First Line Chronic Lymphocytic Leukemia Immunochemotherapy for the Elderly Patients over 79 Years Is Feasible, and Achieves Good Results: A Filo Retrospective Study
Authors: Meunier Godelieve , Ysebaert Loïc , Nguyen-Thi Phi Linh , Lepretre Stephane , Quinquenel Anne , Dupuis Jehan , Lemal Richard , Aurran-Schleinitz Therese , Tomowiak Cecile , Cymbalista Florence , Dilhuydy Marie Sarah , Brion Annie , Morel Pierre , Cazin Bruno , Leblond Veronique , Cartron Guillaume , Ré Daniel , Bene Marie C , Michallet Anne-Sophie , Feugier Pierre 
Published: October 2019

Abstract
Introduction: Median age of Chronic Lymphocytic Leukemia (CLL) patients is 72 years with 40% older than 75 and 22.8% over 80 years. Important therapeutic progresses have been made, including chemo-immunotherapy as well as the recent use of targeted therapies, leading to progression-free-survival (PFS) and overall survival (OS) improvements. Although the elderly represents the largest subgroup of CLL patients, they are underrepresented in clinical studies and little is known about their clinical characteristics, treatment and outcome. Consequently, results from trials cannot be directly translated into clinical practice for these patients. Bairey et al (Ann Hematol, 2011) reported a series of 214 patients (80 years or older) diagnosed in Israel between 1979 and 2009 with a mean age of 84. However, in this cohort, 56% of the patients had a Rai stage 0 and only 53 received treatment. Median survival was 56 months.
Methods: We performed a retrospective study of CLL patients aged 80 or more at initiation of first line therapy. Patients were treated between 2003 and 2013, in 17 hospitals affiliated to the French Innovative Leukemia Organisation (FILO). We report here a cohort of 201 such CLL patients, and describe their clinical and biological characteristics, treatment options and outcome.
Results: Patients' median age was 83.4 years (80-92), 29% were older than 85 years, and the sex ratio was 60% male/40% female. Performance status (97%≤ 2) and nutritional status (median Corporal Mass Index of 25.3 kg/m²) were preserved. The median Cumulative Index Rating Scale (CIRS) comorbidity score was 5. More precisely in term of fitness, 57.8% patients were characterized as "go-go" with a CIRS ≤ 6 and organ comorbidities <3. The median creatinine clearance was 48 mL/min (Cockroft formula). Most patients lived at home (89.5%), often with familial or professional help (72%). A complete geriatric assessment was performed for 6.1% of them.
Diagnosis relied on a Royal Marsden Hospital (RMH) score > 3, and CD38 was positive in 43,4% of the 129 cases tested (64%). Cytogenetic data were available for 42% of the patients. Isolated abnormalities were deletion 13q (38.1%), trisomy 12 (21.4%), deletion 17q (10.7%) or deletion 11q (7.1%). Besides, associated chromosomic abnormalities were detected, mainly by fluorescence in situ hybridization (FISH) and complex karyotypes (1.2%).
At treatment initiation, Binet stage was either A (27.2%), B (28.7%) or C (41.5%).
Therapies consisted mainly in Chlorambucil (65.5%), Bendamustine (10.5%) and Rituximab (44.3%). Indeed, therapy regimens were composed of Chlorambucil alone (45.3%) or chemo-immunotherapy (48.3%) including Rituximab+Chlorambucil (22.7%), Rituximab+Bendamustine (10.4%), Rituximab+Cyclophosphamide+Dexamethasone (5.5%) or Rituximab+Fludarabine+Cyclophosphamide (5.5%).
In term of tolerance, 20.2% of the patients required hospitalization and 10% of these cases were febrile neutropenia. Finally, 31.8% required a dose reduction of chemotherapy.
The Overall Response Rate was 65.9% with 31.4% of clinical complete remission. The median OS and PFS (from treatment initiation) were 48.6 and 18 months, respectively (cf. Survival curves). Afterwards, an important number of patients (41.3%) remained fit enough to receive a second line treatment. In univariate analysis, only comorbidities evaluated by the CIRS had a significant impact on survival (p=0.03). Indeed patients identified as fit by a CIRS score ≤ 6 and no organ comorbidity > 3 had a better outcome.
Conclusion: We report a large series of elderly CLL patients, who received first line treatment at a median age of 83. Median OS was about 4 years, which is less than normal population of the same age. Our results suggest that treatment (including immunochemotherapy) is feasible, even in this very old population. Different bias are possible in this retrospective study including the selection of only fit patients, the low percentage of geriatric evaluation, and the possible undertreatment of this population since chlorambucil was the most frequent treatment. In the future, prospective trials should target this population. Oncogeriatric evaluation and new targeted therapies should be part of such future trials.
Figure 1. Survival curve 1: Overall Survival Figure 1. Survival curve 1: Overall Survival Figure 2. Survival curve 2: Progression Free Survival Figure 2. Survival curve 2: Progression Free Survival

Disclosures
Dupuis: ROCHE: Speakers Bureau; ABBVIE: Membership on an entity's Board of Directors or advisory committees. Aurran-Schleinitz:CSLBehring: Honoraria; Janssen: Honoraria. Cymbalista:Karyopharm: Honoraria; Gilead: Honoraria; Roche: Honoraria; Janssen: Honoraria, Research Funding. Dilhuydy:Roche: Honoraria, Other: Travel reimbursement; Janssen: Honoraria, Other: Travel reimbursement; Mundipharma: Honoraria. Cazin:GILEAD,: Honoraria; ROCHE: Consultancy; MUNDIPHARMA: Honoraria, Research Funding; NOVARTIS: Honoraria. Leblond:Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Mundipharma: Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Cartron:Sanofi: Honoraria; Gilead: Honoraria; Celgene: Honoraria; GSK: Honoraria; Roche: Consultancy, Honoraria.