
2 (1.4) 1 (0.7) 0
2 (1.4) 1 (0.7)
5 (3.6) 10 (7.2)
Observation n=138
80 (58.0) 40 (29.0)
8 (5.8) 4 (2.9) 0
0
2 (1.4) 0
2 (1.4) 2 (1.4) 2 (1.4) 2 (1.4) 2 (1.4) 0
32 (23.2)
4 (2.9) 2 (1.4) 0
2 (1.4) 2 (1.4) 0
2 (1.4) 2 (1.4) 2 (1.4) 2 (1.4)
5 (3.6) 0
Characteristic
Median age, years (range)
Male, n (%)
Ann Arbor stage at diagnosis, n/N (%) I
II III IV
FLIPI score, n (%) Low
Intermediate High
Bone marrow involvement, n (%)
Median lactate dehydrogenase, ukat/L (range)
Type of NHL at screening, n (%) FL
WM/LPL MZL
Induction chemotherapy regimen Bendamustine
CHOP
CVP
Other
R-SC n=138
64 (26-89) 74 (53.6)
13/134 (9.7) 12/134 (9.0) 21/134 (15.7) 88/134 (65.7)
25 (34.2) 22 (30.1) 26 (35.6)
60 (43.5) 3.26 (1.30-11.77)
73 (52.9) 28 (20.3) 36 (26.1)
80 (58.0) 20 (14.5) 26 (18.8) 12 (8.6)
Observation n=138
65 (34-86) 68 (49.3)
8/135 (5.9) 19/135 (14.1) 30/135 (22.2) 78/135 (57.8)
28 (36.4) 27 (35.1) 22 (28.6)
59 (42.8) 3.32 (1.40-9.15)
77 (55.8) 25 (18.1) 35 (25.4)
79 (57.2) 19 (13.8) 22 (15.9) 18 (13.0)
R-SC: subcutaneous rituximab; FLIPI: Follicular Lymphoma International Prognostic Index; NHL: non-Hodgkin lymphoma; FL: follicular lymphoma; WM/LPL: Waldenström macroglobulinemia/lymphoplasmacytic lymphoma; MZL: marginal zone lymphoma; CHOP: cyclophosphamide, doxorubicin, vincristine and prednisone; CVP: cyclophos- phamide, vincristine and prednisone.
were seen in more than one patient (2 patients each). At least one treatment-emergent adverse event leading to death was reported in eight patients (1.6%).
Adverse events were the most common reason for death during Induction and Maintenance I (40/692; 5.8% and 32/494; 6.5%, respectively). Sepsis was the most frequent event leading to death during these phases (7 patients [1.0%] and 2 patients [0.4%], respectively). Rituximab- related sepsis was associated with death in four patients (0.6%) during Induction and one patient (0.2%) during Maintenance I.
Maintenance II
The original wording of the study protocol led to differ- ences in adverse event reporting between the rituximab and observation arms in Maintenance II (see the Online Supplementary Appendix for details). After a protocol amendment to permit retrospective collection of adverse events of grade ≥3 during this phase (allowing adverse event reporting to be consistent between the rituximab and observation arms), neutropenia and pneumonia were the most frequently reported grade ≥3 adverse events in both the rituximab arm (8.7% and 5.1%, respectively) and the observation arm (5.8% and 2.9%, respectively) (Table 2). However, when looking at median neutrophil counts (based on laboratory data), similar values were observed in both treatment arms in Maintenance II. There were three grade ≥3 infusion/administration-related reactions (1 each of lymphopenia, urinary tract infection and hypertensive crisis). There were no reports of grade ≥3 rash, erythema or skin reaction during Maintenance II. The incidence of seri-
ous adverse events was similar for both arms (22.5% with rituximab and 23.2% for observation) (Table 2), with pneu- monia (5.8% and 2.9%, respectively) and sepsis (1.4% for both arms) being most commonly reported. All fatal adverse events (5 in each arm) were considered unrelated to study treatment by the investigators. These events were pneumonia, septic shock, acute myocardial infarction, Crohn disease, abdominal infection and diverticulitis (same patient) in the rituximab arm, and acute myeloid leukemia, cardiopulmonary failure, ventricular tachycar- dia, pneumonia and lung disorder in the observation arm. Five further deaths in the rituximab arm and two in the observation arm were due to disease progression; a single additional death with unknown cause was recorded in the observation arm.
There were no safety concerns or new signals related to hematology, biochemistry or immunological parameters in any phase of the study, and no meaningful changes from baseline in vital signs. There were also no unexpected changes from baseline in worst-on-treatment ECOG scores, and no noteworthy differences in score shifts between the rituximab and observation arms in Maintenance II.
Efficacy
The overall response rate at the end of Induction was 84.7% (95% CI: 81.1–87.3), and was similar across differ- ent chemotherapies: 86.4% (95% CI: 82.7–89.5) for ben- damustine; 87.2% (95% CI: 78.3–93.4) for CHOP; 84.1% (95% CI: 74.4–91.3) for CVP; and 76.9% (95% CI: 67.6–
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