Frontline Imatinib Research Articles

Generic Imatinib in Chronic Myeloid Leukemia: Survival of the Cheapest.

The patent expiration of imatinib mesylate (Gleevec; Novartis) on February 1, 2016, has brought the focus back on generic versions of the drug, and an opportunity to provide a safe and cost-effective alternative. The objective of our study was to determine the molecular and cytogenetic responses, survival endpoints (event-free survival, failure-free survival, transformation-free survival, overall survival), and safety of innovator and generic brands of imatinib. In this retrospective analysis, data from 1812 patients with chronic myeloid leukemia treated with frontline imatinib mesylate (innovator/generic) at a single institution between 2008 and 2014 is included. Of these, 445 were excluded owing to inadequate data and follow-up, and a further 156 were excluded as they were in either the accelerated phase or blast crisis at diagnosis. Thus, data from 1067 patients who were treated with Gleevec (Novartis), and 144 patients with Veenat (NATCO) were available for analysis, and included in the study. There was no significant difference in event-free survival (P= .05), failure-free survival (P= .07), transformation-free survival (P= .12), or overall survival (P= .24) between the 2 groups. The frequency of reported nonhematologic adverse events and hematologic adverse events was comparable between the study groups. The findings of the present study showed comparable efficacy and safety of the generic and innovator versions of imatinib in the treatment of patients with chronic myeloid leukemia.

Changing Treatment May Affect the Predictive Ability of European Treatment Outcome Study Scoring for the Prognosis of Patients with Chronic Myeloid Leukemia.

Objective:Previous studies compared the predictive ability of the European Treatment Outcome Study (EUTOS), Sokal, and Hasford scoring systems and demonstrated inconsistent findings with unknown reasons. This study was conducted to determine a useful scoring system to predict the prognosis of patients with chronic myeloid leukemia (CML) and identify the probable factors that affect the scoring.Materials and Methods:This is a retrospective cohort study. The predictive ability of EUTOS and the factors that affect scoring were analyzed in 234 Chinese chronic-phase CML patients treated with frontline imatinib, including a few patients temporarily administered hydroxyurea for cytoreduction before imatinib. Patients were stratified into different risk groups according to each scoring system to assess the treatment outcomes and the predictive ability of EUTOS scores between patients who received imatinib during the entire follow-up period and patients who received altered treatment because of intolerance, progression, and treatment failure.Results:Sixty-one (26.0%) patients received altered treatments during the follow-up. In the EUTOS low- and high-risk groups, the 5-year overall survival was 94.6% and 84.7% (p=0.011), 5-year event-free survival was 92.6% and 77.6% (p=0.001), and 5-year progression-free survival (PFS) was 95.3% and 82.4% (p=0.001), respectively. The predictive ability of EUTOS was better than that of the Sokal and Hasford scores (p=0.256, p=0.062, p=0.073) without statistical significance. All three scoring systems were valid in predicting early optimal response. Kaplan-Meier analysis showed a high association between overall PFS and the EUTOS scores in the standard-dose imatinib group (p<0.001).Conclusion:This study suggests that the EUTOS scoring system could predict the outcome of chronic-phase CML patients treated with standard-dose imatinib. Altered treatment is a crucial factor that affects the prognostic impact of EUTOS scoring. Achieving complete cytogenetic response at 18 months is an essential factor in predicting the prognosis of patients with CML.

Modelling Predictors of Molecular Response to Frontline Imatinib for Patients with Chronic Myeloid Leukaemia.

BackgroundTreatment of patients with chronic myeloid leukaemia (CML) has become increasingly difficult in recent years due to the variety of treatment options available and challenge deciding on the most appropriate treatment strategy for an individual patient. To facilitate the treatment strategy decision, disease assessment should involve molecular response to initial treatment for an individual patient. Patients predicted not to achieve major molecular response (MMR) at 24 months to frontline imatinib may be better treated with alternative frontline therapies, such as nilotinib or dasatinib. The aims of this study were to i) understand the clinical prediction ‘rules’ for predicting MMR at 24 months for CML patients treated with imatinib using clinical, molecular, and cell count observations (predictive factors collected at diagnosis and categorised based on available knowledge) and ii) develop a predictive model for CML treatment management. This predictive model was developed, based on CML patients undergoing imatinib therapy enrolled in the TIDEL II clinical trial with an experimentally identified achieving MMR group and non-achieving MMR group, by addressing the challenge as a machine learning problem. The recommended model was validated externally using an independent data set from King Faisal Specialist Hospital and Research Centre, Saudi Arabia.Principle FindingsThe common prognostic scores yielded similar sensitivity performance in testing and validation datasets and are therefore good predictors of the positive group. The G-mean and F-score values in our models outperformed the common prognostic scores in testing and validation datasets and are therefore good predictors for both the positive and negative groups. Furthermore, a high PPV above 65% indicated that our models are appropriate for making decisions at diagnosis and pre-therapy. Study limitations include that prior knowledge may change based on varying expert opinions; hence, representing the category boundaries of each predictive factor could dramatically change performance of the models.

Effectiveness of Three Prognostic Scoring Systems in Predicting the Response and Outcome in Pediatric Chronic Myeloid Leukemia Chronic Phase on Frontline Imatinib.

Introduction:The Sokal and Hasford (Euro) scores were developed in the chemotherapy and interferon eras and are widely used as prognostic indicators in patients with chronic myeloid leukemia (CML). Recently, European Treatment and Outcome Study (EUTOS) scoring system was introduced. Data on risk stratification in pediatric CML population was lacking due to its rarity (<3%).Objective:To study the effectiveness in predicting the response and outcome with three prognostic scores in pediatric CML-chronic phase patients on front line Imatinib. Materials and Methods: We retrospectively analyzed the hospital records of newly diagnosed CML CP patients (aged ≤18 years) from 2006 to 2010 for their risk score, cytogenetic response at 18 months and event free survival (EFS) at the end of 4 years. Events include loss of hematological response, loss of cytological response, progression to accelerated/blast phase (AP/BC). All received free Imatinib under Gleevac international patient assistance program.Results:Data of 106 children was analyzed with median age of 13.5 (ranged 5-18 years) and male preponderance (M:F = 1.14:1). The distribution of children was 63%, 32% and 5% in Sokal low, intermediate and high risk respectively, 50%, 43% and 5% in Hasford/Euro low, intermediate and high risk respectively, 71% and 29% in EUTOS low and high risk respectively. The overall cumulative complete hematological response at the end of 3 month was 94%, and complete cytogenetic response at 12 months was 75%. The CCyR at 18 month was seen in 90%,74% and 83% among Sokal low, intermediate and high risk groups respectively, 83%, 86% and 83% among Hasford/Euro low, intermediate and high risk groups respectively, 84% and 86% EUTOS low and high risk groups respectively. The EFS at the end of 48 months was seen in 87%,79% and 83% among Sokal low, intermediate and high risk groups respectively, 83%, 86% and 83% among Hasford/Euro low, intermediate and high risk groups respectively, 86% and 80% EUTOS low and high risk groups respectively.Conclusion:None of the scoring systems predicted the response and outcome effectively in children with CML CP on front line Imatinib.

Cessation of Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia Patients with Deep Molecular Response: Results of the Euro-Ski Trial

▪Background: Tyrosine kinase inhibitors (TKI) have dramatically improved survival in chronic myeloid leukemia (CML) with a high proportion of patients reaching deep molecular responses (DMR). The effectiveness of stopping TKI treatment is a key question regarding the management of CML. Actually, in several studies, it has been proven that a substantial part of patients in DMR can safely and successfully stop TKI therapy. However, the exact preconditions for stopping CML treatments are not yet defined. This is the aim of the European stop TKI (EURO-SKI) trial (ClinicalTrials.gov numbers: NCT01596114).Methods: Chronic phase CML patients without prior TKI failure, treated with either imatinib, nilotinib or dasatinib, in DMR (BCR-ABL <0.01% on the international scale, MR4) for the duration of at least one year were proposed to stop TKI treatment. Molecular recurrence (MR) was defined by the loss of the major molecular response (MMR, BCR-ABL <0.1% IS) at any one point. We estimated molecular recurrence-free survival (MRFS) with the Kaplan-Meier method. The potential prognostic values for MR were tested by univariate and multivariable analyses and the cut-off was identified with the minimal p-value approach.Results: From June 2012 to December 2014, 821 CP CML patients were included in 11 European countries belonging to the European Leukemia Net (ELN). 750 patients had assessable molecular data (European standardization according to Cross et al, Leukemia 2012) for the estimation of MRFS. Of these patients, 348 lost MMR and 5 died in remission ; MRFS was 62% (95% confidence interval (CI): 59% - 67%) at 6 months (m), 56% (CI: 52% - 59%) at 12 m and 52% (CI: 48% - 56%) at 24 m on an "Intention to Treat Basis ". At the time of evaluation most patients regained DMR, and importantly, no progression to advanced disease phase was noted. A prognostic modelling was performed based on 448 patients treated with imatinib. Univariate analysis showed no significant association between age, gender, depth of molecular response (MR4.5 vs. no MR4.5) or any variable part of the Sokal, EURO, EUTOS, or ELTS scores and MMR status at 6 months after treatment stop. Treatment duration with imatinib and MR4duration prior to the stop were significantly (p<0.001) correlated with MMR status at 6 months. The odds ratio for treatment duration was 1.16 (95%-CI: 1.08-1.25), meaning that one additional year of treatment increases the odds to stay in MMR at 6 months by 16%. Molecular relapse-free survival at 6 months was 65.5% for imatinib treatment > 5.8 years and 42.6% for treatment ≤ 5.8 years. This cut-off was identified with the minimal p-value approach.A true pharmaco-economic study will be necessary but taking into account the number of months without treatment in 603 patients, Imatinib front line (with a median observation time of 24 m for patients still off treatment) and the cost of imatinib in each of the 11 European countries (range: 1.734-3.370 Euro per month) the total estimated savings amounted to 27.85 million Euro.Conclusion: Using standardized molecular monitoring, stopping TKI therapy in a very large cohort of CML-patients appears feasible and safe and high MRFS rates are achievable. Longer duration of imatinib-therapy (optimal ≥ 5.8 years) prior to TKI-stop is associated with a higher probability of MRFS. Taking into account the long follow-up without molecular relapse in the historical studies such as STIM1 (Etienne et al; JCO 2016) the "operational" cure of CML with oral TKI is an up-to-date issue. DisclosuresMahon:NOVARTIS PHARMA: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; PFIZER: Honoraria; ARIAD: Honoraria. Richter:Ariad: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Almeida:BMS: Speakers Bureau; Shire: Speakers Bureau; Alexion: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Berger:NOVARTIS PHARMA: Honoraria. Machova Polakova:Bristol Myers-Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Honoraria, Research Funding. Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Saussele:NOVARTIS PHARMA: Consultancy, Honoraria; BMS: Honoraria.

Prediction for Sustained Deep Molecular Response of BCR-ABL Levels in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

IntroductionInitial treatment with tyrosine kinase inhibitors (TKI) induces excellent response in the majority of patients with CML-CP. Current guidelines recommend periodic monitoring of BCR-ABL1 levels to monitor response. During the course of treatment, recognizing early predictors of deeper response and longer-term outcomes can help guide treatment. This is relevant not only at the specified fixed time point typically reported (i.e., 3, 6, 12 months) but at any other time point when an assessment is made. Achievement of sustained deep molecular response is a goal of increasing relevance as it opens the possibility of treatment discontinuation. The objective of this study is suggest optimal BCR-ABL transcript levels at any given time, and to suggest a prediction model for sustained molecular response 4.5 (MR4.5) (BCR-ABL ≤0.0032%) for at least 2 years according to BCR-ABL levels achieved within the first 12 months of TKI therapy.MethodsResponse data for 630 patients with newly diagnosed CML-CP in consecutive prospective clinical trials of frontline imatinib (n=73; NCT00048672), high-dose imatinib (n=208; NCT00038469 and NCT00050531), nilotinib (n=148; NCT00129740), dasatinib (n=150; NCT00254423), and ponatinib (n=51; NCT01570868) were analyzed. Real-time PCR analysis was performed at approximately 3 month intervals during the first year and 6 month intervals thereafter. The "best fit average" molecular response was defined by robust linear regression models, with which the estimated molecular level in patients with complete cytogenetic response (CCyR) within 1 year, major molecular response (MMR) within 1 year, and sustained MR4.5 at any point were defined. The acceptable molecular response was defined by quantile regression for the 95th percentile, with which the worst 5% BCR-ABL levels in patients with CCyR within 1 year, MMR within 1 year, and sustained MR4.5 at any point were identified.ResultsIn 630 patients, 2512 data points of BCR-ABL levels within 1 year of TKI were identified. The median follow-up for the entire cohort was 106 months (range, 0.3-177.8). The regression equations for best fit average PCR for CCyR within 1 year was Log10(PCR) = -0.2159 x (Months) + 0.1957; for MMR within 1 year, Log10(PCR) = -0.2304 x (Months) + 0.1046; for sustained MR4.5 at any point, Log10(PCR) = -0.2154 x Months -0.1161. The regression equations for acceptable PCR for CCyR within 1 year was Log10(PCR) = -0.15796 x (Months) + 1.54839; for MMR within 1 year, Log10(PCR) = -0.20999 x (Months) + 1.54839; for sustained MR4.5, Log10(PCR) = -0.22476 x (Months) + 1.50516 (Figure 1). The best fit average PCR (i.e., estimated levels achieved by the average responder in each category) for CCyR within 1 year was 0.353%, 0.079%, 0.017%, and 0.004% at 3, 6, 9, and 12 months, respectively; for MMR within 1 year was 0.259%, 0.053%, 0.011%, and 0.002% at 3, 6, 9, and 12 months, respectively; for sustained MR4.5 at any point was 0.295%, 0.067%, 0.015%, and 0.003% at 3, 6, 9, and 12 months, respectively (Table 1). To achieve CCyR within 1 year, the acceptable PCR (i.e., levels achieved by 95% of all those who eventually reach the said endpoint) response was 11.872%, 3.987%, 1.339%, and 0.450% at 3, 6, 9, and 12 months, respectively; to achieve MMR within 1 year, 8.287%, 1.943%, 0.455%, and 0.107% at 3, 6, 9, and 12 months, respectively; to achieve sustained MR4.5 at any time, 6.774%, 1.434%, 0.304%, and 0.064% at 3, 6, 9, and 12 months, respectively. Of 289 patients who eventually achieved sustained MR4.5, 288 (99%) achieved CCyR within 1 year; 268 (93%), MMR within 1 year; 201 (70%), MR4 within 1 year; 162 (56%), MR4.5 within 1 year; 72 (25%), CMR within 1 year. Of 359 patients who achieved MMR within 1 year with a minimum follow-up of 48 months, 256 (71%) achieved sustained MR4.5; of 180 patients who achieved MR4.5 within 1 year, 151 (84%); of 72 patients who achieved CMR within 1 year, 65 (90%).ConclusionProper interpretation of early transcript levels at any time during the course of therapy may help predict later response and outcome. Such models can be built to guide therapy for patients in a continuous basis. To achieve sustained MR4.5 for at least 2 years, deeper responses are required at each time point. Our model proposes optimal values that predict the highest probability of reaching such goal. At a minimum, CCyR within 1 year is required to achieve sustained MR4.5. [Display omitted] [Display omitted] DisclosuresKantarjian:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Konopleva:AbbVie: Research Funding; Genentech: Research Funding. Wierda:Novartis: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Daver:Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; Sunesis: Consultancy, Research Funding; BMS: Research Funding; Kiromic: Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

Clinical Application of Artificial Intelligence in Patients with Chronic Myeloid Leukemia in Chronic Phase

▪IntroductionArtificial intelligence (AI) has been applied to a wide range of daily activities to assist in decision-making. Randomized clinical trials can compare the efficacy of treatment between patient groups. However, the best treatment decision for each individual patient, with their own clinical and biological features, and in the context of comparable treatment options, is more difficult to predict. The integrated consideration of various prognostic features can reach the point beyond human recognition. An AI-assisted approach may help with decision-making in complex clinical situations. The aim of this study is to introduce a prototype of AI to predict outcome such as achievement of major molecular response (MMR) within 1 year of the start of tyrosine kinase inhibitor (TKI).MethodsResponse data for 630 patients with newly diagnosed CML-CP in consecutive prospective clinical trials of frontline imatinib (n=73; NCT00048672), high-dose imatinib (n=208; NCT00038469 and NCT00050531), nilotinib (n=148; NCT00129740), dasatinib (n=150; NCT00254423), and ponatinib (n=51; NCT01570868) were analyzed. After multiple imputation for missing variables, neural network analysis with a multilayer perceptron model using the statistically significant variables by stepwise multivariate analysis was performed to predict the cumulative incidence of MMR within 1 year. The hyperbolic tangent and softmax activation function were used to create the architecture of hidden layers and output layers, respectively. Batch training with scaled conjugate gradient optimization algorithm with learning parameters (initial Lambda of 0.0000005, initial Sigma of 0.00005, interval center of 0, and interval offset of ±0.5) was used to train the neural network. To evaluate the accuracy of prediction, the entire cohort was randomly divided into training dataset (70%) and test dataset (30%). The correct prediction in the test dataset was repeatedly assessed 1,000 times to validate this approach. The whole cohort was subsequently used to create the AI model for MMR prediction, and was divided into two cohorts based on the prediction by the AI; AI-predicted response, and AI-predicted nonresponse. Hypothetical choice of TKI was assumed to rank the selection of TKI among imatinib 400 mg/day, imatinib 800 mg/day, dasatinib, nilotinib, and ponatinib to calculate the estimated percentage of MMR within 1 year for each patient. The Kaplan-Meier method with a log-rank test was used for failure-free survival (FFS), transformation-free survival (TFS), event-free survival (EFS), and overall survival (OS). To balance baseline patient characteristics between cohorts, propensity score matching after propensity score calculation by logistic regression was performed with nearest neighbor matching method with a caliper of 0.20. Exact matching was used for the type of cytogenetic, transcript, and TKI.ResultsOf 630 patients treated, 464 (74%) achieved MMR within 1 year. The stepwise multivariate analysis identified the selection of TKI, type of transcript, white blood cell count, albumin, and spleen size at diagnosis were the predictors for MMR within 1 year. Neural network analysis with a multilayer perceptron model is shown in figure 1. Through repeated random selection for training set (70%) and test set (30%), the mean correct prediction for MMR within 1 year was 77.4% (95% confidence interval [CI], 74.2-80.5), and 76.9% (95% CI, 71.4-82.3), respectively. Of 630 patients, the neural network model predicted 539 patients (86%) as responders, and 91 patients (14%) as nonresponders (table 1). Before propensity score matching, the AI-response cohort had higher rates of CCyR, MMR, MR4, MR4.5, and CMR as well as FFS, TFS, EFS, and OS compared to those of the AI-nonresponse cohort (figure 2). After propensity score matching, 25 patients in each cohort were identified, and the baseline differences were minimized (table 1). The AI-response cohort had higher rates of MMR, MR4, and FFS than those of AI-non-response cohort (figure 2).ConclusionAI with a multilayer perceptron model can predict target outcome. Incorporation of additional clinical and biological variables may improve the prediction rates to suggest the best treatment option in each patient with CML-CP. Such strategy is ongoing. [Display omitted] [Display omitted] [Display omitted] DisclosuresKantarjian:ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Ravandi:BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Konopleva:AbbVie: Research Funding; Genentech: Research Funding. Wierda:Novartis: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Daver:Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding; Ariad: Research Funding.

Characterization of the Genomic Landscape of BCR-ABL1 Kinase-Independent Mechanisms of Resistance to ABL1 Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

Despite the well-established success of ABL1 tyrosine kinase inhibitors (TKIs) in the treatment of patients with chronic myeloid leukemia (CML), approximately 20% of patients treated with frontline imatinib develop resistance by 5 years on therapy. The majority (~60%) of such resistant cases are explained by acquired mutations within the BCR-ABL1 kinase domain that compromise inhibitor binding, and nearly all of these mutations are effectively targeted by one or more of the 2nd and 3rd generation ABL1 kinase inhibitors. In contrast, the remaining ~40% of imatinib-resistant cases harbor no explanatory BCR-ABL1 kinase domain mutation, presumably attributable to BCR-ABL1 kinase-independent mechanisms. We hypothesized that resistance in these patients results from acquired auxiliary molecular aberrations which persistently activate signaling pathways downstream despite inhibition of BCR-ABL1 kinase activity. To identify such mechanisms, we performed whole exome sequencing and RNA sequencing on a cohort of 135 CML patients comprising the following subgroups: newly diagnosed/TKI naïve (n=28), BCR-ABL1 kinase-dependent resistance (n=31), and BCR-ABL1 kinase-independent resistance (n=65), and TKI-induced remission (n=7). Resistant patients were required to have demonstrated clinical resistance to one or more ABL1 kinase inhibitors in the form of suboptimal response or loss of cytogenetic response; the subtype of resistance was defined based on the presence or not of an explanatory BCR-ABL1 kinase domain mutation at the time of resistance. The majority of samples collected were from patients with chronic phase CML (n=97), although smaller cohorts of accelerated phase CML, blast crisis CML, and Ph+ ALL were also profiled (n=20, 19, and 9, respectively). Among the 44,413 protein-altering and 902 splice site variants detected across the 120 WES samples, there were on average 908 missense, 146 truncation and 69 splice variants per sample. Genes with truncation and missense variants were compared between BCR-ABL1 kinase-independent and -dependent resistant chronic phase samples. A total of 44 genes were seen with a frequency difference of at least 10%, including PLEKHG5 and NKD2 (30% and 28% difference, respectively), which are involved in regulation of NF-kB and Wnt signaling. Consistent with previous reports, we also detected EZH2 and TET2 as exclusively mutated in the BCR-ABL1 kinase-independent resistance patients (6% and 3%, respectively). Further analyses stratifying variants among resistant patients according to specific ABL1 kinase inhibitor therapy failed and comparing, where available, serial samples from pre- and post-treatment for clonal expansion are underway. Additionally, sufficient material was available to perform ex vivo small-molecule inhibitor screening for 48 patient specimens, the resultant data of which was used to generate putative effective drug target profiles and integrated with exome sequencing variants to prioritize variants of functional relevance (HitWalker; Bottomly et al., Bioinformatics 2013). Among 23 patient samples exhibiting BCR-ABL1 kinase-independent resistance, the mutated genes most frequently ranked in the top 10 functional-prioritized variants were: ABL1 (which included non-kinase domain variants; 34.7%), MAP3K1, MUC4, FGF20 (each 17.4%), ARHGEF15, MEF2A, EPHA8, TYRO3, BMP2K, and IRS1 (each 13.0%). Notably, the top six candidates are members of the neutrophin (ABL1, MAP3K1, and IRS1), EPHA forward (EPHA8, ARHGEF15), and p38 MAPK signaling pathways (MAP3K1 and MEF2A). Taken together, these findings suggest that several of the same pathogenic molecular abnormalities seen in other myeloid malignancies are also present in CML patients with BCR-ABL1 kinase-independent resistance, including a subset which align to persistent re-activation of signaling pathways involved in CML disease pathogenesis and progression. As such, genetic and/or functional profiling of these patients in the clinic may translate to actionable candidates for combination therapy to maximize disease control and improve patient outcomes. DisclosuresAgarwal:CTI BioPharma Corp: Research Funding. Radich:Novartis: Consultancy, Research Funding; BMS: Consultancy; Ariad: Consultancy. Deininger:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Incyte: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Gilead: Research Funding; CTI BioPharma Corp.: Membership on an entity’s Board of Directors or advisory committees; Celgene: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Ariad: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Druker:Pfizer: Patents & Royalties; Dana-Farber Cancer Institute: Patents & Royalties: Millipore royalties via Dana-Farber Cancer Institute; Curis: Patents & Royalties; Array: Patents & Royalties; CTI: Consultancy, Equity Ownership; Pfizer: Patents & Royalties; Curis: Patents & Royalties; Array: Patents & Royalties; Dana-Farber Cancer Institute: Patents & Royalties: Millipore royalties via Dana-Farber Cancer Institute; Oncotide Pharmaceuticals: Research Funding; Novartis: Research Funding; BMS: Research Funding; ARIAD: Patents & Royalties: inventor royalties paid by Oregon Health & Science University for licenses, Research Funding; Roche: Consultancy; Gilead Sciences: Consultancy, Other: travel, accommodations, expenses; D3 Oncology Solutions: Consultancy; AstraZeneca: Consultancy; Ambit BioSciences: Consultancy; Agios: Honoraria; MolecularMD: Consultancy, Equity Ownership, Patents & Royalties; Lorus: Consultancy, Equity Ownership; Cylene: Consultancy, Equity Ownership.

Incidence of Severe (≤ 10g/dl) Chronic Anemia in Elderly Patients with Newly Diagnosed Chronic Myeloid Leukemia Treated with Imatinib and Role of Erythropoietin Therapy

Background Early occurrence of severe (≤ 10 g/dl) anemia has been reported in about 5% of newly diagnosed patients with Chronic Myeloid Leukemia (CML) treated with imatinib and is generally transient: in patients responsive to imatinib, however, severe late anemia seems to occur in a higher rate and seems to be more common in elderly patients.Methods To highlight this issue, we revised retrospectively 81 CML patients aged > 60 years treated at our Institution with frontline imatinib for at least 24 months who achieved a durable complete cytogenetic response (CCyR). The main clinical features of the patients at diagnosis were as follows: male/female 42/39 (51.9%/48.1%), median age 70.5 years [interquartile range (IQR) 64.5 - 76.5], median Hb 12.8 g/dl (IQR 11.2 - 13.7), median WBC 42.5 x 109/l (IQR 25.4 - 78.9), median PLTS 448 x 109/l (IQR 282 - 717). According to Sokal risk classification, 12 patients (14.8%) were low risk, 58 (71.6%) intermediate risk, 11 (13.6%) high risk.Severe late chronic anemia was defined as the presence of persistent (> 6 months) and otherwise unexplained (creatinine level < 2 mg/dl, normal iron balance, bilirubin level < 2 mg/dl, folate and Vitamin B12 in the normal range) Hb levels ≤ 10 g/dl which occurred > 6 months from imatinib start.Results On the whole, a condition of late chronic anemia occurred in 22 out 81 patients (27.2%) at different intervals from imatinib start: the incidence was 13.5% (11/81 patients) at the 12th month, 14.8% (12/81 patients) at the 24th month, 12.3% (9/73 patients) at the 36th month, 7.0% (4/57 patients) at the 48th month and 5.9% (3/51 patients) at the 60th month. Seven out 22 patients (31.8%) needed packed red cell transfusions during the follow-up. Clinical features at diagnosis of patients who had severe late chronic anemia compared to the remaining 59 patients without anemia are shown in the Table:Among the 22 patients with severe late chronic anemia, 6 were treated with subcutaneous recombinant alpha-erythropoietin (EPO) at the standard dosage of 40,000 UI weekly, after a median time from imatinib start of 44.7 months (absolute range 26.8 - 73.8): in all 6 patients, baseline endogenous EPO levels were < 100 mUI/ml. All 6 patients achieved erythroid response, which was complete (achievement of stable Hb levels > 12 g/dl) in 4 patients and partial (stable increment > 1.5 g/dl of Hb levels with Hb levels < 12 g/dl) in 2 patients: one patient had a relapse of anemia after 24.1 months from EPO start and stopped EPO treatment, the remaining 5 patients are still in response and in treatment with EPO. No EPO-related toxicity was observed.Cumulative 4-year Event-Free Survival (EFS) for patients with severe late chronic anemia was 69.7% (CI95% 49.3 - 90.1) compared to 86.2% (CI95% 77.4 - 95.0) for patients without anemia (p=0.075): cumulative 4-year Overall Survival (OS) for patients with severe late chronic anemia was 89.6% (CI95% 75.9 - 100) compared to 94.8% (CI95% 89.1 - 100) for patients without anemia (p=0.204).Conclusions The occurrence of a late severe chronic anemia during long-lasting treatment with imatinib has been observed in > 25% of our responsive elderly patients, with a trend for a worse EFS: its occurrence seems more common in very elderly patients with lower Hb levels at diagnosis. Results with EPO are encouraging, but larger studies are warranted to define the role of such an approach in treating this common late complication of prolonged imatinib therapy. [Display omitted] DisclosuresBreccia:Celgene: Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria.

Generic Imatinib in Chronic Myeloid Leukemia: Survival of the Cheapest

▪Introduction: The patent expiration of Imatinib mesylate (Glivec, ®Novaritis) on February 1, 2016, has brought the focus back on generic versions of the drug, and an opportunity to provide a safe and cost effective alternative. India has witnessed a mushrooming of home grown pharmaceutical companies, that have drawn on Darwinian theory to promote the concept of "survival of the cheapest", in pursuit of a deeper penetrance into the cash strapped population. The launch of Veenat (®NATCO pharma) at a fraction of the price of the innovator drug is a case in point.Objectives: To determine the molecular and cytogenetic responses, survival endpoints (event free survival (EFS), failure free survival (FFS), transformation free survival (TFS), overall survival (OS), and safety of innovator and generic brands of imatinib.Materials and Methods: In this retrospective analysis, data from 1,812 patients with chronic myeloid leukemia (CML) treated with frontline Imatinib mesylate (Innovator/Generic) at a single institution between 2008 and 2014 is included. Of these 1,812 patients, 445 were excluded due to inadequate data and follow up. Thus, data from 1,193 patients who were treated with Glivec (®Novartis), and 174 patients with Veenat (®NATCO) was available.Observations: A higher percentage of patients in the generic arm compared to the innovator arm, were in accelerated phase (9.7% vs 6.7%) and blast crisis (7.4% vs 3.7%), respectively.After a median follow up of 1,347 days, 805 (67.4%) patients achieved complete cytogenetic response (CCgR), 259 (21.7%) achieved major molecular response (MR3), and 205 (17.1%) achieved 4 log reduction in BCR ABL transcripts (MR4) in the innovator arm. After a median follow up of 1,220 days, 112 (64.3%), 24 (13.7%), and 42(24.1%) patients achieved a CCgR, MR3 and MR4 respectively, in the generic arm.Follow up assessments using real-time quantitative polymerase chain reaction (q-PCR) and/ or cytogenetic tests were not available in 230 (19.2%) and 40 (22.9%) patients, in the innovator and generic groups respectively, despite inclusion in a sponsorship program.Adherence to treatment was poor in 192 (16%) and 30 (17.2%) patients in the innovator and generic arms respectively.Results: In a fairly homogenous population of lower economic strata, on a free drug access program, the prime factors influencing adherence were low educational level, assumptions of "cure", recent bereavement, stigma of cancer diagnosis and repeated hospital visits.Transformation to accelerated/blast phase occurred in 7.7% and 7.4% of patients in the innovator and generic arms respectively. Testing for BCR-ABL1 mutations was done in 31 (17.8%) patients in the generic arm and 132(11%) patients in the innovator arm, after failure of treatment or suboptimal response. Mutations were identified in 14 (8%) patients in the generic arm and 52 (4.3%) patients in the innovator arm.The most common subsequent treatments chosen were, dose escalation (249 [20.8%] vs 30 [17.2%]), Nilotinib (26 [2.1%] vs 8 [4.5%]), Dasatinib (11 [0.9%] vs 9 [5.1%]) and hydroxyurea (11 [0.9%] and 4 [2.2%]) in the innovator and generic arms respectively.There was no difference in EFS (p=0.46), FFS (p=0.16), TFS (p=0.9), or OS (p=0.13) between the two groups. The frequency of reported grade 1, or 2 non-hematological adverse events which included musculoskeletal pain, muscle cramps, and peripheral edema, and hematological adverse events was comparable between the study groups. However, the incidence of grade 3 skin rash was higher in the generic group (2.8%) in comparison to the innovator group (0.2%).Conclusion: The findings of the present study showed comparable efficacy and safety of the generic and innovator versions of imatinib in the treatment of patients with chronic myeloid leukemia. DisclosuresNo relevant conflicts of interest to declare.

A Randomized Phase II Trial of Interferon (IFN)/GM-CSF Versus K562/GM-CSF Vaccination in Chronic Phase CML Patients on Frontline Tyrosine Kinase Inhibitor (TKI) Therapy: Potential of IFN to Enhance Molecular Remissions

Background: Tyrosine kinase inhibitors (TKIs) have dramatically improved outcomes in chronic myeloid leukemia (CML), but most patients either never achieve a complete molecular remission (CMR) or recur upon TKI discontinuation due to the persistence of leukemic stem cells. The kinetics of the initial TKI response appear predictive of long term outcomes as front-line imatinib patients who achieve a major molecular response (MMR) at 12 months have a 72% chance of attaining a CMR versus just 5% for those who do not (median time on Imatinib (IM) prior to CMR 66 months) (Branford. Clin Cancer Res. 2007). Interestingly, patients who achieve and maintain a CMR for ≥2 years on single agent IM have been the subject of several TKI discontinuation trials demonstrating that 38-47% of such patients maintain treatment-free remissions (TFR) at 2 years (median time on IM prior to discontinuation of 50-70 months) (Mahon. Lancet Oncol. 2010 and Ross. Blood. 2013). Interferon-alpha (IFN) and K562/GM-CSF vaccines have been shown to enhance the frequency of deep molecular responses to TKIs (Preudhomme. N Engl J Med. 2010 and Smith. Clin Cancer Res. 2010). We have shown that IFN targets LSCs, which may be the mechanism of improved IM responses (Angstreich. Br J Haematol. 2005). We now report initial outcomes for patients randomized between these treatments as a means of achieving TFR.Methods: Patients with Ph+ CML in complete cytogenetic remission on first-line TKI treatment for ≥1 year were randomized to receive either K562/GM-CSF vaccination at 3 week intervals (vaccine) or daily interferon/GM-CSF (IFN/GM) in combination with their TKI. If CMR was achieved after a minimum of 6 months of adjuvant treatment, then all therapy was stopped, and monthly BCR-ABL PCR testing was performed to monitor for relapse. Based on the limits of detection of our assay, CMR is defined as at least MR4.3, which is IS <0.01. At disease recurrence, or if CMR was not achieved at 12 months of combination therapy, patients were allowed to cross-over. The treatment arms were defined as IFN alone (A), vaccine alone (B), IFN followed by vaccine (C), or vaccine followed by IFN (D).Results: 34 patients were enrolled with final treatment allocation shown in Table 1. Most patients were on IM (n=31), nilotinib (n=2) and dasatinib (n=1) with a median duration of TKI use at enrollment of 19 (range 12-80) months. Both arms of the trial were well-tolerated. The vaccine arm was notable for grade 1 and 2 injection site reactions in all patients. Predictably, the IFN arm produced grade 1 and 2 myalgias and flu-like symptoms in the majority of patients. Three patients had to discontinue treatment on the IFN arm due to grade 3 adverse events including a neurological event of unknown causality (1) and ALT elevation (2). Table 1 shows the responses by treatment arm with 62% of patients achieving CMR at a median of 28.6 (range 11-100) months of TKI therapy (compared to 66 months in IRIS). 15 patients (44%) discontinued TKI treatment per study plan after a median of 27.5 (range 19-56) months of TKI treatment (compared to median of 50-70 months of TKI in STIM/TWISTER), and 4 patients (27%) remain off therapy with TFRs of 64, 64, 85, and 92 months. Those with recurrence were off TKI for a median of 3 (range 1-5) months. Importantly, the long term responders who achieved CMR with adjuvant therapy all received IFN adjuvant, and all had relatively little prior TKI treatment (21, 27, 28, and 44 months) compared to published discontinuation studies. As expected in this group, all 4 had achieved a MMR at 12 months on TKI alone (p=0.05). What was unexpected was that 50% of patients treated with one of the IFN arms who had not achieved a MMR at 12 months on TKI alone went on to CMR after treatment on study compared to previous reports and just 15% of historical controls in our institutional database who achieved CMR on TKI alone (p=0.02)Conclusions: Adjuvant therapies may improve the likelihood of achieving CMR and allow for discontinuation of TKI in CML patients with minimal TKI exposure. Even patients predicted to not achieve CMR based on a lack of MMR at 12 months did so at a higher rate than expected following IFN treatment. IFN likely played a role in long term TFR in 4 exceptional responders who successfully discontinued IM sooner than in previously reported discontinuation trials, possibly owing to IFNs effect on primitive CML progenitors. [Display omitted] DisclosuresSmith:Actinium Pharmaceuticals, Inc.: Research Funding.

Exploratory study on the impact of switching to nilotinib in 18 patients with chronic myeloid leukemia in chronic phase with suboptimal response to imatinib.

The phase II, exploratory, open-label Exploring Nilotinib BCR-ABL Effects (ENABL) study [ClinicalTrials.gov identifier: NCT00644878] assessed the impact of switching to nilotinib therapy in patients with chronic myeloid leukemia in chronic phase (CML-CP) who had a suboptimal molecular response with imatinib. Patients with CML-CP who had previously achieved a complete cytogenetic response (CCyR), but had a suboptimal molecular response, with frontline imatinib therapy (N = 18) were assigned to receive nilotinib 300 mg twice daily. The primary endpoint was the change in BCR-ABL1 transcript levels from baseline after 12 months; rates of major molecular response (MMR) and safety were also assessed. At 3 months after switching to nilotinib, 10 of 17 (59%) evaluable patients had achieved MMR. At 12 months, 9 of 12 (75%) evaluable patients had achieved MMR, and the median BCR-ABL1 level among all patients remaining in the study was 0.020% on the International Scale (IS), equivalent to a 3.7-log reduction from the standardized IS baseline (primary endpoint). Adverse events (AEs) were typically grade 1/2 and manageable with dose interruptions. A total of three patients experienced serious study drug-related AEs, including pancreatitis, bradycardia, and vertigo. No deaths were reported. Overall, results from this exploratory study suggest that switching to nilotinib due to suboptimal molecular response with imatinib can result in improved molecular response for patients with CML-CP.

Switching to nilotinib in patients with chronic myeloid leukemia in chronic phase with molecular suboptimal response to frontline imatinib: SENSOR final results and BIM polymorphism substudy

Optimal management of patients with chronic myeloid leukemia in chronic phase with suboptimal molecular response (MR) to frontline imatinib is undefined. We report final results from SENSOR, which evaluated efficacy/safety of nilotinib in this setting. A substudy assessed whether BIM polymorphisms impacted response to nilotinib. In this single-arm, multicenter study, Japanese patients with suboptimal MR per European LeukemiaNet 2009 criteria (complete cytogenetic response, but not major MR [MMR]) after ≥18 months of frontline imatinib received nilotinib 400mg twice daily for 24 months. MR, BCR-ABL1 mutations/variants, and BIM polymorphisms were evaluated in a central laboratory. Primary endpoint was the MMR rate at 12 months (null hypothesis of 40%). Of 45 patients (median exposure, 22.08 months), 39 completed the study and six discontinued. At 12 and 24 months, 51.1% (95% CI, 35.8%–66.3%) and 66.7% (95% CI, 51.0%–80.0%) achieved MMR, respectively. Cumulative MMR incidence by 24 months was 75.6%. Of 40 patients analyzed, 10 of 12 (83.3%) with and 17 of 28 (60.7%) without BIM polymorphisms achieved MMR at 24 months. The safety profile was manageable with dose reductions and interruptions. Nilotinib provided clinical benefit for patients with suboptimal response to imatinib, and BIM polymorphisms did not influence MMR achievement. ClinicalTrials.gov: NCT01043874.

Regorafenib for treatment of imatinib- and sunitinib-resistant metastatic gastrointestinal stromal tumors

ABSTRACTIntroduction: The treatment of gastrointestinal stromal tumors (GISTs) has been transformed by the use of small molecule KIT/PDGFRA tyrosine kinase inhibitors (TKIs). Unfortunately, most GIST tumors develop resistance to front-line (imatinib) and second-line (sunitinib) therapy. Regorafenib, a multi-targeted KIT/PDGFRA/VEGFR oral TKI, has been shown to improve progression-free survival in the third- or fourth-line setting.Areas covered: This review encompasses the pre-clinical and clinical studies of regorafenib for treatment of GIST. The reviewed studies were all those retrievable using the PubMed database as of December 2015.Expert opinion: Based on the results of a randomized, double-blind, placebo-controlled, phase III study, regorafenib is now firmly established as the only proven third-line therapy. Regorafenib’s activity in this setting is believed to be due to its activity against oncogenic forms of KIT/PDGFRA. Side effects are common with this agent; however, they can be effectively managed with a combination of supportive care, dose interruptions and dose reductions. In frail patients, starting at a lower dose with subsequent dose escalation/de-escalation may improve tolerance and optimize treatment. Regorafenib’s toxicity profile is similar to other oral TKIs with anti-VEGFR activity. Regorafenib is primarily metabolized by CYP3A4, and concomitant use of strong inducers/inhibitors of this enzyme should be avoided.

Pregnancy and Accelerated Phase of Myeloid Chronic Leukemia Treated with Imatinib: A Case Report from a Developing Country.

Background. Chronic myeloid leukemia is a hematological malignancy caused by expression of BCR-ABL tyrosine kinase oncogene, product of the t(9;22) Philadelphia translocation. Accelerated phase of this disease marks the onset of advanced rapidly progressive disease unresponsive to many therapies. Pregnancy limits broad number of therapies on patients because of their potential teratogenic effects. We report the case of a pregnant 34-year-old patient on accelerated phase successively managed by imatinib. She achieved a safe pregnancy and delivered at 39 weeks a healthy baby without congenital abnormalities. Our case is unusual because of the accelerated phase of the disease. Case Presentation. A 34-year-old African female with history of chronic phase of myeloid leukemia on imatinib, lost to follow-up for 4 months, presented to the hematological department for abdominal discomfort. Accelerated phase of chronic myeloid leukemia was diagnosed. Complete hematological response was achieved on high doses of imatinib. At the completion of 39 weeks, she delivered a healthy child without congenital anomalies. Conclusion. Despite its teratogenic and embryotoxic effects, front line imatinib is the only effective, well-tolerated treatment for patient on accelerated phase that can be offered to patients in sub-Saharan countries.

The Role of New Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia.

Imatinib mesylate was the first tyrosine kinase inhibitor (TKI) approved for the management of chronic myeloid leukemia. Imatinib produces acceptable responses in approximately 60% of patients, with approximately 20% discontinuing therapy because of intolerance and approximately 20% developing drug resistance. The advent of newer TKIs, such as nilotinib, dasatinib, bosutinib, and ponatinib, has provided multiple options for patients. These agents are more potent, have unique adverse effect profiles, and are more likely to achieve relevant milestones, such as early molecular responses (3-6 months) and optimal molecular responses (12 months). The acquisition of BCR-ABL kinase domain mutations is also reportedly lower with these drugs. Thus far, none of the randomized phase III clinical trials have shown a clinically significant survival difference between frontline imatinib versus newer TKIs. Cost and safety issues with the newer TKIs, such as vascular disease with nilotinib and ponatinib and pulmonary hypertension with dasatinib, have dampened the enthusiasm of using these drugs as frontline options. While the utility of new TKIs in the setting of imatinib failure or intolerance is clear, their use as frontline agents should factor in the age of the patient, additional comorbidities, risk stratification (Sokal score), and cost. Combination therapies and newer agents with potential to eradicate quiescent chronic myeloid leukemia stem cells offers future hope.

Impact of exclusion criteria for the DASISION and ENESTnd trials in the front-line treatment of a 'real-life' patient population with chronic myeloid leukaemia.

Both Dasision and ENESTnd trials had many exclusion criteria, with a possible selection bias compared with the real-life. To address the impact of this bias on the first-line treatment in the current clinical practice, we revised 207 unselected newly diagnosed chronic phase chronic myeloid leukaemia (CML) patients [M/F 108/99, median age 58.8 years, interquartile range 42.3-70.2] treated with front-line imatinib from June 2002 to June 2013 at our Institution, and evaluated how many of them would have been excluded from enrolment in the two trials. Twenty-eight patients (13.5%) should have been excluded by both trials because of polycomorbidities (12), severe cardiomyopathy (five), age > 80 with frailty (three), drug abuse (two) or other severe concomitant diseases (six). In addition, eight patients should have been excluded by Dasision due to isolated chronic obstructive broncopulmonar disease, and 19 patients should have been excluded by ENESTnd due to isolated diabetes (10), arrhythmia (four), acute myocardial infarction > 6 months before CML diagnosis (two), chronic pancreatic disease (two) and peripheral arterial obstructive disease (one). On the whole, 36 patients (17.4%) would have been excluded by Dasision trial and 47 (22.7%) by ENESTnd trial. The patients potentially not eligible for both trials were significantly older and with imatinib had a worse outcome compared with patients potentially eligible. Our data highlight that an automatic transposition of results available in clinical controlled trials into the frontline real-life management of CML patients should be regarded with caution. Copyright © 2015 John Wiley & Sons, Ltd.

Impact of Treatment with Frontline Nilotinib (NIL) vs Imatinib (IM) on Sustained Deep Molecular Response (MR) in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Impact of Treatment with Frontline Nilotinib (NIL) vs Imatinib (IM) on Sustained Deep Molecular Response (MR) in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Switch to Subsequent Line of Treatment in Children and Adolescents with Chronic Myeloid Leukemia (CML) Treated with Imatinib: Experience of the International Registry for Chronic Myeloid Leukemia in Children and Adolescents (I-CML-Ped Study)

Aims: To determine in children and adolescents with chronic myeloid leukemia (CML) in chronic phase (CP) treated with imatinib front line, (i) the probability of switch to a second line therapy, (ii) to characterize the reasons and the type of switch and (iii) to determine the impact of the switch on outcome.Methods: Children and adolescents (<18 years) with CML diagnosed later than the year 2000 and enrolled in the international registry for childhood CML (I-CML-Ped Study) were the subjects of the study.Results: The I-CML-Ped study enrolled 301 children and adolescents with CML in CP treated with imatinib front line. Among them 112 patients subsequently switched to a second line therapy (median duration of imatinib treatment before the switch: 16 months [range: 1-111]).The probability of switch at 38 months was 50% (95% CI: 29-60). Primary resistance was the cause of switch in 47% of the patients: failure to achieve complete hematologic response (CHR, 1%), complete cytogenetic response (CCR, 20%) or major molecular response (MMR, 24%); not detailed (2%). A loss of response (CHR loss [2%] or CCR loss [4%] or MMR loss [13%]) or progression were the cause of switch in 19% and 4% of the patients, respectively. Occurrence of non hematologic toxicity (mainly muscle-skeleton pain) was the cause of switch in 10% of the patients. The reason of switch was the physician's choice in 20% of the patients (switch to hematopoietic stem cell transplantation [HSCT] while the patients were in MMR or deeper molecular response). The second line therapy consisted of second generation tyrosine kinase inhibitors (63%), chemotherapy (4%) or HSCT (33%). With a median follow up of 38 months (range: 2-150), overall, 8 deaths were recorded among switching patients: all were patients transplanted for acute phase (4 patients), hematologic resistance (1 patient), loss of hematologic response (1 patient) or physician's choice (2 patients). The causes of death were treatment related mortality (7 patients) and relapse (1 patient). One death only was recorded among the non switching patients. The probability of overall survival at 48 months was 90% (95% CI: 81% - 95%) for switching patients and 98% (95% CI: 89% - 100%) (p=0.005) for the non switching patients.Conclusion: Treatment failure is the main reason for a switch to a second line therapy in children and adolescents treated with imatinib front line. Efficacy of second line therapy still needs improvement. DisclosuresNo relevant conflicts of interest to declare.

A 20 Gene Expression Signature That Predicts Early Molecular Response Failure in Chronic Phase CML Patients Treated with Frontline Imatinib

▪BACKGROUND: In chronic phase chronic myeloid leukemia (CP-CML) patients treated with frontline imatinib, failure to achieve early molecular response (EMR failure: BCR-ABL1 >10% at 3 months) predicts for subsequent inferior outcomes. Identifying patients at high-risk of EMR failure provides an opportunity to improve outcomes by personalising treatment at the time of diagnosis, as intervention after EMR failure may be less effective.AIM: To utilise a predictive gene signature to identify CP-CML patients at diagnosis, who are at high risk of EMR failure and inferior clinical outcomes.METHODS: Peripheral blood mononuclear cells collected from 119 patients enrolled in the TIDEL-II study were subjected to gene expression microarray profiling (GEP) Illumina HT12. Validations of the identified microarray genes were performed using Taqman qPCR. All patients commenced imatinib treatment, and switched to nilotinib with or without an antecedent trial of high dose imatinib if they failed to achieve time dependent molecular targets. Clinical outcomes included EMR and cumulative incidence of MMR and MR4.5 (BCR-ABL1 ≤0.1% and ≤0.0032% on the international scale, respectively), and comparisons were made using Fine and Gray test. Competing risks included permanent trial discontinuation for any reason (including death or progression). Event-free survival (EFS) and failure-free survival (FFS) were performed using Kaplan-Meier and comparisons were made using the log-rank test.RESULTS: Fourteen of the 119 patients demonstrated EMR failure (12%). Comparing the GEP of these patients with those that achieved EMR identified 4456 aberrantly expressed genes in the EMR failure group. This gene set was significantly enriched for stem cell phenotype/signalling (e.g. Myc, β-catenin, Hoxa9/Meis1), cell cycle, and reduced immune response pathways associated with adverse prognosis in other cancers. From these genes, 20 genes (IGFBP2, CD3E, RASGRP1, BNIP3L, ETS1, PDK1, METTL7A, HECA, COL8A2, PRSS57, TMEM167A, SPAST, FZD7, VPS41, CDKN1B, CPXM1, SEPT7, RPS28, SLX4IP, and SRSF11) validated by qPCR were selected by nearest shrunken centroid model as the high-risk gene expression signature (high-riskGES) to predict EMR failure. Patients who had a high-riskGES exhibited significantly higher rates of EMR failure compared to those with low-riskGES (training cohort: 73.3% vs 8.0%; p<0.0001; n=40, Hazard Ratio (HR): 4.1). This was validated on an independent patient cohort (validation cohort: 50.0% vs 14.8%; p=0.018; n=39; HR: 3.2). Overall, when both cohorts were combined, patients who had a high-riskGES exhibited significantly higher rates of EMR failure compared to those with low-riskGES (63.0% vs 11.5%; p<0.0001; n=79, HR: 3.3; Figure 1A). The overall prediction accuracy of the signature was 80% (82% specificity, 74% sensitivity). Additionally, patients with a high-riskGES demonstrated significantly worse clinical outcome than those with low-riskGES by 24 months (MMR: 41% vs 83%, p=0.0003; MR4.5: 4% vs 42%, p=0.0004; EFS: 52% vs 92%, p<0.0001; FFS: 44% vs 89%, p<0.0001) (Figure 1B-E).This high-riskGES was confirmed as an independent predictor for EMR failure, when Sokal, age and gender were added as covariates based on the Cox-proportional multivariate analysis (HR: 0.34, p=0.003). Patients who had a high-riskGES also had significant inferior outcomes even if they subsequently achieved EMR, compared to the low-riskGES patient group that subsequently achieved EMR (MR4.5: 10% vs 48%, p=0.034; EFS: 68% vs 96%, p=0.0099; FFS: 60% vs 91%, p=0.011). Furthermore, this 20-gene signature compared favourably to Sokal, EUTOS, Hasford, and OCT-1 Activity in predicting EMR failure based on assessing their respective overall performance F -score (harmonic mean of precision and sensitivity). EMR failure was observed in 15% (n=33) of low Sokal score patients overall and 12% of the low-riskGES group (n=49) but amongst patients who had both low-riskGES and a low Sokal score, 0/25 experienced EMR failure.SUMMARY: For the first time in the CML setting, we have identified and validated a 20-gene signature to predict, at the time of diagnosis, patients at high risk of EMR failure and subsequent inferior clinical outcomes. The ability to predict high risk patients at diagnosis may facilitate the assessment of novel therapeutic approaches designed to improve clinical outcomes for patients with aggressive disease. [Display omitted] DisclosuresYeung:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. White:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Hughes:ARIAD: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.