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J.F. Seymour et al.
Post-progression survival and mortality by treatment arm
With a median follow up of 41 months, 56 out of 155 POD24 patients have died: 40 due to PD (G-chemo, n=15; R-chemo, n=25) and 16 for other reasons (n=4 and 12, respectively) (Online Supplementary Table S3). In addition, 16 out of 916 noPOD24 patients have died: one related to PD (allocated to the G-chemo arm but no study treatment received) and 15 for other reasons (G-chemo, n=9; R- chemo, n=6) (Online Supplementary Table S3). Post-progres- sion survival in POD24 patients was similar in the two treatment arms at a median post-progression follow up of 22.6 months (Figure 2 and Online Supplementary Table S4).
Survival and mortality by chemotherapy regimen, Follicular Lymphoma International Prognostic Index risk category, and treatment arm
Fewer POD24 events occurred in G-chemo versus R-chemo patients across all three chemotherapy regimen groups; in each treatment arm, the highest rate of events was observed in those treated with CVP. POD24 events were more common in patients with a high FLIPI score when compared with those patients with an intermediate or low FLIPI score (Online Supplementary Tables S5 and S6).
Histological transformation
Histologically confirmed transformation to more aggressive lymphoma was observed in 35 patients: 13 (2.2%) in the G-chemo arm and 22 (3.7%) in the R-chemo arm, predominantly in the first 24 months (n=30). In POD24 patients, transformation occurred in almost iden- tical proportions of G-chemo- and R-chemo-treated patients [11 out of 57 (19.3%) and 19 out of 98 (19.4%) patients, respectively]. Of 30 patients (19.4%) with trans- formation in the first 24 months, 16 died during study fol- low up (n=8 in each treatment arm). Of the 88 patients in the noPOD24 group with PD events after the 24-month time point, only 5 (5.7%) had transformations [G-chemo, 2 of 40 (5.0%); R-chemo, 3 of 48 (6.3%)]. Cumulative inci- dence data and lymphoma types at transformation are presented in the Online Supplementary Results, Online Supplementary Table S7 and Online Supplementary Figure S2.
New anti-lymphoma treatment
New anti-lymphoma treatment (NALT) of any type was received by 100 of 155 patients (64.5%) with a POD event in the first 24 months after randomization (G-chemo, n=37; R-chemo, n=63) and by 24 of 88 patients (27.3%) with a POD event later than the 24-month time point (G-chemo, n=11; R-chemo, n=13) (Online Supplementary Table S8). A cumulative incidence plot of time from PD to NALT for those with PD before and after 24 months showed that 49.7% (95%CI: 41.3-57.5%) of POD24 patients started NALT within three months of PD, com- pared with 19.4% (95%CI: 11.2-29.3%) of those who pro- gressed after 24 months (Online Supplementary Figure S3). Details of the type of NALT received after PD according to the timing of POD are provided in the Online Supplementary Results and Online Supplementary Table S8.
Time-dependent mortality analysis
Time-dependent regression analysis showed that, at any given time during study follow up, the risk of death was considerably greater following a POD24 event than in those without a POD24 event (stratified HR, 25.5; 95%CI: 16.2-40.3%) (Online Supplementary Table S9).
Landmark analysis of overall survival and mortality
In 110 patients with POD24 events who were still alive at the 24-month landmark (4 censored patients excluded), the OS rate at two years after the landmark was 82.4% (95%CI: 74.2-91.3%), compared with 98.2% (95%CI: 97.1-99.2%) in 916 noPOD24 patients; the age-adjusted HR for OS in this 2-year window was 12.2 (95%CI: 5.6-
Table 1. Baseline disease and patients’ characteristics in POD24 and noPOD24 subgroups with at least 24 months’ response follow up.
Characteristica
PODeventwithin NoPODevent
Age, years
first 24 months (n=155)
58 (31-84)
49 (31.6) 87 (56.1)
11/154 (7.1) 46/154 (29.9) 97/154 (63.0)
80/155 (51.6)
57 (36.8) 63 (40.6) 35 (22.6) 0
within first 24 months (n=916)
59 (23-85)
280 (30.6) 415 (45.3)
77/910 (8.5) 327/910 (35.9) 506/910 (55.6)
468/908 (51.5)
353 (38.5) 437 (47.7) 117 (12.8) 9 (1.0)
1.45 (0.1-129.3) (n=914)
192 (21.0) 354 (38.6) 370 (40.4)
93/890 (10.4) 452/890 (50.8) 345/890 (38.8)
248/912 (27.2) 51/912 (5.6) 18/912 (2.0)
5128.5
(235.2-62,725.0) 392/914 (42.9)
478 (52.2)
438 (47.8)
526 (57.4) 305 (33.3) 85 (9.3)
Aged ≥65 years
Male
Ann Arbor stage at diagnosis (n=1064) I or IIb
III
IV
Bone marrow involvement
(n=1063)
Grade of FL 1
2a 3
Other (incl. missing)
Time from diagnosis to randomization, months
(n=1068)
FLIPI
Low (0-1) Intermediate (2) High (≥3)
FLIPI-2 (n=1043) Low (0) Intermediate (1-2) High (≥3)
Elevated serum lactate dehydrogenase >ULN
>1.5 × ULN
>2 × ULN
(n=1069)
Randomized antibody treatment Obinutuzumab
Rituximab
Allocated chemotherapy treatment Bendamustine
CHOP
CVP
1.35 (0.0-83.5) (n=154)
25 (16.1) 46 (29.7) 84 (54.2)
6/153 (3.9) 68/153 (44.4) 79/153 (51.6)
79/154 (51.3) 26/154 (16.9) 10/154 (6.5)
6531
(514.0-80,720.0) 79/155 (51.0)
57 (36.8)
98 (63.2)
76 (49.0) 55 (35.5) 24 (15.5)
Investigator-assessed SPD
of ≤ 6 target lesions, mm2 Bulky disease ≥7 cm
n: number; CHOP: cyclophosphamide, doxorubicin, vincristine+prednisone; CVP: cyclophosphamide, vincristine+prednisone; FL: follicular lymphoma; FLIPI: Follicular Lymphoma International Prognostic Index; POD: progressive disease or death due to progressive disease; POD24: progressive disease or death due to progressive disease events in the 24 months after randomization; SPD: sum of products of 2 longest per- pendicular dimensions for ≤6 target lesions; ULN: upper limit of normal. aData are n (%), n/N (%), or median (range). b18 patients were randomized to study treatment after being assessed as stage II or above by the investigators, meeting study eligibility criteria, but were reassessed as stage I after medical review. Staging data were missing for 7 patients (POD24, n=1; noPOD24, n=6).
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