ALBERT

Description: Background. A sustained deep molecular response (MR4 or better) is a validated criterion for discontinuation of Tyrosine Kinase Inhibitors (TKI) in patients with Chronic Myeloid Leukemia (CML), but only a minority of patients attain this response. Predictive factors of stable MR4 have been reported in patients treated with different dosages of imatinib (i.e from 400 to 800 mg daily) but data about long-term treatment with standard dose imatinib are lacking. Moreover, various definitions of sustained MR4 have been used in these studies. Aims and methods. To assess the probability and the predictors of a stable MR4 we restrospectively analyzed our cohort of chronic phase CML patients treated with imatinib 400 mg daily, as first-line therapy or after interferon (IFN) failure. IFN-treated patients already in complete cytogenetic response at the time of imatinib start were excluded from the analysis. Major molecular response (MMR) was defined as BCR-ABLIS ratio 0.01% BCR-ABLIS after the achievement of MR4 were defined as unstable MR4. Baseline factors (age, sex, Sokal, Hasford and EUTOS risk score, type of BCR-ABL transcript, pre-treatment with IFN) and response to imatinib at 3, 6, and 12 months according to the European LeukemiaNet (ELN) 2013 recommendations have been examined for the association with stable MR4. Frequencies were compared by Fisher's exact test. Univariate and multivariate regression analysis were performed using the competing risk model of Fine and Gray, where the achievement of the response was the event of interest, and cessation of imatinib 400 mg daily for any reason (including dose increase for resistance, and death) were the competing risks. The significance of individual parameters comprising more than 2 variables was determined by the Wald test. Results. A total of 320 patients (260 treated with imatinib front-line and 60 after IFN) was evaluated. Median age at diagnosis was 57 years (range 20-88). Sokal distribution was 42%, 40% and 15% for low, intermediate and high risk, respectively (3% were not evaluable). After a median follow-up from imatinib start of 74 months, 146 patients (46%) never reached MR4, 84 patients (26%) obtained an unstable MR4 and 90 patients (28%) achieved a stable MR4. The cumulative incidence of stable MR4 was 26.8% (95% CI: 20.8-32.3%) at 5 years and 39.3% (95% CI: 32.1-45.7%) at 10 years. Median time to first MR4 for patients subsequently obtaining a stable MR4 was 25.3 months and all but 5 stable responders achieved the MR4 within 5.5 years of imatinib. As compared to patients with unstable MR4, those with stable MR4 tended to have a higher frequency of e14a2 transcript (63% vs 53%; p=0.07) and had a marginally significant lower frequency of IFN pre-treament (16.7% vs 29.8%; p=0.048) while no differences were observed concerning the other baseline factors, including sex. Predictors of stable MR4 were: type of transcript (e14a2 vs e13a2 HR 2.07; p=0.003), pre-treatment with IFN (no IFN vs IFN HR 2.45; p=0.002), BCR-ABL level at 3- (≤10%IS vs 〉10%IS HR 3.48; p=0.004), 6- (

Description: Introduction Evolution to myelofibrosis (MF) represents a relatively rare but always severe event in patients with essential thrombocythemia (ET) and polycythemia vera (PV). Few reports have focused on the clinical and biological features at diagnosis of ET and PV that correlate with progression to MF. Aims and Methods We retrospectively studied a series of patients with post-ET and post-PV MF and compared with a group of ET and PV patients with a long follow-up without myelofibrotic evolution, with the aim to identify prognostic factors for MF. Forty-three patients with post-ET (n=29) and post-PV (n=14) MF followed at our institution were compared with 125 ET and 75 PV patients with at least 9 years of follow-up without evolution. Diagnosis of ET and PV was confirmed according to WHO criteria (including JAK2 analysis, performed since 2006 and study), evolution to MF was defined according to IWG-MRT proposed criteria. The following parameters, available for all patients at diagnosis of ET or ET, were taken into consideration to find prognostic risk factors for myelofibrosis: age, platelet (PLT) count, hemoglobin (Hb) and hematocrit (Hct) levels, white blood cell (WBC) count. Statistical analyses were conducted using Student t test. Results Median time from diagnosis of ET/PV and progression to MF was 156 months (range: 29-314). Comparing baseline characteristics of patients who evolved to MF and those who did not, we did not found any significant correlation. Mean data at diagnosis for patients with (n = 43) or without (n=200) subsequent evolution to MF were as follow: age 52.1 vs 53.1 years (p=0.79), Hb 15.4 vs 15.7 g/dl (p=0.59), Hct 47.2 vs 47.1% (p=0.67), WBC 9.8 vs 9.1 x 109/l (p=0.11), PLT 713 vs 689 x 109/l (p=0.87). Also when considering only the 29 post-ET MF and the 125 ET patients, there was no clinical feature present at diagnosis that could foresee a future myelofibrotic evolution. Conversely, in the 14 post-PV MF and 75 PV patients, progression to MF was predicted only by higher WBC count (11.4 vs 9.3 x 109/l, p=0.046), while no correlation was found with age, Hb, Hct or PLT [Table 1]. Conclusions Concordant with some previous reports, our data suggest a possible role of leucocytosis as an adverse risk factor for progression to MF in patients with PV, though not in ET. Other clinical characteristics present at diagnosis, such as advanced age, anemia or polycythemia and thrombocytosis do not seem to be associated with higher risk of fibrotic evolution in patients with myeloproliferative neoplasms. Disclosures: No relevant conflicts of interest to declare.

Description: Background. Use of 2nd generation tyrosine kinase inhibitors (2G-TKIs) dasatinib (DAS) and nilotinib (NIL) in chronic phase (CP) chronic myeloid leukemia (CML) patients failing imatinib (IM) results in around 50% of sustained cytogenetic response, and around 40% major molecular response (MMR). However, these are historical data and it's unclear if there's a significant difference in efficacy of the two 2G-TKIs, especially in the long-term. Aims and methods. We retrospectively analysed 163 CP-CML patients resistant or intolerant to IM that received either DAS (n=95) or NIL (n=68) as second-line therapy. We compared the characteristics of the two groups at the time of CML diagnosis and at the time of IM failure, including the cause of switch to 2G-TKI, duration of IM therapy, IM dose escalation and Hammersmith score to predict the probability of response to 2G-TKIs. Cytogenetic and molecular responses were evaluated according to the ELN recommendations. Sustained deep molecular response (DMR) was defined as MR4 or better lasting ≥ 2 years, ongoing at the last contact, and with at least a Q-PCR test every 6 months. Time to treatment failure (TTF) was calculated from the start of 2G-TKI to any of the followings: progression to accelerated or blast phase (ABP), death for any cause at any time, treatment discontinuation for primary or secondary resistance or intolerance. Progression free survival (PFS) was calculated from the start of 2G-TKI to ABP or death. Overall survival (OS) was calculated from the start of 2G-TKI to death. Results. DAS and NIL cohorts were comparable for age, sex and risk score (Sokal and EUTOS) at diagnosis. Median duration of IM therapy was similar (DAS 19 months, NIL 14 months), but 27/95 patients (28%) had IM dose escalation before DAS compared to only 9/68 (13%) before NIL (p=0.03). There was a higher rate of switch to DAS than to NIL for secondary resistance (26/95, 27% vs 7/68, 10%; p=0.01) while more patients changed from IM to NIL due to intolerance (31/68, 46%, vs 21/95, 22% for DAS; p=0.002). Rates of primary resistance did not differ (47/95, 49% for DAS vs 28/68, 41% for NIL; p=0.37), as well as other causes of switch (1/95, 1% for DAS vs 2/68, 3% for NIL; p=0.77). Hammersmith score was almost identical in the two groups. Complete cytogenetic response (CCyR) was attained in 53/73 (73%) patients not in CCyR at the time of DAS start, and in 31/48 (65%) patients not in CCyR at the time of NIL start (p=0.46). Mean time to CCyR was similar (7.1 months for DAS and 5.3 months for NIL; p=0.30). MMR was achieved in 55/89 (65%) patients not in MMR at the time of DAS start and in 39/61 (65%) patients not in MMR at the time of NIL start (p=0.82). Again, mean time to MMR was not different in the DAS e NIL cohorts (12.4 vs. 8.5 months; p=0.14). DMR was obtained in 39/88 (44%) patients not in DMR at the time of DAS start and in 30/65 (46%) patients not in DMR at the time of NIL start (p=0.95). Sustained DMR was evaluable in 127 patients: 37 patients (29%) achieved sustained DMR, without difference between DAS (24/82, 29%) and NIL (13/45, 29%; p=1.00). With a median follow-up of 44 months (range 1-124), 5-year TTF was similar for DAS (65%, 95%CI 52-75%) and NIL (61%, 95%CI 43-74%; p=0.40) [Figure 1a]. Thirty-two of 95 patients (34%) stopped DAS due to toxicity (19/32, 59%), resistance (11/32, 31%) or other causes (3/32, 10%); 22/68 patients (32%) interrupted NIL for toxicity (11/22, 50%), resistance (8/22, 36%) or other causes (3/22, 14%). Probability of survival and progression were almost identical, with a 5-year PFS of 84% (95%CI 68-89%) for DAS and 92% (95%CI 79-97%) for NIL (p=0.27) [Figure 1b] and a 5-year OS of 89% (95%CI 78-95%) and 96% (95%CI 85-99%) (p=0.31), respectively. Conclusions. With the limits of a retrospective analysis, our data suggest similar efficacy of DAS and NIL after IM failure in CP-CML, with rates of cytogenetic and molecular responses higher than those previously reported and excellent long-term survival. Around 30% achieved sustained DMR with second-line therapy, thus being potentially candidate for TKI discontinuation. Disclosures Tiribelli: Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau. Bonifacio:Ariad Pharmaceuticals: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Amgen: Consultancy. Fanin:Novartis: Speakers Bureau.

Description: Background: Response to ruxolitinib (RUX), the only JAK1/2 inhibitor commercially available for the treatment of Myelofibrosis (MF) may vary among patients (pts) and is largely unpredictable at therapy start. Therefore, pts' selection is based only on clinical needs. Aims: To evaluate the impact of pre-treatment clinical/laboratory factors, as well as RUX dose, on response to RUX in a cohort of "real-life" MF pts. Methods: A multicenter observational study on WHO-defined MF was conducted in 18 Italian Hematology Centers. Data were extracted from a database that included retrospective data on pts treated before January 2015. Subsequently, data were prospectively collected and updated at a 6-month interval.Response to RUX was evaluated according to IWG-MRT criteria. Results: Between June 2011 and Apr 2016, 408 pts with PMF (54.4%), or postET (27.7%) / post-PV (17.9%) were treated with RUX. At RUX start, baseline characteristics were (median): age, 68.5 y (range, 26.5-89); ≥65 y, 63.5%; male, 56.4%; hemoglobin (Hb), 10.7 g/dL (7-16.7); transfusion-dependence 27.9%; PLT, 256×109/L (50-1887); PLT 20 (HR: 6.7, 95%CI 3.2-13.8, p