ALBERT

Description: Background Bortezomib (B) is an effective drug alone or in combination in naive and pretreated WM patients. The interest of high dose of dexamethasone (D) with bortezomib (B) has not been evaluated in WM patients and D is systematically added to bortezomib combination with or without Rituximab (R) (BD, BDR). However, D is responsible for side effects in elderly population. We tested in a phase II trial the efficacy and safety of the addition of D to B after 2 B cycles in patients with a stable or progressive disease (SD, PD). Patients and Methods Bortezomib was used at 1.3mg/m2 IV D1, 4, 8 and 11 every 21 days for 6 cycles. In no responding patients, D (20mg) was added at D1,2, 4, 5, 8, 9, 11 and 12 at Cycles 3 to 6. The main endpoint was the overall response rate (ORR) at two months before D adjunction; secondary outcomes were ORR at 4 and 6 months, response duration, overall survival (OS) and progression-free survival (PFS). Two interim analyses were scheduled and performed after the inclusion of 17 and 27 patients, respectively, using Bayesian estimation of ORR with stopping rules. Results Interim analyses did not allow stopping the trial, with probability of ORR above 35% below 0.9. Thus, a total of 34 patients (pts) were enrolled in the study in two years (2009-2011) in 17 centers. The median age was 70.2 (64.2-79.6).ECOG was ≥1 in 53% of the pts. The median of previous lines, hemoglobin, beta 2 microglobulin, IgM, and albumin was 1, 9.8g/dL, 4.35mg/L, 29g/L, 35 g/L respectively. At 2 cycles, there were 6 partial responses and 10 minor responses(group I), with estimated ORR at 44.1% (95%CI: 27.6-61.9%). D was added in 16/18 pts with stable or progressive disease (group 2). At 4 and 6 cycles, 22/28 and 20/26 pts were in response (12 and 8 in group 1, 10 and 12 in group 2), with resulting 4 and 6 cycles ORR estimated at 75% (95%CI: 47.4-91.7) and 50% (95%CI: 28.0-72.0) in group I and 62.5% (95%CI: 35.9-83.7) and 75% (95%CI: 47.4-91.7) in group 2. A total of 62 adverse events grade 〉 2 (first course: 11, second course: 18, subsequent courses: group 1: 14, group 2: 19) were observed in 38 courses. Of these 62 events (49 grade 3 and 13 grade 4), 52 (84%) consisted in hematological adverse events (18: platelets, 15: hemoglobin, 8: leucocytes, 1 lymphocytes, and 10 neutrophils); 3 neurological toxicities grade 〉2 were observed, 1 after the second course and 2 after the third course in group 1. Otherwise, there were 26 peripheral neurological toxicities grade ≤2, namely 5 for the first 2 courses, 11 in group 1 and 10 in group 2. With a median follow up of 36 months, 23 pts experienced disease progression or died (18 had disease progression and 5 died in response). For patients who achieved at least a minor response, the 18-month progression rates were 31.9% in group 1 and 52.1% in group 2 (p=0.43) and WM unrelated death rates were 6.3% in group I and 16.7% in group 2 (p=0.79). The 2-year survival rate was 79.8% [IC95%: 64.7; 98.3]. The median progression free survival time was 16.8 months [IC95%: 13.0-23.6]. Conclusion We showed that addition of D to B in the elderly population was well tolerated and allowed reaching 6-month response in patients who did not respond to two courses of isolated B. Dexamethasone must be associated to bortezomib-based regimen. Disclosures: Leblond: Mundipharma: 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; Roche : Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Bortezomib in Waldenstrom macroglobulinemi. Dilhuydy:Roche: Honoraria. Leleu:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; LeoPharma: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Amgen: Honoraria; Novartis: Honoraria. Tournilhac:MUNDIPHARMA: Consultancy, travel funding Other; GSK: Consultancy, travel funding, travel funding Other; Celgene: Consultancy, teaching, teaching Other.

Description: Abstract 3695 Despite recent immunochemotherapy advances approximately 50% of DLBCL patients relapse. Data emerging from initial clinical trials demonstrated that Lenalidomide has a significant activity against different subtypes of relapsed/refractory aggressive B-cell lymphoma. Clinical responses are histology subtype-dependent and most prominent in mantle cell lymphoma. The results in DLBCL were less encouraging with ORR of 26%, CR of 9%, PFS of 2.7 mo. Concurrently targeting the tumor cell itself with monoclonal antibody and targeting the immune response and microenvironment with Lenalidomide may be a promising therapeutic strategy. Encouraging by our initial results of Lenalidomide-Rituximab (LR) combination in patient with refractory (R/R) DLBCL (Ivanov V. et al., 2010), Institutional Multidisciplinary Meeting proposed this combination for 17 patients with R/R DLBCL. All pts were refractory to three or more (range: 2–5) previous lines of conventional immuno-chemotherapy. All eligible pts, except 4 primary-refractory, were previously autografted. Median age for the whole group was 62,5 years, (range: 43–79), 5 pts are female. 65% of patients were younger than 65 y. Patients received combination of Rituximab 375 mg/m2 on day 1 or day 7; Lenalidomide (Revlimid), 15 mg/d for the first pt and 25 mg/d for other 16 pts, for 21/28 days. Dexamethasone 40mg, day 1–4 was given for first 7 pts. Initial decision on adding Dexamethasone was based on the extrapolation from the recommended regimen used in multiple myeloma, but it was abandoned in last 10 pts. Initially the treatment duration was established for 6 months, but it was prolonged to 7–11 months for patients in CR. Of 17 pts enrolled on study, 3 patients stopped the treatment during the first course: 1 pt because of grade 3 toxicity and 2 pts because of explosive disease progression. Both patients were switched to palliative care. In 14 pts, received more than 1 course of treatment, 7 (50 %) responded to LR combination, including 6 pts (43%) with CR and 1 (7%) patient with PR. One pt with clinical and PET-FDG scan improvement after 3 courses of LR was included into “auto-allo” tandem program and actually in CR at +12 months after PBSCT. Six pts progressed on LR treatment and were switched to palliative regimens. In intention to treat analysis the CR rate for the whole group was 35%. As regards the follow-up, all 7 pts in PR and CR are evaluable for evaluation. The patient in PR progressed after 5 courses of LR. Six patients in CR group received an average of 8 (range: 7–11) courses of LR treatment. Two patients relapsed after 5 and 26 months of CR and other 4 patients are actually in CR at +7, +17, +18 and +24 months. Adverse events were manageable and the most common toxicity included thrombocytopenia and neutropenia. In relapsed/refractory DLBCL modest initial results of Lenalidomide monotherapy emerge the use of new effective combinations. Recently the combination Lenalidomide-Rituximab (LR) was shown to be highly efficacious in phase 2 study in elderly (〉65 y.o.) patients with DLBCL (Zinzani et al., 2011). Into the group of 23 pts the ORR rate at the end of 6-months induction phase was 35%. Our data confirm results of Bologna group in the younger group of patients. Given the poor prognosis of refractory DLBCL, enrolment in already running prospective clinical trials with Lenalidomide are underway and the investigation of the combination of Lenalidomide and Rituximab is further warranted. Disclosures: No relevant conflicts of interest to declare.

Description: Auto-SCT for MM can provide superior outcome to standard treatments. Since its introduction, auto-SCT has usually been limited to MM patients aged up to 60–65 years. However, traditional upper age limits for auto-SCT are being currently challenged along with the definition of “elderly” itself, especially that no obvious differences in MM biology has been elucidated to justify an arbitrary cut-off of 65 years. This retrospective single centre analysis assessed the outcome of 186 consecutive MM patients aged over 60 years treated with auto-SCT, with the specific aim to compare the outcome of the 82 “elderly” (age〉65 y.) patients subgroup, with their 104 “younger” mates aged between 60 and 65 years treated in the same period and in the same auto-SCT program. Median age among the total 186 patients population was 64 (range, 60–77). Except for age, both groups were comparable (P=NS) as for demographic features, disease characteristics (S&D stage, monoclonal component), and prognostic factors (b2-microglobulin). The majority of patients (91%) received homogeneous “induction” VAD chemotherapy, with this being comparable between the “elderly” (87%) and “younger” (94%) group. In this population, and prior to auto-SCT, the calculated hematopoietic cell transplantation-specific comorbidity index (adapted from the Charlson Comorbidity Index) was also comparable between both groups (77% of the “younger” patients with a 0–1 index, vs. 74% in the “elderly” group; P=NS). The peripheral blood stem cells mobilization procedures (G-CSF with or without chemotherapy) were also comparable between both groups. 97% of the patients received high-dose melphalan conditioning for auto-SCT. 33% of the “younger” and 28% of the “older” group (P=NS) completed a second auto-SCT. ANC and platelets recovery were comparable between both groups (P=NS), and the median length of hospitalization for the first auto-SCT was not different between the two groups: 19 (range, 2–32) days in the “younger” group vs. 17 (range, 2–39) in the “older” group; P=NS). Infectious and other “serious” auto-SCT-related complications were also comparable between groups (P=NS). With a median follow-up of 41 (range, 5–227) months after auto-SCT, 120 patients are still alive. Disease progression (n=40; 61%) was the main cause of death, with this being comparable between both groups. Auto-SCT-related mortality was 3.8% (n=4/104) in “younger” and 3.7% (n=3/82) among “older” subjects. Comparing “younger”/”older” subjects, progression-free survival was significantly higher in the younger group (P

Description: Abstract 2447 Background: LFB-R603 is a chimeric anti-CD20 monoclonal antibody with an optimised glycosylation profile leading to a high binding affinity for the FcγRIIIa receptor and a stronger antibody-dependent cellular cytotoxicity (ADCC) than rituximab, particularly against tumor cells that express low CD20 levels. As a result, LFB-R603 represents a drug candidate in patients (pts) with CLL. Aims: An open-label, multicentre, first-in-human study using escalating doses of LFB-R603 was initiated in November 2008 to assess the safety, pharmacokinetics and potential efficacy of LFB-R603 in pts with CLL relapsing after at least one prior course of therapy with fludarabine. Methods: Twenty one patients were included in 5 dose cohorts. Pts received infusions of LFB-R603 as a flat dose once a week for 4 weeks. The dose was escalated based on safety in a 3+3 design. Total dose of LFB-R603 was 75 mg in cohort A (5–10-20–40 mg), 200 mg in cohort B (20–60×3 mg), 510 mg in cohort C (60–150×3 mg), 1050 mg in cohort D (150–300×3 mg) and 1650 mg in cohort E (300–450×3 mg). Premedication consisted in allopurinol, dexchlorpheniramine and paracetamol, combined with methylprednisolone 1mg/kg before the first two infusions. Results: Six pts were included in cohorts A and E and 3 in cohorts B, C and D. Median age was 62 years [43–76], median time from diagnosis was 8.3 years [2.5–14.0], number of prior therapies was 3 [1–6]. Twelve pts (57%) received at least one prior rituximab-containing regimen. Three pts presented with 17p deletion. Median WBC count at baseline was 31.0×109/l [9.3–218.4], hemoglobin 13.0 g/dl [9.1–16.0] and platelets 109×109/l [42–344]. Mean lymphocyte counts and mean relative circulating lymphocyte depletions from baseline at day8, day29, and month2 in the 21 pts are presented in the table below. At month 4, lymphocyte depletions were 80% and 78% in cohorts C and E, respectively. Response was evaluated 3 months after completion of therapy (month 4) according to updated NCI-WG guidelines. Among 18 evaluable pts, overall response rate was 27% (5/18). corresponding to 5 pts in partial response (PR). Seven pts were in stable disease and 6 in progressive disease. Three patients out of 5 were confirmed in PR at month 6. All the patients received the planned 4 infusions without any dose reduction. Preliminary safety data indicate that all the pts reported at least one drug-related adverse event (AE). Most of the AEs (52%) occurred less than 48 hours after LFB-R603 infusion and 35% of the AEs occurred after the first infusion. The most frequent drug-related AEs were pyrexia (62% of the pts), infusion related reactions (IRR)(48%), transient neutropenia (38%), headache (33%), chills (29%), infections (29%), thrombocytopenia (24%) and reversible hepatic cytolysis (19%) Twelve pts experienced grade 3 (CT-CAE v3.0) drug-related AEs (IRR; allergy; infection; neutropenia; hepatic cytolysis; pancytopenia), 5 of them in cohort E, and 5 pts experienced grade 4 drug-related AEs (infection; neutropenia; pancytopenia), 2 of them in cohort E. In contrast with the first dose of 300 mg which was worse tolerated than lower doses, the maximum subsequent dose of 450 mg was well tolerated. Conclusion: LFB-R603 can induce rapid, profound and sustained lymphocyte depletion in pts with advanced stage CLL. Toxicity of LFB-R603 is manageable. Most of the drug-related AEs are related to the first infusion, probably due to cytokines release. LFB-R603 is clinically active in pts with relapsed CLL and induces partial remissions. An ongoing part 2 of this study will examine the clinical efficacy of an escalating 8-dose regimen. Disclosures: Cartron: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria. Cazin: LFB Biotechnologies: Honoraria. Coiffier: LFB Biotechnologies: Honoraria. Feugier: roche: Consultancy, Honoraria. Chartier: LFB Biotechnologies: Employment. Sadoun: LFB Biotechnologies: Employment. Ribrag: LFB Biotechnologies: Honoraria, Research Funding.

Description: Introduction: allogeneic transplantation (allo-HSCT) is a curative treatment for patients with advanced lymphoma. Haploidentical (haplo-SCT) transplantation extended the accessibility to allo-HSCT, overcoming the issue of donor availability. However, alternative donor allo-HSCT is still considered at higher risk of non-relapse mortality due to the HLA disparity and thus an anticipated higher incidence of GVHD. In this context, the use of a non myeloablative conditioning (NMAC) regimen combined with post transplantation cyclophosphamide (PT-Cy) based GVHD prophylaxis may reduce procedure related toxicity. The aim was to evaluate the toxicity and efficacy of haplo-SCT using NMAC with PT-Cy in advanced lymphoma patients. Methods: We here report the retrospective experience of a bicentric transplantation program. We analyzed a cohort of lymphoma patients undergoing Haplo-SCT and homogeneously receiving NMAC and PT-Cy. Inclusion criteria were: 1) first allo-HSCT for advanced lymphoma between 2009 and 2018; 2) haploidentical donor; 3) NMAC (fludarabine cyclophosphamide and 2 gray TBI GVHD prophylaxis consisted of PT-Cy day+3 and +4 , cyclosporine A and MMF starting from day +5. Multivariate analyses included age, disease type (NHL vs HL), HCT-CI (〈 vs ≥ 3), graft source (PBSC vs BM), disease status at haplo-SCT (CR vs other). Results: One hundred forty seven patients (73 NHL; 74 HL) with a median age of 46 years (range: 19-71) were included. PBSC (peripheral blood stem cell) was used as graft source in 96 patients (65%). Patients received a median number of 3 conventional chemotherapy lines before haplo-SCT (1-8). Sixty-five (44%) had relapse after Auto-HCT. At the time of haplo-SCT, 96 patients (66%) were in complete remission. The cumulative incidences of day+100 grade 2-4 and 3-4 acute GVHD were 30% and 3%, respectively. The cumulative incidences of 2-year chronic and moderate or severe chronic GVHD were 13% and 8%, respectively. With a median follow up of 39 months (6-114), 2-year NRM was 14%, with a trend for higher risk in patients with HCT-CI ≥ 3 (HR 0.39, 95CI [0.15-1.04] p = 0.061) while age was not associated with an increased risk of NRM (HR 1.01, 95CI [0.98-1.05], p = 0.450). Two-year cumulative incidence of relapse (CIR) was 21% and 18% in HL and NHL patients, respectively. Disease status at the time of haplo-SCT was strongly associated with relapse (HR 2.99, 95CI [1.41-6.35], p = 0.004) In HL patients, 2-year PFS, OS and GRFS were 65%, 77% and 57%, respectively, while corresponding values in NHL patients were 65%, 69% and 55%, respectively. Two-year PFS and GRFS were significantly higher in patients who underwent haplo-SCT in CR (PFS: CR vs. no CR: 72% vs. 55%, p=0.045; GRFS: CR vs. no CR: 63% vs. 42%, p=0.010). There was a trend for better 2-year OS in CR (OS: CR vs. no CR: 78% vs. 63%, p=0.063. Conclusion: We confirm the feasibility of haplo-SCT using NMAC and PT-Cy with low incidence of GVHD (notably severe forms) and NRM. In addition, we observed a relatively low incidence of relapse (19%) in this cohort of heavily pretreated patients, underlining a potent graft-versus-lymphoma effect after haplo-SCT, leading to promising survivals, including high rate of GRFS (〉50%), suggesting a preserved long term quality of life in survivors. We conclude that NMAC haplo-SCT with PT-Cy should be considered as a valuable curative option for advanced lymphoma patients, with a favorable toxicity profile and promising long term survival. Figure Disclosures Stoppa: celgene: Other: travel fees, lecture fees; takeda: Other: travel fees. Carlo-Stella:MSD: Honoraria; BMS: Honoraria; Janssen: Other: Travel, accommodations; Boehringer Ingelheim: Consultancy; Genenta Science sr: Consultancy; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; Servier: Consultancy, Honoraria, Other: Travel, accommodations; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Takeda: Other: Travel, accommodations; Janssen Oncology: Honoraria; AstraZeneca: Honoraria. Chabannon:EBMT: Other: Working Party Chair, Board member; Fresenius Kabi: Other: research support; Miltenyi Biotech: Other: research support; Terumo BCT: Other: speaker's fees; Celgene: Other: speaker's fees; Novartis: Other: speaker's fees; Gilead: Other: speaker's fees, hospitalities; Sanofi SA: Other: research support, speaker's fees, hospitalities. Santoro:Takeda: Speakers Bureau; BMS: Speakers Bureau; Roche: Speakers Bureau; Abb-Vie: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Servier: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Arqule: Consultancy, Speakers Bureau; Lilly: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Bayer: Consultancy, Speakers Bureau; MSD: Speakers Bureau; BMS: Consultancy. Blaise:Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria; Molmed: Consultancy, Honoraria; Pierre Fabre medicaments: Honoraria.

Description: Abstract 3876 Chronic lymphocytic leukemia (CLL) remains an incurable disease except after allogenic transplantation. Natural killer (NK) cells are one of the main effectors of immune surveillance involved in tumor control. Alterations of NK cells functions have been well characterized in myeloid malignancies. However the role of NK cells in immune escape of CLL in less known and controversial. Here we describe extensive phenotypic and functional characterization of NK cells and primary CLL cells and their interactions in vitro and in vivo. Twenty eight untreated CLL patients, twenty four age-matched healthy donors and ten AML patients were enrolled in the study. We have previously shown that expression and function of NK cell-triggering receptors is defective in AML. We then assessed the phenotypic and functional properties of NK cells from CLL patients. Unlike the results found in AML, no significant differences were observed in term of activating receptors, NKp46, DNAM-1, NKG2D, 2B4 and CD16. Only the natural cytotoxicity receptor (NCR) NKp30 was weakly decreased compared to healthy donors (p=0.0107). There wasn't any difference in the expression of inhibitory receptors CD158a, b, e, ILT2 and NKG2A. Looking at the spontaneous NK-mediated cytotoxicity, CLL NK cells displayed a cytolytic activity similar to that of healthy donors against K562 cell line. To further evaluate the functional consequences of the decreased expression of NKp30, mAb redirected killing assays was performed against P815 cell lines. The NK cells killing was slightly lower in CLL patients compared to healthy donors when anti-NKp30 was used although no difference could be observed with anti-NKp46 and anti-CD16. All these results supported that NK cells cytotoxicity should be effective in CLL. We then studied the susceptibility of CLL B cells to allogenic NK killing both in vitro and in vivo. Unlike AML cells and K562 cells, CLL cells were resistant to NK cytotoxicity mediated by resting cells. Exogenous stimulation of allogenic NK cells with IL2 and IL15 restored partially CLL killing, which was nevertheless still lower than AML blasts and K562 cells killing (p=0.0288 and

Description: 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.

Description: Background Autoimmune cytopenia (AIC) are well-known complications of chronic lymphocytic leukemia, occurring in approximately 4 to 10% of patients. The management of CLL-associated AIC is not consensual and patient with uncontrolled AIC are systematically excluded from clinical trials. Few data evaluating the efficacy of BCR inhibitors on CLL-related AIC are available. If some preliminary data focusing on patients included in clinical trials with controlled AIC suggested that ibrutinib was able to control AIC, the duration of responses were unknown. Moreover, no data regarding the ability of idelalisib to control AIC have been currently reported. The aim of this study was to retrospectively analyze the outcome of CLL patients suffering from autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), Evans syndrome or pure red cell anemia (PRCA) and treated with ibrutinib or idelalisib. Results Forty-four patients from 15 FILO centers were included in this study. First kinase inhibitor (KI) was ibrutinib for 25 patients and idelalisib for 19 patients. Among the ibrutinib treated patients, diagnosis of AIC was AIHA for 16 patients (64%), ITP for 5 patients (20%), Evans syndrome for 3 patients (12%) and PRCA for one patient (4%). In the idelalisib group, 12 patients were treated for AIHA (63%), 6 patients for ITP (32%) and one patient for an Evans syndrome (5%). Most patients presented with adverse prognostic factors such as 11q or 17p deletion by FISH and unmutated IgHV. Most patients had previously been treated either for CLL progression, autoimmune cytopenia or both and median number of prior therapies was 1 (0 to 6). Before starting ibrutinib or idelalisib, 34 patients (77%) had a history of AIC and had previously received corticosteroid monotherapy (N=15), rituximab monotherapy (N=15), a combination of rituximab, cyclophosphamide and dexamethasone (N=23) or rituximab and bendamustine (N=15). At the time of KI initiation, 66% of patients were receiving concomitant AIC therapy, consisting in corticosteroids in 26 patients (59%) or TPO (thrombopoietin) receptor agonists in 3 patients (7%). Overall response rates (ORRs) to ibrutinib and idelalisib on AIC were 92% and 95% respectively, and were not correlated to the AIC type. On ibrutinib therapy, 87.5% of patients with AIHA and 100% of patients with ITP or Evans syndrome achieved at least partial response (PR). In the idelalisib group, the ORR was 92% for AIHA patients and 100% for patients with ITP or PRCA. Considering CLL, Ibrutinib ORR and bone marrow unconfirmed complete response (CR) were 100% and 24% respectively. ORR and BM unconfirmed CR on CLL were 95% and 37% respectively the idelalisib group. KI therapy allowed discontinuing corticosteroids in 86% of ibrutinib patients and in 67% of idelalisib patients. Fifteen patients (34%) of the whole cohort experienced progression of CLL, CAI or both during the follow-up. Among them, nine (20%) experienced relapses of the CAI, and all of them were AIHA. In the ibrutinib arm, 1 patient withdrew ibrutinib shortly after initiation because of uncontrolled AIHA and 2 patients experienced relapse of AIHA while on therapy. In the idelalisib group, treatment failed to control AIHA in one case, but for responding patients, no AIHA relapse was described during idelalisib treatment. Five patients experienced relapse of AIHA after idelalisib discontinuation. With a median follow-up of the entire cohort of 26.8 months, the estimated two years overall survival (2y-OS) of the whole cohort was 88%, while the estimated two years progression free survival (2y-PFS) were 75.3% for CLL and 65.1% for AIC. In the ibrutinib cohort, 2y-OS was 95% and 2y-PFS were 81% for AIC and 94.4% for CLL. In the idelalisib arm, 2y-OS was 80%. Median PFS was 19 months for AIC and 25.7 months for CLL. Conclusion Our results demonstrate that kinase inhibitors are able to induce long-term control of both AIC and CLL and represent new therapeutics options for patients with AIC associated with CLL. Disclosures Quinquenel: Jansen Cilag: Honoraria, Research Funding; Abbvie: Honoraria. Ysebaert:Roche: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Description: Introduction In previously untreated, medically fit patients with chronic lymphocytic leukaemia (CLL) and no 17p deletion, there is current research interest in improving survival outcomes and potentially sparing some patients from the standard 6 cycles of fludarabine, cyclophosphamide and rituximab (FCR). The phase II ICLL-07 (NCT02666898) trial, conducted by the French Innovative Leukemia Organization (FILO), aimed to explore the efficacy of obinutuzumab and ibrutinib treatment induction for 9 months, followed by a minimal residual disease (MRD)-driven strategy. Methods Following assessment at Month 9, patients in complete response (CR) with bone marrow (BM) MRD

Description: Abstract 434 Introduction: The German CLL8 trial has demonstrated that addition of R to FC improves quality and durability of response in CLL (Hallek et al, 2010), which has led to the recommendation of FCR as first line therapy for fit patients. Although elderly patients were included in the CLL8 trial (up to 81 y-old), the median age of the cohort was 61 y, thus at least 10 y younger than median age at CLL diagnosis. The elderly population is underrepresented in clinical trials and it is still not clear how FCR should be applied in this subgroup. In December 2007, the French intergroup launched the LLC 2007 SA trial (NCT00645606) in which CLL patients aged 〉 65 y receive an induction with abbreviated FCR followed by randomization between observation or maintenance with rituximab. We now report the safety and efficacy of the induction part in the first 200 patients enrolled in this study. Patients and methods: Stage B or C previously untreated fit (CIRS ≤ 6, CCR ≥ 60 ml/min, PS ≤ 1) CLL patients aged 〉 65 y needing treatment (NCI criteria) were included. Patients with del17p and/or Matutes scoring 〈 4 were excluded. From these 200 first patients included, 6 were removed because of incorrect inclusion (n=4) or consent withdrawal (n=2). In total, 194 patients (included between Dec/07 and Feb/10) were analyzed. FCR consisted of four monthly cycles of oral FC (F 40 mg/msq/d and C 250 mg/msq/d, × 3d) and iv R (375 mg/msq d1 cycle 1, 500 mg/msq d14 cycle 1, d1 and 14 of cycle 2, and d1 of cycles 3 and 4). Response was assessed by NCI criteria. MRD analysis was done using 6-color FCM in PB and BM. No later than 90 d after the last FCR, patients were further randomized as per protocol. Disease outcome after randomization remains completely blinded to date. Results: The median age was 71 y (range 65–85) and 65% were males. 83% had CIRS between 0 and 3. Binet stage was B in 127 (65.5%) and C in 67 (34.5%). Median (n=143) Beta-2-microglobulin was 4 mg/L (range 2–8). Fifty-six % had unmutated IgVH and FISH revealed 18% with del11q, 15% with trisomy 12, and 57% with del13q. Karyotype (ODN+IL2-stimulated) was abnormal in 67%. Balanced and unbalanced translocations were seen in 16% and 17%, respectively. Complex (〉2 abn) karyotype occurred in 14% of the patients. Toxicity: 167 (86%) received all four cycles of FCR. Only 4.6% and 3.2% of patients did not receive d14 rituximab at cycle 1 and 2, respectively. 158 patients (81%) could proceed to the randomization (the main reason for failure was insufficient marrow recovery). Dose delay (by ≥ 1 w) and dose reduction (by ≥ 25% of F and C) for cycles 2, 3, and 4 were 12% and 7%, 14% and 8%, 15% and 11%, respectively. Neutropenia g3/4 occurred after cycle 1, 2, 3 and 4, in 46% (19% g4), 50% (21% g4), 53% (29% g4), and 46% (26% g4) of the patients. G-CSF was given in 32%, 46%, 48%, and 52% of them after cycles 1, 2, 3, and 4. G4 thrombocytopenia occurred in less than 2% of the cycles. G3/4 anemia was seen in 11%, 7%, 6%, and 3% of the patients after cycle 1, 2, 3, and 4, respectively. G 3/4 infectious events occurred in 6.2%, 4.8%, 7.6%, and 6.2% of the patients after each of the 4 cycles. Seventy SAE (including 46 febrile neutropenia and/or documented infection) were declared in 53 patients during the induction and the period of recovery prior to randomization. In total, 6.3% of the 732 cycles were followed by febrile neutropenia or infection qualified as SAE. Six deaths (all infections) occurred during induction, corresponding to a 3.1% (6/194) death rate from immediate toxicity. Efficacy: Among 188 evaluable patients, complete responses (CR) were observed in 19.7%, nodular partial response (PR) in 2.7%, and PR in 73.9%, for an ORR of 96.3%, using stringent criteria. According to the updated guidelines of 2008 (Hallek), CR, CRi, and PR rates were 19.7%, 13.3%, and 63.3%, respectively. Conclusion: Four cycles of oral FC combined with 6 doses of R appear feasible in elderly patients with CLL; only 14% cannot receive the 4 courses and only 19% cannot proceed to randomization planned at day 90 post FCR4. Dose reduction and treatment interruption are unusual despite strict stopping criteria. Grade 3/4 neutropenia is frequent but rarely translates into serious infection. The response rate is high, and further analysis of MRD eradication is ongoing and will be presented. In conclusion, this approach could enable the safe administration of FCR to elderly fit CLL patients in first line. Long-term toxicity, occurring after randomization, will be scrutinized. Disclosures: Dartigeas: Roche: Consultancy. Van Den Neste:Roche: Consultancy. Leblond:Mundipharma: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria.