Abstract: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia for which we developed a nationwide network to collect data from new cases diagnosed in France. In a retrospective, observational study of 86 patients (2000-2013), we described clinical and biological data focusing on morphologies and immunophenotype. We found expression of markers associated with plasmacytoid dendritic cell origin (HLA-DRhigh, CD303+, CD304+, and cTCL1+) plus CD4 and CD56 and frequent expression of isolated markers from the myeloid, B-, and T-lymphoid lineages, whereas specific markers (myeloperoxidase, CD14, cCD3, CD19, and cCD22) were not expressed. Fifty-one percent of cytogenetic abnormalities impact chromosomes 13, 12, 9, and 15. Myelemia was associated with an adverse prognosis. We categorized chemotherapeutic regimens into 5 groups: acute myeloid leukemia (AML)–like, acute lymphoid leukemia (ALL)–like, lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP])–like, high-dose methotrexate with asparaginase (Aspa-MTX) chemotherapies, and not otherwise specified (NOS) treatments. Thirty patients received allogeneic hematopoietic cell transplantation (allo-HCT), and 4 patients received autologous hematopoietic cell transplantation. There was no difference in survival between patients receiving AML-like, ALL-like, or Aspa-MTX regimens; survival was longer in patients who received AML-like, ALL-like, or Aspa-MTX regimens than in those who received CHOP-like regimens or NOS. Eleven patients are in persistent complete remission after allo-HCT with a median survival of 49 months vs 8 for other patients. Our series confirms a high response rate with a lower toxicity profile with the Aspa-MTX regimen, offering the best chance of access to hematopoietic cell transplantation and a possible cure.

Abstract: In myeloma patients, trisomy 3 improved time to progression and trisomies 3 and/or 5 improved overall survival. In contrast, trisomy 21 significantly worsened overall survival.

Abstract: The combination of 2GTKI+pegylated IFN-α (Peg-IFN) is an attractive approach for first-line treatment of CP CML, inducing high rates of deep molecular responses in phase II trials. Thus, we evaluated nilotinib (NIL) alone versus NIL+Peg-IFN in newly diagnosed CP-CML patients (pts) in a randomised phase III trial (PETALs, EudraCT 2013-004974-82). Newly diagnosed CP CML pts ≤65 y, without prior history of arterial occlusion were randomized 1:1 to get NIL 300 mg BID alone (M0 to M48, arm A) vs Peg-IFN alone for 30 days (M-1→M0) 30 μg/wk as priming, prior to NIL 300 mg BID + Peg-IFN 30 μg/wk 2 wks, upgraded to 45 μg/wk thereafter, for up to 2 y (M0 to M24, arm B) followed by NIL alone for 4 more years unless pts enter treatment-free remission (TFR). The primary endpoint is the rate of MR4.5 by 1 y. As a secondary endpoint, pts reaching MR4.5 ≥2 y are allowed to stop NIL and enter a TFR phase in both arms. The trigger for treatment resumption is loss of MMR. All molecular assessments are centralised, quantifications are expressed as BCR-ABL/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control. Two hundred pts were randomized (99 in A, 101 in B), 130 M and 35 F in each arm, median age of 46 (18-66) y. Median follow-up is 43.8 (34.3-55.9) Mo. Results are analysed in intention-to-treat. Sokal and EUTOS LTS scores were H in 25% and 2.5%, Int. in 33% and 16.5% and L in 42% and 81% pts respectively equally balanced. Median age is 46 (18-66) y, 18 pts (9%) had ACAs, all pts have a "Major" BCR transcript. CHR was obtained in 9.6% of pts at M0 (in B) and 88% of pts in A and 90.4% of pts in B at M1. CCyR rates at M3 were 63% vs 75% in A and B (p=ns), and BCR-ABL1 ≤1% at M6 were 87% in A vs 93% in B (p=ns). By M12, the rates of MMR were 68.1% vs 70.1% (p=0.44), MR4 were 34% vs 47.5% (p=0.041), MR4.5 were 15.9% vs 21.5% (p=0.049), MR5 11.7% vs 23.71% (p=0.023), in A vs B respectively. By M36 the rates of MMR were 83% vs 86.6% (p=0.31), MR4 were 70.2% vs 71.13% (p=0.50), MR4.5 were 37.2% vs 49.5% (p=0.05), MR5 33% vs 42.3% (p=0.12), in A vs B respectively The overall cumulative incidence of MR4.5 is superior in B (54.6 [43.7-65.5] %) vs A (44 [31.5-54]%) close to significance (unilateral Fisher test, p=0.05, see Figure). Seven patients were mutated by Sanger in A (5 Y253, 1 E255K, 1 T315I) vs 2 in B (2 T315I). One pt (A) progressed toward AP and then myeloid BC with a Y253H mutation, is still alive in CMR on Ponatinib. Twenty nine (29%) pts were withdrawn from study in A (toxicity 9, cancer 3, resistance 14, investigator decision 2, lost for FU 1) vs 26 (26%) pts for B (toxicity 13, resistance 8, investigator decision 5), 1 pt died from cervix cancer (A). Median overall doses of NIL delivered by M36 were 600 mg/d in both arms (p=ns). The median overall dose of Peg-IFN delivered in B by M24 was 37.5 mg/wk. The overall rate of grade 3-4 hematologic toxicities was 22%; with 2% and 7% thrombocytopenia, 4% and 6% neutropenia, and 1% and 1% pancytopenia in A vs B respectively. Major grade 3-4 non-hematologic toxicities consisted in 9% of cardiac disorders in A (2 coronaropathies, 1 myocardial infarction, 2 thoracic pains, 2 atrial fibrillation, 1 bradycardia, 1 palpitations, 1 pericarditis) vs 8% in B (2 coronaropathies, 1 myocardial infarction, 3 atrial fibrillation, 1 palpitations, 1 pericarditis), 4% vascular disorders in A (1 thrombophlebitis + PE, 1 transient ischemic attack, 1 PAOD, 1 carotid stenosis) vs 3% in B (1 thrombophlebitis, 1 PAOD, 1 transient ischemic attack). Three % of gastro-intestinal disorders were observed in A (2 pancreatitis, 1 anal fissure) vs 6% in B (2 pancreatitis, 1 anal fissure, 1 abdominal pain, 2 cholecystectomies); 5% auto-immune disorders in B (1 recurrent pericarditis, 2 hemolytic anemia, 1 ITP, 1 thyroiditis); 5 and 8 pregnancies (2 pts + 3 partner Arm 1, 3 pts + 5 partner Arm B), despite recommended contraceptive methods. Secondary tumours were diagnosed in 4% (1 breast, 1 cervix, 1 thyroid, 1 neuroendocrine) in A vs 2% of pts (1 neuroendocrine and 1 testis) in B. Of note 8% psychiatric episodes were reported in B pts (2 unsuccessful suicide attempts), vs 2% in A. We observed 9% lipase elevations in A, 6% in B, 2% cholestatic episodes in A, 6% in B; 3% of transaminase elevations in A vs 2% in B. Infections were detected in 3% A vs 7% in B. The combination of NIL + Peg-IFN seems to provide somewhat higher MR4.5 rates by M36 in newly diagnosed CP CML pts without inducing significant higher toxicities than NIL alone. Whether this will translate in higher TFR rates is under evaluation. Final updated results at M36 will be presented Disclosures Nicolini: Sun Pharma Ltd: Consultancy; Novartis: Research Funding, Speakers Bureau; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau. Etienne:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Huguet:Servier: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Incyte Biosciences: Honoraria; Jazz Pharmaceuticals: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Guerci-Bresler:Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. Charbonnier:Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Consultancy; Pfizer: Consultancy. Legros:Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Incyte Biosciences: Honoraria, Research Funding; BMS: Honoraria. Coiteux:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Cony-Makhoul:BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Consultancy. Roy:Incyte Biosciences: Consultancy. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Quittet:Novartis: Honoraria, Speakers Bureau. Ame:Incyte Biosciences: Honoraria, Speakers Bureau. Rea:Pfizer: 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; Incyte Biosciences: Honoraria; BMS: Honoraria. Dulucq:Novartis: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Mahon:Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. OffLabel Disclosure: Pegylated Interferon alpha 2 a is not licensed in this setting

Abstract: Aims: Combining 2GTKI+pegylated IFN-a (Peg-IFN) represents an attractive approach for first-line treatment of CP CML, while providing somewhat light additional AEs, it induces high rates of deep molecular responses. We evaluated nilotinib (NIL) alone versus NIL+Peg-IFN in newly diagnosed CP-CML patients (pts) in a randomised phase III trial (PETALs, EudraCT 2013-004974-82) and analysed here the proportion of patients reaching Treatment-Free Remission (TFR) and outcome. Methods: Newly diagnosed CP CML pts ≤65 years, without vascular history were randomized 1:1 to get NIL 300 mg BID alone [M0 to M72 (unless TFR), arm A] vs Peg-IFN alone for 30 days (M-1→M0) 30 mg/wk, prior to NIL 300 mg BID + Peg-IFN 30 mg/wk 2 wks, upgraded to 45 mg/wk thereafter, for up to 2 y (M0 to M24, arm B) followed by NIL alone until M72 unless TFR. The primary endpoint was the rate of MR4.5 by M12, and after amendment, the trial was extended to 72 months follow-up in order to add, as a secondary endpoint, the TFR rate in pts reaching MR4.5 ≥2 y. The trigger for treatment resumption was loss of MMR. All molecular assessments were centralised until M36, and in case of TFR, MR4.5 was centrally confirmed at M0 TFR, and further molecular follow-up was then performed locally. All molecular quantifications are expressed as BCR-ABL1/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control in the central lab and in the local labs all involved to the pluri-annual French external quality controls. Results are analysed in intention-to-treat. Results: As previously reported, 200 pts were randomized (99 in A, 101 in B), 130 M and 35 F in each arm, median age of 46 (18-66) y. The median follow-up (FU) since diagnosis is now 47.5 (33.77-62.39) Mo. and the median FU since discontinuation is 9.86 (5.8-23) Mo. in arm A and 15.57 (12.62-22.77) Mo. in arm B. Sokal and ELTS scores were high in 25% and 2.5%, intermediate in 33% and 16.5% and low in 42% and 81% pts respectively, equally balanced. All pts harboured a "Major" BCR transcript. We have previously shown that by M12, the rate of MR4.5 was 15.9% vs 21.5% (primary endpoint met, p=0.049) and that the overall cumulative incidence of MR4.5 was somewhat superior in arm B (54.6 [43.7-65.5] %) vs A (44 [31.5-54] %), p=0.05. Two pts died, one from myeloid blast crisis before TFR (arm A), one from a solid tumour (arm A). Overall, 40 pts (20%) reached the TFR criteria, 21 in arm A with a median FU of 9.86 (5.8-23) Mo. and 19 in arm B with a median FU since Nilo cessation of 15.57 (12.62-22.77) Mo, partly related to slightly different time for obtaining sustained MR4.5 in favour of arm B (16 vs 13 Mo.). For these 40 pts reaching TFR criteria, there was no statistical difference in terms of age at diagnosis and age at TFR, gender, Sokal, ELTS, FU since diagnosis, undetectability at cessation, BCR-ABL1 levels at 3 Mo. after cessation between the 2 arms. The survival without loss of MMR after cessation is illustrated in Figure 1. It looks superior in arm B over arm A, but did not reach statistical difference (p=0.445), but the FU is very short after cessation yet, especially in arm A. Once NIL was resumed in the pts that failed TFR, all pts recovered MMR within 6 Mo., with no difference between arms (p=1.00). In univariate analysis, we did not identify significant factor impacting on the TFR success (age at cessation, sex, undetectability at cessation, Sokal, ELTS) except the BCR-ABL1 value at M3-TFR (undetectable versus detectable, HR 7.15 [2.06-24.75], p=0.002), and the duration of MR4.5 before discontinuation (HR 1.11 [1.03-1.19] , p=0.004). During this TFR phase 7 SAEs were reported in arm A (2 pregnancies, 1 obstructive sleep apnea, 1 fever episode, 1 carotid stenosis and 1 femoral stenosis in the same patient at 2 Mo. after cessation, 1 lung carcinoid tumor) and 2 in arm B (1 persistent atrial fibrillation, 1 cholecystectomy). Conclusions: The combination of NIL + Peg-IFN induces higher MR4.5 rates by M36 in newly diagnosed CP CML pts that may translate in higher successful TFR rates, however a longer follow-up is needed to see consistent significant differences. Updated data will be presented. Figure 1 Figure 1. Disclosures Nicolini: Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Etienne: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Guerci-Bresler: Novartis: Speakers Bureau; Incyte: Speakers Bureau. Charbonnier: Incyte: Speakers Bureau; Novartis: Speakers Bureau. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Deconinck: Stemline Therapetutics: Membership on an entity's Board of Directors or advisory committees; Imunogen: Membership on an entity's Board of Directors or advisory committees; Chugai: Research Funding; Novartis: Research Funding; Pfizer: Other: Travel Grants, Research Funding; Abbevie: Research Funding. Rea: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Background We previously demonstrated that the combination of Nilotinib (NIL) + Pegylated IFN-a2a (Peg-IFN) is able to induce high deep molecular response rates in chronic phase CML (CP CML) patients, as first-line therapy (Nicolini FE et al., Lancet Haematol. 2015). Aims Assessment of the molecular responses obtained with the same combination vs NIL alone prospectively, in newly diagnosed CP-CML. (EudraCT 2013-004974-82). Methods Patients (pts) ≤65 years with no history of arterial damage were randomized 1:1 to get NIL 300 mg BID alone (M0 to M48, arm A) vs Peg-IFN alone (± HU) for 30 days (M-1 to M0) 30 mg/wk as a priming, prior to a combination of NIL 300 mg BID + Peg-IFN 30 mg/wk 2 weeks, upgraded to 45 mg/wk thereafter if proper tolerance for up to 2 years (M0 to M24, arm B) followed by NIL alone for 2 more years. The primary endpoint was the rate of molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised, quantifications were expressed as BCR-ABL/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control. Results Two hundred and one pts were randomized (100 in arm A, 101 in arm B), 65 males in both arms, 35 females in arm A, 36 in arm B. The median follow-up is 20.6 (9.1-34.7) months. Results are analysed in intention-to-treat. Sokal scores were high in 25%, intermediate in 36% and low in 39% of pts; Euro scores were high in 13%, intermediate in 44% and low in 43% of pts; Eutos LTS scores were high in 2%, intermediate in 17%, and 81% low; equally balanced in the 2 arms The median age was 46 (18-66) years, equally balanced. Eight (4%) pts had a cryptic Philadelphia chromosome, 12 (6%) a variant form, and 15 (7.5%) had ACAs, all pts had a "Major" BCR transcript. CHR was obtained in 9.6% of pts at M0 (arm B) and in 88% of pts in arm A and 90.4% of pts in arm B at M1. The rates of CCyR at M3 were 63% vs 65% in arms A and B, and BCR-ABL1≤1% at M6 were 83% in arm A vs 86% and arm B, on evaluable samples. The incidence of molecular responses are shown in Fig. 1. Of note, 90% of the pts had a BCR-ABL1 ≤10% at M3 in arm A vs 84% in arm B (p=ns). By M12, the rates of MMR were 69.9% vs 72.4% (p=0.079), MR4 were 34.65% vs 47.9% (p=0.094), MR4.5 were 17.9% vs 24.11% (p=0.272), MR5 12.1% vs 22.31% (p=0.075), in arm A and arm B respectively. Data from 11 pts in arm A and 16 in arm B at M12 are still pending. Definitive results at 1 year will be presented. One pt progressed toward accelerated phase in arm A with a Y253H mutation. Fifteen pts were withdrawn from study in arm A (toxicity 5, other cancer 2, failure 8) and 12 patients from arm B (toxicity 6, failure 6), no pt died. Interestingly, 5 mutated (ie. failure) pts were found in arm A (3 Y253H, 1 E225K, 1 F317L), vs only 1 pt (T315I) in arm B. The median dose of Peg-IFN delivered in arm B during the first month is 30 (0-30) mg/wk, 30 (0-45) mg/wk at M2, 45 (0-45) mg/wk at M3, 37.5 (0-45) mg/wk at M6, 30 (0-45) mg/wk at M9 and 12. The median doses of NIL delivered were 600 mg daily at M2, 3, 6, 9, 12 as initially planned in both arms. The rate of grade 4 hematologic toxicities overall was 15%, with no anemias, 1% and 4% thrombocytopenias, 3% and 4% neutropenias, 0% and 1% leucopenias, and 0 and 1% pancytopenias in arms A and B respectively. Grade ¾ non-hematologic toxicities consisted in 4% of cardiac disorders in arm A (1 coronaropathy, 2 thoracic pains and 1 atrial fibrillation) vs 1% in arm B (palpitation), 2% vascular disorders in arm A (1 pulmonary embolism, 1 transient ischemic attack) and 1% in arm B (PAOD). Three % of gastro-intestinal disorders in arm A (resolutive pancreatitis) vs 1% in arm B (anal fissure); 1% of skin disorders in arm A; 2% auto-immune disorders in arm B (1 recurrent pericarditis, 1 hemolytic anemia); 2 and 5 pregnancies (of the partner except 1) were observed in arm A and B respectively, despite recommended contraceptive methods. We observed 10% lipase elevations in arm A, 3 in arm B, 2% cholestatic episodes in arm A, 1% in arm B; 1% of transaminase elevations in each arm. There were 2% depressive episodes in arm B, 1% in arm A; infections were detected in 1% arm 1 and 3% in arm B. Finally 3 intercurrent cancers were detected in arm A (cervix, breast, thyroid). Conclusion The combination of NIL + Peg-IFN seems to provide slightly deeper molecular responses rates (especially MR5) by M12, but so far not significantly, in newly diagnosed CP CML pts without increasing the rate of more frequent early SAEs in such a setting. Definitive results at M12 will be updated for the meeting. Disclosures Nicolini: BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ARIAD: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. Etienne: Incyte: Speakers Bureau; BMS: Speakers Bureau; Novartis: Consultancy, Research Funding. Guerci-Bresler: BMS: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Charbonnier: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Legros: BMS: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau. Coiteux: Incyte: Speakers Bureau; BMS: Speakers Bureau. Cony-Makhoul: BMS: Speakers Bureau. Rousselot: Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pfizer: Research Funding. Guyotat: BMS: Speakers Bureau. Ianotto: Novartis: Other: Grant. Rea: BMS: Consultancy, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Mahon: Pfizer: Speakers Bureau; Incyte: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

Abstract: Background: In standard risk APL, ATRA+ATO combinations (without CT) are at least as effective as classical ATRA + anthracycline based chemotherapy (CT) while being less myelosuppressive (Lo Coco, NEJM 2014, Burnett, Lancet Oncol, 2015). In high risk APL (WBC 〉 10G/l), it is still unclear if CT can be avoided or greatly reduced, but addition of ATO to ATRA + CT reduces relapses (Powell, Blood 2010). In a randomized trial (APL2006 trial) in high-risk APL patients (pts) who received ATRA + CT induction treatment, we evaluated the addition of ATO to CT during consolidation. Methods: Between 2006 and 2015, newly diagnosed APL pts 〈 70 years with WBC 〉 10 G/L, after an induction of ATRA 45mg/m2/d until CR with Idarubicin (Ida) 12 mg/m2/dx3 and AraC 200mg/m2/dx7, were randomized for consolidation between CT and CT+ATO. The CT group (standard group) received a first consolidation with Ida 12 mg/m2/dx3 and AraC 200mg/m2/dx7, a second consolidation with Ida 9 mg/m2/dx3 and AraC 1g/m2/12h x4d, and 2-year maintenance with intermittent ATRA and continuous 6 MP + MTX. The CT+ATO group received the same treatment except that ATO 0.15 mg/Kg/d d1 -25 was added during both consolidation courses. After a first interim analysis in Sept 2010, based on 81 pts, AraC was deleted from consolidation cycles of the CT+ ATO group. The primary endpoint was EFS from CR achievement. Results: 211 pts 〈 70 years with WBC 〉 10 G/L were included (after the exclusion of 8 diagnostic errors) in 58 centers. 95.7% achieved CR, 3.3% had early death and 1% resistant leukemia. 193 pts were randomized for consolidation, 97 in the CT and 96 the CT+ ATO groups. Pre-treatment characteristics were well balanced between the 2 groups. 7 pts (3 CT vs 4 CT+ATO) had relapsed (5-year cumulative incidence of relapse (CIR) of 2.5% vs 3.9%; p= 0.39) and 9 pts had died in CR :7 (7.8%), 2 (5.1%), 0 (0%) in the CT, CT (with AraC) + ATO, CT (without AraC) + ATO groups respectively (p=0.04). Causes of death in CR were bleeding (n=5), infection (n=2), previous cancer relapse (n=2). One patient in the CT+ATO arm developed AML/MDS. 5-year OS was 93% vs 94% (p=0.56) and 5-year EFS was 89% vs 93% (p=0.47) in the CT and CT+ATO groups, respectively. Omission of AraC (after the amendment) in the CT+ATO group did not increase CIR (5 year CIR 5.3% with and 3.3% without AraC, p=0.57). In the CT, CT (with AraC) + ATO, CT (without AraC) + ATO groups respectively, median time to ANC 〉 1 G/L after consolidation 2 was 22, 25 and 19 days (p 〈 0.0001), and median time to platelets 〉 50G/l was 24, 26 and 20 days (p 〈 0.0001). Similarly, median duration of hospitalization after the first and the second consolidation courses were 33, 34, 29 d (p 〈 0.0001) and 31, 32, 28 d (p=0.0005), respectively. Conclusion: Very high CR rates and very few relapses are now obtained in high risk APL on a large multicenter basis using classical ATRA and CT (including AraC) for induction and consolidation, and maintenance treatment, but at the expense of 5 to 7% deaths in CR. Addition of ATO to this regimen did not further reduce relapses, and added some myelosuppression if CT contained AraC. However, if ATO was added and AraC omitted from consolidation cycles, relapses were not increased, while myelosuppression and deaths in CR were reduced. ATO therefore appears useful in high risk APL. We are currently comparing, in the international APOLLO trial, the "classical" ATRA-CT approach and a prolonged ATO-ATRA regimen with only 2 days of Ida during induction treatment, hoping to further reduce myelosuppression and possibly relapses. Disclosures Ades: Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher:Celgene, Sunesis, Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene, Sunesis, Amgen, Novartis, Chugai: Research Funding. Pigneux:Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria. Fenaux:Celgene, Novartis, Teva: Honoraria; Celgene, Janssen, Novartis, Astex, Teva: Research Funding.

Abstract: Ph+ ALL accounts for approximately one third of ALL cases in patients aged 55 years or older. The median survival of older Ph+ ALL patients is one year, with practically no long-term survivor (Blood, 98, Supp1 p319a, 2001). Imatinib has demonstrated remarkable, although transient, activity in relapsed and refractory Ph+ ALL, which prompted the GRAALL to implement a treatment protocol associating imatinib and chemotherapy in previously untreated elderly patients: ALL patients aged 55 years or older are treated with steroids during one week and Ph+ve cases are then offered a specific therapy including an induction treatment with steroids, cyclophosphamide, daunorubicin and vincristine, followed, irrespective of response to induction chemotherapy, by imatinib, 600 mg daily, combined with intermittent steroids during 2 months. Patients in complete response are then given 10 blocks of alternating chemotherapy, including 2 additional two-month blocks of imatinib, for a total treatment duration of 2 years. Therapy of occult central nervous system leukemia includes 5 intrathecal injections of methotrexate and cranial irradiation. The study is intended to include 30 patients and its main objective is to improve overall one-year survival to 70%. Results are compared with those obtained in 21 Ph+ ALL elderly patients treated according to our previous protocol. Since January 2003, 21 patients aged 58 to 78 years (median: 64.7 years) were included in the AFR09 protocol. Their median follow-up is 3 months. 15/19 patients are in complete response after induction chemotherapy vs 6/21 in the historical controls given similar induction regimen but with no steroids before chemotherapy (p=0.002). The projected overall survival is 95% at 9 months vs 62% in the control group (p=0.08, log-rank test). The 9-month projected event-free survival is 83% vs 10% (p & lt;0.0001) and the projected 6-month relapse-free survival is 79% vs 22% (p=0.006, log-rank test). In conclusion, although preliminary, this interim analysis suggests that the use of imatinib in elderly patients with Ph+-ALL is very likely to dramatically improve prognosis. Of note, an unexpected high proportion of patients accrued in this study achieved a CR after induction chemotherapy possibly denoting a beneficial impact of steroids given before starting chemotherapy.

Abstract: Introduction Current consensus identifies translocations t(4;14), t(14;16), t(14;20), and del(17/17p) as high-risk cytogenetics in newly diagnosed multiple myeloma (NDMM). However, evidence on outcome of specific abnormalities according to types of transplant as first-line treatment is limited. We analyzed NDMM patients with del(17) and/or t(4;14) reported to the European Society for Blood and Marrow Transplantation (EBMT) registry undergoing either upfront single autologous (auto), tandem autologous (auto-auto) or tandem autologous/reduced-intensity allogeneic (auto-allo) stem cell transplantation. Methods Upfront transplantation was defined as first autologous transplant within 12 months from MM diagnosis and tandem transplant was defined as a second transplant (autologous or allogeneic) within 6 months from first transplant. Survival and cumulative incidence were calculated from date of first transplant (95% confidence interval) and analyses were performed using a landmark approach of patients who were alive and relapse-free by month 6. End points were progression-free survival (PFS), overall survival (OS), relapse and non-relapse mortality (NRM). Results Patients. Within the EBMT registry, 498 NDMM patients with del(17) (n=224), t(4;14) (n=229) or both (n=45) could be analyzed between 2000-2015. First-line auto was received by 337, auto-auto by 99 and auto-allo by 62 patients. Frequencies of del(17)/t(4;14)/or both were 39/51/10% in auto, 58/36/6% in auto-auto, and 55/35/10% in auto-allo (p=0.01). Median age was 60 years in auto and auto-auto, and 52 years in auto-allo (p 〈 0.001) and more than half of patients were male (53% in auto, 63% in auto-auto, 52% in auto-allo). Median time from diagnosis to transplant was 5 months in all groups. 85% received at least 200mg/m2 melphalan conditioning for first autologous transplant. Most patients had IgG subtype (51% in auto, 60% in auto-auto, 58% in auto-allo). Disease stage according to ISS I/II/III was 23/55/22% in auto, 18/69/13% in auto-auto, and 14/63/23% in auto-allo. More patients receiving auto were in complete remission (CR) at time of first transplant (21%) compared with auto-auto (11%) and auto-allo (7%; p=0.01). Posttransplant outcome and cytogenetics. The median follow-up of all patients was 57 months (55 months for auto, 57 months for auto-auto, and 64 months for auto-allo). 5-year PFS according to transplant was 18% (12-23) for auto, 32% (22-43) for auto-auto, and 32% (19-45) for auto-allo (p=0.11) and 5-year OS was 47% (41-54) for auto, 51% (40-63) for auto-auto, and 65% (51-78) for auto-allo (p=0.28). Relapse incidence was 82% (77-87) for auto, 63% (53-74) for auto-auto, and 58% (44-72) for auto-allo (p=0.002) while NRM was 1%, 4%, and 10%. PFS and OS according to cytogenetics was 24% and 58% for del(17), 22% and 42% for t(4;14), and 19% and 55% for presence of both. When stratified according to cytogenetics and transplant, PFS in del(17) was 21% (12-29) for auto, 26% (13-39) for auto-auto, and 30% (13-47) for auto-allo (p=0.78) while OS was 56% (45-67) for auto, 56% (41-70) for auto-auto, and 67% (50-84) for auto-allo (p=0.74). Relapse incidence and NRM were 79% and 1% for auto, 70% and 4% for auto-auto, and 64% and 6% for auto-allo. Single autologous transplant showed significantly worse PFS in t(4;14) resulting in 15% (8-22) compared with 45% (26-63) for auto-auto, and 39% (16-61) for auto-allo (p=0.05). OS was 39% (30-48) for auto, 37% (13-60) for auto-auto, and 63% (38-88) for auto-allo. Relapse incidence was also significantly higher in auto showing 84% (77-91) in comparison with 49% (30-67) for auto-auto and 52% (29-75) for auto-allo (p=0.004). Multivariable analysis. A Cox regression was fitted to compare types of transplant after adjusting for cytogenetics, sex, age, ISS, and remission status. Subsequently, auto-auto (hazard ratio, 0.66) and auto-allo (hazard ratio, 0.58) were associated with better PFS while auto-allo appeared to result in better OS (hazard ratio, 0.71) in comparison with single autologous transplant. Both auto-auto and auto-allo were significantly associated with lower incidence of relapse after fitting a Fine and Gray model (p 〈 0.001, respectively). Conclusion In NDMM patients undergoing upfront transplantation, PFS and relapse incidence were improved in patients specifically with del(17) and t(4;14) receiving tandem autologous or autologous/reduced-intensity allogeneic transplant. Disclosures Leleu: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kobbe:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding. Rambaldi:Novartis: Consultancy; Italfarmaco: Consultancy; Celgene: Consultancy; Roche: Consultancy; Pfizer: Consultancy; Omeros: Consultancy; Amgen Inc.: Consultancy. Garderet:Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Kroeger:Novartis: Honoraria, Research Funding; Sanofi: Honoraria; Riemser: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; JAZZ: Honoraria.

Abstract: Ph+ ALL accounts for approximately one third of ALL cases in patients aged 55 years or older. The median survival of older Ph+ ALL patients is one year, with practically no long-term survivors (Blood, 98, Supp1 p319a, 2001). Imatinib has demonstrated remarkable, although transient, activity in relapsed and refractory Ph+ ALL, which prompted the GRAALL to implement a treatment protocol alternating chemotherapy and imatinib in previously untreated elderly patients: ALL patients aged 55 years or older were treated with steroids during one week and Ph+ cases were then offered a specific therapy including an induction treatment with steroids, cyclophosphamide, daunorubicin and vincristine, followed, irrespective of response to induction chemotherapy, by imatinib, 600 mg daily, combined with intermittent steroids during 2 months. Patients in complete response (CR) were then given 10 blocks of alternating chemotherapy, including 2 additional two-month blocks of imatinib, for a total treatment duration of 2 years. Therapy of occult central nervous system leukemia included 5 intrathecal injections of methotrexate and cranial irradiation. Results are compared with those obtained in 21 Ph+ ALL elderly patients treated according to our previous protocol. From January 2003 to November 2004, 30 patients aged 58 to 78 years (median: 65.8 years) were included in the present study. The median follow-up of surviving patients is 15 months. 20/29 assessable patients were in complete response after induction chemotherapy vs 6/21 in the historical controls given similar induction regimen but with no steroids before chemotherapy (p=0.009). Two patients died during induction treatment vs none in the control group. Out of 6 patients alive with disease at completion of induction, 5 were in CR after salvage with imatinib. The projected overall survival is 71% at 1 year vs 43% in the control group (p=0.008, log-rank test). The 1 year projected relapse-free survival is 58% vs 11% (p=0.003) and the projected 1 year event-free survival (defined as failure to obtain a CR, death or relapse) is 57% vs 5% (p & lt;0.0001). In conclusion, the use of imatinib in elderly patients with Ph+ALL is very likely to dramatically improve prognosis, including overall survival. Compared to our previous study, an unexpected high proportion of patients accrued in this study achieved a CR after induction chemotherapy, possibly denoting a beneficial impact of steroids given before starting chemotherapy.

Abstract: Abstract 2171 Background: Our group (JCO, 1992 10:1430; JCO 2003,21:2123) and others have reported tAPL to occur at increased frequency (from 5% of APL between 1984 and 1993 to 22% between 1994 and 2000 in our experience), generally less than 3 years after a primary neoplasm (mainly breast carcinoma) treated with the combination of anthracyclines (anthr) and cyclophosphamide (CY), radiotherapy (RT) and less often VP 16, but our last published series analyzed patients (pts) diagnosed before 2001. In addition, characteristics and outcome of tAPL are considered similar to those of de novo APL, but all reported comparisons were retrospective. We took advantage of our current multicenter APL 2006 trial, which includes both de novo and tAPL, to analyze possible recent changes in etiological factors of tAPL cases, and to prospectively compare them with de novo APL. Methods: In APL 2006 trial, pts 〈 70 years with WBC 〈 10 G/l, received ATRA+Idarubicin+AraC for induction, followed by 2 consolidation courses with (randomized) Ida+AraC, ida+ATO or Ida+ATRA. Pts 〈 70 y with WBC 〉 10 G/l, received the same induction treatment, followed by 2 consolidation courses with (randomized) ida+AraC or Ida+AraC+ATO. Pts 〉 70y received the same induction course with reduced dose of Ida and two consolidation courses (Ida+ATO and ATO+ATRA). All patients received 2 y maintenance therapy combining continuous 6MP+ MTX and intermittent ATRA. Results: Between Nov 2006 and March 2010, 280 pts entered the trial, including 42 (15 %) tAPL. By comparison to our tAPL diagnosed before 2001 (JCO 2003, 21, 2123) the primary tumor was less often breast carcinoma (35.7% vs 56.6%, p=0.03), and more often prostate carcinoma (26.2% vs 4.7%; p 〈 10-3) and other solid tumors (45.2% vs 18.8% p=0.02). Treatment of the primary tumor, in APL 2006 trial cases and tAPL diagnosed before 2001, respectively, included chemotherapy (CT) alone in 21.4% vs 27.3% pts (p= 0.535), RT alone in 40.5% vs 25.4% pts (p= 0.077) and RT+CT in 28.6% vs 47.2%(p= 0.044), and, in pts who received CT, at least one alkylating agent in 90.5% vs 86% pts (p=ns), at least one topo II inhibitor in 61.9% (including anthr in 47.6% and VP 16 in 14.2%) vs 77% pts (including anthr in 37.9% and VP 16 in 24.1%), and including mitoxantrone in 0% vs in 36.4% pts (p 〈 10-3). Hormone therapy was used in 42.9% (including antioestrogen (n=7), aromatase inhibitors (n=7) GnRH analogues (n=4), and anti androgens (n=4)) vs 24.5% (no details available), resp. Median interval from primary tumor to tAPL was 48 months (range 6.9 to 299) in tAPL included APL 2006 trial, compared to 25 months in our previous tAPL series. In APL 2006 trial, characteristics of tAPL were similar to those of de novo APL, with regards to WBC count (21.4% WBC 〉 10 G/l vs. 22.3% in de novo APL, respectively) and M3 variant (14% in the 2 groups). However, tAPL were older (mean 60.2y vs 48.7y in de novo cases, p 〈 0.0001) and had a higher frequency of bcr3 breakpoint (36% vs 54%, p=0.015). The CR rate was 97.6% (41/42) in tAPL and 93.4% in de novo APL (p=0.48). The 18-month cumulative incidence of relapse was 0% and 1.2% in tAPL and de novo APL respectively (p=0.43). 18 months OS was 96.4% and 97.0%, respectively (p=0.83, log-rank test). The 18 month rate of death in CR was 3.6% in both tAPL and de novo APL (p=0.97), Conclusion: In this series of recently diagnosed tAPL, by comparison to our tAPL diagnosed before 2001, the primary tumor was less often breast carcinoma and more often another solid tumor (especially prostate). A combination of CT and RT had been less often used, hormone therapy more often, and mitoxantrone had no more been used. Prospective comparison with de novo APL included in the same trial showed tAPL to be characterized by older age and more frequent bcr3 breakpoint, but there were no differences in outcome between the 2 subgroups Disclosures: Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.