ALBERT

Description: Background.Treatment of APL in the elderly with conventional ATRA-anthracycline based CT regimens is associated, like in younger patients, with very few relapses, but high death rates (CR rate of 87.3%, 10-year CIR of 9.3%, 21.7% deaths in CR, and a 10-year OS of 58% in patients aged〉 65 years in our previous APL trials ;Blood 2010 115:1690). Recent results have shown that, in standard risk APL, ATRA+ATO combinations (without CT) are at least as effective as classical ATRA + CT regimens while being less myelosuppressive (Lo Coco, NEJM 2014; Burnett, Lancet Oncol, 2015) thus constituting a very appealing approach for elderly patients. However, when our APL 2006 trial started, the feasibility of treatment of APL without CT was unknown. Furthermore, access to ATO still remains limited for frontline treatment of APL in most countries. We present results of APL 2006 trial, where we combined ATO to ATRA and reduced CT in patients aged older than 70 with standard risk APL (baseline WBC 70 years with WBC 1 G/L and platelets〉 50G/l after the first consolidation course was 16.2 and 11.9 days in the original vs 5.6 and 4.0 days in the amended protocol (p

Description: Background: In standard risk APL, ATRA+ATO combinations (without CT) are at least as effective as classical ATRA + anthracycline based chemotherapy (CT) while being less myelosuppressive (Lo Coco, NEJM 2014, Burnett, Lancet Oncol, 2015). In high risk APL (WBC〉 10G/l), it is still unclear if CT can be avoided or greatly reduced, but addition of ATO to ATRA + CT reduces relapses (Powell, Blood 2010). In a randomized trial (APL2006 trial) in high-risk APL patients (pts) who received ATRA + CT induction treatment, we evaluated the addition of ATO to CT during consolidation. Methods: Between 2006 and 2015, newly diagnosed APL pts 10 G/L, after an induction of ATRA 45mg/m2/d until CR with Idarubicin (Ida) 12 mg/m2/dx3 and AraC 200mg/m2/dx7, were randomized for consolidation between CT and CT+ATO. The CT group (standard group) received a first consolidation with Ida 12 mg/m2/dx3 and AraC 200mg/m2/dx7, a second consolidation with Ida 9 mg/m2/dx3 and AraC 1g/m2/12h x4d, and 2-year maintenance with intermittent ATRA and continuous 6 MP + MTX. The CT+ATO group received the same treatment except that ATO 0.15 mg/Kg/d d1 -25 was added during both consolidation courses. After a first interim analysis in Sept 2010, based on 81 pts, AraC was deleted from consolidation cycles of the CT+ ATO group. The primary endpoint was EFS from CR achievement. Results: 211 pts 10 G/L were included (after the exclusion of 8 diagnostic errors) in 58 centers. 95.7% achieved CR, 3.3% had early death and 1% resistant leukemia. 193 pts were randomized for consolidation, 97 in the CT and 96 the CT+ ATO groups. Pre-treatment characteristics were well balanced between the 2 groups. 7 pts (3 CT vs 4 CT+ATO) had relapsed (5-year cumulative incidence of relapse (CIR) of 2.5% vs 3.9%; p= 0.39) and 9 pts had died in CR :7 (7.8%), 2 (5.1%), 0 (0%) in the CT, CT (with AraC) + ATO, CT (without AraC) + ATO groups respectively (p=0.04). Causes of death in CR were bleeding (n=5), infection (n=2), previous cancer relapse (n=2). One patient in the CT+ATO arm developed AML/MDS. 5-year OS was 93% vs 94% (p=0.56) and 5-year EFS was 89% vs 93% (p=0.47) in the CT and CT+ATO groups, respectively. Omission of AraC (after the amendment) in the CT+ATO group did not increase CIR (5 year CIR 5.3% with and 3.3% without AraC, p=0.57). In the CT, CT (with AraC) + ATO, CT (without AraC) + ATO groups respectively, median time to ANC〉1 G/L after consolidation 2 was 22, 25 and 19 days (p50G/l was 24, 26 and 20 days (p

Description: Introduction Next generation sequencing (NGS) studies have documented the highly heterogeneous landscape of somatic mutations in CLL. Beside the mere genetic diversity of the disease, frequency and clinical impact of mutations vary between analyzed cohorts since samples may be collected at variable clinical stages. To address this point, we undertook an integrative systematic genomic study of patients included in a prospective clinical trial. Material and methods We performed conventional karyotype (K), fluorescence in situ hybridization (FISH) and investigated 31 genes and 2 non-coding regions, in pretreatment samples obtained from 146 patients enrolled on a phase 3 trial comparing fludarabine (F)-cyclophosphamide (C)-rituximab vs. F-C-alemtuzumab (Lepretre et al, Blood 2012). All patients were Binet stage B (n=115) or C (n=31) and devoid of 17p deletion. All gave their informed consent according to the declaration of Helsinki. We studied by targeted deep sequencing exonic regions of 31 genes including TP53, SF3B1, NOTCH1, ATM, BIRC3, FBXW7, NFKBIE, MED12, MYD88 and POT1. DNA was extracted from total blood mononuclear cells (fraction of tumor cells determined by flow cytometry 〉80%). Targeted regions were PCR-amplified using an AmpliSeq (Life technologies) approach and PCR products sequenced in a MiSeq (Illumina) instrument with a mean depth of 1000X. We used a variant allele frequency (VAF) minimal threshold of 5% to detect mutation. EGR2, PAX5 enhancer and NOTCH1 3'UTR regions were analyzed by Sanger sequencing. For each identified mutation, clinical and biological variables were compared between mutant and wild-type patients using either Wilcoxon or Fisher exact test. For each mutation present in a sufficient number of samples, prognostic impact on overall survival (OS) and progression free survival (PFS) was assessed using log-rank test. For important clinical and molecular prognostic variables, adjusted prognostic effect was assessed using a multivariate Cox model for OS and PFS with a stepwise-forward selection based on Akaike criteria. Results Chromosomal abnormalities were observed by K in 63% of 126 patients, 11% showing complex K and 23% carrying translocations. FISH revealed 78/144 (54%) 13q deletion, 25/144 (17%) trisomy 12 (tri12), 30/146 (21%) 11q deletion. Unmutated (UM) IGHV status was observed in 84/146 (58%) cases. At least one mutation was observed in 118/146 (81%) patients, with 1, 2, 3 and 4 or 5 mutations in, respectively, 34%, 23%, 17% and 7%. The most frequently mutated genes were SF3B1 (23%), NOTCH1 (16%), ATM (14%), NFKBIE (10%), XPO1 (10%), MED12 (7%), EGR2 (6%), TP53 (5%), BIRC3 (5%), FBXW7 (5%), PAX5 enhancer (5%), CHD2 (5%), PCLO (5%), MYD88 (4%), POT1 (4%), KMTD2 (4%) and NOTCH1 3'UTR (4%). MYD88 and SAMHD1 mutations were always observed as clonal (VAF〉40%) whereas BIRC3 and BRAF mutationsalways observed as sub-clonal. NOTCH1 mutations were associated with high CD38 expression (P

Description: Introduction: Anemia is the most common hematological abnormality in patients with cancer and hematological malignancies, and is associated with poor prognosis and outcomes that have a detrimental impact on the patient's condition and quality of life (QOL). Erythropoiesis-stimulating agents (ESA) represent a good treatment option in order to increase the hemoglobin level in patients with anemia. Anemia can also be treated by red blood cell transfusion, but this has a transient effect and is associated with risks such as exposure to infectious agents, iron overload, or transfusion-related acute lung injury. ESA also have safety concerns, including the established increased risk of venous thromboembolic events. However, they are currently the only therapeutic alternative to transfusions. We performed a prospective observational study in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematological malignancies, with the primary objective of evaluating the effect of a new ESA biosimilar, epoetin zeta (Hospira) on patient QOL. Secondary objectives included hemoglobin (Hb) and platelet (Pt) recovery, safety, overall survival (OS) and relapse incidence. Results of this study were compared to two reference populations, one receiving epoetin beta (Roche) and one control group not treated with ESA. Here, we present preliminary results for the secondary objectives. Materials and methods: The study included adult patients with Hb level ≤11g/dl occurring after all types of allo-HSCT for any hematological disease (Table 1). Epoetin zeta (30,000 IU) was administered s.c. once per week for up to 6 months, and Hb levels were monitored weekly. Injections were stopped once the Hb level reached 12g/dl without transfusion. If after 4 injections, no improvement was observed, doses were doubled, and if after 8 injections, no improvement was observed, the patient was withdrawn from the study. The QOL was measured at baseline and at 1, 2, 3 and 6 months by the Functional Assessment of Cancer Therapy-Anemia (FACT-An) scale. Epoetin zeta responders were defined as having Hb level ≥12g/dl (complete response, CR) or a ≥2g/dl increase (partial response, PR) compared with baseline value, in the absence of transfusion. Patients receiving epoetin zeta (group 1) were compared to a similar population receiving epoetin beta with the same procedures (group 2) and to a matched population not treated with ESA (group 3), taking into account the following variables: sex, age, diagnosis, disease status at allo-HSCT, conditioning regimen and HSC source. Results: Between December 2011 and September 2014, 58 patients (from 168 screened) were included in group 1, and compared to 59 patients in group 2 and 65 patients in group 3. The main exclusion criteria were ESA contra-indication and patient refusal. Patients in group 1 had lower Hb baseline levels compared to group 2; patient characteristics for each group are summarized in Table 1. The median number of injections/patient was 10 (range: 6-14) in group 1 and 8 (range: 2-28) in group 2. The cumulative incidence of CR was 80% in group 1 and 71% in group 2. The median time to achieve CR was 48 days (range: 35-70) in group 1, and 39 days (range: 14-180) in group 2. Eight patients withdrew due to ESA inefficacy in group 1 and 8 in group 2. Adverse events were all thromboembolic: 2 events in group 1 and 5 events in group 2, compared to 2 events in group 3 (p=0.34). The multivariate analysis studying different confounding factors on the cumulative incidence of CR showed a significant positive impact of younger age (p=0.001), and a negative impact of being female or having major ABO incompatibility. We did not find any significant difference in terms of OS and relapse rate between the 3 groups. Conclusion: We describe here, for the first time, preliminary data for ESA biosimilar epoetin zeta (Hospira) in allo-HSCT patients showing comparable efficacy and safety to an existing ESA, epoetin beta (Roche) with no impact on OS and relapse incidence, compared to a control group. The QOL and transfusion evaluations as well as a cost-effectiveness study are ongoing and results will be presented. Disclosures Nicolini: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: A diagnosis of hairy cell leukemia was made by optic microscopy, phase- contrast microscopy, electron microscopy, scanning microscopy, and histochemistry of the abnormal blood cells. In vivo these cells were found to have a half-time in the blood of approximately 150 hr. In vitro they had the capacity to adhere firmly to plastic, making it possible to obtain a pure population of hairy cells. Neither T-rosette formation nor phytohemagglutinin (PHA) transformation could be demonstrated in these cells. On the other hand, the presence of immunoglobulins on the surface of the hairy cells (HC) by immunofluorescence, and the synthesis and secretion by these cells of IgM type lambda-chains shown by radioimmunodiffusion, were in favor of their B-type lymphocyte origin. Similarities to chronic lymphocytic leukemia were apparent.

Description: Introduction: CLL is a heterogeneous disease in terms of response to treatment, with some patients reaching complete and prolonged remissions, while others relapsing early and requiring several lines of treatments. This highly variable course is partly explained by the existence of a heterogenic panel of genetic alterations (mutations, chromosomal abnormalities) that allow the development of drug-resistant aggressive CLL subclones. Therefore, a functional characterization of the cytogenetic alterations associated to CLL drug resistance may provide new means of improving the current therapeutic strategies. We and others have already reported that the gain of 2p (2p+) is recurrent in CLL. However, the candidate gained gene(s) on the 2p remain to be identified. Previously data: we have observed that the 2p gain is frequent in previously untreated CLL Binet stages B/C (21/132, 15.9%), and is associated with bad prognostic factors, such as 11q deletion (p=0.0008) and unmutated IGHV (p=0.02). Using a SNP-array approach, we have identified a minimally gained region of 1.28Mb on 2p16.1-15. This region included the gene CRM1/XPO1 (Chromosome Region Maintenance 1/Exportin-1), a gene also recurrently mutated in CLL. A qPCR assessment confirmed that XPO1 was overexpressed in the 2p+/CLL patients (1.4-fold increase compared to 2p-/CLL; p=0.02). The objective of our work was to identify the potential role of XPO1 in CLL drug resistance by using the selective XPO1 inhibitor Selinexor (KPT-330, provided by Karyopharm Therapeutics), which is currently in Phase II human clinical trials in hematological and solid cancers. Methods: We have analyzed 36 2p+/CLL and we have searched for XPO1 mutations in 436 CLL samples. CLL drug resistance associated to XPO1 overexpression/mutation was assessed by measuring the rate of programmed cell death (PCD) on cells from 2p- and wildtype (wt) XPO1/CLL (n=20), 2p+/XPO1 wt/CLL (n=8) and on XPO1 mut/CLL (n=6). After 24 hours treatment with Fludarabin + Cyclophosphamid + Rituximab (FCR), Ibrutinib (Ibru), Idelalisib + Rituximab (Ide+R) and Selinexor, cells were stained with Annexin-V and propidium iodide and PCD was assessed by flow cytometry. KPT-301 was used as a negative control. For the inhibition assay, the inhibitor Q-VD-Oph was added 30 min before inducing cell death. Mitochondrial membrane depolarisation was assessed using tetramethyllrhodamine ethyl ester probe and flow cytometry analysis. Results: (i) Using a FISH approach, we fully confirmed the gain of XPO1 in 2p+/CLL samples. Additionally, we found that the XPO1 gain was often subclonal, suggesting that it tends to arise late in leukemic development. Longitudinal FISH analyses, performed on 8 2p+/CLL-treated patients, showed a similar or increasing percentage of cells carrying XPO1 gain at relapse, when compared to diagnosis; (ii) XPO1 was mutated in 23/436 (5.3%) CLL and in 2/30 (6.7%) 2p+/CLL; (iii) Selinexor induced PCD in 2p-/XPO1 wt/CLL (35% of PCD). The results were similar in all tested CLL, independently of prognostic factors (del13q, tri12, del11q, del17p, IGHV status), while sparing the non leukemic cells from patients or B cells from healthy donors; (iv) Selinexor induced CLL PCD through a caspase-dependant apoptotic pathway, as evidenced by inhibition of cell death by Q-VD-Oph, and cleavage of the caspase-3. Selinexor also induced mitochondrial depolarization and was associated with upregulation and activation of the pro-apopototic Bax protein; (v) XPO1 mut/CLL were significantly resistant to PCD induced by Selinexor (p=0.003). In contrast, the mutations in XPO1 had no effect in FCR and Ibru PCD induction; (vi) 2p+/CLL cells were resistant to PCD induced by all tested drugs: FCR (p=0.01), Ibru (p=0.003), Ide+R (p=0.004) and Selinexor (p=0.0001). Conclusion: Our data show that 2p+/CLL is associated to FCR, Ibru and Ide+R drug resistance. Strikingly, Selinexor, a new XPO1 inhibitor, is unable to induce PCD in 2p+ and/or XPO1 mut CLL, which strongly suggests a key role for XPO1 in the CLL drug resistance associated to the 2p gain. Altogether, our work provide substantial progress in the understanding of the role of XPO1 in CLL drug resistance and suggests that the assessment of the 2p gain and the mutations in XPO1 will be considered before to decide a CLL therapy. As 2p gain could be observed in other B malignancies, it is tempting to extend these recommendations to all Selinexor treatments. Disclosures Choquet: Janssen: Consultancy; Roche: Consultancy. Leblond:Janssen: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Mundipharma: Honoraria.

Description: Background: Minimal residual disease (MRD) obtained at the end of Induction (EOI) is a powerful prognostic indicator for assessing relapse risk in pediatric acute lymphoblastic leukemia (ALL). We have shown that low absolute lymphocyte count at the end of induction (EOI-ALC) is a significant and independent adverse prognostic factor in childhood ALL that further refines MRD-based risk stratification algorithms (Gramatges and Rabin, 2011). However, the mechanisms underlying the relationship between EOI-ALC, MRD, and prognosis have not yet been determined. Here, we investigated associations between clinical and biological host factors and EOI-ALC. Given that hematopoiesis is highly sensitive to telomere shortening and that inflammation further contributes to cellular stress, we hypothesized that shortened lymphocyte telomere length and evidence for systemic inflammation at EOI would be associated with a lower EOI-ALC. The relationship between EOI-ALC and risk for microbiologically documented bacterial infections (MDBI) during the first three months of leukemia therapy was also assessed. Methods: Children between the ages of 1 and 21 years with newly diagnosed B- or T-cell acute lymphoblastic leukemia (ALL) and enrolled to the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) study were included. Blood samples were collected at EOI, and patient demographics and relevant clinical information including EOI MRD, ALC, and MDBI within the first 90 days of treatment were abstracted from the medical record. EOI lymphocyte telomere length was measured with telomere flow fluorescence in situ hybridization, and age-based percentiles assigned based on population norms (Repeat Diagnostics). Mean fluorescence intensity (MFI) of cytokines, including interferon-γ, interleukin (IL)-1ra, IL-1α, IL-1β, IL-3, IL-6, IL-7, IL-8, tumor necrosis factor (TNF)-α, and TNF-β was measured in plasma using a MILLIPLEX® MAP kit (EMD Millipore) on Luminex® equipment. Samples with at least one analyte with detectable MFI above normal range was considered evidence of systemic inflammation. Each sample was assessed in triplicate and analyzed with Belysa™ software. Clinical factors, systemic inflammation, lymphocyte telomere length ≤10th percentile for age, and number of MDBIs in the first 90 days of treatment were then compared between subjects with high or low EOI-ALC using Fisher's Exact Test. The EOI-ALC cutoff applied for this analysis was 〉 or 〈 1500/µl (EOI-ALC-high and EOI-ALC-low, respectively), as applied in our prior study. All research activities were conducted under local IRB-approved protocols. Results: Forty subjects were enrolled, and their clinical, demographic, and biological characteristics are reported in Table 1. Of these subjects, 23 had EOI-ALC-low and 17 had EOI-ALC-high. Subjects with EOI-ALC-low were 9 times more likely to report Hispanic ethnicity (18/21 EOI-ALC-low subjects, vs. 5/15 EOI-ALC-high subjects, p=0.01). No significant differences in age, sex, or induction therapy regimen were noted between the EOI-ALC groups. Although there was no association between Hispanic ethnicity and MRD status (p=0.26), those with EOI-ALC-low were ~3 times more likely to have positive EOI MRD (p=0.17). We observed no relationship between EOI lymphocyte telomere length, evidence for systemic inflammation, and EOI-ALC. There was also no relationship observed between EOI-ALC and MDBIs in the first 90 days of treatment. Conclusion: In addition to EOI MRD, EOI-ALC is a low-cost, clinically relevant prognostic indicator in pediatric ALL. The relationship between ALC and MRD noted in this study was consistent with our prior observations, albeit not significant due to the relatively small sample size of this cohort. Our results suggest that Hispanic ethnicity is a primary host factor determinant of EOI-ALC, rather than other demographic, treatment, or biological factors. Given that a number of studies have demonstrated poorer survival among Hispanic children diagnosed with ALL, further work is needed to investigate whether genetic ancestry-associated determinants of host immunity may contribute to outcome disparities. Disclosures Aubert: Repeat Diagnostics: Employment.

Description: Background :AZA improves overall survival (OS) in higher risk MDS, but only 50-60% of the patients respond, and median OS with AZA is only 20-24 months. As OS improvement is obtained at modest response rates, OS rather than response should probably remain the primary endpoint for all combinations with AZA, requiring large phase III trials with significant follow up. On the other hand, combinations that do not increase response will likely not improve OS. We therefore tested, based on a "pick the winner" approach, AZA combinations with the HDAC inhibitor VPA, LEN or IDA to identify, based on response, the most promising combination with AZA in higher risk MDS, that could be subsequently compared with AZA alone in a larger phase III study. Methods : AZA-PLUS (#NCT01342692)was an adaptive two-stage phase II trial based on Jung design (Stat Med.2008;27:568) that randomly assigned higher-risk MDS, low blast count AML (20-30%) and CMML to: AZA (75 mg/m2/d d1-7 of 28-day cycles); AZA plus LEN (10 mg/d on d1-14); AZA plus VPA( 50 mg/kg/d on d1-7; 35 mg/kg/d in patients〉 60y) or AZA plus IDA (10 mg/m2on d1 for the first 9 cycles). The primary end point was response rate (RR, including CR, PR, marrow CR, based on IWG 2006) of the combination arms vs AZA alone. Given a 30% RR with AZA alone, we considered that a ≥45% RR would make combination(s) promising. Controlling for type I and type II errors at 0.15 and 0.20, 40 patients per arm were to be enrolled at each stage. Any experimental arms with RR lower than those observed in the AZA arm at the first stage should be stopped. At the second stage, any arm with 〉 6 more responses than AZA alone should be selected for further testing. Secondary endpoint were ORR (RR+ stable disease with HI (HI) and OS. Results : After inclusion of 40 pts/arm (first stage) all experimental arms had at least the same number of responses as the control arm and were continued in second stage. Overall, 322 pts were enrolled from 06/2011 to 07/2017: 81, 80, 80, 81 in the AZA, AZA+VPA, AZA+LEN and AZA+IDA arms, respectively. Baseline characteristics were well-balanced across arms. Median age was 74.6 y, 213 pts were male, IPSS was INT-2 in 54% and High in 46%. IPSS Karyotype was fav, int and poor in 40%, 26% and 34%, respectively. Pts received a median of 7 cycles and median follow-up was 15.1 months. Prevalence of trial discontinuation due to adverse events was 32%, 29%, 28% and 31% in the AZA , AZA+VPA , AZA+LEN and AZA+IDA arms, respectively (p=0.95). Rates of hospitalization during the first 6 cycles were 38%, 44.7% , 55.1%, 59.7% in the AZA, AZA +VPA, AZA+LEN and AZA+IDA arms, respectively (p=0.028), suggesting increased myelosuppression in the experimental arms, especially in the LEN and IDA arm. In the control arm, 29 responses (CR+PR+mCR) after 6 cycles were observed, with 29, 25 and 29 responses observed in AZA+VPA , AZA+LEN and AZA+IDA arms, respectively. Thus, no combination demonstrated benefit over AZA. The RR was estimated at 34.8% (18.6% CR, 3.1% PR, and 13.0% mCR) and the ORR after 6 cycles was 40.4%. The RR after 6 cycles (35.8% for AZA, 36.2% for AZA+VPA, 31.2% for AZA+LEN, and 35.8% for AZA+IDA) and the ORR after 6 cycles (41.9% for AZA; 41.2% for AZA+VPA, 40.0% for AZA+LEN and 38.3% for AZA+IDA) were close across study arms. By multivariate analysis, factors associated with better ORR were higher Hb level (p=0.05), low fibrinogen (p=0.008) and low LDH (p=0.01). 17 (5%) pts were bridged to allogeneic SCT: 6 on AZA, 5 on AZA+VPA, none in the AZA+LEN arm and 6 on AZA+IDA arm (p=0.03). At the reference date of July 2018, median EFS was 16.6 months for in AZA, 14.5 months for in AZA+VPA, 15.1 months for in AZA+LEN and 13.2 months for in AZA+IDA (p=0.74) (Fig A). Multivariable Cox model selected Hb level (p=0.02), presence of circulating blasts (p

Description: Background: Azacitidine (AZA) is the current standard of care for patients treated for higher risk MDS, but 40-50% patients do not respond and most responders eventually relapse. Median survival after AZA failure is only 5 months and no standard of care is defined for this population. Preclinical studies and positive results of phase I-II trials support a synergistic effect of the histone deacetylase (HDAC) vorinostat (VOR) and AZA in terms of response, although no survival advantage of the combination has as yet been demonstrated. We hypothesized that adding VOR to AZA in patients with primary or secondary AZA resistance could rescue response and prolong survival. Methods: inclusion criteria inGFM AZAVOR study (NCT 01748240) were: 1/IPSS int 2 or high risk MDS at the time of initiation of AZA 2/treatment with at least 6 cycles of AZA and either failure to achieve any response or loss of response (per IWG2006 criteria) 3/a maximum of 3 months between AZA failure and inclusion with no other treatment in between. Patients received VOR 300mg bid from day 3 to day 9 of each cycle. AZA was given at standard 75mg/m2/d day 1 to 7 or at the maximum previously tolerated dose in case of dose reduction. Patients were evaluated after 6 cycles and responding patients treated until progression. The trial used a two-stage design, and accrual was to be stopped if less than 3 responses were seen in the first 14 evaluable patients. Results 21 patients were included between march 2013 and September 2014. Nineteen patients were treated (1 patient died and 1 progressed before treatment). Median age was 72 years. All pts had higher risk MDS and had received a median of 6 cycles of AZA before entering the trial. The median number of AZA+ VOR cycles administered was 3 (range: 1-12). No unexpected SAEs were seen, and the most common AEs were infection, thrombocytopenia, GI toxicities, and fatigue. After 6 cycles of treatment, only 2 patients (11%) achieved response (1 erythroid hematological improvement, 1 partial remission), , which, per protocol, triggered the stop of accrual. At last follow-up, 18 patients were off study and one patient was still on treatment. Nine patients stopped treatment because of progression (42%), 4 stopped treatment for lack of response (21%), 2 stopped treatment because of intolerance (11%), 1 patient stopped at his request (5%), and 1 patient died of complications of cytopenias while on treatment (5%). Median overall survival was 13 months. Conclusion This is the first report of an add-on study in high risk MDS, a strategy that may be useful for the early evaluation of drugs for which synergy with AZA is expected. Our results show that the proposed regimen of AZA +VOR can be used safely. However, the observed response rate was not above the "background" response rate expected from AZA alone continuation in a comparable patient population, indicating that the addition of VOR cannot reverse resistance to AZA. Disclosures Prebet: CELGENE: Research Funding. Off Label Use: lenalidomide. Wattel:Janssen: Consultancy, Honoraria, Research Funding; PIERRE FABRE MEDICAMENTS: Research Funding; CELGENE: Research Funding, Speakers Bureau; NOVARTIS: Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding. Cony-Makhoul:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Fenaux:Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Vey:Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria.

Description: Background Quantification of monoclonal immunoglobulins in serum is the foundation of IMWG multiple myeloma (MM) response criteria for patients with intact immunoglobulin disease. However, electrophoretic methods for quantifying M-Ig in serum are subject to well documented limitations including inaccuracy at high concentrations (due to dye saturation) and poor sensitivity at low concentrations. Moreover, the methods require skilled interpretation and can be time consuming; however their clinical utility is well established. Recently heavy/light chain (HLC) assays, which quantify kappa and lambda isotypes of intact immunoglobulins have become available. Here we compare responses assigned by the immunoassays to IMWG criteria and evaluate the clinical impact of discordance. Methods Sequential sera, from enrolment to progression, were available for 107 MM patients (59 IgGκ, 29 IgGλ, 12 IgAκ, 7 IgAλ) enrolled onto either the IFM 2009-02 end-stage relapsed or refractory MM or the IFM 2010-02 in del17p and t(4;14) relapsed or refractory MM trials. The inclusion criterion was a measurable intact immunoglobulin MM according to IMWG criteria (M spike ≥ 10 g/L), using serum and/or urine protein electrophoresis. IgA HLC (IgAκ and IgAλ) and IgG HLC (IgGκ and IgGλ) analysis was compared to historic SPEP, IFE, UPEP, uIFE and serum free light chain (sFLC) results (measured using polyclonal antisera based assays). Responses were assigned at approximately 90 days (median 90, range 61-107 days) and at maximum response (if different) according to IMWG criteria using changes in monoclonal protein concentrations measured either by SPEP or dHLC (clonal - non clonal). Complete response was assigned either by the absence of monoclonal protein on IFE or by a normal HLC ratio. Results At the time of enrolment, 87/88 IgG and 17/17 IgA patients had abnormal HLC ratios which were concordant with IFE results, and quantification of the monoclonal protein by dHLC was similar (median (range): 29.2 (2.5-77.5) g/L) and SPEP (30.7 (1.8-66.9) g/L). After 3 months of treatment, responses assigned by HLC/FLC assays showed near-perfect agreement with responses assigned using SPEP and IFE (Weighted Kappa 〉0.81, p