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Rituximab maintenance therapy in CLL
tinuation were myelotoxicity (n=14; 18.9%), clinical pro- gression (n=8; 10.8%), consent withdrawal (n=3; 4.0%) investigator’s decision (n=1; 1.3%), protocol violation (n=1; 1.3%), infection (n=3; 4.0%) and death (n=2; 2.7%). During the follow-up period, all patients who were ana- lyzed maintained CR or PR.
At the end of maintenance therapy, MRD assessed at cycles 9, 12, 15 and 18 was negative in 44 of the 72 patients (61.1%) evaluable for response. Interestingly, 29 patients who had detectable BM-MRD immediately after induction converted to an undetectable BM-MRD status following rituximab maintenance therapy. In detail, after nine cycles, 13 patients with detectable BM-MRD con- verted to having undetectable BM-MRD and two with undetectable BM-MRD became MRD-positive. After 18 cycles, 16 patients with detectable BM-MRD converted to being MRD-negative and five with undetectable BM- MRD became BM-MRD-positive (2 CR relapsed after 18 months, 1 CR interrupted treatment at 12 months because of toxicity, 1 PR progressed after 13 months and 1 CR relapsed after 4 months) (Table 2).
Survival
At the end of the study, with a median follow-up of 6.3 years, the estimated proportions of patients who were alive and progression-free were 0.76 and 0.61, respective- ly. Analyzed according to their MRD status, patients with a CR and either undetectable or detectable MRD did not reach the median PFS and OS, while for patients with
Table 2. Measurable residual disease assessment.
detectable MRD and a PR the median PFS was 2.04 years (95% CI: 0-4.3 years) and the median OS was 4.60 years (95% CI: 3.0-6.1 years). Regarding response duration, a total of 56 patients (71.2%) maintained their response throughout the whole study: the median response dura- tion was 6.4 years (95%CI: 6.08-6.68). Univariate Cox regression analysis showed that IGHV status affected PFS: the PFS rate at 7.3 years in patients with mutated IGHV was 0.85, whereas it was 0.39 in those with unmutated IGHV. However, the median OS for patients with either mutated or unmutated IGHV was not reached (Figure 1). No correlations were identified between the other clinical, biological or molecular factors and the achievement of undetectable MRD.
When MRD values were categorized into low (<0.01%, i.e. less than 1 CLL cell per 10,000 leukocytes), intermedi- ate (0.01% to 1%) and high (>1%), the median PFS and OS were not reached in patients with low and intermedi- ate MRD levels and were 2.0 years (95% CI: 0-4.3) and 4.6 years (95% CI: 4.2-4.9), respectively, in patients with high MRD levels (Figure 2, and Table 3A and 3B).
Safety
As per protocol, 86 patients were evaluated for safety after FCR induction. The most common adverse events were grade 1-2 rituximab infusion reactions (65.1%), grade 3-4 myelosuppression (29 patients, 33.7%) and infections (grade 1-2: 30 patients, 34.9%; grade 3-4: 3 patients, 3.5%). In addition, there were 11 (12.8%) grade
MRDstatus
Negative
Positive
Induction(n=74) 6Rmcycles(1year)(n=56) 12Rmcycles(2years)(n=35)
18Rmcycles(3years)(n=42)
33 36 23 31
41 20 12 11
MRD: measurable residual disease; Rm: rituximab maintenance therapy.
Figure 2. Progression-free survival and overall survival according to IGHV mutational status. PFS: progression-free survival; OS: overall survival.
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