Search

Introduction: Tyrosine kinase inhibitors (TKIs) have dramatically changed the outcome of chronic myeloid leukemia (CML) patients. Recent research focused on TKI discontinuation after achieving a deep molecular response (DMR) has revealed that about half of the patients maintain the response. DMR is a key criterion for TKI discontinuation. Our retrospective, ‘real-life’ study was aimed at to estimating the proportion of patients treated with first-line imatinib (IM) who achieved DMR and thus may be candidates for discontinuation of TKI treatment in a real life setting. Material and methods: Two hundred and twenty-three patients were enrolled. All patients started IM at 400 mg daily. The median age at the time of diagnosis was 57 years (range: 17–92). Results: Eighty-five patients (43%) in the whole group achieved DMR. Early molecular response (EMR) was achieved by 136 (69%) patients and correlated with the DMR rate (53% with EMR vs 14% without, p < 0.001). Major molecular response (MMR) after a year of treatment was confirmed in 108 (55%) patients, and was predictive for achieving DMR at any time (69% with MMR vs. 24% without, p < 0.001). Conclusion: DMR can be achieved in a significant proportion of patients in a real-life setting. We observed that both the achievement of an EMR at three months and MMR at 12 months were associated with a significant advantage in terms of DMR.

Objective To assess the circulating micro-RNA-150 (miR-150) expression in patients with chronic myeloid leukemia (CML) in relation to imatinib response. Methods Sixty patients with CML and 20 age- and sex-matched control subjects were enrolled. Circulating miR-150 levels were assessed by quantitative real-time polymerase chain reaction on days 0, 14, and 90 of imatinib therapy for patients and once for control subjects. Results The baseline miR-150 expression was significantly lower in patients with CML than in control subjects with subsequent elevation at 14 and 90 days after the start of imatinib treatment. Early treatment response (ETR) at 90 days was the main study outcome. The miR-150 expression had a significantly higher level in patients with CML with ETR. On multivariate analysis, miR-150 on day 14 was significantly related to ETR in patients with CML with predictive efficacy (area under the curve = 0.838, 72.9% sensitivity, and 84.2% specificity). Conclusion We found that miR-150 expression on day 14 of imatinib treatment is a useful early predictive candidate for imatinib response in patients with CML.

AimsNovel prognostic markers are warranted for gastrointestinal stromal tumours. Caveolin-1 is a multifunctional protein that proved to be associated with outcome in multiple tumour types. Aim of this study was to investigate Caveolin-1 expression and prognostic efficacy in a series of gastrointestinal stromal tumours.MethodsCaveolin-1 expression was assessed by immunohistochemistry in a retrospective series of 66 gastrointestinal stromal tumours representative of the different molecular subtypes. Correlations with clinical, histopathological and molecular features were investigated. Statistical analyses were performed as appropriate.ResultsThirty-five cases out of 66 (53.0%) expressed Caveolin-1. Presence of Caveolin-1 expression correlated with favourable histopathologic and clinical traits, including a lower mitotic count (p=0.003) and lower relapse rate (p=0.005). Caveolin-1 expression also resulted associated with the presence ofPDGFRAmutations (p=0.010). Outcome analyses showed a favourable prognostic significance of Caveolin-1 expression in terms of relapse-free survival (HR=0.14; 95% CI=0.03 to 0.63) and overall survival (HR=0.29; 95% CI=0.11 to 0.74), even after adjusting for the mutational subgroup (relapse-free survival: HR=0.14, 95% CI=0.04 to 0.44; overall survival: HR=0.29, 95% CI=0.11 to 0.51) and imatinib treatment (relapse-free survival: HR=0.14, 95% CI=0.02 to 0.81; overall survival: HR=0.29, 95% CI=0.17 to 0.48).ConclusionCaveolin-1 represents a novel prognostic marker in gastrointestinal stromal tumours. Further studies are warranted to validate these results and to explore the mechanisms linking Caveolin-1 expression with thePDGFRAoncogenic pathway.

In a developing country like Yemen, data are limited regarding the outcome of imatinib treatment of chronic myeloid leukemia and the effect of nonadherence to imatinib treatment and previous duration of hydroxyurea treatment.A longitudinal cohort study, which included 164 Yemeni patients, was performed. Data regarding the disease characteristics, adherence to treatment (the medication possession ratio) and outcome were analyzed.After a median follow-up of 60 months and a median duration of imatinib treatment of 46 months, 79 (48.2%) patients were adherent to treatment. In adherent patients, the overall survival and progression-free survival (PFS) were 78 (98.7%) and 73 patients (92.4%), respectively and major molecular response (MMR) rates at 12 months and at 46 months were 32 (41.0%) and 45 patients (57.0%), respectively, compared with 67 (78.8%), 51 (60%), 5 (6.9%), and 2 patients (2.4%), respectively, in nonadherent patients (P .001 for all parameters). Nonadherence to imatinib treatment and duration of hydroxyurea treatment of more than 12 months before starting imatinib were found to adversely affect PFS in univariate (hazard ratio [HR], 7.5 and 9.7, respectively and P .001 for both) and multivariate (HR, 5.6 and 9.3; P = .001 and P .001, respectively) analysis. High risk Sokal score was found to adversely affect PFS in univariate analysis (HR of high to low risk, 2.8; P .022) but not in multivariate analysis.Yemeni patients who were adherent to imatinib therapy achieved response rates similar to that of international standards. Nonadherence to imatinib treatment and previous duration of hydroxyurea treatment for more than 12 months, as a proxy of long interval between diagnosis and starting imatinib treatment, reduced the optimal response to imatinib therapy.

Background In the European LeukemiaNet (ELN) 2013 recommendations, chronic myeloid leukemia (CML) patients with warning response (WR) were suggested to be monitored closely continuing with the same tyrosine kinase inhibitor (TKI). Differently, the guidelines of the National Comprehensive Cancer Network considers switching to another TKI as an option. Patients and Methods We retrospectively evaluated 73 CML patients receiving first-line imatinib, who were followed and managed in accordance with ELN recommendations. We compared patients with molecular WR with patients with optimal response (OR) and failure regarding short- and long-term outcomes. Results The cumulative major molecular response (MMR) rates in patients with OR were significantly higher at any time point than those achieved by the WR group. Patients with WR at 3 months had significantly inferior failure-free survival (FFS) than optimal responders, but overall survival (OS) was similar. For 6 and 12 months, the WR and OR groups had similar FFS and OS. Twenty of 23 patients with WR at 12 months achieved MMR during imatinib treatment. Conclusion It takes longer to get to ELN time points with imatinib than second-generation TKIs (2GTKIs). Treatment might fail in a small proportion of the patients with WR during imatinib treatment, but close and careful monitoring and timely switching to 2GTKIs might translate into favorable outcomes. Avoiding early switch to 2GTKIs would prevent patients from experiencing potential toxicities. There is still a need for prospective comparative studies (ie, continuing imatinib treatment vs. switching to 2GTKIs) in patients with WR, to justify the validity of this response category and to explore the benefit of treatment change in these patients.

Studies on polymorphisms in ABCB1 (ATP Binding Cassette subfamily B member 1) gene have shown importance in CML treatment. 42 CML patients comprising 18 males (42.86%) and 24 females (57.14%) aged from 7 to 75 years, of which 19 (45.24%) belonged to age group of ≤45 years and the rest 23 (54.76%) were >45 years of age. A case-control analysis of 3435C>T and 2677G>T ABCB1 single nucleotide polymorphisms (SNPs) with respect to imatinib treatment outcome and evaluation of correlation, if any, with molecular (both qualitative & quantitative) and cytogenetic responses of the patients at 01 year was done by Multiplex RT-PCR, PCR-RFLP, quantitative real time PCR and cytogenetics. No association of any statistical significance was noted between either of the two SNPs and the imatinib treatment outcome.

The introduction of molecularly targeted drugs, including imatinib, has greatly improved the prognosis of gastrointestinal stromal tumor (GIST), and based on the different response image, the methods of response evaluation have been established for GISTs. Furthrmore, the best response evaluation using them has been reported to be associated with progression-free survival (PFS) in imatinib treatment. However, since it is more important to predict the clinical outcomes of imatinib treatment in “early treatment phase”, new predicting factor in earlier stage is desired to work out the whole strategy of each patient. Early morphological change (EMC) was previously reported as a predictive marker for molecularly targeted drugs in metastatic colorectal cancer. The purpose of the present study was to verify the efficacy of EMC in predicting the outcome in patients with GIST receiving imatinib at early evaluation. We retrospectively reviewed 66 patients. EMC in computed tomography (CT) image was evaluated, and the patients were categorized into two groups: active MR (morphological response) (+) group and active MR (−) group. We investigated the association between the presence of active MR and clinical outcomes. Forty-five patients had active MR ( +). The median progression-free survival (PFS) in patients with/without active MR was 49/23 months (P = 0.0039). The evaluation criteria based on EMC could be a sensitive method to predict the clinical outcome of imatinib treatment for patients with unresectable GIST.

Background: MicroRNAs (miRNAs) have been observed to exhibit altered expression patterns in chronic myeloid leukemia (CML). Therefore, this study was aimed to evaluate the clinical importance of miR-126 and miR-122 expression in concert to imatinib response in CML patients. Methods: The present study included 100 CML and 100 healthy subjects. The expression of the 2 miRNAs was performed using TaqMan probe chemistry, and snU6 was used as internal control. Results: The expression of miR-126 and miR-122 was downregulated in CML patients, with a mean fold change ± SD 0.20 ± 0.33 and 0.22 ± 0.37, respectively. While the expression of both miRNAs was analysed before and after imatinib treatment, it was observed that the expression levels of both were increased after imatinib treatment by 26.25-fold (5.33 against 0.20) and 13.95-fold (3.07 against 0.22) and the increase was statistically significant (p < 0.0001 and p < 0.0001, respectively). The expression of miR-126 was not conclusive when compared in different clinical stages of the CML disease as it showed a decreased expression in patients with accelerated phase compared to chronic phase (mean fold change = 0.03 and 0.27, respectively), but patients with chronic phase and blastic phase had comparable expression (mean fold change = 0.27 and 0.24, respectively). We also observed an increased expression of both miRNAs after imatinib therapy in each clinical phase. Conclusion: The study concludes that expression of miR-126 and miR-122 increases after imatinib treatment in CML patients and that miR-126 defines the good responders of imatinib therapy.

Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.

Objectives: BCR-ABL1 fusion transcripts with contrasting data on response to imatinib therapy have been reported from different parts of the world. Hence, the present study aimed to determine the frequencies of transcripts and their association with response to imatinib therapy in chronic myeloid leukemia (CML) patients. Methods: A total of 170 (76 follow-up and 94 imatinib-resistant) CML samples were included in the study. BCR-ABL1 fusion transcripts and expression status were analyzed in all cases using multiplex reverse transcriptase PCyR and real-time PCyR. Sanger sequencing was used for tyrosine kinase domain (TKD) mutation screening in imatinib mesylate-resistant patients. Results: Of 170 CML patients, 36.36% showed b2a2, 63.53% had b3a2, and 2.94% had b2a2 + b3a2 isoforms. Mean platelet counts and blasts were significantly lower in b2a2 carriers (P = 0.0092; P ≤ 0.0001). Patients with b2a2 transcript were found to be more in responders group (both hematological and cytogenetic), whereas b3a2 patients were more in partial responders group and death (P = 0.763; P = 0.309). In follow-up patients, mean baseline BCR-ABL1 expression levels are significantly higher in b2a2 versus b3a2 carriers (P = 0.0351). Of 94 imatinib-resistant patients, 36 (38.29%) had acquired TKD mutations. Among 36 patients, mean BCR-ABL1 levels are significantly higher in b2a2 and b2a2 + b3a2 group (P = 0.0002; P ≤ 0.0001). TKD mutation frequency was more in b3a2 (61.11%) compared to other types. With respect to follow-up status in 36 patients, 17 patients died while 19 were on imatinib higher doses or 2nd-generation tyrosine kinase inhibitors. Of 17 patients, 41.66% had b2a2 transcript and 54.54% had b3a2 transcript. Conclusion: Patients with b3a2 transcripts might be associated with poor response and worse prognosis in CML with imatinib treatment.

Imatinib mesylate and the newer BCR-ABL tyrosine kinase inhibitors are the standard therapy for chronic myeloid leukemia. Although these are remarkably effective drugs, some mechanisms of resistance have been identified including drug-to-drug interactions. Here we present the case of a chronic myeloid leukemia patient with an inadequate response to imatinib due to concurrent phenytoin administration. Conspicuously low imatinib plasma trough levels were documented. Imatinib dose was increased from 400 to 800 mg with good response. In conclusion, drug-to-drug interactions should be ruled out in cases of resistance to tyrosine kinase inhibitor treatment. Potent inducers of cytochrome P450 isoenzyme CYP3A4, as phenytoin, could induce inadequate responses due to increased imatinib clearance and low imatinib trough plasma levels. Thus, this interaction should be avoided. When this is not possible, dose escalation of imatinib and measurement of plasma levels, if available, is recommended.

11535 Background: Gastrointestinal stromal tumors (GISTs) are characterized molecularly by oncogenic KIT or platelet-derived growth factor alpha ( PDGFRA) mutations. Malignant progression of primary GISTs occurs through stepwise accumulation of additional chromosomal aberrations, such as losses of chromosome arms 14q, 22q, 1p, 15q and Xp. After surgical resection of primary GIST, three years of adjuvant imatinib treatment is recommended for patients with an estimated high risk of recurrence. Still, nearly half of high-risk patients are cured by surgery alone, indicating that selection of patients could be improved. We hypothesized that high-risk GISTs with few chromosomal aberrations had a favorable outcome, and might not benefit from adjuvant therapy. The aim of the study was to investigate if chromosomal complexity could be used as a biomarker in de-escalation of adjuvant imatinib treatment. Methods: GIST patients undergoing surgical resection of their primary tumor between 1998 and 2020 were identified in the sarcoma database at Oslo University Hospital. All samples with available karyotype analysis made on fresh tumor tissue were included. Karyotypes were categorized as simple if they had ≤5 chromosomal changes, and complex if there were > 5 chromosomal aberrations. Results: Chromosomal aberrations were detected in 226 tumors, of which 181 (80.1 %) were gastric. The most frequent resulting imbalances were loss of 14q (75.9 %), 22q (43.5 %), 1p (36.6 %), and 15q (29.6 %). One-hundred and thirty-six tumors (60.2 %) had simple karyotypes whereas 90 (39.8 %) were complex. Cytogenetically complex tumors were larger ( P< 0.001), had a higher mitotic count ( P= 0.009), and were more often non-gastric ( P< 0.001). There was a strong association between chromosomal complexity and risk classification according to the modified NIH criteria ( P< 0.001). Thirty-eight of 58 (65.5 %) high-risk tumors were karyotypically complex compared to 37 of 144 (25.7 %) tumors that were not high-risk. In the high-risk group, 17 patients experienced disease recurrence, of whom one had a simple and 16 had a complex tumor karyotype. Estimated 5-year recurrence-free survival (RFS) for patients with simple tumor karyotypes was 94 % compared to 51 % for patients with cytogenetically complex tumors ( P= 0.004). Adjuvant and/or neoadjuvant imatinib treatment was administered to 40 high-risk patients with a median treatment duration of 33 months (range 2-60 months). A complex karyotype was associated with poor RFS both in patients with ( P= 0.016) and without ( P= 0.046) adjuvant imatinib. Conclusions: Chromosomal complexity was strongly associated with poor RFS in localized, high-risk GIST. Recurrences were infrequent for tumors with simple karyotypes, indicating that de-escalation of adjuvant imatinib treatment should be further explored in patients with cytogenetically simple GISTs.

7038 Background: Although adherence to imatinib treatment has been shown to be critical for attaining treatment response among patients with CML, some studies have suggested a 7.3-9.9% nonadherence tolerance margin before loss of treatment effects. We aimed to model probabilistically the margin of tolerance required to ensure treatment response among patients prescribed imatinib and the margin, if any, before treatment response is at risk. Methods: We performed a post hoc analysis of the ADAGIO study conducted in Belgium on 169 evaluable patients ( Blood 2009). Using the pill count ratio as, what in conventional survival analysis would be, the time variable, we modeled the cumulative likelihood of treatment response as a function of increasing pill count adherence. We applied Kaplan-Meier methods to model the likelihood of complete cytogenetic (CCyR), complete hematological (CHR), major molecular (MMR) and optimal (OR) (as defined by the European Leukemia Net) response as a function of 90-day pill count adherence. Kaplan-Meier methods thus estimated the tolerance for nonadherence to imatinib by calculating the 1 minus Kaplan-Meier estimate for treatment response. Results: Analyses (see Table) showed that ̃100% adherence of prescribed dose is associated with probabilities (rounded) of 0.84 for CHR, 0.83 for CCyR, 0.82 for OR, and 0.77 for MMR; compared to, 0.37 (CHR and CCyR), 0.35 (OR), and 0.39 (MMR) at 90% adherence. (of 0.7698 (MMR). Increasing the intake of imatinib from 90% to 100% of the prescribed dose increased the likelihood of the various treatment responses by 1.95 to 2.35-fold. Conclusions: Our findings challenge any previously estimated tolerance for nonadherence. There is virtually no margin for nonadherence if the objective is to optimize the likelihood of treatment response, and only a minimal margin to avoid impaired treatment response. Under such adherence, response rates similar to those in the pivotal IRIS trial can be obtained. Clinicians must assess and promote patient adherence, and patients must be perfectly adherent.[Table: see text]

Context The chronic myeloid leukemia (CML) cytogenetic hallmark t (9; 22) (q34; q11.2) generates different transcripts, which had been postulated to play a role in imatinib treatment response. Objective To assess the molecular response, loss of response, and disease progression as a function of the BCR-ABL transcript variant in a group of CML patients treated with imatinib. Patients and methods 61 CML chronic-phase patients were analyzed for imatinib molecular response according to the variant of the transcript detected by RT-PCR. Square Chi test was used to evaluate a set of variables that included the following: major molecular response (MMR), major molecular response according to imatinib dose, time to MMR, deep molecular response (DMR), loss of response, and disease progression. Results All three variants of the transcript were identified. However, the b3a2/b2a2 variant was only presented in 1 case and is, therefore, excluded from the analysis. E13a2 (b2a2) variant was identified in 27 (45%) patients and E14a2 (b3a2) in 33 (55%) patients. Results are as following: E13a2 (b2a2) variant: MMR, 74%; major molecular response by dose 400 mg, 63%; 600 mg, 3%; 800 mg, 12%; time to MMR 48 months, 22%; loss of MMR, 8%; progression, 18%; DMP, 63%. E14a2 (b3a2) variant: MMR, 78%; major molecular response by dose 400 mg, 44%; 600 mg, 18%; 800 mg, 11%; time to MMR 48 months, 42%; loss of MMR, 3%; progression, 9%; DMP, 63%. No significate statistical differences were found between these variants regarding the set of analyzed variables. Conclusions In this group of patients, the BCR-ABL p210 transcript variants had no impact on disease response to imatinib mesylate.

BACKGROUND Imatinib is generally well tolerated in the treatment of advanced gastrointestinal stromal tumors (GIST). Gastrointestinal vascular ectasia (GIVE) and gastric antral vascular ectasia (GAVE), while rare, are significant under-reported complications of imatinib therapy. CASE REPORT We present one patient with GIVE complicating imatinib therapy with a literature review of this rare side-effect. RESULTS A 68-year-old woman was diagnosed with advanced GIST, wild-type CKIT. After 3 months of treatment with imatinib, she had partial response. However, she was diagnosed with GAVE and, later, also with GIVE. During her 3-year imatinib treatment, she suffered from severe anemia and required blood transfusions. Conservative treatments were not helpful and the ectatic lesions resolved only with cessation of imatinib. CONCLUSION This confirms a causal relationship between GIVE and imatinib. GIVE and GAVE should be considered possible causes of anemia and upper gastrointestinal bleeding in patients receiving imatinib therapy.

The aim of the present study was to evaluate the efficacy and safety of imatinib mesylate in unresectable gastrointestinal stromal tumor (GIST) and to discuss its therapeutic regimen. A patient with unresectable GIST is described, and several key clinical studies are reviewed, including the clinical trials B2222 and S0033, which contain recently reported results of the long-term clinical outcome of imatinib in patients with unresectable or metastatic GIST. The recent results of the two studies demonstrate the long-term efficacy and safety of imatinib for unresectable or metastatic GIST. A positive response to imatinib treatment was observed in the present patient, which is consistent with the data of the B2222 and S0033 trials. However, further long-term, large-scale, multicenter and controlled trials are required to determine the relative efficacy of combining imatinib agents with surgical procedures or administering imatinib alone.

The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first-line imatinib treatment

Background: Only limited data are available concerning the long-term outcomes of imatinib treatment among Japanese or Asian patients with advanced or recurrent gastrointestinal stromal tumors (GIST). Our multicenter study, which was conducted in northern Kanto, Japan, aimed to assess the efficacy of imatinib mesylate against advanced or recurrent GIST. Summary: The clinicopathological data of 234 GIST patients who were treated at one of the 11 participating hospitals from 2001 to 2011 were retrospectively reviewed (GREAT study). Imatinib was administered as a first-line therapy in cases involving unresectable disease or postoperative recurrence (41 cases). The patients treated with imatinib (n = 41) exhibited 1-, 3-, and 5-year overall survival (OS) rates of 92.3, 74.9, and 53.8% respectively. In univariate and multivariate analyses, imatinib continuation with dose reduction and achieving a complete or partial response were found to be associated with increased OS. The results of 2 large-scale, long-term trials demonstrate that the risk of tumor progression decreases with increased treatment duration. Furthermore, the interruption of imatinib treatment in responsive and controlled patients results in a high risk of disease progression. Key Messages: Long-term imatinib treatment is recommended for patients with nonprogressive disease. If patients experience significant toxicities, temporary dose reduction and treatment continuation might be useful.

Objectives Achieving a major molecular response (MMR) is the goal of imatinib therapy for chronic myeloid leukemia. However, the association between gender, BCR-ABL transcript type, and age with MMR is not well understood and often controversial. Methods We retrospectively analyzed 166 patients who have been treated with imatinib for up to 10 yr. Results Men had a lower MMR rate than women (63.3% vs. 81.6%, P = 0.006) and a shorter time to relapse (median 354 vs. 675 d, P = 0.049), while patients with b3a2 or with both b3a2 and b2a2 break point transcripts had higher MMR rate than those with b2a2 (81.8%, 77.1% vs. 60.7%, P = 0.023 for b3a2 vs. b2a2, P = 0.043 for both vs. b2a2). A striking difference was found between men with b2a2 and women with both b2a2 and b3a2 in terms of MMR rate (43.8% vs. 88.9%), MMR rate within 6 months (7.1% vs. 62.5%) and the time to MMR (median d 493 vs. 159, P = 0.036). Conclusions Both gender and BCR-ABL transcript, but not age, were significantly associated with the molecular response. Men with b2a2 represent a less favorable group in their response to imatinib treatment and may need alternative therapy regimen and closer monitoring.

Background and Objectives This multicenter study, which was conducted in northern Kanto, Japan, aimed to assess the efficacy of imatinib mesylate against advanced or recurrent gastrointestinal stromal tumors (GIST). Methods The clinicopathological data of 234 GIST patients who were treated at one of the 11 participating hospitals from 2001–2011 were retrospectively reviewed. Imatinib was administered as a first-line therapy in cases involving unresectable disease or postoperative recurrence (41 cases). The median follow-up period was 4.0 years. Results After a median follow-up period of 4.0 years, the patients treated with imatinib (n = 41) exhibited 1-, 3-, and 5-year overall survival (OS) rates of 92.3%, 74.9%, and 53.8%, respectively. In univariate and multivariate analyses, imatinib dose reduction and achieving a complete or partial response were found to be associated with increased OS. Conclusions Long-term imatinib treatment is recommended for patients with non-progressive disease. If patients experience significant toxicities, temporary dose reduction might be useful. J. Surg. Oncol. 2014; 110:942–946. © 2014 Wiley Periodicals, Inc.

Only limited data are available concerning the long-term outcomes of imatinib treatment among Vietnamese or Asian patients with unresectable or recurrent gastrointestinal stromal tumors (GISTs). Our study, which was conducted in 188 patients, aimed to assess the efficacy of imatinib mesylate against unresectable or recurrent GISTs. Imatinib had a high response rate and long survival. Some predictors favorable for progression-free survival and overall survival are good performance status and response with imatinib. Findings are discussed in relation to clinical practice in low- and middle-income country.

This study investigated the treatment patterns and outcomes for US veteran patients with chronic myeloid leukemia-chronic phase (CML-CP) initiated on imatinib (IM).Patients (age≥18 years) with at least one CML diagnosis (International Classification of Diseases, Ninth Edition Clinical Modification: 205.1x) during the period January 1, 2000, to June 30, 2011, and initiated on IM as first-line therapy were identified in the VISN 16 data warehouse (N=137). Accelerated and blastic phases (AP/BP) were identified on the basis of WHO classification using complete blood count (CBC) data. Rates of IM dose adjustment, discontinuation, and switching to another drug therapy were estimated. Time to discontinuation, progression to AP/BP, and survival were assessed using Kaplan-Meier analysis (KM).During follow-up, 19.0% of patients had at least one dose increase; of these, 19.2% switched to another therapy. Dose reductions occurred in 25.6% of patients. Among patients who discontinued IM (n=74; 54.0%), whereas 16.2% switched to other therapies, 27.0% neither restarted IM nor switched to other therapies. KM showed that 25.6% and 42.4% of patients discontinued IM treatment by year 1 and 2, and 8.1% and 16.0% demonstrated disease progression by year 1 and 2, respectively. Among patients who experienced disease progression (n=28), 32.1% continued IM postprogression, 32.1% discontinued IM before progression, 28.6% discontinued IM postprogression without switching, and 7.1% switched to other therapies postprogression. The mortality rates were 3.0% and 9.5% after IM initiation, and 21.7% and 42.7% after disease progression by year 1 and 2, respectively.In this veteran population, a substantial number of IM-treated patients, including those with disease progression, either discontinued or interrupted IM use without switching to other therapies.

Imatinib is an effective and approved treatment for advanced gastrointestinal stromal tumor (GIST). Continuous imatinib treatment is recommended by current guidelines. This review summarizes the long-term efficacy and safety of imatinib for patients with metastatic GIST.Key clinical studies were reviewed-including B2222, S0033, and BFR14-with particular emphasis on recently reported results of the long-term clinical outcome of imatinib for metastatic GIST.The B2222 and S0033 studies recently reported 10-year follow-up results that demonstrate the long-term efficacy of imatinib. Furthermore, results from the BFR14 study demonstrate that imatinib treatment should not be interrupted and that the efficacy of imatinib following reintroduction is inferior compared with the continuous administration group. The S0033 study also supports the importance of dose optimization and dose escalation of imatinib in patients with KIT exon 9 mutations or progressive disease. These studies demonstrate that individual patient characteristics should be evaluated for optimal patient management. Managing adverse events proactively is very important to maintain compliance.The results from these studies demonstrate that long-term imatinib extends survival in patients with advanced GIST. Furthermore, these studies support the safety of long-term imatinib therapy in this patient population.

Summary Background Imatinib is a highly effective drug in up-front treatment of chronic myeloid leukemia (CML). In children impaired longitudinal growth has been reported as side effect exerted by this drug under prolonged therapy. We therefore prospectively evaluated alterations of bone biochemical markers in pediatric patients with CML under ongoing imatinib exposure. Material/Methods Bone metabolic markers (calcium, phosphate, magnesium, parathyroid hormone, vitamin D, procollagen type l N propeptide [PINP], and C-terminal cross-linking telopeptide of collagen [CTX-I], osteocalcin [OC]; pyridinoline [PYD], and desoxypyridinoline [DPD]) were determined in 17 patients with CML aged 4–17 years under imatinib treatment in three-month intervals over a 2.5 year period. Results Hyperparathyroidism developed in 8/17 patients and low 25-hydroxyvitamin-D3 levels were found in 15/17 patients. Increased OC levels were detected in 58% of all specimen showing a linear significant decline of −0.30 μg OC per l per week (p=0.04). Serum PINP was lowered in 25% and serum CTX-I was above the normal range in 57% of the specimen originating exclusively from prepupertal patients. Urine PYD and Urine DPD levels were above the normal range in 10% and 9%, respectively, of all specimen collected and a statistically significant linear decline of −0.16 nmol DPD/mg creatinine/week was calculated (p=0.01). Conclusions Bone remodeling may be dysregulated by imatinib. Data suggest that impaired bone formation exceeds that of decreased bone resorption. Regular evaluation of the skeletal actions during long-term imatinib treatment in childhood CML is warranted.

To investigate the impact of the combination of early molecular and cytogenetic responses on the achievement of MR4.5, 228 newly diagnosed chronic phase chronic myeloid leukemia patients treated with imatinib were categorized into 3-month and 6-month concordant optimal, discordant, concordant warning, and failure groups. Among them, 85.3% at 3 months and 78.1% at 6 months had concordant molecularly and cytogenetically defined responses. At both 3 and 6 months, patients with discordant, concordant warning and failure responses had similar 3-year MR4.5 rates, and all were significantly lower than the rate in patients with concordant optimal responses. Patients with concurrent 3-month and 6-month concordant optimal responses had a significantly higher 3-year MR4.5 rate than those with other responses, and 3-month and 6-month concurrent molecular optimal, but not cytogenetic optimal responses. Therefore, achieving concordant optimal molecular and cytogenetic responses at both 3 and 6 months with imatinib treatment are associated with MR4.5 achievement.

International audience

Background. In Syria, CML patients are started on tyrosine kinase inhibitors (TKIs) and monitored until complete molecular response is achieved.BCR-ABLmRNA transcript type is not routinely identified, contrary to the recommendations. In this study we aimed to identify the frequency of differentBCR-ABLtranscripts in Syrian CML patients and highlight their significance on monitoring and treatment protocols.Methods. CML patients positive forBCR-ABLtranscripts by quantitative RT-PCR were enrolled.BCR-ABLtranscript types were investigated using a home-made PCR method that was adapted from published protocols and optimized. The transcript types were then confirmed using a commercially available research kit.Results. Twenty-four transcripts were found in 21 patients. The most common was b2a2, followed by b3a2, b3a3, and e1a3 present solely in 12 (57.1%), 3 (14.3%), 2 (9.5%), and 1 (4.8%), respectively. Three samples (14.3%) contained dual transcripts. While b3a2 transcript was apparently associated with warning molecular response to imatinib treatment, b2a2, b3a3, and e1a3 transcripts collectively proved otherwise (P=0.047).Conclusion. It might be advisable to identify theBCR-ABLtranscript type in CML patients at diagnosis, using an empirically verified method, in order to link the detected transcript with the clinical findings, possible resistance to treatment, and appropriate monitoring methods.

Variant Philadelphia (Ph) chromosome can be observed in 5-10 % of chronic myelogenous leukemia (CML) patients. However, there are only a few studies which have analyzed the prognostic implications of these complex translocations in CML patients after the advent of imatinib mesylate and the results found are conflicting. We investigated the clinical features and cytogenetic response of Brazilian chronic phase (CP) CML patients with variant Ph treated with imatinib mesylate. Among 93 CP CML patients, eight (8.6 %) exhibited complex translocations, involving one (n = 6), two (n = 1), or three (n = 1) additional chromosomes. At 6, 12, and 18 months, a complete cytogenetic response was observed in 100 % of variant Ph patients, respectively. No significant difference was found between variant Ph and standard translocation patients regarding the response to IM treatment at 6, 12, and 18 months. Likewise, there was no statistically significant difference between the two groups concerning the overall survival, failure-free survival, progression-free survival, and event-free survival. The results obtained in our study, despite our sample size, suggest, in agreement to other data found in the literature, that the presence of variant Philadelphia chromosome does not bestow a prognostic disadvantage when compared to the group with classic Ph. This observation does not suggest the need to adjust the treatment protocol due to the presence of variant Ph. However, further studies with larger sample sizes and evaluating both the cytogenetic and molecular response to IM treatment should be conducted to confirm our findings.

Background The optimal duration of Imatinib adjuvant treatment for patients with high-risk gastrointestinal stromal tumors (GISTs) is uncertain. Patients and Methods A total of 90 patients with high-risk GISTs after curative resection were recruited into this non-randomized case–control study, including 35 having Imatinib adjuvant therapy and 55 having follow-up alone. The recurrence-free survival (RFS) was compared. Results After a median follow-up of 44.0 months, a significantly reduced recurrence rate was observed in the treatment group than the control group (17.1% vs. 78.2%, P = 0.000). One-year, 2-year, and 3-year RFS rates were 100% vs. 70.9%, 88.0% vs. 37.8%, and 88.0% vs. 27.5%, respectively; with a significant advantage for Imatinib adjuvant therapy versus the surgery only (P = 0.000, HR 0.122, 95% CI 0.041–0.363). Continuation Imatinib treatment further improved RFS by comparison with the interruption treatment (both 2-year and 3-year RFS were 95.8% vs. 63.6%, P = 0.011, HR 0.103, 95% CI 0.012–0.883). There were no serious adverse events in the adjuvant therapy group. Conclusions Imatinib Adjuvant therapy could significantly prolong the RFS of patients with high-risk GISTs. Extended Imatinib adjuvant treatment strategy may further reduce the risk of relapse with a low drug resistance rate and toxicity profile. J. Surg. Oncol. 2011; 104:760–764. © 2011 Wiley Periodicals, Inc.

BCR-ABL fusion gene t(9;22)(q34;q11) occurs in only 3% of pediatric acute lymphoblastic leukemia (ALL) cases. Previously, less than 40% of Philadelphia-positive ALL patients were cured with intensive chemotherapy. The use of imatinib (340 mg/m2/day) added to an intensive chemotherapy regimen has improved the outcome in this population at 3 years to an event-free survival of 80%. Imatinib treatment alone was administered after remission induction chemotherapy to a patient with Philadelphia-positive ALL who presented with serious chemotherapy toxicity, so that intensive chemotherapy could not be maintained. This is the only patient in the literature who survived remission for more than 2.5 years with imatinib treatment only. Copyright © 2011 S. Karger AG, Basel.

PURPOSE OF REVIEW: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract and is a paradigm of targeted therapy for solid tumors. Elucidation of the biology of GIST enabled use of imatinib, which revolutionized the prognosis of advanced GIST. Whereas surgical resection continues to be the standard of care for primary GIST, judicious and individualized use of adjuvant and neoadjuvant imatinib may enhance the potential for cure in select patients. RECENT FINDINGS: Prospective trials utilizing adjuvant and neoadjuvant imatinib have established the safety and efficacy of these modalities adjunct to surgical resection. Correlative tissue studies derived from these trials have examined gene expression patterns, metabolic and radiographic response, and apoptosis during the first few days of imatinib therapy. As appropriate use of adjuvant and neoadjuvant imatinib requires proper patient selection, development of a predictive nomogram, and advances in mutational analysis represent progress toward individualized care. SUMMARY: Imatinib is well tolerated and beneficial as adjuvant and neoadjuvant therapy, but its utility in these settings continues to be refined. The greatest benefit will derive from an individualized approach that considers multiple patient, drug, and tumor characteristics to assess risk and likelihood of benefit for each patient.

Although imatinib is an effective treatment for chronic myelogenous leukemia (CML), and nearly all patients treated with imatinib attain some form of remission, imatinib does not completely eliminate leukemia. Moreover, if the imatinib treatment is stopped, most patients eventually relapse (Cortes et al. in Clin. Cancer Res. 11:3425-3432, 2005). In Kim et al. (PLoS Comput. Biol. 4(6):e1000095, 2008), the authors presented a mathematical model for the dynamics of CML under imatinib treatment that incorporates the anti-leukemia immune response. We use the mathematical model in Kim et al. (PLoS Comput. Biol. 4(6):e1000095, 2008) to study and numerically simulate strategic treatment interruptions as a potential therapeutic strategy for CML patients. We present the results of numerous simulated treatment programs in which imatinib treatment is temporarily stopped to stimulate and leverage the anti-leukemia immune response to combat CML. The simulations presented in this paper imply that treatment programs that involve strategic treatment interruptions may prevent leukemia from relapsing and may prevent remission for significantly longer than continuous imatinib treatment. Moreover, in many cases, strategic treatment interruptions may completely eliminate leukemic cells from the body. Thus, strategic treatment interruptions may be a feasible clinical approach to enhancing the effects of imatinib treatment for CML. We study the effects of both the timing and the duration of the treatment interruption on the results of the treatment. We also present a sensitivity analysis of the results to the parameters in the mathematical model.

After identification of activating mutations of the KIT gene in gastrointestinal stromal tumor (GIST)-the most common sarcomaof the gastrointestinal tract-a phase 2 study demonstrated efficacy of imatinib mesylate in patients with metastatic GIST harboring a KIT exon 11 mutation. Initial results of long-term follow-up have found a survival benefit in this subgroup of patients.To assess the long-term survival of patients with GIST who were treated in SWOG study S0033 and to present new molecular data regarding treatment outcomes.In this follow-up of randomized clinical trial participants (from December 15, 2000, to September 1, 2001), patients were required to have advanced GIST that was not surgically curable. Postprotocol data collection occurred from August 29, 2011, to July 15, 2015. Using modern sequencing technologies, 20 cases originally classified as having wild-type tumors underwent reanalysis. This intergroup study was coordinated by SWOG, a cooperative group member within the National Clinical Trials Network, with participation by member/affiliate institutions. This follow-up was not planned as part of the initial study.Patients were randomized to 1 of 2 dose levels of imatinib mesylate, including 400 mg once daily (400 mg/d) vs 400 mg twice daily (800 mg/d), and were treated until disease progression or unacceptable toxic effects of the drug occurred.The primary end point was overall survival. Updated survival data were correlated with clinical and molecular factors, and patterns of postprotocol therapies were enumerated and described in long-term survivors.Of 695 eligible patients (376 men [54.1%]; 319 women [45.9%]; mean [SD] age, 60.1 [14.0] years), 189 survived 8 years or longer, including 95 in the 400-mg/d dose arm and 94 in the 800-mg/d arm. The 10-year estimate of overall survival was 23% (95% CI, 20%-26%). Among 142 long-term survivors, imatinib was the sole therapy administered in 69 (48.6%), with additional systemic agents administered to 54 patients (38.0%). Resequencing studies of 20 cases originally classified as KIT/PDGFRA wild-type GIST revealed that 17 (85.0%) harbored a pathogenic mutation, most commonly a mutation of a subunit of the succinate dehydrogenase complex.A subset of patients with metastatic GIST experiences durable, long-term overall survival with imatinib treatment. Although this study provides guidance for management of GIST harboring the most common KIT and PDGFRA mutations, optimal management of other genotypic subtypes remains unclear.clinicaltrials.gov Identifier: NCT00009906.

This review analyzes the state of the art of targeted therapies for several tumors, starting from the paradigmatic example of Imatinib treatment in chronic myelogenous leukemia (CML). We discuss how rare tumors can be models for various mechanisms of receptor tyrosine kinase (RTK) activation, and provide the opportunity to develop new therapies also for more common cancer types. We discuss the activation of the downstream RTK effectors as further targets for therapies in colorectal cancer. Finally, we highlight how a novel multidimensional approach which adds an in silico dimension to the in vitro and in vivo approach, can predict clinical results.

OBJECTIVE. The purpose of this study was to correlate findings on the first follow-up CT after treatment with imatinib in patients with residual or recurrent gastrointestinal stromal tumors (GISTs) with the different types of KIT mutation present at initial resection.CONCLUSION. Residual and recurrent GISTs with KIT mutation of exon 11 deletion more frequently showed both tumor shrinkage and cystic change on 2-month follow-up CT images after the start of imatinib treatment than did other mutation types.

To explore the long-term efficacy of imatinib to chronic myeloid leukemia, a total of 46 late chronic phase (CP) patients were assessed after achieving complete cytogenetic response (CCyR). The median duration of imatinib treatment was 68 (61-74) months. Two hundred fifty-three bone marrow samples were detected BCR-ABL messenger RNA (mRNA) levels by TaqMan-based real-time quantitative reverse transcription-polymerase chain reaction. The median time when CCyR was first achieved was eight (3-72) months. Thirty-four patients achieved major molecular response (MMoR), and their median time when MMoR was first achieved was 35 (3-65) months. More patients achieving CCyR within 18 months obtained MMoR than those after 18 months (85% vs 42%, p = 0.006). One patient progressed into blastic crisis, and four patients suffered cytogenetic relapse later. The estimated 6-year event-free survival (EFS) rate of all patients was 81%. The BCR-ABL mRNA levels at the time of first CCyR of relapsed patients were significantly higher than those in continuous CCyR (p = 0.011). The 6-year estimated EFS rate of MMoR patients was significantly higher than that of non-MMoR patients (100% vs 44%, p = 0.0001). Achieving CCyR within 18 months had a higher probability of achieving MMoR within 6 years. The 6-year estimated EFS rate was significantly higher for patients achieving CCyR within 12 months than those after 12 months (97% vs 55%, p = 0.05). The time when MMoR was first achieved did not affect 6-year estimated EFS. Therefore, imatinib could induce most late CP patients to achieve long-term durable responses after achieving CCyR. Both the time when CCyR was first achieved and the depth of BCR-ABL reduction after CCyR are relevant to long-term EFS.

The BCR/ABL tyrosine kinase inhibitor imatinib mesylate produces a high rate of cytogenetic responses in patients with Philadelphia (Ph)-positive chronic myeloid leukemia (CML), but secondary clonal chromosome abnormalities may develop in Ph-negative cells, and acute myeloid leukemia (AML) has been reported in patients with secondary chromosome abnormalities. We report a patient who developed AML during imatinib treatment of Ph-positive CML despite a cytogenetic response and absence of secondary chromosome abnormalities. Thus, development of AML as a rare event in CML patients with cytogenetic responses to imatinib therapy does not depend on the development of secondary cytogenetic abnormalities.

International audience; Imatinib mesylate is approved for the adjuvant treatment of KIT-positive gastrointestinal stromal tumor (GIST) following surgical resection. However, uncertainty remains in terms of patient eligibility for adjuvant treatment and the optimal duration of treatment. Here, we present two challenging patient cases encountered in clinical practice that highlight the ambiguity in the current recommendations for adjuvant imatinib in GIST and discuss our approaches and rationales for treatment. The first case involves a 36-year-old man with a 7 cm duodenal GIST and possible tumor rupture during surgical resection. This patient's risk of GIST recurrence was either intermediate or high depending on which risk stratification criteria were used. The patient was treated with adjuvant imatinib for 3 years and experienced disease recurrence 14 months after the completion of treatment. Imatinib treatment was reintroduced, and the patient is in partial response 17 months later. The second case involves a 46-year-old woman at high risk of recurrence following surgical resection. Adjuvant treatment with imatinib was initiated. After considering the patient's initial high risk and good side-effect profile, the decision was made to continue adjuvant imatinib treatment for 5 years. As of May 2013, the patient has been receiving continuous imatinib treatment for 52 months, with no sign of progression. These reports exemplify the challenges faced in clinical practice because of uncertainties in optimal risk stratification criteria and duration of treatment. They stress the importance of individualized treatment and shared decision making between the physician and the patient

11043 Background: Imatinib-induced side effects are common, although most of these side effects are mild, some will be severe and lead to disruption of Imatinib treatment in gastrointestinal stromal tumor (GIST). It is necessary to explore a biological predictors to predict and optimal therapeutic strategy. But there were few studied conducted to explore the mechanisms of Imatinib-induced side effects. The present study comprehensively investigated the effects of genetic polymorphisms of cytokines involved in cell proliferation and metabolic enzymes and transporters involved in Imatinib metabolism on these side effects. Methods: A total of 154 GSIT patients treated with Imatinib were enrolled. 22 SNPs (single nucleotide polymorphisms) in KIT/ PDGFRA/ PDGFRB/ SHC1/ FLT1/ MAPK1/ EGFR/ CCL5/ CXCL14were detected using Agena Massarray matrix-assisted laser desorption / ionization-time of flight (MALDI-TOF) platform. Logistic regression analyses were performed to evaluate their effects on Imatinib-induced toxicities. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: Imatinibdose, FLT1 rs9951465, MAPK1 rs13515, PDGFRB rs55712339 and SHC1 rs3766920 were found to be correlated with the incidence of myelosuppression ( P= 0.027, 0.009, 0.002, 0.008, < 0.001, respectively), moreover, FLT1 rs9554314 was correlated with severe myelosuppression (Grade 0,1 vs. 2+, P= 0.009, OR (95%CI) = 3.042 (1.314-7,042)). Meanwhile, EGFR rs10228436 was found to be correlated with the incidence of skin rash ( P= 0.027), moreover, CCL5 rs4796120 and CXCL14 rs7716492 were correlated with severe skin rash (Grade 0,1 vs. 2+), with OR (95%CI) and p value were 8.542 (0.934-78.107), 13.504 (2.308-79.004) and 0.057, 0.020, respectively. Conclusions: This is the first comprehensive report on the biomarkers for Imatinib toxicities. These biomarkers might be able to distinguish patients with mild or more severe forms of Imatinib toxicities, thus enabling the optimization of Imatinib therapy and lead patients benefit from Imatinib treatment in a long-term.

Acquired clonal cytogenetic abnormalities have been described in Philadelphia (Ph)-negative cells from chronic myeloid leukaemia (CML) patients treated with both interferon-α and imatinib [1-13]. T...

Chronic myelogeneous leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the BCR-ABL1 fusion gene, which is usually the result of the t(9;22)(q34;q11.2) translocation k...