Page 148 - 2019_11 Resto del Mondo-web

J.A. García-Marco et al.
3-4 non-hematologic serious adverse events.
The most common adverse event during rituximab maintenance therapy was grade 3-4 myelosuppression, which occurred in 28 patients (37.8%). In more detail, neutropenia between cycles and anemia were observed in 27 patients (36.5%) and one patient (1.4%), respectively. Grade 1-2 infections were detected in 43 patients (58.1%), while grade 3-4 infections were documented in ten patients (13.5%) and were pneumonia (n=5), respiratory tract infections (n=2), meningitis (n=1), viral myocarditis (n=1), and gastroenteritis (n=1). Febrile neutropenia was
observed in five patients (6.8%).
Discussion
Despite the improved efficacy of currently approved chemoimmunotherapy in CLL patients, the majority of patients, including those who achieve CR, eventually relapse as a consequence of residual malignant cells still present after therapy. The high CR rate recorded in this study indicates that FCR induction followed by rituximab maintenance therapy produces a high overall response rate in patients considered fit for fludarabine-based thera- py. By increasing the quality of clinical responses through obtaining a high undetectable MRD CR rate, the PFS of patients with a clinical response is prolonged. Ultimately, this confirms the role and value of undetectable MRD sta- tus in CLL.
In our study, MRD in BM was undetectable at the 10-4 level in 44% of the 80 patients evaluated after the induc- tion treatment and in 68% of 59 patients at the end of maintenance therapy. Furthermore, rituximab mainte- nance therapy significantly increased the number of patients with undetectable MRD in BM. Indeed, 40 patients with detectable BM-MRD converted to an unde- tectable BM-MRD status from cycle 9 and subsequent
cycles. Additionally, although small numbers limited our subgroup analysis, it is remarkable that 41%, 58% and 60% of patients with undetectable MRD following ritux- imab maintenance therapy (n=40) harbored factors well- known to be associated with lower response and poor long-term outcomes.16-18 Our data suggest a PFS benefit from rituximab maintenance therapy in IGHV-mutated vs. unmutated patients (PFS at 7.2 year: 84.5% vs. 39.1%, respectively). Overall, clinical outcomes were encouraging in this study as the median OS and PFS were not reached. The estimated 7-year PFS and OS rates were 56.2% and 78.0%, respectively. Of note, the median OS and PFS for patients with a CR and either undetectable BM-MRD or detectable BM-MRD were not reached. However, despite these data suggesting a benefit on time-to-event curves, it is important to note that this was not a randomized study. Nevertheless, although direct comparisons between trials
Table 3A. Progression-free and overall survival according to measura- ble residual disease group assessment at the staging following treat- ment with fludarabine, cyclophosphamide, and rituximab.
MRD Group
PFS
OS
Low Intermediate (<0.01%) (0.01%-1%)
NR NR
NR NR
High (>1%)
2.0 years (95% CI: 0-4.3)
4.6 years (95% CI: 0-4.3)
MRD: measurable residual disease; PFS: progression-free survival; OS: overall survival; NR: not reached; 95% CI: 95% confidence interval.
Table 3B. Seven-year progression-free and overall survival rates after 36 months of maintenance therapy according to measurable residual disease group.
MRD Group
PFS
OS
Low Intermediate (<0.01%) (0.01%-1%)
93.2% 25.0%
100% 100%
High (>1%)
28.6 %
68.6%
Figure 3. Progression-free survival and overall survival according to measurable residual disease status. PFS: progression-free survival; OS: overall survival; MRD: measurable residual disease; NR: not reached.
MRD: measurable residual disease; PFS: progression-free survival; OS: overall survival.
2254
haematologica | 2019; 104(11)