ALBERT

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 Twenty nine (29%) pts were withdrawn from study in A (toxicity 9, cancer 3, resistance 14, investigator decision 2, lost for FU 1) vs 26 (26%) pts for B (toxicity 13, resistance 8, investigator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: Abstract 1684 The early assessment of molecular responses to tyrosine kinase inhibitors (TKI) used as a front line therapy for chronic phase chronic myeloid leukemia (CML) might represent an attractive surrogate marker for survival and help to discriminate poor prognosis patients (pts). So, we studied in a retrospective bicentric institutional analysis a series of 142 de novo CP CML pts diagnosed between 2000 and 2011, receiving imatinib (IM) 400 mg daily (n=85 pts), second generation TKI (TKI2) (n=57 pts) with 37 dasatinib (DAS) pts 100 mg daily and 20 nilotinib (NIL) pts 600–800 mg daily as front-line therapy, enrolled or not in clinical trials. All pts were assessed for their cytogenetic and molecular responses (local RQ-PCR for BCR-ABL, expressed as BCR-ABL/ABL ratios (IS) in %). Failure to TKI was defined as progression to accelerated phase or blast crisis, death, loss of complete hematologic response, loss of complete cytogenetic response, confirmed loss of major molecular response (MMR), discontinuation of TKI because unacceptable toxicity, primary cytogenetic resistance. The definition of progression included the same variables except the two last. Pts were considered in MMR with a BCR-ABL/ABL ratio ≤0.1% (IS). There were 87 males (61%) and 55 females with a median age of 55 years (21–83) at diagnosis. Six pts (4%) had an additional clonal abnormality, 4 a masked Philadelphia (Ph) chromosome, and 4 a variant Ph. Three pts had an atypical BCR-ABL transcript, all in IM400 group. Sokal scores were low for 37 (26%), intermediate for 61 (43%) and high for 43 (31%) (1 NA), and Euro scores were low for 49 (35%), intermediate for 78 (55%), and low for 14 (10%) (1 NA). These scores were similarly balanced in the IM400, NIL and DAS groups. The median time between diagnosis and TKI was 1 (0.9–1.28) month, not significantly different between TKI groups. The median follow-ups were 56, 37, and 19 months for IM400, NIL and DAS groups respectively. Fifteen percent, 6%, and 14% of pts achieved MMR at 3 months (M3) (p=ns); 31%, 37%, and 40% at M6 (p=ns); 55%, 70% and 71% at M12 (p=ns); 67%, 90% and 87% at M18 (p=ns) in IM400, NIL and DAS groups respectively, taken into account the limited numbers of pts at latest time-points in the 2 TKI2 arms. Twenty-three pts achieved 4-log molecular response MR4 in IM400, 10% in NIL and 11% in DAS at latest follow-ups. Four pts died, 3 in blast crisis in IM400 group and 1 for unrelated reason to disease or treatment in NIL group. A multivariate analysis adjusted on progression-free survival (PFS) performed, did not identify any significant parameter including age, gender, Sokal and Hasford scores, ACA, type of transcript, interval between diagnosis and TKI start. The progression-free survival (PFS) was 94 (83–100)% for pts achieving M3 MMR vs 86 (74–100)% if MMR occurred at later time points vs 86 (73–100)% for pts that never achieved MMR (p=0.02). There was no difference for PFS between the 3 TKI (log-rank p=0.9). None of the M3 MMR switched to another treatment, whereas 10 % of other pts did so for resistance (n= 10, 1 and 2 for IM400, NIL and DAS respectively), 9% for intolerance (n=10, 1 and 4), and 3% for other reasons (n=4, 0 and 0) with no difference between the 3 drugs (p=0.74). The failure-free survival (FFS) was 95% for M3 MMR pts vs 65% for pts with MMR occurring at later time points, versus 0% if MMR has not been achieved (p

Description: Abstract 3410 The ABL T315I mutation confers resistance to all approved tyrosine kinase inhibitors (TKIs) for the treatment of CML and Ph1+ ALL. The survival of patients harboring a T315I mutation, associated or not with other factors, is dependent on disease phase at the time of mutation detection. In vitro, in cell lines, this mutation alters kinase function and phosphorylation activity that increases oncogenicity (Skaggs et al., PNAS 2006). Using a matched-pair analysis, we aim to confirm whether or not these in vitro findings correlate into the clinic and provide higher rates of progression and poorer outcome specifically among CML patients remaining in chronic phase (CP) at T315I detection. A cohort of CP CML patients at T315I detection were identified from a database of an earlier epidemiologic study (Gr 1) was compared to a single-center, matched cohort of CML patients resistant to imatinib (IM), in CP, but not harboring the T315I mutation (Gr 2). All patients had had IM. These patients were matched on the 3 following variables: i) age at diagnosis, ii) time from diagnosis to IM initiation, iii) IM duration. The general characteristics of the 2 groups are displayed in table 1. Univariate analysis demonstrated that patients were equivalent for all factors except for the intervals from diagnosis to IM resistance and from diagnosis to TKI2 initiation that were significantly longer in Gr 1. Sixty-two percent of the patients in Gr 1 and 100% in Gr 2 took a TKI2. The duration of treatment with a 1st TKI2 was significantly longer in Gr 2, as a significant proportion of IM-resistant patients might respond to these agents. The cumulative incidence of switches for TKI2 was similar between the 2 groups (p=0.33). In a multivariate analysis the presence of the T315I mutation had a highly significant negative impact on overall survival (OS) from any time-point (HR since IM resistance=21.6, [5.4-87.3], p

Description: Introduction Imatinib has indeed revolutionized the treatment of chronic myelogenous leukemia (CML) since more than 15 years now, especially in CP. The first patients (pts) in this setting were treated with this compound within the IRIS phase III trial from Novartis, started in January 2000. Regular updates of the results of this study have been presented during various meetings until year 7, and academic studies have recently reported the outcomes of IM first-line CP CML pts after 66 months follow-up. However, little is known about the very long-term outcomes (〉8 years) of such first-line pts and these data might be of interest while generic forms of IM will be soon launched in this setting. In this study, we aimed to look at long-term outcomes in terms of efficacy and toxicities in first-line CP CML pts treated with branded form of IM (Glivec®). Methods This is a comprehensive retrospective analysis of first-line CP CML pts treated with IM first-line 400 mg daily since diagnosis and followed in 2 university reference centers for CML between 2000 and 2015, inside or outside academic or industrial clinical trials. All living pts have given their agreement for participation in this retrospective analysis. Pts have been analyzed in intention-to-treat, CML was defined according to ELN criteria [CP, accelerated phase (AP) and blast crises (BC)], Sokal, Euro and EUTOS scores have been calculated as published. Molecular biology tests have been performed according to ELN guidelines and BCR-ABL1/ABL1 were expressed as % on the international scale and 3 ELN conversion factors have been applied successively along time according to material exchanges performed with the central European laboratory in Mannheim. Cytogenetic and molecular responses have been defined according to the ELN criteria. Overall survival (OS) was calculated from the date of IM initiation until death at any time and for any reason; until progression to AP or BC at any time for progression-free survival (PFS); and until death, progression to AP or BC, failure on IM or IM treatment discontinuation for any cause including treatment-free remission (TFR), for event-free survival (EFS). The cut-off date for this analysis was the 20th of July 2,015. Results At time of analysis, 120 pts could be analyzed, with a median follow-up of 85.5 (1-194) months, 70 (58%) were males, with a median age of 55 (11-85) at IM initiation. Sokal score was high for 24(20%) pts, intermediate for 58 (49%), low for 34 (30.5%), unknown in 4 (0.5%) pts. Four (3.5%) pts had a variant Ph chromosome, 7 (6%) with additional chromosomal abnormalities, and 2 a masked Ph chromosome, 6 harbored atypical BCR-ABL1 transcripts excluded from analysis. Early molecular response (M3) was achieved in 86 (72%) pts, unreached in 20 (16%) pts, and unknown for 15 (12.5%) pts. It was predictive of Major Molecular Response (MMR) at 12 months (p=0.01, OR 5.35, 95%CI [1.3-31.94]), for MR4 rates at 24 months (p=0.03, OR 7.35 95%CI [1-328]) and for EFS (p=0.006) but not for OS and PFS in a multivariate Cox model analysis. MMR was achieved in 42% of evaluable pts at 12 months. Eutos, Euro and Sokal scores had no impact on OS, PFS and EFS. Five pts progressed to BC (1 myeloid, 4 lymphoid) within the 5 first years and died after allogeneic stem cell transplantation. The PFS rates were 97.5% at 2 years, 92% at 5 years, 88.6% at 10 and 14 years, EFS rates were 76% at 2 years, 60% at 5 years, 45% at 10 years and 21% at 14 years (figure 1), OS rates were 98% at 2 years, 95% at 5 years, 87% at 10 and 14 years. Figure 1: PFS and EFS in pts on IM first-line. (Dashed lines represent 95%CI). MR4.5 was achieved in 58 (48.5%) pts after a median of 46 (3-191) months and TFR strategy (or trial) was proposed in 28 pts (23.5%) and successful in 15 (12.5%) pts. At latest follow-up, after a median of 85.5 (4-180) months, 64 (53.5%) pts are still on IM, and 44 (37%) have switched to an alternative therapy for intolerance (17 pts, 14%) or resistance (16 pts, 13.5%, 7 with a BCR-ABL mutation) to IM and 11 for other causes (pregnancy, secondary tumors…). Overall, at latest follow-up, 10/120 pts died, 5 of CML progression and 5 from other causes. Conclusions After a very long median follow-up of more than 85 months, IM still consistently provides high rates of remission and survival, without disease progression and severe long-term toxicities. In addition, half of the pts reached the MR4.5 level, ≥2 years stable in 23.5% of the pts offering the possibility of a treatment-free strategy. Figure 1. Figure 1. Disclosures Nicolini: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mahon:Novartis: Consultancy, Honoraria; ARIAD: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria. Etienne:Novartis: Consultancy, Honoraria; BMS: Honoraria.

Description: Abstract 1669 Most epidemiologic studies performed in chronic myelogenous leukemia (CML) relate that the disease occurs preferentially in males with a sex ratio of ∼1.2. In addition, CML can be diagnosed in young adults and masculine fertility is a matter of concern, particularly because tyrosine kinase inhibitors (TKI) may impact on spermatogenesis by a selective inhibition of Src kinases, PDGF-R and c-kit. Sperm cryopreservation is recommended by some authors at diagnosis in males that would expect to have children later on. In a retrospective analysis we have analysed the spermograms of 62 chronic phase (CP) and 2 onset blast crisis (BC) CML males referred to our 3 centres between 2001 and 2012, collected at diagnosis before TKI treatment, and we have compared the results obtained to those of 15 healthy volunteer donors from the cryopreservation bank database, after informed consent. In 10 patients we could collect some data for patients being on imatinib mesylate (IM). CML patients had a median age of 31 (16–48) years, significantly younger than that in the control group of healthy donors: 37 (34–45) years (p=0.001). Sokal scores were 24% high, 27% intermediate and 49% low for evaluable patients (13 patients unknown or not available). The median BCR-ABLIS value at diagnosis was 77.65%. Patients had a median duration of 26 (0–38) days of hydroxyurea prior to commencing any TKI and 65% of evaluable patients had HU before TKI. None of the patients got interferon prior to TKI. The semen cryopreservation was performed within a median of 10 (2–102) days after CML diagnosis and after a median abstinence of 5 (0.5–30) days. The median volume of semen obtained in CML patients was 2.95 (0.5–14.9) ml and 3 (1.4–5.3) ml for normal donors (p=0.3). Williams test showed 72 (0–87)% of necrospermia in patients versus 18 (4–32)% in donors (p=0.00003). The median number of spermatozoa obtained was not different in patients [46 (0.03–200) 106/ml] than that in donors [74 (19.2–253) 106/ml] (p=0.24), as well as the number of spermatozoa per ejaculate observed (p=0.49). The motility of spermatozoa at 30 minutes after collection was not different between patients (median = 47.5%) and donors (median = 50%) (p=0.12), however higher numbers of atypical spermatozoa were observed in patients [median = 77.5 (16–100)%] rather than in donors [median = 45% (22–89)%], p=0.008, and the multiple abnormalities index (MAI) was significantly higher in patients [median = 1.99 (1.14–2.7)] than that in donors [median = 1.33 (1.09–1.55)], p=0.00006. There was no correlation between age at diagnosis, Sokal index and the number of spermatozoa per ml obtained (p=0.7 and 0.21 respectively). Ten CP CML patients had spermograms after a median of 1440 (9–1456) days of IM treatment and the results obtained were compared to i) the results of each individual patient at CP diagnosis and ii) to the results of healthy comparators. In comparison to the characteristics observed at diagnosis, the semen volume (median = 3.1 ml), Williams test (median = 65%), the motility at 30 minutes (median = 37.5%) and the MAI (median = 1.71) were not different (p=ns for all), however, the numbers of spermatozoa (median = 14.9 106/ml and = 37.05 ml per ejaculate) collected on IM were significantly lower (p=0.014 and p=0.045 respectively). The different parameters evaluated on IM were compared to those of normal controls and showed significant alterations. The semen volume was not different (p=0.94), neither the motility of spermatozoa (p=0.24), but the Williams test was highly perturbed on IM [median 65 (24–79)% versus 18 (4–32)% in donors] p=0.00003, as well as the numbers of spermatozoa as 106 per ml, collected on IM [median 14.9 (0.67–179)) versus normal [74 (19.2–253)], p=0.0036 or as 106 per ejaculate collected on IM [median 37.5 (2.68–572.8)) versus normal [149 (30–535.3)], p=0.026. Atypical forms were significantly more abundant on IM [median = 80 (68–90)%] versus healthy controls [median = 45% (22–89)], p=0.0058. Finally, the MAI was severely altered on IM [median = 1.71 (1.61–1.98)] versus normal individuals [median = 1.33 (1.09–1.55)], p=0.00013. In conclusion, this work demonstrates the existence of significant sperm alterations in young males with CML at diagnosis of undetermined origin, prior to any treatment. These alterations persist on IM treatment and little is know about the impact of second generation TKI. Thus the most appropriate approach remains a matter of debate in thus setting. Disclosures: Nicolini: Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Huguet:Novartis, BMS: Speakers Bureau. Michallet:Novartis, Pfizer, Teva, Genzyme, Janssen Cilag, BMS, Merck, Pfizer, Gilead, Alexion: Consultancy, Speakers Bureau. Etienne:Novartis, Pfizer, speaker for Novartis, BMS: Consultancy.

Description: Despite its high efficacy on CML, long-term exposure to nilotinib, a second generation tyrosine kinase inhibitor (TKI2), has been reported to increase the onset of arterial cardiovascular events (CVE) in chronic phase (CP) CML patients (pts), especially in pts with cardiovascular risk factors. However, some pts without any cardiovascular risk factors may experience arterial thrombotic events and the pathogenesis of this phenomenon remains obscure. Homocystein (HC) is a key sulphured amino-acid derived from methionin, independently associated with increased frequencies of thrombo-embolic events, early arteriosclerosis and increased cardiovascular mortality (Nygard NEJM 1997). In addition, in vitro, this amino-acid induces the proliferation of smooth muscle cells, endothelial cell dysfunction, increased collagen synthesis and exerts pro-inflammatory rearrangements within the arterial wall. In the present study, we wanted to determine if hyperhomocysteinemia might influence the onset of cardio-vascular events in a series of 114 CP CML pts on nilotinib. We have prospectively analysed in a multicentric study, on-nilotinib cohorts of CP CML pts between September 2011 and July 2014 with standard clinical assessments [height, weight, body mass index (BMI)], onset of any CV events, and basic routine blood metabolic laboratory assessments (fasting glucose, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glycosylated haemoglobin, homocysteinemia (Biorad kit on HLPC on Summit Dionex system, Thermo Fischer scientific, France), vitamines B9 and B12. All the 114 pts were in CP-CML on nilotinib [43 as first-line, 71 as second-line or more, since a median of 51.5 (3-164) months], 49 were males, with a median age of 51.7 (18-81) at CML diagnosis and 58 (82-20) at nilotinib initiation. Twenty-eight (24.5%) pts presented some CV risk factors prior to nilotinib initiation, and 24 (21%) had an active tobacco abuse at assessment (4 patients unknown). Median weight was 69 (44-149) kg and median BMI was 24.5 (16.5-46) kg/m2 (8 patients 〉30). Overall, 21 (18.5) pts presented new or worsened pre-existing CVE on nilotinib after a median follow-up of 51.5 months since TKI2 initiation. These CVE occurred after a median of 47 (7.5-82.3) months with a regular increase along the years (Cumulative incidence (CI) 3% at 1 year, 4.12% at 2, 5.15% at 3, 9.30 at 5 and 20.62% at 8.3 years). In total, 3 pts died, 2 from brain stroke, 1 from sudden death in a pt with a history of myocardial infarction. In an univariate analysis we compared our cohort of nilotinib pts to a similar cohort of 17 pts on imatinib as control [median age 56 years since CML diagnosis (p=ns), median duration of imatinib 39 months (p=ns), median weight 70.5 kg (p=ns), BMI 25.9 kg/m2 (p=ns)]. None of these imatinib pts had shown any CVE during follow-up. HC was significantly lower in imatinib-treated pts (p=0.029), in female pts (p=0.018) and increased with age (p

Description: 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.

Description: Abstract 3756 The introduction of second generation tyrosine kinase inhibitors (TKI2) in the treatment of chronic phase chronic myelogenous leukemia (CML) has improved the response rates in the second, and now, in the first line setting. Nilotinib, a TKI2 with a restricted kinase inhibition profile, demonstrated higher rates of response over imatinib (IM) as front line therapy with a very good short-term tolerability profile. Even if the proportion of patients (pts) in undetectable disease increases with time, the majority will have to continue this treatment for several yrs to avoid progression. In this perspective, mid- and long-term safety issues are of concern, and recent reports point out the onset of arteriopathies in such pts with a suspected abnormal frequency. We have prospectively analysed our on-nilotinib cohort of CP CML between September 2011 and July 2012 with standard clinical assessments [height, weight, body mass index (BMI), ankle-brachial index (ABI)], and basic routine metabolic laboratory assessments (fasting glucose, total, HDL and LDL cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glycosylated hemoglobin) and BCR-ABL (IS), to explore and detect at early stages abnormalities that may have some later cardio-vascular consequences for pts on this drug. We analysed a series of 54 CML pts all in CP. The median age at diagnosis was 50 (18–73) and 55 (20–78) yrs at nilotinib initiation. The Sokal score was low for 27%, intermediate for 55%, high for 8%, unknown for 10 pts. At CML diagnosis, 13 pts had hypertension, 4 diabetes mellitus, 2 previous peripheral arterial disease (PAD), 4 coronary artery disease (CAD), and 9 pts had tobacco addiction. Thirty-seven pts had IM first line for a median of 4.2 (0.2–11) yrs, then nilotinib for IM-intolerance (14 pts) or IM-resistance (16 pts), or entering a clinical trial (5 pts) and 2 for unknown reasons for a median of 2.8 (0.5–5.6) yrs. Seventeen pts had nilotinib first line for a median of 1 (0.3–4.7) year. The disease duration ranged from 0.4 to 19.3 yrs (median 5.6). Overall, the median duration of nilotinib was 2.2 (0.3–6.8) yrs. Two pts were in CHR, 11 pts in CCyR, 28 in MMR, 13 in undetectable disease (MR4.5) at assessment. In pts on nilotinib without statins at time of assessment, 62% (n=40) showed high total cholesterol values (〉2 g/l), 46% (n=37) had high LDL cholesterol (〉1.5 g/l) and 57% (n=37) low HDL cholesterol values (1.48 g/l) in 18% of pts (n=49). Glycosylated hemoglobin was high (〉6%) in 18% of the pts treated (n=38), and glucose (〉 5.8 mmol/l) in 20% (n=11). Seven pts (13%) were overweight (BMI〉30) and the median BMI was 24.6 (16.7–47). On 54 pts, 25% of pts (n=13) had an abnormal ABI (

Description: Abstract 166 Background Imatinib mesylate combined to pegylated interferon alfa 2a (Peg-IFN) has been reported to significantly enhance the molecular responses for de novo chronic phase chronic myeloid leukemia (CP-CML) patients compared to Imatinib alone in a Phase 3 study (Preudhomme et al. NEJM 2010). Second generation tyrosine kinase inhibitors (TKI2) such as nilotinib induce significantly higher levels of cytogenetic and molecular responses than imatinib as front line therapy for CP-CML (Saglio et al., NEJM 2010). Aims Test the combination of nilotinib + Peg-IFN as front line therapy in CP-CML patients in order to check the safety and evaluate the molecular response rates (EudraCT 2010–019786–28). Methods In this 2-step French national study, patients were assigned first to Peg-IFN (± HU) for a month at 90 mg/wk prior to a combination of nilotinib 300 mg BID + Peg-IFN 45 mg/wk for ≥ 1 year. The primary endpoint was the rate of confirmed (on 2 datapoints) molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised for all patients and expressed as BCR-ABLIS in %. Results In the first cohort, 40+1 patients (1 screen failure) were enrolled and a second cohort of 20 patients was planned once the last patient of cohort 1 attained 1 year of treatment, if the primary endpoint would have not been reached. The current median follow-up is 13.6 (10.1–16.3) 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. Euro score was high for one patient. The median age was 53 (23–85) years. Two patients had a masked Philadelphia chromosome, 3 a variant form, and 1 had additional chromosomal abnormalities, all patients had a “major” BCR transcript. Five percent of patients were in CHR at 1 month of Peg-IFN and 100% at month (M) 2 (after 1 month of combination therapy). The rates of Complete Cytogenetic Responses (CCyR) at 3, 6, and 12 months of combination (i. e. at 2, 5, 8 and 11 months of TKI2) were 47%, 71%, 100% respectively on evaluable samples. The incidence of molecular responses are mentioned in figure 1. Of note, 87% of the patients had a BCR-ABLIS ≤10% at M3. The rates of molecular responses broke down by major molecular response (MMR): 27%, 4 log reduction (MR4): 36%, and ≥4.5 log BCR-ABL reduction (MR4.5, MR5 and undetectable): 21% with a total number of 84% patients in ≥MMR and beyond (17.5% and 67.5% in intention-to-treat respectively) at 1 year. Confirmed molecular results at 1 year will be presented. Nilotinib trough levels centrally analysed at M3, 6 and 12 for the vast majority of patients were ≥ 1000 ng/ml and Peg-IFN did not seem to impact on its pharmacokinetics. One patient went on unmutated myeloid blast crisis at M6 and is alive after allogeneic stem cell transplantation. Four additional patients were withdrawn from study: At M2 for non observance, at M6 for seizures related to an extra-dural hematoma, at M6 for recurrent grade 3 hepatic toxicity, at M9 for recurrent grade 3 pruritus. The median dose of Peg-IFN delivered to the patients during the first month was 90 (0–180) mg/wk, 45 mg/wk at M2, 3, 9, 12, and 33.75 mg/wk at M6. The median doses of nilotinib delivered to the patients were 600 mg daily at M2, 3, 6, 9, 12 and 15 as initially planned. The rate of grade 3–4 hematologic toxicities overall were anemia 2.5%, thrombocytopenia 41%, neutropenia 41% and pancytopenia 5%. These were observed mainly during M2 (16% neutropenia, 24% thrombocytopenia, 3% anemia), M3 (16% neutropenia, 13% thrombocytopenia, 3% pancytopenia) and M6 (12.5% neutropenia, 5% thrombocytopenia) and disappeared thereafter. Grade 3–4 toxicities occurred mostly during the first 3 months with 15% cholestatic episodes, 5% of ALAT elevation, 2.5% of lipase elevation, 2.5% arthro-myalgias, 2.5% abdominal pain without lipase elevation, 2.5% of depression. No PAO was observed and, to date, no dyslipidemia. Conclusion The combination of nilotinib and Peg-IFN seems relatively well tolerated despite frequent initial and transient hematologic and hepatic toxicities, and provides very high rates of molecular responses at 1 year and beyond. According to the initial methodology of this trial, the second cohort of patients will not be enrolled as the MR4.5 rates at M12 are beyond the initial expectations. A randomised phase III study testing nilotinib versus nilotinib + Peg-IFN is warranted. Disclosures: Nicolini: Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Etienne:Novartis, Pfizer, speaker for Novartis, BMS: Consultancy. Roy:Novartis, BMS: Speakers Bureau. Huguet:Novartis, BMS: Speakers Bureau. Legros:Novartis, BMS: Research Funding, Speakers Bureau. Giraudier:Novartis: Speakers Bureau. Coiteux:Novartis, BMS: Speakers Bureau. Guerci-Bresler:Novartis, BMS: Speakers Bureau. Rea:Novartis, BMS: Consultancy, Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Hermet:Novartis, BMS: Speakers Bureau. Rousselot:Novartis, Pfizer, speaker for Novartis, BMS: Consultancy, Speakers Bureau. Guilhot:Novartis, Ariad, and BMS: Consultancy, Speakers Bureau. Mahon:Novartis, BMS: Consultancy, Speakers Bureau.

Description: Abstract 3407 It has been demonstrated that obtaining early complete cytogenetic response (CCyR) in chronic phase (CP) chronic myeloid leukemia (CML) represents a guarantee for a better long-term outcome on imatinib 400 mg/day (IM400) (D. Marin et al. Blood 2008; 112: 4437). Very recently, the introduction in the therapeutic arsenal of second generation tyrosine kinase inhibitors (TKI2) as front-line therapy for CP CML has provided very high and early CCyR rates (~80% at 12 months) that might erase the prognostic value of this last endpoint. We analysed in a retrospective single center study the impact of early major molecular response (MMR) rates to see whether or not the early achievement of MMR on TKI (here IM400) front-line represents a favourable prognostic factor on outcome. All patients (n=83) were de novo CP CML, treated with IM 400 as single therapy since diagnosis and assessed for their cytogenetic and molecular responses (RQ-PCR for BCR-ABL, expressed as BCR-ABL/ABL ratios (IS) in %) centrally. Failure to IM was defined as progression to accelerated phase or blast crisis, death, loss of CHR, loss of CCyR, confirmed loss of MMR, discontinuation of IM because unacceptable toxicity, primary cytogenetic resistance to IM. The definition of progression included the same variables except the last two. Patients were considered in MMR with a BCR-ABL/ABL ratio ≤0.1% (IS). There were 47 males (56%) and 36 females with a median age of 53 years (17-82.5) at diagnosis. Three patients (3.5%) had isolated additional clonal abnormalities (ACA) at diagnosis, 4 had a variant Ph 1 and 3 had a masked Ph 1. Two patients (2.5%) had atypical BCR-ABL transcripts (one e1a2 and one a TEL(ETV6)-ABL transcript). Sokal scores were low for 20 (25%), intermediate for 39 (49%) and high for 21 (26%) (3 NA), and Hasford scores were low for 27 (34%), intermediate for 47 (59%) and high for 6 (7%) (3 NA). The median time between diagnosis and IM400 start was 27 days (0-257) and the median follow-up was 41 months (6-116). Twelve percent of patients achieved MMR at 3 months (M3), 31% at M6, 49% at M12, 65% at M18 and 89% at latest follow-up. Three patients died all from BC, none being in the M3 MMR group. Early (M3) MMR was not dependent on Sokal or Hasford scores (p=0.21 and p=0.63 respectively). Multivariate analysis on progression-free survival (PFS) for M3 MMR did not detect any significant parameter including age, gender, prognostic scores, ACA, type of transcript, delay between diagnosis and IM400 start. The PFS was 100% for M3 MMR patients vs 77% (64.2-92.8) for the others (p