Abstract: Mantle cell lymphoma (MCL) accounts for approximately 6% of non-Hodgkin's Lymphoma (NHL) in adults. MCL commonly responds to initial therapy but inevitably patients relapse and response duration decreases from one salvage therapy to the next. Indeed, there is an urgent need to control and/or eradicate residual MCL cells that are responsible for early and late relapses. Maintenance with Rituximab (RM) after R-CHOP has been shown to prolong OS in elderly MCL patients treated with R-CHOP (Kluin-Nelemans et al. NEJM). Induction with high-dose cytarabine followed by autologous stem cell transplant (ASCT) consolidation is standard of care for young patients but RM after ASCT has never been investigated so far. The LyMa trial (ClinicalTrials.gov, NCT00921414) is a prospective international randomized phase III trial that investigated RM after ASCT in young previously untreated MCL patients. Patients were included at diagnosis ( 〈 66y; stage 〉 I, untreated, diagnosis of MCL according to WHO 2008 classification). Induction immuno-chemotherapy consisted of 4 courses of R-DHAP every 21 days (Rituximab, Dexamethasone, High-dose cytarabine, salt Platinum) followed by ASCT consolidation. Patients who were not in response (CR/CRu or PR) after R-DHAP received 4 additional courses of R-CHOP-14 before ASCT. The conditioning regimen for ASCT was R-BEAM. Patients in response after ASCT were randomized (1:1) between RM or no RM. RM consisted of one infusion of Rituximab (375mg/m2) every 2 months for 3 years. The primary endpoint was event-free survival (EFS) calculated from time of randomization; events were defined as disease progression, relapse, death, severe infection or allergy to Rituximab. Progression-free survival (PFS) and overall survival (OS) from time of diagnosis and time of randomization were secondary endpoints. The interim analysis showed a trend for a longer EFS and PFS in favor of RM arm. (Le Gouill et al, ASH 2014, abs 146). Herein, we present the results of the final analysis. RESULTS. Two hundred and ninety nine patients were enrolled from September 2008 to August 2012. Demographic and clinical characteristics of the patients were as followed: median age of 57y (27-65), 79% of male, MIPI-low in 53.2%, MIPI-I in 27.4% and MIPI-H in 19.4%. After inclusion, 277 patients completed the 4 courses of R-DHAP. The CR/CRu rate after R-DHAP was 77.3% and ORR was 89.3%. Twenty patients received R-CHOP. In all, 257 patients (including 12 patients who received R-DHAP/R-CHOP) underwent ASCT. After ASCT, 240 patients were randomized (RM, n=120; no RM, n=120). Median follow-up (mFU) from inclusion and from randomization were 54.4m (52.7-59.2) and 50.2m (46.5-54.2), respectively. The mPFS and mOS from inclusion in an intention to treat analysis were not reached; the 4y-PFS and OS were 67.8% (95%CI, 62.1 to 72.8) and 78% (95%CI; 72.8 to 82.3), respectively. According to EFS definition, 47 (39.2%) patients had an event in the no RM versus 25 (20.8%) in the RM arm. The mEFS from randomization was not reached in both arms. The 4y-EFS was 61.4% (95%CI; 51.3 to 69.9) in the no RM arm vs 78.9% (95%CI; 69.6 to 85.6) in the RM arm (p=0.0012). The EFS duration was significantly superior in the RM arm with a 54.3% reduction in the risk of event (Hazard ratio (HR)= 0.457; 95%CI, 0.28 to 0.74; p=0.0016). The median PFS and OS from randomization were not reached in both arms. The 4y-PFS and OS from randomization were superior in the RM arm: 82.2% (95%CI; 73.2 to 88.4) vs 64.6% (95%CI; 54.6 to 73) (p=0.0005) and 88.7% (95%CI; 80.7 to 93.5) vs 81.4% (95%CI; 72.3 to 87.7)(p=0.0413). Patients in the RM arm had a 60% reduction of risk of progression (HR=0.4; 95%CI, 0.23 to 0.68; p=0.0007) and a 50% reduction of risk of death (HR=0.5; 95%CI, 0.25 to 0.98; p=0.0454). The per protocol analysis yielded similar results. In conclusion, The LyMa trial demonstrates for the first time that RM after ASCT prolongs EFS, PFS and OS. Thus, 4 courses of R-DHAP plus ASCT (without TBI) followed by RM maintenance (one infusion every 2 month for 3 years) is a new standard of care for young MCL patients. Disclosures Thieblemont: Gilead: Consultancy; Roche: Consultancy; Janssen: Consultancy. Ribrag:Pharmamar: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; NanoString: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding. Casasnovas:BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; ROCHE: Consultancy, Honoraria, Research Funding. Haioun:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hermine:Celgene: Research Funding; AB science: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Novartis: Research Funding; Alexion: Research Funding.

Abstract: Introduction.The BCL-2 inhibitor venetoclax has demonstrated high efficiency in relapsed/refractory (R/R) CLL patients with an overall response rate (ORR) of 79%, regardless of the TP53gene status. Venetoclax has then been EMEA-approved for CLL patients with TP53disruption who are unsuitable for or have failed a BCR inhibitor (BCRi) and those without TP53 inactivation who have failed both immunochemotherapy and a BCRi. Whether this agent provides a well-balanced safety/efficacy profile and a prolonged survival in real-world practice remains to be investigated. Methods. An early access program (ATU) of venetoclax was available in France between July 22thand December 4th, 2016 for R/R CLL patients as per EMEA label. We retrospectively analyzed the outcome of patients included in this program who had received at least one day of venetoclax. Data quality was ensured using on-site data verification and computerized discrepancy errors. Results. Data concerning both clinical features andoutcome were available for 72 of the 93 patients for whom venetoclax was requested in this program. Among them, only 63 patients received at least one day of venetoclax for progressive CLL or Richter syndrome (RS) and were included in the present analysis. Median age was 69 years (range, 25-89) and sex ratioM/F was 47/16. A total of 56 patients received venetoclax for CLL and 7 for RS. Patients had previously received a median of 4 prior therapeutic lines (range, 0-7) including FCR in 43 (68%) of them, BTK inhibitor (BTKi) in 46 (73%) and PI3Kδ inhibitor (PI3Kδi) in 21 (33%); 5 had prior autologous stem cell transplantation (SCT) and 4 allogeneic SCT. At time of treatment with venetoclax, 32 (76%) patients carried TP53disruption (data available for 42 patients) and 19 (61%) had complex karyotype (CK) defined as ≥ 3 abnormalities (data available for 31 patients). IGHV mutational status was available for 26 patients. Treatment was administered as per label recommandations with a 5-week ramp up phase until the target dosage of 400 mg per day. Median follow-up was 17 months. Median time on therapy was 11.9 months (range, 0.1-24.6). Among adverse events of interest, tumor lysis syndrome (TLS) was observed in 19% of case, most of them being biological TLS and 3% were clinical TLS, and 15 (24%) patients developed infections requiring hospitalization. Autoimmune cytopenia was seen in 9.5% of patients. Four (7%) patients developed RS while on venetoclax for progressive CLL. To date, a total of 30% of patients remains on therapy. Three patients proceeded to allo-SCT after venetoclax therapy. Among the 7 patients who received venetoclax for RS, 2 had an objective response that lasted 7 and 14 months. However, median overall survival (OS) was only 1.1 months (95% CI, 0.7-1.5). Regarding the CLL cohort, ORR was 73%. It did not significantly differ according to the TP53status (90% with TP53disruption vs 69%, P= 0.189). Conversely, CK was associated with a lower ORR (92% vs 56%, P= 0.024). No impact of the type of prior BCRi (BTKi vs PI3Kδ inhibitor) was noted. 2-year progression-free survival (PFS) was 62% without significant impact of the TP53status (59% in case of TP53disruption vs 68% if wt-TP53,P= 0.587). Patients with CK had 2-year PFS of 44% compared to 78% for those without CK (P= 0.182). 2-year overall survival (OS) was 65% for the whole cohort and significantly better for responding patients than for non responders (76% vs 31%, P 〈 0.001). TP53disruption was associated with 2-year OS of 65% vs 90% (P= 0.176). Patients with CK had 53% of 2-year OS vs 62% for the remaining cohort (P= 0.236). There was no difference for the type of prior therapies (BTKi, PI3Kδ inhibitor or prior SCT) or IGHV mutational status. Patients who stopped venetoclax therapy had a very poor outcome with a median OS of 5 months. Conclusions.Our real-life study shows response rates and survival data that are in line with those observed in pioneer venetoclax clinical trials. CK should be evaluated as a predictive factor for response to venetoclax. Disclosures Herbaux: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead Sciences, Inc.: Consultancy, Honoraria. Laribi:Roche: Other: Grant; Teva: Other: Grant; Hospira: Other: Grant; Sandoz: Other: Grant; Gilead: Other: Personal fees; Novartis: Other: Grant and personal fees; Takeda: Other: Grant and personal fees; Amgen: Other: Personal fees. Feugier:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Guieze:abbvie: Honoraria; janssen: Honoraria; gilead: Honoraria.

Abstract: Introduction CLL2007FMP (fit medically patients) is a Randomized Phase-III Trial conducted by the French Cooperative Group on CLL and WM (FCGCLL/WM) and the “Groupe Ouest-Est d'Etude des Leucémies et Autres Maladies du Sang” (GOELAMS), comparing FC plus Rituximab (FCR) to FC plus Campath (FCCam) in previously untreated fit patients with chronic lymphocytic leukemia (CLL). Early results showed that the FCCam regimen was associated with an unfavourable safety profile limiting significantly its use in this indication (Blood 2012). We present here the results of the extended follow up of the CLLFMP2007 trial, with particular emphasis on survival data, minimal residual disease (MRD) and late adverse events. Methods In this trial, 178 younger ( 〈 65) fit patients (pts) (cumulative illness rating scale (CIRS) score of up to 6), were enrolled between November 2007 and January 2009. Cases with del(17p) were excluded. Pts were randomly assigned to receive 6 oral courses of FCR (n=83) or FCCam arm (n=82). The primary endpoint of the study was 3-year progression-free survival (PFS). Secondary endpoints were safety, response to treatment, overall survival (OS) and MRD. MRD evaluation was performed by 6-color flow cytometry in an oligocentric manner. MRD testing was scheduled before therapy initiation and at final evaluation, (i.e. 3 months after completion of immunochemotherapy) where it was to be assessed for all responding patients in both peripheral blood (PB) and bone marrow (BM). Recruitment was interrupted in January 2009 after 165 pts had been randomized due to an excess of mortality in the FCCam arm. Results PFS and OS were not significantly different between the two arms. With a median follow-up of 55.5 months (interquartile range, 50-60), 57 pts in the FCCam arm were free of disease progression compared with 50 in the FCR arm, with a 3-year estimated PFS at 81% in both arms (p=0.80). Fourteen pts died in the FCCam arm (7 from progression and 7 from toxicity) and 9 died in the FCR arm (all from progression), with a 3-year estimated survival at 90% vs. 88% (p=0.85). PFS was significantly impacted by IGHV mutational status (p=0.001), Binet stage (p=0.0002) and MRD level. At final evaluation, MRD was established using the result in PB samples (available for 120 patients) and was determined in 103 pts by combining the results from blood and BM samples. Interpretation was based firstly on the use of the classical 10-4 threshold as reference and secondly on the limit of detection of the technique (0.7x10-5). In MRD-positive patients, the median PFS was 44.7 months (PB) whereas it was not reached in the group with MRD lower than 10-4 (p 〈 0.0001, figure 1) ; similar data were found in MRD-positive PB+BM patients with a median PFS of 46 months whereas it was not reached in the group with MRD lower than 10-4 (p=0.002). No significant difference was found regarding OS but follow-up is still short for this evaluation. Similar results were observed when considering the limit of detection of the MRD technique (data not shown). Late toxicities (occurring after the final evaluation at 3 months after the end of treatment or at the ninth month when treatment was prematurely stopped) included : 1 bile duct cancer, 1 myelodysplastic syndrome, 1 transient ischemic attack, 1 lung adenocarcinoma and one prostate cancer in the FCR arm and 3 febrile neutropenia, 3 pneumonia (1 due to legionella), 1 pneumococcal sepsis, 1 bronchitis, 1 toxoplasma eye infection, 1 pyelonephritis, 2 herpes zoster, 1 acrodermatitis, 1 subdural hematoma, 1 autoimmune thrombocytopenia, 1 agranulocytosis, 1 autoimmune haemolytic anaemia in the FCCam arm. Conclusion Results of this extended follow-up of the CLL2007FMP trial confirm the absence of superiority of the FCCam regimen on OS and PFS. Interestingly, longer follow-up did not reveal a higher rate of late toxicity in FCCam arm, notably in terms of secondary malignancies; Similarly to early toxicity, late was adverse events were mainly infectious. Finally, MRD status determined by 6-color technique in PB and/or BM at post-treatment evaluation was predictive of PFS whatever the treatment arm. This finding is in line with recent reports in other studies pointing out to the powerful value of MRD as prognostic factor, supporting its use as PFS surrogate primary endpoint in clinical trials. Disclosures: Feugier: roche: Honoraria. 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.

Abstract: Despite improvement in treatment strategies, virtually all chronic lymphocytic leukemia (CLL) patients will relapse and experience tumor resistance. The 17p deletion resulting in loss of the TP53 gene, found in up to 20-40% of relapsing patients, is strongly associated with impaired response to genotoxic agents, reduced progression free survival and poor overall survival. The 17p deletion usually coincides with TP53 mutation, leading to the impairment of the p53-associated pathway. In addition, sole TP53 mutations (without 17p deletion) appear also associated with poor outcome in prospective trials. However, TP53 mutation screening is time consuming, can be not exhaustive, and the respective impact of different patterns of TP53 gene impairment on p53 function and prognostic remains unclear. We previously developed a functional assay to detect p53 dysfunction (Le Garff-Tavernier, 2011) and we aim to validate this analysis on a large prospective trial. Clinical and laboratory data were collected from CLL patients (pts) enrolled in the ICLL001 – BOMP phase II trial of the French CLL intergroup (NCT01612988) evaluating a prephase of ofatumumab (300 mg) followed by 6 monthly courses of BOMP including bendamustine (70 mg/m2 d1-2), ofatumumab 1000 mg TD (d1 and d15 on 1st and 2nd courses) and high dose methylprednisolone (1 g/m2 d1-3) in fit patients with relapsing CLL and IWCLL treatment criteria. In addition to conventional screening, we focused on p53 evaluation. FISH analysis for 17p deletion was done with a 10% cut-off for positive result, TP53 gene mutation screening was performed using Sanger sequencing of the entire coding region (exons 2–11) and the p53 functional status in CLL cells was determined by a flow cytometry assay based on induction of p53 and p21 protein expression after etoposide and nutlin-3a exposition. Data from the first 55 enrolled pts are available. Sex ratio M/F was 3.3 and median age was 63.8 yrs (44.6-76.4). CLL diagnostic had been done 7,2 (1,9-16,8) years before inclusion. All patients had according to IWCLL criteria an active disease of Binet stage of A (11%), B (57%) and C (32%) respectively. Patients had been previously pretreated with a median of 1 (1-3) lines, including FCR (or FCR-like) in 51 (93%) pts and 22 (42%) pts had experienced high-risk relapses within 24 months post-FCR, with 7 (13%) pts being fludarabine refractory (less than PR after fludarabine regiment and/or response lasting less than 6 months). IGVH gene status was unmutated in 90%, elevated β2-microglobulin ( 〉 4) was found in 52%. Karyotypes were complex (≥ 3 abnormalities) in 18/46 (39%) successful cases. Using FISH, we found 15/55 (27%) del17p (median of positive cells 71%, range 10-98), 6/55 (11%) tri12, 18/55 (33%) del11q, 35/55 (64%) del13q. Results of p53 functional assay was available for 52 pts with the following results: normal in 31 pts and abnormal in 21 pts including type A (n=4), type B (n=13) and type C (n=4) dysfunction. Mutation screening was available in 55 pts. No mutation were detected in 38 pts, one significant mutation was detected in 14 pts within exon 5 (n=1), exon 6 (n=2), exon 7 (n=2), exon 8 (n=6), exon 10 (n=1) and intronic splice site (n=2) ; 3 pts had 2 mutations within exons 7 and 8 (n=1), exons 7 and 10 (n=1), exons 5 and 7 (n=1). Among the 52 pts with available functional results we found the 7 following groups (Table). In this study, the sensitivity and specificity of the p53 functional test to detect patient with 17p deletion and/or TP53 mutation was 89.5% (66.9 –99.7) and 87.9% (71.8 – 96.6) respectively. Response to p53/21 functional assay 17p deletion TP53 mutation n % Group 1 Normal No No 29 56 Group 2 Abnormal Yes Yes 13 25 Group 3 Abnormal Yes No 1 2 Group 4 Abnormal No Yes 3 5.5 Group 5 Abnormal No No 4 7.5 Group 6 Normal Yes No 1 2 Group 7 Normal No Yes 1 2 This study shows that an in vitro p53 functional analysis can predict with an acceptable sensitivity the presence of TP53 gene disruption and could be useful to identify pts with TP53 mutation without 17p deletion. Interestingly, this functional assay coupled with cytogenetic and mutational screening could reveal 3 sub-groups of pts with potential clinical consequences: i) normal p53 function despite a del17p deletion (group 6) ii) normal p53 function despite a TP53 mutation (group 7) and in contrast iii) abnormal p53 function without any TP53 gene disruption (group 5) allowing to describe alternative alterations of p53 pathway. Disclosures: Dilhuydy: Roche: Honoraria. 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. Feugier:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Tournilhac:MUNDIPHARMA: Consultancy, travel funding Other; GSK: Consultancy, travel funding, travel funding Other; Celgene: Consultancy, teaching, teaching Other.

Abstract: Introduction: The 17p deletion (del(17p)) resulting in loss of the TP53 gene is associated with impaired response to genotoxic agents and has an impact on PFS following BTK inhibitor and possibly also venetoclax. The del(17p) usually coincides with TP53 mutation, leading to the impairment of the p53-associated pathway. Sole TP53 mutations appear also associated with poor outcome in prospective trials. The iwCLL guidelines recommend to look for del(17p) and TP53 mutation before each line of treatment. An original approach is the functional assay, which highlights the functional abnormalities of p53 whether it is a TP53 gene disruption (del(17p) and/or TP53 mutation) or a defect of another actor in the p53 pathway. We aim to validate this functional assay on a prospective trial and to study the impact of p53 status on the clinical response regardless of the biological method. Methods: Clinical and biological data were collected from 74 CLL patients (pts) enrolled in the BOMP phase II trial of the French Innovative Leukemia Organization (FILO) (NCT01612988) evaluating 6 monthly courses of BOMP including bendamustine, ofatumumab and high dose methylprednisolone in fit pts with relapsing CLL. In addition to conventional screening, we focused on p53 evaluation at time of inclusion. FISH analysis for del(17p) was done with a 5% cut-off for positive result. TP53 gene mutation screening was performed by Sanger sequencing of the coding region (exons 2-11). A targeted NGS screening (19 genes including TP53, Illumina MiSeq) was also performed. The p53 functional status was determined by a flow cytometry assay based on induction of p53 and p21 protein expression after etoposide and nutlin-3 exposition, as previously described (Le Garff-Tavernier M., 2011), which allows the detection of 3 types of p53 dysfunction (A, B and C), irrespective of an ATM default. Clinical response was evaluated by PFS, OS and TTNT Kaplan-Meier analyses (MedCalc stat). Results: Data from the whole cohort are available. Median age was 64 yrs. Pts had a median of 1 (1-3) lines of treatment previous to this trial, including FCR in 〉 90%. Concerning p53 evaluation, a del(17p) was found in 30% of cases by FISH (22/73 pts with a median of 68% positive cells, range 10-98). The percentage of p53 abnormalities increased to 41% when TP53 mutations were screened (30/73 pts with 1 to 8 mutations, median VAF 10 %, range 1.6-90). Results from the p53 functional assay were available for 69 pts showing the highest level of p53 abnormalities. Indeed, p53 dysfunction was observed in 48% of pts (33/69) including type A (n=11), type B (n=17) and type C (n=5) dysfunction. Thus, the sensitivity and specificity of the p53 functional assay to detect pts with del(17p) and/or TP53 mutation were of 87% and 84% respectively (n=68 pts for which the 3 tests were available). Interestingly, discordant results were observed in 10 pts: 4 pts with a functional p53 despite a TP53 gene disruption (3 with TP53 mutation only and 1 with del(17p) only) and conversely 6 pts with a p53 dysfunction (all with type B dysfunction) but without any TP53 gene disruption, suggesting alternative alterations of the p53 pathway. The only similarity for those latter pts is the occurrence of at least one ATM abnormality (del(11q) and/or ATM mutation). The combination of the 3 assays defines 3 groups: (1) "intact p53" (no TP53 disruption and functional p53, n=32), (2) "altered p53" (TP53 disruption and p53 dysfunction, n=26) and (3) "discordant p53" (n=10). PFS and TTNT were higher in pts without (n=38) compared to those with TP53 gene disruption (n=30) (p=0.04 for both). The OS, even though not significant, presented a similar trend. When considering the functional status, a similar profile is observed but with a better discrimination between pts with normal p53 function (n=36) and pts with p53 dysfunction (n=32) (p=0.002 and 0.003, respectively). Combining the 3 assays, PFS and TTNT of the group 3 "discordant p53" profiles' appeared intermediate (Figure 1). Conclusion: This study shows that a p53 functional analysis can predict with an acceptable sensitivity the presence of a TP53 gene disruption. Interestingly, this functional assay coupled with cytogenetic and mutational screening could reveal a sub-group of pts with discordant results for which PFS and TTNT appeared intermediate. Evaluation of other discordant cases is mandatory to confirm these results and could lead to a wider use of this global functional approach. Figure 1. Figure 1. Disclosures Feugier: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sylvain:Gilead: Other: scientific advisor board. Schuh:Giles, Roche, Janssen, AbbVie: Honoraria. Guieze:abbvie: Honoraria; janssen: Honoraria; gilead: Honoraria. Leblond:Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Sandoz: Honoraria; Amgen: Honoraria.

Abstract: A French and Belgian multicenter phase 3 trial was conducted in medically fit patients with untreated chronic lymphocytic leukemia. Of 178 patients enrolled in the study, 165 were randomly assigned to receive 6 courses of oral fludarabine and cyclophosphamide (FC) in combination with rituximab (FCR; 375 mg/m2 in cycle one, 500 mg/m2 in all subsequent cycles) or alemtuzumab (FCCam; 30 mg subcutaneously injected on cycle days 1-3); each cycle was 28 days. Recruitment was halted prematurely because of excess toxicity; 8 patients died in the FCCam group, 3 from lymphoma and 5 from in-fection. Overall response rates were 91% with FCR and 90% with FCCam (P = .79). Complete remission rates were 33.75% with FCR and 19.2% with FCCam (P = .04). Three-year progression-free survival was 82.6% with FCR and 72.5% with FCCam (P = .21). Three-year overall survival was similar between the 2 arms at 90.1% in the FCR arm and 86.4% in the FCCam arm (P = .27). These results indicate that the FCCam regimen for the treatment of advanced chronic lymphocytic leukemia was not more effective than the FCR regimen and was associated with an unfavorable safety profile, representing a significant limitation of its use. This study is registered with www.clinicaltrials.gov as number NCT00564512.