ALBERT

Description: Introduction The acquisition of ABL1 Kinase Domain (KD) mutations represent the most frequent resistance mechanism in CP-CML patients (pts) treated with tyrosine kinase inhibitors (TKI). Currently, the standard assay relies on a poorly sensitive technique, Sanger Sequencing (SS). Thus, the detection of these mutations using SS might be too late to trigger a timely treatment change. In a national phase III academic trial (PETALs, EudraCT 2013-004974-82), we evaluated prospectively the value of a more sensitive technique, Next Generation Sequencing (NGS) to detect KD ABL1 mutations in newly diagnosed CP-CML patients randomized to get nilotinib 600 mg/d for 6 years ± Pegylated-IFN-α2a (Peg-IFN) 45 μg/wk for 2 years in combination. Methods Newly diagnosed CP CML pts ≤65 years 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 mg/wk as priming, prior to NIL 300 mg BID + Peg-IFN 30 μg/wk 2 weeks, 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 a treatment-free remission phase. In addition to KD mutational analysis performed by SS as per protocol, patients also had KD mutational analysis performed by NGS at M3, M6, M12 and 6-monthly thereafter until achievement of a stable MMR, regardless of response. NGS assay was performed as previously described (Kizilors et al. Lancet Haematol 2019). Results Two hundred pts were randomized (99 in A, 101 in B), of which 96 patients (51/99 in A, 45/101 in B, p=0.399) underwent a KD mutational analysis performed by NGS as part of this study. The remaining 104 patients are currently being screened and the full dataset will be presented. Among the 96 patients tested, there was no difference in the distribution between the 2 arms with respect to gender, age [median 45 years (18-66)] or risk factors distribution (p=0.862 and 0.328 for Sokal and ELTS respectively in patients tested at 3 months). The median follow-up of this cohort is 45.0 (33.2-58.7) months. By 12 months, 11 patients [8/51 (11.8%) in A, 3/45 (6.6%) in B] had developed a KD mutation. After only 3 months of TKI therapy, 3 patients were found mutated (Y253H 2 pts, T315I 1 pt), of whom 2 pts were only detected using NGS. At M6, a KD mutation was found in 8 pts [A: 7 patients, B: 1 pt, (p= 0.055), of which 6/8 were not detected by SS, due to either low level Variant Allele frequency (VAF, n=5) or low level BCR-ABL transcript levels (n=1). Y253H mutations were found in 4 pts, T315I in 2 pts and E255K in 1 pt. Consecutively to KD mutation identification, 6/8 patients lost their response and were withdrawn from study (1 pt with a Y253H detected at M3 progressed to advanced phase), while 1 pt lost MMR at last follow-up and another pt with a mutation sensitive to nilotinib achieved MMR. KD mutations were detected while pts were in optimal response at M6 [BCR-ABL

Description: 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

Description: Background: Although azacitidine (AZA) improves survival over conventional treatments in higher risk MDS (Lancet Oncol, 2009), median overall survival (OS) with AZA is only about 2 years, the CR+PR rate about 30%, and further improvements are needed. Gene hypomethylation appears to be a major mechanism of action of AZA but, with the typical 7 days of administration every 28 days, reversal of gene hypomethylation is seen at the end of each cycle (Braiteh F, Clin Cancer Res 2008), suggesting that increasing the number of treatment days could improve AZA results. This trial tested the hypothesis that an AZA regimen with more days of drug administration (ie using the standard daily dose of 75 mg/m2, but during 5 days every 14 days) could increase the response rate, and that this improvement could translate into better OS. Methods: Patients (pts) aged 18-75 years with ECOG performance status (PS) of 0-2 and no major comorbidities preventing administration of an intensified regimen of AZA, with IPSS int-2 or high MDS, CMML with WBC 〈 13,000/mm3 and marrow blasts 〉 10% , or AML with 20-30% marrow blasts (ie EU label for AZA) who had received no prior treatment for their MDS/AML except ESAs could be included. Treatment consisted of AZA 75mg/m2/d for 5 days every 14 days for 4 cycles (AZA-14, cycles 1-4). Patients achieving CR or PR then received 4 cycles of AZA 75mg/m2/d during 5 days every 21 days (AZA-21, cycles 5 to 8) followed by classical cycles of AZA 75mg/m2/d for 7 days every 28 days, to be continued until progression/relapse or toxicity arose. This schedule corresponded to a 30% increase in the number of days of AZA during the first 3 months of treatment. Patients not obtaining CR or PR after the initial 4 cycles of AZA-14 received 4 additional cycles of AZA 14 (cycles 5 to 8). Patients not obtaining CR, PR or HI after 8 cycles of AZA-14 were excluded from the trial. The primary endpoint was response after 4 and 8 cycles (IWG 2006 criteria). Median [IQR] are reported unless specified. Results: 27 patients were included, of whom 1 was excluded for consent withdrawal. 26 patients (M/F: 19/7, median age 66) enrolled between 2011 and 2013, were thus analyzed, including 1 ARSI, 2 RCMD, 3 RAEB1, 13 RAEB2, 2 CMML and 5 AML (with 20 to 30% marrow blasts). Karyotype (IPSS) was favorable in 11 pts, intermediate in 6 patients and unfavorable in 9 pts. Median marrow blast was 13.5% (IQR 9.7-18.0), baseline platelet count was 72.5 G/l (43.5-177.0) including 69% with platelet

Description: Background: Combination of Pegylated-Interferon alpha (Peg-IFNa) 2a and imatinib (IM) has been reported to significantly induce higher rates of molecular responses (including undetectable BCR-ABL transcript) over IM alone, as frontline therapy for CP-CML patients (pts) in a randomized phase 3 trial (SPIRIT, Preudhomme et al, NEJM 2010). Second generation TKIs such as dasatinib (DASISION, Kantarjian et al, NEJM 2010) enhance the speed and depth of molecular response (MR) in comparison to IM. Phase II trial using nilotinib and PegIFNa2a has recently reported high rates of deep molecular response (MR4.5) within 24 months (Nicolini FE et al, Lancet Haematology 2015). Aims: To determine the efficacy and safety of the combination of dasatinib and Peg-IFNa2b in CP-CML frontline. (EUDRACT Number: 2012-003389-42, Dasa-PegIFN trial). Methods: Newly diagnosed Ph+ CP-CML pts less than 65-year-old started dasatinib 100 mg/day. At 3 months, they were assigned to receive Peg-IFNa2b associated to dasatinib when platelets (plt) 〉 100 X 109/L, Neutrophils (ANC) 〉 1.5 X 109/L) and lymphocytes 〈 4.0 X 109/L counts were achieved. Otherwise, dasatinib was continued alone in the study according to the current international ELN guidelines. The maximum duration of the combination dasatinib and Peg-IFNa2b is 21 months. The primary endpoint is the cumulative rate of Molecular Response 4.5log (MR4.5 defined as BCR-ABL1/ABL1IS≤0.0032%) at 12 months. Molecular analyses were centralized and expressed according to the international scale (IS). Secondary endpoints included efficacy (cytogenetic and molecular responses at several time-points) and safety endpoints. Preliminary results are reported here. Results: 81 pts were enrolled between October 2013 and July 2014. All pts will have completed the 12 months follow-up time-point in August 2015. 79/81pts were included in the analysis (1 pt died of a CML-related haemorrhage before receiving dasatinib, 1 screening failure (masked Ph)). Median age was 48 (20-65) years. 54% of pts were male. Sokal scores were low, intermediate and high in 51%, 32% and 17% of pts respectively. After the first 3 months of therapy (M3), sixty-one patients (77%) started Peg-IFNa2b at the dose of 30 microg/week in association with dasatinib. For these pts after M3, reported hematologic adverse events (AE) were neutropenia (G3/4 n=11; G1/2 n=17), thrombocytopenia (G3/4 n=0; G1/2 n=7), anemia (G3/4 n=0; G1/2 n=7). Extra-hematologic AE were essentially of low grade (overall, G3/4 n=3; G1/2 n=113). According to NCI CTCAE V4.0, most frequent AE were infections (16%), general symptoms (15%), skin lesions (10%), hepato-biliary abnormalities (7.7%), nervous system/headache (7.7%) musculoskeletal pain (7%), psychiatric (7%), GI (6%) disorders. Eight serious AE (SAE) were reported after Peg-IFNa2b initiation: G4 neutropenia n=2, dysthyroitidis n=1, dyspnea n=1, pleural effusion n=1, lymphoid hyperplasia n=1, hemorrhoids n=1, rectal fistula (SUSAR) n=1. Efficacy was analysed according to the intention-to-treat principle (ITT), and considering missing data as no response to avoid inflated results. Overall at M3, 85% of pts had a BCR-ABL1/ABL1 ratio ≤10%. For eligible patients who received combined therapy (n=61), rates of MMR were 16%, 51%, 70%, and 70% (pending n=5) at M3, M6, M9 and M12, including MR4.5 rates 10%, 20%, 30% at M6, M9 and M12 respectively. Eighteen pts (22.7%) were not eligible to receive Peg-IFNa2b. Reasons, according to protocol criteria, were ANC

Description: Background: ATO is very effective in the treatment of APL and recent results have shown that ATRA+ATO combinations (without CT) were at least as effective as classical ATRA + anthracycline based chemotherapy (CT) while being less myelosuppressive (Lo Coco, NEJM 2014, Burnett, Lancet Oncol, in press). However, access to ATO remains limited for frontline treatment of APL in most countries, which must mainly rely on ATRA+CT combination. In those combinations, investigators have suggested that the amount of CT could be reduced and the incidence of relapses further diminished by introducing ATRA (Sanz) or ATO (Powell) during consolidation cycles. In a randomized trial (APL 2006 trial), we compared for consolidation treatment (after ATRA CT induction treatment) ATO, ATRA and the "classical" Ara C in standard risk APL (ie with baseline WBC 〈 10G/L). Methods: Between 2006 and 2013 newly diagnosed APL patients (pts) 〈 70 years with WBC 〈 10 G/L , after an induction treatment consisting of ATRA 45mg/m2/d until CR with Idarubicin (Ida) 12 mg/m2/dx3 and AraC 200mg/m2/dx7 started on day 3, were randomized for consolidation between AraC, ATO and ATRA. The AraC group ( standard group) received a first consolidation course with, Idarubicin (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 a maintenance during two years with intermittent ATRA 15d/ 3 months and continuous 6 MP + MTX,). The ATO and ATRA groups received the same treatment as the AraC group, but AraC was replaced respectively by ATO 0.15 mg/Kg/d d1 to 25 and ATRA 45 mg/m2/d d1 to 15 for both consolidation courses. We present here results of an analysis made at the reference date January 1st 2014 in the 398 pts aged 〈 70 years with WBC1 G/L after the first consolidation course was 24, 24 and 17 in the AraC, ATO and ATRA group, respectively (AraC vs ATO: p= 0.96; ATO vs ATRA: p1 G/L after the second consolidation course was 23, 19 and 13 days (AraC vs ATO: p= 0.02; ATO vs ATRA: p

Description: 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.

Description: Background: Characteristics and outcome of older patients (pts) with acute promyelocytic leukemia (APL) are unclear due to lack of clinical data. Aims: To describe a large series of older APL pts and compare outcome according to treatment strategy. Methods: We retrospectively studied 475 APL pts (median age, 73.8 yrs; range, 70-90.3 yrs), treated between 1990 and 2018 within four study groups/institutions of the US and Europe (Acute Leukemia French Association, n=228; Programa Espanol de Tratamientos en Hematologia, n=211; Study Alliance Leukemia, n=28; Johns Hopkins School of Medicine, Baltimore, n=8). APL was confirmed either by cytogenetics, fluorescence in situ hybridization and/or polymerase chain reaction. For analysis, pts were grouped according to treatment: i) chemotherapy/all-trans retinoic acid (CTX/ATRA, n=260; consisting of daunorubicin/idarubicin and ATRA for induction and different CTXs+ATRA for consolidation), ii) ATO/ATRA±CTX, n=177 (according to Lo-Coco F, et al. NEJM, 2013, n=23 or CTX/ATO/ATRA, n=154), iii) less intensive therapy, n=26 (reduced CTX, n=2 or ATRA only, n=24) and iv) no treatment/unknown, n=12. Results: Median white blood cell (WBC) and platelet counts at diagnosis were 1.5/nl (range, 0.1-242/nl) and 37/nl (range, 2-261/nl), respectively. Two-hundred twenty-nine pts (48%) were female. Cytogenetic analysis was available in 408 pts and 85 (21%) had additional abnormalities. BCR3 was positive in 138 (44%) of 316 available pts. Only 15 (22%) of 69 tested pts were FLT3-ITD positive. One hundred (22%) of 464 pts had a WBC count 〉10/nl. Median WBC was significantly lower (P

Description: Background Data on causes of death (COD) in patients with lower-risk (LR-MDS) is limited and sometimes conflicting. In contrast to higher-risk MDS, many LR-MDS patients die from conditions associated with advanced age, not directly associated with the underlying disease. Infections and cardiovascular disorders (CVD) have been reported as frequent COD in LR-MDS, but whether the incidence is higher than in age-matched population, is not known. The EUMDS Registry has been collecting prospective observational data on LR-MDS since 2008. The comprehensive clinical and laboratory data provides a unique chance to assess the impact of LR-MDS on survival either by causes related to MDS or indirectly related to MDS by aggravation of co-morbidities. Objectives To assess the impact of MDS and associated co-morbidities on COD in patients with LR-MDS and to evaluate the COD in the whole group and across participating countries. Methods: We evaluated clinical and laboratory data of LR-MDS patients registered in EUMDS registry from 2008 to 2018. Data were obtained by 145 centers from 16 European countries and Israel. MDS related causes of death were defined as infection, bleeding, MDS progression and AML transformation. Overall survival(OS) and relative survival(RS) were estimated using the Stata program 'strel' with age, sex and country specific background obtained from national life tables for the CONCORD program. RS is a standard approach used to take into account competing causes of death by adjusting for the age and sex specific mortality in the general population, estimating the excess mortality in these patients compared to that seen in the general population of each country. Results Overall data on 2235 LR-MDS patients was available in the EUMDS registry. Of these, 822 (36,7%) patients had died at the time of analysis. Median age was 77 years and 65% of the patients were male. Nearly half of them (46.9%) were diagnosed as IPPS low risk. The MDS-Comorbidity Index was low, intermediate and high in 55.7%, 37.5% and 6.8% of patients respectively. The most common COD were those considered as related to MDS 41.7% (Table 1). Deaths due to cardiovascular and pulmonary diseases were reported in 10.1% and 4.9% respectively. Other reasons (e.g. liver, renal failure, second malignancy) were found in 18.2%. In 25% of patients, the precise reason of death remained unknown. The proportion of MDS related COD were different between participating countries with lower rates in Germany (30%), France (31.3%) and higher in Portugal (55%), Greece (55.2%) and Romania (63.1%). Median follow-up was 2.1 years (0.1-10 years). Five-year overall survival in the whole cohort was 47.1% (95% CI: 44.1%-49.9%) and 5-year relative survival (attributed to MDS/AML only) was 59.1% (95% CI:55.4%-62.5%)(Figure 1). One year overall and relative survival was 90.4% (95% CI:89.1%-91.6%) and 94.4% (95% CI:93%-95.5%) respectively. Conclusions: MDS- related complications are the most common causes of death in LR-MDS patients. Comparison of overall and relative survival supports that observation and indicates that excess mortality in LR-MDS patients can be mainly explained by MDS/AML related causes. Interestingly, the strongest influence of MDS/AML attributable deaths was observed during the first year from diagnosis. Disclosures Fenaux: Janssen: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria; Otsuka: Honoraria, Research Funding. Stauder:Teva: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Germing:Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. de Witte:Novartis: Research Funding; Celgene: Honoraria, Research Funding; Amgen: Consultancy, Research Funding. Smith:Jazz Pharmaceuticals: Research Funding; Johnson & Johnson: Research Funding; Gilead Sciences: Consultancy; Novartis: Research Funding.

Description: Key Points First-line or subsequent dasatinib or nilotinib can be safely stopped in CML patients with deep and long-lasting molecular responses. A suboptimal response or resistance prior to dasatinib or nilotinib is associated with significantly worse treatment-free remission.

Description: Background: In France, as in many other countries, nationwide data on prevalence are rarely available and recent prevalence estimates of Chronic Myeloid Leukemia (CML) are scarce. Improved overall survival following the introduction of tyrosine kinase inhibitors (TKIs) is expected to have increased the prevalence of CML in Western countries. Aim: We sought to estimate and analyze the prevalence of CML in France for the year 2014 using a large health care claim-based dataset. Methods: Using the French national health insurance database that covers 98.8% of the French population (66 million people) we implemented a 3-step approach. First, focusing on the 2006-2014 period, we selected: 1) all patients treated with a TKI (ie, imatinib, dasatinib, nilotinib, bosutinib or ponatinib) and/or 2) identified by the ICD-10 diagnosis code C92.1 (Chronic Myeloid Leukemia, BCR/ABL-positive) among hospital discharge diagnoses and/or 3) identified by the ICD-10 diagnosis code C92 (myeloid leukemia) for coinsurance exemption. Then, we developed a claim-based algorithm to identify CML cases. Case definition was based on 1) identifying any TKI reimbursement lasting ≥ 2 months and 2) excluding patients receiving TKIs for diseases other than CML including Phi+ Acute Lymphoblastic Leukemia, Gastrointestinal Stromal Tumor, Stromal or other connective tissue tumor, and hypereosinophilic disease. Finally, prevalent CML cases were those identified by the algorithm above and having ≥ 1 healthcare reimbursement during the year 2014 and still alive on December, 31st 2014. The internal validity of the algorithm was tested on a random sample of 100 potential CML cases fulfilling ≥ 1/3 selection criteria in step 1 by comparing the results of the algorithm with the opinion of two hematologists (gold standard). For each individual, hematologists reviewed patient demographics and the sequence of care from 2006 to 2014 including healthcare resource utilization (ie, all hospitalizations and ICD-10 diagnosis codes, all medication use, all specialist consultations with date and specialist type). In addition, we assessed the external validity of the algorithm by comparing the number of incident CML patients in 2014 as identified in the French national health insurance database with the number of incident CML cases recorded in the French cancer registries for respective departments (i.e. ~ 20% of the French territory). Results: There were 10,789 prevalent CML cases in 2014 out of 68,067 individuals from the French national health insurance database who fulfilled the selection criteria for the overall 2006-2014 period. Eighty-nine percent of the prevalent CML cases were identified by at least two out of three selection criteria (TKI, ICD-10 code C92.1 among hospital discharge diagnoses, ICD-10 code C92 for coinsurance exemption). There was a 96% concordance rate (internal validity) between the algorithm and the opinion of the hematologists. For the year 2014, 162 and 150 incident CML patients were identified by the algorithm and the French cancer registries, respectively (high external validity). Median age [Inter-Quartile Range] of the prevalent population of CML patients was 63 years [51-73], with slightly more males affected (55%). On December, 31st 2014, the crude prevalence of CML was estimated at 16.3 per 100,000 inhabitants [95% confidence interval (CI) 16.0-16.6]. The crude prevalence of CML was 18.5 per 100,000 in men (95% CI 18.0-19.0) and 14.2 per 100,000 in women (95% CI 13.8-14.6). The crude prevalence of CML was less than 1.6 per 100,000 (95% CI 1.2-2.0) before 20 years of age, progressively increasing to 19.4 per 100,000 (95% CI 18.1-20.7) among those with 50-54 and reaching a peak of 48.2 per 100,000 (95% CI 45.3-51.1) at 75-79 years. There was a male preponderance in CML prevalence in all age groups. The crude prevalence of CML varied in a ratio of one to two throughout the French territory (from 10.2 to 23.8 per 100,000 inhabitants). Conclusion: Healthcare claims data are increasingly used to estimate epidemiological parameters worldwide. This approach is particularly relevant for rare diseases and administrative databases with high population coverage. Countries without national cohorts or cancer registries could easily use our algorithm to estimate their prevalence of CML. Disclosures Cony-Makhoul: Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Incyte: Other: Travels for attending to Congress; Novartis: Consultancy, Other: Writing support, Travels for attending to Congress. Guerci-Bresler:Pfizer: Other: Fees for symposiums and boards; Novartis: Consultancy, Other: Fees for symposiums and boards; Incyte: Other: Fees for symposiums and boards; BMS: Other: Fees for symposiums and boards; Pfizer: Other: Travel fees for Congress. Delord:Incyte: Consultancy.