Months Of Imatinib Research Articles

Correlation between BCR::ABL1 Transcript LEVEL in Circulating Extracellular Vesicles and BOTH the Molecular Response and the Ongoing Therapy: A Study on Adult CML Patients

Small extracellular vesicles (sEVs) have been shown to play a function in tumor growth and have been studied in Chronic Myeloid Leukemia (CML). Analysis of sEVs and their contents offers a non-invasive strategy that might identify messages transmitted by persisting leukemic cells. The sEVs recovered from CML patients may contain the BCR::ABL1 transcript, but its relationship to clinical and biological factors is still unclear. This study aims to connect the disease status and several clinical features with the BCR::ABL1 transcript levels in sEVs (BCR::ABL1-EV). sEVs were isolated by a commercial kit from 104 plasma samples of adult CML patients in molecular response: 18/104 (17%) in MMR and 86/104 (83%) in DMR assessed by RT-qPCR following the international scale. At sampling, 21/104 (20%) patients were treated with imatinib, 14/104 (13.5%) with nilotinib, 6/104 (5.5%) with dasatinib, 1/104 with bosutinib (1%), 27/104 (26%) with intermittent TKI therapy, and 24/104 (23%) were in treatment free remission (TFR). Taking advantage of digital PCR's (dPCR) sensitivity, it was used to detect the presence of BCR::ABL1 transcript in sEVs. The undetectable samples by RT-qPCR on cells were 38/104 (36.5%), while by dPCR on sEVs were 13/104 (12.5%). This difference resulted statistically significant (p<0.0001) (Fig 1A). In terms of sensitivity, dPCR was able to detect more BCR::ABL1 transcript in the sEVs than in the cells (p= 0.0052), suggesting the release of sEVS shuttling BCR::ABL1 transcript by CML cells resident in the bone marrow (Fig 1B). Considering the quantity of BCR::ABL1 transcript molecules, the BCR::ABL1-EV showed a decrease at the deepening of the MR classes and there was a significant difference between MR3.0 and MR4.5 and MR5.0 (p= 0.0226 and p=0.0101, respectively) (Fig 1C). By gathering overall samples according to MMR and DMR definition, the BCR::ABL1-EV resulted statistically different (p= 0.0017), presenting an increased significance when compared with the analysis on the different MR classes (Fig 1D). A significant difference between BCR::ABL1-EV and the ongoing therapy was observed. For this analysis, nilotinib, dasatinib, and bosutinib were considered together as “2 nd generation TKI”. The BCR::ABL1-EV were significantly higher in samples from patients in intermittent therapy compared to those from patients treated with imatinib (p=0.0398). No statistical difference resulted by other comparisons, even if a trend can be appreciated (Fig 1E). This evidence may be due to the therapy duration, since the mean therapy duration is 111 months and 45 months for imatinib and 2 nd generation TKI, respectively. Despite that, no linear regression between therapy duration and BCR::ABL1-EV. Another fascinating hypothesis is that the difference could be related with mechanisms activated by the different drugs. Further analysis will clarify this point. Interestingly, when comparing the results obtained by dPCR on cells and sEVs, a significant difference was observed in samples of patients under intermittent treatment. A trend can be appreciated in the other conditions, with except for imatinib (Fig 1F). In conclusion, dPCR associated with sEVs analysis confirmed its higher sensitivity to detect even low levels of target and it is able to identify the presence of not-circulating leukemic cells releasing BCR::ABL1 positive sEVs. Moreover, the analysis of the BCR::ABL1 transcript on sEVs revealed a transcript reduction at the deepening of the MR classes, discriminated between MMR and DMR, and correlates with the ongoing therapeutic strategy. Further analysis will clarify the mechanisms at the bases of this correlation. This is the first report about the application of this approach on a cohort of adult CML patients, but strongly suggests how a liquid biopsy approach is able to identify active leukemic cells not otherwise detectable. It opens to the identification of different sub-sets of patients presenting different vesicular BCR::ABL1 transcript levels. The different sub-sets could be related to the therapy response as well as the eligibility to TKI suspension, two of the main hot points in the present CML patients' management.

Ponatinib Versus Imatinib in Patients with Newly Diagnosed Ph+ ALL: Subgroup Analysis of the Phase 3 Phallcon Study

Background: BCR::ABL1 tyrosine kinase inhibitors (TKIs) in combination with chemotherapy or steroids remain the standard of care in patients with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Most patients treated with first- or second-generation TKIs eventually experience disease progression due to treatment resistance. Ponatinib is the only currently approved pan-BCR::ABL1 inhibitory TKI that potently inhibits wild-type and single resistance mutation variants of BCR::ABL1, including T315I. Multiple studies have shown promising minimal residual disease (MRD) negativity (neg) rates and survival outcomes with ponatinib in combination with chemotherapy or chemotherapy-free regimens. PhALLCON (NCT03589326) is the first randomized study comparing frontline TKIs in adults with Ph+ ALL. The primary endpoint for PhALLCON was met, with a clinically significantly higher MRD-neg complete remission (CR) rate at end of induction (EOI) with ponatinib vs imatinib (34.4% vs 16.7%; risk difference: 0.18 [95% confidence interval (CI): 0.06‒0.29]; P=0.0021) and a manageable safety profile comparable with imatinib. Here we report subgroup efficacy analyses from PhALLCON. Methods: This global, registrational, phase 3, open-label study randomized newly diagnosed adult patients with Ph+ ALL 2:1 to receive ponatinib (30 mg once daily [QD]) or imatinib (600 mg QD) plus reduced-intensity chemotherapy through EOI (Cycles 1-3), consolidation (Cycles 4-9), and post-consolidation (Cycles 10-20). Following post-consolidation, patients continued to receive single-agent ponatinib or imatinib until disease progression or unacceptable toxicity. The composite primary endpoint was MRD-neg ( BCR:: ABL1 ≤0.01% [MR4])CR for 4 weeks at EOI. Event-free survival (EFS; any-cause death, failure to achieve CR by EOI, relapse from CR) was a key secondary endpoint. A post-hoc analysis of progression-free survival (PFS; EFS-defined events, failure to achieve MRD-neg by the end of treatment, and loss of MRD-neg) was conducted. Subgroup analyses were performed relative to baseline demographic and disease characteristics. Results: Of 245 randomized patients, 232 (ponatinib, n=154; imatinib, n=78) had baseline BCR::ABL1 p190/p210 variants verified by central lab (efficacy-evaluable population); median age was 54 years (37.1% ≥60 years). As of Aug 2022, 78 patients (ponatinib/imatinib: 68 [41.5%]/10 [12.3%]) remained on study treatment; the top 3 reasons for discontinuation were hematopoietic stem cell transplantation (HSCT; 30.5%/37.0%), adverse events (12.2%/12.3%), and lack of efficacy (7.3%/25.9%). Median follow-up in the ponatinib and imatinib arms was 20 months and 18 months, respectively. Benefit for ponatinib was observed across all subgroups analyzed ( Table). All age subgroups had higher rates of MRD-neg CR with ponatinib vs imatinib, with the greatest benefit observed in patients ≥60 years (40.0% ponatinib vs 10.3% imatinib; P=0.0005). MRD-neg CR rate was higher for ponatinib vs imatinib among those with the BCR::ABL1 p190 variant (38.6%/17.0%; P=0.0017); it was higher for the p210 variant as well, but not significantly (22.5% vs 16.0%; P=0.51). Median PFS was longer with ponatinib vs imatinib regardless of age, with the greatest difference observed in the subgroup of patients ≥60 years (22.5 months for ponatinib vs 8.3 months for imatinib; hazard ratio: 0.594 [95% CI: 0.332-1.063]). Conclusions: Ponatinib was superior to imatinib in combination with reduced-intensity chemotherapy in the front-line setting for patients with Ph+ ALL, with a clinically significantly higher MRD-neg CR rate at EOI. Benefit was observed across all subgroups, particularly for patients ≥60 years and for those with the BCR::ABL1 p190 variant.

Challenges of the Treatment with Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia – Case Presentation

We present the case of a 33-year-old male patient diagnosed with chronic phase chronic myeloid leukemia in June 2008. According to treatment protocols enforced at that time, the patient started oral treatment with imatinib 400 mg/day, reaching a major molecular response (MMR) in 18- month time. The molecular response improved over time, with an undetectable BCR-ABL1 transcript level after 36 -48 months of treatment. However, the profound molecular response did not last, requiring a switch to the second line of therapy after 75 months of imatinib. Taking nilotinib 400 mg x2/day, the patient achieved a major molecular response in 12 months, and after 18 months of treatment, the level of BCR-ABL1 became undetectable. However, two vasooclusive events occurred in 2018 – a transient left parietal ischemic stroke and a left femoral artery occlusion – and by ESMO 2017 recommendations, nilotinib treatment was interrupted. The treatment-free remission decision was made with monthly monitoring of the BCR-ABL1 transcript level, but since the 4th month of monitoring, the deep molecular response disappeared. Administration of dasatinib, the third tyrosine kinase inhibitor, resulted in a deep molecular response which currently lasted until now, during the 58 months of treatment. The presented case represents the evolution of the concept of treatment in this haemato-oncological disease during the last decade.

Outcomes in Patients with Chronic Myeloid Leukemia in the Chronic Phase Randomized to Dasatinib or Imatinib after Suboptimal Responses to 3 Months of Imatinib Therapy: Final 5-Year Results from DASCERN

Introduction: Dasatinib has demonstrated superior responses versus imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in the chronic phase (CML-CP) (Cortes JCO 2016). Achievement of early molecular response (EMR; BCR::ABL1 ≤ 10% International Scale [IS]) at 3 months increases the probability of subsequent deep molecular response (DMR) and improves survival (Cortes JCO 2016, Hochhaus Leukemia 2016). However, ⅓ of pts treated with imatinib did not reach an EMR (Hughes Blood 2014); there are no standard treatment strategies for these pts. DASCERN (NCT01593254) is the first prospective, randomized, phase 2b trial to demonstrate the potential benefit of switching early to dasatinib in pts with no EMR after 3 months of initiating imatinib. At 12 months, pts randomized to dasatinib had significantly higher major molecular response (MMR) rates versus imatinib (29% vs 13%, primary endpoint) (Cortes Leukemia 2020). At 3 years, cumulative MMR rates were 67% and 40% with dasatinib and imatinib, respectively (Cortes EHA 2020 EP756). Switching to dasatinib did not increase the incidence of treatment-emergent adverse events (AEs). Here we report the results from the final 5-year analysis. Methods: Pts with complete hematologic response but no EMR at 3 months after initiating imatinib 400 mg were randomized 2:1 to an early switch to dasatinib (100 mg) or continue imatinib (≥ 400 mg). Pts who experienced subsequent failure with imatinib (per European LeukemiaNet 2013 recommendations at the time of the study) crossed over to dasatinib. The intent-to-treat (ITT) population included all pts randomized to each arm, irrespective of crossover status. Study endpoints included time to MMR and molecular response 4.5 (MR4.5; 4.5-log reduction in BCR::ABL1 levels; ≤ 0.0032% IS), progression-free survival (PFS), overall survival (OS), and safety. Results: At a median follow-up of 80 months (data cutoff, April 24, 2022), 174 and 86 pts with no EMR after imatinib were randomized to dasatinib and imatinib, respectively; 46 (53%) imatinib-randomized pts experienced subsequent imatinib failure and crossed over to dasatinib in a median of 9.5 months. Detailed baseline characteristics have been previously reported (Cortes EHA 2020 EP756). The median age was 37 years, and 73% of patients were Asian. All pts discontinued treatment, mainly due to study drug toxicity (26 [10%]), and other reasons (176 [68%], mostly study completion); 6 (2%) discontinued due to death. The MMR rate by 5 years in the ITT population was 77% and 44%, respectively, for pts in the dasatinib and imatinib arms. After accounting for crossover, cumulative MMR rates were 74% with dasatinib and 44% with imatinib; 65% of pts who crossed over from imatinib to dasatinib achieved MMR (Figure). Across the 5-year study period, more pts randomized to dasatinib than imatinib achieved MR4 and MR4.5 (MR4, 52% vs 31%; MR4.5, 36% vs 26%). Only 1/46 pts who later crossed over to dasatinib after imatinib failure achieved MR4.5. PFS in the ITT population was 94% in both treatment arms. PFS was numerically lower in pts who later crossed over to dasatinib after imatinib failure (90%). OS in the ITT population was similar between both arms (96% vs 95%). OS in pts who crossed over to dasatinib was 94%. Six additional deaths were reported since the 3-year follow-up. Any grade treatment-related AEs were experienced by 149 pts (87%) randomized to dasatinib, 69 (80%) randomized to imatinib, and 37 patients (80%) who crossed over to dasatinib. Treatment-related pleural effusion occurred in 31 pts (18%) randomized to dasatinib (n = 6 grade 3/4), 9 pts (20%) who crossed over to dasatinib after imatinib failure (n = 2 grade 3/4), and 0 pts who remained on imatinib (no crossover). Conclusions: At the final 5-year follow-up, sustained clinical benefit was observed from an early switch to dasatinib after suboptimal responses to 3 months of imatinib. MMR and DMR rates were higher in pts randomized to dasatinib versus imatinib. Overall, the safety profile was consistent with previous reports. These results complement the previous findings that switching to dasatinib promptly after a lack of EMR with imatinib increases the chance of achieving DMR, which may improve outcomes in pts with CML-CP. Therefore, this study further highlights the significance of achieving optimal responses early during treatment. Study support: Funded by Bristol Myers Squibb. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Use of Neoadjuvant Imatinib to Facilitate Minimally Invasive Resection of Gastric Gastrointestinal Stromal Tumors

Neoadjuvant imatinib is used to downstage surgery for large and/or unfavorably located gastric gastrointestinal stromal tumors (GISTs), but data regarding minimally invasive surgery (MIS) after neoadjuvant imatinib are limited. We analyzed patients undergoing resection of nonmetastatic primary gastric GISTs larger than or equal to 4.5 cm in diameter at our institution between 2009 and 2020, as no tumors below this size received neoadjuvant imatinib. We identified 71 patients, 43 of whom (61%) received neoadjuvant imatinib. Patients receiving neoadjuvant imatinib had larger tumors at diagnosis [median diameter 8.6 cm (range 4.5-25 cm) versus 5.9 cm (range 4.5-11 cm), p < 0.01]. After a median 7.2 months of imatinib, tumors shrank by a median 34% in diameter, such that there was no longer a significant size difference at time of surgery between groups (median 6.3 cm versus 5.9 cm, p = 0.69). Of 29 patients for whom neoadjuvant imatinib was used to facilitate MIS, 21 (72%) underwent successful MIS, which accounted for 49% of the entire neoadjuvant cohort. In a multivariable regression model, smaller tumor size at time of surgery was predictive of successful MIS, but tumor location was not. Neoadjuvant imatinib caused significant tumor shrinkage, and MIS was successful in 72% of cases for which neoadjuvant imatinib was intended to facilitate it. Smaller tumor size at time of surgery, but not tumor location, was associated with successful MIS, which may help inform patient selection for neoadjuvant imatinib.

Pro-Inflammatory and Pro-Oxidative Changes during Nilotinib Treatment in CML Patients: Results of a Prospective Multicenter Front-Line TKIs Study (KIARO Study)

Background: Tyrosine kinase inhibitors (TKI) may offer a normal life expectancy to Chronic Myeloid Leukemia (CML) patients. However, during treatment with nilotinib, a higher than expected incidence of arterial occlusive events (AOEs) was observed. We retrospectively showed an “inflammatory status” during nilotinib treatment that may explain this increased incidence of AOEs. Here, we report results of a prospective multicenter (KIARO) study including 186 CML patients (89 imatinib, 59 nilotinib, 38 dasatinib) in which pro/anti-inflammatory cytokines were measured at diagnosis and during treatment, with the aim to investigate potential changes in each patient's inflammatory status possibly favoring AOEs.Aims: The aims of this study are: 1) to analyze prospectively inflammation status during TKI treatment; 2) to record AOEs; 3) to calculate the SCORE and evaluate its predictive role for AOEs; 4) to analyze possible associations of AOEs with altered inflammation status.Methods: Inflammatory status was evaluated by measuring IL6, IL10, TNFα, oxLDL and hs-CRP plasma levels at diagnosis and during treatment (+1, +3, +6, +12 months); additionally, clinical and biochemical pro-atherothrombotic profiles and the 10-year SCORE chart were also evaluated.Results: 186 newly-diagnosed CML patients starting either imatinib, nilotinib or dasatinib treatment, entered this study. Regarding the inflammation status, we observed that TNFα and IL6 levels were high at diagnosis and decreased during the first 12 months of treatment regardless the type of TKI; instead, IL10 levels were comparable among the 3 TKI cohorts at baseline, but showed a remarkably different evolution during treatment. In fact, IL10 levels were significantly higher after 6 and 12 months of imatinib (p=0.012 and p=0.009, respectively) and dasatinib (p=0.032 and p=0.014, respectively) compared to nilotinib. Consequently, TNFα/IL10 ratio was significantly higher in nilotinib cohort at 6 and 12 months respect to imatinib (p=0.044 at 6 months and p=0.041 at 12 months) and dasatinib (p=0.040 at 6 months and p=0.044 at 12 months). As well, IL6/IL10 ratio was significantly higher in nilotinib cohort compared to imatinib and dasatinib both at 6 (p=0.042 and p=0.049, respectively) and 12 months (p=0.040 and p=0.041, respectively) (Figure 1). OxLDL levels were similar in the 3 groups for the first 6 months. At 12 months we detected a significant increase of oxLDL levels in the nilotinib cohort (p=0.041), respect to imatinib and dasatinib. We did not find significant differences in hs-CRP levels across the 3 TKIs, although a trend for higher levels was observed in nilotinib cohort. Overall, these results suggest a TKI-driven pro-inflammatory status in nilotinib treated patients.After a median follow-up of 23.3 months of TKI treatment, 10 patients (5.4%) suffered an AOE, specifically: 6 ACS, 2 PAOD, 1 TIA and 1 stroke. 5 events (50%) occurred in patients treated with nilotinib, either in first line (4 patients) or in third line (1 patient, after failure following brief treatment with imatinib and dasatinib). In this subgroup of 10 patients experiencing an AOE, we observed a trend of increased IL6 and TNFα median values both at diagnosis and at each time point, compared with the remaining no-AOE patients. IL10 and oxLDL had similar median concentrations in both AOE and no-AOE cohorts, except for oxLDL at 12 months which resulted higher in patients who experienced AOEs. Moreover, regarding AOEs, nilotinib treatment showed a 3.1 times increased risk compared to other TKIs (HR 3.1, 95% CI 2.6-4.4 p< 0.001), whereas 10-year SCORE was not predictive in the whole cohort (HR 0.6, 95% CI 0.33-0.94 p= 0.094) or in any subgroup (imatinib HR 0.8, 95% CI 0.49-1.03 p= 0.067; nilotinib HR 0.4, 95% CI 0.29-0.76 p= 0.112, dasatinib HR 0.6, 95% CI 0.37-0.92 p= 0.082).Conclusions: Our results showed a pro-inflammatory/oxidative milieu increasing along treatment with nilotinib compared with imatinib or dasatinib, as demonstrated by higher IL6/IL10 and TNFα/IL10 ratios, higher levels of oxLDL and a trend for higher hs-CRP only in nilotinib cohort. However, due to the low number of observed events, a formal statistical analysis for any association between AOEs and pro/anti-inflammatory cytokines levels was not possible. Therefore, a longer follow-up is needed to further confirm the active role of nilotinib in AOEs pathogenesis. [Display omitted] DisclosuresAbruzzese: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Galimberti: Incyte: Speakers Bureau; AbbVie, Janssen: Honoraria, Other: Travel grants. Stagno: Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; InCyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding.

Assessment of Adherence to Imatinib and Health-Related Quality of Life Among Patients with Gastrointestinal Stromal Tumor: A Cross-Sectional Study in an Oncology Clinic in Malaysia.

PurposeTo evaluate the rate and predictors of non-adherence to imatinib in gastrointestinal stromal tumor (GIST) patients, as well as to compare the difference in health-related quality of life (HRQOL) between adherent and non-adherent patients.Patients and MethodsA cross-sectional study at the Oncology Clinic, Hospital Kuala Lumpur was conducted from March to August 2018. All patients with metastatic and/or unresectable GIST aged ≥18 years old and on at least 3 months of imatinib were included. Adherence to imatinib was assessed using the 10-item validated Medication Compliance Questionnaire, with a score of <100% indicating non-adherence. Non-adherence predictors were determined by multiple logistic regressions. HRQOL was evaluated by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The difference in the mean HRQOL scores between adherent and non-adherent groups was determined by multivariate analysis of variance.ResultsA total of 89 patients were enrolled, of which 49 (55.1%) were considered non-adherent. The significant predictors of non-adherence were age (adjusted odds ratio [OR] 0.93; CI 0.89–0.98; P = 0.007), presence of nausea and vomiting (OR 5.63; CI 1.25–25.27; P = 0.024), and presence of comorbidities (OR 4.56; CI 1.44–14.40; P = 0.010). Patients who were in the adherent group showed significantly better score in overall HRQOL, F (15, 73) = 2.09, P < 0.02; Pillai’s trace = 0.3, partial eta squared = 0.30.ConclusionNon-adherence to long-term treatment with imatinib among patients with GIST should not be underestimated. Significant predictors of non-adherence among this population are younger age, presence of nausea and vomiting, as well as comorbidities. Patients with good adherence portrayed better HRQOL.

Imatinib therapy for patients with recent-onset type 1 diabetes: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Type 1 diabetes results from autoimmune-mediated destruction of β cells. The tyrosine kinase inhibitor imatinib might affect relevant immunological and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our aim was to evaluate the safety and efficacy of imatinib in preserving β-cell function in patients with recent-onset type 1 diabetes. We did a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients with recent-onset type 1 diabetes (<100 days from diagnosis), aged 18-45 years, positive for at least one type of diabetes-associated autoantibody, and with a peak stimulated C-peptide of greater than 0·2 nmol L-1 on a mixed meal tolerance test (MMTT) were enrolled from nine medical centres in the USA (n=8) and Australia (n=1). Participants were randomly assigned (2:1) to receive either 400 mg imatinib mesylate (4 × 100 mg film-coated tablets per day) or matching placebo for 26 weeks via a computer-generated blocked randomisation scheme stratified by centre. Treatment assignments were masked for all participants and study personnel except pharmacists at each clinical site. The primary endpoint was the difference in the area under the curve (AUC) mean for C-peptide response in the first 2 h of an MMTT at 12 months in the imatinib group versus the placebo group, with use of an ANCOVA model adjusting for sex, baseline age, and baseline C-peptide, with further observation up to 24 months. The primary analysis was by intention to treat (ITT). Safety was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, NCT01781975 (completed). Patients were screened and enrolled between Feb 12, 2014, and May 19, 2016. 45 patients were assigned to receive imatinib and 22 to receive placebo. After withdrawals, 43 participants in the imatinib group and 21 in the placebo group were included in the primary ITT analysis at 12 months. The study met its primary endpoint: the adjusted mean difference in 2-h C-peptide AUC at 12 months for imatinib versus placebo treatment was 0·095 (90% CI -0·003 to 0·191; p=0·048, one-tailed test). This effect was not sustained out to 24 months. During the 24-month follow-up, 32 (71%) of 45 participants who received imatinib had a grade 2 severity or worse adverse event, compared with 13 (59%) of 22 participants who received placebo. The most common adverse events (grade 2 severity or worse) that differed between the groups were gastrointestinal issues (six [13%] participants in the imatinib group, primarily nausea, and none in the placebo group) and additional laboratory investigations (ten [22%] participants in the imatinib group and two [9%] in the placebo group). Per the trial protocol, 17 (38%) participants in the imatinib group required a temporary modification in drug dosing and six (13%) permanently discontinued imatinib due to adverse events; five (23%) participants in the placebo group had temporary modifications in dosing and none had a permanent discontinuation due to adverse events. A 26-week course of imatinib preserved β-cell function at 12 months in adults with recent-onset type 1 diabetes. Imatinib might offer a novel means to alter the course of type 1 diabetes. Future considerations are defining ideal dose and duration of therapy, safety and efficacy in children, combination use with a complimentary drug, and ability of imatinib to delay or prevent progression to diabetes in an at-risk population; however, careful monitoring for possible toxicities is required. Juvenile Research Diabetes Foundation.

New insights into halting type 1 diabetes

During the past four decades, several studies have attempted to identify ways in which to halt the type 1 diabetes disease process to preserve β-cell function. For the most part, the results have been disappointing, with interventions either having no effect or having a transient beneficial effect.1–2 In The Lancet Diabetes and Endocrinology, Stephen E Gitelman and colleagues published a randomised phase 2 trial on imatinib therapy for patients with recent-onset type 1 diabetes.3 Similar to previous studies, they observed a transient effect, in that it met the primary endpoint at 12 months (a significant mean difference in 2-h C-peptide response at 12 months for imatinib vs placebo), but the effect was not sustained up to 24 months.

Mutation Screening at Diagnosis Reveals a High Frequency of ASXL1 Mutations in CML Patients Who Fail to Achieve Molecular Remission Criteria after One Year of TKI Treatment

Background: Tyrosine kinase inhibitors (TKI) revolutionized treatment of chronic myeloid leukemia (CML). While response rates are high, a subset of patients does not show the expected decrease or eradication of BCR-ABL1 . According to ELN guidelines (Baccarani et al. 2013) BCR-ABL1/ABL1 ratio>1% after one year of TKI is considered failure. Mechanisms of failure include the acquisition of additional genetic changes, e.g. cytogenetic aberrations and mutations in the ABL1 kinase domain but also in other genes. Here, we ask the question, if specific mutations are not only acquired but may already be present at initial diagnosis of patients with slow or no TKI response (primary failure according to ELN). Aim: To screen CML patients at diagnosis, who failed ELN remission criteria after one year, for mutations in genes, which are frequently mutated in myeloid malignancies. Patients and Methods: In a backtracking approach, we selected diagnostic samples of 48 CML patients (25 males, 23 females) with a median age of 64 (range: 23-84) years, who failed first year molecular remission criteria. Median BCR-ABL1/ABL1 ratio was 3.603 [1.158-58.318] after 12 (11-16) months of imatinib (n=42), second generation TKI (n=5) treatment or both (n=1). Patients had a p210 BCR-ABL1 fusion (e13a2 [n=24], e14a2 [n=18], both [n=6]) and no additional cytogenetic aberrations at diagnosis. We sequenced DNA of bone marrow (n=28) or peripheral blood (n=20) samples drawn at diagnosis on NextSeq or MiSeq sequencers after TruSeq library preparation (Illumina, San Diego, CA). We used SeqNext 4.3 for data analysis (JSI, Kippenheim, Germany). The panel covered 48 genes including the epigenetic regulators: ASXL1, ASXL2, BCOR, DNMT3A, EZH2, IDH1, IDH2 and TET2 . Results: We identified mutations in 13/48 samples at initial diagnosis (27%). Only one patient had two mutations (total, n=14 mutations). There was no correlation of mutations with types of transcript, age, gender, hemoglobin level, WBC count, percentage of Ph+ cells by FISH, BCR-ABL1/ABL1 ratio at diagnosis or with BCR-ABL1/ABL1 ratio after one year of TKI. Twelve of the 14 (86%) mutations were found in genes involved in chromatin modification or DNA methylation. We screened four splicing machinery genes (SF3B1, SRSF2, U2AF1, ZRSR2), which are frequently mutated in other myeloid malignancies, but no mutation was found. In 8/48 (17%) patients, we found an ASXL1 mutation (57% of all mutations). Other mutated genes were ASXL2, BCOR, CALR, NRAS (n=1 each) and DNMT3A (n=2). The comparison of ASXL1 mutation types in this CML cohort to other myeloid malignancies revealed a significant shift in mutation types: e.g. in myelodysplastic syndrome (Haferlach et al. 2014) and chronic myelomonocytic leukemia (Meggendorfer et al . 2012), c.1934dup and c.1900_1922del (ENS0375687) constitute the majority of mutations (64 [42%] and 23 [15%] of 152, respectively), whereas there was only one c.1900_1922del and no c.1934dup in our CML cohort (p=0.023). Further, we used follow-up samples after one year of TKI to evaluate if mutations are derived from the CML clones. In all patients with available data for ASXL1 (n=6), mutation burdens showed a quantitative course which paralleled BCR-ABL1 ratio indicating that ASXL1 mutations are part of the CML clone present at diagnosis. In the patient with a CALR mutation, the CALR burden remained unchanged despite BCR-ABL1 reduction, indicating a BCR-ABL1 gain in a preexisting CALR mutated myeloproliferative neoplasm. In comparison to ASXL1 mutation rates (4/74 [5%]) in a published cohort with optimal responders (Kim et. al. 2017), we found a significantly higher number of ASXL1 mutations (8/48 [17%]) at diagnosis of our CML patients, who failed first year molecular remission criteria (p=0.041). Conclusions: (1) At diagnosis of CML, mutations were detected (esp. in ASXL1) in 27% of patients with TKI failure according to ELN criteria after one year. Compared to other myeloid malignancies, patients showed a different pattern of ASXL1 mutations. (2) No mutations in spliceosome genes were found. (3) Stringent BCR-ABL1 monitoring allows early adjustment of therapy in case of suboptimal response, but analysis of additional mutation patterns could help understanding the biology of failure and would allow up-front adjusted therapy decisions or different monitoring strategies. (4) Mutations such as ASXL1 at diagnosis may contribute to suboptimal TKI response. Disclosures Baer: MLL Munich Leukemia Laboratory: Employment. Kern: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

S3032 Extra-Gastrointestinal Stromal Tumor (EGIST): An Unusual Case of Worsening Exertional Dyspnea

INTRODUCTION: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gut. GISTs are rare, composing 0.1-3% of all gastrointestinal tumors. Exceedingly rare cases of GISTs have been identified outside of the GI tract and named extra-gastrointestinal stromal tumors (EGISTs). Here, we present a case of a large EGIST with multiple metastasis that initially presented with worsening exertional dyspnea. CASE DESCRIPTION/METHODS: An 83-year-old female with past medical history significant for hypertension and breast cancer status post lumpectomy and radiation therapy presented with worsening shortness of breath on exertion for 6 weeks. She also reported mild left upper quadrant abdominal pain, weakness, and decreased appetite. On physical exam, her abdomen was distended with splenomegaly noted. CTA of the chest shows right-sided pulmonary emboli without right ventricular strain and intra-abdominal ascites with a markedly enlarged spleen. US of lower extremities was positive for right femoral deep vein thrombosis. The patient was placed on heparin drip, which was later changed to Lovenox. Abdominal US shows multiple intrahepatic lesions and epigastric mass. CT of the abdomen and pelvis shows a large mass occupying a majority of the abdominal and pelvic cavities and multiple metastasis noted to liver and adrenal glands. Core biopsy of the abdominal mass showed high grade (Grade 2, x > 5 mitotic figures per 5 mm) GIST with necrosis. Tumor cells were positive for DOG1, CD117, and CD34. EGD revealed antral gastritis with biopsy positive for H. pylori. She was discharged and placed on Imatinib with repeat imaging after several months of Imatinib to evaluate for possible resection of disease. DISCUSSION: EGISTs are rare mesenchymal tumors that have been identified in the retroperitoneum and pelvis. GISTs result from activating mutations of proto-oncogenes c-KIT (CD117) or PDGFR-alpha. These activated proto-oncogenes increase tyrosine kinase receptor activity and result in stem cell proliferation. Roughly one third of GISTs have malignant potential and are prone to metastatic spread. GIST prognosis is multifactorial, depending on tumor size, mitotic potential, and metastatic invasion. Imatinib, a tyrosine kinase inhibitor, is the first-line therapy of metastatic GIST. In addition, surgical resection is the mainstay of therapy, especially in cases where the lesion is > 2 cm. In the 3 to 5 years post-treatment, close surveillance is warranted due to high risk of GIST recurrence.Figure 1.: Abdominal and Pelvic GIST on CT of the abdomen and pelvis.Figure 2.: Abdominal and Pelvic GIST on CT of the abdomen and pelvis.

Complete Molecular Response in Chronic Myeloid Leukemia After Six Months of Imatinib: A Single Center Experience.

Introduction: The hallmark of chronic myeloid leukemia (CML) is the development of the fusion gene, BCR-ABL which has unopposed tyrosine kinase activity. The first tyrosine kinase inhibitor (TKI) imatinib is claimed to have superior efficacy and side effect profile as compared to traditional treatment options. This study was conducted to see our patients’ molecular response to imatinib treatment. The objective of this study was to determine the frequency of complete molecular response in patients after six months of imatinib therapy.Methods: A descriptive case series was designed and conducted in Oncology department, Jinnah hospital Lahore (May-November 2016). Newly diagnosed patients of CML aged between 20 and 65 years were enrolled. They were prescribed 400 mg imatinib daily and complete molecular response was assessed after six months of treatment.Results: Mean age was 39.76 ± 9.072 years. Some 66 of them were males while 69 were females. Some 40 patients (29.6%) were found to be in complete molecular response after six months of imatinib therapy.Conclusion: Imatinib at a dose of 400 mg/day is optimal as the primary therapy for CML.

Generic Versus Branded Imatinib As Frontline Therapy in Chronic-Phase Chronic Myeloid Leukemia Patients in Italy: A Case-Control Study

Introduction. Imatinib is the most commonly used frontline drug in chronic phase (CP) chronic myeloid leukemia (CML) patients worldwide. In early 2017 a generic formulation of imatinib was introduced in Italy and uniformly replaced branded imatinib (Glivec®), upon requirement of regional health authorities. In the last years various groups reported on the efficacy and safety of generic imatinib with conflicting results, partly related to substandard pharmaceutical quality of some products used in developing countries. In a multicenter cohort of 294 patients treated in Italy with branded imatinib for at least 6 months and then switched to generic imatinib we observed that the majority of patients maintained or improved their molecular response. Here, we analyzed patients who received generic imatinib since diagnosis. Aims. To analyze the rates of molecular responses at 3, 6 and 12 months and of treatment discontinuation in CML patients treated frontline with generic imatinib, compared to a case-matched historical cohort of CML patients who received frontline branded imatinib at our institutions. Methods. We analyzed 31 newly diagnosed CP-CML patients consecutively enrolled in a prospective observational registry between January 2017 and July 2018, treated frontline with generic imatinib 400 mg/day (diverse manufacturers) and evaluable for all the ELN2013 molecular milestones (if not discontinued earlier). They were compared to a retrospective cohort of 31 patients, matched for age, gender, and Sokal risk, diagnosed between 2007 and 2014 and treated with branded imatinib 400 mg/day for at least 24 months before eventual switching to a generic formulation. Definitions of molecular responses were made according to the ELN2013 recommendations. Results. A total of 62 patients were included in the analysis: 31 patients (21 males and 10 females) treated with generic imatinib ("cases") and 31 treated with branded imatinib ("controls"). Median age at diagnosis of the cases was 68 years (range 33-89), Sokal score was low/intermediate/high in 8 (26%), 19 (61%) and 4 (13%) patients, respectively. The controls were matched for gender, age (+/- 4 years, median age 68, range 35-85) and Sokal score. As median follow-up time for the cases was 18.6 months (range 2.2-28.5), controls were censored at 24 months after imatinib start. Optimal molecular response at 3 months was attained in 23/30 (76.7%) cases and in 18/29 (62%) controls (p=0.35); one case died after 2 months of imatinib therapy for a CML-unrelated cause, while 2 controls were molecularly not evaluable. At 6 months, 17/29 (58.6%) cases and 17/30 (56.7%) controls achieved BCR/ABL transcript &lt;1%, respectively (p=1). At 12 months, MMR was attained by 14/30 (46.7%) cases and by 13/29 (44.8%) controls (p=1). Twelve out of 31 patients (38.7%) permanently discontinued generic imatinib due to warning/failure response (n=6), intolerance (n=4) or death while on treatment at 2 and 13 months (meningoencephalitis of unknown origin and cardiovascular event, respectively). Among patients treated with branded imatinib, 12/31 (38.7%) stopped within the 24th month of therapy for resistance (n=8), intolerance (n=3) or death at 16 months (acute renal failure). No patient receiving generic imatinib progressed to advanced phase, while one control developed a blast crisis at 6 months of branded imatinib and deceased shortly after. Estimated overall survival at 24 months in cases and controls was 92.5% and 93.1%, respectively. Conclusions. Our preliminary data suggest an equivalent efficacy of generic imatinib compared to a matched population of historical patients treated with the originator drug in Italy. A continue pharmacovigilance by reporting efficacy and safety outcomes of generic drugs is needed to ensure an optimal management of CML patients. Disclosures Bonifacio: Novartis: Honoraria, Research Funding; Amgen: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Tiribelli:Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Krampera:Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

RNA Splicing Defects in Cancer-Linked Genes Indicate Mutation or Focal Gene Deletion and Are Associated with TKI Resistance in CML

Background Mutated cancer genes in patients (pts) with TKI failure and blast crisis (BC) CML have recently been described. RUNX1 mutations, namely single nucleotide variants (SNVs) and indels, were the most frequently detected besides BCR-ABL1 [reviewed in Branford, Kim Leuk 2019]. They were found in ~18% of pts, although splice variants were rarely described. RNA splicing events were associated with focal deletion of IKZF1 and RUNX1 in TKI resistant pts that were identified by copy number analysis and RNAseq [Branford Blood 2018]. Novel splicing associated with mutation of cancer genes is an unexplored area of study in resistance. RNA sequencing can assess the functional effect of splice site variants, which lead to splicing errors due to the use of alternative or cryptic splice sites and cause alterations to protein function. Aim We determined whether novel splicing can identify cancer genes with potential altered function. Methods RNAseq analysis was performed for 48 pts at diagnosis and 33 at BC using a protocol that preserved intron-retaining precursor RNA. Coverage of intron-exon borders was sufficient to detect intronic splice region variants. The STAR aligner was used to bioinformatically collate unannotated RNA splice junctions. 54 cancer genes were assessed and aberrant splice events were filtered based on the number of samples in which a splice junction occurred. Manual inspection of the splice junctions was performed using the Integrative Genomics Viewer. This approach identified previously verified aberrant splicing associated with IKZF1 and RUNX1 deletions. Results Ten previously undetected novel splice junctions were revealed in 9/33 pts (27%) in BC within key tumor suppressor genes CDKN2A/B (5), RB1 (1), ATM (1), and RUNX1 (3). The aberrant splicing pattern of CDKN2A and RB1 (Fig A/B) in 6 pts suggested large deletions, as previously described in our cohort with IKZF1 and RUNX1 deletions. Breakpoints associated with deletions ranging from 53 to 181 Kb were detected in the 5 pts with CDKN2A aberrant splicing. Similarly, a 90 Kb deletion of exons 18-27 of the RB1 gene led to the aberrant splicing. The pts transformed to lymphoid BC (median 5 months). 4 of these 6 pts were tested at diagnosis and the deletions were not detected, indicating they were gained at resistance. The aberrant splicing patterns of ATM and RUNX1 did not predict large deletions. These were related to somatic SNVs at canonical splice sites in ATM and in 2 of the pts with RUNX1 aberrant splicing. A splice acceptor site SNV in ATM resulted in skipping of exon 61 (Fig C) and protein truncation. This novel SNV has not been reported in any population or somatic variant database. Two pts in myeloid BC at 28 and 48 months after diagnosis had an identical somatic RUNX1 mutation at the canonical splice donor site of exon 5. The SNV was not detectable prior to imatinib treatment in both pts. The splice site SNV led to activation of a cryptic splice site within exon 5 in both pts (Fig D), which predicted premature termination. While this mutation is novel, an adjacent intronic SNV occurs in familial platelet disorder, leading to activation of the same cryptic splice site. The atypical RUNX1 splicing of the 3rd patient was associated with retention of 55 bp of intron 6 as a cryptic exon (Fig E), leading to protein truncation. A deep intronic SNV identified at lymphoid BC at 6 months of imatinib was detected near the cryptic exon by RNAseq and verified as somatic by DNA Sanger sequencing. This was predicted to activate cryptic RNA splicing elements and lead to intron sequence retention in a RUNX1 transcript. We sequenced the diagnosis sample using an RNA-based gene panel method under development that provides enhanced sensitivity of variant detection. The same pattern of atypical splicing was observed and the intronic SNV was present at low level. The RUNX1 mutation at diagnosis may have contributed to early BC. To our knowledge this is the first report of a RUNX1 truncating variant in CML involving a cryptic exon. Conclusion Enhanced bioinformatic analysis of RNAseq data has revealed a high proportion of pts with truncating mutations in cancer genes indicated by novel RNA splicing (27% pts in BC). Using RNA-based sequencing allows an evaluation of the potential functional effect of variants that are not apparent by DNA-based mutation analysis. We suggest that future studies include RNA sequencing to detect a broader spectrum of mutations associated with TKI resistance. Disclosures Shanmuganathan: Gilead: Other: Travel Support; Janssen: Other: Travel Support; Amgen: Other: Travel Support; Bristol-Myers Squibb: Honoraria, Other: Travel Support; Novartis: Honoraria, Other: Travel Support. Yeung:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Honoraria. Scott:Celgene: Honoraria. Hughes:Novartis, Bristol-Myers Squibb, Celgene: Research Funding; Novartis, Bristol-Myers Squibb: Consultancy, Other: Travel. Branford:Cepheid: Consultancy, Honoraria; Qiagen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau.

Cost effectiveness of treatment-free remission in chronic myeloid leukemia patients: A report from a developing country.

131 Background: Current recommendations for first line therapy in chronic phase chronic myeloid leukemia (CP-CML) is life-time use of tyrosine kinase inhibitors (TKI's). Unfortunately, the financial burden of continuous TKI therapy is unsustainable especially in developing countries. In Pakistan, an access-program for Imatinib (IM) and Nilotinib is available; the cost of therapy is subsidized with the Government paying for 3 months and Novartis for 9 months. Updated results from several trials support continued long term durability of treatment free remission (TFR). We attempted TFR in our patients in an attempt to reduce financial burden and improve quality of life for the patients. We aimed to evaluate the economic impact of discontinuing imatinib versus continuous use of imatinib in patients taking IM 400mg. Methods: 57 patients of CP-CML taking Imatinib 400 mg for the last 10 years who were negative by FISH for at least 3 years or in MR 4.5 at least once in 12 months were evaluated. Of these 30 were screening failures, 4 patients refused consent prior to screening and 25 were eligible for the trial. Two consecutive RQ-PCR were performed 3 months apart prior to enrollment. Patients were eligible if they achieved MR 4.5 for at least 3 months prior to entering the study. Molecular response was assessed by Quantitative BCR-ABL RQ-PCR every 4 weeks after discontinuation for year 1 and 8 weeks at year 2. Cost of Imatinib 400 mg per month was calculated as well as the cost of BCR-ABL RQ-PCR by gene expert for the trial. Results: Of the enrolled 25 patients, 10 lost their deep molecular response and were restarted on therapy, 5 withdrew consent after screening.10 patients are currently on trial at varying time intervals (10-14 months) of cessation of imatinib. The cost of one month of imatinib is US $ 800 and the cost of RT PCR is $ 67. TFR translated into approximately US 1.2 million saved. Conclusions: The discontinuation of TKI in this small subset of patients has resulted in remarkably large savings with significant impact on the meager health budget in our resource limited setting.

PF420 RESULTS OF A PROSPECTIVE MULTICENTER STUDY ON PRO‐ATHEROTHROMBOTIC EFFECT INDUCED BY TYROSINE‐KINASE INHIBITORS FOR FIRST‐LINE TREATMENT OF CML PTS (KIARO TRIAL)

Background:Tyrosine kinase inhibitors (TKI) revolutionized treatment and prognosis of chronic myeloid leukemia (CML), but some patients (pts) still suffer from potentially severe TKI‐related toxicity. Of particular relevance is cardiovascular (CV) toxicity, mostly associated to Nilotinib (NILO) and Ponatinib. In a previous retrospective, cross‐sectional, multicenter study we confirmed a higher CV risk for pts treated with NILO, particularly those harboring the unfavorable OLR1 genetic polymorphism and we found a NILO‐associated pro‐inflammatory/oxidative effect, with increased IL6/IL10 and TNFα/IL10 ratios and levels of oxidized LDL (oxLDL) compared to Imatinib (IMA). We here report clinical, genetic and serologic results of a prospective multicenter Italian trial including CML pts treated with any of current first‐line TKIs (IMA, NILO, DASA).Aims:(1) to assess CV toxicity in CML pts in which first‐line TKI choice was made according to current CV risk guidelines (2) to assess pts’ genetic predisposition to CV events (3) to confirm a pro‐oxidative/inflammatory effect induced by NILO during treatment.Methods:A clinical CV risk score (S) was calculated using the algorithm from the European SCORE project. Integrating clinical with genetic information from 12 Single Nucleotide Polymorphisms (SNPs) associated with CV risk (ANRIL, SORT1, MIA3, CXCL12, MRPS6, PHATCR1, WDR12, LDLR, MRAS, CYP17A1, OLR1, IL10) an integrated score (IS) was obtained. CV‐relevant clinical and biological parameters were collected at specific timepoints (diagnosis, +1, +3, +6, +12 months) together with blood samples for IL6, IL10, TNFα and oxLDL plasma levels assessment.Results:Between September 2013 and September 2018, 177 newly‐diagnosed CML pts starting either IMA, NILO or DASA treatment, entered this study. After a median follow‐up of 22.4 months (range: 35 days – 5.4 years), a CV event has occurred in 5 pts, with a median time to event of 15 months (range: 44 days – 31.4 months). This accounts for an incidence of 5.9 per 1000 patient‐year, superior to that of a general age‐ and sex‐matched population (3.85 per 1000 patient‐year, OR 3.27, 95%CI 2.16–4.63; p = 0.013). Pts treated with NILO had lower CV risk at diagnosis (S = 6.9 ± 2.8) compared to those treated with DASA (S = 8.1 ± 3.2; p = 0.042) or IMA (S = 9.9 ± 4.9; p = 0.019). Nonetheless, 3/57 (5.2%) NILO‐treated pts developed CV toxicity, as opposed to 1/83 (1.2%) IMA‐treated (HR 2.9, 95% CI 1.8–4.4; p = 0.021) and 0 out of 37 DASA‐treated pts. One CV event occurred in a patient treated with first‐line IMA 23 months after being switched to Bosutinib, and therefore was not attributed to IMA.Levels of anti‐inflammatory cytokine IL10 were higher after 6 and 12 months of IMA or DASA compared to NILO. Also IL6/IL10 and TNFα/IL10 ratios in IMA‐ and DASA‐treated pts were lower compared to NILO‐treated pts. Increased levels of oxidation marker oxLDL were observed after 12 months of NILO, but not during IMA or DASA treatment. The few CV events registered did not allow for any correlation between genetic polymorphisms and increased CV risk in our population.Summary/Conclusion:This study confirms a higher CV risk for pts treated with NILO, even in a contemporary setting where pts were carefully selected for having a low pre‐treatment CV risk. This may be a consequence of a NILO‐induced pro‐inflammatory/oxidative status, as shown by reduced levels of IL10 and increased levels of oxLDL in pts treated with NILO. A longer follow up is necessary to identify possible specific genetic polymorphisms conferring higher CV risk in this population of CML pts treated with TKI.image

Various treatment responses in Imatinib treated CML patients with emphasis on marrow profile: a descriptive study in a tertiary care centre in South India

Background: CML is a clonal stem cell neoplasm characterised by reciprocal translocation between chromosomes 9 and 22.Imatinib is used in its treatment which induces hematological, cytogenetic and molecular response. Yet, marrow response is less well defined than hematological and cytogenetic response (HR and CR). Hence our aims were1.To study the hematologic response in CML patients after 3 months of Imatinib2.To study the cytogenetic response in CML patients after 6 months of Imatinib. 3.To study and categorize morphological changes in marrow at the end of three months of treatment. Materials and methods: Forty six newly diagnosed patients of CML (BCR-ABL positive), irrespective of phase, were included. HR and CR was evaluated at the end of three months and six months of Imatinib therapy, respectively. A bone marrow aspirate and biopsy was performed at the end of three months, marrow responses were classified and parameters were analysed.Results: Of 46 patients, 91.3% of patients attained complete hematological response.30/46 patients had a follow up FISH analysis at 6 months, of whom 70% attained complete cytogenetic response(table/figure 3). Twenty nine (64.5%) of the post treatment aspirates were diluted and imprints/biopsy yielded information. Twenty eight (63%) patients showed marrow normalization, eleven (23%) persistence of disease, four (8%) progression of disease to blast crisis (BC) and three (6.5%) hypo cellular marrow.Conclusion: Post therapy BM in CML, when undertaken should have biopsy rather than an aspirate alone, as aspirates are often diluted and biopsy may yield useful information like impending blast crisis.DOI: 10.21276/APALM.1514

Serial monitoring of imatinib pharmacokinetics (PK) in perioperative imatinib treatment in patients (pts) with gastrointestinal stromal tumors (GISTs): Results from the multinational phase II trial.

118 Background: Imatinib plasma levels may be affected by the duration of exposure to imatinib and resection of the stomach. Therefore, we performed PK study to monitor imatinib plasma levels serially in the multinational phase II trial of perioperative imatinib for pts with large ( ≥ 10 cm) gastric GISTs without distant metastasis. Methods: In this trial conducted in Japan and Korea, 53 pts received neoadjuvant imatinib 400 mg daily and 40 pts received adjuvant imatinib after surgery. Blood samples for imatinib trough levels (Cmin) were collected after 1, 3, 6 months of each neoadjuvant and adjuvant imatinib and measured by using liquid chromatography-tandem mass spectrometry. For the comparison of imatinib Cmin between different time points, values were dose-adjusted and log-transformed. Results: During the neoadjuvant treatment, imatinib Cmin (mean ± standard deviation) was 2253.0 ± 1148.0 ng/mL (n = 49), 1623.3 ± 832.4 ng/mL (n = 47), and 1852.0 ± 1572.4 ng/mL (n = 45) after 1, 3, and 6 months of imatinib, respectively. During the postoperative treatment, imatinib Cmin was 1436.1 ± 852.8 ng/mL (n = 31), 1357.8 ± 646.4 ng/mL (n = 33), and 1084.2 ± 360.8 ng/mL (n = 31) after 1, 3, and 6 months of imatinib, respectively. In the neoadjuvant setting, imatinib Cmin was significantly reduced after 3 months (p = 0.0001) and 6 months (p = 0.004) compared to the value at 1 month. In 36 patients that imatinib Cmin was measured at both preoperative and postoperative setting, imatinib Cmin was significantly reduced after surgery (1732.4 ± 997.9 ng/mL vs 1282.8 ± 557.3 ng/mL; p = 0.04). The magnitude of changes in imatinib Cmin after surgery was greatest in patients who underwent total gastrectomy (10.6%, n = 2) followed by proximal gastrectomy (8.4%, n = 3), and wedge resection (3.3%, n = 30). There were no significant relationships between imatinib Cmin and toxicity or objective response. Conclusions: Imatinib exposure was reduced until approximately 3 months after imatinib treatment. It was also significantly reduced after surgery and the magnitude of changes might be affected by the extent of surgical resection of stomach.

A rare case of osteonecrosis of the jaw related to imatinib

Osteonecrosis of the jaw (ONJ) is commonly described as an adverse effect of the use of bisphosphonates. A few cases of ONJ associated with tyrosine kinase inhibitors (sunitinib, imatinib) have been reported in the literature and usually they occurred in patients simultaneously treated with bisphosphonates. We report an atypical case of ONJ related only to imatinib. A 72-year-old male patient was treated with imatinib for metastases from gastrointestinal stromal tumors (GISTs). The patient developed ONJ after 22 months of imatinib only therapy. During his whole life, the patient had never been treated with bisphosphonates or radiotherapy. Microscope examination of the tissues confirmed the clinical diagnosis of diffuse osteonecrosis and showed absence of neoplastic cells. Thus, secondary localisations from GISTs were ruled out. Osteonecrosis of the lower jaw appeared 22 months after initial and exclusive therapy with imatinib. Therefore, imatinib monotherapy can induce ONJ in patients that have never been treated with bisphosphonates or radiotherapy.

Comparison of ABL1 and Gusb Reference Genes in the qRT-PCR Analysis of Halving Time and Early Molecular Response to TKI Therapy in Patients with Chronic Myeloid Leukemia

Objectives and background: Early molecular response (EMR) to tyrosine kinase inhibitors (TKI) therapy defined as BCR-ABL1 transcript level ≤ 10% at 3 months is a well-established predictive factor in CML patients. Recently, several study groups presented the concept of BCR-ABL1 decline velocity or "halving time" as a new predictive factor for optimal TKI treatment response. Different reference genes were used in the quantitative RT-PCR (qRT-PCR) analysis to calculate halving time and EMR rate, potentially influencing results of these analyses. The aim of the study was to compare ABL1 and beta-glucuronidase (GUSB) as reference genes used for calculation of halving time and EMR rate in chronic phase CML patients (pts) treated with imatinib 400 mg/d in the clinical settings.Methods: A total of 52 chronic phase CML pts with blood samples collected at baseline and at 3 months of imatinib therapy were investigated. Transcript levels of BCR-ABL1 were determined by qRT-PCR with the use of ABL1 and GUSB as control genes for each patient. Halving time for BCR-ABL1 transcripts was calculated using baseline transcript levels, transcript levels at 3 months of treatment, and number of days between these two points according to methodology reported elswhere1. Using receiver operating characteristic (ROC) analysis, the optimal halving time thresholds for achievement of EMR for each control gene were determined. Optimal thresholds along the ROC curves were calculated using the Youden index.Results: 40 of 52 (76.9%) and 44 of 52 (84.6%) pts achieved EMR with BCR-ABL1 transcripts levels calculated with GUSB and ABL1 as control genes, respectively (p=0.55). In 4 pts there was no BCR-ABL1 transcript reduction from baseline at 3 month using GUSB as a control gene resulting with negative halving times. The GUSB based halving times of these 4 patients were imputed to the longest positive halving time (8530 days) calculated for the patient with the smallest BCR-ABL1 decline. Transcript reduction occurred in all pts when ABL1 was used as a control gene. ROC curve analysis resulted in the optimal halving time thresholds for achievement of EMR of 39 days (area under the curve [AUC ] 0.96, ;95% CI 0.9-1.0, ) and 31 days (AUC 0.95; 95% CI 0.87-1.0, ) for GUSB and ABL1 control gene, respectively.Discussion and Conclusions: Lack of linearity in qRT-PCR analysis observed in blood samples collected in CML patients at diagnosis, with high amount of BCR-ABL1 and wild type ABL1 transcripts could affect the accuracy of early kinetics decline of BCR-ABL1 transcript calculations when ABL1 is used as a reference gene. The analysis with the use of GUSB as a control gene is not biased by this phenomenon. In this study, a non - statistically significant differences in the rate of EMR achieved at 3 months of imatinib therapy and halving time were observed. Analyses performed in our study with ABL1 and GUSB as reference genes suggest that both GUSB and ABL1 are able to identify relevant cut-offs for EMR achievement and could be used for halving time calculation.Reference:Branford S, Yeung DT, Parker WT, et al. Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood 2014 Jul 24;124(4):511-8 DisclosuresZawada:Novartis: Speakers Bureau. Czekalska:Novartis: Speakers Bureau. Sacha:Pfizer: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria.