Real world data are becoming a crucial tool to understand how cancer is treated in routine daily practice. This real-world analysis aims to describe the characteristics of patients with CML in 2nd or ≥3rd tyrosine kinase inhibitors (TKI) lines of therapy, to evaluate their treatment sequence and utilization in settings of Italian clinical practice in Italy. A retrospective analysis was performed using an administrative databases covering around 15.3 million cases. All adult patients prescribed with TKI as 2nd or ≥3rd lines (L) of therapy for CML during January 2015–December 2018 were included. A total of 491 patients in 2nd and 144 in ≥3rd L was included. In both cohorts, hypertension was the most reported comorbidity, followed by metabolic and blood count alterations. In each calendar inclusion year, an increment of 97.6% was observed in the number of patients treated in ≥3rd L. In the 2nd L cohort, 18.7% had a switch to 3rd L, while 26.4% of ≥3rd L patients switched to a subsequent line. Around 40% in both lines discontinued their treatment after a median time of 5.5 (2nd L) and 4.3 (≥3rd L) years. The results provided insights into CML management clinical practice, indicating a heavy disease burden for patients in later lines that showed an increasing complex management, and suggest that a need for novel treatment strategies might exists.

Introduction: Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is demonstrated to be achievable and recommended for patients (pts) in sustained deep molecular response (sDMR) who can discontinue tyrosine kinase inhibitor (TKI) treatment and maintain responses in ~50% of cases. While the feasibility and safety of TKI cessation have been largely demonstrated, the strategies of TFR optimization are yet to be clarified. Studies (eg. DESTINY) investigating de-escalation, mainly after imatinib, suggested that a stepwise approach may favor TFR outcome. We present the interim results of the phase 2, prospective, multicenter DANTE study (NCT03874858) evaluating de-escalation and TFR in Italian pts with CML in chronic phase (CML-CP) treated with nilotinib (NIL). Methods: Adults with CML-CP treated with NIL 300 mg twice daily (bid) in first-line for ≥3 years who achieved sDMR for ≥1 year (≥MR 4.0; BCR-ABL level ≤0.01% IS) were enrolled in 27 centers. The study consisted of 4 phases: screening (week [wk] −4-0), consolidation (wk 0-48), TFR (wk 48-144), and follow-up (until wk 144). Ongoing treatment with ≥400 mg/day dose was allowed at study entry. During consolidation, pts were treated with NIL 300 mg once daily (qd). At the end of consolidation phase, pts with sDMR entered TFR phase and discontinued NIL; indeed, pts with at least major molecular response (MMR; BCR-ABL ≤0.1% IS), but without sDMR, continued NIL 300 mg qd. At any time, pts with loss of MMR returned to NIL 300 mg bid. During TFR phase, BCR-ABL levels were monitored monthly from wk 52-96, and then every 3 months. Pts on half-dose or full-dose NIL were monitored every 3 months. The primary endpoint is the percentage of pts in full treatment-free remission (FTFR) 96 wks after the start of consolidation phase. FTFR is defined as pts with MMR or better, including those who remained in discontinuation during TFR phase and those who are treated with half the standard dose. Key secondary endpoints include percentage of pts with sDMR at wk 48; TFR rate at wk 96 and 144; BCR-ABL kinetics and safety. The predictive role of digital droplet PCR is also evaluated as an exploratory objective. Results: Overall, 113 pts were screened and 107 entered consolidation phase. This interim analysis included 52 pts who reached the end of consolidation phase by data cut-off period (February 8, 2021). Of these 52 pts, 49 (94.2%) were ongoing by data cut-off and 3 (5.8%) discontinued the study (1 patient due to adverse event (AE) and 2 per patient's decision). Median age at study entry was 49.5 years. Median time from diagnosis was 5.6 years and median dose of prior NIL treatment was 600 mg/day for all pts except one who was on NIL 450 mg/day at baseline. Median duration of last sustained MR4 and MR4.5 were 30 and 16.5 months, respectively. Further details are listed in Table 1. At screening, molecular response categories were MR4.0 in 13.7%, MR4.5 in 23.1% and undetectable MR4.5 in 63.5% of pts. During consolidation phase, 5 (9.6%) pts discontinued prematurely: 2 pts restarted NIL full dose (3.8%) for MMR loss, 2 (3.8%) discontinued for AEs and 1 (1.9%) for pt decision. Overall, 47 pts completed consolidation: of them 40 (76.9%) sustained DMR and 7 (13.5%) maintained MMR but not sDMR. Of the 7 pts not sustaining DMR during consolidation, 6 regained DMR after a median of 4.4 months, while 1 pt was still in MMR by data cutoff. The 2 pts who lost MMR after 5 and 8 months regained MMR and 1 regained DMR by data cutoff after increasing NIL to 300 mg bid. Median time spent in consolidation phase was 11.7 months, and the evolution of response categories over time is shown in Figure 1. During consolidation phase, AEs were observed in 16 pts (30.8%), of them 2 (3.8%) pts had serious AEs: 1 patient had skin ulcers and COVID-19 related pneumonia, while 1 patient had unstable angina. No deaths and disease progressions were observed. Conclusions: DANTE is the first study that showed the safety and feasibility of NIL de-escalation before TFR in CML-CP pts with sDMR. Interim results suggest that loss of MMR during de-escalation is rare. De-escalation strategy may lead to further improvement of TFR outcome and tolerability and may also preemptively support the identification of pts who may not be ready for discontinuation, with a tailored approach. To date, accuracy in predicting TFR outcome is still low, and the de-escalation setting may sharpen biological and clinical predictive factors, including the potential role of digital PCR. Figure 1 Figure 1. Disclosures Breccia: Abbvie: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Bristol Myers Squibb/Celgene: Honoraria. Abruzzese: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: 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: Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Lemoli: Jazz, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Daiichi Sankyo, Servier: Honoraria, Speakers Bureau; Celgene: Other: Support for attending meetings and/or travel. Siragusa: Novartis, CSL, Behring, Amgen, Novonoridsk, SOBI, Bayer: Consultancy, Honoraria, Speakers Bureau. Chiodi: Novartis: Current Employment.

Introduction Chronic myeloid leukemia (CML) is a hematopoietic myeloproliferative disorder that accounts for 20% of all leukemias of adults. The introduction of tyrosine kinase inhibitors (TKIs) (imatinib, bosutinib, dasatinib, nilotinib, ponatinib) has yielded significant benefits for patients with CML in terms of survival and quality of life. This real-world analysis evaluated the economic burden for managing patients with CML in 2nd or ≥ 3rd TKI lines in Italian settings of clinical practice. Methods A retrospective observational analysis was performed exploiting the administrative databases of a sample of entities covering around 15 million inhabitants. From 2015 to 2018, the study included adult patients with at least one prescription for TKIs, (and for some TKI with at least one hospitalization discharge diagnosis for CML, or at least one prescription for BCR–ABL examination). The index date was the first TKI prescription. Healthcare resource consumption and costs for patients with CML in 2nd and ≥ 3rd line treatment with TKIs were analyzed for drug prescriptions, hospitalizations, specialist visits, and diagnostic services. Results In total 635 patients were included, 491 in 2nd line and 144 in 3rd line with TKIs. Dasatinib was the most frequently prescribed drug in 2nd line (28.9%) and imatinib in later lines (26.4%). With progressing lines of treatment, healthcare consumption showed a trend towards increased non-TKI prescriptions per patient (8 for 2nd line and 9.7 for ≥ 3rd line). The management of patients with CML in later lines resulted in increased overall healthcare burden, with hospitalizations accounting for about half of total expenditure, whatever the treatment line and type of TKI. Conclusions This analysis in Italian real-life clinical practice reported economic expenditure for patients with CML in 2nd or ≥ 3rd lines with TKIs, mostly burdened by hospitalizations. Such clinical complexity suggests that further efforts are needed to improve the therapeutic management of later lines of CML.

Background The use of real-world data in oncology is gaining increasing interest, as it can provide valuable insights into treatments and related outcomes in routine daily oncology practice, thus integrating the evidence coming from clinical trials. The study aims to describe the characteristics of patients (pts) with chronic myeloid leukemia (CML) in 2 nd or ≥3 rd tyrosine kinase inhibitors (TKI) lines of therapy, analyze their drug utilization and evaluate healthcare direct costs for the Italian National Health Service in order to estimate the impact of disease burden. Methods This retrospective observational analysis was based on administrative databases covering around 15.3 million subjects in Italy. All adult pts with prescription of the TKIs bosutinib (BOS), dasatinib (DAS), imatinib (IMA), nilotinib (NIL), ponatinib (PON) in 2 nd or ≥3 rd line of therapy during 01/2015-12/2018 were included. Specifically, those with IMA, DAS or PON prescription were enrolled if they also presented ≥1 CML hospitalization or previous prescription for NIL or BOS or ≥1 BCR-ABL1 RQ-PCR test without hospitalization for acute lymphoid leukemia. Pts enrolled in clinical trials were not captured. Index date was 1 st prescription date for a TKI in 2 nd or ≥3 rd line. Comorbidities were assessed by hospitalization diagnosis codes and/or presence of specific drugs as proxy of diagnosis. Mean annual healthcare resource costs were evaluated during follow-up (from index date to end of study) in terms of drugs other than TKI (excluded), visits, tests, hospitalizations (overall and comorbidity-related during treatment). Results Overall, 491 pts in 2 nd and 144 in ≥3 rd line were included. In each calendar year from 2015 to 2018, the incidence of pts who entered a 2 nd line changed from 22.6% to 28.7%, whereas the ≥3 rd line fluctuated from 37% to 46.7%. An increment of 97.6% was observed in the number of pts treated in ≥3 rd line from 2015 to 2018 (figure 1). As 2 nd line, 40.9% was represented by DAS, 28.9% NIL, 12.2% BOS, 10.2% PON and 7.8% IMA. Mean age ranged from 56.1 (PON) to 68.2 (BOS) years. At baseline, hypertension was the most reported comorbidity (from 64.1% for NIL to 91.7% for BOS), followed by metabolic (from 27.9% in DAS pts to 63.2% for IMA) and blood count (from 28.4% for DAS to 58.0% for PON) alterations. Among pts in ≥3 rd line, 26.3% received imatinib, 22.2% PON, 18.8% NIL, 16.7% BOS, 16% DAS. Mean age was 57 years for NIL, 64.8 PON and 69.5 BOS pts. Same trend of comorbidities was reported in the ≥3 rd line cohort, with hypertension detected in all pts starting BOS to a minimum of 65.2% pts in DAS group, followed by blood count alteration (34.8% for DAS to 59.4% for PON) and metabolic alterations (37.0% for NIL to 50.0% for BOS). Baseline cardiovascular comorbidities were present in 22.8% of pts starting a 2 nd line and in 35.4% of pts starting ≥3 rd line. After a median follow up of 3.0 and 2.6 years, 13% and 19% of pts died in 2 nd and ≥3 rd lines, respectively, around 40% in both lines discontinued their treatment. Median time to discontinuation was 5.5 (95%CI: 4.7-6.2) (2 nd line) and 4.3 (95%CI: 3.2-5.2) (≥3 rd line) years. Mean number of annual hospitalizations was 0.6 (from 0.4 for NIL to 1.1 for PON) in 2 nd line, and 0.5 (from 0.4 for IMA and NIL to 0.7 for PON) in ≥3 rd line. Total mean annual costs/pts (TKI excluded) were of €10,168 (PON), €6,106 (BOS), €5,086 (DAS), €4,779 (NIL) and €3,905 (IMA), with hospitalizations comorbidity-related accounting for €3,245 among PON, €2,820 BOS, €1,739 NIL, €1,573 DAS and €1,448 IMA pts. Mean annual costs per lines are shown in figure 2. Conclusions This real-world study provided a demographic and clinical profile of CML pts in 2 nd and ≥3 rd TKI lines and described drug utilization and resource consumption in the Italian clinical practice setting. An increase of pts treated with TKIs in ≥3 rd line was reported, reflecting the availability of multiple TKIs over the years; moreover, a highly comorbid population suggests an increasingly complex CML management. Our results underlined a heavy clinical and economic burden for pts in 2 nd or ≥3 rd lines, especially in terms of comorbidities, treatment discontinuation and hospitalizations suggesting the need of novel therapeutic options for management of later lines CML. Figure 1 Figure 1. Disclosures Breccia: Novartis: Consultancy; Pfizer: Consultancy; BMS: Consultancy; INCYTE: Consultancy; Abbvie: Consultancy. Chiodi: Novartis: Current Employment. Valsecchi: Novartis Farma SpA: Current Employment. Rendace: Novartis Farma S.p.A.: Current Employment. Coco: Novartis Farma S.p.A.: Current Employment. Premoli: Novartis Farma SpA: Current Employment.