Page 149 - 2019_11 Resto del Mondo-web

Rituximab maintenance therapy in CLL
is not recommended, these results (along with published data), suggest that maintenance treatment with a chemotherapy-free approach would improve long-term outcomes with acceptable toxicity. Furthermore, when MRD values were categorized into low (<0.01%), inter- mediate (0.01% to 1%) and high (>1%), low and interme- diate MRD levels were associated with longer PFS and OS following rituximab maintenance therapy (OS: P<0.0001) compared with higher MRD levels which were associated with significantly shorter PFS and OS (2.0 and 4.6 years, respectively), suggesting a favorable prognostic effect of MRD level for patients given rituximab maintenance ther- apy.
The relationship between undetectable MRD following frontline therapy and long-term outcomes, namely PFS and OS, has been investigated extensively in recent years. Nevertheless, to our knowledge, our study has one of the longest maintenance phases given to CLL patients in first remission. The German CLL Study Group (GCLLSG) updated the CLL8 trial which compared FCR to fludara- bine plus cyclophosphamide in untreated CLL patients. With a median follow-up of 5.9 years, the median PFS for the patients treated with FCR was 56.8 months, and the median OS was not reached in the FCR group.5,6 Furthermore, patients achieving undetectable MRD had a significantly longer PFS (64.0 months) while the median OS was not reached. The rituximab-containing arm pro- duced twice the number of patients achieving unde- tectable MRD.
In our study, median PFS and OS were not reached for patients with undetectable BM-MRD. We hypothesized that this difference was probably due to the source of samples. These data suggest that higher response rates and longer response durations could be expected by inten- sifying therapy through prolonged maintenance treatment with anti-CD20 immunotherapy.19 In addition, a com- bined analysis of the CLL8 and CLL10 trials showed that PFS was significantly longer in patients with undetectable MRD than in those with detectable MRD, despite being unaffected by the residual tumor load, thus supporting the prognostic significance of undetectable MRD in CLL patients.20 In another study Greil et al. enrolled patients who had achieved a CR, CRi or PR after first- or second- line rituximab-based chemoimmunotherapy.21 PFS was significantly longer in the rituximab maintenance arm (47.0 vs. 35.5 months, HR 0.50, 95% CI: 0.38-0.66; P<0.0001), suggesting that remission maintenance is an effective and safe option for CLL patients. In that study, MRD progression was documented more frequently in patients on observation than in those on rituximab main- tenance therapy (P<0.0001) and, interestingly, conversion to undetectable MRD status occurred more frequently in the rituximab maintenance arm (12 patients vs. 1 patient; P=0.003). Based on these data, it seems that maintenance therapy may improve the quality of remission in CLL sub- jects and prolong PFS.
Although firm conclusions are limited by the number of subjects in our trial, patients who discontinued chemoim- munotherapy after achieving undetectable BM-MRD CR at cycle 4 and continued with the maintenance phase had similar PFS and OS rates to those of patients who achieved undetectable MRD but continued treatment for all six cycles: 93.3% and 76.5% were alive at 7 years, while 80.0% and 60.6% were free of disease at 7 years, respec- tively. In the light of these data, it might be useful to eval-
uate the efficacy and efficiency of a strategy that adapts the duration of treatment to achieve undetectable MRD. Although a high rate of falsely negative MRD in peripher- al blood up to 12 months has been reported with ritux- imab-containing regimens (20-30%), our hypothesis was based on the predictive model published by Dimier et al., testing the effect of treatment on PFS using MRD as a sur- rogate endpoint.22 Thus, we only stopped FCR after four cycles when MRD was undetectable in both peripheral blood and BM. Although MRD-tailored therapy has not been validated prospectively, Strati et al. showed that patients who discontinued frontline FCR after achieving undetectable MRD after three cycles of treatment had similar PFS and OS to those who achieved undetectable MRD but continued treatment for all six cycles.23 Furthermore, PFS in the subgroup of patients who discon- tinued frontline FCR after three cycles of treatment because they had achieved undetectable MRD was better than the PFS of patients who remained with detectable MRD at the end of the course of six cycles, despite the shorter duration of treatment in the former group. In addi- tion, Thompson et al. recently reported that undetectable MRD after course 3 of FCR predicted a greater likelihood of undetectable MRD at the end of therapy.24
Although the study was designed before the ERIC rec- ommended diagnostic markers were published, with a median number of BM leukocytes of around 410,000 (range, 150,000-610,000) and a sensitivity of MRD detec- tion of ≥10-4, the immunophenotypic CLL analysis per- formed in this study was robust. The methodology for assessing MRD was similar to the flow cytometry methodology established by the ERIC consortium, as three of the tubes were similar to the subsequently pub- lished ERIC recommendations.15,25,26 The potential limita- tion of the flow cytometry assay is the need for at least 106 cells per tube and a total of four tubes, which may be an issue to keep in mind when small samples are available. In addition, selection of the sample source remains a chal- lenge, as a significant discrepancy between MRD status determined in peripheral blood and BM has been report- ed.27 A paired analysis of peripheral blood and BM samples in our study revealed that 60 patients did not have detectable MRD in peripheral blood, while only 37 achieved undetectable MRD in the BM. This discrepancy is partially a result of the compartmental nature of CLL, with disease reservoirs in the BM, blood, lymph nodes, liver, and spleen. As rituximab targets CD20 on mature, malignant and benign B cells, rituximab-based therapy will achieve undetectable MRD much more rapidly in peripheral blood than in BM. Indeed, in the REM trial we decided to use the CD20 marker in two of our MRD tubes for two reasons, (i) CD20 as a single marker provides the most powerful separation of CLL cells from normal B cells, and (ii) in patients treated with rituximab-containing regimens, the correlation between real-time quantitative polymerase chain reaction findings and the results of assays with combinations including the CD20 marker was not weaker than that with combinations not including the CD20 marker.28
Based on the results described above, it appears that 3 years of rituximab maintenance therapy was beneficial for enrolled patients, improving the quality of remissions and prolonging survival. The reason for the high response rates, undetectable MRD and favorable PFS and OS rates compared to those from clinical trials with similar entry
haematologica | 2019; 104(11)
2255