Frontline Imatinib Research Articles

Management of Chronic Myeloid Leukemia that is Intolerant or Resistant to Front-Line Treatment

With advances in treatment for chronic myeloid leukemia (CML), the natural history of chronic phase (CP) CML has changed, with most individuals expected to live a normal life expectancy. The goal of therapy for most is to achieve a long-term deep molecular response (DMR) with the potential for medication discontinuation and treatment-free remission (TFR).1 Currently, six oral therapies have been approved for CP-CML in Canada: (1) imatinib, a first-generation tyrosine kinase inhibitor (TKI); (2) dasatinib, (3) nilotinib, and (4) bosutinib, the second-generation TKIs (2G-TKIs); (5) ponantinib, a third-generation TKI; and (6) asciminib, specifically targeting the ABL Myristoyl pocket (STAMP) inhibitor. Classically, treatment for CP-CML has consisted of front-line imatinib and switching to a 2G-TKI upon treatment resistance or intolerance. Increasingly, patients are being prescribed an upfront 2G-TKI with the goal of achieving quicker and deeper molecular remissions and a TFR.2 Challenges arise in CML when treatment with either two TKIs (imatinib + 2G-TKI) or one 2G-TKI fails, given the lack of evidence to inform clinical decision-making at this juncture. This paper aims to define TKI failure and help guide the selection of second-line treatment after failure of front-line therapy.

Long-term outcomes of frontline imatinib therapy for chronic myeloid leukemia in China.

Imatinib is the first-line therapy recommended for chronic myeloid leukemia (CML) patients in China. We reported a long-term follow-up study of patients on imatinib as first-line treatment for chronic phase (CP) CML to provide an important reference for the actual clinical treatment regimen of CML patients in China. We evaluated the long-term efficacy, safety, low-dose attempt after years of treatment, and treatment-free remission (TFR) of 237 CML-CP patients receiving first-line imatinib therapy. The median age was 46 years (interquartile range: 33-55). After a median follow-up of 6.5 years, the cumulative complete cytogenetic response, major molecular response (MMR), and MR4.5 rates were 82.6%, 80.4%, and 69.3%, respectively. The 10-year transformation-free, event-free, and failure-free survival rates were 97.3%, 87.2% and 53.5%, respectively. Fifty-two (21.9%) patients with sustained deep molecular response (DMR) were treated with low-dose imatinib after years of imatinib treatment. No significant differences in the 1-year and 2-year molecular relapse-free survival in MMR and MR4 were observed between the standard-dose and low-dose groups. Twenty-eight (11.8%) patients discontinued imatinib, and the median time to maintain DMR before discontinuation was 8.43 years. Thirteen patients (5.5%) remained in TFR for a median of 43.33 months. No patients transformed to accelerate or blast phase or died. No new, late toxicity was observed, and the most frequent grade 3/4 adverse events were neutropenia (9.3%), anemia (7.6%), thrombocytopenia (6.3%), and rash (4.2%). This study confirmed the long-term efficacy and safety of imatinib for treating Chinese CML patients. Additionally, it demonstrated the feasibility of imatinib dose reduction and TFR attempts in patients with sustained stable DMR after years of imatinib treatment in real-life settings.

Additional Mutational Events at Diagnosis of CML Confer Inferior Failure-Free Survival and Molecular Response for Patients Treated with Frontline Imatinib but Not for Patients Treated with Frontline Second-Generation Tyrosine Kinase Inhibitors

Background We previously performed an integrative genomic analysis for 47 chronic phase (CP)-CML patients at diagnosis who were specifically selected based on optimal or very poor outcome to tyrosine kinase inhibitors (TKIs). Patients who subsequently progressed to blast phase (BP) had a significantly higher frequency of cancer-related gene mutations at diagnosis compared with patients who achieved an optimal response (54% versus 16%). A novel mutational subtype associated with the formation of the Philadelphia (Ph) chromosome, termed Ph-associated rearrangements, were also described and included novel fusions, deletions and inversions adjacent to the BCR::ABL1 junction. These occurred at a higher frequency of patients who progressed to BP compared to those with an optimal response (33% versus 11%). Consequently, we sought to investigate the true incidence and effect of cancer-gene mutations and Ph-associated rearrangements (collectively termed additional mutational events, AMEs) detected at diagnosis and whether outcomes differ based on the TKI initiated. Aim To assess the impact on outcome and molecular response of AMEs detected at diagnosis for patients consecutively treated with imatinib compared to patients treated with second-generation TKIs (2G-TKI). Methods A recently validated hybridization capture sequencing method targeting genes involved in both myeloid and lymphoid malignancies was applied to available diagnostic RNA of consecutive clinical trial patients treated with either frontline imatinib or 2G-TKIs. The 200 imatinib-treated patients (TIDEL II; CML9) were commenced on 600mg daily of imatinib and managed with a highly proactive treatment intervention strategy for suboptimal response, which was either imatinib dose increase or switch to nilotinib. The 2G-TKI patients were enrolled in either DIRECT;CML12 (n=72), where patients commenced dasatinib 100mg daily before dose modification, or either ENESTxtnd or PINNACLE;CML11 (n=44) where patients commenced nilotinib 300mg twice daily. Variants in cancer genes with variant allele frequencies ≥5%, including single nucleotide variants, RNA splice altering variants, small insertions/deletions, gene fusions and focal gene deletions were assessed for pathogenicity using strict criteria. Ph-associated rearrangements were identified. Clinically relevant variants were confirmed as somatic and validated. Kaplan-Meier and cumulative incidence analyses were performed to assess the effect of AMEs on failure-free survival and key molecular outcomes by 36 months. Failure events were as defined by the European LeukemiaNet 2020. Results The incidence of AMEs for imatinib-treated patients was 31% (61/200): 33 (16%) cancer gene mutations and 36 (18%) Ph-associated rearrangements; 8 patients had both subtypes. In the 2G-TKI group, 41 AMEs were identified in 29% (34/116) of patients: 20 (17%) cancer gene mutations and 16 (14%) Ph-associated rearrangements; 2 patients had both subtypes. In total, 14 cancer genes were mutated. Consistent with other studies, ASXL1 mutations were most frequently detected: 18/200 imatinib patients (9%) and 9/116 2G-TKI patients (8%). Using 36-month outcomes as comparison, imatinib-treated patients with AMEs had inferior failure-free survival (84% versus 69%, P=.03), major molecular response (84% versus 72%, P=.02) and MR4 (62% versus 37%, P=.001). In contrast, outcomes in the 2G-TKI cohort were similar irrespective of the presence of AMEs, with regards to failure-free survival (94% versus 91%, P=.47) and achievement of major molecular response (88% versus 83%, P=.71). Interestingly, achievement of MR4 was delayed for patients with AMEs compared to those without AMEs at diagnosis: 51% versus 69%, P=.02 by 24 months; and 63% versus 70%, P=.40 by 36 months. No differences were observed for overall survival or transformation-free survival in either the frontline imatinib or 2G-TKI cohorts. Conclusion These results indicate that while the presence of AMEs do predict for inferior outcomes and molecular responses when patients are treated with frontline imatinib, the more potent 2G-TKIs may overcome the negative impact of the AMEs. The effect for imatinib treated patients was evident despite a starting dose of 600mg and more stringent treatment intervention than currently recommended. This supports a strategy of mutation analysis at diagnosis of CP-CML for optimal TKI selection. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Management of Chronic Myeloid Leukemia in Bosnia and Herzegovina: Treatment Patterns, Molecular Monitoring, and Outcomes

Introduction Chronic myeloid leukemia (CML) patients in low- and middle-income countries have limited access to tyrosine kinase inhibitor (TKI) therapies. Long delays in the start of TKI treatment may have significant consequences on patients' outcomes; therefore, monitoring and therapy management of these patients is undoubtedly challenging. The aim of the study was to conduct a comprehensive long-term analysis of CML management in a developing country in the era of limited TKIs. Methods Newly diagnosed CML patients in chronic phase (n=265) treated with imatinib (Glivec or generics) or nilotinib (Tasigna) in the period from 6/2005 to 6/2022 in the Federation of Bosnia and Herzegovina were included in this multicenter study. Glivec was available from 6/2005 to 9/2013, generic imatinib from 9/2013 to present, and Tasigna from 11/2011 to present. From 2005 to 2013, the waiting list was created due to the limited number of TKIs. Introduction of generic imatinib in 9/2013 led to the cancellation of the waiting list; branded imatinib was ceased and patients were switched to generics. Patient cohort consisted of 171 patients started on front-line imatinib, 60 patients on front-line nilotinib, 19 patients who died while waiting for TKI, 7 patients who discontinued therapy (pregnancy (n=3) or voluntarily (n=4)), and 8 patients did not have complete data. Patients were categorized based on the type of therapy: Group 1 (front-line imatinib, n=171) and Group 2 (front-line nilotinib, n=60). In Group 1, patients were furthermore subcategorized: Group 1a (front-line Glivec, n=83) and Group 1b (front-line generic imatinib, n=88). Patients from Group 1 and Group 2 were additionally categorized and compared according the length of wait period before therapy initiation: <6 months wait (n=120 vs. n=43), 6-12 months wait (n=20 vs. n=7), and >13 months wait (n=31 vs. n=10). BCR-ABL1 was confirmed by nested PCR/FISH/karyotype and BCR-ABL1 QPCR was evaluated every three months from 2012. Complete cytogenetic response (CCyR) was defined as <1% BCR-ABL1-positive nuclei of at least 200 nuclei by FISH or 20 metaphases using CBA. Major molecular response (MMR) was defined as ≤0.1% BCR-ABL1 expression. Standard patients' variables were collected and survival probabilities were estimated using the Kaplan-Meier method and compared with the log-rank test. The study was conducted according to the Declaration of Helsinki. Results We compared overall survival (OS), CCyR, and MMR in 265 patients based on the type of therapy (branded or generic imatinib and nilotinib) and delayed treatment. We first compared outcomes of patients based on initiating therapy alone, imatinib (Group 1, 42 months median follow-up) and nilotinib (Group 2, 45 months median follow-up). In Group 1, 39% (n=66) of patients were switched to nilotinib. In Group 2, 7% (n=4) were switched to imatinib. In Group 1, 27 patients died on front-line imatinib, 14 patients on second-line nilotinib, and one on third-line imatinib (overall 25%); in Group 2, 6 patients died on front-line nilotinib, and 1 on second-line imatinib (overall 12%). At 120 months, OS was 69% vs. 81% for Group 1 and Group 2, respectively (p=0.057); CCyR at 36 months was 73% vs. 89%, respectively (p=0.000); MMR at 36 months was 69% vs. 88%, respectively (p=0.000). Comparing the outcomes of branded (Group 1a) vs. generic imatinib (Group 1b), we found that at 72 months, OS, CCyR, and MMR were not significantly different (85% vs. 84%, p=0.876; 90% vs. 90%, p=0.051; 88% vs. 92%, p=0.11, respectively). Among imatinib treated patients, subgroups <6 months wait, 6-12 months wait, and >13 months wait showed deleterious effects on long-term patients outcomes; OS at 120 months was 78%, 76%, and 42% (p=0.040), CCyR at 48 months was 90%, 87%, and 58% (p=0.000), MMR at 60 months was 87%, 65%, and 44% (p=0.000), and MR4 at 60 months was 74%, 42%, and 37% (p=0.020). However, patients treated with nilotinib after the delay showed no significant differences in OS, CCyR, and MMR compared to immediate nilotinib treatment. Conclusion The long-term study from Bosnia showed that OS, cytogenetic, and molecular reponses were similar to previously published real-world data. Outcomes on generic imatinib were comparable to branded imatinib. However, nilotinib showed superiority over imatinib, especially in patients whose start of treatment was delayed.

Choice of Tyrosine Kinase Inhibitor and Early Events during the First Year of Therapy in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia (CML) Patients with Concomitant Diabetes: A "Campus CML" Study

Background Tyrosine kinase inhibitors (TKIs) have dramatically changed the treatment of chronic myeloid leukemia (CML). Most of data on the TKIs safety derive from sponsored controlled trials, where patients with multiple comorbidities had fewer opportunities to be included. Many questions about the management of newly diagnosed CML can only be answered by analysing large cohorts in real world practice. Methods To evaluate the choice of TKI and the incidence of early events during the 1st year of therapy in newly diagnosed chronic phase CML patients with concomitant diabetes, we retrospectively studied 1732 CP-CML patients diagnosed from 1/2012 to 12/2019 at 33 Italian Hematology Centres and treated with frontline imatinib (IM) or second-generation TKIs (2G). Among these, 197 patients (11.4%) had concomitant diabetes. Results The main clinical features at diagnosis of the entire cohort and in patients with diabetes are reported in the Table. Compared with non-diabetic patients, subjects with diabetes were older, had higher Sokal and ELTS scores (Sokal intermediate + high 74.5% vs 59.2%, ELTS intermediate + high 62.6% vs 41.1%) and were more likely affected by other comorbidities as arterial hypertension, COPD, ischemic heart disease/cerebrovascular events and previous neoplasms: as a consequence, diabetic patients reported a higher number of concomitant drugs (> 5 in 38.6% vs 10.1%, p<0.001). The number of white blood cells at diagnosis was lower in diabetic patients (44.9x109/l vs 59.3 x109/l, p=0.008)). Significant differences were observed in the choice of frontline TKI: comparing diabetic with non-diabetic patients, IM was prescribed in 72% vs 54%, dasatinib in 23.4% vs 15.3% and nilotinib in 4.6% vs 30.7% of cases (p<0.001). There were 51 early events (25.9%) in the 1st year of treatment leading to permanent frontline TKI discontinuation in the diabetic patients, compared to 285 (18.7%) in non-diabetic patients (p=0.037). One-year cumulative incidence of TKI permanent discontinuation was 25.9% (95%CI 19.8 - 32.0) in diabetic patients compared to 18.5% (95%CI 16.6 - 20.4) in non-diabetic patients (p=0.015). Conclusions This real-world study on over 1700 CML patients shows that concomitant diabetes is an important factor in newly diagnosed CML patients, affecting both the clinical presentation and the frontline treatment choice: in addition, concomitant diabetes is linked to a high incidence of early events and frontline TKI permanent discontinuation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Permanent Discontinuation of Tyrosine Kinase Inhibitor Frontline Therapy in Patients with Chronic Phase Chronic Myeloid Leukemia Patients during the First 36 Months of Treatment: A "Campus CML" Study

Background Tyrosine kinase inhibitors (TKIs) have changed prognosis and treatment results of chronic myeloid leukemia (CML). However, the first years of therapy are crucial to achieve optimal response, defined as the achievement of deep molecular response: in this early phase, however, different toxicities or suboptimal response/resistance may occur, leading to permanent frontline TKI discontinuation and need for a second-line switch. Methods To evaluate in a large real-life cohort of CML patients the incidence and the different pattern of events leading to a permanent frontline TKI discontinuation during the first 3 years of therapy, 1168 CP-CML patients diagnosed from 1/2012 and 12/2019 at 21 Hematology Centres and treated with frontline imatinib (IM) or second-generation (2G) TKIs dasatinib or nilotinib were retrospectively analysed. Results Frontline TKI was IM in 737 (63.1%) and 2G-TKIs in 431 (36.9%) cases: the main clinical features at diagnosis of the entire cohort and according to frontline treatment are reported in the Table 1. Commonest comorbidities were arterial hypertension (37.4%), previous neoplasm (14.1%), diabetes (10.9%), peripheral vascular diseases (8.4%), ischemic heart disease (6.9%) and COPD (6.7%). IM-treated patients were older (p<0.001) and had more comorbidities (p=0.002 for COPD and p<0.001 for all other diseases). Total number of patients who had discontinued frontline TKI at the 36th month of observation was 391/1168 (33.5%), being higher with IM (294/737, 39.8%) than with 2G-TKIs (96/431, 22.3%) (p<0.001). Cumulative incidence of permanent TKI discontinuation was 19.6% [95% confidence interval (CI) 17.3-21.9] at 12 months, 29.7% (95%CI 27.0-32.4) at 24 months and 34.2% (95%CI 31.5-36.9) at 36 months, respectively: cumulative incidence of discontinuation according to frontline TKI is shown in the Figure (p<0.001 at any time-point). Among the 391 patients who discontinued frontline TKI, the main causes were hematologic toxicity in 27 (6.9%), extra-hematologic toxicity in 106 (27.1%), primary resistance in 166 (42.4%), secondary resistance in 18 (4.6%), evolution in blastic phase in 17 (4.3%), unrelated deaths in 36 (9.2%) and other causes in 21 (5.4%). At univariate analysis, in addition to IM as frontline TKI, baseline factors predictive for an higher rate of TKI discontinuation were age > 65 years (p=0.001), WBC ≥ 100 x 109/l (p<0.001), Hb < 10 g/dl (p<0.001), spleen enlargement ≥ 5 cm below costal margin (p<0.001) and high Sokal score (p<0.001). At multivariate regression logistic analysis, frontline IM (HR 3.22; 95%CI 2.34 - 4.42, p<0.001), WBC ≥ 100 x 109/l (HR 2.18; 95%CI 1.57 - 3.02, p<0.001), spleen enlargement ≥ 5 cm (HR 1.91; 95%CI 1.22 - 3.00, p=0.005) and Sokal high risk (HR 1.78; 95%CI 1.16 - 2.72, p=0.007) retained an independent predictive role on TKI discontinuation. Conclusions This real-world study on over 1100 CML patients reveals that about one third of newly diagnosed CML patients discontinued frontline TKI during the first 3 years of therapy, mostly for primary resistance or toxicity. Discontinuation rates were higher with IM compared to 2G-TKIs at any time-point: however, the impact of older age, higher risks and heavier burden of comorbidities in IM patients should be considered. Other factors seemed to affect the risk of frontline TKI discontinuation but their role needs further refined investigations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CML-187 Association of Molecular Remission With Eutos and ELTS Risk Scores Among CML Patients in the Armenian Cohort

Current research focusing on chronic myeloid leukemia (CML) includes a prediction of treatment outcomes with risk scores and the possibility of treatment-free remission (TFR) with regular molecular monitoring. In Armenia, a low-income country, regular molecular monitoring and monitoring-based treatment has been underway since January 2021. Yet, since 2003, frontline Imatinib therapy was performed among all CML patients. Ponatinib and Nilotinib have been available since 2018. The aim of this retrospective study is to evaluate the association of molecular response with EUTOS and ELTS risk status. The data was taken from Hematology Center after prof. R. Yeolyan (Molecular Biology Department, Blood Disease Registry and Armenian CML Database). The study includes 234 newly-diagnosed CML patients during 2010-2020. Frontline therapy was performed with Imatinib in all patients, of whom 23 switched it to other TKI based on qRT-PCR results. Statistical analysis was performed by SPSS 22. The scores were measured only on the basis of CML Database, which is still being completed. EUTOS was evaluated in 114 patients: 4 (3.5%) high and 110 (96.5%) low risk. ELTS was measured in 110 patients: 16 (14.5%) high, 34 (30.9%) intermediate, and 60 (54.5%) low risk. Of the 4 high-risk patients with EUTOS, 1 achieved MR4, 1 had MR5, 1 had MR4.5, and one reached no MR. Of the 110 low-risk Eutos patients, 28 had MMR, 9 had MR4, 13 had MR5, 24 had MR4.5, and 36 reached no MR. Among 16 high-risk patients with ELTS, MMR was obtained in 3 patients, MR4 in 1, MR5 in 3, MR4.5 in 2, and 7 patients did not reach MR. Among 34 intermediate-risk patients with ELTS, MMR was achieved in 9 patients, MR4 in 4, MR5 in 5, MR4.5 in 8, and 8 achieved no MR. Of the 60 patients at low risk for ELTS, 16 patients achieved MMR, 4 patients MR4, 4 patients MR5, 15 patients MR4.5, and 21 patients did not reached MR. Overall, in the Armenian cohort, CML patients achieved MR regardless of their risk status with EUTOS and ELTS. However, based on the small number of high-risk patients, further analysis is needed for a definitive conclusion.

Abstract 147: Bezuclastinib is a differentiated KIT inhibitor that exhibits unique selectivity to KIT A-loop mutations, minimal brain penetration, and favorable pharmacokinetic properties in preclinical models

Abstract KIT is a well characterized oncogenic driver, mutated in up to 80% of gastro-intestinal stromal tumors (GIST). Front-line imatinib is effective in many patients but durable responses in the setting of imatinib failure are rarely achieved due to complex secondary mutations that arise in the KIT ATP-binding pocket (exons 13/14) or the activation (A)loop (exons 17/18). Second-line sunitinib is active against exon 13/14 mutations but not A-loop mutations and identifying inhibitors that target the spectrum of possible mutations without incurring off-target toxicities related to broad-spectrum kinase inhibition has been challenging. Bezuclastinib (CGT9486) is a novel type I tyrosine kinase inhibitor that was designed as a potent and selective inhibitor of KIT A-loop mutations to address this unmet medical need. Herein, we present nonclinical data on the differentiated selectivity profile of bezuclastinib compared with other KIT inhibitors. We show that bezuclastinib is a low nanomolar inhibitor of KIT A-loop mutants which uniquely avoids targeting closely related kinases with known liabilities (e.g., PDGFRA, PDGFRB, CSF1R, and KDR) versus other approved inhibitors. In vivo pharmacokinetic/pharmacodynamic (PKPD) relationships have been evaluated utilizing either HMC1.2 human mast cell leukemia tumors for KIT phosphorylation or a Ba/F3-KIT-D816V splenomegaly model. In these models, plasma exposure associated with 50% reduction in splenomegaly or KIT phosphorylation was observed at 3-10 mg/kg/day corresponding to exposures 1.5-2.2 µg∙hr/mL. This correlated well with plasma exposure required to cause significant tumor growth inhibition in a GIST patient-derived xenograft model harboring an A-loop mutation (~1.3 µg∙hr/mL). Maximal efficacy in the PKPD models and tumor regression in GIST disease models was observed in exposure ranges of 19-36 or 11-44 µg∙hr/mL, respectively, which corresponds to clinically reached exposures in a recent GIST combination study of bezuclastinib with sunitinib. Importantly, in nonclinical studies, we also show that bezuclastinib has minimal brain penetration, a preferred feature of an anti-KIT molecule due to CNS-related adverse events observed in this targeted class. We present a tissue distribution study which demonstrates a brain:plasma ratio &amp;lt;0.1 following a 3-day administration at a dose that correlates with clinical exposure. This attractive selectivity and nonclinical safety profile, combined with early clinical data in advanced solid tumors, supports the potential for a best-in-class KIT inhibitor. Bezuclastinib is currently under clinical investigation in advanced SM (Phase 2, Apex NCT04996875), non-advanced SM (Phase 2, Summit), and imatinib-resistant GIST (Phase 3, Peak). Citation Format: Anna Guarnieri, Karyn Bouhana, LouAnn Cable, Rob Rieger, Leyla Haygood, John Robinson, Shannon Winski. Bezuclastinib is a differentiated KIT inhibitor that exhibits unique selectivity to KIT A-loop mutations, minimal brain penetration, and favorable pharmacokinetic properties in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 147.

Abstract 660: Predicting imatinib responses in exon 18 PDGFRA-mutant GIST

Abstract Gastrointestinal stromal tumor (GIST) is the most common GI sarcoma and frequently harbor oncogenic mutations in KIT or platelet derived growth factor receptor alpha (PDGFRA) receptor tyrosine kinases. While type II tyrosine kinase inhibitors (TKIs) revolutionized the treatment of KIT-mutant GIST, they are thought to be ineffective for many PDGFRA-mutant GIST cases. Over 80% of PDGFRA mutations in GIST occur in exon 18 and patients with the most common mutation, D842V, are resistant to imatinib and other type II TKIs, leading to poor outcomes. However, beyond D842V, numerous other PDGFRA exon 18 mutations have been observed. From curated data of a large cohort of PDGFRA-mutant GISTs, we have identified nearly 50 unique PDGFRA exon 18 mutations, including both point mutations and complex indels. Although it is largely unknown how these mutations respond to imatinib, currently most, if not all, PDGFRA exon 18 mutations are assumed to be imatinib resistant. Using cell models, we tested some of the most commonly observed mutations in this cohort. Contrary to dogma, we observed that some exon 18 mutations tested were imatinib sensitive. We also observed that imatinib sensitivity seemed to be dependent on the properties of the residue in the 842-codon position, which encodes a key auto-inhibitory residue. We then hypothesized that imatinib sensitivity of every known or future reported PDGFRA exon 18 mutation might be predicted based on the 842 residue. To test the predictive potential of the 842 residue, we created mutagenic libraries that included every amino acid substitution at the 842 position. We expressed each mutation in Ba/F3 cells and assessed imatinib sensitivity via immunoblotting for phosphorylated-PDGFRA. Overall, 40% of tested mutations were sensitive to imatinib, further debunking the belief that all PDGFRA exon 18 mutations are imatinib resistant. In agreement with our hypothesis, we found that any hydrophobic residue at the 842 position conferred imatinib resistance (IC50 &amp;gt; 100nM), and all other amino acids tested to date were imatinib sensitive (IC50 &amp;lt; 100nM). Based on these data alone, over 55% of the 50 unique mutations identified from our PDGFRA-mutant GIST patient cohort would be predicted to be imatinib sensitive, demonstrating the importance of understanding the biochemical properties of various exon 18 mutations to predict treatment outcomes. Our predictive model would help identify patients with PDGFRA exon 18 mutations that could benefit from using front-line imatinib as an alternative to avapritinib, which has been recently approved for first-line treatment for all PDGFRA exon 18 mutant GIST. Imatinib, which has been used clinically for over 20 years, has a superior safety and tolerability profile compared to avapritinib. This paradigm shifting approach has the potential to transform patient care and outcomes by optimizing the sequencing of TKIs for PDGFRA-mutant GIST patients. Citation Format: Homma M. Khosroyani, Lillian R. Klug, Johanna Falkenhorst, Sebastian Bauer, Michael C. Heinrich. Predicting imatinib responses in exon 18 PDGFRA-mutant GIST [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 660.

Event-free Survival in Patients with Chronic Myeloid Leukemia Receiving Front-line Imatinib Mesylate

Objective: Chronic myeloid leukemia (CML) prognostication at the time of diagnosis is critical to determine the intensity of initial treatment. Event-free survival (EFS) has become a prominent concept of prognosis in the patients with chronic phase CML (CML-CP). The aim of this study is to assess the prognostic impact of bone marrow (BM) and peripheral blood (PB) cellular components, in correlation with the clinical parameters. Materials and Methods: One hundred forty-three patients with CML-CP on the front-line imatinib mesylate therapy were recruited into this study. Clinical and laboratory characteristics, therapeutic responses were recorded. Sokal, Euro/Hasford, The EUropean Treatment Outcome Study (EUTOS) and The EUTOS long-term survival (ELTS) scores were calculated for the studied patients. Results: Median follow-up time was 84 (IQR: 54-125) and median front-line therapeutic duration was 56 (IQR:23-89) months. Five-year EFS rate was 62.3% (95% CI: 53.9-70.7). The blast percentage in the BM, EUTOS scores, and basophil percentage in PB were related with the poor therapeutic outcomes in frontline therapy (p=0.002, p=0.002 and p=0.042, respectively). Although Sokal risk classification showed that the intermediate class had a higher event risk compared to the low-risk class (p=0.001), the predictive association disappeared in high-risk classes. Conclusion: EUTOS score system has better predictive capability for front-line imatinib therapy comparing with other indices. Higher blast percentage in BM and increased basophil percentage in PB are independent risk factors, adversely related with EFS in patients with CML.

P-264 The molecular-metabolic interplay in metastatic gastrointestinal stromal tumors (GISTs): The predictive role of body mass index

KIT exon 11 Pathogenic Variants (PVs) are the most frequent mutations in Gastrointestinal Stromal Tumors (GISTs). These patients represent a heterogeneous subgroup in terms of biological and clinical behavior: despite most GISTs with KIT exon 11 mutations are highly sensitive to front-line imatinib, the Progression Free Survival (PFS) may vary greatly. We investigated the predictive role of Body Mass Index (BMI), Neutrophil–Lymphocyte Ratio (NLR), and type and codon location of KIT exon 11 mutations in metastatic GIST patients treated with first-line imatinib 400 mg/die. Clinico-pathological characteristics, mutational status, BMI and NLR, were analyzed from a GIST System database prospectively collected. The primary outcome investigated was the Time to Treatment Failure (TTF). We classified the patients in 2 groups: i) KIT Exon 11 deletion or insertion/deletion in codons 557 and/or 558 (named “D-557/8”); ii) other than D-557/8 mutations (named “No-D-557/8”). The NLR was recorded from the routinely performed blood cell count as the absolute count of neutrophils divided by the absolute count of lymphocytes from peripheral blood samples collected at baseline. Sixty (60) KIT exon 11 mutated patients were included in the study: 25 (31.3%) showed exon 11 deletion or delins involving 557 and/or 558 codons (D-557/8 group), and 35 patients (43.7%) had a deletion in codons other than 557/558 or other PV types (duplication, insertion or SNV)(No-D-557/8 group). A total of 41 events (progression or death) were observed (68.3%): 18 events in the D-557/8 group of 25 patients (72%); 23 events in the No-D-557/8 group of 35 patients (65.7%). Overall median TTF was 37 months (95% confidence interval [CI]: 26.8-47.1). Median TTF was 24 months (95% CI: 21.3, 26.7) for the D-557/8 Group, and 49 months (95% CI: 39.4, 58.6) for the No-D-557/8 Group (p 25 (median TTF: 57.4 months (range 32-92) vs 24.2 months (range 3-45); p=0.001). In the KIT exon 11 mutated patients, who are the most common molecular-based subgroup of advanced GIST patients, our results reveal the important impact of BMI on TTF. These data support the functional cross-talk between metabolic and molecular features also in GISTs, paradigmatic model of oncogene addiction, and represent the rationale to better investigate whether factors of metabolic interest, such as BMI, could have a further impact on response to treatment.

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

Contemporary “Real World” Molecular Testing and Tyrosine Kinase Inhibitor Adherence Patterns Among Older Pts with Chronic Myeloid Leukemia in the United States

Contemporary “Real World” Molecular Testing and Tyrosine Kinase Inhibitor Adherence Patterns Among Older Pts with Chronic Myeloid Leukemia in the United States

CD34+/CD38- Stem Cell Burden Could Predict Chronic Myeloid Leukemia Patients' Outcome.

Background:The current predictor of the Chronic myeloid leukemia (CML) patients’ outcome is the degree of response to targeted therapy; here we search for a biomarker predicting CML outcome before start of therapy. This study aimed to assess the impact of the CD34+/CD38- stem cells (SCs) burden in chronic myeloid leukemia (CML) on treatment response and patients’ outcomes. Methods:Our study included 65 CML patients in the chronic phase. The patients’ CD34+/CD38- stem cells were quantified using flowcytometry before and after treatment by frontline imatinib (IM) therapy. The median follow-up for all patients was 18 months. Results:CD34+/CD38- stem cells frequency at diagnosis and after therapies are correlated to known prognostic markers (blast cells count, spleen size, total White cell count, and clinical scores). After therapy, the leukemic stem cells count dropped rapidly. The pretreatment CD34+/CD38- stem cells burden predicts response to frontline therapy. In addition, high SCs frequency at diagnosis predicts poor molecular response, transformation to AML, and poor patients’ outcomes. Conclusion:The percentage of CD34+/CD38- SCs burden at diagnosis reflects the CML disease behavior and is considered a biomarker for predicting CML patients’ response to first-line Tyrosine kinase inhibitors (TKI) therapy.

Early prediction of stable MR4.5 by depth of molecular response at 6 months in patients with chronic myeloid leukemia treated with frontline imatinib

Treatment-free remission is achievable in approximately half of patients with chronic myeloid leukemia who attain a sustained, deep molecular response with tyrosine-kinase inhibitor (TKI) therapy. We aimed to identify potential predictors of future achievement of stable MR4.5, defined as a sustained 4.5-log reduction in BCR-ABL1 transcripts for a minimum of 2 years, in 593 patients treated with imatinib as first-line TKI therapy. In multivariable analyses of patient and disease variables including baseline blood counts, disease phase, additional cytogenetic abnormalities, prior therapy, depth and rapidity of molecular response, the only predictor for future achievement of stable MR4.5 was molecular response at 6 months. In this study, patients failing to attain a molecular response of BCR-ABL1≤ 0.16%IS after 6 months of imatinib therapy were unlikely to subsequently achieve stable MR4.5 with imatinib. Our data suggest that achievement of BCR-ABL1≤ 0.16%IS at 6 months is predictive of future stable MR4.5.

Treatment status of tyrosine kinase inhibitors in Chinese patients with chronic myeloid leukemia in 2020

目的调查中国慢性髓性白血病（CML）患者的治疗现状。方法横断面研究，2020年4月末至5月中旬，以填写调研问卷的形式在全国范围内调研CML患者，分析酪氨酸激酶抑制剂（TKI）一线选择、目前用药、药物转换和获得主要分子学反应（MMR）的比例及其影响因素。结果2933份来自全国31个省市自治区CML受访者的问卷可供分析，男性1683例（57.4％），中位年龄38（16～87）岁。一线选择：伊马替尼2481例（84.6％），原创性新药（原研药）1803例（61.5％）。填写问卷时用药：伊马替尼1765例（60.2％），原研药1791例（61.1％）。共1185例（40.4％）受访者曾经历TKI药物转换。1944例初发慢性期受访者TKI中位治疗45（3～227）个月，1417例（72.9％）获得≥MMR的疗效。多因素分析显示，城镇户籍（OR＝0.6，95％CI 0.5～0.8，P<0.001）、≥大学学历（OR＝0.5，95％CI 0.4～0.7，P<0.001）和进展期（OR＝0.5，95％CI 0.3～0.8，P＝0.001）受访者更少首选仿制TKI，而来自中部地区受访者比东部地区更多首选国产仿制TKI（OR＝1.7，95％CI 1.4～2.0，P<0.001）。进展期受访者更多首选二代TKI（OR＝5.4，95％CI 3.6～8.2，P<0.001），≥60岁受访者更少首选二代TKI（OR＝0.4，95％CI 0.2～0.7，P＝0.002）。诊断时处于进展期（OR＝2.2，95％CI 1.6～3.2，P<0.001）、首选伊马替尼（OR＝2.0，95％CI 1.6～2.6，P<0.001）、首选国产仿制药（OR＝1.3，95％CI 1.1～1.6，P＝0.002）、诊断距开始TKI治疗的时间更长（OR＝1.2，95％CI 1.1～1.2，P<0.001）和服用TKI的时间更长（OR＝1.1，95％CI 1.0～1.1，P<0.001）与药物转换比例增高显著相关。城镇户籍（OR＝0.7，95％CI 0.6～0.8，P<0.001）、获≥MMR（OR＝0.6，95％CI 0.5～0.8，P<0.001）和疗效未知（OR＝0.7，95％CI 0.6～0.9，P＝0.003）与药物转换比例低显著相关。女性（OR＝1.4，95％CI 1.1～1.7，P＝0.003）、城镇户籍（OR＝1.6，95％CI 1.3～2.0，P<0.001）、初始服用伊马替尼（OR＝1.4，95％CI 1.1～1.9，P＝0.016）和TKI治疗时间更长（OR＝1.2，95％CI 1.2～1.3，P<0.001）与获得≥MMR显著相关，而年龄≥60岁（OR＝0.7，95％CI 0.4～1.0，P＝0.047）和药物转换（OR＝0.6，95％CI 0.5～0.7，P<0.001）与未获得MMR显著相关。结论截至2020年，中国CML患者中大多数首选并持续服用伊马替尼，半数以上服用原研药。社会人口学特征和疾病分期影响了患者的TKI选择、药物转换和治疗反应。

The Impact of Early Molecular Response at 3 Months on Long-Term Survival Was Enhanced in the CP CML Patients Treated with Second-Generation Tyrosine Kinase Inhibitors

Background: Recent studies have demonstrated that early molecular milestones were able to identify high-risk chronic myeloid leukemia patients treated with frontline imatinib (IM) and second-generation tyrosine kinase inhibitors (2G-TKIs). 2G-TKI treated patients achieved faster and deeper molecular responses compared with IM treated patients. Because CML patients currently have multiple treatment options, the impact of early molecular milestones on long-term outcomes needs to be determined in each agent treated patients. The aim of this study is to evaluate the impact of 3-month early molecular response (EMR) on long-term outcomes of CML patients treated with IM and different 2G-TKIs, as additional information to guide clinical decisions on switching to a different TKI.Methods: 646 new CP CML patients who were treated with frontline IM (n = 362) or 2G TKIs (n = 284) were analyzed. Molecular responses were monitored using qRT-PCR assay with 3 month intervals, and then 6 month intervals after achieving major molecular response (MMR). Main study objectives were to evaluate the long-term outcomes, including failure-free survival (FFS), progression-free survival (PFS), and overall survival, according to 3-month EMR. FFS was measured from the date of treatment start until death, progression to AP or BP, or ELN failure on treatment, whichever came first. PFS and OS collected survivals on patients who were treated with other TKIs after frontline therapy discontinuation.Results: A total of 646 patients were treated with IM (n = 362), dasatinib (DAS; n = 117), nilotinib (NIL; n = 85), and radotinib (RAD; n = 82). The median age was 43 years (range, 11-87). The percentages of patients with low, intermediate, and high Sokal risk scores were 37%, 39% and 22%, respectively, with 2% unknown risk. With a median follow-up of 75.4 (IM; range, 4.4-195.9) and 34.1 (2G-TKIs; range, 5.2-138.4) months, 383 (59.3%; 168 IM and 215 2G-TKIs) patients continue on the frontline therapy and 263 (40.7%) patients were permanently discontinued or changed to other TKIs due to intolerance (72 IM, 26 DAS, 2 NIL, 21 RAD), ELN failure (36 IM, 3 DAS, 2 RAD), progression (3 IM, 1 DAS, 2 NIL, 1 RAD), death (1 IM, 1 DAS, 1 NIL), and others (10 warning, 9 pregnancy, 59 treatment-free remission study, and 13 follow-up loss). In 362 patients treated with IM, patients achieving BCR-ABL1 ≤ 10% at 3 months (n = 270, 74.6%) had a better outcomes in terms of 8-y FFS (91.7% vs 64.4%, P<0.001), 8-y PFS (95.5% vs 84.2, P<0.001), and 8-y OS (97.0% vs 83.2%, P <0.001) compared with those of the patients with BCR-ABL1 >10%. In 284 patients treated with 2G-TKIs, achievement of 3-month EMR (n = 252, 88.7%) was associated with a higher 6-y FFS (95.5% vs 82.1%, P = 0.001), 6-y PFS (97.2% vs 36.0, P<0.001), and 6-y OS (100% vs 66.2%, P <0.001). The prognostic impact of 3-month EMR was observed in both IM and 2G-TKIs treated groups. However, in IM treated group, 3-month EMR failure showed relative risk (RR) of 4.96 (P <0.001) for PFS and 4.54 (P = 0.001) for OS, respectively, whereas in 2G-TKIs treated group, 3-month EMR failure showed RR of 10.71 (P <0.001) for PFS and 26.42 (P = 0.005) for OS, respectively.Conclusions: Our data showed the 3-month EMR provided long-term prognostic information in patients treated with frontline IM and 2G-TKI. However, the prognostic impact of 3-month EMR failure was enhanced in the patients treated with 2-G TKIs. However, further investigations in a larger patient population with longer follow-up are needed. DisclosuresKim:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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.

Dasatinib Induced Reversible Nephrotic Range Proteinuria Occurs More Frequently Compared to Other Tyrosine Kinase Inhibitors in the Treatment of Chronic Myeloid Leukemia

Introduction: Dasatinib is an oral inhibitor of Abl and Src family of kinases. Dasatinib can cause a pleural effusion in 14% to 30% of patients as well as pulmonary arterial hypertension. Its mechanism is not fully elucidated although vascular endothelial growth factor (VEGF)-mediated mechanism has been proposed. In the literature, there are sporadic case reports of dasatinib-induced proteinuria/nephrotic syndrome. It is also suggested that dasatinib-induced kidney injury involves the interruption of VEGF signaling pathway.In the present study, we present a series of 6 patients, who developed nephrotic-range proteinuria while on dasatinib therapy that resolved after switch to other TKIs or discontinuation. Also, we have analyzed the risk of TKI-associated proteinuria according to the TKI subtype in 256 CML patients having available results of urine protein level.Patients and Methods: A total of 256 patients with CML on TKIs, with available urine testing were reviewed. TKI therapy was as follows: Imatinib (n=147), dasatinib (n=67), nilotinib (n=13), ponatinib (n=13) and bosutinib (n=16). First, we have reviwed spot urinalysis result for proteinuria screening, and further reviewed in detail the result of 24-hour urine protein measurement. If proteinuria is detected, we had in-depth chart review on the case to exclude other causes of proteinuria such as diabetes, renal failure, urinary tract infecion or urinary tract malignancies, etc. After excluding other causes of proteinuria, we have calculated the incidence rate of proteinuria using 1,000 person-year considering duration of exposure to TKI therapy.Results: With median duration of 35 months of dasatinib therapy, 6 patients (8.9%) developed nephrotic range proteinuria, after excluding other secondary causes of proteinuria. All received dasatinib as 2nd line following Imatinib front line therapy. Out of 6 patients with proteinuria, 4 patients developed pleural effusion prior to the development of proteinuria. All of them showed optimal molecular response to dasatinib therapy at the time of proteinuria development including MR4.5 (n=4), MR4.0 (n=1) or MMR (n=1).One patient underwent renal biopsy which showed chronic glomerular endothelial cell injury and thin basement membrane nephropathy, consistent with finding of minimal change disease. All 6 cases had discontinued (n=3) or switched to other TKI therapy (imatinib n=1; botutinib n=1; nilotinib n=1) with complete resolution of proteinuria. In the 3 patients who had MR4.5 or deeper response when dasatinib was discontinued due to proteinuria, one lost MMR after 3 months, one maintained MMR (+13 months), and another without losing undetectable transcript level (+21 months).The incidence rate of TKI-associated proteinuria was analyzed according to the TKI subtype in 256 CML patients. Median follow-up duration was 31 months for 35 months for dasatinib (1-105 months), imatinib (1-172 months), 27 months for nilotinib (1-63 months), 5 months for bosutinib (1-22 months), and 1 month for ponatinib (1-14 months), respectively. The exposure year was 201.8 years in dasatinib (n=67), 523.2 years in imatinib (n=147), 31.4 years in nilotinib (n=13), 6.1 years in bosutinib (n=16) and 1.4 years in ponatinib (n=13). The incidence rate of proteinuria in dasatinib treated group was calculated as 29/1,000 person-year, while it was 0 in imatinib, nilotinib, bosutinib, ponatinib-treated group, respectively due to no case confirmed to have proteinuria after excluding secondary causes of proteinuria (Fisher's exact test p<0.001).Conclusion: Development of nephrotic range proteinuria can be a toxicity from dasatinib therapy in CML treatment. Incidence rate is unexpectedly high at 29/1,000 person-year while there are no cases of nephrotic range proteinuria with exposure to other TKIs. All the proteinuria events were reversed completely after discontinuation/switch of dasatinib. Medical attention is to be paid for this unusual toxicity related to dasatinib therapy. Further study is strongly warranted to reach a clear conclusion for the incidence of this toxicity in a larger cohort. DisclosuresKim:BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Paladin: Consultancy; Pfizer: Consultancy.