Frontline Tyrosine Kinase Inhibitors Research Articles

Chronic myeloid leukemia: 2022 update on diagnosis, therapy, and monitoring.

Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100 000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults. CML is characterized by a balanced genetic translocation, t (9;22) (q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR::ABL1 fusion oncogene, which in turn translates into a BCR::ABL1 oncoprotein. Four tyrosine kinase inhibitors (TKIs), imatinib, dasatinib, bosutinib, and nilotinib are approved by the United States Food and Drug Administration for first-line treatment of newly diagnosed CML in chronic phase (CML-CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses but had no impact on survival prolongation, likely because of the availability of effective TKIs salvage therapies for patients who have a cytogenetic relapse with frontline TKI therapy. For CML post failure on frontline therapy, second-line options include second and third generation TKIs. Although potent and selective, these TKIs exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities, disease stage, and BCR::ABL1 mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib, asciminib, and olverembatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP and failure (due to resistance) of at least two TKIs, and for all patients in advanced phase disease. Older patients who have a cytogenetic relapse post failure on all TKIs can maintain long-term survival if they continue a daily most effective/least toxic TKI, with or without the addition of non-TKI anti-CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine, busulfan and others).

Treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML) following the discontinuation of tyrosine kinase inhibitors.

7050 Background: Tyrosine kinase inhibitors (TKIs) discontinuation in patients (pts) with CML is increasingly considered. We evaluated the outcome of pts with CML who discontinued TKIs and determined the factors associated with differences in the success rates of TFR. Methods: We reviewed data from 284 pts with CML treated with TKIs at our institution between October 1999 and February 2017 and who subsequently discontinued therapy. Major molecular response (MMR) was defined as a BCR-ABL1/ABL1 transcripts ratio ≤0.1% as determined by real time (RT)-PCR, MR4 as a ratio ≤0.01% IS, and MR4.5 as a ratio ≤0.0032%. TFR failure was defined as the loss of MMR on any single test. We analyzed TFR rates according to duration and depth of response and conducted a multivariate analysis for factors associated with loss of MMR. Results: Median age was 63 years (range, 25-93). 199 pts (70%) had electively discontinued their TKI while 70 pts (24%) stopped therapy because of adverse events. 92 pts (32%) had switched ≥1 TKI prior to discontinuation due to drug intolerance or resistance. The median time from the initiation of frontline TKI to discontinuation was 117 months (range, 16-242). The median duration of MR4 and MR4.5 before TKI discontinuation was 74 months (range, 2-207) and 64 months (range, 0-207), respectively. At a median follow-up of 36 months (95% CI, 32-40) after TKI discontinuation, 53 pts (19%) lost MMR, translating into a 5-year TFR rate of 79%. 50 pts (94%) resumed TKI therapy and, among 47 evaluable pts, all but one pt regained MMR, with 41 pts (88%) achieving MR4.5. The estimated 5-year TFR rates were 91%, 76% and 70% in pts achieving MR4.5 for ≥6 years, between 5 and 6 years, and < 5 years, respectively (P < 0.0001). The estimated 5-year TFR rates were higher with MR4 and MR4.5 ≥5 years, compared with MR4 < 5 years (87% vs 92% vs 64%; P < 0.0001). Pts who remained on their frontline TKI at the time of discontinuation had a 5-year TFR rate of 82%, compared with 75% and 72% among pts who switched to a second line TKI or beyond because of intolerance or resistance, respectively (P = 0.417). TFR rates did not vary according to the type of frontline TKI used (P = 0.761). By multivariate analysis, only durations in MR4 or MR4.5 ≥5 years before stopping treatment were associated with a lower risk of loss of MMR, with hazard ratios of 0.37 (95% CI, 0.18-0.76; P = 0.007) and 0.20 (95% CI, 0.09-0.45; P < 0.0001), respectively. We evaluated the impact of the frequency of molecular monitoring on the success rate of TFR. The estimated 5-year TFR rate was 79% for pts monitored monthly compared with 85% for pts monitored every 6-8 weeks following discontinuation (P = 0.263). Conclusions: Our findings suggest that achieving MR4 for ≥5 years was associated with a very high probability of maintaining TFR, and that less frequent molecular monitoring could be more cost-effective without any negative impact on outcomes.

Pro-Inflammatory and Pro-Oxidative Changes During Nilotinib Treatment in CML Patients: Results of a Prospective Multicenter Front-Line TKIs Study (KIARO Study).

Tyrosine kinase inhibitors (TKI) may offer a normal life expectancy to Chronic Myeloid Leukemia (CML) patients. However, a higher than expected incidence of arterial occlusive events (AOEs) was observed during treatment with nilotinib. We previously showed an “inflammatory status” during nilotinib that may explain the increased incidence of AOEs. Thus, we conducted this prospective KIARO study involving 186 CML patients (89 imatinib, 59 nilotinib, 38 dasatinib). Interleukin 6 (IL6), interleukin 10 (IL10), Tumor Necrosis Factor-α (TNFα), oxLDL, and high-sensitivity C-reactive protein (hs-CRP) plasma levels were measured at diagnosis and during treatment, with the aim to investigate changes in the inflammatory status favoring AOEs of each patient. Clinical and biochemical pro-atherothrombotic profiles and the 10-year SCORE chart were also evaluated. We showed a pro-inflammatory/pro-oxidative milieu increasing along treatment with nilotinib compared with imatinib or dasatinib, as demonstrated by higher hs-CRP and oxLDL levels and increased IL6/IL10 and TNFα/IL10 ratios only in nilotinib cohort. After median follow-up of 23.3 months starting from TKI, 10/186 patients (5.4%) suffered an AOE. Approximately 5/10 (50%) AOEs occurred during nilotinib treatment despite a lower 10-year SCORE and a lower median age in this subgroup. A longer follow-up is needed to further confirm the active role of nilotinib in AOEs pathogenesis.

Choice of Frontline Tyrosine-Kinase Inhibitor in Very Elderly Patients with Chronic Myeloid Leukemia: A “Campus CML” Study

Introduction Treatment of chronic phase (CP) chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) proved to be almost equally effective in young and elderly patients. Three TKIs, imatinib (IM), dasatinib (DAS) and nilotinib (NIL), are approved for frontline therapy in Italy. Choice of frontline TKI is based on a combined evaluation of patient's characteristics and expectations, with age usually playing a prominent role. However, to date, few data are available on patterns of TKI selection in very elderly patients.Aim To analyse the use of frontline TKI therapy in a large and unselected cohort of very elderly CP-CML patientsMethods We retrospectively evaluated 332 patients aged ≥75 year diagnosed from 1/2012 to 12/2019 at 36 Hematology Centres participating at the “Campus CML” project.Results Clinical features at diagnosis for the whole cohort and according to frontline TKI are reported in Table 1. As to frontline TKI, 285 patients (85.8%) received IM and 47 (14.2%) a 2G-TKI (DAS n=28, 59.5%; NIL n=19, 40.5%). Of the 285 IM-treated patients, 192 (67.3%) started with standard dose (400 mg/day) and 93 (32.7%) with a reduced dose (300 mg/day n=64, 22.5%; <300 mg/day n=29, 10.2%). Among the 47 patients starting a 2G-TKIs, 35 (74.4%) received standard dose and 12 (25.6%) a reduced dose (NIL <600 mg/day n=3; DAS 80 mg/day n=4 and 50 mg/day n=5). There were no differences between patients treated with imatinib or 2G-TKI (Table 1); only a previous cerebrovascular event was reported in a significantly higher rate of IM-treated patients. It is however evident that the distinct toxicity profiles of NIL and DAS had an impact on TKI choice as, for example, no patient with diabetes or ischemic heart disease received NIL.Following widespread introduction of generic IM in Italy in early 2018, patients were divided in 2 groups: among 238 patients diagnosed from 2012 to 2017, 198 (83.1%) received IM and 40 (16.9%) a 2G-TKI, while patients diagnosed in 2018-2019 were treated with IM in 87/94 (92.5%) cases and with a 2G-TKI in 7 (7.5%) cases only (p=0.028).Conclusions IM remains the frontline drug of choice in very elderly CML patients, and this trend seems to increase after the introduction of the generic formulation. However, 2G-TKI are used in a small but sizeable group of patients, without a clear correlation with baseline CML features, thus probably reflecting a physician's evaluation of patient's fitness and/or expectation. Efficacy and safety of initial reduced TKIs doses in the setting of very elderly patients warrant further analyses. [Display omitted] DisclosuresLatagliata: Novartis: Honoraria; BMS Cellgene: Honoraria; Pfizer: Honoraria. Bonifacio: Novartis: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Elena: CELGENE: Other: funding for meeting participation; PFIZER: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees. Iurlo: Novartis: Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Stagno: Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; InCyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding. Abruzzese: Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Breccia: Bristol Myers Squibb/Celgene: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria; Novartis: Honoraria.

Analysis of Early Events during the First Year of Tyrosine Kinase Inhibitor Therapy in Patients with Chronic Phase - Chronic Myeloid Leukemia: A “Campus CML” Study

Background Tyrosine kinase inhibitors (TKIs) revolutionized treatment of chronic myeloid leukemia (CML). However, the first months of therapy are crucial, as optimal response is defined as the achievement of molecular milestones at 3, 6 and 12 months (mo.) and as many toxicities, also causing a TKI switch, are more frequent in the 1st year.Methods To evaluate achievement of early molecular response (MR) and incidence of events leading to a TKI change during the 1st year of therapy, we retrospectively studied 1650 CP-CML patients diagnosed from 2012 and 2019 at 31 Hematology Centres and treated with frontline imatinib (IM) or second-generation (2G) TKIs dasatinib or nilotinib. Optimal MR at 3, 6 and 12 mo. were assessed according to 2020 ELN recommendations.Results Frontline TKI was IM in 926 (56.1%) and 2G-TKIs in 724 (43.9%) cases: the main clinical features at diagnosis of the entire cohort and according to frontline treatment is reported in the Table 1. Commonest comorbidities were arterial hypertension (38.7%), previous neoplasm (13.6%), diabetes (11.3%), peripheral vascular diseases (7.8%), COPD (7.5%) and ischemic heart disease (6.8%). IM-treated patients were older (p<0.001), with higher ELTS score (int/high 47.6% vs 35.6%, p<0.001) and more comorbidities (p<0.005 for all diseases).Optimal MR was achieved at 3 mo. by 1186/1430 (82.9%), at 6 mo. by 1025/1352 (75.8%) and at 12 mo. by 826/1264 patients (65.3%), respectively.Total number of patients discontinuing TKI in the 1st year was 321/1650 (19.4%), being higher with IM (237/926, 25.5%) than 2G-TKIs (84/724, 11.6%) (p<0.001). Main causes were primary resistance (8.7%, 12.3% IM vs 4.2% 2G-TKIs, p<0.001), extra-hematologic toxicity (6.4%, 8.2% IM vs 4.2% 2G-TKIs, p>0.001), hematologic toxicity (1.7%, 2.0% IM vs 1.4% 2G-TKIs, p=0.25) and progression (1.0%, 1.2% IM vs 0.8% 2G-TKIs, p=0.56). Cumulative incidence of discontinuation at 3, 6 and 12 mo. were 5.6%, 10.7% and 19.3%, respectively; values for IM and 2G-TKIs at the three timepoints were 8.1%, 15.0%, 25.5% and 2.5%, 5.3%, 11.5% (p<0.001) (Fig. 1).Conclusions This real-world study on over 1600 CML patients shows that almost 20% discontinue frontline TKI during the 1st year, mostly for primary resistance or toxicity. Discontinuation rates are higher with IM compared to 2G-TKIs, mostly at 3 mo. and are probably due to a lower attainment of early MR. The impact of older age, higher risks and heavier burden of comorbidities in IM patients should be considered and need deeper investigation. [Display omitted] DisclosuresElena: GILEAD: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; CELGENE: Other: funding for meeting participation. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Stagno: InCyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding. Iurlo: Pfizer: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Bonifacio: Novartis: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Breccia: Pfizer: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Novartis: Honoraria. Latagliata: Novartis: Honoraria; Pfizer: Honoraria; BMS Cellgene: Honoraria.

Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Following the Discontinuation of Tyrosine Kinase Inhibitors

Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Following the Discontinuation of Tyrosine Kinase Inhibitors

Pro-Inflammatory and Pro-Oxidative Changes during Nilotinib Treatment in CML Patients: Results of a Prospective Multicenter Front-Line TKIs Study (KIARO Study)

Background: Tyrosine kinase inhibitors (TKI) may offer a normal life expectancy to Chronic Myeloid Leukemia (CML) patients. However, during treatment with nilotinib, a higher than expected incidence of arterial occlusive events (AOEs) was observed. We retrospectively showed an “inflammatory status” during nilotinib treatment that may explain this increased incidence of AOEs. Here, we report results of a prospective multicenter (KIARO) study including 186 CML patients (89 imatinib, 59 nilotinib, 38 dasatinib) in which pro/anti-inflammatory cytokines were measured at diagnosis and during treatment, with the aim to investigate potential changes in each patient's inflammatory status possibly favoring AOEs.Aims: The aims of this study are: 1) to analyze prospectively inflammation status during TKI treatment; 2) to record AOEs; 3) to calculate the SCORE and evaluate its predictive role for AOEs; 4) to analyze possible associations of AOEs with altered inflammation status.Methods: Inflammatory status was evaluated by measuring IL6, IL10, TNFα, oxLDL and hs-CRP plasma levels at diagnosis and during treatment (+1, +3, +6, +12 months); additionally, clinical and biochemical pro-atherothrombotic profiles and the 10-year SCORE chart were also evaluated.Results: 186 newly-diagnosed CML patients starting either imatinib, nilotinib or dasatinib treatment, entered this study. Regarding the inflammation status, we observed that TNFα and IL6 levels were high at diagnosis and decreased during the first 12 months of treatment regardless the type of TKI; instead, IL10 levels were comparable among the 3 TKI cohorts at baseline, but showed a remarkably different evolution during treatment. In fact, IL10 levels were significantly higher after 6 and 12 months of imatinib (p=0.012 and p=0.009, respectively) and dasatinib (p=0.032 and p=0.014, respectively) compared to nilotinib. Consequently, TNFα/IL10 ratio was significantly higher in nilotinib cohort at 6 and 12 months respect to imatinib (p=0.044 at 6 months and p=0.041 at 12 months) and dasatinib (p=0.040 at 6 months and p=0.044 at 12 months). As well, IL6/IL10 ratio was significantly higher in nilotinib cohort compared to imatinib and dasatinib both at 6 (p=0.042 and p=0.049, respectively) and 12 months (p=0.040 and p=0.041, respectively) (Figure 1). OxLDL levels were similar in the 3 groups for the first 6 months. At 12 months we detected a significant increase of oxLDL levels in the nilotinib cohort (p=0.041), respect to imatinib and dasatinib. We did not find significant differences in hs-CRP levels across the 3 TKIs, although a trend for higher levels was observed in nilotinib cohort. Overall, these results suggest a TKI-driven pro-inflammatory status in nilotinib treated patients.After a median follow-up of 23.3 months of TKI treatment, 10 patients (5.4%) suffered an AOE, specifically: 6 ACS, 2 PAOD, 1 TIA and 1 stroke. 5 events (50%) occurred in patients treated with nilotinib, either in first line (4 patients) or in third line (1 patient, after failure following brief treatment with imatinib and dasatinib). In this subgroup of 10 patients experiencing an AOE, we observed a trend of increased IL6 and TNFα median values both at diagnosis and at each time point, compared with the remaining no-AOE patients. IL10 and oxLDL had similar median concentrations in both AOE and no-AOE cohorts, except for oxLDL at 12 months which resulted higher in patients who experienced AOEs. Moreover, regarding AOEs, nilotinib treatment showed a 3.1 times increased risk compared to other TKIs (HR 3.1, 95% CI 2.6-4.4 p< 0.001), whereas 10-year SCORE was not predictive in the whole cohort (HR 0.6, 95% CI 0.33-0.94 p= 0.094) or in any subgroup (imatinib HR 0.8, 95% CI 0.49-1.03 p= 0.067; nilotinib HR 0.4, 95% CI 0.29-0.76 p= 0.112, dasatinib HR 0.6, 95% CI 0.37-0.92 p= 0.082).Conclusions: Our results showed a pro-inflammatory/oxidative milieu increasing along treatment with nilotinib compared with imatinib or dasatinib, as demonstrated by higher IL6/IL10 and TNFα/IL10 ratios, higher levels of oxLDL and a trend for higher hs-CRP only in nilotinib cohort. However, due to the low number of observed events, a formal statistical analysis for any association between AOEs and pro/anti-inflammatory cytokines levels was not possible. Therefore, a longer follow-up is needed to further confirm the active role of nilotinib in AOEs pathogenesis. [Display omitted] DisclosuresAbruzzese: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Galimberti: Incyte: Speakers Bureau; AbbVie, Janssen: Honoraria, Other: Travel grants. Stagno: Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; InCyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding.

Hemoglobin Changes during Long-Lasting Frontline Treatment with Tyrosine-Kinase Inhibitors in Patients with Chronic Myeloid Leukemia

Introduction Chronic Myeloid Leukemia (CML) has become highly curable after introduction of Tyrosine-Kinase Inhibitors (TKIs). However, several side-effects have been reported with the prolonged use of TKIs: in particular, severe cardiovascular and pulmonary toxicities were observed with 2 nd generation TKIs (2G-TKIs), nilotinib and dasatinib. Imatinib is generally considered safer, even if some concerns were recently raised on its renal toxicity and occurrence of late anemia.Aims To evaluate the impact of imatinib compared to 2G-TKIs on the hemoglobin (Hb) levels in the long-lasting frontline treatment of CML patients.Methods From 1/2002 to 12/2015, 365 CML patients were diagnosed and treated frontline with TKIs in 2 different Centres in Italy: of them, 123 permanently discontinued the treatment before the 5 th year from the start due to intolerance (31 cases, 25.2%), primary resistance (41, 33.3%), secondary resistance (16, 13.0%), blastic evolution (4, 3.2%), unrelated death (12, 9.8%) or were lost to follow-up (19, 15.5%). At 5 years, the remaining 242 patients were still receiving frontline TKI treatment and were considered for the present analysis. Hb levels were recorded at baseline and thereafter every 12 months up to the 5 th year of treatment.Results As to frontline treatment, 186 patients (76.8%) received imatinib and 56 (23.2%) 2G-TKIs (nilotinib in 44 cases and dasatinib in 12, respectively). The main clinical features at diagnosis of the entire cohort and according to frontline treatment are reported in the table: median Hb value at baseline was significantly lower in patients treated with 2G-TKIs. Median Hb values at different time-points according to frontline treatment are reported in the Figure. In patients treated with imatinib, median Hb levels at 12 th (12.5 g/dl, IQR 11.6-13.5) and 60 th month (12.4 g/dl, IQR 11.4-13.3) were stable compared to baseline (12.8 g/dl, IQR 11.3-13.8) (p=0.248 and p=0.075, respectively). On the contrary, median Hb levels at 12 th (13.4 g/dl, IQR 12.2-14.3) and 60 th month (13.6 g/dl, IQR 12.0-14.6) showed a significant increase compared to baseline (11.8 g/dl, IQR 10.6-13.7) in patients treated with 2G-TKIs (p<0.001 in both cases). As a consequence, during the treatment median Hb values became significantly higher at any different time-point in patients treated with 2G-TKIs compared to patients treated with imatinib (p=0.005 at the 12 th month, p=0.010 at the 60 th month). At baseline, the rate of patients with mild to moderate anemia (Hb < 11 g/dl) was significantly lower in those treated with imatinib [34/186 (18.2%) vs 20/56 (35.7%) treated with 2G-TKIs, p=0.006]: at the 12 th month, no difference was observed [15/186 (8.0%) in patients treated with imatinib vs 3/56 (5.3%) in patients treated with 2G-TKIs, p=0.498], while at the 60 th months the rate of patients with mild to moderate anemia became significantly higher in those treated with imatinib [29/186 (15.6%) vs 2/56 (3.6%) treated with 2G-TKI, p=0.018].Conclusions Present data highlight that long-lasting treatment with imatinib can have a negative late effect on erythropoiesis, with incomplete recovery of hemoglobin levels and occurrence of late anemia in about 15% of patients at the 60 th month of therapy.This possible adverse event, which is still unrecognized and seems very rare with 2G-TKIs, could affect quality of life and should be recognized in the long-term management of CML patients. [Display omitted] DisclosuresLatagliata: BMS Cellgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Martelli: Novartis: Other: advisory board; Gilead: Other: advisory board. Breccia: Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Abbvie: Honoraria.

Impact of Tumor Suppressor Gene Co-Mutations on Differential Response to EGFR TKI Therapy in EGFR L858R and Exon 19 Deletion Lung Cancer

BackgroundIn most studies, patients with EGFR L858R mutant non-small cell lung cancer (NSCLC) have a shorter duration of response to EGFR tyrosine kinase inhibitor (TKI) therapy than do patients with EGFR exon 19 deletion NSCLC. The role that co-mutations play in this observation is unknown. MethodsWe performed a single-institution retrospective analysis of patients with EGFR-mutant NSCLC (exon 19 deletion or L858R mutation) who received frontline EGFR TKI for metastatic disease between 2014 and 2019, and who had STAMP next-generation sequencing (NGS), a 130-gene platform. Time to treatment failure (TTF) and overall survival were calculated using Cox models adjusted for age, race, and brain metastases. Co-mutations in key tumor suppressor genes (TP53, RB1, KEAP1, CDKN2A, or CTNNB1) were identified and their effects on outcomes were evaluated. Analyses were stratified according to receipt of osimertinib versus nonosimertinib as frontline EGFR TKI. ResultsOf 137 patients, 72 (57%) had EGFR exon 19 deletions and 65 (43%) had EGFR L858R mutations. Median TTF and OS on frontline TKI was shorter for the L858R cohort versus the exon 19 deletion cohort in univariate analysis. In adjusted models, this difference persisted for TTF but was no longer significant for OS. The difference in TTF in L858R mutant tumors was driven by the presence of co-mutations in key tumor suppressor genes. ConclusionPatients with metastatic NSCLC with mutations in EGFR L858R had shorter TTF on frontline TKI compared to patients with EGFR exon 19 deletions. Co-mutations in tumor suppressor genes may play an important role in the differential response to TKI therapy.

Philadelphia-positive B-lymphoblastic leukemia in a middle-income country – A real-world multicenter cohort

Outside of clinical trials, few studies have addressed the outcomes of Ph+ acute lymphoblastic leukemia (ALL) in adults, especially from developing world. In this study, we conducted a multicenter analysis on the outcomes of patients aged > 15 years with Ph+ ALL, aiming to get to know an overview of the Brazilian experience as well as to explore baseline factors associated with relapse and mortality in our setting. Over these 10 years, patients were treated with diverse protocols, all of them always combined with a frontline tyrosine-kinase inhibitor. A total of 123 Ph+ ALL patients was included. Imatinib was the first line TKI in 97 %. The complete response rate was 79 %. The early death rate was 15 %, being associated with increasing age at diagnosis (p = 0.06). The use of intensive versus attenuated induction regimen was not associated with higher induction mortality (p = 0.99). Overall, 29 % of patients aged ≤ 60 years underwent allogeneic transplantation, 87 % in first CR. 4-year overall survival (OS) and relapse-free survival were 25 % and 24 %, respectively. The incidence of relapse (death as a competitor) was 29 %, while the non-relapse mortality was 42 %. Only age was independently associated with OS, and lactate dehydrogenase level and central nervous disease at diagnosis were related to relapse in our cohort. This is the first historical cohort multicenter study on Ph+ ALL from Brazil. Reporting these outcomes is essential to encourage public policies to expand access to new drugs and transplantation in middle-income countries.

Comparison of the Outcome between Newly Diagnosed Patients in the Accelerated Phase and Chronic Phase with Chronic Myeloid Leukemia Treated with Frontline Tyrosine Kinase Inhibitors

Background: Accelerated phase (AP) chronic myeloid leukemia (CML) has an aggressive clinical course. Some patients with CML present as AP at the time of diagnosis. Although many studies have confirmed that tyrosine kinase inhibitors (TKIs) significantly improved survival in patients with CML in the chronic phase (CP), there is limited data on the outcome of newly diagnosed CML-AP patients in the era of TKIs.Aims: To compare progression-free survival and overall survival in CML-AP patients with those in CML-CP patients treated with frontline TKIs and identify factors associated with the outcome.Methods: According to the definition of European LeukemiaNet 2013, data of newly diagnosed CML-AP and CML-CP patients receiving TKIs at least 3 months from 2002 to 2016 were retrospectively analyzed. Kaplan-Meier curves were used to compare the probabilities of PFS and OS. Uni- and multivariate Cox regression models were built to identify independent variables (demographics; co-morbidity; disease phase and risk, CBC, and additional cytogenetic aberrations in Ph-positive cells at diagnosis; interval from diagnosis to start TKI-therapy; initial TKI used and early treatment-response) associated with the outcome.Results: In total, 101 CML-AP patients [with excess blasts (blasts ≥15%), n=13; with excess basophils (basophils ≥20%), n=88] and 656 CML-CP patients (Sokal low-risk, n=291; intermediate-risk, n=194; high-risk, n=111; unknown, n=60) were included. 463 (61%) were male. Median age was 39 (14-87) years. Patients received initial therapy with imatinib (n=660), nilotinib (n=85), or dasatinib (n=11) within 6 months from diagnosis. At 3 months, CML-AP patients with excess blasts (62%, 15% and 23%) and excess basophils (65%, 27% and 8%) achieved similar response (optimal, warning and failure) rates to CML-CP patients in Sokal intermediate-risk (66%, 20% and 14%) and high-risk (58%, 26% and 16%) (p=0.338), but significantly lower than those in Sokal low-risk (83%, 13% and 4%) and unknown (77%, 17% and 7%) (p<0.001). With a median follow-up of 39 months (range, 3-184 months), probabilities of PFS (p=0.014) and OS (p=0.152) at 5 years were the lowest in the CML-AP patients with excess blasts (78% and 92%), followed by CML-CP patients in Sokal high-risk (87% and 91%), intermediate-risk (92% and 95%), low-risk (95% and 97%), CML-AP patients with excess basophils (95% and 97%), and those with unknown-risk (96% and 98%). In multivariate analyses, while analyzing baseline and initial therapy variables, interval from diagnosis to starting TKI-therapy >2 months [HR 2.4 (1.1-4.9), p=0.020 and HR 2.6 (1.1-6.5), p=0.037) was associated with inferior PFS and OS; in addition, CML-CP patients in Sokal high-risk [HR 3.6 (1.1-6.5), p=0.038] was associated with inferior PFS, >60 years [HR 3.9 (1.2-13.3), p=0.027], inferior OS. While involving early therapy response, interval from diagnosis to starting TKI-therapy >2 months [HR 3.1 (1.4-6.6), p=0.009 and HR 3.2 (1.2-8.4), p=0.016] and achieving a response of “failure” at 3 months [HR 7.6 (3.7-15.6), p<0.001 and HR 8.1 (3.1-21.3), p<0.001] were variables associated with inferior PFS and OS; in addition, >60 years [HR 4.8 (1.4-16.1), p=0.010], inferior OS. There was no impact of initial TKI used (imatinib or 2nd generation TKI) on the outcome.Conclusions: Newly diagnosed CML-AP patients have comparable outcome to CML-CP patients treated with frontline TKIs, especially CML-AP patients with excess basophils. However, delayed therapy and poor early response to TKIs are significantly associated with unfavorable prognosis in either AP or CP patients with CML. Our data indicates timely and proper TKI-therapy and close monitoring will be a reasonable option for the treatment strategy in CML-AP patients in the era of TKIs. DisclosuresNo relevant conflicts of interest to declare.

Long-Term Outcome of CML Patients Treated with Second-Generation Tyrosine Kinase Inhibitors in the Second Line: A Single Center Experience

Background: Since the introduction of tyrosine kinase inhibitors (TKI), most patients (pts) with chronic myeloid leukemia (CML) have a favorable outcome with their initial therapy. However, some pts experience resistance or intolerance. Second generation TKI dasatinib, nilotinib and bosutinib are effective (and approved) for pts with failure to one prior TKI. In the absence of specific mutations or patient comorbidities driving the selection of a specific TKI, selecting the next TKI remains at the physician discretion, especially in the lack of randomized data comparing 2nd generation TKI. Methods: We analyzed the outcomes of 621 consecutive patients with CML treated at a single institution with 2nd generation TKI in the 2nd line following failure of frontline TKI. For this analysis we focused on the 572 pts that received dasatinib, nilotinib or bosutinib as 2nd line TKI (not including 49 pts treated with ponatinib, imatinib or investigational TKI). Results: The median age at diagnosis was 47 years (range, 12-86) and 49% were male. 516 pts received TKI as frontline treatment and 105 had other therapies (interferon, chemotherapy) prior to TKI. Pts were switched to a 2nd generation TKI for resistance (n=337; 54%) or intolerance (n= 279; 45%). The median time from diagnosis to start of 2nd line TKI was 32 mo (0 to 206 mo). Dasatinib, nilotinib and bosutinib were used as 2nd line TKI in 338 (54%), 194 (31%), and 40 (6%) pts, respectively. Overall, out of 572 pts who received one of these three TKIs, 401 had cytogenetic evaluation of which 323 (81%) achieved major cytogenetic response (34 (8%) partial (PCyR) and 289 (72%) complete (CCyR)). Out of 428 who had a molecular evaluation, 75% achieved molecular response (94 (18%) MMR, 52 (6%) MR4, 217 (51%) MR4.5). The rates of major cytogenetic response (MCyR) were, with dasatinib 85% (76% CCyR), nilotinib 76% (70% CCyR), and bosutinib 67% (50% CCyR) (p=0.015). Rates of molecular response (MMR or better) were with dasatinib 72% (55% MR4.5), nilotinib 65% (46% MR4.5), and bosutinib 55% (39% MR4.5), (p=0.07). At a median follow-up from diagnosis of 96 mo (range, 4-283), 39 (7%) pts transformed either to accelerated (n=26, 5%) or to blast phase (n=13, 2%) while on 2nd line TKI. Median overall survival (OS) and transformation-free survival (TFS) were not reached and the median event-free survival (EFS) was 121 mo. Seven-year probabilities of OS, TFS and EFS were 66%, 91% and 55%, respectively. Higher OS, TFS, and EFS were found in patients who received frontline TKI (7-yr 70%, 92% and 59%, respectively) vs those who failed another treatment prior to any TKI (49%, 83%, and 38%, respectively) (p Conclusion: This analysis shows that dasatinib, nilotinib and bosutinib remain largely effective in inducing cytogenetic and molecular response when used as a 2nd line TKI with similar OS, TFS and EFS in the overall pts population. A multivariate analysis to identify predictors of long-term outcome, including specific TKI as a variable, is ongoing. Disclosures Kantarjian: Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Delta-Fly Pharma: Research Funding; Pfizer: Research Funding. DiNardo: Daiichi-Sankyo: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Daver: Bristol-Myers Squibb Company: Consultancy, Research Funding; Incyte Corporation: Honoraria, Research Funding; Pfizer Inc.: Consultancy, Research Funding; Jazz: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy; Immunogen: Research Funding; Kiromic: Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Daiichi-Sankyo: Research Funding; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding. Pemmaraju: Incyte Corporation: Consultancy, Honoraria; cellectis: Research Funding; novartis: Consultancy, Honoraria, Research Funding; abbvie: Research Funding; roche diagnostics: Consultancy, Honoraria; affymetrix: Research Funding; LFB: Consultancy, Honoraria; stemline: Consultancy, Honoraria, Research Funding. Burger: Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Jabbour: Bristol-Myers Squibb: Consultancy. Cortes: Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Sun Pharma: Research Funding; Teva: Research Funding.

Real-world utilization of EGFR TKIs and prognostic factors for survival in EGFR-mutated non-small cell lung cancer patients with brain metastases.

Brain metastases (BMs) cause morbidity and mortality in patients with non-small cell lung cancer (NSCLC). The optimal management of epidermal growth factor receptor (EGFR)-mutated NSCLC with BM is debatable. We aimed to investigate the impact of different treatments among patients with EGFR-mutated NSCLC. A cohort of 2058 lung cancer patients with BM between 2013 and 2018 was retrospectively studied. A total of 571 patients with EGFR-mutated NSCLC and BM were enrolled. All patients had received EGFR tyrosine kinase inhibitors (TKIs). Overall survival (OS) was measured from the diagnosis of BM to death or last follow-up. With a median follow-up of 35.2months (95% confidence interval [CI], 31.8-38.6), the median survival after BM was 21.3months (95% CI, 19.0-23.6). Osimertinib resulted in significantly superior survival after resistance to front-line TKIs (P < 0.0035); the median OS reached 28.0months (95% CI, 23.0-32.9), and the T790M status showed no difference in clinical effectiveness (P=0.386). The combination of TKIs and chemotherapy/vascular endothelial growth factor (VEGF) inhibitors (anti-VEGF) tended to have longer OS (P=0.271). Intracranial local radiotherapy significantly improved survival (P=0.0008). In multivariable analysis, we noted that age, Karnofsky performance score, EGFR mutation type, number of BMs and the presence of extracranial metastasis were independent pretreatment prognostic factors. In conclusion, EGFR TKIs have a significant effect on patients with EGFR-mutant BM, and the application of osimertinib further improves survival outcomes regardless of T790M status. Patients who undergo intracranial local therapy can achieve a survival benefit.

Relevance of treatment-free remission recommendations in chronic phase chronic leukemia patients treated with frontline tyrosine kinase inhibitors.

BackgroundTyrosine kinase inhibitors (TKI) can be safely discontinued in chronic phase chronic myeloid leukemia (CP‐CML) patients who had achieved a sustained deep molecular response. Based on the results of discontinuation trials, recommendations regarding patient selection for a treatment‐free remission (TFR) attempt had been proposed. The aims of this study were to evaluate the rate of patients eligible for TKI discontinuation and molecular recurrence‐free survival (MRFS) after stop according to recommendations.MethodsOver a 10‐year period, newly diagnosed CP‐CML patients and treated with first‐line TKI in the nine French participating centers were included. Eligibility to treatment discontinuation and MRFS were analyzed and compared according to selection criteria defined by recommendations and first‐line treatments.ResultsFrom January 2006 to December 2015, 398 patients were considered. Among them, 73% and 27% of patients received imatinib or either second or third generation tyrosine kinase inhibitors as frontline treatment, respectively. Considering the selection criteria defined by recommendations, up to 55% of the patients were selected as optimal candidates for treatment discontinuation. Overall 95/398 (24%) discontinued treatment. MRFS was 51.8% [95% CI 41.41–62.19] at 2 years and 43.8% [31.45–56.15] at 5 years. Patients receiving frontline second‐generation TKI and fulfilling the eligibility criteria suggested by recommendations had the lowest probability of molecular relapse after TKI stop when compare to others.ConclusionOne third of CP‐CML patients treated with TKI frontline fulfilled the selection criteria suggested by European LeukemiaNet TFR recommendations. Meeting selection criteria and second‐generation TKI frontline were associated with the highest MRFS.

Current status and novel strategy of CML.

The advent of tyrosine kinase inhibitors (TKIs) has dramatically improved the outcome of patients with chronic myeloid leukemia (CML). Currently, four TKIs are available for the frontline treatment, including the first-generation TKI (imatinib) and the second-generation TKIs (dasatinib, nilotinib, and bosutinib). The second-generation TKIs lead to a faster and deeper molecular response without a survival benefit compared with imatinib. However, the opportunity for the treatment discontinuationand functional cure requires the achievement of durable deep molecular remission. Therefore, the second-generation TKIs should be considered as initial therapy for chronic-phase CML. Switch of therapy is warranted in case of treatment failure, including resistance and/or intolerance. The life expectancy of patients with CML is approaching that of the general population. Given an expected lifespan, future perspectives should consider the strategy for the optimal choice of TKIs, allowing for long-duration of effective TKI therapy with less toxicity to aim for a functional cure. A novel prediction approach such as artificial intelligence-driven analysis on the accumulated data from clinical trials paves a promising path for the personalized recommendation on frontline TKIs and precise survival prediction.

Contemporary practice patterns of tyrosine kinase inhibitor use among older patients with chronic myeloid leukemia in the United States.

Introduction:The choice of BCR-ABL1 tyrosine kinase inhibitors (TKI) for the first line of therapy (LOT) for chronic-phase chronic myeloid leukemia (CML) is tailored to disease risk and patient characteristics like comorbidities, which become more prevalent with age. However, contemporary evaluations of frontline TKI choice and the factors associated with TKI switching in this specific patient population are lacking.Methods:We sought to describe TKI use in older patients (age: 66–99 years) with CML in the United States. Using the Surveillance, Epidemiology, and End Results–Medicare-linked database, we identified 810 older (median age: 75 years, interquartile range: 70–80 years) patients diagnosed during 2007–2015.Results:Imatinib was the most common frontline TKI (63.1%) throughout the study period, but its utilization as such decreased from 76% in 2010 to 47% in 2015. Most patients (65.3%) used only one TKI, but 12.5% of the 281 patients who switched from frontline TKI received ⩾4 LOT. Among the 167 patients switching from frontline imatinib, 18.6% eventually returned to imatinib with nearly all as the third LOT, supporting its favorable safety profile and indicating that the initial switch from imatinib might have been premature. Older patients within our cohort, white patients and those with greater comorbidity were less likely to switch from frontline TKI. Diagnosis year, geographic region, and surrogates for socioeconomic status and healthcare access had no impact on TKI switching.Conclusion:As expected, our findings highlight the frequent use of imatinib as the treatment option for older CML patients despite the availability of second-generation TKIs.

A Phase II study of nab-Paclitaxel (nab-P) in patients with advanced non-small cell lung cancer with EGFR mutations after frontline tyrosine kinase inhibitor therapy

BackgroundPatients with metastatic non-small cell lung cancer (NSCLC) harboring a sensitizing EGFR mutation have effective targeted therapy options initially but most patients eventually progress and receive cytotoxic chemotherapy. In this single-institution phase II study, we evaluated the role of nab-paclitaxel monotherapy in this patient population. Patients and MethodsPatients with metastatic NSCLC with an activating EGFR mutation whose disease progressed after frontline tyrosine kinase inhibitor therapy and who were chemotherapy naïve received nab-paclitaxel 125 mg/m2 on days 1, 8 and 15 in a 28-day cycle. The primary endpoint was response rate per RECIST 1.1 and secondary endpoints were duration of response, progression free survival, toxicity and overall survival. ResultsA total of 27 patients were enrolled and 21 patients were evaluable for response. Median age was 65 (range 52–81), 69% of patients were women, 42% of patients did not having a smoking history. 31% of patients had central nervous system (CNS) metastatic disease at baseline. Confirmed partial response was documented in 9 of 26 patients (35%, 95% CI 17–56) and disease control rate was 58% (95% CI 35–73). CNS was a common first site of progression. Median progression free survival was 4.0 months (95% CI 1.8–5.2). No new safety signals were observed. ConclusionSingle agent nab-paclitaxel showed modest antitumor activity in patients with EGFR mutation positive NSCLC and may be an option in patients who are platinum ineligible. Patients often progressed in the CNS and the results underscores the importance of CNS activity of systemic therapies in this patient population.

Outcomes of Patients with Chronic Myeloid Leukemia Treated with Third-Line Tyrosine Kinase Inhibitors

Outcomes of Patients with Chronic Myeloid Leukemia Treated with Third-Line Tyrosine Kinase Inhibitors

Serological Prevalence of Sars-Cov-2 Infection Among Chronic Myeloid Leukemia Patients Undergoing Tyrosine Kinase Inhibitor Treatment in Italy (COVID-19-HEM Study)

Background. Clinical course of the novel Coronavirus (SARS-CoV-2) Disease 2019 (COVID-19) is extremely heterogeneous, and infected individuals may be asymptomatic or develop acute respiratory manifestations. Elderly people and patients with pre-existing comorbidities, including malignancies, may be at higher risk due to their immunological impairment. On the other hand, still limited evidence suggests that some target drugs used to treat hematological cancers, including tyrosine kinase inhibitors (TKI), may have a direct antiviral action or an indirect immunomodulatory effect on the abnormal inflammatory host response to SARS-CoV-2.Aims. To describe the prevalence of symptomatic and asymptomatic SARS-CoV-2 infection in a cohort of chronic myeloid leukemia (CML) patients.Methods.This is an ongoing prospective study ideated and conducted in the Centers of the regional network Rete Ematologica Veneta (REV). According to the Italian Ministry of Health data as of Jul 22, 2020, prevalence of SARS-CoV-2 infection in Veneto, as documented by molecular test on pharyngeal swab, was 0.4%. For comparison, two other centers from Regions with lower prevalence (Lazio and Friuli-Venezia Giulia) were included. All consecutive CML patients coming to the participating Centers were offered to participate to the study, which was approved by local IRBs. Patients in Treatment Free Remission (TFR) phase (i.e. not taking TKI at the time of pandemic) were included as a control group. After collecting information about risk factors for COVID-19 (travels, work exposure, cohabitation with infected subjects) and respiratory or general symptoms experienced from mid Feb 2020, patients were tested for anti-SARS-CoV-2 IgM and/or IgG antibodies through a immunochromatographic qualitative assay (COVID-19 IgG/IgM Rapid Test Cassette, Menarini Diagnostics, IT; sensitivity IgG 97.2%, IgM 87.9%, specificity IgG/IgM 100%). Patients with positive results underwent a pharyngeal swab for molecular detection of the virus.Results. From May 18 to Jul 29, 2020 a total of 339 patients were enrolled (238 from REV centers and 101 from other centers). Males were 183 (54%), median age was 63.2 (range 26.5-93) years. Median time from CML diagnosis was 8 (range 0.1-29.6) years. The majority of patients were in frontline TKI treatment (n=174, 51.3%), and the remaining were in 2ndline (n=80, 23.6%), 3rdor further line of treatment (n=35, 10.3%), or in TFR (n=50, 14.7%). The type of TKI currently assumed was imatinib (n=134, 39.5%), nilotinib (n=63, 18.6%), dasatinib (n=52, 15.4%), bosutinib (n= 24, 7.1%), ponatinib (n=14, 4.1%) or experimental (n=2, 0.6%). The majority of patients was in major (n=79, 23.3%) or deep molecular response (n=204, 60.2%).Thirteen and 3 patients declared close contact with COVID-19 infected individuals at work and/or at home, respectively. The frequency of newly onset or worsening symptoms during the last months was as follows: anosmia (2.4%), ageusia (2.1%), cough (4.7%), pharyngitis (2.6%), dyspnea (2.4%), fever (3.2%), headache (7.7%), asthenia (13.6%), arthralgia (14.9%), dizziness (6.5%), nausea/vomiting (2.7%), and diarrhea (4.4%).Five patients out of the 238 in the REV cohort (2.1%) had a positive IgG test, and two of them were also IgM-positive. All resulted negative at swab performed after the serological assay. They were 4 males and 1 female, aged between 53 and 72 years. One of them, in treatment with nilotinib, had a symptomatic infection in early March, confirmed at that time by molecular tests, and reported close contact with infected subjects both at work and at home. All the other patients (2 in treatment with imatinib, 1 with nilotinib and 1 with bosutinib) reported no or only mild symptoms and had not performed diagnostic tests for SARS-CoV-2 before. Anosmia, ageusia and fever were the only symptoms significantly associated with anti-SARS-CoV-2 IgG positive test (p<0.001). All the patients from the other two Regions and all the patients in TFR had a negative IgG/IgM test.Conclusions. We reported for the first time the serological prevalence of SARS-CoV-2 infection in CML patients. Serological studies in the general Italian population are ongoing and will be used to make comparisons with our cohort. Prospective enrollment in the present study is ongoing and updated results will be presented at the Meeting.Acknowledgment. This work was supported by Fondazione Cariverona (ENACT Project).DisclosuresSemenzato:Abbvie: Honoraria; Roche: Honoraria; Takeda: Honoraria. Pizzolo:janssen: Speakers Bureau; Abbvie: Speakers Bureau. Krampera:Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

Determinants of Choice of Front-Line Tyrosine Kinase Inhibitor for Chronic Phase CML: A Study from the “Registro Italiano LMC & Campus CML”

Introduction : therapy of chronic phase (CP) chronic myeloid leukemia (CML) is based on tyrosine kinase inhibitors (TKIs) in virtually all patients. Three TKIs are approved for first-line therapy in Italy: imatinib and two second-generation (2G) TKIs, dasatinib and nilotinib. Choice of the front-line TKI is based on a combined evaluation of patient's and disease characteristics, age, risk, comorbidities and concomitant medications. Treating physician's preference and, in some cases, economic considerations, particularly after the advent of generic imatinib, may play a role in TKI selection. However, to date, few data are available on TKI use in a whole nation and on the possible drivers of treatment choice. Aim of the present work was to analyse the use of front-line TKI therapy in a large, unselected cohort of Italian CP-CML patients, correlating patient's features to drug choice. Methods: in the framework of the national Campus CML program, we retrospectively evaluated 1422 patients with CP-CML diagnosed from 2012 and 2019 in 21 haematologic Centres, mostly in academic and/or tertiary hospitals, widespread through the entire Italian territory and treated frontline with imatinib, dasatinib or nilotinib. Results: median age at diagnosis was 59.9 years [interquartile range (IQR) 47.1 - 71.7], with 317 (22.3%) patients under 45 years, 552 (38.8%) between 45 and 65 years and 553 (38.9%) older than 65 years; 821 (57.7%) patients were males. Among 1364 evaluable patients, CML risk according to Sokal score was low in 540 (39.6%), intermediate in 610 (44.7%) and high in 214 (15.7%) patients respectively; the number at low, intermediate or high risk according to the novel ELTS score among 1325 evaluable patients was 759 (57.3%), 402 (30.3%) and 164 (12.4%) respectively. Considering comorbidities, 1003 (70.6%) patients had at least one active disease at the time of CML diagnosis, the most common being hypertension (n=547, 38.5%), previous neoplasms (n=185, 13.0%), diabetes (n=150, 10.6%), chronic bronchopulmonary diseases (n=114, 8.0%), acute myocardial infarction (n=95, 6.7%), previous stroke (n=36, 2.5%) and other vascular diseases (n=98, 6.9%). Among 1335 evaluable patients, 813 (60.9%) were taking at least one concomitant medication, with 280 (21.0%) taking 3-5 drugs and 140 (10.5%) taking 6+ drugs at time of TKI start. As to the frontline therapy, 794 (55.8%) received imatinib and 628 (44.2%) were treated with 2G-TKIs, (226 dasatinib and 402 nilotinib) respectively. According to age, 2G-TKIs were chosen for majority of patients aged &amp;lt;45 (69.1%) while imatinib was used in 76.9% of patients over 65 (p&amp;lt;0.001). There was a predominance of imatinib use across all Sokal (51.1% in low, 61.3% in intermediate and 51.4% in high) and ELTS (50.3% in low, 60.4% in intermediate and 66.5%) risk categories. We observed a prevalent use of 2G-TKIs in patients presenting with higher WBC counts (55.1% if WBC &amp;gt;100,000/mm3 vs 38.2% if WBC &amp;lt;100,000/mm3; p&amp;lt;0.001), lower Hb (53.8% if Hb &amp;lt;10 g/dl vs 41.9 if Hb &amp;gt;10 g/dl; p=0.001) and bigger spleen (65.1% if spleen &amp;gt;5 cm vs 44.8% if spleen 1-5 cm vs 37.3% if spleen not palpable; p&amp;lt;0.001). There was a decreasing use of 2G-TKIs with higher number of concomitant drugs: 64.4% for 0, 47.7% for 1-2, 27.0% for 3-5 and 13.6% for &amp;gt;5 drugs, respectively (p&amp;lt;0.001). Concordantly, there was a significant higher use of imatinib in patients with hypertension (69.8%), diabetes (70.0%), COPD (73.7%), previous neoplasms (73.0%), AMI (86.3%) or stroke (97.2%) history (p&amp;lt;0.001 for all conditions). Lastly, we observed a wider use of imatinib (61.1%) in patients diagnosed in years 2018-19, compared to those of the period 2012-17 (53.7%; p=0.01). In multivariable analysis, factors correlated with imatinib use were age &amp;gt; 45 years, intermediate or high Sokal risk, presence of some comorbidities (2nd neoplasia and stroke) and number of concomitant medications. Conclusions: preliminary results of this observational study on almost 1500 patients show that around 55% of newly diagnosed Italian CP-CML patients receive imatinib as front-line therapy, and that the use of 2G-TKI is prevalent in the younger patients and in those with no concomitant clinical conditions. The counterintuitive finding of imatinib prevalence as frontline treatment in high risk patients might be explained by the older age of these patients. Introduction of the generic formulation in 2018 seems to have fostered the use of imatinib. Figure Disclosures Breccia: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria. Cavazzini:Pfize: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Saglio:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Roche: Research Funding.