We report a randomized prospective phase 3 study (CLL7), designed to evaluate the efficacy of fludarabine, cyclophosphamide, and rituximab (FCR) in patients with an early-stage high-risk chronic lymphocytic leukemia (CLL). Eight hundred patients with untreated-stage Binet A disease were enrolled as intent-to-treat population and assessed for four prognostic markers: lymphocyte doubling time <12 months, serum thymidine kinase >10 U/L, unmutated IGHV genes, and unfavorable cytogenetics (del(11q)/del(17p)/trisomy 12). Two hundred and one patients with ≥2 risk features were classified as high-risk CLL and 1:1 randomized to receive either immediate therapy with 6xFCR (Hi-FCR, 100 patients), or to be observed according to standard of care (Hi-W&W, 101 patients). The overall response rate after early FCR was 92.7%. Common adverse events were hematological toxicities and infections (61.0%/41.5% of patients, respectively). After median observation time of 55.6 (0–99.2) months, event-free survival was significantly prolonged in Hi-FCR compared with Hi-W&W patients (median not reached vs. 18.5 months, p < 0.001). There was no significant overall survival benefit for high-risk patients receiving early FCR therapy (5-year OS 82.9% in Hi-FCR vs. 79.9% in Hi-W&W, p = 0.864). In conclusion, although FCR is efficient to induce remissions in the Binet A high-risk CLL, our data do not provide evidence that alters the current standard of care “watch and wait” for these patients.

The mean age at diagnosis of chronic lymphocytic leukemia (CLL) is 72 years, with 22.8% of patients being older than 80 years. However, the elderly are underrepresented in clinical studies of CLL. We performed a retrospective study of CLL patients aged 80 years or older at the initiation of first-line therapy in hospitals affiliated with the French intergroup on CLL (French Innovative Leukemia Organization) between 2003 and 2013. Here, we describe the clinical and biological characteristics, treatment, and outcomes for 201 patients. The median age of the cohort was 83.2 years (80-92 years). The median Cumulative Index Rating Scale comorbidity score was 5 and the median creatinine clearance was 48 mL/min (Cockcroft-Gault formula). At treatment initiation, Binet stage was A (26.4%), B (27.9%), or C (40.3%). Therapy consisted mainly of chlorambucil (65.7%), bendamustine (10.5%), and rituximab (44.3%) as follows: chlorambucil alone (45.3%) or immunochemotherapy (48.3%) with rituximab + chlorambucil (22.7%), rituximab + bendamustine (10.4%), or rituximab + cyclophosphamide + dexamethasone (5.5%). The overall response rate was 66.2% with 31.8% dinical complete remission. The median overall and progression-free survival from treatment initiation was 53.7 and 18.3 months, respectively. These results suggest that treatment is feasible in this age group. even with immunochemotherapy. Thus. prospective trials should target this population and oncogeriatric evaluation and new targeted therapies should be part of such future trials.

We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255.

Elderly patients with chronic lymphocytic leukemia (CLL) are underrepresented in trials evaluating fludarabine, cyclophosphamide, and rituximab (FCR). We assessed four cycles of FCR with two additional rituximab doses on day 14 of cycles 1 and 2 in 194 untreated CLL patients > 65 years (median age 71.2) without del17p. Four FCR cycles were administered to 90.7% (176/194), with (n = 74) or without (n = 102) dose-delay and/or dose-reduction. A total of 50% grade 3/4 neutropenia occurred after each cycle. Only 6.2% cycles were associated with severe infection. Complete remission (CR) was achieved in 19.7%, and partial remission (PR) in 73.9% of patients. Minimal residual disease (MRD) was negative in 36.7%. Overall survival at 36 months was estimated at 87.4%. Oral FC and dose-dense rituximab is feasible and active in fit elderly CLL patients. However, myelosuppression is significant and frequent dose adaptations are required implying that these results cannot be generalized to unfit or frail elderly CLL.

The optimal management of patients with relapsed chronic lymphocytic leukemia (CLL) is dictated by the type of prior therapy, duration of prior response, presence of genomic aberrations, age, and comorbidities. The patterns of relapses and the clinical outcomes of second‐line options after fludarabine‐cyclophosphamide‐rituximab (FCR) is given as a frontline treatment are currently unknown. In this retrospective and non‐randomized study, we report the outcomes of 132 patients from databases of 14 French CLL study group centers who needed a second‐line treatment after FCR frontline. Bendamustine + rituximab (BR) was the most frequently used second‐line regimen, followed by alemtuzumab‐based regimens, R‐CHOP, and FCR. Median progression‐free survival (PFS) was 18 months after BR with a median overall survival (OS) not reached. We also found that response durations of < 36 months and the presence of del(17p) are critical factors that contribute to poor overall survival. BR appears to be an effective salvage regimen in our series, both in terms of progression‐free and overall survival. Patients who relapsed less than 36 months after FCR have a poor outcome, not significantly different in this study from patients with early relapses less than 12 or 24 months. Am. J. Hematol. 90:511–514, 2015. © 2015 Wiley Periodicals, Inc.

Abstract Background: An increased incidence of second primary malignancies (SPM) is described in chronic lymphocytic leukemia (CLL). Current hypothesis to explain this phenomenon mainly relies on immunosuppression conferred by both CLL itself and CLL treatment. The imputability of fludarabine has been long recognized but the risk associated with monoclonal antibodies, especially rituximab recently shown to improve overall survival in CLL when combined with fludarabine and cyclophosphamide (FC), remains unknown. Materials and methods: We conducted a retrospective study of the incidence of secondary cancers in 1255 CLL patients diagnosed since 1980 in the University Hospital of Lille to better characterize the possible risk of SPM associated with rituximab Results: Of 1255 patients, 651 (52%) received therapy including rituximab (38%), FC (26.7%), F alone (22.4%), chlorambucil (27.5%), alemtuzumab (15.5%) and bendamustine (9.3%). Rituximab was given either in combination with FC (27.5%), other chemotherapy (2.6%) or as a single-agent (3.5%). There was no significant difference in terms of age (58 versus 62 years), gender, Binet stage, cytogenetic abnormalities and number of regimen received between patients treated with or without rituximab. Median follow-up was 6 years for all patients (range 2-23), 4.8 years (range, 2-8) since initiation of therapy for patients treated without rituximab and 3.6 years (range, 0.2-11) for patients who received rituximab. Median overall survival (OS) was 18 years for patients treated with R-chemotherapy versus 11 years for patients treated with chemotherapy alone (p<0,001). Of 1255 patients, 21.5% were diagnosed with SPM. The incidence of SPM was 17.1% in patients who did not receive treatment compared to 10% in those treated. Among treated patients, the incidence of SPM was significantly higher (19% v 2%) in patients who received rituximab (p <0.001). SPM incidence was increased after R-FC (24.4%), FC (10.5%) compared to other regimen (p<0,001) (table1). Most frequent SPM were skin (25%)-and urologic cancers (23%). Median onset of SPM was 5 years (range, 2-20) without rituximab and 2 years (range, 1-7) with rituximab. Table 1. Incidence of SPM p Treatment, %- Purine analogs- FC- RFC- Chlorambucil- Bendamustine- Alemtuzumab- CorticothŽrapie - 1,9 10,5* 24,4* 4,9 0 3,5 0 <0,001 Conclusion: In this large single center retrospective study, we found an earlier and significantly increased incidence of SPM, mainly skin cancers, in CLL patients treated with R-chemotherapy compared to those given chemotherapy alone. It remains to be determined whether this increased SPM incidence is a due to a direct toxicity of rituximab or merely a collateral consequence of improved OS observed after rituximab. Disclosures Facon: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Cazin:ROCHE: Consultancy; MUNDIPHARMA: Honoraria, Research Funding; NOVARTIS: Honoraria; GILEAD,: Honoraria. Morschhauser:Genentech Inc./Roche: Other: Advisory boards.

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.

CLL with deletion 17p (17p-) or refractory to fludarabine (F)-based regimens is characterized by poor prognosis. The cooperative French/German CLL2O study aimed at achieving deep and durable response in this population by combining alemtuzumab (A) and dexamethasone (D) induction, followed by consolidation with A maintenance or allogeneic stem-cell transplantation (allo-SCT).

T-cell prolymphocytic leukaemia (T-PLL) is an aggressive T-cell neoplasm with a mature post-thymic T-cell phenotype. Most patients present with markedly elevated leucocyte counts, splenomegaly, lymphadenopathy, hepatomegaly, skin lesions, pleuroperitoneal effusions or central nervous system involvement (Matutes et al, 1991). The most frequent chromosome abnormalities in T-PLL are inv(14)(q11q32), t(14;14)(q11;q32) or the less common t(X;14)(q28;q11) (Maljaei et al, 1998). Activation of TCL1A or MTCP1 via the inv(14)/t(14;14) or t(X;14) respectively, are thought to be the primary genetic events in T-PLL. Frontline, high response rates have been reported with intra-venous alemtuzumab (Dearden et al, 2001). After 4 months of therapy, consolidation with stem cell auto- or even allo-transplantation is recommended whenever feasible. Various purine analogues have been used for front line therapy with limited efficacy (Mercieca et al, 1994). Sequential chemoimmunotherapy based on fludarabine, mitoxantrone and cyclophosphamide induction followed by alemtuzumab consolidation (FCM+A) also seems to offer an alternative to alemtuzumab alone (Hopfinger et al, 2013). Still, with current treatment options, outcomes remains poor, with early relapses and a median survival time of 20 months (Dearden, 2012). Bendamustine is an original alkylating agent that shows only partial cross-resistance with other DNA-binding anticancer agents and no cross-resistance with other alkylating agents. Bendamustine is widely used in the treatment of indolent B-cell lymphomas, including chronic lymphocytic leukaemia (CLL). Two studies have focused on the effect of bendamustine in refractory or relapsed mature T cell neoplasms (Damaj et al, 2013; Zaja et al, 2013) showing encouraging response rates and acceptable toxicity. To our knowledge, only three T-PLL treated by bendamustine have been reported to date. Here, we report the largest series of T-PLL managed with bendamustine in frontline and relapse settings. In this multicentre retrospective study, 15 patients with a diagnosis of T-PLL according to World Health Organization criteria (Herling et al, 2004) were treated by bendamustine between 2009 and 2013. Approval of this study was obtained from the local Institutional Review Board of the Regional Hospital and of Lille and was in accordance with the declaration of Helsinki. Seven patients received bendamustine after frontline alemtuzumab failure (three non-responders, four relapsed), two were treated after multiple therapies and six patients were treated by bendamustine frontline (after good response rates were observed prior to relapse). Table 1 summarizes baseline characteristics of the patients. Median age at T-PLL diagnosis was 62 (range: 45–86) years; 73% of patients were male. Thirteen patients had successful cytogenetic analysis, all karyotypes were complex (≥3 abnormalities). Seventy-nine percent of cases had chromosome 14 abnormalities (15% t(14q11);(14q32); 30% inv(14)(q11;q32); 23% t(Xq28;14q11)). Del(11q) and del(17p) were found in 50% and 38%, respectively. Bendamustine was given intravenously (70–120 mg/m2/d over 30–60 min, days 1 and 2, every 3 weeks) for an intended total of six cycles. Prophylactic antibiotics (including anti-virals) were used in addition to bendamustine. Sixty percent of patients had received a prior therapy, which always included alemtuzumab (Table 1). Responses to previous treatment were poor with a 5 months median (range 2–24) progression-free survival (PFS). Responses were evaluated on clinical and haematological data, including bone marrow aspiration. Detection of minimal residual disease by flow cytometry and polymerase chain reaction (PCR) was not included in the response criteria. PFS and overall survival (OS) were plotted according to Kaplan–Meier product-limit method and calculated from the beginning of bendamustine therapy to the occurrence of T-PLL relapse or death, respectively. After bendamustine treatment, three patients (20%) achieved complete response (CR) and five patients (33·3%) partial response (PR), for an overall response rate (ORR) of 53·3%. The median PFS was 5 months (Fig 1A) and the median OS was 8·7 months (Fig 1B). PFS and OS were not correlated to alemtuzumab exposure, line of treatment (Fig 1C, D), karyotype or clinical features. The patients with at least PR had a longer PFS (Fig 1E) and OS (Fig 1F) than those who did not respond (logrank P = 0·001 and P = 0·01 respectively). A trend toward a shorter PFS was found in patients with CD4+/CD8+ immunophenotype (logrank P = 0·07). Two patients managed to proceed to autologous and two others to allogeneic bone marrow transplantation. Median daily bendamustine dosage was 100 (70–120) mg/m². Four out of six patients (67%) who received bendamustine 120 mg/m², responded. In contrast, only 4/9 (44%) patients who received bendamustine 100 mg/m² or less were responders. Interestingly, two of the three patients who were refractory to the last prior treatment regimen, responded to bendamustine (CR = 1, PR = 1) with a duration of response of 13 and 27 months, respectively. Among the six patients who received bendamustine as first line therapy, 4 (67%) responded (CR = 2, PR = 2) but response duration was short (2–10 months). The safety profile of bendamustine in these 15 patients appears similar to that in other studies in mature T cell neoplasms. Premature termination (<3 cycles) occurred in five patients due to progressive disease (PD, n = 3) or infections (n = 2). Patient 2 died of infection (grade 5) related to bendamustine but also related to PD, in fourth line of treatment. Patient 8 developed a grade 2 infection related to bendamustine (neutropenia). The most frequent adverse events were haematological. Grade 3–4 neutropenia and thrombocytopenia were documented in three patients (20%) and two patients (13%), respectively. Our results confirm the good ORR of single-agent bendamustine in mature T cell neoplasms. For those patients refractory to alemtuzumab or unsuitable for alemtuzumab retreatment, the recommandation is to use a purine analogue-based therapy (Dearden, 2012). Nelarabine and/or fludarabine are usually an alternative for which there is some evidence of activity. In a phase 1 study in 11 T-PLL patients (Gandhi et al, 2008), ORR was 20% for nelarabine as a single agent, rising to 63% (13% CR) for the combination with fludarabine, on a mixed population of T-PLL (three patients) and CLL (six patients). Furthermore, grade 3–4 neutropenia and thrombocytopenia complicated 38% and 36% of courses of nelarabine treatment in this study. Therefore, bendamustine seems to be a good alternative in this indication, with similar response rates and better safety. In conclusion, our restrospective study in 15 patients showed that bendamustine is a valuable treatment option for T-PLL, particularly in patients who are refractory to alemtuzumab. Combinations with alemtuzumab or other new therapies effective in T-cell lymphomas (histone deacetylase inhibitors, pralatrexate) or targeting oncogenic pathways (phosphatidylinositide 3-kinase inhibitors) are warranted. This work was partly supported by the CAPTOR project (Investissements d'avenir “ANR-11-PHUC-001”). LY and BC designed the research, LY and CH wrote the manuscript, all authors performed the data collection, LY, GD and CH analysed data.

Abstract Introduction: For relapsed or refractory (R/R) CLL patients (pts), combination of bendamustine and rituximab appears safe and effective (Fischer 2011). Ofatumumab monotherapy gives 58% ORR in heavily pre-treated (median 4 prior lines) R/R CLL pts (Wierda JCO 2010). High doses (HD) steroids are also active in poor prognosis pts with bulky nodal involvement or p53 impairment (Castro 2008, Xu 2010). We report a planned interim analysis of the ICLL01-BOMP phase II trial evaluating the association of Bendamustine, Ofatumumab and high-dose MethylPrednisolone for fit R/R CLL pts after 1-3 previous lines (NCT01612988). Patients and Methods: Primary endpoint was CR rate after 6 cycles (cy) of the BOMP regimen [i.e. bendamustine (70 mg/m2 d1, d2), ofatumumab (1000 mg d1;15 on cy#1-2 and d1 on cy#3-6) and HD methylprednisolone (1 g/m2 d1-3)]. The c#1 was preceded by an ofatumumab (300 mg) prephase. Response evaluation (IWCLL 2008) was done 3 months (m) after the last cy along with blood and bone marrow 10-color flow MRD analysis. Results: Among the 55 pts of this analysis, median age was 64 years (44-76). CIRS-G comorbidity score was 2-6 in 61% and pts had received 2-3 lines in 37% of the cases. Prior FCR-like regimens (50 (91%) patients) had been followed by relapse within 2y in 22/55 and 5/55 pts were fludarabine-refractory (FR). IGVH was unmutated (UM) in (47/52) 90.4%. Karyotypes were complex in 18/46 (39%) cases. Distribution according to FISH hierarchical model was: del(17p) in 15 (27%), del(11q) in 14 (26%), trisomy 12 in 4 (7%), del(13q) in 17 (31%) and normal in 5 (9%). Mutations on the TP53, SF3B1 and NOTCH1 genes occurred in 17 (31%), 14 (26%) and 5 (9%) pts, respectively. According to published risk stratification (Zenz, 2012), 34/55 pts (62%) belonged to the “highest-risk” group with either TP53 disruption (deletion and/or mutation) (n=19) and/or early relapse within 2 years post-FCR (n=22). The remaining patients belonged to either the “high-risk” group (UM-IGVH and/or Highb2mic and/or del11q) accounting for 17 pts (31%) or to the “low-risk” group (or non evaluable) accounting for 4 (7%) pts. Overall, 292 BOMP cy (mean 5.3 cy/pts) were delivered. Safety analysis recorded 158 grade 3-4 adverse events (G3-4/AE) with according to cy: neutropenia: 20.8%, thrombocytopenia: 11.3%, anemia: 2.4%, infection: 5,8%, hyperglycemia: 7,5%, liver enzyme elevation: 1,4%, cutaneous reaction: 1,4%, ofatumumab infusion related reaction: 0,3% and other AE: 3,4%. Overall 43 out of 55 pts (78.2%) had at least one G3-4/AE. Twenty-eight severe adverse events were reported in 20 pts. Treatment interruption before planned 6 cy occurred for pts' decision (n=3), excessive toxicity (n=5) or early progressive disease (PD) (n = 4). Response in the ITT population was 76.4% ORR with 20% CR (n=11), 56.4% PR (n=31 including 5 nPR and 1 CRi), 9.1% stable disease (n=5), 10.9% PD (n=6) and 3.6% (n=3) non evaluable. Blood MRD obtained in 45 pts was negative (<10-4) in 13 (28.8%) cases. Following evaluation, 5 responding pts (9%) had RIC allogeneic (RIC-Allo) transplantation with a persistent remission. With median follow-up of 16.2 (5.1-23.6) months (m) we observed 9 deaths, related to PD (n=5), EBV-induced lymphoproliferation (n=1), PML encephalitis (n=1), sepsis/pancytopenia (n=1) or unknown origin (n=1). We recorded 22 relapses (including 4 Richter Syndromes) resulting in treatment in 17 cases, with a BTK inhibitor in 8 cases. The median OS has not been reached (estimation 84% at 18 m) (Fig 1B). The median PFS was 18.4 m (95%CI, 14.6-22.2) and the median time to next treatment 17.6 m (95%CI, 12.9-22.4). With 5 cases censored at time of RIC-Allo, the PFS (censored analysis) was 17.5 m (95%CI, 13.2-21.8). (Fig 1A) After univariate analysis, ORR was lower in the “highest-risk” (64,6%, p=0.01), del(17p) (40%, p=0.003), TP53 mutation (47.1%, p=0.01) and complex karyotype (61.2%, p=0.024) groups. PFS was shorter in the “highest-risk” (14 m, p=0.046), FR (4.96 m, p<0.001), del(17p) (9.5 m, p=0.017) and TP53 mutation (9.5 m, p=0.007) groups. Conclusion: Relapse treatment of CLL is a challenge especially after prior FCR-like treatments, accounting for >90% of this trial population. These results in terms of response and survival appear noteworthy considering that >60% are “highest-risk” pts. This study provides important information for forthcoming comparison with next emerging CLL therapies. Figure 1 Figure 1. Disclosures de Guibert: Roche: Honoraria. Feugier:Roche: Honoraria. Schuh:Roche, Gilead, GSK, NAPP, Celgene: Honoraria. Leblond:Roche: Honoraria, Speakers Bureau. Tournilhac:mundipharma: Honoraria, Other, Research Funding; GSK: Honoraria, Other, Research Funding; Roche: Honoraria, Other, Research Funding.

Abstract Introduction Patients with asymptomatic early Rai or Binet stage chronic lymphocytic leukemia (CLL) do not benefit from mono-chemotherapy. Therefore, clinical observation without treatment (watch&wait; W&W) has been the gold standard for the management of these patients. Chemoimmunotherapy with FCR improves the outcome of patients with advanced CLL, but its efficacy in early stage disease has not been investigated. Several clinical and biological variables identify those patients who have a high risk of an aggressive disease course and who might benefit from early interventions. Consequently, this trial was conducted to test the value of FCR treatment in patients with early stage, high-risk CLL. Methods This report represents the endpoint and safety analysis of a randomized German-French cooperative phase III trial comparing the efficacy of early versus deferred FCR therapy in treatment-naïve Binet stage A CLL patients with a high risk of disease progression. Risk assessment was performed using 4 prognostic markers: Lymphocyte doubling time <12 months, serum thymidine kinase >10 U/L, an unmutated immunoglobulin heavy chain variable region gene (IGHV) status, and presence of unfavorable cytogenetics (del11q, del17p, trisomy 12) by fluorescence-in-situ hybridization. Presence of at least 2 versus less than 2 of these factors defined “high-risk” versus “low-risk” CLL. High-risk CLL patients were further randomized to receive either 6 cycles FCR (HR-FCR) or to be followed by a W&W strategy (HR-W&W). Patients with low-risk CLL were observed only (LR-W&W). Results Between 2005 and 2010, a total of 824 patients was enrolled, 423 patients in 69 centers of the German CLL Study Group and 401 patients in 25 centers of the French Cooperative Group on CLL. The diagnosis of CLL needed to be established no longer than 12 months prior to enrollment and patients were required to present with previously untreated stage Binet A CLL at the time of inclusion. Overall, 800 patients (97.1%) were stratified, 201 of them categorized as high-risk CLL (25.1%). There was no significant difference between high-risk patients from the two study groups regarding common baseline characteristics (e.g., age, sex, comorbidity, immunophenotype) and the distribution of risk factors used for stratification. 100 out of 201 high-risk patients were randomized to receive FCR therapy (HR-FCR), while 101 patients were allocated to the HR-W&W arm. 18 out of 100 patients (18%) withdrew consent for FCR therapy before treatment was started. 71 (86.6%) of 82 treated patients completed ≥4 cycles. The most common of 228 CTC grade III/IV adverse events reported within 12 months after treatment initiation were hematotoxicity (73.2% of patients) and infections (19.5% of patients). Three patients (3.7%) developed fatal CTC grade V infections (2 septic bacteremias, 1 of them with pulmonary aspergillosis; 1 encephalitis). Out of 79 patients available for response assessment until month 12 after treatment start, 76 showed a complete or partial remission (ORR 96.2%), 2 patients had stable disease (2.5%) and 1 patient had progressed (1.3%). After a median follow up of 46 months (range 0-88 months), HR-FCR patients demonstrated a significantly improved event-free survival (EFS) compared to HR-W&W patients (median EFS not reached versus 24.5 months, respectively, P<0.0001, Fig. 1). Overall survival was not significantly different between HR-FCR and HR-W&W with 181 high-risk patients (90%) being alive at last follow up. Both, HR-FCR and HR-W&W patients exhibited a significant shorter event-free and overall survival than LR-W&W patients, demonstrating an efficient prognostic segregation of patients by the risk assessment used for this trial (analysis based on the German LR-W&W cohort only, complete German-French LR-W&W data will be presented at the meeting). Conclusion This is the first randomized phase III trial investigating the efficacy of FCR chemoimmunotherapy in early stage CLL. So far, the study has revealed two major results: 1. A combination of clinical and biological factors can be used to identify early stage CLL patients who experience a rapid disease progression with unfavorable outcome, 2. FCR chemoimmunotherapy substantially improves event-free survival in early stage high-risk CLL. Disclosures: Langerbeins: Roche: travel grants Other. Cazin:roche: meeting invitation Other, Membership on an entity’s Board of Directors or advisory committees; GSK: meeting invitation, meeting invitation Other, Membership on an entity’s Board of Directors or advisory committees. Fischer:Mundipharma: Travel grants, Travel grants Other; Roche: Travel grants Other. Stilgenbauer:Roche: Consultancy, Research Funding, Travel grants Other; Mundipharma: Consultancy, Research Funding. Leblond:Roche : Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hallek:F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding.

Background: To date, the majority of trials on chronic lymphocytic leukemia (CLL) focused on patients considerably younger than the median age of onset for CLL. As a result, no definitive treatment exists for elderly patients, especially less medically fit patients.Objectives: The objectives of this study are to examine the impact of comorbidities on outcome as well as to compare three different therapeutic regimens in outcome efficacy.Materials and Methods: We retrospectively identified 143 patients aged >65 years, who received fludarabine, cyclophosphamide, and rituximab (FCR) (n=49), fludarabine and rituximab (FR) (n=74), or rituximab with chlorambucil (R-CLB) (n=20) as first initial immunochemotherapy.Results: At current follow-up (median: 24 months), the proportion of patients with a clinical response was higher with FCR (75%) than FR (57%) and R-CLB (28%). For FCR, FR, and R-CLB patients, 2-year overall survival (OS) was 94%, 76%, and 73%, respectively, (p=0.14), while 2-year progression-free survival (PFS) was 90%, 58%, and 30% (p<0.001). In the fludarabine based regimen (FR and FCR) population, higher rituximab doses (500 mg/m(2) vs. 375 mg/m(2)) correlated with prolonged PFS.Conclusion: Despite the retrospective nature of this study, we demonstrate that elderly patients with CLL benefit from frontline immunochemotherapy, and emphasize the importance of maintaining rituximab dose intensity. (C) 2013 Elsevier Ltd. All rights reserved.

hma.2013.0854 Auteur(s) : Bruno Cazin b-cazin@chru-lille.fr Service des maladies du sang, CHRU de Lille, Hopital Huriez, Lille Comment traiter une leucemie lymphoide chronique (LLC) ? Avant de repondre a cette question, se pose une question prealable : dois-je traiter ce patient atteint de LLC ? Si oui, il importera d’evaluer la capacite du patient a recevoir tel ou tel traitement. De nouvelles evolutions therapeutiques s’annoncent, mais nous donnerons ici la priorite [...]