Imatinib Failure Research Articles

Starting Imatinib at 400 mg Daily in Patients with Gastrointestinal Stromal Tumors Harboring KIT Exon 9 Mutations: A Retrospective, Multicenter Study.

Retrospective analyses suggest that patients with advanced KIT exon 9-mutated gastrointestinal stromal tumors (GISTs) receiving imatinib 800 mg (rather than 400 mg) daily have better outcomes. In the adjuvant setting, the question of the optimal dose of imatinib remains unsettled. We aimed to retrospectively assess the activity of imatinib 400 mg in both the adjuvant and the advanced settings. We performed a multicenter study of patients with KIT exon 9-mutated GIST starting imatinib at 400 mg daily. We examined the relapse-free survival (RFS) among high-risk patients either receiving or not receiving adjuvant imatinib. In patients with advanced disease, progression-free survival (PFS, progression under imatinib 400 mg), time to imatinib failure (TIF, progression under imatinib 400, then 800 mg upon first progression), and overall survival (OS) were analyzed. In the post-operative setting (n = 37), 20 patients received adjuvant imatinib. Median RFS in high-risk patients receiving adjuvant imatinib (n = 14) was not reached (95% CI 17.5-46.6) versus 13.6 months (95% CI 4.7-13.6) for those who did not (p = 0.37), after a median follow-up of 58 months. RFS at 36 months was 63% (30.3-96.6) versus 40% (95% CI 0-82.9), p = 0.2. In advanced disease (n = 28), median PFS, TIF and OS were 12.7 months (95% CI 6.1-18.2), 21.0 months (95% CI 17.4-28.1) and 47.0 months (95% CI 33.5-69.2), respectively. Despite the limitations of a retrospective analysis and the small number of patients, the benefit of adjuvant imatinib 400 mg daily in high-risk patients appeared relevant. Patients with advanced disease receiving imatinib 400 mg with subsequent dose escalation had a TIF similar to that observed with an initial dose of 800 mg. Intra-patient dose escalation in this setting might be an option.

Second-line bosutinib (BOS) for patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML): Final 10-year results of a phase 1/2 study.

7009 Background: BOS is approved for Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and newly diagnosed Ph+ CP CML. In a phase 1/2 study, second-line BOS showed durable efficacy and manageable toxicity in pts with imatinib-resistant (IM-R) or -intolerant (IM-I) Ph+ CP CML. Methods: This final efficacy and safety analysis of the phase 1/2 study and extension study was based on ≥10 y of follow-up (FU). Ph+ CP CML pts who received BOS starting at 500 mg/d after prior treatment (Tx) with imatinib only were included. Results: 19% of pts were on BOS at y 10, and 13% were still on BOS at study completion after ≥10 y; 19% completed ≥10 y of FU. Median duration of Tx and FU were 26 and 54 mo, respectively. Median (range) dose intensity was 436 (87–599) mg/d. The most common primary reasons for permanent Tx discontinuation were lack of efficacy (unsatisfactory response or disease progression; 27%) and adverse events (AEs; 26%). In pts with a valid baseline assessment, cumulative complete cytogenetic response (CCyR), major molecular response (MMR) and MR4 rates (95% CI), respectively, were 50% (43–56), 42% (35–49) and 37% (30–44) (IM-R: 48% [41–56], 46% [37–55] and 39% [31–48]; IM-I: 53% [41–64], 36% [25–48] and 33% [22–45]). Responses were durable, with estimated probabilities of maintaining CCyR, MMR and MR4 > 50% after ≥10 y (Table). At 10 y, cumulative incidence of on-Tx progression/death was 24% and Kaplan-Meier (K-M) overall survival 72% (Table); 55 deaths (IM-R: n = 41; IM-I: n = 14) occurred on study, none BOS-related. Any grade Tx-emergent AEs (TEAEs) in ≥40% of pts were diarrhea (86%), nausea (46%) and thrombocytopenia (42%). Pleural effusion, cardiac and vascular TEAEs occurred in 13%, 12% and 11% of pts, respectively. 28% of pts had AEs leading to permanent Tx discontinuation; most common (≥2% of pts) were thrombocytopenia (6%), neutropenia (2%) and alanine aminotransferase increased (2%). Conclusions: These 10-y data are consistent with prior results of durable efficacy and manageable toxicity with second-line BOS and support long-term BOS use in CP CML pts after imatinib failure. Clinical trial information: NCT00261846 and NCT01903733. [Table: see text]

Liquid Biopsy in Gastrointestinal Stromal Tumors: Ready for Prime Time?

Gastrointestinal stromal tumor (GIST) constitutes a paradigm for clinically effective targeted inhibition of oncogenic driver mutations. Therefore, GIST has emerged as a compelling clinical and biological model to study oncogene addiction and to validate preclinical concepts for drug response and drug resistance. Oncogenic activation of KIT or PDGFRA receptor tyrosine kinases is the essential drivers of GIST progression throughout all stages of the disease. Interestingly, KIT/PDGFRA genotype predicts the response to first-line imatinib and to all tyrosine kinase inhibitors (TKIs) approved or in investigation after imatinib failure. Considering that TKIs are effective only against a subset of KIT or PDGFRA resistance mutations, close monitoring of tumor dynamics with non-invasive methods such as liquid biopsy emerges as a necessary step forward in the field. Liquid biopsy, in contrast to solid tumor biopsy, aims to characterize tumors irrespective of heterogeneity. Although there are several components in the peripheral blood, most recent studies have been focused on circulating tumor (ct)DNA, due to the technological feasibility, the stability of DNA itself and DNA alterations, and the therapeutic development in precision oncology largely based on the identification of genetic driver mutations. In the present review, we systematically dissect the current wealth of data of ctDNA in GIST. To do so, a critical understanding of the promises and limitations of the current technologies will be followed by an exposition of the knowledge gathered with such studies in GIST. Collectively, our goal is to establish clear premises that can be used as the foundations to build future studies towards the clinical implementation of ctDNA evaluation in GIST patients.

Four-Dimensional Echocardiographic Evaluation of Left Ventricular Systolic Functions in Patients with Chronic Myeloid Leukaemia Receiving Tyrosine Kinase Inhibitors.

Tyrosine kinase inhibitors (TKIs) are established treatment for haematological malignancies. However, cardiac adverse effects, including the reduction in left ventricular ejection fraction and symptomatic heart failure remain clinical problems. The purpose of this study was to evaluate the left ventricular systolic functions in patients with chronic myeloid leukaemia receiving TKIs. A cross-sectional and observational study was conducted of 37 patients with chronic myeloid leukaemia receiving dasatinib or nilotinib after imatinib failure. Left ventricular systolic functions were evaluated using four-dimensional speckle tracking echocardiography derived global longitudinal (GLS), circumferential (GCS), radial (GRS), and area (GAS) strain indices. Mean ejection fraction, stroke volume, cardiac output and left ventricular mass index were similar between control and patient groups and within normal limits. GLS (- 16.7% vs - 20.8%, p < 0.001), GCS (- 13.0% vs - 15.6%, p = 0.002), and GAS (- 26.2% vs - 31.0, p < 0.001) values were significantly higher in the patient population than those of the controls. Dasatinib and nilotinib groups did not show differences regarding strain indices. In multivariate regression analysis, only the usage of dasatinib or nilotinib was found to be an independent risk factor for diminished GAS (β = 4.406, p = 0.016), GLS (β = 3.797, p = 0.001), and GCS (β = 2.404, p = 0.040). Although imatinib, nilotinib, and dasatinib seem to be clinically safe in terms of cardiac function, monitoring of systolic functions using strain imaging, and long-term observation of patients may provide early detection of the possible cardiac toxicity.

Repurposing of Acriflavine to Target Chronic Myeloid Leukemia Treatment.

Drug repurposing has lately received increasing interest in several diseases especially in cancers, due to its advantages in facilitating the development of new therapeutic strategies, by adopting a cost-friendly approach and avoiding the strict Food and Drug Administration (FDA) regulations. Acriflavine (ACF) is an FDA approved molecule that has been extensively studied since 1912 with antiseptic, trypanocidal, anti-viral, anti-bacterial and anti-cancer effects. ACF has been shown to block the growth of solid and hematopoietic tumor cells. Indeed, ACF acts as an inhibitor of various proteins, including DNA-dependent protein kinases C (DNA-PKcs), topoisomerase I and II, hypoxia-inducible factor 1α (HIF-1α), in addition to its recent discovery as an inhibitor of the signal transducer and activator of transcription (STAT). Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the expression of the constitutively active tyrosine kinase BCR-ABL. This protein allows the activation of several signaling pathways known for their role in cell proliferation and survival, such as the JAK/STAT pathway. CML therapy, based on tyrosine kinase inhibitors (TKIs), such as imatinib (IM), is highly effective. However, 15% of patients are refractory to IM, where in some cases, 20-30% of patients become resistant. Thus, we suggest the repurposing of ACF in CML after IM failure or in combination with IM to improve the anti-tumor effects of IM. In this review, we present the different pharmacological properties of ACF along with its anti-leukemic effects in the hope of its repurposing in CML therapy.

Regorafenib treatment outcome for Taiwanese patients with metastatic gastrointestinal stromal tumors after failure of imatinib and sunitinib: A prospective, non-randomized, single-center study.

The present study aimed to conduct a prognosis analysis of Taiwanese patients with metastatic gastrointestinal stromal tumors (GISTs), who are resistant to or were unable to tolerate imatinib or sunitinib, and were subsequently treated with regorafenib. The study considered the survival, potential prognostic factors and safety of these Taiwanese patients. A total of 28 patients with pre-treated metastatic GIST, receiving regorafenib treatment, were analyzed between April 2014 and December 2017. Data were collected prospectively, and patients were followed up for a median of 14.8 months. It was reported that 50% (10/20) of male patients and 50% (4/8) of female patients demonstrated response and clinical benefit to regorafenib. The median progression-free survival (PFS) and overall survival (OS) time in all patients receiving regorafenib were 4.4 and 29.3 months, respectively. Good performance status and disease control mediated by regorafenib were independently associated with a more favorable PFS time. Good performance status, higher pre-treated albumin level, lower neutrophil:lymphocyte ratio (NLR) and lower platelet:lymphocyte ratio (PLR) were independent favorable predictors of OS time. Overall, poor performance status and poor disease control predicted a less favorable PFS time in Taiwanese patients with GISTs, who were pre-treated with regorafenib. Meanwhile poor performance status, high NLR, PLR and low albumin level predicted a less favorable OS time.

Bosutinib (BOS) for chronic phase (CP) chronic myeloid leukemia (CML) after imatinib (IMA) failure: ≥8-y update of a phase I/II study.

7549 Background: BOS is approved for newly diagnosed CP CML and CML resistant/intolerant to prior therapy. In a phase I/II study, BOS showed durable efficacy and manageable toxicity in patients (pts) with CP CML after IMA failure. We report an ≥8-y update of this phase I/II and ongoing extension study. Methods: Pts with CP CML resistant/intolerant to IMA (CP2L) or IMA + dasatinib and/or nilotinib (CP3L) or with accelerated/blast phase (AP/BP) CML or Philadelphia chromosome+ acute lymphoblastic leukemia with prior tyrosine kinase inhibitor (TKI) therapy (ADV) received BOS starting at 500 mg/d. Results: 54/284 (19%) CP2L pts were still on BOS after ≥9 y and 8/119 (7%) CP3L and 5/167 (3%) ADV pts after ≥8 y; 61 CP2L pts discontinued BOS since y 5 and 21 CP3L and 12 ADV pts since y 4. Overall, the most common reason for discontinuation was disease progression/lack of efficacy in CP2L (27%), CP3L (42%) and ADV (50%) pts; last dose before discontinuation was ≥500 mg/d in 59 (21%), 28 (24%) and 46 (28%) pts, respectively. In CP2L pts, median (range) of follow-up was 54 (1–155) mo, treatment duration 26 (&lt;1–155) mo and dose intensity 438 (87–599) mg/d; responses were durable (Table) and overall survival (OS) at 9 y was 74% vs 84% at 5 y. OS at 8 y was 69% in CP3L, 54% in AP CML and 23% in BP CML pts vs 78%, 59% and 23% at 4 y. 55 CP2L, 29 CP3L and 98 ADV pts died on study (10, 3 and 2 since the 4/5-y reports); 15, 5 and 3 had on-treatment transformations to AP/BP. Most common new treatment-emergent adverse events since y 5 in CP2L pts were pleural effusion (n=13), arthralgia (n=12) and increased blood creatinine (n=11). Conclusions: After ≥8 y, BOS continued to show durable efficacy and no new safety signals in pts with CP CML on long-term treatment, providing further support for BOS use after prior TKIs. Clinical trial information: NCT00261846 and NCT01903733 . [Table: see text]

LENVAGIST - A multicenter, comparative, placebo-controlled, double-blinded, phase II study of the efficacy of lenvatinib in patients with locally advanced or metastatic GIST after failure of imatinib and sunitinib.

TPS11568 Background: GastroIntestinal Stromal Tumors (GIST) are paradigmatic models of cancers with a driver mutation of an oncogene, in which imatinib is recommended as adjuvant therapy or treatment of locally advanced and metastatic forms. After failure of imatinib (either progression or toxicity), sunitinib and regorafenib are indicated as 2nd and 3rd lines, respectively. Beyond approved drugs, tyrosine kinase inhibitors (TKI) can bring clinical benefit because some clones remain sensitive to TKI. Lenvatinib is a broad spectrum TKI targeting KIT, RET, PDGFRA, VEGFR 1-3 and FGFR 1-4, that is approved in the treatment of differentiated thyroid carcinoma and metastatic renal cell carcinoma and hepatocellular carcinoma. Methods: This prospective, randomized, placebo-controlled, double-blinded, multicenter trial evaluates the efficacy and safety of Lenvatinib in adult GIST patients (pts) who failed at least to previous imatinib and sunitinib. Seventy-four pts will be randomly allocated in a 1:1 ratio to receive either oral lenvatinib, at a daily dose of 24mg, or its matching placebo, continuously, until progression of disease (PD) or unacceptable toxicity. Randomization will be stratified according to the number of different previous anticancer drugs (2 or &gt; 2). The primary objective is to compare the Progression-free survival (PFS) between arms. The expected median PFS are 1.5 month in the control arm and 3.0 months in the experimental arm (HR = 0.5). Seventy one events will provide 90% power to show significant improvement in PFS, using a 2-sided log-rank test at a 10% level. Secondary endpoints include the overall survival, the objective response rate, the best overall response, the quality of life and the safety profile. Patients allocated in the placebo arm who experience PD (RECIST 1.1) may switch to active lenvatinib. Radiological endpoints will be evaluated using the RECIST 1.1. Translational objectives will be to identify blood and tumor parameters as predictive markers of lenvatinib efficacy. Recruitment has been activated in January 2020. Ten participating sites of the French Sarcoma Group will participate in the trial. Clinical trial information: NCT04193553 .

Comprehensive review into the challenges of gastrointestinal tumors in the Gulf and Levant countries.

Although gastrointestinal stromal tumors (GISTs) are rare, with an incidence of 1/100000 per year, they are the most common sarcomas in the peritoneal cavity. Despite considerable progress in the diagnosis and treatment of GIST, about half of all patients are estimated to experience recurrence. With only two drugs, sunitinib and regorafenib, approved by the Food and Drug Administration, selecting treatment options after imatinib failure and coordinating multidisciplinary care remain challenging. In addition, physicians across the Middle East face some additional and unique challenges such as lack of published local data from clinical trials, national disease registries and regional scientific research, limited access to treatment, lack of standardization of care, and limited access to mutational analysis. Although global guidelines set a framework for the management of GIST, there are no standard local guidelines to guide clinical practice in a resource-limited environment. Therefore, a group of 11 experienced medical oncologists from across the Gulf and Levant region, part of the Rare Tumors Gastrointestinal Group, met over a period of one year to conduct a narrative review of the management of GIST and to describe regional challenges and gaps in patient management as an essential step to proposing local clinical practice recommendations.

Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors

BackgroundGastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients.MethodsWe performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR).ResultsWe were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib.ConclusionsctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics.

Outcomes of patients with metastatic gastrointestinal stromal tumors (GIST) treated with multi-kinase inhibitors other than imatinib as first-line treatment

BackgroundImatinib is the standard first-line therapy in metastatic gastrointestinal stromal tumours (GIST). Investigational multi-kinase inhibitors (MKIs) such as nilotinib, dasatinib or masitinib have been tested as first-line therapies in phase II/III studies. This might theoretically result either in increased survival or in early emergence of resistance to approved MKIs.MethodsTo assess whether using MKIs other than imatinib in first line decreases imatinib efficacy in second line for patients with GIST, a retrospective chart review was performed from 2005 to 2011 in two French tertiary centres of patients with GIST who received investigational MKIs (in phase II/III trials) as first-line treatment, followed by imatinib as second line.ResultsOf 46 patients, (55% women, median age 55 years (range 24–81)), 22 (47%) had a KIT exon 11 mutation, 1 a KIT exon 9 mutation (2%), 1 a PDGFRA D842V mutation (2%). Out of 46 patients, 21 (46%) received masitinib, 17 (37%) received dasatinib and 8 (17%) received nilotinib as first-line treatment with a median progression-free survival of 18.0 months (95% CI: 8.5 to 25.5). Median time to imatinib failure was 19.7 months (95% CI: 13.5 to 29.0). Median time to second relapse was 48.7 months (95% CI: 31.2 to 72.0). Median overall survival from time of initial metastasis diagnosis was 5.7 years (95% CI: 4.5 to 7.4).ConclusionsPatients with GIST who received investigational MKIs as first-line treatment and imatinib as second line had a time to second relapse longer than that observed historically with imatinib in first line, suggesting that using MKIs other than imatinib in first line does not decrease the efficacy of subsequent treatment lines.

On a Long Way to the Treatment Free Remisson: The Results of the Long-Term Observation of the Chronic Myeloid Leukemia Patients in Russian Part of EUTOS Population-Based Study

Background: A success of the tyrosine kinase inhibitors (TKI) therapy in patients (pts) with chronic myeloid leukemia (CML) allowed to set a new goal: a treatment-free remission (TFR). A stable and long-lasting deep molecular response (DMR) is required for a successful TKI discontinuation. The number of CML pts with stable DMR increases on late terms of TKI therapy. With the relationship to this new goal it is relevant to evaluate the proportion of the potential candidates for TKI discontinuation in accordance with the country-specific features of the CML pts population in routine clinical practice. Aim :To characterize the cohort of CML pts treated in routine clinical practice in Russian Federation and to evaluate the proportion of CML pts eligible for TFR. Methods: The analyzed cohort consisted of 197 pts from 6 regions of Russia covering the population of 10 million inhabitants. All pts with CML diagnosed from 01.10.2009 to 31.12.2012 were included into the prospective multicenter EUTOS Population Based Study (EUTOS PBS). Median (Me) age was 50 (18-82)years, 49% were males. Chronic phase, accelerated phase and blast crisis was diagnosed in 93,4%, 6% and 0,6% pts respectively. Imatinib as a 1st line was used in 97% pts. The 2nd generation TKIs (TKI2) were used as 1st and 2nd -3rd line in 3% and 12% pts respectively; imatinib failure was the main reason of switch to TKI2. Overall survival (OS) and cumulative (CI) of DMR were evaluated and adjusted to the new ELTS (EUTOS long-term-survival) score. A proportion of pts with sustained DMR eligible for TFR was calculated. DMR was considered as BCR-ABL&lt;0,01% IS. A TFR eligibility was considered as a sustained DMR lasting for &gt;2 years and TKI therapy &gt;3 years. Results:Me follow-up in Russian CML pts cohort of EUTOS PBS was 77 (0,7 - 107) months (mo). The ELTS score available in 179 pts was low, intermediate and high in 86(48%), 50(28%) and 43(24%) pts accordingly. The 7-year OS was 76% in total cohort (figure 1a). The 7-year OS in low, intermediate and high ELTS group was 87%, 68% and 55% respectively (p=0,001). Me time of DMR achievement was 38mo (11,2 - 89 mo). The 7-year CI of DMR was 62%. The CI of 7-year DMR achievement in ELTS low, intermediate and high group was 62%, 42% and 38% respectively with significant difference between low and non-low score pts (p= 0,001) (figure 1b). The data for the molecular response at data cut-off April 2019 were available in 114/123 pts who were alive and treated by TKIs with Me time 85 (range 65 - 105) mo. DMR, major molecular response (MMR, (BCR-ABL &gt;0,01%- 0,1% IS) and no MMR (BCR-ABL&gt; 0,1% IS) was in 76 (66,7%), 8 (7%) and 30 (26,3%) pts respectively. A sustained DMR was in 38 (50%) of 76 pts or 19% of the total cohort of 197 pts. Conclusion: A significant proportion of CML pts reach a sustained DMR on late terms of TKI therapy. In total 19% of CML pts in Russian part of the EUTOS PBS study can be eligible to treatment-free observation after 7 years of TKI therapy. The low ELTS score predicts better survival and better chance of DMR achievement. The evaluation of the TFR perspective in routine clinical practicein important from diagnosis to late terms of treatment. Disclosures Chelysheva: Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Vinogradova:Novartis: Consultancy; Fusion Pharma: Consultancy. Turkina:Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; fusion pharma: Consultancy; Novartis: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy.

Ten Years of Treating Chronic Myeloid Leukemia in Rural Rwanda: Feasible Approaches for Low-Resource Settings

Objective: To describe the characteristics and outcomes of chronic myeloid leukemia (CML) patients treated through the Glivec Patient Assistance Program (GIPAP) in Rwanda. Methods: We retrospectively reviewed all BCR-ABL positive CML patients treated with imatinib at two rural hospitals between 2009 and 2018. Clinical data were analyzed using descriptive statistics, Kaplan-Meier method, and proportional hazards regression. Results: One hundred twenty-four patients were included; median age 35 (range: 9-81), 60% male, 88% without comorbidities. All patients presented with symptomatic disease, median duration 11 months (IQR: 4-24) and median WBC count 225.5 x 109/L (IQR: 117.7-308.5). At diagnosis, 71% were in chronic phase. On imatinib, 91% achieved complete hematologic remission (CHR); 67% within 90 days. Of those who achieved CHR, 51 (45%) lost it at some point and, of which, 36 (71%) regained CHR. At four years, overall survival was 79% (95% CI:69%-86%) for the entire cohort; 93% (95% CI: 79%-98%) for 53 patients who remained in CHR, 89% (95% CI: 69%-96%) for 34 patients who lost but regained CHR, 19% (95% CI: 1%-54%) for 12 patients who lost and never regained CHR. Never achieving CHR was associated with increased mortality (HR: 40.89; 95% CI: 9.88-169.32; p&lt;0.001) as was losing CHR without regaining it (HR 15.73; 95% CI: 4.14-59.81; p&lt;0.001) compared to never losing CHR. Conclusions: Here we demonstrate the feasibility of coupling molecular diagnostics with chronic targeted therapy in a rural low-resource setting through health systems strengthening and international collaboration. Our CML patients are younger, slower to achieve CHR with imatinib, and have higher rates of primary and early hematologic resistance than historical cohorts, suggesting biological differences that warrant further investigation. It is uncertain what role non-adherence to medication influences these data. Without molecular response assessment, hematologic response is an accurate marker of disease control and survival. Our imatinib failure rates highlight the need for access to resistance testing and second generation tyrosine kinase inhibitors, as well as adherence rates. Disclosures No relevant conflicts of interest to declare.

270O - Imatinib induced toxicity and its influence on cytogenetic and molecular response in newly diagnosed patients with chronic myeloid leukemia

BackgroundIncidence of imatinib-induced toxicity and its influence on clinical outcomes in Indian patients with CML is not well-studied. We investigated the influence of imatinib-induced toxicity on therapeutic outcomes in newly diagnosed patients with CML. We also studied the effect of drug levels on imatinib-induced hematological toxicity. MethodsTwo hundred and fifty newly diagnosed patients with chronic-phase CML, started on imatinib therapy, were enrolled and followed-up for 24 months. Toxicity due to imatinib were assessed and graded as per CTCAE. Cytogenetic and molecular responses were assessed by conventional bone-marrow cytogenetics and qRTPCR using international scale, respectively, based on which patients were categorized as imatinib responders and non-responders. Imatinib trough levels were measured using LC-MS/MS. Multivariate analysis was done to find the influence of various covariates on imatinib response. ResultsA total of 719 adverse reactions due to imatinib occurred among 250 enrolled patients. Hematological toxicity was the most common imatinib-induced toxicity and its incidence was significantly higher in non-responders than responders (65% vs. 35%; P < 0.001). Patients with thrombocytopenia [RR = 1.768; 95%CI (1.357, 2.302); P < 0.001] and neutropenia [RR = 1.654; 95%CI (1.322, 2.070); P < 0.001] were at high risk of imatinib failure. Patients without any hematological toxicity were at lower risk for failure of imatinib therapy [RR = 0.520; 95%CI (0.388, 0.698); P < 0.001]. Although patients with hematological toxicity had higher imatinib levels than those without (2039.1±1361.6 vs. 1833.8±1335.3 ng/mL), the difference was not statistically significant [mean difference 205.2; 95% CI (590.4, -180); P = 0.295]. Hematological toxicity requiring dose interruption or reduction emerged as an independent factor predicting cytogenetic and molecular response to imatinib in multivariate analysis. ConclusionsImatinib induced hematological toxicities significantly influence cytogenetic and molecular response in patients with CML. Active monitoring and prompt management of imatinib induced adverse events is indispensable to achieve optimal therapeutic outcomes. Clinical trial identificationNot Applicable. Editorial acknowledgementNot Applicable. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

1702P - Efficacy and safety of apatinib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib: An open-label, multicenter, single-arm, phase II trial

BackgroundGastrointestinal stromal tumors (GISTs) patients (pts) who develop resistance to imatinib and sunitinib have few therapeutic options. Apatinib is a multiple tyrosine kinase inhibitor and targetsVEGFR2, PDGFRβ and c-Kit, which is effective in several solid tumors. We aimed to assess the efficacy and safety of apatinib in pts with advanced GISTs who failed previous standard tyrosine kinase inhibitors. MethodsIn this single-arm, open-label, phase II study, we enrolled pts (aged ≥18 years) with advanced GISTs resistant to imatinib and sunitinib from 3 comprehensive cancer centers or university hospitals in China and assigned them to 500mg oral apatinib once daily in 4-week cycles. Pts were assessed for response by RECIST 1.1 every 2 cycles. The primary endpoint was investigator-assessed progression-free survival. The secondary endpoints included response rate, overall survival and advent events. ResultsBetween September 2017 and February 2019, 10 pts were enrolled (7 evaluable for response), and pts are still being accrued to the trial. Here we present the preplanned early analysis of clinical outcomes. The median follow-up was 16.6 months. Four pts reached stable disease. The median PFS was 5.4 months (95% CI 2.0–9.8), and the 4-month PFS rate was 57.1%. Drug-related adverse events were reported in 9 (90%) pts and the most common apatinib-related adverse events of grade 3 or higher were hypertension (3 of 10, 30%), hand-foot skin reaction (4 of 10, 40%), fatigue (5 of 10, 50%) and proteinuria (2 of 10, 20%). There was no treatment-related death. ConclusionsApatinib appears to have promising anti-tumor activity and an acceptable toxicity profile in pts with advanced GISTs previously treated with imatinib and sunitinib. Apatinib warrants further investigation in GISTs. Clinical trial identificationChiCTR1800020407. Legal entity responsible for the studyThe authors. FundingChinese Society of Clinical Oncology. DisclosureAll authors have declared no conflicts of interest.

1098P - Incidence of imatinib resistance in chronic myeloid leukemia (CML) patients: Experience from resource poor center of eastern India

BackgroundThe management of Chronic Myeloid Leukemia (CML) has undergone a paradigm shift with advent of the tyrosine kinase inhibitor (TKI), namely imatinib. Despite a high remission rate, a significant proportion of patients showed resistance and/or intolerance to imatinib therapy, be it primary or secondary. However, the scenario of resistance along with the prevalence and clinical route of CML in the Eastern part of India remains elusive. To observe the incidence of resistance to TKI after years of therapy, we performed a study in a tertiary cancer care centre, serving patients from Eastern Indian states as well as neighbor countries like Bangladesh and Bhutan. Based on the CML cases registered at the centre for the last 13 years, we performed a longitudinal assessment of the disease history and molecular management to portray the incidence of imatinib resistance in CML patients.Table: 1098PTable: 1098PNo. of registered CML cases (2005-2017)Median period of Imatinib treatmentNo. of patients showing Loss of MMR (BCR-ABL >1.0%)No. of patients undergoing BCR-ABL KD mutation testing (% affordability)No. of patients showing BCR-ABL KD mutationPatients with Imatinib failure but no detectable BCR-ABL KD mutation98626 months10120 (20%)11 (55% of resistant pool)9 (45% of resistant pool) MethodsThe methods in schematic are described below: No. of CML cases with disease history ↓ Patients showing loss of Major Molecular Response (MMR), detected by Real-Time quantitative PCR ↓ Mutation analysis in BCR-ABL kinase domain (KD) (by Sanger sequencing) ↓ Calculation of type and incidence of KD mutation ↓ The survival analyses performed by Kaplan-Meier analysis. ResultsThe results are presented in tabular form as below:.After years of therapy, KD mutations are seen in 55% of imatinib-resistant patients. The survival analysis showed significant difference between treatment-sensitive and –resistant pools. ConclusionsThe incidence of imatinib resistance has been increasingly detected in Eastern-Indian region after long term therapy with imatinib. However, the full scenario could not be depicted due to resource constraints. More numbers of patients are to be tested to achieve robust evidence. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

1096P - Outcomes of chronic myeloid leukemia with T315I mutation in the absence of targeted therapy or hematopoietic stem cell transplantation

BackgroundFew chronic myeloid leukemia (CML) patients may stop responding to tyrosine kinase inhibitors (TKI). On mutational analysis, the most common mutation detected is T315I conferring resistance to all TKIs except ponatinib, availability of which is limited. Management of these patients, in the absence of ponatinib is allogenic hematopoietic stem transplantation. Data on outcomes of the patients with this mutation in the absence these modalities is limited. The present study was planned to study the profile and outcomes of CML patients with T315I mutation treated with hydroxyurea and supportive care. MethodsData of CML patients with T315I mutation who failed on imatinib diagnosed between 2004 and 2018 was retrospectively analyzed. ResultsA total of 2162 patients were analyzed. Of these, 312 (14.4%) were imatinib failures. Mutations were seen in 120 (38.5%) patients, of which 45 (37.5%) patients had T315I mutation. Reasons for mutational analysis testing were not attaining MMR at 1 year, loss of molecular response and loss of hematological response in 3(6.7%), 35(77.8%) and 7(15.6%) patients respectively. The median duration from diagnosis to T315I detection was 38 months (range, 6-146). At the time of detection of T315I mutation, CP, AP and BP were detected in 19 (42.2%), 12(26.7%) and 14 (31.1%) patients respectively. At a median follow up of 18 months, 19 patients were alive and 26 patients were dead with a median overall survival (mOS) of 18 months (range, 0-122). mOS of patients with CP, AP and BP were not reached (range, 2-122) 12 (range, 1-81) and 3 (range, 0.3-34) months respectively (p=0.001). Table.Table: 1096PTable: 1096PCharacteristicN (%)Median age (years)37 (range, 6-60)Gender Males Females32 13Phase CP AP BP35 (77.8) 8 (17.8) 2 (4.4)EUTOS risk Low High22 (48.9) 23 (51.2) ConclusionsT315I was the most common mutation detected in patients who had not attained MMR or progressed on imatinib. Majority of patients were in chronic phase at time of T315I detection. Phase at the time of detection of T315I had significant impact on outcomes in the absence of targeted therapy or allogenic stem cell transplantation. Legal entity responsible for the studyNizam’s Institute of Medical Sciences. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Efficacy and Safety of Anlotinib in Patients With Advanced Gastrointestinal Stromal Tumor After Failure of Imatinib: a Prospective, Single Arm and Multicenter Trial

Efficacy and Safety of Anlotinib in Patients With Advanced Gastrointestinal Stromal Tumor After Failure of Imatinib: a Prospective, Single Arm and Multicenter Trial

Prognostic value of the pretreatment neutrophil-to-lymphocyte ratio in patients with advanced gastrointestinal stromal tumors treated with sunitinib after imatinib failure.

The neutrophil-to lymphocyte ratio (NLR) has been proven to be correlated with outcomes in various cancer types, including gastrointestinal stromal tumors (GIST). There is limited data regarding the clinical value of NLR during second line therapy after failure of imatinib and there is an urgent need for more precise predictive factors for therapy. The aim of this study was to assess the association of the pretreatment NLR with progression free survival (PFS) and overall survival (OS) in patients with unresectable/metastatic GIST treated with sunitinib in a second line of treatment. In this analysis 146 out of 230 patients with unresectable/metastatic GIST were included, who were treated between 2005 and 2016 with sunitinib after failure of imatinib, with complete clinical data. In all patients, the NLR was assessed at baseline. The NLR cutoff of 2.4 was selected. The Kaplan-Meier method with the long-rank test and Cox proportional hazards model were applied for statistical analysis. Median PFS was 12.4 months with a 2-year rate of 27.1% and a 5-year rate of 4.8%. Median OS was 22.8 months, whereas 2- and 5-year rates were 47.8 and 13.8%, respectively. Patients with NLR>2.4 had significantly shorter OS: Median OS was 30 months for NLR≤2.4 vs. 16.4 months for NLR>2.4 (P=0.002); median PFS was 18.2 vs. 9.6 (P=0.075), respectively. In a multivariate model adjusted for mitotic index, primary location of tumor and driver mutation in KIT exon 11, NLR was proven to be independently associated with OS (HR 1.92, 95% CI 1.27-2.9, P=0.002) but not PFS (HR 1.31, 95%CI 0.89-1.93, P=0.17). The present data demonstrate that NLR can serve as an independent prognostic factor for patients with advanced GIST treated with sunitinib.

SIGNIFICANCE OF ADDITIONAL CHROMOSOMAL ABNORMALITIES FOR THE OUTCOMES AFTER THE SECOND LINE NILOTINIB THERAPY IN THE CHRONIC MYELOID LEUKEMIA PATIENTS

Background. There is limited information about impact of additional chromosome aberrations (ACA) on the efficacy of the 2nd line nilotinib therapy. Objective. The aim of the study was to analyze significance of ACAs for the outcome after second line tyrosine kinase inhibitors (TKI) therapy with nilotinib in the chronic myeloid leukemia (CML) patients, who experienced previous imatinib therapy failure. Methods. The CML patients in chronic phase treated with nilotinib after imatinib failure were analyzed for outcomes. Results. Among a total of 114 patients, 18 patients (15.8%) had ACAs at the beginning of the 2nd line therapy with nilotinib. Seven patients (38.9%) of 18 had variant translocations and 11 patients (61.1%) had other chromosomal abnormalities in addition to t(9;22), known as clonal evolution. Complete cytogenetic response (CCR) at 12 months was achieved in 37.5%, 42.8% and 45.5% (p=0.842) of patients with classic t(9;22) translocation, variant translocations and ACAs respectively. In the patients with variant translocations t(9;V;22) or clonal evolution treated with nilotinib after the imatinib failure, the CCR and major molecular response (MMR), event free survival (EFS), progression free survival (PFS) and overall survival (OS) rates did not differ from those in the CML patients with t(9;22) only. At the same time quantitative characteristics of leukemic and ACA clones had prognostic value for CCR. The increased number of Ph-positive cells and the number of cells with the ACA at the start of nilotinib therapy reduced the probability of CCR. Conclusions. Higher nilotinib inhibitory activity compare with imatinib allows us to overcome imatinib resistance in the CML patients regardless of the ACA presence at the beginning of nilotinib therapy.