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The French protocol LALA 87 was designed to compare three different postinduction strategies in adult acute lymphocytic leukemia (ALL): chemotherapy, autologous transplantation, and allogeneic transplantation. This trial demonstrated a significant superiority of allogeneic bone marrow transplantation (BMT) in high-risk ALL patients. Similarly, there was a trend in favor of autologous BMT over chemotherapy in those same patients. Allogeneic BMT was not superior to autologous BMT or chemotherapy in less aggressive leukemia (standard-risk ALL). Further improvements are warranted in the treatment of adult ALL. The authors' current ongoing study is stratifying patients to allocate them to regimens with risk-adapted treatment intensity.

The purpose of this study was to assess the safety and efficacy of stem cell transplantation (SCT) mainly autologous SCT as consolidation therapy in APL patients who relapsed and achieved a second complete remission (CR2). Fifty adult patients with a first relapsed APL, of whom 39 had been previously treated with ATRA, entered a multicenter trial of oral ATRA until complete remission (CR) achievement followed by timed sequential chemotherapy (EMA combining etoposide 200 mg/m2/day for 3 days, mitoxantrone 12 mg/m2/day for 3 days, and cytarabine 500 mg/m2/day for two sequences of 3 days). EMA was started either after CR achievement, or on day 1 of ATRA because of initial white blood cell (WBC) counts >5 x 10(9)/l, or rapidly added to ATRA in order to prevent ATRA syndrome because WBC count increased under ATRA. Forty-five patients (90%, 95% CI 78%-97%) were in CR after induction therapy. Five patients died from infection during aplasia following EMA chemotherapy. Eleven patients who achieved CR had a familial HLA-identical donor and were allografted. The median disease-free survival (DFS) of allografted patients was 8.2 months. The 34 other CR patients were scheduled for autologous peripheral blood (PB) SCT (intent-to-treat group). Actually, autologous transplantation was only carried out in 22 patients (65%) (17 PBSCT and five autologous bone marrow transplantation (BMT)). Reasons for not autografting were early relapse (three patients), severe toxicity of EMA chemotherapy (six patients), and refusal or failure of stem cell harvest (three patients). The 3-year DFS rate of patients actually autografted was 77%. Among the 17 autografted patients still in CR2, nine patients have already reached a longer CR2 than first CR (CR1). Results of detection of PML/RARalpha by RT-PCR after autologous transplantation show negative findings in eight of the nine patients tested. We conclude that (1) ATRA combined to EMA chemotherapy is effective in the treatment of relapsed APL; (2) allogeneic BMT may be too toxic after salvage treatment including EMA intensive chemotherapy; (3) clinical outcome of autografted patients and preliminary molecular results regarding detection of PML/RARalpha after autologous PBSCT are encouraging.

All transretinoic acid (ATRA) followed by daunorubicin (DNR)-AraC chemotherapy (CT) has improved the outcome of acute promyelocytic leukemia (APL) by comparison to CT alone. In a randomized trial, (1) we compared 2 induction schedules (ATRA followed by CT [ATRA-CT] and ATRA plus CT [ATRA+CT, with CT added on day 3 of ATRA treatment]) and (2) we assessed the role of maintenance treatment. Four hundred thirteen patients less than or equal to 75 years of age and with newly diagnosed APL were included. Induction treatment was stratified on white blood cell (WBC) count and age: patients less than or equal to 65 years of age and with an initial WBC count of less than or equal to 5,000/pL (n = 208) were randomized between ATRA-->CT and ATRA+CT (initially randomized patients); patients with a WBC count greater than (high WBC count group, n = 163) and patients 66 to 75 years of age with a WBC count greater than 5,000/mu L (elderly group, n = 42) were not initially randomized and received ATRA+CT from day 1 and ATRA-->CT, respectively. All patients achieving CR received 2 additional DNR-AraC courses (only 1 in patients 66 to 75 years of age) and were then randomized for maintenance between no treatment, intermittent ATRA (15 days every 3 months) for 2 years, continuous low-dose CT (6 mercaptopurine+methotrexate) for 2 years, or both, using a 2-by-2 factorial design. Overall, 381 (92%) of the patients achieved complete remission (CR), 31 (7%) suffered an early death, and only 1 patient had leukemic resistance. ATRA syndrome occurred in 64 patients (15%) and was fatal in 5 cases. The CR rate was similar in all induction treatment groups. Event-free survival (EFS) was significantly lower in the high WBC group (P = .0002) and close to significance in the elderly group (P = .086) as compared with initially randomized patients. Relapse at 2 years was estimated at 6% in the ATRA+CT group, versus 16% in the ATRA-->CT group (P = .04, relative risk [RR] = .41). EFS at 2 years was estimated at 84% in the ATRA+CT group, versus 77% in the ATRA-CT group (P = .1, RR = .62). Two hundred eighty-nine patients were randomized for maintenance. The 2-year relapse rate was 11% in patients randomized to continuous maintenance CT and 27% in patients randomized to no CT (P = .0002) end 13% in patients randomized to intermittent ATRA and 25% in patients randomized to no ATRA (P = .02). An additive effect of continuous maintenance CT and intermittent ATRA was seen, and only 6 of the 74 patients who received both maintenance treatments had relapsed. Overall survival was improved in patients who received maintenance CT (P = .01), and there was a trend for better survival in patients who received maintenance ATRA (P = .22). Our findings strongly suggest that early addition of chemotherapy to ATRA and maintenance therapy combining continuous CT end intermittent ATRA can reduce the incidence of relapse in APL. This effect already translates into significantly better survival for maintenance treatment with continuous CT. (C) 1999 by The American Society of Hematology.

A 75-year-old man with splenic marginal zone lymphoma had been treated by fludarabine. The 3 first courses were very well tolerated, with no cytopenia. To treat diabetes mellitus, metformin was added at day 6 after the beginning of the fourth course of fludarabine treatment. He had previously been briefly treated with metformin a few months before. Four days later, at day 10, haemogram revealed severe neutropenia (neutrophils: 0.7 g/l). Neutrophil count continued to decrease reaching 0.283 g/l at day 17. A bone marrow aspirate was performed and showed very active granulopoiesis with maturation arrest at the promyelocyte stage. Metformin was discontinued on day 22 (16 days after reintroduction) and neutropenia promptly reversed during next week with 1.9 g/l (day 29). Direct and indirect granulocyte immunofluorescence test were used to detect anti-neutrophil autoantibodies. The antibodies were related to metformin and were detectable by granulocyte agglutination test and the monoclonal antibody-specific immobilization of granulocyte antigens assay. A possible explanation is the fludarabine-metformin combination, since fludarabine could deplete regulator T-lymphocytes and lead to the emergence of metformin-induced anti-neutrophil antibodies.

A collaborative overview, using individual patient data, has been performed to compare idarubicin versus daunorubicin or other anthracyclines, when used with cytosine arabinoside as induction chemotherapy for newly diagnosed acute myeloid leukaemia. There were 1052 patients in five trials versus daunorubicin, 100 in one trial versus doxorubicin, and 745 in one trial versus zorubicin. In the trials of idarubicin versus daunorubicin, early induction failures were similar with the two treatments (20% idarubicin v 18% daunorubicin; P = 0.4), but after day 40 the later induction failures were fewer with idarubicin (17% v 29%; P

In the present study, we address the issue of the discontinuation of imatinib mesylate (Gleevec) in chronic myelogenous leukemia with undetectable residual disease for more than 2 years. Twelve patients were included. The median duration of real-time quantitative–polymerase chain reaction (RTQ-PCR) negativity and imatinib therapy were, respectively, 32 months (range, 24-46 months) and 45 months (range, 32-56 months) before imatinib interruption. Six patients displayed a molecular relapse with a detectable BCR-ABL transcript at 1, 1, 2, 3, 4, and 5 months. Imatinib was then reintroduced and led to a novel molecular response in most patients. Six other patients (50%) still have an undetectable level of BCR-ABL transcript after a median follow-up of 18 months (range, 9-24 months). We hypothesize that relapses observed within 6 months reflect the kinetics of undetectable dividing chronic myelogenous leukemia (CML) cells. Those cells may be eradicated or controlled in long-term nonrelapsing patients, as described in our study.

We report the outcome of 50 consecutive patients with CR1 acute leukemia (AML = 22; ALL = 28) treated with autologous BMT, after cyclophosphamide and TBI, followed with a sequential high dose rIL2 regimen. rIL-2 (RU 49637 from Roussel-Uclaf, Romainville, France) was started after hematological reconstitution an average of 72 +/- 22 days post transplant. The schedule consisted of a continuous infusion over 5 cycles (Cycle 1: 5 days starting on day 1; cycle 2-5: 2 days starting on day 15, 29, 43 and 57). Patients were treated at 4 different dosages (12 (N = 40), 16 (N = 3), 20 (N = 2), 24 (N = 5) x 10(6) IU/m2/day). Toxicities were mainly related to capillary leak syndrome and thrombocytopenia. Patients received an average of 122 +/- 49 10(6) IU/m2. Two patients with AML died from toxicity. rIL-2 infusion was associated with very a high level of immune stimu-lation of both T-cells (P0.05) and natural killer (NK) cells (P0.05) and associated cytolytic functions (P0.05). With a minimal and median follow-up of 21 and 46 months, 3 year leukemia free survival is 41 +/- 6% overall, 39 +/- 10% and 43 +/- 8% for AML and ALL respectively. Relapse probabilities at 3 years are 59 +/- 11% for AML and 57 +/- 8% for ALL. We conclude that this short infusion of rIL-2 over 2 months, resulting in an increased immune stimulation, is not associated with a better leukemic control for patients with acute leukemia transplanted early after reaching first complete remission.

Purpose The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse. Patients and Methods In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion). Results N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001). Conclusion These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.

All-trans retinoic acid (ATRA) combined to anthracycline-based chemotherapy is the reference treatment of acute promyelocytic leukemia (APL). Whereas, in high-risk patients, cytarabine (AraC) is often considered useful in combination with anthracycline to prevent relapse, its usefulness in standard-risk APL is uncertain. In APL 2000 trial, patients with standard-risk APL [i.e., with baseline white blood cell (WBC) count

International audience; We report here the results of the GRAAPH-2003 trial with long-term follow-up in 45 patients with de novo Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Imatinib-based strategy improved the 4-year overall survival (OS) up to 52% versus 20% in the pre-imatinib LALA-94 trial (P = .0001). Despite the selection in patients who actually underwent transplantation, these results suggest that allogeneic or autologous stem cell transplants (SCTs) still have a place in overcoming the poor prognosis of Ph+ ALL in the era of imatinib therapy. OS was 50% after allogeneic SCT (24 patients), 33% in patients without a transplantation (9 patients), and 80% after autologous SCT (10 patients without allogeneic donor or >55 years, including 7 patients in complete molecular response).

Somatic mutations of isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) genes are found in 7-14% and 8-19% of AML. IDH1R132, IDH2R140 and IDH2R172mutations are most frequent in cytogenetically normal AML (25-30% of cases) and significantly associated with NPM1 mutations (except for IDH2R172). Their prognostic significance depends on mutational context (NPM1 and FLT3-ITD status) and on type of mutation: IDH1R132 has a possible adverse effect, IDH2R140 is associated with a favorable effect while the IDH2R172 effect remains controversial (Green C, Blood 2011; Papaemmanuil E, NEJM 2016). IDH1/2 mutations induce a neomorphic enzyme that overproduces the 2-hydroxyglutarate oncometabolite and thus have emerged as promising therapeutic targets. Indeed, AG-120 (IDH1 inhibitor) and AG-221 (IDH2 inhibitor) have shown encouraging activity in phase I trials including Rel/Ref AML pts though median OS are not yet reported. The prognosis of IDH mutated pts at this phase of the disease is not well described in routine practice outside clinical trials. The primary objective of this study was to describe characteristics and outcome of AML pts with IDH1/2 mutations treated in routine practice by intensive chemotherapy from both diagnosis and Rel/Ref phase of the disease. This study included 1603 pts admitted at the Toulouse University Hospital and/or registered in the Oncomip regional Network from January, 1st, 2000 to December, 31st, 2014. This database included all cases of AML pts treated by intensive chemotherapy since 2000 then, starting from 2007, all consecutive patients whatever their treatment (Bories P, Am J Hematol 2014; Bertoli S, Blood 2013). Molecular analyses were performed at diagnosis or retrospectively from stored samples. Only first relapses after standard intensive chemotherapy were considered for this analysis and refractory disease was defined as failure following one course of induction chemotherapy including or not a second course for patients with more than 5% bone marrow blasts at day 15. Treatment distributions were as follows: 984 pts received intensive chemotherapy, 224 azacitidine and 312 best supportive care. Mutational status of IDH1 and IDH2 was available for 465 pts of whom, 422 received intensive chemotherapy as first line therapy, 21 azacitidine and 20 BSC. The study focalized on pts treated by intensive chemotherapy: 349 IDH1/2wt (82%), 32 IDH1R132 (7.5%), 31 IDH2R140 (7.3%) and 11 IDH2R172 (2.6%). IDH2R140 (59y, IQR, 54-66.5) and IDH2R172 (60y, 42.5-64) pts were older than IDH1R132 (53y, 43.8-59.3) and IDHwt (52y, 39-62) pts. IDH2R172 pts had lower WBC count (2.1 G/l, 1.35-4.6) as compared to IDHwt (18 G/l, 4.3-66.9), IDH1R132 (14.7 G/l, 2.1-47.5) and IDH2R140 (21.5 G/l, 4.1-43). De novo AML was found in 85%, 94%, 74% and 73% of IDHwt, IDH1R132, IDH2R140 and IDH2R172 pts, respectively. Only 3 IDH1R132 and 3 IDH2R140 pts had unfavorable karyotype whereas 2 IDH2R140 pts had CBF-AML. Complete response was achieved in 80%, 91%, 74% and 100% of IDHwt, IDH1R132, IDH2R140 and IDH2R172 pts, respectively. Median overall survival (OS) from diagnosis was 23.6, 20.9, 35.8 and 41.1 months in IDHwt, IDH1R132, IDH2R140 and IDH2R172 pts, respectively. 185 Rel/Ref patients with IDH1/2-defined mutational status received salvage therapy with intensive chemotherapy (68%); azacitidine (18%) or other treatments (14%): 144 IDHwt (36 Ref/108 Rel), 18 IDH1R132 (3 Ref/15 Rel) and 23 IDH2R140/R172 (8 Ref/15 Rel). Complete response was achieved in 62 IDHwt (43%), 9 IDH1R132 (50%) and 12 IDH2R140/R172 (52%) pts, respectively. Median OS and 3-year OS from failure or relapse were: IDHwt: 7.6 months/19%; IDH1R132: 5.9 months/8% and IDH2R140/R172: 11 months/23%. Observational data should be considered complementary to that provided by randomized clinical trials. They provide data collected in a non-selected general population, while participants in clinical trials are generally under very restrictive eligibility criteria. In refractory or relapsed patients who received salvage therapy, substantial differences may be observed according to the subtype of mutations, IDH1R132 having the poorest prognosis. IDH2R172 appears to confer a more favorable outcome (3-year OS from diagnosis: 61%). Disclosures Tavitian: Novartis: Membership on an entity's Board of Directors or advisory committees. Huguet:Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Récher:Celgene, Sunesis, Amgen, Novartis, Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Purpose: Hyper-CVAD developed by the MD Anderson group a few years ago, is one of the standard salvage regimen used for younger relapsed/refractory ALL patients. Recently, targeted therapies using monoclonal antibodies directed against such surface antigens as CD19, CD20 or CD22 have allowed to obtain complete remission (CR) in B ALL expressing these markers. We hypothesized that combining Hyper-CVAD and an anti-CD22 monoclonal antibody could improve the response of such patients. Materials and Methods: This study evaluated the Cheprall salvage regimen, where epratuzumab, a humanized therapeutic monoclonal antibody against CD22 with mainly ADCC property, was associated to Hyper-CVAD, in younger patients (18-59 years old) with relapsed/refractory CD22+ (>30% of expression) B-ALL. Cheprall consisted of epratuzumab 360 mg/m²/d iv on days 1, 8, 15 and 22, cyclophosphamide 300 mg/m²/12h iv on days 1 to 3, vincristine 2 mg iv on days +4 and +11, doxorubicin 50 mg/m² iv on day +4 and dexamethasone 40 mg po on days 1 to 4 and 11 to 14. The main objective of the study was the overall response rate (CR + CR with incomplete platelets recovery (=50% of bone marrow (BM) blasts decrease or CR with persistent extramedulladory disease) evaluated between 4 and 6 weeks from day+1. Secondary objectives were overall (OS) and leukemia free (LFS) survivals and minimal residual disease (MRD) evaluated by flow cytometry. Results: Between January 2011 and April 2016, 31 patients from 11 French centres were enrolled in the study. A combination of epratuzumab + vincristine and dexamethasone (EVD) only was given to one patient subsequently excluded from the analysis. Among the 30 patients ultimately considered for analyses, 19 were males and the median age was 35 years (range: 21-59). The median time between diagnosis and Cheprall was 14.5 months (range: 4-130) and 13 patients had been allotransplanted. Disease status at time of Cheprall was as follows: primary refractory n=3; first relapse non treated n=13; refractory first relapse n=6, second relapse non treated n=7 and fourth relapse n=1. Median percentage of white blood cells and BM blasts were 4525/mm3(range: 90-86790) and 60% (range: 15-100), respectively. The median CD22 expression of BM blasts was 100% (range: 36-100). Four patients had extramedullary disease: breast n=2, parotid n=1, nervous central system n=1 (deviation). Cheprall was overall well tolerated including mostly pancytopenia as grade ¾ toxicities. Three patients died during aplasia (septis n=1; cerebral haemorrhage n=1, fusariosis n=1) and were not evaluable for response. The overall response rate was 50% (n=15) including 9 CR (30%), 1 CRp (3%) and 5 PR (17%). The number of CR/CRp was higher for patients in first non-treated relapse (54% vs 18%) with an age below 36 years (50% vs 14%), with 18 months (54% vs 17%). Four out of 9 evaluated CR/CRp patients (45%) were documented with negative MRD. All patients in CR/CRp and 1 patient in PR received a consolidation consisting of a second cycle of Cheprall n=5, EVD n=5 or blinatumomab n=1. At the time of analysis (July 2016), all patients have died (during aplasia n=3, progression n=23, multiple organ failure n=1), except three responders still in CR, but yet recently enrolled (2015 n=1, 2016 n=2). Six patients received allogeneic transplant after Cheprall: 4 in CR2, 1 as salvage treatment and 1 in CR3. The last patient included and who achieved CR2 should be allografted in August 2016. Median OS was 3 months (range: 0.2-34.8). Median LFS for those achieving CR/CRp was 4.5 months (range: 1-12). Conclusion: Hyper-CVAD + epratuzumab allowed to obtain 50% of response in this cohort of patients at high risk of failure with refractory/relapsed younger CD22+ B-ALL. Disease improvement was however short-lived, which could be explained either by an insufficient disease load decrease and/or by escape of the blast cells to epratuzumab. This partial efficacy in a population of poor prognosis may suggest that epratuzumab should be tested within first-line chemotherapies as it may participate to decrease MRD level, especially before transplantation. The trial was registered at http://clinicaltrials.gov/ct no.NCT01219816. This study was supported by a grant from the French National Cancer Institute (PHRC 2010). Disclosures Huguet: Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Thomas:Pfizer: Consultancy. Goldenberg:Immunomedics: Employment, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Wegener:Immunomedics: Employment, Honoraria.

Patients with AML and hyperleukocytosis (HL) are at increased risk for early death and relapse. HL is associated with a leukostasis syndrome that can potentially lead to acute respiratory distress syndrome or strokes. HL is independently associated with a shorter RFS (Rollig C, Blood 2015). Mediators of inflammation induced by leukemic blasts and endothelial cells contributed to the pathogenesis of leukostasis and could induce chemoresistance (Stucki A, Blood 2001). We hypothesized that a short course of Dexamethasone (DEX) at induction chemotherapy could improve outcome of HL AML pts. From Jan 2004 to Dec 2013, 662 pts (18-75y) were treated in our center by intensive chemo: dauno (60-90 mg/m² d1-3) or idarubicin (8 mg/m² d1-5) with AraC (100-200 mg/m² d1-7); lomustin 200 mg/m² (d1) being added in patients >60y. Hydroxyurea (HU) could be started promptly at diagnosis. Leukapheresis were not performed. Starting from Jan 2010, DEX 10 mg bid d1-3 was systematically added on the chemo backbone of all pts with a WBC > 100 x109/L or 50 x109 /L with leukostasis. Supportive care was given according to standard guidelines that did not change across the study period. This retrospective study included 137 patients with WBC >50 x109 /L. The median age was 59.7y (47% ≥60y). Median FU was 4.2 years. 49 pts received DEX and were more likely to have poorer PS, leukostasis syndrome, de novo AML and higher WBC count compared to the 88 pts of the non-DEX group whereas cytogenetics risk and ELN classification were similar. HU was given in 27 pts of the DEX group and in 51 pts of the non-DEX group. AlloSCT was performed in 14 pts of the DEX group and in 19 pts of the non-DEX group. CR rate were 78% (DEX) and 74% (no-DEX), respectively (p=0.357). At d60, 7 pts (14%) had died in the DEX group compared to 17 pts (19%) in the no-DEX group (p=0.457). There were no difference in fungal (p=0.351) or bacterial (p=0.96) infections during induction. There were more grade 3-4 bleeding events (18% vs 7%, p=0.038) and more admissions in ICU (31% vs 15%, p=0.028) in the DEX group. DEX significantly improved DFS (HR 0.41; 95% CI, 0.23-0.74, p=0.003) and OS (HR 0.62; 95% CI, 0.39-0.99, p=0.046) (Figure). In a Fine and Gray model, DEX was associated with a lower risk of relapse (aHR ratio 0.13; 95% CI, 0.05-0.33, p Because of the statistical interaction with NPM1 mutations, we hypothesized that NPM1mut-AML might be particularly sensitive to DEX. Interrogation of transcriptomic data set (Verhaak RG, Haematologica 2009) and data mining algorithm revealed that the NPM1 mutation signature is highly enriched in genes responsive to DEX. OCI-AML3 (NPM1/ DNMT3A mutated) was one of the most sensitive cell line and NPM1mut-AML samples (n=16) were more sensitive to apoptosis induction by DEX compared to non-NPM1mut samples (n=18). Further transcriptomic analyses with TCGA data set (NEJM 2013) revealed more complex molecular interactions between AML subgroups and DEX (DNMT3A, RUNX1 mutations, CBFB-MYH11A were predicted to be responsive). In NSG mice xenografted with OCI-AML3, the combination of DEX+AraC significantly improved mice survival compared to AraC alone (p=0.0001). Lastly, in a PDX-NSG model of chemoresistance (Aroua N, ASH 2015), transcriptomic analyses of in vivo AraC-resistant leukemic cells (after 5 daily doses of 60mg/kg) showed a strong up regulation of genes involved in immune and inflammatory response (including NF-kB network) and a highly significant interaction with DEX-modulated genes suggesting that DEX could downregulate inflammatory pathways responsible for in vivo chemoresistance. DEX improves outcome of AML pts treated by chemotherapy by reducing the risk of relapse. The impact of DEX has been adjusted on several factors to limit biases inherent to non-randomized studies and a strong biological rationale was provided to strengthen the clinical finding. Thus, this finding could be easily translated in routine practice by adding DEX to chemotherapy at least for HL AML pts and/or NPM1 mutations. Figure Figure. Disclosures Récher: Celgene, Sunesis, Amgen, Novartis, Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding. Tavitian:Novartis: Membership on an entity's Board of Directors or advisory committees. Vergez:Novartis: Research Funding. Huguet:Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Sarry:GSK, Novartis: Research Funding.

Background: Tyrosine kinase inhibitors (TKIs) are able to induce, in some chronic myeloid leukemia (CML) patients, long-term undetectable molecular disease (UMD). Several studies have now demonstrated that TKIs could be safely discontinued in those patients previously treated with imatinib (STIM, TWISTER, EUROSKI) and more recently with nilotinib and dasatinib (STOP 2G-TKI). All these studies show a Treatment-Free Remission (TFR) rate reaching ~50%. However, a major issue needs to be resolved for the ~50% of patients that fail such TFR strategies. Methods: We have previously reported the possibility of a second imatinib discontinuation in 16 patients who obtained a second UMD state according to the STIM criteria (RE-STIM observational study, Legros et al. Blood 2012). Here, we report a larger cohort of patients who attempt twice TKI-discontinuations with enlarged inclusion criteria: Adults CML patients without prior allogeneic transplantation or progression to advanced phase CML undergoing a 2nd attempt of TKI discontinuation for sustained deep molecular response after a 1st failure. All patients were followed in CML reference centers and according to the EUTOS-ELN accreditation criteria for BCR-ABL assessments with minimal numbers of 32,000 ABL copies/sample. Results: At the time of analysis (1st July 2016), 67 patients (median age: 51 years (range: 25-80 years)) were included. At CML diagnosis, 64 patients were in chronic phase (CP) and 3 patients in accelerated phase (AP). The Sokal risk and the EUTOS long-term survival scores (ELTS) were respectively low in 47% and 68%, intermediate in 36% and 16%, high in 11% and 2% and unknown in 6% and 14% of patients. All patients were treated initially with imatinib and 16% of patients switch to nilotinib (6/11) or to dasatinib (5/11) for intolerance/resistance reasons prior to the 1st TKI discontinuation. The median time on TKI prior to the 1st discontinuation was 63 months (range: 30-146) and the median duration of 1st CMR was 35 months (range: 20-85). The 1st molecular relapse occurred with a median of 2.5 months (range: 0-22) and the second UMD after TKI re-challenge was obtained with a median of 4.4 months (0-40). The reason of the TKI re-challenge was loss of UMD in 43%, loss of MMR in 55% and unknown in 1%. The TKI re-challenge (imatinib 73%, nilotinib 16%, dasatinib 11%) was then administered during a median of 31 months (range: 9-72 months) before the 2nd attempt of discontinuation. At 2nd TKI cessation, 85% of patients were in UMD, 3% in MR4.5, 6 % in MR4, 3% in MMR and 3% unknown. Thirty out of sixty-eight (44%) patients remained treatment-free after a median follow-up of 21.5 months (1-106), see figure. Similarly to 1st attempts, the majority of loss of MMR occurred during the first 6-12 months in this 2nd attempt cohort. Gender, age, disease phase, prognosis scores, prior interferon exposure, initial TKI type, and duration of UMD were not found to have any impact on the outcome after the 2nd attempt in a multivariate analysis. In contrast, a longer time to obtain the first UMD before the 1st attempt was associated with a significantly lower molecular disease-free survival rate after the 2nd discontinuation (p = 0.048). All patients are alive at last follow-up except one who died from an unrelated CML reason (heart attack under imatinib). Conclusion: TKIs could safely and successfully be discontinued a second time in CML pts despite a 1st failure. Figure. Figure. Disclosures Nicolini: BMS: Consultancy, Honoraria; Ariad pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Etienne:BMS: Speakers Bureau; Pfizer: Speakers Bureau; ARIAD: Speakers Bureau; novartis: Consultancy, Speakers Bureau. Huguet:Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Guerci-Bresler:Pfizer: Consultancy; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; ARIAD: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Mahon:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ARIAD: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria.

Background: Treatment of younger adults with Ph-negative ALL has markedly evolved since the early 2000s. Survivals have substantially improved using pediatric or pediatric-inspired protocols with higher doses of steroids, vincristine (VCR), methotrexate (MTX) and L-asparaginase (L-Aspa), as was done in the GRAALL-2003 trial (Huguet et al. JCO 2009). However, the upper age limit for a pediatric-like strategy remained undetermined. In the GRAALL-2005 study (NCT00327678), we aimed to address this age issue in a larger trial and to randomly evaluate a reinforced hyper-fractionated (hyperC) vs standard (standardC) dose of cyclophosphamide (CPM) during induction and late intensification. Patients with CD20-positive B-cell precursor (BCP) ALL were also randomized in the rituximab GRAALL-2005/R study, as specifically reported last year (Maury et al. ASH 2015). Patients and Methods: Patients aged 18-59 years old with newly-diagnosed Ph-negative ALL were eligible. Chemotherapy comprised a steroid prephase, a 5-drug induction, two 3-block dose-dense consolidation phases, a late intensification, a third consolidation phase, CNS irradiation, and a 2-year maintenance (Beldjord et al. Blood 2014). Allogeneic transplantation was offered in first complete remission (CR) to patients with conventional high-risk factors (Dhédin et al. Blood 2015). During induction and late intensification, CPM was given at 750 mg/m2 on day 1 followed by 750 mg/m2 on day 15 (standardC) or 300 mg/m2/12h on day 15 to 17 (hyperC), according to randomization arm. The primary endpoint was event-free survival (EFS). Secondary endpoints were cumulative incidences of failure (CIF, including primary refractoriness and relapse) and CI of non-refractoriness/relapse mortality (CINRM, including toxic death during induction and death in first CR), overall survival (OS), compliance and safety. Compliance was assessed by comparing the median doses of specific drugs actually received by patients who completed specific treatment phases. Results: Between 2006 and 2014, 787 evaluable patients were randomized (398 standardC, 389 hyperC; 525 BCP-ALL, 262 T-ALL). Median age was 36y, with 200, 172, 171, 151 and 93 patients in the 18-24y, 25-34y, 35-44y, 45-54y and 55y+ age subgroups, respectively. Overall CR rate was 91.9% and 278 patients were transplanted in first CR. With a median follow-up of 5.2 years, 5y-EFS and OS were 52% (48-56) and 58% (55-62), respectively, confirming previous GRAALL-2003 results. No difference in outcome was observed in T- vs BCP-ALL patients. At 5 years, EFS was 60%, 58%, 54%, 50% and 26% in the youngest to the oldest age subgroup, respectively (HR, 2.2 [1.7-2.8]; p Conclusions: Taken together, these results indicate that 55 years is likely to be the upper age limit for a pediatric-like strategy in younger adults with ALL, because of excessive toxicity and worse treatment compliance observed above this age. Older adults could probably benefit from alternative front-line approaches such as hyper-fractionated CPM or new agents such asinotuzumabozogamicin. Disclosures Rousselot: BMS: Research Funding; Ariad: Research Funding; Pfizer: Research Funding.

Platelet transfusion refractoriness (PTR) is defined by the repeated failure to appropriately increment platelet count after platelet transfusion. PTR represents a real concern in the management of patients (pts) who require iterative platelet transfusions, in particular those undergoing intensive treatment (Stanworth, Br J Haematol 2015). PTR can be secondary to non-immune and immune causes and is associated with adverse events including longer hospital stays, severe hemorrhages and increased risk of early deaths. After induction chemotherapy for acute myeloid leukemia (AML), intensive transfusion support is required during the 4-6 weeks of treatment-induced aplasia. There is few data regarding management and outcome of AML pts with PTR in this setting. This study included all consecutive pts treated by intensive chemotherapy for non-promyelocytic AML in Toulouse University Hospital between January 2001 and December 2014 who developed PTR during the induction phase. Platelet count is measured daily and transfusion of ABO-identical platelets is performed when 60y. We identified 41 cases of PTR among 897 pts in our database (4.8%; 2.9 patients/y). PTR patients were mostly women (78.1% vs 42.4% in non-PTR pts, p 50.109/L) was 19 days (IQR 15 - 25.5). Management of PTR-pts was as follows: a twice-daily prophylactic transfusion strategy in 30 pts (73.2%) regardless of bleeding events, one or more HLA-matched platelet transfusion in 15 pts (83.3% of 18 patients with matched donors), corticosteroids (n=15, 36.6%), intravenous immunoglobulins (n=14, 34.2%), TPO agonists (n=10, 24.4%) or rituximab (n=1). Median time between PTR diagnosis and first HLA-matched platelet transfusion was 12.5 days (IQR, 6.5-15). There were 7 early deaths in the PTR group (17.1%) compared to 80 (9.3%) in the non-PTR group (p=0.1). Grade 3-4 bleeding events during induction, early death rate (before end of aplasia) by grade 3-4 bleeding and death rate by bleeding regardless of the phase of treatment (induction+consolidation) were significantly higher in the PTR group (respectively 22% vs 4.1%, p HLA-matched transfusions have induced an increment in platelet count >10.109/L in 37% of cases.TPO agonists did neither shorten PTR duration (11.5 days with TPO agonists [IQR, 5.5-15] vs. 10.5 days [IQR, 6-16.5]), nor reduce severe bleeding or early death rate (40% and 20% with TPO agonists vs. 21.9% and 17.1% without). PTR during induction therapy for AML pts significantly increases the risk of early and late deaths by severe bleeding. While TPO agonists did not appear as a relevant strategy for PTR pts, the efficacy of both massive prophylactic and HLA-matched transfusion could have reduced the risk of severe bleeding but remains to be clearly established. Since steroids, immunoglobulins or even rituximab did not prove efficacy in this setting, a better understanding of platelet destruction is needed to design mechanism-based therapeutic strategies for this very high risk condition. Table Table. Disclosures Tavitian: Novartis: Membership on an entity's Board of Directors or advisory committees. Huguet:Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Récher:Celgene, Sunesis, Amgen, Novartis, Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Intermediate dose cytarabine (IDAC) defined by daily intravenous bolus of 1g/m² during 5 days has been recently defined as the standard control arm in phase 3 placebo-controlled randomized trials for patients with relapsed or refractory acute myeloid leukemia (R/R AML). In these trials assessing clofarabine/IDAC (CLASSIC-1 study, Faderl S et al., JCO 2012) or vosaroxin/IDAC (VALOR study, Ravandi F. et al., Lancet Oncol 2015) vs placebo/IDAC, complete remission rates and median overall survival with placebo/IDAC were 17.8%/18.9% and 6.3/6.1 months in the CLASSIC-1 and VALOR studies, respectively. However, the dose-intensity of this IDAC regimen remains questioned in routine practice since many centers still use higher doses of cytarabine often in combination with an anthracycline and a third drug including fludarabine, etoposide or gemtuzumab ozogamycin (FLAG-ida, MEC or MIDAM regimen for example) although these regimen have proved little efficacy and higher toxicity. We assessed the outcome of R/R AML patients that fulfilled main VALOR inclusion criteria consecutively treated in our center with intensive salvage regimen. All patients with a diagnosis of AML in first relapse or with refractory disease were eligible for this study. Acute promyelocytic leukemia were excluded. Relapse was defined as re-emergence of at least 5% leukemia blasts in bone marrow or at least 1% blasts in peripheral blood 90 days to 24 months after first complete remission or complete remission with incomplete platelet recovery. Refractory AML was defined as persistent disease at least 28 days after initiation of induction therapy, or relapse less than 90 days after first complete remission (CR) or CR with incomplete platelet recovery (CRi). All patients have received previous induction therapy with an anthracycline. Salvage regimen used were mainly cytarabine 3 g/m²/12h, d1-4 plus idarubicine 12 mg/m²/d, d1-3 or dauno 60 mg/m²/d, d1-2 or amsacrine 200 mg/m²/d, d1-3; less frequently MiDAM (mitoxantrone 12mg/m² d1-3, cytarabine1 g/m²/12h d1-5, GO 4-6mg/m², d4) or FLAG-Ida. Cytarabine dose for patients >60 was reduced to 1g/m²/12h, d1-5. We found, in our database, 151 R/R AML according to VALOR criteria treated between 2000 and 2013: 72 patients (48%) had refractory diseases (primary refractory: n=60, 40% and relapse less than 90 days after CR: n=12, 8.0%) and 79 (52%) had relapsed (early relapse more than 90 days after CR and less than one year: n=52, 66%; late relapse between one and two years: n=27, 34%). Patients characteristics were as follows: 85 (56%) were male, median age was 48 years (interquartile range [IQR], 36-60.5; 38 (27%) were 60 years or older). Cytogenetics at diagnosis was favorable in 18 (12%); intermediate in 93 (62%); adverse in 38 (25%) or unknown in 2 (1%) patients, respectively. They were treated as first line therapy with one (42%) or two cycles (58%). Early death rates at day 30 and day 60 were 7% and 17% in the whole cohort; 6% and 12% in younger patients and 12% and 29% in patients 60 years or older. Combined CR rate (defined as CR and CRi) was 53% for the whole cohort, and 57%/42%/56%/52%/63%/50% for Using VALOR inclusion criteria, age is the main factor that discriminate R/R AML patients selected for clinical trials using IDAC as control arm compared to patients of daily practice. Thus, those patient populations remain hardly comparable. However, as far as CR is concerned, IDAC seems suboptimal as compared to higher-intensity regimen used in daily practice. Yet, this higher CR rates do not translate into a significant gain in survival since median OS remains close to that of IDAC with the possible exception of refractory patients who seem to benefit from higher-intensity regimen. Thus, although unsatisfactory, IDAC could be considered as a fair control arm for overall survival endpoint especially in patients older than 60 year of age. Table Table. Disclosures Tavitian: Novartis: Membership on an entity's Board of Directors or advisory committees. Huguet:Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Recher:Celgene, Sunesis, Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene, Sunesis, Amgen, Novartis, Chugai: Research Funding.

Acute Myeloid Leukemia (AML) is one of the hematological malignancies in which no key development in specific treatment has been achieved in opposition to B-cell malignancies or CML. Yet, few recent studies have reported an improvement in overall survival (OS) of adult AML patients (pts) (Sant, Lancet Oncol 2014; Derolf, Blood 2009; Pulte, Haematologica 2008). However, these studies are mainly based on registries or compilation of clinical trials and reasons for this improvement are not defined. We analyzed the outcome of AML pts treated between 2000 and 2014 by intensive chemotherapy in order to determine whether there has been an improvement in OS over time and independently of classic prognostic factors. From January, 1st, 2000 to December, 31st, 2014, 976 AML pts received intensive chemotherapy at the Toulouse University Hospital. With regards to routine practice evolution, voriconazole or caspofungin were used from 2003 as prophylaxis of fungal infections (Chabrol, Haematologica 2010), then posaconazole from 2008. Indications for alloSCT have evolved from geno to pheno-identical (Id) in first complete response (CR) and more recently to haplo-Id in high risk pts, whereas autologous-SCT was progressively abandoned. Molecular stratification for alloSCT indications based on NPM1, FLT3-ITD and CEBPA mutations started from 2006. A specific unit dedicated to acute leukemia was created in the Hematology department in 2005. Starting from 2010, dexamethasone was added to chemotherapy in pts with WBC>100 or >50 G/L with leukostasis. Since therapeutic strategies differed between younger and older pts, we analyzed separately the outcome of pts In pts 1 (22.8, 10.5 and 24.2%), median WBC count (11, 13 and 9 G/l), favorable/unfavorable karyotypes (14.0/25.6, 15.5/22.7 and 11.5/21.0%), FLT3-ITD (23.7, 20.7 and 22.9%) or NPM1 mutations in intermediate-cytogenetic risk (24.5, 33.6, 33.3%) according to 2000-2004; 2005-2009 and 2010-2014 periods. Median FU of pts still alive was 67.4 months (84.0, 74.1 and 38.1 months for 2000-2004, 2005-2009 and 2010-2014, respectively). Patients were censored at 7 years. Table 1 shows response to induction, treatment distribution and outcome. There were no differences in term of cumulative incidence (CI) of death in CR1 or non-relapse mortality in allografted pts over time. However, multivariate analyses with regards to d60 death (HR 0.43, 95% CI, 0.17-1.13; p=0.089), CI of relapse (SHR 0.72, 95%CI 0.50-1.03; p=0.071) and disease-free survival (HR 0.76, 95%CI 0.54-1.06; p=0.104) showed a trend for better outcome in the 2010-2014 period than in 2000-2004. The period of time was significantly associated with a better OS (p=0.031) with HR of 0.92 (95%CI 0.70-1.20; p=0.536) and 0.68 (95%CI, 0.50-0.92; p=0.012) for 2005-2009 and 2010-2014 respectively, compared to 2000-2004. The 2010-2014 period effect was still significant in multivariate analysis when adjusted on age (≥50y), secondary AML, cytogenetics and WBC >50 G/L (HR 0.62, 95%CI 0.46-0.85; p=0.003). Characteristics of pts 60y+ were: median age (68.0, 68.7 and 66.9y), secondary AML (34.6; 20.2 and 25.7%), PS>1 (28.4, 20.0 and 21.7%), median WBC count (10.7, 8.3 and 11.2 G/l), favorable/unfavorable karyotypes (3.1/24.2, 3.8/21.3 and 4.8/19.8%), FLT3-ITD (12.0, 25.9 and 21.2%) or NPM1 mutations in intermediate-cytogenetic risk (41.3, 34.6, 32.8%) according to 2000-2004; 2005-2009 and 2010-2014 periods. Median FU of pts still alive was 52.5 months (84.0, 70.6 and 35.6 months for 2000-2004, 2005-2009 and 2010-2014, respectively). There was no difference in OS over time (table 2). However, there was a significant interaction between period of time and WBC in the multivariate analysis for OS meaning that the 2010-2014 period had an impact only in pts with WBC > 50 G/L (HR 0.41, 95%CI 0.24-0.71; p=0.002). The same interaction was also found for CR achievement (OR 3.90, 95%CI 1.30-11.7; p=0.015). Progresses have been made in each phase of the therapeutic course of younger AML pts (less early deaths, more alloSCT without increased NRM, less relapses, more second remissions) resulting in survival improvement. In older pts, though outcome of hyperleukocytic patients has improved, significant advances remain to be made. Disclosures Tavitian: Novartis: Membership on an entity's Board of Directors or advisory committees. Attal:sanofi: Consultancy; celgene: Consultancy, Research Funding; janssen: Consultancy, Research Funding; amgen: Consultancy, Research Funding. Huguet:Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Récher:Celgene, Sunesis, Amgen, Novartis, Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Cytomegalovirus (CMV) serological status of donor and recipient as well as CMV reactivation have been associated with a lower risk of relapse in acute myeloid leukemia (AML) patients after allogeneic stem cell transplantation (alloSCT). Since immunosuppression following transplant allows resurgence of many other viruses, we retrospectively evaluated the impact of viral reactivations on relapse and survival in a cohort of 136 AML patients undergoing alloSCT in first remission from sibling (68%) or unrelated (32%) donors. Myeloablative and reduced-intensity conditioning regimen were given to 71 and 65 patients, respectively. Including CMV reactivations, at least 1 viral reactivation was recorded in 76 patients. Viral reactivations were associated with a lower risk of relapse (adjusted HR 0.14; 95% CI 0.07–0.30; P

To the editor: Recent results from the STop IMatinib (STIM) trial suggest that imatinib may be safely discontinued in some chronic myeloid leukemia (CML) patients with long-lasting complete molecular response (CMR).[1][1] However, 60% of patients experienced molecular recurrence (MR; detection of

The efficacy of bendamustine versus chlorambucil in a phase III trial of previously untreated patients with Binet stage B/C chronic lymphocytic leukaemia (CLL) was re-evaluated after a median observation time of 54 months in May 2010. Overall survival (OS) was analysed for the first time. At follow-up, investigator-assessed complete response (CR) rate (21·0% vs 10·8%), median progression-free survival (21·2 vs 8·8 months; P 0·0001; hazard ratio 2·83) and time to next treatment (31·7 vs 10·1 months; P 0·0001) were improved for bendamustine over chlorambucil. OS was not different between groups for all patients or those ≤65 years,65 years, responders and non-responders. However, patients with objective response or a CR experienced a significantly longer OS than non-responders or those without a CR. Significantly more patients on chlorambucil progressed to second/further lines of treatment compared with those on bendamustine (78·3% vs 63·6%; P = 0·004). The benefits of bendamustine over chlorambucil were achieved without reducing quality of life. In conclusion, bendamustine is significantly more effective than chlorambucil in previously untreated CLL patients, with the achievement of a CR or objective response appearing to prolong OS. Bendamustine should be considered as a preferred first-line option over chlorambucil for CLL patients ineligible for fludarabine, cyclophosphamide and rituximab.

PURPOSE We conducted a dose-finding study of mitoxantrone (MITO) in combination with high-dose cyclophosphamide, carmustine (BCNU), and etoposide (CBV) in refractory lymphoma undergoing autologous bone marrow transplantation (ABMT). The objective were to determine the following: (1) the maximum-tolerated dose of MITO, (2) the extramedullary toxicity of this regimen, (3) its antitumor activity, and (4) the pharmacokinetic characteristics of MITO at each dose level. PATIENTS AND METHODS Escalating doses of MITO (15 to 90 mg/m2, single bolus infusion on day -8) followed by CBV were administered to 20 patients (mean age, 38.5 years) with refractory lymphoma. MITO concentrations were determined by high-performance liquid chromatography (HPLC). RESULTS No toxic death occurred. The maximum-tolerated dose appears to be 75 mg/m2. Two of five patients treated with 90 mg/m2 developed severe organ toxicity, versus zero of 15 treated with doses up to 75 mg/m2. Duration of neutropenia was longer for patients treated with 90 mg/m2 (31.7 days) than for patients treated with doses up to 75 mg/m2 (22.1 days) (P < .05). A linear relationship was observed between administered dose of MITO and (1) plasma peak value, (2) area under the curve (AUC), and (3) plasma concentration on the day of marrow infusion (day 0). Hematologic toxicity was related to the terminal half-life (T1/2) of MITO, and day-0 plasma concentration. A high complete response (CR) rate was observed (60%), and eight of 11 (73%) patients treated with MITO > or = 60 mg/m2 achieved a CR. CONCLUSION MITO (up to 75 mg/m2) and CBV can be administered with acceptable toxicity and a promising CR rate in this poor-risk population, justifying further phase II studies.

The diagnosis of adult acute lymphoblastic leukemia (ALL) and the recognition of immuno-genetic entities according to the WHO classification require a comprehensive clinical and biological work-up. The diagnosis of Burkitt mature B-cell ALL is an emergency, since intensive chemotherapy and tumour lysis syndrome prevention lead to an 80% cure rate. Within one week, distinction must be established between B-cell Philadelphia chromosome-positive (Ph+) ALL on one side, Philadelphia-negative B-cell ALL and T cell ALL on the other. The once severe Ph+ ALL now displays a 70% long-term survival rate when treated by associations of chemotherapy and targeted therapy by tyrosine-kinase inhibitors. In Ph-negative ALL, identification of new relapse risk factors, mostly minimal residual disease, justifies to revisit the indications for allogeneic hematopoietic stem cell transplantation, in comparison to pediatric-inspired chemotherapy regimens, with the goal of curing 60% of the patients. However, the outcome of patients above the age of 60 remains dismal.

International audience; l-asparaginase encapsulated within erythrocytes (GRASPA(®) ) should allow serum asparagine depletion over a longer period than the native form of the enzyme, using lower doses and allowing better tolerance. The GRASPALL 2005-01 study, a multicentre randomized controlled trial, investigated three doses of GRASPA(®) for the duration of asparagine depletion in a phase I/II study in adults and children with acute lymphoblastic leukaemia (ALL) in first relapse. Between February 2006 and April 2008, 18 patients received GRASPA(®) (50 iu/kg: n = 6,100 iu/kg: n = 6, 150 iu/kg: n = 6) after randomization, and six patients were assigned to the Escherichia coli native l-asparaginase (E. colil-ASNase) control group. GRASPA(®) was effective at depleting l-asparagine. One single injection of 150 iu/kg of GRASPA(®) provided similar results to 8 × 10,000 iu/m(2) intravenous injections of E. colil-ASNase. The safety profile of GRASPA(®) showed a reduction in the number and severity of allergic reactions and a trend towards less coagulation disorders. Other expected adverse events were comparable to those observed with E. colil-ASNase and there was also no difference between the three doses of GRASPA(®) .

Idarubicin (IDR) is an anthracycline that can be administered orally. Low dose cytarabine (LDARAC) has been commonly used in the treatment of acute myeloid leukemia (AML) in elderly patients. A comination of oral IDR (20 mg/m(2) for 3 days) and LDARAC (10 mg/m(2) q12 hours for 10 days) was given in 32 patients aged 65 to 82 years (median 76) with de novo AML. Eight patients whose marrow remained blastic by day 20 received a second course (IDR for 2 days and LDARAC for 5 days). Complete remission (CR) was achieved in 13 cases (40.5%), (one course 12, two courses 1). There was 1 early death, 3 deaths in aplasia, 2 partial remissions and 13 failures. All but 5 patients were entirely managed in hospital. The median duration of neutropenia was 18 days and only 1 patient obtained CR without therapeutic aplasia. The extrahematologic toxicity was mild with 3 reversible cardiac events. These results are comparable to those obtained with conventional chemotherapy and this regimen could be proposed as induction treatment of AML in elderly patients.

Elevated levels of tumor necrosis factor alpha (TNF-alpha) have been reported to correlate with the development of transplant-related complications after bone marrow transplantation (BMT). In a recent phase I-II trial, oral administration of pentoxifylline (PTX), a xanthine derivative capable of downregulating TNF-alpha production in vitro, was reported to reduce morbidity and mortality in patients undergoing BMT. We conducted a prospective randomized trial of PTX therapy among 140 patients undergoing either allogeneic (n = 51) or autologous BMT (n = 89). Patients were randomized to receive (n = 70) or not receive (n = 70) oral PTX, 1,600 mg/d in four divided doses from day -8 until day + 100 post-BMT. The incidence of mucositis requiring morphine sulfate (MSO4) was similar in both groups (42.9%), with the mean number of days with MSO4 being 7.8 (SD = 3.4) in the PTX group versus 8.2 (SD = 3.4) in the control group (NS). The incidence of renal insufficiency was not affected by PTX administration (15.7% in the PTX group v 21.4% in the control group [NS]) and the highest serum creatinine value during the first 100 days post-BMT was 119 mumol/L (SD = 82.4) in the PTX group versus 103.9 mumol/L (SD = 57) in the control group (NS). The incidence of grade > or = 2 graft-versus-host disease was similar in each group (11/25 [44%] in the PTX group v 12/26 [46%] in the control group). No significant difference was observed in hematologic toxicity, transfusion requirements, duration of fever, and hepatic toxicity between the treatment groups. In conclusion, our study failed to show a prophylactic effect of PTX in transplant-related toxicities after BMT. On the basis of these findings, we cannot recommend that PTX be part of early mortality and morbidity prevention programs after BMT.

The 5 q deletion is frequently found in myelodysplastic syndromes and acute non lymphoid leukemia, but this anomaly is usually found in secondary diseases and associated with many other chromosomal aberrations. This report describes four cases of "de novo" acute leukemia with a sole 5q- anomaly. They had no cytological, genetic or clinical characteristics of secondary disorders. It is important to note that of the four patients studied, three had proliferation of immature blast cells. One case was classified as a MO AML and two as "undifferentiated" acute leukemia. Furthermore, these four cases of acute leukemia showed a deletion of the same portion of the long arm of chromosome 5: q22q33. On the same part of this chromosome many hematopoietic growth factor genes have been located, like IL3 and GM-CSF which have early undifferentiated hematopoietic stem cells as a their target.

Summary Background Imatinib treatment significantly improves survival in patients with chronic myeloid leukaemia (CML), but little is known about whether treatment can safely be discontinued in the long term. We aimed to assess whether imatinib can be discontinued without occurrence of molecular relapse in patients in complete molecular remission (CMR) while on imatinib. Methods In our prospective, multicentre, non-randomised Stop Imatinib (STIM) study, imatinib treatment (of >2 years duration) was discontinued in patients with CML who were aged 18 years and older and in CMR (>5-log reduction in BCR–ABL and ABL levels and undetectable transcripts on quantitative RT-PCR). Patients who had undergone immunomodulatory treatment (apart from interferon α), treatment for other malignancies, or allogeneic haemopoietic stem-cell transplantation were not included. Patients were enrolled at 19 participating institutions in France. In this interim analysis, rate of relapse was assessed by use of RT-PCR for patients with at least 12 months of follow-up. Imatinib was reintroduced in patients who had molecular relapse. This study is registered with ClinicalTrials.gov, number NCT00478985. Findings 100 patients were enrolled between July 9, 2007, and Dec 17, 2009. Median follow-up was 17 months (range 1–30), and 69 patients had at least 12 months follow-up (median 24 months, range 13–30). 42 (61%) of these 69 patients relapsed (40 before 6 months, one patient at month 7, and one at month 19). At 12 months, the probability of persistent CMR for these 69 patients was 41% (95% CI 29–52). All patients who relapsed responded to reintroduction of imatinib: 16 of the 42 patients who relapsed showed decreases in their BCR–ABL levels, and 26 achieved CMR that was sustained after imatinib rechallenge. Interpretation Imatinib can be safely discontinued in patients with a CMR of at least 2 years duration. Imatinib discontinuation in this setting yields promising results for molecular relapse-free survival, raising the possibility that, at least in some patients, CML might be cured with tyrosine kinase inhibitors. Funding French Ministry of Health (Programme Hospitalier de Recherche 2006 grants), Institut National du Cancer (INCA).

Objectives Investigating the role of occupational exposure to solvents in the occurrence of lymphoid neoplasms (LNs) in men. Methods The data were generated by a French hospital-based case-control study, conducted in six centres in 2000–2004. The cases were incident cases aged 18–75 years with a diagnosis of LN. During the same period, controls of the same age and gender as the cases were recruited in the same hospitals, mainly in the orthopaedic and rheumatological departments. Exposure to solvents was assessed using standardised occupational questionnaires and case-by-case expert assessment. Specific quantification of benzene exposure was attempted. The analyses included 491 male patients (244 cases of non-Hodgkin9s lymphoma (NHL), 87 of Hodgkin9s lymphoma, 104 of lymphoproliferative syndrome and 56 of multiple myeloma) and 456 male controls. Unconditional logistic regressions were used to estimate OR and 95% CI. Results Solvent exposure, all solvents considered together, was marginally associated with NHL (OR=1.4 (1.0 to 2.0) p=0.06), but not with other LNs. No association with the main chemical series of solvents was observed. There was no trend with the average intensity or frequency of exposure. Exposure to pure benzene was not significantly related to NHL (OR=3.4 (0.8 to 15.0)). The highest maximum intensities of benzene exposure were associated with diffuse large cell lymphoma (OR=2.1 (1.0 to 4.6)). Conclusion The results of the present study provide estimates compatible with the hypothesis that exposures to pure benzene and high benzene intensities may play a role in some NHL. There was no evidence for a role of other organic solvents in the occurrence of LN.

Background The median survival of patients with chronic myelogenous leukemia in myeloid blast crisis (MBC-CML) is poor even for patients treated with tyrosine kinase inhibitors (TKIs). Design and methods We conducted a dose-escalating study of daunorubicin combined to fixed doses of IM (imatinib mesylate, 600 mg/d) and cytarabine (200 mg/d for 7 days), followed by hematopoietic stem cell transplantation or maintenance therapy with single-agent IM in patients with MBC-CML at onset or after failure of therapy excluding TKIs. Results Thirty-six patients were evaluated. Median follow-up is 6.1 years. Daunorubicin was escaladed up to 45 mg/m 2 /d 3 days. Twenty eight patients (77.7%) had hematologic response including 20 patients (55.5%) in complete hematologic response (CHR). Patients who received daunorubicin at 30–45 mg/m 2 /d had higher CHR rates compared to other patients. Median overall survival was 16 months. Overall survival in patients with hematological response was 35.4 months. Better results were observed in patients diagnosed with MBC-CML at onset. Conclusions The combination of IM with a standard “3 + 7” regiment was well tolerated and provided a high response rate. More than 55% of the patients achieved CHR and hematopoietic stem cell transplantation (SCT) was feasible in half of the cases. This trial was registered at www.clinicaltrials.gov as # NCT00219765 .

Abstract 2449 Introduction: Bendamustine (BEN), either alone or in combination with Rituximab, is increasingly used in the treatment of chronic lymphocytic leukemia (CLL) and various types of low grade Non Hodgkin's Lymphoma (NHL). The approval to treat CLL with BEN is based on a prospectively randomized trial (Knauf et al., J Clin Oncol. 2009; 27: 4378–4384) comparing single drug BEN with chlorambucil (CLB). Here, we report on follow-up data of this pivotal trial with specific reference to survival times, time to next treatment, and efficacy of second line regimens. Since CLL is a disease of the elderly and potentially co-morbid patients, we also analyzed quality of life (QoL) parameters in relation to the treatment with both BEN and CLB. Patients and Methods: The efficacy and safety of BEN and CLB have been compared in a randomized, open-label, multicenter, phase III trial in patients with previously untreated advanced (Binet stage B/C) CLL. Patients were randomized to receive either BEN (100 mg/m2 on days 1 + 2) or CLB (0.8 mg/kg on days 1 and 15) for up to 6 treatment cycles. The primary endpoints were overall response rate (ORR), which was defined as complete (CR) or partial response (PR), and progression-free survival (PFS). Secondary endpoints included overall survival (OS), and QoL. The latter was analyzed by using both the EORTC questionnaires QLQ C30 and QLQ-CLL25. We also looked at time to next treatment and efficacy of second line regimens. The response to treatment was evaluated by a blinded Independent Response Assessment Committee. Results: A total of 319 patients were randomized (162 BEN and 157 CLB), all of whom were included in the efficacy analysis, while 308 patients were evaluable for QoL analysis (158 BEN and 150 CLB). Median age was 64 years (range 35 to 78). The mean number of treatment cycles was 5 in both study arms, regardless of an age above or below 65 years. The median observation time was 54 months. ORR was significantly higher with BEN than with CLB (68% versus 31%, P Conclusion: This study has shown that BEN offers significantly greater response rates, PFS, and a much longer time to next treatment than CLB. OS is prolonged significantly in all responders and especially in those patients who achieve CR after BEN. In comparison to CLB, the additional efficacy of BEN was achieved without compromising QoL. BEN should be considered as a backbone drug in first-line chemotherapy of patients with advanced CLL. Disclosures: Knauf: Mundipharma: Consultancy, Honoraria. Klein: Mundipharma: Honoraria. Merkle: Mundipharma: Honoraria.

The prognostic significance of CD20 expression in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has been mostly studied in children and yielded conflicting results. In 143 adults with Philadelphia chromosome-negative BCP-ALL treated in the multicentric GRAALL 2003 trial, CD20 positivity over 20% was observed in 32% of patients. While not influencing complete remission achievement, CD20 expression was associated with a higher cumulative incidence of relapse (CIR) at 42 months (P=0.04), independently of the ALL high-risk subset (P=0.025). Notably, the negative impact of CD20 expression on CIR was only observed in patients with a white blood cell count (WBC) over 30x10(9)/L (P=0.006), while not in those with a lower WBC. In the former subgroup, this impact translated into lower event-free survival (15% vs. 59% at 42 months, P=0.003). CD20 expression thus appears to be associated with a worse outcome, which reinforces the interest of evaluating rituximab combined to chemotherapy in CD20-positive adult BCP-ALL. ClinicalTrials.gov ID, NCT00222027.

Hepatic veno-occlusive disease (VOD) is a major regimen-related toxicity after bone marrow transplantation (BMT). Endothelial injury, leading to deposition of coagulation factors within the terminal hepatic venules, is believed to be the key event in the pathogenesis of VOD. To evaluate the benefit and the safety of a VOD prophylaxis with anticoagulants, we conducted a prospective randomized trial of continuous infusion of low-dose heparin among 161 patients under-going either allogeneic (n = 79) or autologous BMT (n = 81). Patients were randomized to receive (n = 81) or not receive (n = 80) prophylactic heparin 100 U/kg/d by continuous infusion from day -8 until day +30 post-BMT. Heparin was found to be highly effective in preventing VOD, which occurred in 11 of 80 patients (13.7%) in the control group versus 2 of 81 (2.5%) in the heparin group (P less than .01). Furthermore, none of the 39 patients in the heparin group developed VOD after allogeneic BMT, versus 7 of 38 (18.4%) in the control group (P less than .01). This prophylactic effect was achieved without added risk of bleeding. Indeed, the low-dose heparin we used did not prolong the partial thromboplastin time and did not increase the red blood cell and platelet requirements. It is therefore recommended that heparin prophylaxis be part of early mortality prevention programs after BMT.

A trial was initiated to determine the feasibility and efficacy of a three-phase treatment including: (1) induction chemotherapy (IC); (2) high-dose melphalan with total body irradiation supported by unpurged autologous bone marrow transplantation (ABMT); and (3) interferon (IFN) alpha maintenance treatment, in previously untreated aggressive myeloma. Thirty-five consecutive patients, ages under 65 years, were enrolled. Initial induction therapy was randomized between the VAD regimen (vincristine, doxorubicin, dexamethasone) or the VMCP regimen (vincristine, melphalan, cyclophosphamide, prednisone) that were found to give similar results as IC. Thirty-one of 35 (89%) patients, with good performance status and normal renal function after IC, received ABMT. IFN alpha was started soon after ABMT and was well tolerated. Fifteen of 35 (43%) patients achieved complete response (CR) and 14 of 35 (40%) achieved partial response (PR). Low pretreatment beta 2 microglobulin was the only predictive factor for accomplishing CR. The duration of response was significantly affected by the magnitude of response. The 33-month, post-ABMT probability of progression-free survival was 85% for patients in CR versus 24% for patients in PR. The 42-month, post-diagnosis probability of survival was 81%. This overall strategy may represent an advance in the management of multiple myeloma. Furthermore, the high rate and long duration of CR that we observed in patients with low beta 2 microglobulin suggest that such patients may preferentially benefit from this strategy.

Background Invasive aspergillosis is a common life-threatening infection in patients with acute leukemia. The presence of building work near to hospital wards in which these patients are cared for is an important risk factor for the development of invasive aspergillosis. This study assessed the impact of voriconazole or caspofungin prophylaxis in patients undergoing induction chemotherapy for acute leukemia in a hematology unit exposed to building work.Design and Methods This retrospective cohort study was carried out between June 2003 and January 2006 during which building work exposed patients to a persistently increased risk of invasive aspergillosis. This study compared the cumulative incidence of invasive aspergillosis in patients who did or did not receive primary antifungal prophylaxis. The diagnosis of invasive aspergillosis was based on the European Organization for Research and Treatment of Cancer/Mycosis Study Group criteria.Results Two-hundred and fifty-seven patients (213 with acute myeloid leukemia, 44 with acute lymphocytic leukemia) were included. The mean age of the patients was 54 years and the mean duration of their neutropenia was 21 days. Eighty-eight received antifungal prophylaxis, most with voriconazole (n=74). The characteristics of the patients who did or did not receive prophylaxis were similar except that pulmonary antecedents (chronic bronchopulmonary disorders or active tobacco use) were more frequent in the prophylaxis group. Invasive aspergillosis was diagnosed in 21 patients (12%) in the non-prophylaxis group and four (4.5%) in the prophylaxis group (P=0.04). Pulmonary antecedents, neutropenia at diagnosis and acute myeloid leukemia with high-risk cytogenetics were positively correlated with invasive aspergillosis, whereas primary prophylaxis was negatively correlated. Survival was similar in both groups. No case of zygomycosis was observed. The 3-month mortality rate was 28% in patients with invasive aspergillosis.Conclusions This study suggests that antifungal prophylaxis with voriconazole could be useful in acute leukemia patients undergoing first remission-induction chemotherapy in settings in which there is a high-risk of invasive aspergillosis.

Purpose Retrospective comparisons have suggested that adolescents or teenagers with acute lymphoblastic leukemia (ALL) benefit from pediatric rather than adult chemotherapy regimens. Thus, the aim of the present phase II study was to test a pediatric-inspired treatment, including intensified doses of nonmyelotoxic drugs, such as prednisone, vincristine, or l-asparaginase, in adult patients with ALL up to the age of 60 years. Patients and Methods Between 2003 and 2005, 225 adult patients (median age, 31 years; range, 15 to 60 years) with Philadelphia chromosome–negative ALL were enrolled onto the Group for Research on Adult Acute Lymphoblastic Leukemia 2003 protocol, which included several pediatric options. Some adult options, such as allogeneic stem-cell transplantation for patients with high-risk ALL, were nevertheless retained. Results were retrospectively compared with the historical France-Belgium Group for Lymphoblastic Acute Leukemia in Adults 94 (LALA-94) trial experience in 712 patients age 15 to 55 years. Results Complete remission rate was 93.5%. At 42 months, event-free survival (EFS) and overall survival (OS) rates were 55% (95% CI, 48% to 52%) and 60% (95% CI, 53% to 66%), respectively. Age remained an important bad prognostic factor, with 45 years of age as best cutoff. In older versus younger patients, there was a higher cumulative incidence of chemotherapy-related deaths (23% v 5%, respectively; P < .001) and deaths in first CR (22% v 5%, respectively; P < .001), whereas the incidence of relapse remained stable (30% v 32%, respectively). Complete remission rate (P = .02), EFS (P < .001), and OS (P < .001) compared favorably with the previous LALA-94 experience. Conclusion These results suggest that pediatric-inspired therapy markedly improves the outcome of adult patients with ALL, at least until the age of 45 years.

Abstract 2367 Poster Board II-344 Introduction: Bendamustine is a purine analog/alkylator hybrid agent with a unique mechanism of action, which has shown good clinical efficacy and acceptable tolerability in various hematological malignancies. Chronic lymphocytic leukemia (CLL) is a disease of the elderly, and presents with a variety of clinical characteristics which influence the prognosis. We analyzed tolerability and efficacy of bendamustine (BEN) in comparison to chlorambucil (CLB) in clinical risk groups defined by age and specific indicators of disease activity. Patients and Methods: The efficacy and safety of BEN and CLB have been compared in a randomized, open-label, multicenter, phase III trial in patients with previously untreated advanced (Binet stage B/C) CLL. Patients were randomized to receive BEN (100 mg/m2 on days 1 + 2) or CLB (0.8 mg/kg on days 1 and 15) for up to 6 treatment cycles. The primary endpoints were overall remission rate (ORR), which was defined as complete or partial response, and progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. The response to treatment was evaluated by a blinded Independent Response Assessment Committee. Results: A total of 319 patients were randomized (162 bendamustine, 157 chlorambucil), of whom all were included in the efficacy analysis, while 312 were evaluable for safety. Median age was 64 years (35 to 78). The median number of treatment cycles was 6 in both study arms, regardless of an age above or below 65 years. The median observation time was 35 months. ORR was significantly higher with BEN than with CLB (68% versus 31%, P0.3; and 28.4 % versus 32.5 % with CLB, p>0.6). PFS was not influenced by age above 65 years, stage of disease (Binet stage B versus C), or elevated LDH. However, patients without B symptoms had a longer median PFS with BEN than those patients with B symptoms (30.4 months versus 17.7 months; p Conclusion: This study has shown that bendamustine offers significantly greater efficacy than chlorambucil in the elderly and across clinically defined major risk groups, even in the presence of B symptoms. BEN should be considered as first-line chemotherapy for patients with advanced CLL. Disclosures: Knauf: mundipharma: Consultancy, Honoraria; cephalon: Consultancy, Honoraria. Klein:mundipharma: Consultancy, Honoraria. Merkle:mundipharma: Consultancy, Honoraria. Montillo:mundipharma Italy: Consultancy, Research Funding.

Many somatic genetic abnormalities have been identified in T-cell acute lymphoblastic leukemia (T-ALL) but each individual abnormality accounts for a small proportion of cases; therapeutic stratification consequently still relies on classical clinical markers. NOTCH1 and/or FBXW7 mutations both lead to activation of the NOTCH1 pathway and are among the most frequent mutations in T-ALL. We screened 141 adult diagnostic T-ALL samples from patients treated on either the Lymphoblastic Acute Leukemia in Adults (LALA)-94 (n = 87) or the GRAALL-2003 (n = 54) trials. In 88 cases (62%) there were demonstrated NOTCH1 mutations (42% heterodimerization [HD], 10% HD+proline glutamate serine threonine [PEST], 6% PEST, 2% juxtamembrane mutations, 2% transactivation domain [TAD]) and 34 cases (24%) had FBXW7 mutations (21 cases had both NOTCH1 and FBXW7 mutations); 40 cases (28%) were wild type for both. There was no significant correlation between NOTCH1 and/or FBXW7 mutations and clinico-biologic features. Median event-free survival (EFS) and overall survival (OS) were 36 versus 17 months (P = .01) and not reached versus 32 months (P = .004) in patients with NOTCH1 and/or FBXW7 mutations versus other patients, respectively. Multivariate analysis showed that the presence of NOTCH1/FBXW7 mutations was an independent good prognostic factor for EFS and OS (P = .02 and P = .01, respectively). These data demonstrate that NOTCH1 pathway activation by either NOTCH1 or FBXW7 mutation identifies a large group of patients with a favorable outcome that could justify individual therapeutic stratification for T-ALL.

International audience; Lymphoid neoplasms (LNs), including non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL), lymphoproliferative syndrome (LPS) and multiple myeloma (MM), are among the most frequent cancers ( approximately 17,000 new cases per year in France), after those related to smoking. LNs were investigated using the data from the ENGELA study. ENGELA is a multicenter hospital-based case-control study that was carried out in France over the period September 2000-December 2004. In all, 822 cases (397 NHL, 149 LH, 168 SLP and 108 MM) and 752 controls were included and described 5,481 and 5,188 first-degree relatives, respectively. A positive association with a familial history of hematopoietic cancer was observed for LN (OR = 1.7 [1.0-2.8]) overall and for LPS (OR = 3.2 [1.4-6.8]). The associations with HL (OR = 10.4 [2.0-53.8]) and NHL (OR = 2.4 [1.0-5.9]) were stronger for men. The associations were also stronger when the disease had been diagnosed before the relatives were aged 45 years. The results mainly support the involvement of genetic factors and suggest that at least some of those factors may be sex-linked. However, the slight overrepresentation of affected spouses among the cases might also support the responsibility of environmental factors.

International audience; OBJECTIVES: Investigating the relationship between occupational exposure to pesticides and the risk of lymphoid neoplasms (LNs) in men. METHODS: A hospital-based case-control study was conducted in six centres in France between 2000 and 2004. The cases were incident cases with a diagnosis of LN aged 18-75 years. During the same period, controls of the same age and sex as the cases were recruited in the same hospital, mainly in the orthopaedic and rheumatological departments. Exposures to pesticides were evaluated through specific interviews and case-by-case expert reviews. Four hundred and ninety-one cases (244 cases of non-Hodgkin's lymphoma (NHL), 87 of Hodgkin's lymphoma (HL), 104 of lymphoproliferative syndromes (LPSs) and 56 of multiple myeloma (MM) cases) and 456 controls were included in the analyses. The odds ratios (ORs) and 95% CI were estimated using unconditional logistic regressions. RESULTS: Positive associations between HL and occupational exposure to triazole fungicides and urea herbicides were observed (OR = 8.4 (2.2 to 32.4), 10.8 (2.4 to 48.1), respectively). Exposure to insecticides, fungicides and herbicides were linked to a threefold increase in MM risk (OR = 2.8 (1.2 to 6.5), 3.2 (1.4 to 7.2), 2.9 (1.3 to 6.5)). For LPS subtypes, associations restricted to hairy-cell leukaemia (HCL) were evidenced for exposure to organochlorine insecticides, phenoxy herbicides and triazine herbicides (OR = 4.9 (1.1 to 21.2), 4.1 (1.1 to 15.5), 5.1 (1.4 to 19.3)), although based on small numbers. Lastly, despite the increased ORs for organochlorine and organophosphate insecticides, carbamate fungicides and triazine herbicides, no significant associations were evidenced for NHL. CONCLUSIONS: The results, based on case-by-case expert review of occupation-specific questionnaires, support the hypothesis that occupational pesticide exposures may be involved in HL, MM and HCL and do not rule out a role in NHL. The analyses identified specific pesticides that deserve further investigation and the findings were consistent with those of previous studies.

International audience; OBJECTIVES: Investigating the relationship between skin type, UV exposure, and lymphoid malignancies (LM). METHODS: We conducted a hospital-based case-control study in France, including 813 incident cases of non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL), lymphoproliferative syndrome (LPS) or multiple myeloma and 748 controls. RESULTS: Positive associations between HL and blond/red hair (OR = 1.8 [0.8-3.8]), very fair/fair skin (OR = 1.6 [1.0-2.5]) were observed. High propensity to burn was associated with HL (OR = 1.5 [1.0-2.2]) and LPS (OR = 1.4 [1.0-2.1]). Poor ability to tan was significantly associated with HL (OR = 1.7 [1.0-2.8]). Having light hair with high propensity to burn was associated with NHL (OR = 1.5 [0.9-2.5]) and significantly with HL (OR = 3.4 [1.4-8.4]). Having dark hair with high propensity to burn was significantly associated with LPS (OR = 1.5 [1.0-2.2]). The associations with HL and NHL were significant for men only, with significant interactions. Outdoors activities since leaving school or in the last decade were not related to LM. Only an almost negative trend was observed. Prior exposure to artificial UV was not associated with LM. CONCLUSION: These results suggest a positive association between the most reactive and palest skin types and NHL or HL in men and do not rule out a slight negative relationship between UV exposure and LM.

Introduction: Bendamustine is a purine analog/alkylator hybrid agent with a unique mechanism of action, which has shown good clinical efficacy and acceptable tolerability in various hematological malignancies, including Hodgkin’s disease, non-Hodgkin’s lymphoma, and multiple myeloma. Patients and Methods: The efficacy and safety of bendamustine and chlorambucil have been compared in a randomized, open-label, multicenter, Phase III trial in patients with previously untreated advanced (Binet stage B/C) B cell chronic lymphocytic leukemia: an updated analysis from this trial is presented here. Patients were randomized to receive bendamustine (100 mg/m2 on days 1 + 2) or chlorambucil (0.8 mg/kg on days 1 and 15) for up to 6 treatment cycles. The median cumulative dose per patient was 1820 mg and 517 mg for bendamustine and chlorambucil, respectively. The primary endpoints were overall remission rate (ORR), which was defined as complete response, nodular partial response or partial response, and progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. The response to treatment was evaluated by a blinded Independent Response Assessment Committee. Results: A total of 319 patients were randomized (162 bendamustine, 157 chlorambucil), of whom all were included in the efficacy analysis and 312 were evaluable for safety. The mean (± SD) number of treatment cycles was 4.8 ± 1.7 in the bendamustine group and 4.6 ± 1.7 in the chlorambucil group; the median duration of follow-up was 29.2 months (29.8 bendamustine, 27.8 chlorambucil). The ORR was significantly higher with bendamustine than with chlorambucil (67% versus 30%, P Conclusion: This study has shown that bendamustine offers significantly greater efficacy than chlorambucil, with manageable toxicity, and should be considered as first-line chemotherapy for patients with advanced B-CLL.

International audience; OBJECTIVES: Investigating relationships between potential occupational risk factors and lymphoid malignancy (LM). METHODS: We conducted a multicenter hospital-based case-control study in France between 2000 and 2004, including 824 incident cases of non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), multiple myeloma, and "lymphoproliferative syndrome" and 752 frequency-matched controls. Data were collected through face-to-face standardized and detailed interviews. RESULTS: Farming was significantly associated with NHL (odds ratio [OR] = 1.4 [1.0 to 2.0]) and, although not significantly, with lymphoproliferative syndrome and multiple myeloma. ORs were higher for longest durations of exposure. Self-declared exposure to pesticides was significantly associated with NHL (OR = 1.8 [1.2 to 2.7]) and HL (OR = 2.2 [1.0 to 4.7]). Neither solvent-related jobs nor self-reported exposure to solvents were related to LM. Systematic screening based on job titles did not evidence any other association. CONCLUSIONS: The results support the hypothesis that farming plays a role in most types of LM.

All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) LPA 99 trial, where patients received no AraC in addition to ATRA, high cumulative dose idarubicin, and mitoxantrone, and APL 2000 trial, where patients received AraC in addition to ATRA and lower cumulative dose daunorubicin. In patients with white blood cell (WBC) count less than 10 × 109/L, complete remission (CR) rates were similar, but 3-year cumulative incidence of relapse (CIR) was significantly lower in LPA 99 trial: 4.2% versus 14.3% (P = .03), although 3-year survival was similar in both trials. This suggested that AraC is not required in APL with WBC count less than 10 × 109/L, at least in trials with high-dose anthracycline and maintenance treatment. In patients with WBC of 10 × 109/L or more, however, the CR rate (95.1% vs 83.6% P = .018) and 3-year survival (91.5% vs 80.8%, P = .026) were significantly higher in APL 2000 trial, and there was a trend for lower 3-year CIR (9.9% vs 18.5%, P = .12), suggesting a beneficial role for AraC in those patients.

This phase 2 study evaluated the efficacy and safety of the oral farnesyltransferase inhibitor tipifarnib in adults with refractory or relapsed acute myeloid leukemia (AML). Patients (n = 252) received tipifarnib 600 mg twice a day for 21 days in 28-day cycles. Median age was 62 years; 99 (39%) patients were 65 years or older. Eleven (4%) of 252 patients achieved complete remission (CR) or complete remission with incomplete platelet recovery (CRp; 9 CR and 2 CRp). Nineteen patients (8%), including those who achieved CR/CRp, achieved a reduction in bone marrow blasts to less than 5% blasts. Bone marrow blasts were reduced more than 50% in an additional 8 patients (total = 27; 11%). Median survival was 369 days for patients who achieved CR/CRp. Myelosuppression was the most common adverse event. The most common nonhematologic toxicities were fever, nausea, and hypokalemia. Single-agent treatment with tipifarnib induced durable CR/CRp, which was associated with prolonged survival, in some patients with refractory or relapsed AML. The response rate observed in this heavily pretreated group of patients suggests the requirement to enhance the response rate either by combining tipifarnib with other active agents or determining factors that are predictive of response.

Upon differentiation, hematopoietic stem cells (HSC) give rise to multipotent progenitors (MPP) that retain the ability to produce all blood lineages but have lost their self-renewal capacity. MPP are then orientated towards either the lymphoid or myeloid lineages, developing into common myeloid progenitors (CMP) or lymphoid-primed multipotent progenitors which can still produce certain myeloid cell types. CMP can differentiate into either granulocyte-macrophage progenitors (GMP) or megakaryocyte-erythroid progenitors. GMP finally differentiate into granulocyte or monocyte progenitors (GP/MP). This study aimed to investigate whether acute myeloid leukemia (AML) samples can be sub-classified based on the stage of arrest in differentiation (Stage of Leukemia Arrest, SLA). Understanding which critical differentiation program is specifically altered could be of special interest to design new therapeutic strategies aimed at re-inducing the differentiation process in AML. Based on CD34/CD117/CD13/CD33/MPO expression, we defined phenotypic signatures that identify all normal hematopoietic stem and progenitor cells (HSPC). Applied to leukemic hematopoiesis, these signatures allowed us to sub-classify 932 AML patients from Toulouse University Hospital (test cohort) and 142 AML patients from The Cancer Genome Atlas Network, published in NEJM in 2013 (control cohort). Globally, AML with an HSC phenotype (henceforth termed HSC-L) represented 1% of the cases, while MPP-L, CMP-L, GMP-L and GP/MP-L accounted for 15%, 30%, 22% and 30% of the cases, respectively. To validate our phenotypic signature and SLA, we generated a transcriptomic signature of normal hematopoietic differentiation from three databases including normal HSPC assessment (GSE21973, GSE42414 and E-TABM-978). Unsupervised clustering and gene set enrichment analysis (GSEA) of a test cohort (n=40) and a control cohort (n=142) confirmed that AML shared a common transcriptomic signature with their SLA. To strengthen the relationship between SLA and HSPC, we then compared their energetic metabolism. Using metformin as an enhancer of glycolytic (GLY) metabolism (e.g. Pasteur effect), we constructed transcriptomic signatures for AML cell lines with either a GLY or with an oxidative (OX) metabolism. We showed that, as expected normal HSC and MPP were enriched in GLY genes, whereas CMP and GMP were enriched in OX genes set. Similarly, HSC-L and MPP-L highly expressed genes related to GLY metabolism; CMP-L samples could be subdivided between GLY AML and OX AML; and GMP-L highly expressed genes related to OX metabolism. Each AML subgroup defined accordingly to the SLA had a particular clinical presentation (Table). Interestingly, the least differentiated AML (HSC-L, MPP-L and CMP-L) were enriched in HSC and LSC genes sets. These AML samples blocked at early stage of hematopoiesis gave higher engraftment levels in NSG mice compared to GMP-L and GP/MP-L (21%, vs 5%, panel of 59 AML tested in 376 mice, p We then sought to investigate the distribution of AML mutations according to SLA classification. We took advantage of the fully annotated TCGA database and found that 80% of HSC-L and 25% of MPP-L had RUNX1 mutations, 80% of GMP-L had either CEBPA mutation or RUNXL1-RUNX1/CBFB-MYH11 AML, and 80% of GP/MP-L had NPM1 mutation. The subgroups of CMP-L showed a greater molecular heterogeneity. AML and normal HSPC shared phenotypic, transcriptomic and metabolic signatures. This is of special interested for differentiation therapy as specific critical dysregulated transcriptional factors (e.g. CEBPA) could be related to specific stage of arrest. Identifying each of them could allow to propose targeted differentiating therapy and maximize therapeutic responses. Table. HSC-L MPP-L CMP-L GMP-L GP/MP-L frequency 1% 15% 30% 22% 30% Median WBC at diagnosis (G/L) 4 25 20 35 54 organ infiltration NA spleen varied lymph nodes gengiva or lymph nodes CFU-L (% of blasts) 0.7 8.1 9.6 8.7 6.9 metabolism GLY GLY GLY/OX OX NA oncogenic event RUNX1m RUNX1m/TP53m unknown CEBPAm/CBF NPM1c BAALC/ERG/MN1 expression high high mid mid low stem cell signature high high high low low Median DFS (months) 5 22.9 13.7 41.3 >120 Median OS (months) 6.6 26.6 16.3 >120 83.3 Disclosures Huguet: Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; PFIZER: Consultancy, Speakers Bureau.

Background & aims In the Nilopeg trial (EudraCT 2010-019786-28), we have previously demonstrated that the combination of nilotinib (Tasigna® Novartis), a second generation inihibitor (TKI2), combined to pegylated interferon-alpha 2a (Peg-IFN, Pegasys®, Roche) in de novo chronic phase chronic myeloid leukemia (CP-CML) patients is able to induce high rates of molecular responses with an acceptable additional toxicity (F. E. Nicolini et al. Lancet Haematology 2015) within 24 months of follow-up. We report here the ≥4-year follow-up of such patients for toxicity and efficacy. Methods In a phase 2 study, newly diagnosed CP-CML patients were assigned to a priming strategy by Peg-IFN (± HU) for a month at 90 mg/wk, prior to a combination of nilotinib 300 mg BID + Peg-IFN 45 micro.g/wk for ≥ 1 year, maximum 2 years. After 2 years nilotinib was continued alone. The primary endpoint was the rate of confirmed molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised for all patients and expressed as BCR-ABLIS in % for 2 years and then performed in each center [all expressed in % on the international scale (IS)]. All data presented here are in intention-to-treat. Events were defined as death, progression to AP or BC, failure on nilotinib or nilotinib treatment discontinuation for any cause excluding treatment-free remission (TFR). Results Fourty-two patients were enrolled in this trial (one withdrawn its consent prior to treatment initiation), and the median follow-up is now 50.7 (47.8-52.8) months. Sokal and Euro scores were high for 12% and 2%, intermediate for 49% and 55% and low for 39% and 43% of the patients respectively. The median age at treatment initiation was 53 (23-85) years, 2 patients had a masked Philadelphia chromosome, 3 a variant form, and 1 additional chromosomal abnormalities, all patients had "major" BCR-ABL1 transcripts. The rates of Complete Cytogenetic Responses (CCyR) at "6", and "12" months of combination (i. e. at 5 and 11 months of TKI2) were 71%, and 100% respectively. Eighty seven percent of patients had a BCR-ABLIS ≤10% at M3 (i. e. after 2 months TKI). The rates of molecular responses respectively at 12, 24, 36 and 48 months were 76%, 78%, 83%, 73% for MMR, 51%, 58.5%, 66%, 58.5% for 4 log reduction (MR4), 17%, 34%, 34%, 44% for 4.5 log reduction (MR4.5), 12%, 32%, 29%, 41.5% for ≥5 log reduction (MR5), shown as cumulative incidence curves for MR4.5 in figure 1. The median doses of Peg-IFN delivered to the patients during the first year were 45 (0-45) micro.g/wk, and for nilotinib 600 (300-600) mg daily. Interestingly, logistic regression analysis adjusted on MR4.5 responses showed a significant relationship with the mean doses of Peg-IFN delivered to the patients at 12 months (p=0.003, OR = 1.09 [1.03-1.16]), 24 months (p=0.005, OR = 1.08 [1.02-1.14]) and 48 months (p=0.024, OR = 1.09 [1.01-1.17], but not with the mean doses of nilotinib [p=0.84, OR = 0.99 [0.99-1.01], p=0.087, OR = 1 [0.99-1.01], and p=0.88, OR = 1 [0.99-1.01] respectively. Eight patients (19.5%) were in TFR for a median of 6.8 (0.5-9.5) months after 2-year consecutive MR4.5, and none lost MMR yet at last follow-up. One patient died of progression (unmutated myeloid blast crisis at M6, who relapsed after unrelated allogeneic stem cell transplantation). There was no additional grade 3-4 hematologic or biochemical toxicities occurring after 24 months. At last follow-up 10 patients switched for another TKI (2 for dasatinib, 5 for imatinib, and 3 for imatinib followed by dasatinib), for unsufficient cytogenetic or molecular response (2 patients) or for toxicity (7 patients). Overall, 4 patients presented some cardio-vascular events 3 coronary stenoses, one brain stroke). Conclusion Despite additional initial toxicities Peg-IFN priming strategy, followed by the combination of nilotinib and Peg-IFN during the first year induces very high rates of durable deep molecular responses (MR4 and MR4.5) at later time-points, offering TFR for number of patients. To date, no emerging severe adverse events occurred. However, to confirm these promising results, a randomised phase III study testing nilotinib versus nilotinib + Peg-IFN is absolutely warranted and in progress. Figure 1. Cumulative incidence of MR4.5 Figure 1. Cumulative incidence of MR4.5 Disclosures Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Roy:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Huguet:Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; PFIZER: Consultancy, Speakers Bureau. Legros:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Giraudier:Novartis: Speakers Bureau. Coiteux:BMS: Speakers Bureau; ARIAD: Speakers Bureau; Novartis: Speakers Bureau. Guerci-Bresler:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; PFIZER: Speakers Bureau. Rea:Pfizer: Honoraria; Ariad: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Amé:BMS: Speakers Bureau; Novartis: Speakers Bureau. Cony-Makhoul:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Hermet:Novartis: Speakers Bureau; BMS: Speakers Bureau. Rousselot:Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Mahon:ARIAD: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy; Novartis: Consultancy, Honoraria.

[Graphic][1] Background Imatinib mesylate (IM) at 400 mg/d remains a standard for first line therapy in patients (pts) with newly diagnosed chronic phase CML (CP-CML). A sub analysis of the IRIS study (Larson et al. Blood, 2008) demonstrated that pts with high IM trough levels achieved higher rates of major molecular response (MMR). The level of 1000 ng/ml was established as the [C]min value threshold to predict molecular response (Picard et al. Blood, 2007). We conducted a randomized trial to evaluate the value of IM dose optimization based on the monitoring of [C]min levels in newly diagnosed CP-CML pts (OPTIM-imatinib trial, EudraCT number 2008-006854-17). Patients and Methods Pts diagnosed with CP- CML for less than 3 months, not previously treated or treated with IM for less than 3 months were eligible and treated with IM 400 mg/d. IM [C]min was determined by chromatography-tandem mass-mass spectrometry 15 days after enrollment. Pts with a [C]min < 1000 ng/ml were randomized between a dose-increase strategy aiming to reach the threshold of 1000 ng/ml (arm A1) versus standard IM management (arm A2). Pts with [C]min levels ≥1000 ng/ml were observed (arm A3). All pts were managed according to the ELN 2009 recommendations (amended with ELN 2013 recommendations). IM [C]min levels were assessed monthly in A1 and A2 and every 3 months in A3. BCR-ABLIS was assessed every 3 months. The primary end-point was MMR rates at 12 months. Results One hundred thirty nine pts were enrolled. Median follow-up was 31 months. Median age was 64y (25 to 88y), sex ratio (M/F) was 1.4 and Sokal score distribution was 21%, 41% and 38% for high, intermediate and low categories respectively, equally distributed in the 3 arms. In 6 pts the initial [C]min was not assessed (3 were intolerant and 3 declined the dosage). Thus 133 pts were studied. In 86 pts (65%), initial [C]min value was < 1000 ng/ml. These pts were randomized between A1 (43 pts) and A2 (43 pts). [C]min was ≥1000 ng/ml in the 47 remaining pts followed in A3. Table 1 shows the significant improvement of the median IM [C]min after dose adjustment in A1 ( p