P699: REAL-LIFE OUTCOMES OF PONATINIB TREATMENT IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) OR PHILADELPHIA CHROMOSOME-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA (PH+ALL): 5-YEAR-DATA FROM A BELGIAN REGISTRY
Timothy DevosViolaine HavelangeKoen TheunissenStef MeersFleur Samantha BenghiatAlain GadisseurGaëtan VanstraelenHélène VellemansBenjamin BaillyNikki GranacherPhilippe LewalleAnn De BeckerKoen Van EygenMarie LejeuneM. JanssenA. TriffetInge VrelustDries DeerenDominiek MazureMarshall BeckHinde SebtiD. Selleslag
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Background: Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) indicated for adult patients with chronic, accelerated or blast phase CML resistant or intolerant to nilotinib or dasatinib or with Ph+ALL resistant or intolerant to dasatinib or for patients with the T315I mutation. Real-world data on ponatinib treatment are limited but are important to evaluate the effectiveness and safety of ponatinib and optimize its use in daily practice. Aims: To report 5-year-Belgian registry data on ponatinib use in CML and Ph+ALL patients in routine clinical practice. Methods: This ongoing prospective multi-center registry (NCT03678454) includes ≥18-year-old patients with CML or Ph+ALL eligible for ponatinib treatment per product label. Data on demographics, effectiveness (major molecular response [MMR] rate) and safety were collected for patients enrolled from 01-March-2016 onwards and are presented here up to 17-May-2021. Results: In this interim analysis, 77 patients from 21 hospitals were enrolled (50 CML, 27 Ph+ALL). Of the 28 patients (39%; 14 CML, 14 Ph+ALL) with mutations in the BCR-ABL1 kinase domain, 17 (8 CML, 9 Ph+ALL) had the T315I mutation at entry. Median age at ponatinib start was 61 years for CML and 56 years for Ph+ALL patients. 88% of CML and 96% of Ph+ALL patients had received ≥2 prior TKIs. Potential pre-existing risk factors for TKI cardiovascular toxicity were observed: history of cardiovascular disease (27 patients), hypertension (23), smoking (15), diabetes (13), hypercholesterolemia (8), hyperlipidemia (6). The most frequently reported risk factor was history of cardiovascular disease (36% CML, 33% Ph+ALL). Median follow-up was 545 (14-3190) days for CML and 210 (26-2933) days for Ph+ALL patients. Reasons for starting ponatinib therapy were intolerance to previous TKIs (26 CML, 11 Ph+ALL), relapse on/refractoriness to previous TKIs (11 CML, 8 Ph+ALL), T315I mutation (6 CML, 6 Ph+ALL) and disease progression (7 CML, 2 Ph+ALL). Ponatinib starting doses were: 45 mg/day (66%), 30 mg/day (10%), 15 mg/day (22%) in CML patients (1 patient started with 15 mg every 2 days) and 45 mg/day (67%), 30 mg/day (15%), 15 mg/day (19%) in Ph+ALL patients. MMR was achieved in 58% of CML and 52% of Ph+ALL patients. The median time-to-MMR was 170 days in CML and 86 days in Ph+ALL patients. Of the 37 patients who started ponatinib due to intolerance to previous TKIs, 59% (15 CML, 7 Ph+ALL) achieved MMR. Adverse reactions (ARs) were reported in 63 patients (82%); the most common were rash (23% of all), constipation (18% of CML) and headache (11% of Ph+ALL patients). Seventeen patients developed 26 serious AR. Serious cardiovascular ARs were reported in 7 patients (coeliac artery stenosis [in 2 patients], ischemic stroke [1], worsening hypertension [1], hypertension [1], deep venous thrombosis [1], possible transient ischemic attack [1]). Eight deaths were recorded, none related to ponatinib treatment. 56% of CML and 24% of Ph+ALL patients discontinued ponatinib treatment due to an AR. Summary/Conclusion: This real-world Belgian registry over 5 years supports the use of ponatinib in CML and Ph+ALL patients resistant or intolerant to previous TKIs or carrying the T315I mutation. Results obtained in routine clinical practice are in concordance with clinical trials, including PACE, in which CML patients had durable and clinically meaningful responses to ponatinib. Funding: Incyte Biosciences Benelux BV Acknowledgements: Medical writing support was provided by Adina Truta (Modis)Keywords:
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The clinical outcome for patients with chronic myeloid leukemia (CML) has improved radically in the past 15 years. Imatinib led to high rates of complete cytogenetic responses and improved survival for patients with this disease. However, approximately 25-35% of patients in chronic phase treated with imatinib developed treatment failure.Development of next-generation Tyrosine kinase inhibitors (TKIs), such as dasatinib, nilotinib, radotinib, bosutinib, and ponatinib, has provided new therapeutic option for the patients resistant or intolerant to imatinib. Second generation (2G) TKIs were active in most clinically relevant BCR-ABL mutations, except highly resistant T315I.Through the phase 3 international randomized studies of 2G TKIs (dasatinib, nilotinib, and bosutinib) vs. imatinib, 2G TKIs emerged as the standard treatment for CML and have successfully prolonged the duration of both the chronic phase (CP) and the disease-free state. The majority of newly diagnosed patients treated with 2G TKIs achieved a complete cytogenetic response (CCyR), and over time, most of these eventually achieved major molecular responses (MMRs) and even complete molecular responses (CMRs). More recently, both dasatinib and nilotinib were approved for frontline use, and dasatinib, nilotinib, radotinib and bosutinib were approved for second-line use in patients with CML.Ponatinib represents the third generation of TKI, and this drug has been developed with the aim of targeting a specific BCR-ABL1 mutation (T315I), which arises in the setting of prolonged TKI therapy and leads to resistance to all commercially available TKIs. (Korean J Med 2012;83:718-723) Keywords: Chronic myeloid leukemia; Imatinib; Nilotinib; Dasatinib; Radotinib; Ponatinib ì¤ì¬ ë¨ì´: ë§ì±ê³¨ìì±ë°±íë³; ì´ë§¤í°ë; ëë¡í°ë; ë¤ì¬í°ë; ë¼ëí°ë; í¬ëí°ë
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There have been few reports of a response to dasatinib or nilotinib after failure of two prior sequential tyrosine kinase inhibitors. We report the outcome of 82 chronic phase patients who received nilotinib or dasatinib as third-line alternative tyrosine kinase inhibitor therapy. Thirty-four patients failed to respond to nilotinib and were started on dasatinib as third-line tyrosine kinase inhibitor therapy while 48 patients were switched to nilotinib after dasatinib failure. Overall, we obtained a cytogenetic response in 32 of 82 patients and major molecular response in 13 patients; disease progression occurred in 12 patients. At last follow up, 70 patients (85.4%) were alive with a median overall survival of 46 months. Our results show that third-line tyrosine kinase inhibitor therapy in chronic myeloid leukemia patients after failure of two prior sequential tyrosine kinase inhibitors may induce a response that, in some instances, could prolong overall survival and affect event-free survival.
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The approval of imatinib in 2001 changed the landscape of chronic myeloid leukemia (CML) management, becoming the standard of care and improving the survival rates of patients. With the prevalent use of imatinib worldwide, it was observed that up to one-third of patients are resistant to or intolerant of imatinib therapy, fueling the search for safer and more effective agents. The newer and more potent tyrosine kinase inhibitors nilotinib and dasatinib were first indicated for the treatment of imatinib-resistant/-intolerant patients, for whom these agents are both safe and efficacious. More recent clinical studies have examined nilotinib and dasatinib in the frontline setting in newly diagnosed patients. Data reported from the phase III ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) study and the DASISION (Dasatinib versus Imatinib in Patients with Newly Diagnosed Chronic-phase CML) trial support the use of nilotinib and dasatinib as potential new standards for frontline care of newly diagnosed patients with CML in chronic phase. Furthermore, both agents have received regulatory approval for use as frontline agents. These agents have demonstrated significantly superior efficacy compared with imatinib, as measured by complete cytogenetic response and major molecular response rates. In addition, progression to advanced disease was significantly lower for nilotinib, and a trend toward lower progression was observed with dasatinib. Although both nilotinib and dasatinib are generally well tolerated in the frontline setting, they have different safety profiles that may affect their selection as treatment. Understanding the efficacy, safety profiles, and patterns of resistance to various BCR-ABL1 mutations of these newer agents, as well as implementing management strategies to treat adverse events, will help physicians to provide the best therapy options for their patients with CML.
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Newer tyrosine kinase inhibitors (TKIs) (bosutinib, ponatinib) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be utilized as a salvage therapy in patients with chronic myeloid leukemia (CML) who failed two lines (imatinib → nilotinib or imatinib → dasatinib) of TKI therapy. However, these TKIs are not available in many countries and not all patients can undergo allo-HSCT.In this study, CML patients who received dasatinib or nilotinib as a third-line treatment were retrospectively evaluated.Out of 209 patients, third-line dasatinib/nilotinib was administered in 21. During the follow-up, 16 out of 21 patients gained and/or maintained an optimal response, and 4 patients died due to progression. Seventeen patients were alive at the time of the analysis, of which 13 were still on TKI, whereas 4 patients quit treatment.In patients failing two lines of TKI, dasatinib or nilotinib can be beneficial and safely administered as a third-line treatment especially in nations with restricted resources.
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The tyrosine kinase inhibitors (TKIs), nilotinib, ponatinib, and dasatinib (but not bosutinib or imatinib), are associated with vascular adverse events (VAEs) in chronic myeloid leukemia (CML). Though the mechanism is inadequately understood, an effect on vascular cells has been suggested. We investigated the effect of imatinib, nilotinib, dasatinib, bosutinib, and ponatinib on tube formation, cell viability, and gene expression of human vascular endothelial cells (HUVECs). We found a distinct genetic profile in HUVECs treated with dasatinib, ponatinib, and nilotinib compared to bosutinib and imatinib, who resembled untreated samples. However, unique gene expression and molecular pathway alterations were detected between dasatinib, ponatinib, and nilotinib. Angiogenesis/blood vessel-related pathways and HUVEC function (tube formation/viability) were adversely affected by dasatinib, ponatinib, and nilotinib but not by imatinib or bosutinib. These results correspond to the differences in VAE profiles of these TKIs, support a direct effect on vascular cells, and provide direction for future research.
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