Imatinib Intolerance Research Articles

Overall survival and long-term safety with ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib: Final analyses from INTRIGUE.

748 Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with 3 or more kinase inhibitors, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. In the second interim analysis of overall survival (OS) from the phase 3 INTRIGUE study, the OS event rate was 41% in the all-patient (AP) intent-to-treat (ITT) population, and OS was similar between treatment arms in both the KIT exon 11 ITT and AP ITT populations. Here, we present the final OS and updated safety from INTRIGUE. Methods: INTRIGUE (NCT03673501) is an open-label, phase 3 study of adults with advanced GIST who had disease progression on or intolerance to imatinib. Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 weeks on/2 weeks off) and was stratified by KIT mutational status and imatinib intolerance. OS was a key secondary endpoint (the primary endpoint of progression-free survival was reported previously); final OS analysis was prespecified to occur with ≥200 and ≥145 events in the AP ITT and KIT exon 11 ITT populations, respectively. Data cutoff was March 15, 2023. Results: Of 453 pts, 444 received treatment; 40 remain on treatment (ripretinib, 28/223 [13%]; sunitinib, 12/221 [5%]). Treatment discontinuation was due to progressive disease (PD) by independent radiologic review (56%), PD by investigator (11%), clinical PD (6%), withdrawal of consent (6%), and adverse events (AEs; 5%). Fewer pts discontinued treatment due to AEs with ripretinib vs sunitinib (3% vs 6%). There were 211 OS events (47%) in the AP ITT population and 151 OS events (46%) in the KIT exon 11 ITT population. OS was similar with ripretinib vs sunitinib in the 2 ITT populations (Table). Fewer pts had grade 3/4 treatment-emergent AEs with ripretinib vs sunitinib (43% vs 67%). Dose interruptions and reductions were lower with ripretinib vs sunitinib. Median treatment duration for ripretinib vs sunitinib was 7.9 vs 6.5 months. Conclusions: In the finalOS analysis from the INTRIGUE study, OS was similar between treatment arms. The safety profile remained consistent and more favorable for ripretinib vs sunitinib in pts with advanced GIST previously treated with imatinib. Clinical trial information: NCT03673501 . [Table: see text]

Overall survival and long-term safety in patients with advanced gastrointestinal stromal tumor previously treated with imatinib: Updated analyses from INTRIGUE.

11524 Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 kinase inhibitors, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. In the first interim analysis (IA) for overall survival (OS) in the INTRIGUE trial, data were immature (OS event rate, 22.3%), and median OS was not reached in either arm for the KIT exon 11 intent-to-treat (ITT) and all-patient (AP) ITT populations (S Bauer, et al. J Clin Oncol. 2022). Additionally, ripretinib had a more favorable safety profile with fewer grade 3/4 treatment-emergent adverse events (TEAEs) than sunitinib. Here, we present the second IA of OS and updated safety from INTRIGUE. Methods: INTRIGUE is a global, open-label, phase 3 study that enrolled adult pts with advanced GIST who had disease progression on or intolerance to imatinib (NCT03673501). Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off) and was stratified by KIT mutational status and imatinib intolerance. OS was a key secondary endpoint; data cutoff for the second IA was Sept 1, 2022. Results: Of 453 pts in the AP ITT population, 444 received treatment; 51 remain on treatment (33/223 [14.8%] with ripretinib and 18/221 [8.1%] with sunitinib). Common reasons for treatment discontinuation were progressive disease (PD) assessed by independent radiologic review (55.4%), PD assessed by investigator (10.6%), clinical PD (5.9%), withdrawal of consent (5.4%), and adverse event (AE; 4.5%); fewer pts discontinued due to an AE for ripretinib vs sunitinib (2.7% vs 6.3%). Following study treatment discontinuation, 58 pts (25.6%) from the sunitinib arm received ripretinib; 139 pts (61.5%) from the ripretinib arm later received sunitinib. There were 185 OS events (40.8%) in the AP ITT population; median duration of follow-up was 28.7 and 28.5 months for ripretinib and sunitinib, respectively. OS was similar with ripretinib vs sunitinib in the AP ITT (median 35.5 vs 30.9 months; HR 0.88, 95% CI 0.66 to 1.18; nominal P = 0.39) and KIT exon 11 ITT populations (median 34.0 vs 31.5 months; HR 1.05, 95% CI 0.75 to 1.48; nominal P = 0.77). The updated safety profile was consistent with the primary analysis; fewer pts had grade 3/4 TEAEs with ripretinib vs sunitinib (95 [42.6%] vs 149 [67.4%]). Dose interruptions and reductions were lower with ripretinib vs sunitinib. The median (range) treatment duration was 7.9 (0.2–38.2) months for ripretinib and 6.5 (0.2–38.3) months for sunitinib. Conclusions: In the second IA from INTRIGUE, OS was similar between treatment arms. The safety profile remained consistent with additional data, and results demonstrate favorable safety with ripretinib in pts with advanced GIST previously treated with imatinib. Clinical trial information: NCT03673501 .

Follow-up of Chronic Myeloid Leukemia Patients whose Tyrosine Kinase Treatment Was Stopped: Case Series

Chronic Myeloid Leukemia (CML) is a myeloproliferative disease characterized by the formation of the BCR ABL1 fusion protein with translocation t(9;22) (Philadelphia chromosome-Ph). With recent studies, it has been understood that the treatment of adult chronic phase CML patients who have achieved a deep molecular response with the use of TKI and can maintain this response for a long time can be safely terminated; It has been observed that it is possible for patients to remain in long-term molecular remission without the use of TKI. Based on these studies, we will try to present the follow-up processes of chronic phase CML patients, who were followed up in our clinic and whose TKI treatment was stopped. First case; A 69-year-old female patient was diagnosed with Ph positive chronic phase CML in 2008. The imatinib treatment of the patient, who had been using imatinib for about 13 years and was bcr-abl negative for the last 3 years, was discontinued in December 2021. In the 2nd and 4th months, the requested bcr-abl was negative. Second case; a 42-year-old male patient was diagnosed with Ph-positive chronic phase CML in 2006. The patient, who had been using imatinib for about 16 years and was bcr-abl negative for the last 3 years, was discontinued in April 2022. bcr-abl came back negative. Third case; a 42-year-old female patient was diagnosed with Ph positive (IS: 31,824) chronic phase CML in 2019. He received Nilotinib and Dasatinib treatment after he had an allergic skin reaction using imatinib for about 2 years. The patient had drug intolerance and was bcr-abl negative for about 2 years, and the treatment was stopped. The 1-month follow-up was negative for bcr-abl. Fourth case; Imatinib was started in a 50-year-old female patient with the diagnosis of Ph-positive chronic phase CML in 2012. Due to imatinib intolerance, the treatment of the patient who was using nilotinib and was bcr-abl negative for the last 3 years was discontinued in February 2021. The bcr-abl negativity continues in the follow-ups. Fifth case: A 58-year-old female patient was diagnosed with Ph-positive chronic phase CML in 2013. The imatinib treatment of the patient, who has been using imatinib for about 8 years and has been negative for bcr-abl for the last 3 years, was discontinued in November 2021. The bcr-abl negativity continues in the follow-ups. STIM 1(Stop Imatinib) study is the first multicenter, non-randomised, prospective study on TKI termination.Then, TWISTER, A-STIM, ENEST, STOP2GTKI, EURO SKI studies were carried out.In these studies, TKI treatment was discontinued in patients who used TKI for at least 3 years and had a major molecular response for the last 2 years. Remission was achieved in approximately 50% of the patients who were followed up without medication. In our study; The treatment of patients who had been using TKI for 5 years and had a major molecular response for about 2 years was stopped. The follow-up of the patients (minimum: 1 month, maximum: 15 months) continues, and all of them are in remission.

Outcome of pediatric chronic myeloid leukemia with management focusing on the monitoring of BCR-ABL fusion gene transcript levels.

Background and objectiveClinical, laboratory and outcome data were reviewed for pediatric patients who were diagnosed with chronic myeloid leukemia (CML) and managed at two tertiary care hospitals in Saudi Arabia, between January 2011 and December 2017 to assess the response to tyrosine kinase inhibitors (TKI) focusing on the monitoring of BCR-ABL fusion gene transcript levels and to look at the overall outcome.MethodsCML patients were identified based on the cytogenetic and molecular results.ResultsTwelve pediatric patients diagnosed with CML at a median age of 8.4 year; treated with TKI as first-line therapy, 11 (91.7%) patients were started with imatinib (first-generation TKI), while one received dasatinib (second-generation TKI) due to his three-way Philadelphia chromosome sensitivity. Eight patients (72.7%) starting on imatinib were switched to dasatinib (six patients due to drug resistance, and two patients due to intolerance of Imatinib) and two patients (25%) of whom had already achieved major molecular response (MMR) on Imatinib. Response rate to imatinib in terms of achieving MMR as first-line therapy was achieved in five out of 11 patients (45.5%) and only three of them continued to maintain their MMR. Six out of eight patients who were switched to dasatinib achieved MMR. Two patients underwent hematopoietic stem cell transplant (SCT): one due to blast crisis and one due to the side effects of TKI. With a median follow-up time of 78 months (range, 40.5–108), all of our patients were alive at last update.ConclusionWe report an excellent outcome with an overall survival (OS) of 100% at 5-year and disease-free survival (DFS) of 91.7% (8.0%). All our patients achieved MMR and only one patient had loss of MMR on follow-up. Eight patients (66.7%) achieved complete molecular response (CMR).

Safety and Efficacy of Elective Switch from Nilotinib to Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

The treatment of newly diagnosed chronic phase chronic myeloid leukemia (CML) with nilotinib has resulted in a higher rate of major molecular (MMR) and complete cytogenetic response (CCyR) at 12 months compared to imatinib but at a higher cumulative cost and increased risk of serious adverse events. To maintain long-term efficacy and minimize both toxicity and costs, we aimed at evaluating in a prospective single-center trial the efficacy and safety of a response-directed switch from nilotinib to imatinib after 12 months in patients newly diagnosed with chronic phase CML. Thirteen adult patients were enrolled. Twelve patients started on nilotinib 300 mg twice daily. Eleven patients completed one year of nilotinib and were switched to imatinib 400 mg daily as per protocol. At 3 months, all patients achieved a complete hematologic response, with 7 (58%) patients had early molecular response. At 12 months, all patients achieved CCyR, of whom 5 (42%) and 4 (33%) patients achieved MMR and MR4.5, respectively. Three (27%) patients switched back to nilotinib after 18, 24, and 51 months respectively: 1 patient because of loss of CCyR after 18 months, and 2 patients because of imatinib intolerance. At last follow-up, all patients (n = 12) were alive and in MMR, 6 (50%) of them in continuous MR4.5. These findings suggest that response directed switch from nilotinib to imatinib at 12 months is capable of maintaining long-term response, with manageable side effects. This approach warrants further exploration with larger prospective trials. Clinical trial registration: Clinicaltrials.gov identifier: NCT01316250, https://clinicaltrials.gov/ct2/results?cond=&term=NCT01316250&cntry=&state=&city=&dist=.

INTRIGUE: A phase III, randomized, open-label study to evaluate the efficacy and safety of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib

359881 Background: Sunitinib is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib, a broad-spectrum KIT and PDGFRA switch-control tyrosine kinase inhibitor (TKI), is indicated for the treatment of adult patients (pts) with GIST who received prior treatment with 3 or more TKIs, including imatinib. We compared the efficacy and safety of ripretinib vs sunitinib in pts with advanced GIST who progressed on or were intolerant to imatinib. Methods: This multicenter, global, randomized, open-label phase 3 study (NCT03673501) enrolled adult pts with GIST who progressed on or had intolerance to imatinib. Pts were randomized 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off). Randomization was stratified by KIT mutational status and imatinib intolerance. The primary endpoint was progression-free survival (PFS) by independent radiologic review (IRR) using modified RECIST version 1.1. Key secondary endpoints were objective response rate (ORR) by IRR and overall survival (OS). Hierarchical testing was performed for primary and key secondary endpoints in a prespecified sequence; testing pts with a KIT exon 11 primary mutation (Ex11 intention-to-treat [ITT] population) preceded the all-patient (AP) ITT population. Data cutoff was 1 Sep 2021; final analyses of PFS and ORR and the first interim analysis of OS were conducted. Results: A total of 453 pts were randomized to ripretinib (n = 226; Ex11 ITT, n = 163) or sunitinib (n = 227; Ex11 ITT, n = 164). Median age was 60 yrs (range 18–88) and most pts were white (66.2%) males (62.0%). PFS was not statistically different between ripretinib and sunitinib in the Ex11 ITT (hazard ratio [HR] 0.88, 95% CI 0.66, 1.16; P = 0.36; median 8.3 vs 7.0 mos) or in the AP populations (HR 1.05, 95% CI 0.82, 1.33; P = 0.72; median 8.0 vs 8.3 mos). ORR was numerically higher for ripretinib vs sunitinib in the Ex11 ITT (23.9% vs 14.6%; difference 9.3%, 95% CI 0.7, 17.8; nominal P = 0.03) and AP ITT populations (21.7% vs 17.6%; difference 4.2%, 95% CI −3.2, 11.5; nominal P = 0.27). OS data was highly immature; median OS was not reached in either arm. Fewer pts in the ripretinib arm experienced Grade 3-4 (G3-4) treatment-emergent adverse events (TEAEs) vs sunitinib (41.3% vs 65.6%). Among G3-4 TEAEs with a difference ≥5% between arms, ripretinib had fewer events vs sunitinib (hypertension [8.5% vs 26.7%], palmar-plantar erythrodysesthesia [1.3% vs 10.0%], neutropenia [0% vs 6.3%], and neutrophil count decreased [0% vs 7.2%]). Conclusions: The PFS in both arms was longer than PFS achieved by sunitinib in its pivotal phase 3 trial. While the PFS for ripretinib did not meet the primary endpoint of superiority vs sunitinib, meaningful clinical activity and fewer G3-4 TEAEs were observed in pts with advanced GIST treated with ripretinib after imatinib failure. Clinical trial information: NCT03673501.

Concomitant Medications and Comorbidities Affect Early Response in CML Patients Treated with Imatinib: A Retrospective Analysis of 340 Patients from the Polish Adult Leukemia Group (PALG) Registry

Background : It has been consistently shown that early molecular response is associated with positive long-term outcome in terms of overall survival and progression-free survival in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). Achieving a BCR-ABL(IS) <10% at three months has thereby become an important goal of treatment. According to current European LeukemiaNet recommendations, the optimal treatment response is defined as BCR-ABL(IS) ≤ 10% at three months and BCR-ABL(IS)<1% and/or complete cytogenetic response (CCyR) at six months. Factors influencing the early response are still largely unknown.Our previous study demonstrated that more than half of newly diagnosed CML patients in Poland had comorbid conditions and received concomitant medications. TKIs are metabolized by the CYP3A4 isoenzyme and have been reported to be substrates of ABCB1 (MDR1) and ABCG2 (BCRP) transporters. Importantly, numerous commonly used drugs are transported and metabolized through the same pathways as TKIs. Drug interactions should therefore be considered when administering inhibitors or inducers of CYP3A4, ABCB1 and ABCG2 in combination with TKIs. Furthermore, it has been shown that the presence of comorbidities and the necessity of additional therapies may significantly affect treatment compliance.Objectives: The primary objective of the study was to investigate whether the presence of comorbidities and additional therapies affected early response in CML patients treated with imatinib.Patients and methods : We retrospectively analyzed patients with newly diagnosed CML who were receiving imatinib as the initial therapy for CML at nine Polish hematological tertiary care centers. Inclusion criteria were as follows: 1) age ≥18 years and 2) diagnosis of chronic phase CML between January 1st 2005 and December 31st 2014. Data on presence of comorbid conditions, concomitant drugs, cytogenetic and molecular response were anonymously collected through electronic case reports forms. Patients in whom therapy was changed because of imatinib intolerance were excluded. Influence of potential prognostic factors on probability of response at three and six months was tested by univariate and multivariate logistic regression.Results : We enrolled 340 patients with CML in the chronic phase, with median age 53 years (range, 41-62) where 50 % were males. According to the Sokal score, 190 patients (55.9%) were classified as low risk, 107 (31.5%) as intermediate risk and 43 (12.5%) as high risk. Overall, 142 (41.8%) patients reported no comorbidities, 121 (35.6%) reported one or two comorbidities and 77 (22.7%) had more than two comorbid conditions. The most common comorbidities were: hypertension (30%), hypercholesterolemia (16%), ischemic heart disease (10%) and diabetes (9%). One hundred thirty (38.2%) patients received no additional therapies, 110 (32.4%) patients received one or two therapies and 100 patients (29.4%) more than two. The most frequently used drugs were: beta blockers (22% of patients), ACE inhibitors (19%) and statins (15%). At three months, a molecular analysis was done in 194 patients and 144 (74%) achieved BCR ABL(IS) of less than 10%. At six months, 217 patients underwent molecular analysis and 305 had cytogenetic assessment. One hundred thirty five patients (62%) achieved BCR-ABL(IS) < 1% and 198 (65%) achieved CCyR. Multivariate analysis revealed that at three months patients who had a low Sokal score, more than two comorbidities and received more than two concomitant therapies, significantly more often achieved BCR-ABL <1% (p=0.013, p=0.054 and p=0.005 respectively). At six months, patients who received more than two concomitant medications still tended to have a higher probability of optimal response: BCR-ABL(IS) <1% (p=0.062) and CCyR (p=0.035). Other potential prognostic factors analyzed including patients' age, sex and BMI had no impact on the probability of optimal response.Conclusions: We found that comorbidities and concomitant therapies did not adversely affect early response to imatinib in CML patients. In contrast, patients with more than two additional therapies and comorbidities seem to more often achieve treatment goals. The potential explanations for these findings are drug interactions that increase imatinib exposure and better adherence to therapy of patients accustomed to systematic use of medications. DisclosuresGora Tybor:BMS: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Sacha:Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Lewandowski:BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Warzocha:BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Jamroziak:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria.

Molecular Responses and Outcomes of Pediatric CML Treated with Front-Line Imatinib and a Comparison between Pediatric and Adult Cohorts

Background and PurposeChronic myeloid leukemia (CML) is a rare disease in children and constitutes 2% to 3% of pediatric leukemia. Imatinib, a potent tyrosine kinase inhibitor (TKI), is well established as a standard treatment for newly diagnosed adults with CML in chronic phase. Many pediatric oncologists have followed the treatment guidelines that originally designed for adult patients. There have been rare studies reporting the molecular responses to imatinib in children with CML. The aim of this multi-center study in Taiwan was to assess the treatment responses and outcomes of front-line imatinib therapy in pediatric CML. A comparison between pediatric and adult CML patients was also performed.Patients and MethodsBetween 2002 and 2017, there were 53 newly diagnosed children, age < 18 years old, with CML in chronic phase receiving front-line imatinib therapy with a daily dosage of 300 mg to 400 mg. b3a2, b2a2, b3a2+b2a2, and b3a3 BCR-ABL1 transcripts were detected in 32, 19, 1 and 1 patient(s) respectively. Fifty-two patients with b3a2 and or b2a2 were enrolled in this study. Peripheral blood BCR-ABL1 levels expressed as International Scale (IS) were measured by TaqMan RQ-PCR assay with the lab-specific conversion factor every 3 months in a central laboratory. The criteria of the European LeukemiaNet regarding optimal response were adopted: major cytogenetic response (MCyR, IS < 10%) at 3 months, complete cytogenetic response (CCyR, IS < 1%) at 6 months and major molecular response (MMR, IS < 0.1%) at 12 months (Blood 2013). Molecular response of a patient was censored if the patient received hematopoietic stem cell transplantation (HSCT), switched to 2nd-generation TKI, or died. An adult cohort of 685 patients who had molecular measurements in the same central laboratory, presented partly in ASH 2014 (Blood 2014. 124: 4544a), was updated for the comparison analysis.ResultsOf the 52 pediatric CML patients, 31 were males, the median age at diagnosis of 14.2 years (range, 1.4-17.9). The WBC count ranged from 24.5 to 806.5×109/L (median, 294.4). High Sokal risk group was only observed in 4% and 14.6% for score adopted for younger than 45 years old, respectively. Eight patients went on to receive HSCT, and 20 patients were shifted to 2nd-generation TKIs (14 dasatinib, 6 nilotinib), including 3 achieved optimal responses because of imatinib intolerance. Compared with the adult cohort, there was no statistical difference in the frequency of transcript subtypes. Pediatric patients classified as Sokal high-risk group were significantly lower than those in adult cohort (P < 0.0001).The molecular responses and outcomes of the pediatric cohort are summarized in Table 1. The median followed-up duration was 74.6 months (range, 3.0-182.1). Optimal responses at 3 months, 6 months and 12 months following imatinib therapy were achieved in 52.0%, 39.1% and 21.7%, respectively. MMR and MR4.5 (IS ≤ 0.0032%) were achieved in 48% and 15% of pediatric patients, respectively. The cumulative incidences (% ± SE) of CCyR by 12 months, MMR by 18 months and MMR by 24 months were 42.6 ± 7.1, 26.5 ± 6.3 and 35.2 ± 6.9, respectively. The cumulative incidence of MMR in pediatric patients was inferior to that in adult cohort (P < 0.0001) (Figure 1). Progression to accelerated phase and blast crisis occurred in 2 patients each. The 10-year progression-free survival (PFS) and overall survival (OS) (% ± SE) were not significantly different between pediatric and adult cohorts (90.4 ± 4.7 vs. 93.0 ± 1.3, P= 0.533; 90.6 ± 4.7 vs. 94.3 ± 1.6, P= 0.176).The IS levels at 3 months among three different Sokal risk groups did not differ in pediatric CML. Patients achieving MMR in Sokal low-risk group of pediatric cohort were significantly lower than those of adult patients (P= 0.002) whereas the PFS and OS by Sokal risk group in pediatric and adult CML patients did not show statistical difference.ConclusionsThe molecular responses in pediatric CML patients receiving front-line imatinib therapy were inferior to those of adult cohort, but the PFS and OS did not differ between the two cohorts. The Sokal scores did not predict outcome in pediatric CML. [Display omitted] DisclosuresShih:Novartis (Taiwan) Co., Ltd.: Research Funding.

A Nomogram Predicting Progression Free Survival in Patients with Gastrointestinal Stromal Tumor Receiving Sunitinib: Incorporating Pre-Treatment and Post-Treatment Parameters.

Simple SummarySunitinib has been approved as the second-line targeted treatment for gastrointestinal stromal tumor (GIST) after imatinib failure. It is thus necessary to effectively assess prognosis after sunitinib use. However, the current assessment remains insufficient for the contemporary period. We examined prognostic factors influencing progression-free survival. Furthermore, we constructed a prognostic nomogram model using these significant pre-treatment and post-treatment variables.The present study aimed to construct a prognostic nomogram incorporating pre-treatment and post-treatment factors to predict progression-free survival (PFS) after use of sunitinib in patients with metastatic gastrointestinal stromal tumors (GISTs) following imatinib intolerance or failure. From 2007 to 2018, 109 metastatic GIST patients receiving sunitinib at Chang Gung Memorial Hospital, Taiwan, were enrolled. A prognostic nomogram to predict PFS was developed. Sixty-three male and forty-six female metastatic GIST patients, with a median age of 61 years (range: 15–91 years), received sunitinib. The median PFS for 109 patients is 9.93 months. For pre-treatment factors, male gender, body mass index more than 18.5 kg/m2, no sarcopenia status, higher lymphocyte count, lower platelet/lymphocyte ratio, good performance status, higher sunitinib dose, and non-liver metastasis were significantly associated with favorable PFS. For post-treatment factors, adverse events with hypertension, hand–foot skin reaction, and diarrhea were significantly associated with favorable PFS. However, only eight clinicopathological independent factors for PFS prediction were selected for prognostic nomogram establishment. The calibration curve for probability of PFS revealed good agreement between the nomogram prediction and actual observation. High risk patients will experience the lowest PFS. A prognostic nomogram integrating eight clinicopathological factors was constructed to assist prognostic prediction for individual patients with advanced GIST after sunitinib use.

Wczesny nawrót molekularny po odstawieniu terapii nilotynibem

Pojawienie się imatynibu, a następnie kolejnych inhibitorów kinaz tyrozynowych (TKI), doprowadziło do zrównania długości życia chorych na przewlekłą białaczkę szpikową (CML) z czasem przeżycia oczekiwanym w zdrowej populacji. Obecnie celem terapeutycznym dla dużej grupy pacjentów jest uzyskanie remisji wolnej od leczenia. Wyniki licznych badań wskazują, że spośród pacjentów, którzy osiągnęli stabilną głęboką odpowiedź molekularną (DMR) i odstawili leczenie TKI, 40–50% może pozostać w remisji. Kluczowe jest to, że pacjenci, u których następuje nawrót molekularny, nie doświadczają progresji choroby do fazy zaawansowanej i prawie zawsze odzyskują DMR po ponownym wdrożeniu leczenia. Poniżej przedstawiono opis przypadku pacjenta z CML, u którego z powodu nietolerancji imatynibu wdrożono nilotynib, a po kilku latach terapii lek odstawiono. Cztery tygodnie po przerwaniu leczenia u pacjenta doszło do utraty większej odpowiedzi molekularnej. Niezwłocznie wznowiono terapię nilotynibem i już po 3 miesiącach chory odzyskał DMR.

Skuteczne odstawienie nilotynibu po nietolerancji terapii imatynibem

Wobec wysokiej skuteczności terapii przewlekłej białaczki szpikowej (CML) w fazie przewlekłej inhibitorami kinaz tyrozynowych (TKI) w ostatnich latach coraz istotniejszym celem terapeutycznym staje się zapewnienie pacjentom wysokiej jakości życia, dzięki ograniczaniu toksyczności leczenia, a optymalnie — uzyskaniu remisji wolnej od leczenia (TFR). Można go osiągnąć poprzez efektywne zarządzanie działaniami niepożądanymi TKI oraz próbę zaprzestania leczenia u chorych, którzy osiągnęli stabilną DMR. Poniżej przedstawiono opis przypadku pacjentki z CML, u której z powodu licznych działań niepożądanych terapii imatynibem wdrożono nilotynib. Mimo bardzo dobrej subiektywnej tolerancji w przebiegu leczenia obserwowano hiperlipidemię i hiperglikemię. Ze względu na utrzymującą się stabilną DMR po kilku latach nilotynib odstawiono. Blisko rok od tego momentu pacjentka pozostaje w TFR.

Prognostication of Molecular Relapses after Dasatinib or Nilotinib Discontinuation in Chronic Myeloid Leukemia (CML): A FI-LMC STOP 2G-TKI Study Update

Rea: Incyte Biosciences: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nicolini:Sun Pharma Ltd: Consultancy; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Etienne:Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Guerci:INCYTE: Consultancy, Honoraria. Legros:Pfizer: Honoraria, Research Funding; BMS: Honoraria; Novartis: Honoraria; Incyte Biosciences: Honoraria, Research Funding. Coiteux:Pfizer: Honoraria; BMS: Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Mahon:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau.

Cross-Intolerance with Bosutinib after Prior Tyrosine Kinase Inhibitors in Patients with Chronic Phase Chronic Myeloid Leukemia: BYOND Phase 4 Study

Cross-Intolerance with Bosutinib after Prior Tyrosine Kinase Inhibitors in Patients with Chronic Phase Chronic Myeloid Leukemia: BYOND Phase 4 Study

Impact of Early Switching to Nilotinib As Second Line TKI in Patients with Chronic Myeloid Leukemia Who Were Intolerant to, Suboptimal to and Failed Imatinib: The Thai Multi-Centered Study

Introduction: To date, the ELN recommendation and NCCN guidelines are the principle mile stones to follow up the treatment response and to make the decision of TKIs switching. However, in real life practice, many factors influence changing the real switching date from the date had an indication. This study aims to analyze the impact of early switching to second line TKI, nilotinib, in real life practice, for the CML patients who failed, had sub-optimal response or were intolerant to imatinib.Methods: This prospective study was conducted through 7 medical centers in Thailand between 1st of September 2009 and 31st of August 2011. Adult CML patients of age ≥ 18 years old, in chronic and accelerated phase, who had failure, suboptimal response or intolerance to imatinib, based on ELN 2009 guideline, were included and were eligible with nilotinib 400 mg twice daily. Prospective data collection for 24 months of each patient was performed. The main objective was to identify the impact of early switching to nilotinib on major molecular response (MMR). The other objectives were to observe the efficacy of nilotinib including overall survival, progression free survival and the safety. The survival results were presented as Kaplan-Meier survival curves. For the comparison of the treatment groups, the Kaplan-Meier estimator with the corresponding log-rank test for equality of survivor functions across treatment group was applied.Results: The final 108 cases were analysed. The median age was 47 (17-79) years with the proportion of male to female of 1.4:1 respectively. The median duration of the prior imatinib treatment was 18 months (2-142 months). The median duration between the date of indication and the date of real switching was 3.1 months (0-62.8 months) with 50% changing less than 3 months, 26.9% between 3 months and 12 months, and 23.1% changing longer than 12 months. The indication of switching included 63.6% failure to imatinib, 29% intolerance to imatinib and 7.4% suboptimal to imatinib. On the nilotinib switching, 70.4% completed 24 months follow-up, and 29.6% discontinued treatment mostly because of unsatisfactory results or adverse events.Evaluation was made every 3 months based on 2009 ELN recommendation. At 3 months, 57%, 20%, and 8% of the patients achieved CHR, CCyR and MMR, respectively. Those who did not achieve CHR at 3 months never achieved MMR, while 86 % of those who achieved CCyR at 3 months achieved MMR. All CML achieving MMR at 3 months had sustained MMR throughout the study period (24 months). Imatinib suboptimal response had better outcome than imatinib failure and imatinib intolerance groups.A preliminary analysis of BCR-ABL mutation was performed on 90 cases, and mutations were found on 21 cases. Two of them were T315I which were excluded from the study. The cases with mutation had poorer response to treatment than those without mutation. There was one case with initial G250E mutation developing T315I mutation after treatment with nilotinib. At 24 months, one case progressed to accelerated phase and 3 cases progressed to blastic transformation. The 2-year overall survival and 2-year progression-free survival and were 98.9% and 96.9% (figure 1 and 2), respectively. The interquatile analysis was done to identify the groups of cumulative MMR according to the duration between the date of indication and the date of real switching to nilotinib. The patients who switched to nilotinib within 12 months after date of indication could have a greater chance to achieved MMR than those who switched treatment later than 12 months (p(log-rank) = 0.002) (figure 3).Skin rash, musculoskeletal pain, and infection were the three most common non-hematologic adverse events, However, most of them were grade 1-2, except for 4 cases with grade 3-4 infections. Grade 3-4 hematologic adverse events included thrombocytopenia (12%), neutropenia (11%), anemia (5%) and leucopenia (4%), and most of them were manageable. Although biochemical abnormalities were commonly found, most of them were mild.Conclusions: Nilotinib, as a second line treatment showed excellent efficacy and tolerability. Indication for nilotinib treatment, initial mutation status and depth of response at 3 months after treatment can predict outcomes of the patients. However, the patients will have a greater chance to achieve MMR if they switched to nilotinib within 12 months after the date of indication for changing. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Imatinib Mesylate Is Safe and Effective in Maintaining Cytogenetic and Molecular Response Achieved with 1 Year Nilotinib First Line in Newly Diagnosed Chronic Myeloid Leukemia: Preliminary Results of a Prospective Clinical Trial

Background: Achieving complete cytogenetic response (CCyR) at 12 months for patients with chronic phase chronic myeloid leukemia (CML) treated with imatinib as first line, is associated with significantly improved progression-free survival. Nilotinib has shown a faster and higher rate of CCyR and molecular response as compared to imatinib. However, nilotinib use is associated with diet restriction, higher financial costs, and its long-term use is incriminated in cardiovascular and metabolic complications.Methods: In this prospective single center trial, we evaluated the ability of imatinib to maintain a CCyR achieved after 12 months of first-line treatment with nilotinib. Inclusion criteria were adult patients with previously untreated Philadelphia -positive CML in chronic phase, with a WHO performance status ≤ 2. Patients received 1-year treatment with nilotinib (300mg twice daily) then were shifted to imatinib 400mg daily.Results: Eleven patients (5 females) were so far enrolled in the study, with a median age at diagnosis of 50 years (range 31-83). Patients were started on Nilotinib at a median of 29 days (range 2-32) from diagnosis. One patient had to discontinue nilotinib after 6 months and start dasatinib due to recurrent pancreatitis that resolved upon interruption of nilotinib. Eight patients completed one year of nilotinib, and were switched to Imatinib. The remaining 2 patients are currently on nilotinib as per protocol (less than 12 months since inclusion). Three patients on imatinib had to be switched back to nilotinib, because of imatinib intolerance (n=2; elevated liver transaminases and myositis) or because of loss of MMR (n=1). Therefore, at last follow up (median 64 months), 5 patients are on imatinib, 5 on nilotinib and 1 on dasatinib. All patients (100%) achieved complete hematological response (CHR) and CCyR at 3 and 18 months respectively, and maintained them thereafter. At 12 months, 6 out of 8 eligible patients achieved complete molecular response (CMR; n=3) or major molecular response (MMR; n=3). At 36 months, all eligible patients (n=7) were either in CMR (n=2) or in MMR (n=5). All patients who reached 4 years (n=6), 5 years (n=5) or 6 years (n=3) of follow up remained in either MMR or CMR. No patient developed long-term serious adverse event including cardiovascular or metabolic complications.Conclusion: These findings suggest that imatinib can maintain MMR achieved on short-term nilotinib therapy. This strategy is a potentially safe and effective long-term treatment approach, minimizing costs and cardiovascular and metabolic complications. This however, needs confirmation with a larger number of patients. DisclosuresNo relevant conflicts of interest to declare.

PSY53 - Cost-Effectiveness Analysis of Nilotinib Versus High-Dose Imatinib for the Second-Line Treatment of Chronic Myeloid Leukemia In China : Based on Nation-Wide Data

The incidence of Chronic Myeloid Leukemia (CML) in China has increased rapidly. The first-line imatinib (400 mg QD), as the first generation of tyrosine kinase inhibitor, can make CML reach a 10-year overall survival rate of 85-90% and a progression-free-survival rate of 92%. However, some patients caught imatinib-resistance (ImR) or imatinib-intolerance (ImI) in the first-line therapy, who had to begin second-line therapy replacing with nilotinib or high-dose imatinib (600/800 mg QD). Therefore, CML has become a chronic disease, aggravating the burden of both patients and society. This study assessed whether nilotinib or high-dose imatinib for the second-line treatment of ImR/ImI CML Chinese patients is more cost-effective from the perspective of both clinical medical cost and the medical insurance system. This study presented a cost-effectiveness analysis of nilotinib versus high-dose imatinib for ImR/ImI CML patients in China. The study used a model to simulate disease burden based on overall survival rate and a progression-free-survival rate over a 5-yeat time horizon. Results were presented as an incremental cost per quality adjusted life year (QALY) gained. Sensitivity analyses were performed. In the second-line treatment of CML patients, nilotinib plan was associated with lower costs (RMB 5.97 million) and improved QALYs (170.7), over 5 years, resulting in incremental cost-effectiveness ratio of RMB 154,330.8/QALY gained. Sensitivity analysis showed that the results of this study were reliable and stable. At the used threshold of RMB 139,593/QALY, the new policy was cost-effective. Treatment of ImR/ImI CML Chinese patients by nilotinib plan is more cost-effective based on the used threshold of RMB 154,330.8/QALY. The results implying that nilotinib is an absolute advantage as a second-line treatment for ImR/ImI CML patients, and if it could be included in the China’s medical insurance directory, Chinese medical insurance fund will be greatly saved in the payment for CML treatment.

Second-Line Bosutinib in Patients with Chronic Phase Chronic Myeloid Leukemia (CP CML) Resistant or Intolerant to Prior Imatinib: An 8-Year Update

Bosutinib is an orally active, dual SRC/ABL tyrosine kinase inhibitor (TKI) approved for treating adult patients with chronic phase, accelerated phase (AP), or blast phase (BP) Philadelphia chromosome-positive (Ph+) CML with resistance or intolerance to prior therapy. In an open-label, phase 1/2 study (NCT00261846), second-line bosutinib demonstrated durable hematologic and cytogenetic responses and good tolerability in patients with Ph+ CP CML who were imatinib resistant (IM-R) or imatinib intolerant (IM-I) (Cortes, Am J Hematol, 2016). Here we report a 96-month update of this study and its ongoing extension study (NCT01903733).Adult patients with Ph+ CP CML who were resistant or intolerant to first-line imatinib were included in this analysis. 195 IM-R and 89 IM-I patients received bosutinib starting at 500 mg/d. Median age (range) was 53 yr (18-91 yr), time from CML diagnosis was 3.7 yr (0.1-15.1 yr), treatment duration was 25.6 mo (0.2-133 mo), and follow-up duration was 53.7 mo (0.5-133 mo). Bosutinib dose was increased to 600 mg/d in 13% of patients. For the last enrolled IM-R and IM-I patients, time from first dose of bosutinib to data cutoff was 96.5 mo and 94.2 mo, respectively. At 8 yr, 26% of patients were still receiving bosutinib.Major cytogenetic response (MCyR) was achieved by 60% of patients in both groups (Table). Median duration of MCyR was not reached as of the minimum follow-up, and the Kaplan-Meier probability of maintaining MCyR at 8 yr was 60% (IM-R) and 75% (IM-I). Complete cytogenetic response (CCyR) was achieved by 49% (IM-R) and 51% (IM-I) of patients. Median duration CCyR was not reached as of the minimum follow-up, and the Kaplan-Meier probability of maintaining CCyR at 8 yr was 57% (IM-R) and 69% (IM-I) of patients. On-treatment transformation to accelerated phase or blast phase occurred in 7% (IM-R) and 2% (IM-I) of patients with no new events since the 5-yr follow-up. The cumulative incidence of on-treatment progression or death at 8 yr was 28% (IM-R) and 11% (IM-I), respectively (Table). Overall survival at 8 yr on study was 75% for the IM-R group and 87% for the IM-I group.Dose delays due to adverse events (AEs) occurred in 133 (68%) and 76 (85%) of IM-R and IM-I patients, resulting in median cumulative treatment delays of 25 d and 27 d, respectively. Dose reductions due to AEs occurred in 93 (48%) and 54 (61%) of IM-R and IM-I patients, respectively. Median cumulative duration of dose reduction was 357 d and 267 d, and median time to dose reduction was 49 d and 54 d in the IM-R and IM-I cohorts, respectively. By 8 yr, treatment was discontinued in 141 (72%) and 69 (78%) of IM-R and IM-I patients, respectively. The most common reasons for discontinuation were disease progression (23%) and AEs (16%) in the IM-R cohort, and AEs (42%) and patient request (13%) in the IM-I cohort. In the IM-R cohort, the most frequent AEs leading to permanent treatment discontinuation were thrombocytopenia (4%), increased ALT (2%), and diarrhea (2%). In the IM-I cohort the most frequent AEs leading to permanent treatment discontinuation were thrombocytopenia (11%), neutropenia (5%), increased ALT (3%), and rash (3%). Among the 40 patients (21%) in the IM-R cohort who died on study, the most frequent reasons for death were disease progression (12%) and AEs unrelated to study drug (7%). For the 11 patients (12%) in the IM-I cohort who died on study, the most frequent reasons were disease progression (7%) and unknown (3%). No patients died due to an AE related to study drug and 13 patients (5%) died within 30 days of last dose. Five subjects died since the 5-yr follow-up; 3 within 30 days of last dose.These long-term (8-yr) data are consistent with previous findings associating second-line bosutinib therapy with similar rates of durable major cytogenetic responses in the majority of patients with imatinib-resistant and imatinib-intolerant CP CML. Most AEs could be managed through temporary treatment interruptions and dose reductions. [Display omitted] DisclosuresBrümmendorf:Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Gambacorti-Passerini:BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Pagnano:Roche: Speakers Bureau; Amgen: Consultancy; Bristol-Meirs Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy. Aguiar:Pfizer: Employment, Equity Ownership. Leip:Pfizer: Employment, Equity Ownership. Cortes:Teva: Research Funding; Pfizer: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding.

Nilotinib As Second-Line Therapy in Patients with Chronic Myeloid Leukemia in Chronic Phase: Thailand Experience

Background: Nilotinib, a second generation tyrosine kinase inhibitor, was proved to have high efficacy on treatment of Philadelphia chromosome positive CML patients who failed or were intolerant to imatinib. Limited data was available on its efficacy and safety in Asian population.Methods: Chronic phase CML patients who have failure, suboptimal response or intolerance to imatinib according to ELN 2009 guideline were treated with nilotinib 400 mg twice daily on 7 centers in Thailand. Prospective data collection for 24 months was performed.Results: There were 106 cases participated in this study, 2 cases with initial T315I mutation were excluded from the study, total 104 cases were analysed. The median age was 46 (16-79) years with a slight male predominance over female at the ratio of 1.4:1 respectively. Twenty five percent received imatinib less than 12 months whilst 20% received imatinib longer than 60 months. The median duration of the prior imatinib treatment was 18 months (2-142 months). Best response to imatinib treatment were major molecular response (MMR) 5.8%, complete cytogenetic response (CCyR) 26%, major cytogenetic response (MCyR) 12.5%, complete hematologic response (CHR) 47%, and no CHR 8.7%. The reasons for nilotinib switching were imatinib failure 65%, imatinib intolerance 28%, imatinib suboptimal response 7%. Sixty-eight percent were completed 24 months follow up. Of those, 32% early discontinued treatment mostly because of unsatisfactory results or adverse events. Two patients died of infection and CNS bleeding during the study period.Evaluation were made every 3 months based on ELN 2009 criteria . Best response to nilotinib treatment included MMR 57%, CCyR 16%, MCyR 6%, CHR 16%, and no CHR 5%. At 3 months, 91%, 35%, and 14% of the patients CHR,CCyR, and MMR, respectively. Achieving CCyR or MMR at 3 months predicted a chance of achieving MMR (P= 0.00001) Those who did not achieve at least CHR at 3 months never achieved MMR, while 86 % of those who achieved CCyR at 3 months achieved MMR and 100% of those achieving MMR at 3 months had sustained MMR throughout the study period (24 months). Imatinib suboptimal response had significantly better outcome as compared to imatinib failure and imatinib intolerance group (P = 0.017). All of suboptimal response cases achieved CCyR , 86% achieved MMR, no early discontinue treatment in this group. While 75% of failure group achieved CCyR, 62% achieved MMR and 62% of intolerance group achieved CCyR, 38% achieved MMR. The reason for poorer response of intolerance group was high rate of early discontinue due to side effects, 17% vs 5% in the imatinib failure group.Initial BCR-ABL mutation analysis was performed on 90 cases, mutations were found on 16 cases, 2 of them were T315I which were excluded from the study. The cases with mutation significantly had poorer response to treatment than those without mutation (P = 0.001). There was one case with initial G250E mutation, who developed T315I mutation after treatment with nilotinib. At 24 months, 1 case progressed to accelerated phase and 3 cases progressed to blastic transformation. The 2-year progression-free survival and 2-year overall survival was 96% and 98%, respectively.Skin rash, musculoskeletal pain, and infection were the three most common non-hematologic adverse events found in 18%, 13%, and 6% of the patients, respectively; however, most of them were grade 1-2, except for 4 cases with grade 3-4 infections .Grade 3-4 hematologic adverse events included thrombocytopenia (12%), neutropenia (11%), anemia (5%), and leucopenia (4%); and most of them were manageable. Although biochemical abnormalities were commonly found, most of them were mild. Grade 3-4 events found were hypophosphatemia (6%), hyperglycemia (4%), and elevated serum lipase (4%). Only 10 cases (9%) permanently discontinued nilotinib due to its adverse effects.Conclusions: Nilotinib, as a second line treatment for Thai patients with chronic phase CML showed excellent efficacy and tolerability. Indication for nilotinib treatment, initial mutation status and depth of response at 3 months after treatment can predict outcomes of the patients.Author contact: KanchanaChansung M.D. Division of Hematology, Department of Medicine, Faculty of Medicine, Khonkaen University, Khonkaen, Thailande-mail: kchansung@gmail.com DisclosuresNo relevant conflicts of interest to declare.

Upfront Imatinib with Selective Early Switching to Nilotinib Leads to Excellent Achievement of Deep Molecular Response in Chronic Phase CML: 5 Year (Final) Analysis of the TIDEL-II Study

Upfront Imatinib with Selective Early Switching to Nilotinib Leads to Excellent Achievement of Deep Molecular Response in Chronic Phase CML: 5 Year (Final) Analysis of the TIDEL-II Study

Physicians' Attitude Towards Selection of Second Line Therapy with Nilotinib and Dasatinib in Chronic Myeloid Leukemia Patients

Background:One of the main challenges in the treatment of chronic myeloid leukemia (CML) is the selection of second line therapy. While Nilotinib (NILO) and dasatinib (DASA) are available for use as second line treatment for several years, few evidence-based data is available on how physicians make decisions on the use of one drug over another.Aim:We performed a pilot study to describe which factors physicians consider most relevant when deciding therapy with either NILO or DASA in patients who previously failed or were intolerant to Imatinib (IMA) therapy.Patients and methods:Analyses are based on a sample 67 CML patients, recruited as part of a larger international study, who switched from IMA therapy to either NILO (N=36; 53.7%) or DASA (N=31; 46.3%). Patients had to be in second line treatment for at least three months to be eligible for this analysis. Also, in all participating centers, NILO and DASA should have been equally available for use. There were 15 physicians involved in the management of these patients and they were asked to complete an ad-hoc questionnaire investigating reasons based on which they made the decision to either use one drug over another. All questions were phrased as follows: "To what extent have the following issues been determinant to make a decision on which agent (NILO or DASA) to use for this patient?" All answers were rated on a four point likert-scale (ie, not at all, a little, quite a bit and very much). Items investigated were: 1) accessibility of the drug in the hospital; 2) cost of drug; 3) patients' comorbidities; 4) patients' age; 5) patients' personality profile; 6) discussion with patients about Pro and Cons; 7) different treatment schedule of drugs; 8) type of mutation during IMA therapy. Physician characteristics were also collected and analyzed. Other treatment-related variables were investigated such as main reason for changing of TKI (IMA intolerance or resistance), high grade adverse events (AEs) experienced during IMA treatment, or previous duration of IMA therapy.Results:Physicians' experience in treating CML patients was on average 14 years (range 4-32). Patient median age at the time of treatment switch was 47 and 55 years in the NILO and DASA group, respectively. Median time of duration of IMA therapy, before receiving second line therapy, was 1.4 years and 3.3 years for those who switched respectively to NILO or DASA. No differences existed between groups with regard to reasons for switching from IMA therapy (intolerance or resistance) or AEs reported with previous IMA therapy. The top issue considered as most relevant when making the decision was previous discussion with patients on advantages and disadvantages of drugs, being reported as "quite a bit" and "very much" important in 73% of evaluations. Cost of the drug was not considered relevant at all, in the selection of which drug to use, in 97% of the 69 evaluations considered. Also, type of mutation during IMA therapy was considered as of negligible relevance for the decision, but it should not be overlooked that mutations were detected in few patients. Patient's comorbidity or personality profile was quoted as a 'quite a bit' or 'very much' relevant reason for the selection of 2nd line TKI, respectively in 43% or 48% of all questionnaires. Low relevance was assigned to patient age and different treatment schedule: 'not at all' or 'a little' relevance was reported respectively in 64% and 70% of all questionnaires. The analysis of physician-reported grading distribution according to the type of second line treatment did not show any significant difference (no reason lead to a preferential selection of one drug), see table 1.Conclusions:No differences were detectablein selected factors, driving the decision to switch either to NILO or DASA when physicians consider switching from first line IMA therapy. Also, type of TKI selection does not seems to be guided by only one factor. Further research is needed to elucidate on potential reasons underlying clinical decision making in 2nd TKI selection. [Display omitted] DisclosuresEfficace:Seattle Genetics: Consultancy; TEVA: Consultancy, Research Funding; Lundbeck: Research Funding; Bristol Myers Squibb: Consultancy. Rosti:Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau. Breccia:Celgene: Honoraria; Pfizer: Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Ariad: Honoraria. Baccarani:Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau.