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J.A. GarcĂa-Marco et al.
induction no longer had detectable disease in the BM following maintenance therapy. After a median follow- up of 6.30 years, the median overall survival (OS) and PFS had not been reached in patients with either unde- tectable or detectable residual disease in the BM, who had achieved a complete response at the time of start- ing maintenance therapy. Interestingly, univariate analysis showed that after rituximab maintenance OS was not affected by IGHV status (mutated vs. unmutated OS: 85.7% alive at 7.2 years vs. 79.6% alive at 7.3 years, respectively). As per protocol, 15 patients (17.8%), who achieved a complete response and undetectable peripheral blood and BM residual disease after four courses of induction, were allowed to stop fludarabine and cyclophosphamide and complete two additional courses of rituximab and continue with maintenance therapy for 18 cycles. Surprisingly, the outcome in this population was similar to that observed in patients who received the full six cycles of the induction regimen. These data show that, compared to historic con- trols, patients treated with FCR followed by rituximab maintenance have high-quality responses with fewer relapses and improved OS. The tolerability of this regime is favorable. Furthermore, attaining an early unde- tectable residual disease status could shorten the duration of chemoimmunotherapy, reducing toxicities and preventing long-term side effects. The analysis of BM MRD after fludarabine-based induction could be a powerful predictor of post-maintenance outcomes in patients with CLL undergoing rituximab maintenance and could be a valuable tool to identify patients at high risk of relapse, influencing further treatment strate- gies. This trial is registered with EudraCT n. 2007-002733-36 and ClinicalTrials.gov Identifier: NCT00545714.
Introduction
Chronic lymphocytic leukemia (CLL) is a mature B-cell neoplasm characterized by a clonal proliferation and com- partmentalized accumulation of neoplastic B cells within the blood, bone marrow and secondary lymphatic organs. The neoplastic B cells typically co-express CD5, and CD19, CD20, and CD23; compared with normal B cells, the levels of CD20 and CD79b on CLL cells are usually diminished.1-4 Mutations of immunoglobulin heavy vari- able chain (IGHV) genes and chromosomal abnormalities are the most important predictors of disease course.
For physically fit patients requiring treatment according to the International Workshop on CLL criteria, the combi- nation of fludarabine, cyclophosphamide and the chimeric anti-CD20 antibody rituximab (FCR) is the standard of care for first-line treatment, based on the improvement of progression-free survival (PFS) and overall survival (OS) of patients treated with this combination compared with those treated with combination chemotherapy alone.5 Following the introduction of purine analogs as a treat- ment option, higher response rates and a higher propor- tion of complete remissions were observed, and even bet- ter outcomes have been reported in patients carrying mutated IGHV genes (excluding 11q or 17p deletions); patients treated with combination therapies such as FCR may achieve a life expectancy close to that observed in the matched normal general population.6-8
Achieving higher CR rates with chemoimmunotherapy has translated into a documented increase in PFS and seems to lead to an OS benefit, as shown in the CLL8 trial, which reported a 33% reduced risk of death (P=0.01) with the FCR regimen when compared to fludarabine plus cyclophosphamide as first-line therapy. However, while attainment of a CR has historically been considered the gold-standard for treatment response, many of these patients have persistent disease that cannot be easily iden- tified by routine testing approaches.9 This, coupled with the development of extremely sensitive testing technolo- gies, has led to the emergence of measurable residual dis- ease (MRD) as an important endpoint in the treatment of
CLL, especially in the era of chemoimmunotherapy. Indeed, achieving undetectable MRD after chemoim- munotherapy is a desirable goal, as MRD below a thresh- old of 10-4 (0.01%) results in improvement of PFS and OS.8 We hypothesized that using MRD as a surrogate of treat- ment effectiveness would allow determination of the effi- cacy of new treatments without the need for prolonged observation.
Several studies have shown that sequential use of induc- tion/maintenance treatment can improve the quality of response achieved with induction. Abrisqueta et al. recent- ly reported an analysis of whether maintenance therapy can improve the response achieved with induction chemotherapy.10 Sixty-seven patients responding to induc- tion therapy with FCR plus mitoxantrone (R-FCM) received rituximab maintenance therapy (375 mg/m2) every 3 months for 2 years. Approximately 40.6% of patients achieved a CR with undetectable MRD at the end of the maintenance treatment. It is important to note that 21% of the patients who had detectable MRD at the end of R-FCM induction had an improved response after ritux- imab maintenance therapy. Another study showed that after responding to a fludarabine induction, patients who had detectable MRD and were consolidated with four monthly cycles of rituximab followed by a maintenance regimen of 12 monthly rituximab doses had significantly longer responses,compared to those who did not receive consolidation (5-year OS: 87% vs. 32%; P<0.001). The estimated 5-year PFS after induction was 73%.11
However, despite the improvements achieved with rit- uximab maintenance therapy, there are some biological features which confer a poor response to consolidation plus maintenance therapy. Dal Bo et al. showed that patients harboring the NOTCH1 mutation had a signifi- cantly shorter OS compared with those with unmutated NOTCH1. The independent prognostic impact of NOTCH1 mutation on OS was confirmed in multivariate analysis.12
In the light of these observations, we conducted a mul- ticenter, non-randomized phase II clinical trial that aimed to evaluate the efficacy, in terms of CR rate, of FCR as
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haematologica | 2019; 104(11)