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J.F. Seymour et al.
OS in the GALLIUM study. However, this is not unexpect- ed with current follow up given the available salvage ther- apies.
Our results suggest that POD24 events are more com- mon in patients treated with CVP compared with patients treated with CHOP or bendamustine. However, it is diffi- cult to draw firm conclusions from these results, as patient numbers within the subgroups are low. Furthermore, sta- tistical comparisons across chemotherapy regimens were not performed, as chemotherapy allocation was not ran- domized; rather the chemotherapy treatment was select- ed by the investigator, with all patients at each individual center receiving the same regimen.
As previously reported, fewer patients with FL in the G- chemo arm than in the R-chemo arm started NALT during GALLIUM (estimated proportions without NALT at three years: 87% and 81%, respectively).9 However, the current analysis shows that patients who progressed early (within 24 months of randomization) were much more likely to receive NALT within three months of progression than patients who had PD later, irrespective of treatment arm.
Transformation to a more aggressive lymphoma at the time of PD occurred in just under 20% of those patients with POD24 events, with no discernible difference in these proportions by treatment arm. However, transfor- mations appear to be much less frequent in patients with later progression; at the current data cutoff, only 5.7% of patients in the noPOD24 group experienced transforma- tion.
The increase in mortality risk associated with POD24 in the current analysis (HR from stratified Cox regression analysis, 25.5) was much larger than in a recent pooled analysis of POD24 in 5453 patients from 13 clinical trials (HR for OS, 5.24)5 and the National LymphoCare Study (NLCS) analysis by Casulo et al.,4 which reported an HR of 8.1 in an exploratory analysis that used the same method as in the current analysis, i.e. POD24 as a time-varying co- variate and adjusting for FLIPI. Importantly, the follow-up duration in our analysis was shorter than in the NLCS (medians, 3.4 and 7 years, respectively); as the follow-up
duration in GALLIUM increases, the HR value is likely to fall, as we showed that the risk of death is higher for patients with earlier progression. However, survival data for the first two years of follow up in our study look remarkably similar to the NLCS analysis. In GALLIUM, the proportion of POD24 patients surviving at two years after progression was 66% (95%CI: 58.3-73.9%) whereas for the noPOD24 group, the proportion surviving at two years after the 24-month landmark was 98.2% (95%CI: 97.1-99.2); in NLCS, the corresponding proportions were 68% (95%CI: 58.2-76.3) and 97% (95%CI: 94.6-98.1), respectively.4
Our findings also suggest that the earlier progression occurs, the greater the subsequent mortality risk. This subset of patients with FL in whom the disease follows a relatively aggressive clinical course may benefit from alter- native initial therapies. Therefore, identifying these patients is crucial. The baseline factor in the current analy- sis most strongly associated with risk of POD24 was serum LDH level, in line with previous studies that have identified LDH as a prognostic factor for progression in patients with FL.12,13 Other factors associated with greater POD risk were FLIPI risk group, disease stage and histo- logical grade, male sex, and treatment with CVP chemotherapy; although the extent of difference in POD risk accounted for by these was not as great as the influence of anti-CD20 antibody treatment.
Promising prospective identification of patients with a high risk of early PD events has been achieved by using the m7-FLIPI, a clinicogenetic risk model incorporating the impact of mutations in the genes EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11.14 The m7-FLIPI had higher predictive accuracy for POD24 than either the FLIPI or another specific clinicogenetic risk model, the POD24 Prognostic Index (POD24-PI), in an analysis of 258 patients from two independent cohorts.10 A new 23-gene expression model was also reported to predict early pro- gression.15 Additionally, TP53 mutation status has been evaluated as a prognostic factor in patients with FL and found to be significantly correlated with shorter PFS, OS,
Figure 2. Overall survival in POD24 patients post-pro- gression by treatment arm. Shaded sections of lines show 95% Hall-Wellner confidence bands for the peri- od during which patients died. G-chemo: obinutuzum- ab plus chemotherapy; R-chemo: rituximab plus chemotherapy; N: number. POD24: progressive dis- ease or death due to progressive disease events in the 24 months after randomization.
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haematologica | 2019; 104(6)