Characteristics of chronic lymphocytic leukemia patients achieving 5+ years of remission after <scp>FC</scp>‐based first‐line treatment: Retrospective observations from the <scp>FILO</scp> group
Authors: Yann Guillermin, Charles Herbaux, Fabien Subtil, Thérèse Aurran‐Schleinitz, Florence Cymbalista, Remi Letestu, Stéphane Leprêtre, Sandrine Vaudaux, Kamel Laribi, Véronique Leblond, Yasmina Defoi, Raouf Benchikh, Gilles Salles, Pascal Godmer, Henry Jardel, Fréderic Vallais, Pierre Feugier, Frédérique Orsini, Brigitte Pegourié, Vincent Lévy, Anne‐Sophie Michallet
Journal: American Journal of Hematology (2017)

Indication for treatment in chronic lymphocytic leukemia (CLL) is still dependent on clinical stage and disease activity, with only one biological marker considered mandatory for the decision to treat, the 17p deletion. Despite the large interest in targeted therapies, chemo-immunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) remains the standard therapy for fit untreated CLL patients. Though this combination leads to improved survival, it apparently cannot cure the disease, which can theoretically only be achieved by allogeneic stem cell transplantation. Recent updates of large cohorts of patients treated by FCR have confirmed great efficacy with a significant proportion of patients experiencing long-lasting responses. The MD Anderson and German CLLSG trials demonstrated 6-year progression-free survival (PFS) of 60% and 46.8% respectively, with 5-year overall survival (OS) of 77% and 78.6%, respectively.1-3 On the other hand, targeted therapies led by B-cell receptor (BCR) inhibitors like ibrutinib and idelalisib have achieved interesting results in the relapse and first-line settings for del17p patients, with good short-term toxicity profile. On the contrary to chemotherapy, these treatments achieved disease control for most patients, with a large, though not profound overall response rate, a few complete responses, yet no eradication of the disease.4-6 Moreover, this strategy needs to be continued with no interruption, and questions have emerged concerning when these new drugs should be initiated, as well as regarding the associated long-term toxicities. Now it has become a standard of care in the settings of relapse or del17p, the question of how to approach the challenge of first-line management of fit patients is open to debate. Our study sought to define the profile of long-term responders after chemo-immunotherapy to further identify patients susceptible to particularly benefit from FCR. Given this perspective, this retrospective study of the French Innovative Leukemia Organization (FILO) group analyzed the long-term results (over 5 years in complete remission) CLL patients who received only one line of chemo- or chemo-immunotherapy. This retrospective analysis involved 76 patients treated and followed in 11 French centers between years 2000 and 2011. Principal inclusion criteria were adults (aged >18 years) with CLL treated in first-line by a FC-based regimen, achieving PFS ≥ 5 years. The procedure was approved by the FILO scientific committee and the appropriate health authorities, according to national ethical recommendations, and conducted in accordance with the Declaration of Helsinki. Majority of patients were males (n = 45, 59.2%) with a median age of 70 years (37–82) and a mean lymphocytosis of 57.5 G/L at diagnosis. At time of treatment initiation, 14 (18.4%) patients had Binet stage A with active disease, 46 (60.5%) stage B, and 16 (21.5%) stage C. The profile of these long responders patients was associated with good prognosis factors such as mutated IgHV status (65.8%), low beta-2 microglobulin (76.8%), low tumor burden, negative CD38 status (76.6%), and equally good cytogenetic (normal or del 13q; 67%). The median time to treatment was 37.4 months, with 79% receiving the FCR combination. The median number of FC cycles was 6. In terms of toxicity, 57.5% of patients displayed grade III/IV neutropenia during the treatment courses with 16.4% of grade III and IV infection (Figure 1A). With a median follow-up of 99 months (62–199), only 10% of patients developed prolonged and retarded neutropenia, none related to myelodysplasia. There were 25 (32%) patients that experienced at least one infection, comprising 38 infections in total (31.5% bacterial, 29% viral, 7.9% pneumocystis, 2.9% aspergillus), 37.8% occurring within the first 12 months. Grade III/IV infection was observed during follow-up for 28.1% (Figure 1A). Immune complications were not frequent, with only 4.2% presenting immune anemia and 4.2% immune thrombocytopenia. Median time of CD4+ T lymphocyte reconstitution (>200/mm3) was 32.4 months. Hypogammaglobulinemia was observed in 32 (58.9%) patients at the last follow-up, for 19 (59%) of them, this hypogammaglobulinemia already existed at diagnosis. Secondary cancers occurred in 14 (18.5%) patients with 5 prostatic carcinoma, 3 pulmonary cancers, 2 melanomas, 1 epidermoid cutaneous cancer, 1 cervix cancer, 1 kidney cancer, and 1 myelodysplasia. The cumulative incidence of secondary cancer in this cohort was 15% at 8 years (Supporting Information Figure 1B). At treatment evaluation (average 3 months after treatment cycle), minimal residual disease (MRD) assessed by flow cytometry (with a cut off at 10−4) was negative in 77.4% of patients. At last follow-up, among 27 evaluable patients, 59.3% were MRD negative. The originality of our work was to start from our cohort of long-term responders and describe their pre- and post-treatment characteristics. It allowed a real life observation without any selection bias. It confirmed the pre-treatment profile of these long-term responders to be one of good prognosis: mutated IgHV status, low B2M level, negative CD38 status, and good cytogenetic. These characteristics ensured very good PFS with a median of 99 months. The median age at CLL diagnosis was 70 years, which is usual in CLL patients treated by FCR, and the importance of the capacity to receive this chemo-immunotherapy regimen was underlined by a median of 6/6 cycles of FC-based chemotherapy received without excess of toxicity. Concerning the long-term safety in our cohort of chemo-immunotherapy patients, we reported fewer delayed neutropenia cases than other cohorts. Infectious toxicity was similar to that reported in the literature, with a few severe infections occurring during chemotherapy. Undetectable MRD was confirmed as a significant post-treatment characteristic and probably a goal to reach as a surrogate to the outcome with immuno-chemotherapy, as more than 75% of evaluable patients had MRD negative after treatment completion and nearly 60% remained negative at the last follow-up, underlining the depth of the response in patients that are probably not cured but in long-term control of their disease. Our cohort confirms the profile of those “long-term responders.” It underlines the need for complete initial patients staging, particularly including IgHV mutational status, and for targeting MRD negativity after treatment completion. New perspectives now need to be developed, with evaluation of risk adapted and MRD driven strategy possibly used to orientate individualized therapy and constituting an endpoint predicting the outcome. A, Baseline demographic and treatment characteristics and long-term toxicities and follow-up of the entire cohort. B, Cumulative incidence of the secondary cancers The authors would like to thank the FILO group for providing the eCRFs, and all the physicians for their involvement in fulfilling these eCRFs. The authors declare no competing financial or non-financial interests in relation to this manuscript. YG and ASM made substantial contributions to the conception and design of this manuscript, along with the data acquisition, analysis, and interpretation, and were also involved in drafting the manuscript. YG, CH, TA, FC, RL, SL, KL, SV, VL, YD, RB, GS, PG, HJ, FV, PF, FO, BP, VL, and ASM were involved in data acquisition. All authors have provided final approval of the version submitted for publication. Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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