ALBERT

Description: INTRODUCTION: Ponatinib is a potent TKI indicated in T315I mutated CML and not mutated CML resistant to other drugs. Deep responses were reported in PACE trial in patients who had failed all other TKIs in chronic and advanced phase CML with acceptable toxicity profile. Ponatinib use is authorized in United States and Europe but compassionate use allows access in Argentina with no previous reports of local results. OBJECTIVE: To analyze a cohort of CML resistant patients treated with ponatinib: clinical characteristics, outcome and adverse events. MATERIALS AND METHDOS: Retrospective, multicentric, observational, descriptive study. Data was collected from charts review of patients with resistant CML treated with ponatinib at 8 different centers. Mutational status was reported. Frequency of Complete Hematologic Response (CHR), Complete Cytogenetic Response (CCgR) and Major Molecular Response (MMR) at 3, 6 and 12 months, adverse events and death were analyzed. RESULTS Twenty three patients were included with median follow-up from CML diagnosis 119 months (m) (IQR: 12-215) and 6 m (IQR: 2-21) from ponatinib first dose. Median age at CML diagnosis was 41 year-old (5-61). At the moment of ponatinib first dose 74% (17/23) patients were in chronic phase (CP), 13% (3/23) in accelerated phase and (AP) and 13% (3/23) in blast crisis (BC). Ponatinib was indicated as second line treatment in 4% (1/23), third line treatment in 9% (2/23), fourth line 83% (19/23) and fifth line 4% (1/23). Mutations were detected in 83% (19/23) patients with presence of T315I mutation in 44% (10/23). Median time from mutation detection to ponatinib start was 6 m (1-12). Ponatinib dose was 45 mg/d in 48% (11/23) and 55% (6/11) of these patients required dose reduction, 52% (12/23) received 30mg/d. Treatment have been discontinued in 8% (2/23) due to safety reasons. All patients in CP with evaluable response achieved CHR with median time to CHR of 1m, 27% (3/11) achieved CCgR, and 18% (2/11) obtained MMR by 3 m y 6 m, and 37% (3/8) by 12 m. Of patients in AP/BC 83% (5/6) achieved no molecular response and only 1patient have received ponatinib associated with standard chemotherapy, obtained MR4.5 and underwent unrelated bone marrow transplantation and is alive --- months after BC T315I mutated CML. Disease progression occurred in 6% (1/17). Death occurred in 4/23 (17%) all advanced phase at start of ponatinib. Adverse events are reported in table 1:Table 1.ADVERSE EVENTINCIDENCETOXICITY GRADEHematologic21% (5/23)1-2- 3Dermatologic13% (3/23)1-2-3Hypertension9% (2/23)2- 3Mialgia4% (1/23)3Palpitations4% (1/23)2Hipertriglyceridemia4% (1/23)4Hepatotoxicity4% (1/23)2Disnea4% (1/23)3Arterial Thrombosis4% (1/23)4Grade 4 toxicities occurred in 2 patients receiving 30 mg/d. Arterial thrombosis was the cause of death of one patient and cardiac toxicity mandated drug interruption in another. CONCLUSION: This is the first report of ponatinib use in daily practice in Argentina.Response rates are lower than those reported in the literature. Drug was safe with low discontinuation rates although severe cardiac toxicity occurred as reported. Time to first dose in Argentina may be a relevant factor to explain the lower rates of response in patients who have failed other ITKs. Disclosures Varela: Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Enrico:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Pavlovsky:Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau. Bengio:Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Pavlovsky:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Moiraghi:Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau.

Description: Background: Data on the safety and efficacy of copy drugs is usually unavailable. Imatinib mesylate is used to treat chronic myeloid leukemia (CML) patients in Argentina since 2002. During the last decade more than ten different imatinib copies are marketed by the different health-care systems in the country, usually for cost issues. In spite of the undoubted benefit of this tyrosine-kinase inhibitor indication in CML, there is no solid evidence that supports copy drug equivalent outcomes for this patient population. Aim: To compare the clinical presentation, treatment response and outcome of a chronic phase (CP) CML patient cohort treated with branded and copy imatinib in the real-life setting. Methods: Multicentric, retrospective trial based on data obtained from medical charts of adult CP CML patients treated with imatinib in 9 centers in Argentina from 2002 to 2020.We analyzed demographic characteristics and clinical characteristics described for branded and copy imatinib treated cohorts. Frequency of complete cytogenetic response (CCyR) at 12 months, Major molecular response or better(≥MMR) at 12, 18 and 24 months and overall MR4.0, MR4.5 and deep molecular response (MR4.0 +MR4.5 IS) were analyzed. Event was defined as failure, progression or CML related death. Kaplan Meier comparison of event free, progression free and overall survival. Statistics: IBM SPSS version 1. Results: A total of 568 CP CML adult patients (pt) treated with imatinib were included. Mean age at diagnosis: 45.7 years (range 18 - 85). Male 55.6% (316/568). Sokal Score was recorded in 471 pt: 57% (269/471) low, 26% (122/471) intermediate and 17% (80/471) high-risk. Median follow-up 107 months (RIQ: 36-149). Branded imatinib treatment 330 (58%) and imatinib copies 238 (42%). For branded and copy imatinib cohorts mean age 46,1 (18-85) and 45.3(18-80), male 53% (175/330) and 59% (141/238), median follow up 102 (RIQ 101-130) and 61 (RIQ 62-146) respectively. Sokal score low 58% (164/284) and 56% (105/187), intermediate 27% (77/284) and 24% (45/187) and high 15% (43/284) and19% (37/187). Frequency of CCyR at 12 months 71% (67/94) and 69% (41/59), ≥MMR at 12 months 57% (79/138) and 43% (39/89), ≥MMR 18m 66 % (61/92) and 71% (43/60), ≥MMR 24m 65% (96/147) and 79% (58/73). Overall MR4, MR 4.5 and Deep MR with branded imatinib 62.4% (186/298), 42% (118/276) and 63% (189/300), compared to 45(97/214), 24% (50/207) and 46% (99/215) with copies. Difference in evaluation throughout the treatment periods with loss of data did not allow response rate statistical comparison in predetermined timepoints. Kaplan Meier Event free survival median 229 months vs 75 months p 0.001, Progression free survival mean 318 months vs 208 pt 0.034 and Overall Survival mean 275 months vs 206 months for branded and copy imatinib respectively. Discussion: Several case reports have shown poor outcomes in patients treated with imatinib copy drugs, including loss of responses previously attained with branded imatinib. This study reports data from a large cohort of CP CML patients treated in daily practice during a long period of time. Treatment results at determined timepoints is comparable. Although management and treatment decisions were performed in different time periods, results show different outcomes in EFS and PFS between patients treated with branded vs copy imatinib. Overall survival in both cohorts is comparable. As studies assesing the safety and efficacy of the copy drugs compared with branded imatinib will hardly be performed this evidence calls for careful attention and strict follow up measures when managing CML patients with copy imatinib. Figure Disclosures Varela: Novartis: Consultancy, Speakers Bureau. Pavlovsky:Pint Pharma: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Freitas:Pfizer: Consultancy, Other: Advisory Board. Pavlovsky:Varifarma: Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau. Moiraghi:Novartis: Speakers Bureau; BMS: Speakers Bureau.