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J.A. García-Marco et al.
criteria is probably multifactorial, but may include the age and Performance Status of the patients: their median age was 59.5 years and up to 70.5% patients had an Eastern Cooperative Oncology Group Performance Status of 0. Additionally, the protocol-defined anti-microbial prophy- laxis scheduled for this trial allowed a treatment compli- ance of around 80%. Furthermore, the secondary end- point of undetectable MRD is strongly associated with outcome: at the post-maintenance assessment, 68% of assessed patients had undetectable MRD. Finally, the median follow-up of 75.6 months is long enough to allow solid interpretation of both PFS and OS.
A weakness of this trial is that, since its design, new drugs targeting signaling pathways, and newer monoclon- al antibodies have become available, and the interest in chemoimmunotherapy, such as FCR, has weakened. Additionally, since OS findings have been inconsistent and one could argue that prolonged maintenance use of certain molecules could expose CLL patients to increased toxicity and ultimately reduce their quality of life, the debate should be whether to use rituximab for maintenance or to watch and wait and give these therapies when the patients relapse. Upon closer examination of our results, patients with unfavorable cytogenetics, unmutated somatic IGHV genes, and CD38 and ZAP70 expression benefited from rituximab maintenance therapy. Further research is now needed to identify subgroups of patients who may benefit while on maintenance therapy.
Of the 957 treatment-emergent adverse events, 54% occurred during induction treatment; most were classed as neutropenia or lymphopenia, and almost half (47.4%) were suspected to be related to rituximab. However, the same adverse events could be related to more than one of
the drugs administered. The most frequent of the 440 treatment-emergent adverse events recorded during the maintenance period was neutropenia, which was record- ed in 43.3% of the patients. Of the total of 957 treatment- emergent adverse events, 26.6% were assessed as grade ≥3 and the majority were associated with disorders in the blood and lymphatic systems. Sixteen out of 20 deaths reported in the study occurred during the maintenance period. There was only one treatment-related death, which happened during the maintenance period. Overall, the safety profile of rituximab in the maintenance setting was consistent with its expected safety profile and no new unexpected adverse events were reported.
In summary, this study provides the first insights into the potential clinical use of FCR treatment followed by a 3-year period of rituximab maintenance as a treatment strategy. Our study suggests that maintenance therapy with rituximab further prolongs responses in CLL patients with detectable MRD (when judged against his- torical outcomes after FCR treatment), with significantly improved PFS and OS for patients who achieved at least a PR after FCR induction. Based on these results, unde- tectable MRD is confirmed as a predictive biomarker associated with treatment response following rituximab maintenance therapy. Prospective studies aimed at evalu- ating long-term outcomes following early treatment dis- continuation and the potential benefit in terms of reduc- ing acute and delayed toxicity are necessary before MRD testing can be used to guide treatment decisions in clinical practice.
Funding
This work was funded by Roche Farma, S.A., Madrid, Spain.
References
1. Müller-Hermelink HK, Montserrat E, Catovsky D, et al. Chronic lymphocytic leukaemia/small lymphocytic lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008.pp.180-182.
2. Ginaldi L, De Martinis M, Matutes E, Farahat N, Morilla R, Catovsky D. Levels of expression of CD19 and CD20 in chronic B cell leukaemias. J Clin Pathol. 1998;51 (5):364-369.
3. Moreau EJ, Matutes E, A'Hern RP, et al. Improvement of the chronic lymphocytic leukemia scoring system with the mono- clonal antibody SN8 (CD79b). Am J Clin Pathol. 1997;108(4):378-382.
4. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111 (12):5446-5456.
5. HallekM,FischerK,Fingerle-RowsonG,et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376
(9747):1164-1174.
6. Rossi D, Terzi-di-Bergamo L, De Paoli L, et
al. Molecular prediction of durable remis- sion after first-line fludarabine-cyclophos- phamide-rituximab in chronic lymphocytic leukemia. Blood. 2015;126(16):1921-1924.
7. Fischer K, Bahlo J, Fink AM, et al. Long- term remissions after FCR chemoim- munotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127(2):208-215.
8. Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide, and ritux- imab treatment achieves long-term disease- free survival in IGHV-mutated chronic lym- phocytic leukemia. Blood. 2016;127(3): 303-309.
9. Thompson PA, Wierda WG. Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL. Blood. 2016;127(3):279-286.
10. Abrisqueta P, Villamor N, Terol MJ, et al. Rituximab maintenance after first-line ther- apy with rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R- FCM) for chronic lymphocytic leukemia. Blood. 2013;122(24):3951-3959.
11. Del Poeta G, Del Principe MI, Buccisano F, et al. Consolidation and maintenance immunotherapy with rituximab improve clinical outcome in patients with B-cell chronic lymphocytic leukemia. Cancer. 2008;112(1):119-128.
12. Bo MD, Del Principe MI, Pozzo F, et al.
NOTCH1 mutations identify a chronic lymphocytic leukemia patient subset with worse prognosis in the setting of a ritux- imab-based induction and consolidation treatment. Ann Hematol. 2014;93(10): 1765-1774.
13. Garcia Vela JA, Delgado I, Benito L, et al. CD79b expression in B cell chronic lym- phocytic leukemia: its implication for min- imal residual disease detection. Leukemia. 1999;13(10):1501-1505.
14. Wang YH, Fan L, Xu W, Li JY. Detection methods of ZAP70 in chronic lymphocytic leukemia. Clin Exp Med. 2012;12(2):69-77.
15. Rawstron AC, Fazi C, Agathangelidis A. et al. A complementary role of multiparame- ter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study. Leukemia. 2016;30(4):929-936.
16. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggres- sive form of chronic lymphocytic leukemia. Blood. 1999;94(6):1848-1854.
17. Hamblin TJ, Orchard JA, Ibbotson RE, et al. CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocyt- ic leukemia, but CD38 expression may vary during the course of the disease. Blood. 2002;99(3):1023-1029.
18. Dürig J, Nuckel H, Cremer M, et al. ZAP-70
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