ALBERT

Description: This prospective phase II trial (Nov 2011- Dec 2012), supported by the LYSA group, aimed to evaluate the impact on PFS of the RiBVD regimen in newly diagnosed, previously untreated, elderly MCL patients (〉65 years or not eligible for ASCT) (NCT01457144). Inclusion criteria were: WHO 2008 MCL not previously treated, CD20 positive, ECOG 0-2, AA stage II-IV, no CNS involvement or active HBV/HCV/HIV infection. Patients were scheduled to receive a total of 6 cycles of the RiBVD regimen, if they responded (IWG criteria) after 4 cycles. The regimen was administered every 4 weeks with Rituximab 375 mg/m² IV on day(D)1, Bendamustine 90 mg/m² IV on D1 and 2, Dexamethasone 40 mg/m² IV on D2 and bortezomib (Velcade®) 1.3 mg/m² subcutaneously on D1, 4, 8 and 11. Primary prophylaxis with acyclovir was mandatory for Herpes virus reactivation, but there was no recommendation for bacterial prevention. Herein we present preliminary analysis of the trial after 4 RiBVD cycles. Results: A total of 76 patients were included, one was excluded because of HBV active disease and 5 had insufficient data reported in the database. To date we analyzed 70 patients. Patients characteristics: sex ratio M/F 49/21, median age 72 years (y) [64-83] (2 patients were 64 y old), AAstage II/III-IV 5/65, ECOG 0-1/2 59/11, MIPI score low/intermediate/high 3/19/48. Response: 61 responded (ORR=87%), with 19 in PR (26%) and 42 in CR/CRu (60%). Four patients died from pneumonia (n=1), cardiac arrest (n=2) and one following Progressive Multifocal Leukoencephalopathy. Three patients have progressed after 3 cycles. Sixty one patients were analysed by PETscan after 4 cycles, 39 (64%) reached a CR (30 were in CR/CRu and 9 in PR) and 22 remained PET positive (11 patients were in CR/CRu, 10 in PR and 1 stable). RiBVD cycles: 271 cycles were administered out of 280 planned (97%). Twenty four (9%) were delayed, 10 for toxicity. All but one planned Bendamustine doses (n=542) were administered with dosing modified 17 times (3%), mostly for hematological toxicity (n=14). Regarding Bortezomib, 79% (1028/1084) of planned doses were administered, it was prematurely stopped (56, 4%) for neurotoxicity (10 instances) or hematological side effects (46). Rituximab was not administered in 4 instances. Hematologic toxicities: Over the 271 cycles administered, neutropenia was reported in 104 cycles [56 grade 3/4 (g3/4) (21%)], 2.5% with fever; thrombopenia in 181 cycles [41 g3/4 (15%)]; anemia in 210 cycles, [6 g3/4 (2%)]. Non-hematologic toxicities:Reported in 〉10% of the cycles were : allergic reactions (10.3%, g3/4

Description: Background The proliferation index (PI), defined by KI67 protein expression has been identified as a key prognostic factor (PF) in mantle cell lymphoma (MCL) (1, 2). A GOELAMS/LYSA study (n = 113 patients) identified a cut point of 26% for KI67 positivity as an independent predictor of overall survival together with LDH levels, B symptoms and ECOG-PS, in MCL (GOELAMS index : GI). (1) Recently, the European MCL network confirmed the independent prognostic power of KI67 protein expression levels to predict OS in MCL (n = 508) and proposed a new score "MIPIc" (KI67cut-off of 30%). (2) While these scores show prognostic impact in the immuno-chemotherapy setting, with or without ASCT and / or maintenance therapy, their predictive power in the setting of targeted therapy remains uncertain. Objective The aim of this study was to test the predictive power of the MIPIc and GI prognostic indices in a cohort of elderly MCL patients treated by a proteasome-inhibitor-based immunochermotherapy regimen within a prospective phase II trial of the LYSA group (LyMa SA 2010 ; Rituximab, Bendamustine, Velcade and Dexamethasone regimen : RiBVD). (3) Material and method The final analysis of the LyMA SA 2010, presented at ASH 2014 (3), showed overall clinical and molecular response rates of 86.5% and 85%. The 24 months estimated OS and PFS was respectively 80% and 70%. (3) In order to assess the prognostic power of KI67 expression levels for OS, all survival data were updated. KI67 staining was performed and reviewed centrally by one pathologist of the LYSA-P, according to the European guidelines. (4) The MIPIc and GI scores were calculated and their impact on survival analyzed (Logrank). In addition, all 6 variables comprising the MIPc and the GI indices were assessed separately by univariate analyzes for prognostic value (these were LDH, ECOG and KI67 that are common to the 2 indices, and Age and WBC for the MIPIc and B Symptoms for GI). Finally a Logrank permitted to define 3 groups of patients with a high statistically impact on survivals with the 3 common variables of MIPIc and GI. Results Among the 74 elderly MCL patients treated in first line by the RiBVD regimen, 59 are alive with a median follow up of 40 months. Estimated OS and PFS at 36 months are respectively 78.4% and 65%. The MIB1 was evaluated on 58 samples for which the MIPIc and GI could be calculated for 57 patients (no LDH value for one patient). MIPIc and GI were not able to define relevant prognostic subgroups for OS (p =0.55 and 0.11). Only the 3 common variables LDH (N vs 〉N), ECOG (O-1 vs 〉1) and MIB1 (with a cut-off at 46% corresponding to the fourth quartile of MIB1 expression levels) were individually predictive of OS by univariate analysis (respectively with p=0.0006, p=0.048 and p=0.0031). With these three variables the Logrank test separated three groups that were statistically discriminant for OS and PFS: one group with 0 risk factors n=24 patients, 42%), a second group with one risk factor (n=20 patients, 32%) and the last group with 2 or 3 risk factors (n=13 patients, 23%). Hence the 3 year OS of these 3 groups was respectively 96%, 75% and 30% (p

Description: Abstract 1525 Trastuzumab (rhu-mAb-HER2, Herceptin®, F. Hoffmann-La Roche, Basel, Switzerland) is the humanized equivalent of the murine 4D5 monoclonal antibody targeted against the HER2 cell-surface receptor. In combination with chemotherapy, trastuzumab has significantly improved the outcome of women with HER2+ breast cancer. We have previously shown that HER2 surface antigen is up-regulated in around one third of adult B-ALL and is associated with chemoresistance in these patients (Chevallier et al, Haematologica, 2004). We report here for the first time the results of a Phase II study evaluating the safety and efficacy of trastuzumab in refractory/relapsed HER2 + adult B-ALL patients. Prior to patient inclusion, HER2 positivity was assessed using multicolor flow cytometry with the phycoerythrin-conjugated HER2 Neu 24.7 antibody (BD) and a CD19+ CD45+low blast cell gating strategy. The mean fluorescence intensity (MFI) ratio was obtained by dividing the MFI of HER2 with that of its isotypic control. HER2 positivity threshold was defined by a ratio intensity (RI) 〉= 2. Also, HER2 oncogene amplification was assessed by FISH analysis using the HER2 DNA probe kit (Vysis, Downers Grove, IL, USA). Relapsed/refractory B-ALL patients aged 〉=18 years and with a HER2+ expression for at least 30% of the leukemic blast population in peripheral blood (PB) and/or bone marrow (BM) were included. Left ventricular ejection fraction has to be 〉 50%. All patients gave informed consent and the protocol was approved by the required regulatory authorities. The trial was registered at http://clinicaltrials.gov/ct no.NCT00724360. Trastuzumab was administered according to the approved schedule in breast cancer patients at 4 mg/kg intravenous loading dose followed by 2 mg/kg weekly. There was no corticosteroid premedication. Trastuzumab was provided by Roche. Out of 50 patients screened for the HER2 expression, 15 patients (30%) (male n=8; female n=7), with a median age of 62 years (range: 24–80), have been included in the study between November 2006 and July 2011. This was considered as a very high-risk population: 2 patients had refractory disease after 2 induction courses, 2 patients were in first untreated relapse while 11 patients had a refractory first relapse or were beyond first relapse. Median percentage of HER2+ leukemic blast population was 94% (range: 0–100) in PB and 100% (range: 31–100) in BM. Surprisingly, no HER2 gene amplification was detected in samples assayed by FISH. Normal and complex karyotype were detected in 7 and 3 patients respectively. Three patients had a Phi+ B-ALL, and 1 patient a monosomy 7 (unknown karyotype n=1). Currently, 3 patients are still receiving therapy. Considering the 12 other patients, the median number of trastuzumab infusions was 4 (1 month of treatment) (range: 2–20). No grade 3–4 toxicities were observed, with no cardiotoxic events. The overall response rate (CR or PR (decrease 〉=50% of blast population) or blast clearance in BM or PB) was 33%. No CR was observed. Two patients achieved partial response in BM (92% vs 12% after 9 infusions with loss of HER2 expression on blast population, total number of infusions (TNI) n=18); 25% vs 11% after 4 injections, TNI n=13) while blast clearance was observed in 2 other patients (96% vs 57% of blasts in BM after 8 infusions with loss of HER2 blast expression, TNI n=20; 20.5% vs 2% of blasts in PB after 3 infusions, TNI n=3). In all, we conclude that trastuzumab in monotherapy can allow for some responses in this very high-risk refractory/relapsed HER2+ adult B-ALL population. Combination of trastuzumab with chemotherapy or other therapeutic monoclonal antibodies should be tested in the future. An updated follow-up of the study will be provided during the meeting. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Eight RCHOP/21 cycles followed by Rituximab maintenance is considered the standard of care for first line therapy in elderly MCL patients in Europe (1). However,complete clinical (CR) and molecular responses (MR) to therapy remain suboptimal(CR rate 30-35%, MR after 8 cycles 67 %). Regimen combining Rituximab and Bendamustine and more recently proteasome inhibitor Bortezomib (Velcade®) with CHOP regimen (VcR-CAP) demonstrated superior CR rates and PFS compared to R-CHOP. We have investigated the RiBVD regimen (Rituximab, Bendamustine,Velcade® and Dexamethasone) in a prospective phase II trial by the LYSA group. Aims of the study: The primary objective was to improve the median PFS by 6 months over the current 18 months PFS obtained with RCHOP when given without maintenance (ref Lenz, JCO 2005). The secondary objectives were to investigate the prognostic impact of molecular and FDG-PET responses on survival.. Methods and Material: All patients aged 65 or older with a diagnosis of MCL were treated by the RiBVD regimen if they fulfilled the following inclusion criteria: AAstage II-IV, PS 〈 3, no other neoplasm, no active HIV or HBV or HCV infections, no renal (creatinin clearance 〉 20ml/mn) or cardiac dysfunction, no diabetes. The RiBVD regimen was administered every 4 weeks with Rituximab 375 mg/m² IV on day(D)1, Bendamustine 90 mg/m² IV on D1, 2, Dexamethasone 40 mg IV on D2 and Bortezomib (Velcade®) 1.3 mg/m² subcutaneously on D1, 4, 8 and 11. Primary prophylaxis with valacyclovir was mandatory for Herpes virus reactivation, but there was no recommendation for bacterial prevention. Patients were scheduled to receive a total of 6 cycles, if they achieved at least PR at 4 cycles. The IWG criteria, with and without FDG-PET, were used to define responses after 4 and 6 cycles. FDG-PET response was evaluated in each center with the five-point scale visual method of Deauville. Molecular responses (MR) were evaluated centrally by RQ-PCR using patient specific IGH VDJ targets as previously described (2). Results: Seventy six patients were recruited in one year (from November 2011 to December 2012), 74 were evaluable [2 patients were excluded because HBV positivity (n=1) or misdiagnosis (n=1)]. Fifty four samples were centrally reviewed for diagnosis, 45 were classic form of MCL, 9 pleomorphic variant and one patient had a DLBCL. Clinical characteristics of the 74 patients were: Median age 73 yo (64-83), sex ratio M/F = 2 (49/25), AAstage II/III-IV = 4/70, PS 0-1/2 = 63/11, MIPIscore low/intermediate/high= 3/19/50 (2 undetermined). The median follow-up is 21 months. Thirteen patients died because of lymphoma progression (n=7), cardiac arrest (n=2) or in one case each,pneumonia, Progressive Multifocal LeukoEncephalopathy, pancreatic carcinoma or of unknown causes. After 4 cycles the ORR was 86% (n=64) and CR/CRu 57% (n=42). After 6 cycles, the CR/CRu raised to 74% (n=55) the PR rate was 9% (n=7), 2 patients had a stable disease, 4 progressed and 5 had died during the treatment. The complete MR rate after 6 months on blood samples or bone marrow was respectively 83% (43/50) and 74 % (32/43). At 24 months, the PFS was 69% and the OS 80%. The MIPI score (high vs low/int) and the blood MR after 6 cycles were the only two statistically prognostic factors for PFS and OS. Toxicities were essentially hematologic with grade 3 or 4 neutropenia and thrombocytopenia in 51% and 36% of the cases, respectively. The main grade 3 or 4 extra-hematologic toxicities were fatigue (19%), neuropathy (14%), cardiac (7%) or febrile neutropenia (5%). Conclusion: The RiBVD regimen can be safely administered as first line therapy to elderly patients with MCL. Toxicities are mild and manageable. With 74% of CR/CRu, a 2 year PFS of 69% and 86% of patients achieving an MRD negative status in the blood after 6 cycles, without maintenance therapy, the RiBVD regimen is identified as a highly effective, well tolerated, first line treatment for elderly MCL patients. Reference : 1 - Kluin Nelemans HC et al, NEJM 2012, 2 - Gimenez E et al, BJH 2012 Disclosures Gressin: mundipharma: Consultancy. Off Label Use: Bendamustine and Bortezomib did not have authorization to their use in first line for MCL in France. Karlin:Janssen: Honoraria; celgene: Consultancy, Honoraria; Sandoz: Consultancy. Le Gouill:Mundipharma: Honoraria; Roche: Honoraria; Janssen: Consultancy.

Description: Introduction: Continuous improvement in the management of Hodgkin Lymphoma (HL) has brought to favorable outcome for the majority of patients. However, patients with advanced stages still present unsatisfactory results with ABVD. The GOELAMS group conducted a prospective multicentric phase 2 trial for advanced stage HL with front-line therapy by VABEM and early salvage therapy followed by ASCT in case of absence of complete metabolic response to test a global PET adapted strategy with early salvage (LH 2007 trial, NCT00920153). Patients & Methods: Patients with advanced stage according to prognostic system score (PSS〉3) received VABEM in front-line and interim 18F-FDG PET restaging using visual analysis after 2 courses. In case of negative PET-2 patients continued their therapy with a third course. In case of positive interim PET they underwent early salvage therapy by platin, gemcitabine and dexamethasone combination followed by intensification in case of metabolic response. Results: 51 patients were included in the advanced arm. Median age was 40.5 years (range 18.2-64.8). Ann Arbor stage was IV in 35 (78%). B symptoms were observed in 44 (88%) patients; bulky disease in 22 (43%) of cases. The complete remission rate at the end of the strategy was 88% (n=45/51), with 34/37 patients in CR after 3 VABEM courses and 11/12 patients in CR after salvage therapy and ASCT. The metabolic complete response rate after 2 VABEM courses was 76% (37 above 49 assessable patients). The median follow up is 4.2 years (range: 0.02-5.8). Estimated 2-yrs EFS and OS (n=51) were respectively 82.3% (IC95% 72.5% to 93.5%) and 92.1% (IC95% 85% to 99.8%). 9 events occurred during the first 2 years and led to 4 deaths. The comparison by the one sample log-rank test of the observed EFS to a reference curve with a 2years EFS of 70% was statistcally significant (p=0.0004). No difference was observed in 2yrs-EFS and OS depending on interim PET-2 status. 2yrs-EFS and 2yrs-OS were respectively 83.7% (IC 95 72.6%-96.5%) and 97.2% (IC95 92.0%-100.0%) for PET-2 negative population vs 91.7% (IC 95 77.3%-100%) and 91.7% (IC95 77.3%-100.0%) for PET-2 positive population. Discussion & conclusion: VABEM is an efficient first line treatment choice for Advanced HL. We demonstrate here that a PET-guided strategy with early salvage therapy and intensification for interim PET-2 positive patients is safe and feasible and that this global strategy permits to obtain interesting results in a population of patients associated with poor prognosis. Finally, we suggest that salvage by non-cross-resistant drugs and intensification may erase the unfavourable prognostic of positive interim PET-2 status in HL. Disclosures No relevant conflicts of interest to declare.

Description: The aim of this phase 2 study was to evaluate the efficacy and safety of trastuzumab, a humanized monoclonal antibody targeted against the human epidermal growth factor receptor 2 (HER2), for adult patients with relapsed/refractory HER2-positive B-ALL. Fifteen patients, with a median age of 62 years, received trastuzumab according to the schedule approved for breast cancer patients (ie, 4 mg/kg intravenous loading dose followed by 2 mg/kg weekly). The overall response rate was 13% with 2 patients achieving partial response and partial remission cytolytic response, respectively. Two other patients were documented with blast clearance. Only 1 reversible grade 3 cardiac toxic event occurred. This phase 2 study showed that trastuzumab monotherapy can allow for some responses in a very high-risk refractory/relapsed HER2-positive adult B-ALL population. Combination of trastuzumab with chemotherapy or other therapeutic monoclonal antibodies should be tested in the future. This trial was registered at www.clinicaltrials.gov/ct as NCT00724360.