Difference In Event-free Survival Research Articles

Treatment of High Risk DLBCL with DA-R-EPOCH in Those Unable to Tolerate Intensive Chemotherapy: Well-Tolerated and Effective, but Inadequate in Double/Triple Hit or Expressing DLBCL

Treatment of High Risk DLBCL with DA-R-EPOCH in Those Unable to Tolerate Intensive Chemotherapy: Well-Tolerated and Effective, but Inadequate in Double/Triple Hit or Expressing DLBCL

The Correlation Studies between Central Nervous System Involvement By Flow Cytometry and the Prognosis of Children Acute Lymphoblastic Leukemia: A Single Chinese Center's Experience By Cclg- ALL 2008

[Abstract]Objective To explore the relationship between the involvement of central nervous system by flow cytometry and prognosis in childhood acute lymphoblastic leukemia (ALL) by CCLG-ALL 2008 scheme. Methods We retrospectively assessed the data of 601 cases of children with acute lymphoblastic leukemia in our institute from Apr 2008 to Jun 2013 and analysed the effect of central nervous system involvement by flow cytometry on their prognosis. All patients who had cerebrospinal fluid (CSF) positive by flow cytometry had been done intrathecal therapy until CSF got negative. Results Among these 601 cases at diagnosis, the mean age of onset was 5.7(0.4-15.0) years old. Male and female were 368:233(1.6: 1). 50 cases (8.3%), 12 cases (2.0%) had central nervous system involvement at diagnosis and consolidation therapy. We followed these cases until Dec 2016. The median time of follow-up was 59(1-104) months. The number of lost case was 17 (2.8%), 584(97.2%) cases could be estimated. There was statistically significance difference in 5-year overall survival(OS)in CSF positive and negative by flow cytomety at diagnosis(82.0±1.7% & 70.3±6.7%, X2=4.853 P=0.028). there were no statistically significant difference in event free survival(EFS)and relapse free survival(RFS) in these two groups at diagnosis(X2=2.983 P=0.084 & X2=0.280 P=0.596).During the consolidation therapy, there were significant difference in 5-year OS, EFS, RFS with central nervous system involvement or not by flow cytometry(81.3±1.6% & 50.0±14.4%, X2=9.611 P=0.002; 92.8±1.1% & 38.9±14.7%, X2=14.741 P=0.000; 96.6±0.8% & 40.0±14.6%, X2=29.033 P=0.000). Conclusions No matter at diagnosis or consolidation period in childhood ALL, central nervous system involvements by flow cytometry were all poor prognosis factors. CSF positive by flow cytometry is an indicator for intensified CNS-directed therapy. DisclosuresNo relevant conflicts of interest to declare.

OUTCOME OF TREATING PEDIATRIC LANGERHANS HISTIOCYTOSIS WITH LCH III IN TERTIARY CENTER, SAUDI ARABIA

Background: Langerhans cell histiocytosis (LCH) is a rare disease affects any age and any organ; its presentations and outcome vary from self-healing lesions to life-threatening disseminated disease. This study evaluated the outcome of treating children diagnosed with Langerhans cell histiocytosis (LCH) at Oncology Center, Saudi Arabia.
 Methodology: Through a retrospective study design, the researchers reviewed the medical records and electronic files of all children (aged from 0-≤ 14 years) who had been diagnosed and treated for LCH at Princess Norah Oncology Center (PNOC), King Abdelaziz Medical City, Saudi Arabia, in the period from January 2000 to December 2019 (n=33).
 Findings: Males constituted (66.7%), with remarkable dominance of Saudis (93.9%). The median age at diagnosis was 28 months (IQR=49 months); (42.4%) were diagnosed before reaching their second birthday. Fourteen patients (42.4%) had multisystem (MS-LCH) involvement, of which 13 patients with risk organ (RO) (+) and one patient without risk organ (RO) (-). Most of the patients received LCH III protocols. Reactivation occurred in 11 patients (33.3%), and two deaths (6.1%) occurred in cases with MS (RO) (+) progressive disease. The overall survival was 93.9%; with no statistically significant difference in event free survival observed between patients with multisystem compared to single system involvement.
 Conclusion and recommendations: Excellent outcome of LCH is associated with single system involvement and worse outcome (reactivations, or morality) is determined by multi-organ involvement especially at younger age less than 24 months. Better understanding of pathophysiology and genetic molecular background could lead to a striking transformation to novel therapy that warrants a prospective clinical trial. A high mortality in patients with progressive disease demands an earlier aggressive salvage in such group. Prospective clinical trials are required for improved treatment strategies in these subgroups

Clinical, immunophenotypic and genomic findings of NK lymphoblastic leukemia: a study from the Bone Marrow Pathology Group.

Natural killer (NK) cells are lymphocytes of the native immune system that play a pivotal role in host defense and immune surveillance. While the conceptual view of NK-neoplasms is evolving, little is known about the rare NK lymphoblastic leukemia (NK-LL), which remains as a provisional entity in the 2016 WHO Classification. The goal of this study is to characterize NK-LL cases and compare with other CD56 co-expressing acute leukemias. We identified 105 cases, diagnosed as NK-LL (6), CD56+ acute undifferentiated leukemia (AUL) (6), CD56+ T-lymphoblastic leukemia (T-LL) (51), and CD56+ acute myeloid leukemia (AML) (42). Compared to AUL patients, NK-LL patients were significantly younger (p = 0.021) and presented with higher white blood cell (WBC) (p = 0.037) and platelet counts (p = 0.041). Flow cytometry showed more frequent expression of cytoplasmic CD3 (cCD3, p = 0.064) and CD33, (p = 0.065), while HLA-DR was significantly absent from NK-LL (p = 0.035) compared to AUL. Compared to T-ALL, NK-LL cases showed less frequent cCD3 (p = 0.002), CD4 (p = 0.051), and CD10 expression (p = 0.06). The frequency of abnormal karyotypes was similar between NK-LL, AUL, and T-ALL. The mutational profile differed in four leukemia groups, with a significance enrichment of NOTCH1 (p = 0.002), ETV6 (p = 0.002) and JAK3 (p = 0.02) mutations in NK-LL as compared to AML. As compared to T-ALL, NK-LL cases showed a higher number of total mutations (p = 0.04) and significantly more frequent ETV6 mutations (p = 0.004). Clinical outcome data showed differences in overall survival between all four groups (p = 0.0175), but no difference in event free survival (p = 0.246). In this largest study to date, we find that that NK-LL shows clinical presentation, immunophenotypic and molecular characteristics distinct from AUL, T-ALL, and AML. Our findings suggest NK-LL is a distinct acute leukemia entity and should be considered in the clinical diagnosis of acute leukemias of ambiguous lineage.

Clinical Features, Treatments and Outcomes of HIV-Associated Diffuse Large B-Cell Lymphoma: A Single-Center Experience

INTRODUCTION Recent studies have suggested that the prognosis of HIV-associated diffuse large B-cell lymphoma (HIV-DLBCL) may be improving with advances in anti-retroviral therapies (ART). A pooled analysis of clinical trial data showed that EPOCH may be associated with superior outcomes as compared to CHOP (Barta et al. Blood. 2013), but about two-third of patients in the combined analysis were treated without rituximab. A recent French study, however, showed similar overall survival (OS) between R-CHOP and R-EPOCH treated patients (Besson et al. AIDS 2017) and a phase III trial showed similar efficacy of R-CHOP vs. R-EPOCH in HIV-uninfected DLBCL (Bartlett et al. JCO 2019). The optimum frontline therapy in HIV-DLBCL is unknown as most clinical trials exclude HIV-infected patients or restrict accrual to those with undetectable HIV viral load and minimum CD4 count cut-off. Moreover, most existing studies include a majority (>60%) Caucasian population, and there is a paucity of studies on outcomes in African-American population. In this retrospective study, we describe the clinical features and outcomes of HIV-DLBCL patients seen at our institution and compare them with HIV negative DLBCL patients. METHODS We conducted a retrospective review of HIV+ DLBCL cases diagnosed and treated at our institution from 2008-2020. We used the Kaplan-Meier method to assess overall survival (OS). Univariate and multivariate analyses were performed to assess prognostic factors. HIV-DLBCL patients were matched 1:2 with HIV negative DLBCL by age and stage of lymphoma at diagnosis. Comparison of OS analysis was conducted using log-rank method and predictors of progression or death using Cox proportional hazards regression. RESULTS We included a total of 33 patients with HIV-DLBCL in our study. Median age was 46.6 years (IQR 40-53.3), 25 (76%) were males, and 20 (61%) were African-Americans (Table). 28 (85%) patients had stage III/IV and 24 (73%) had extranodal disease at diagnosis. The median CD4 count at diagnosis was 252 (IQR 89.5-409). 6 (18%) had CNS involvement at diagnosis, for which the median OS was 8.3 months. First-line treatment included rituximab-chemotherapy combinations in 25 (76%) patients. All patients continued ART during first line treatment. Median follow up duration of the entire cohort was 2.06 years (IQR 0.53-5.02 years) and 5 (15.2%) were lost to follow up. The 2-year OS for R-CHOP treated patients was 63% vs. 38% for R-EPOCH treated patients, although this failed to reach statistical significance (p=0.125). On multivariate analysis, the only factor significantly associated with difference in event free survival (EFS; progression or death) was female sex (HR 19.86; [2.652-148.7]; p=0.004). Trends were seen towards shorter EFS among patients who were tobacco smokers at time of DLBCL diagnosis (HR 2.69; 0.463-15.6]; p=0.271), CD4+ count <200 at time of DLBCL diagnosis (HR 2.39; [0.519-11.0]; p=0.264), IPI score >3 (HR 2.98; [0.480-18.5]; p=0.241), and presence of MYC gene rearrangement (HR 3.93; [0.569-27.2]; p=0.165). Treatment type (R-CHOP, R-EPOCH), ART use prior to lymphoma diagnosis, race, and insurance status were not correlated with EFS. 11 (33.3%) patients died within 1 year of diagnosis. The 2-year OS for the entire cohort was 64% vs. 68% in matched HIV-negative DLBCL patients (p=0.651). Median OS for HIV+ patients was 2.14 years (IQR 0.23-5.77) vs 2.97 years (IQR 0.76-6.48) in matched HIV-negative DLBCL patients (p=0.3996). One patient died from acute hypoxemic respiratory failure prior to starting treatment. Four patients died of complications during their first inpatient chemotherapy administration. CONCLUSION In our cohort, most HIV-DLBCL patients were African-Americans, presented with advanced stage and extranodal disease. The survival of HIV-associated DLBCL was similar to HIV-negative counterparts. All HIV-DLBCL continued ART during chemotherapy, suggesting the feasibility of this approach. There was no difference in OS between patients treated with R-CHOP vs. R-EPOCH, however there was a trend towards increased OS in patients treated with R-CHOP. CNS involvement at diagnosis was frequently seen. Despite limited sample size, we observed a significant association with gender, and a trend toward significant factors including tobacco use and low CD4 count at time of diagnosis. Disclosures Mehta: TG Therapeutics:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Merck:Research Funding;Roche-Genentech:Research Funding;Kite/Gilead:Research Funding;Innate Pharmaceuticals:Research Funding;Seattle Genetics:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Oncotartis:Research Funding;Gelgene/BMS:Research Funding;Juno Parmaceuticals/BMS:Research Funding;fortyseven Inc/Gilead:Research Funding;Takeda:Research Funding;Incyte:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Affimed:Research Funding.

LAG-3 overexpression in pediatric Hodgkin lymphoma.

10531 Background: The role of the PD-1/PD-L1 axis in Hodgkin Lymphoma (HL) has led to FDA approval for use of inhibitors in chemotherapy-refractory HL. Numerous additional immune checkpoints may be useful targets, but have not yet been evaluated in HL. LAG-3, a related checkpoint, has been demonstrated to be overexpressed on tumor infiltrating lymphocytes (TILs) of a variety of cancers with associated poor outcomes. LAG-3 is known to inhibit T cell proliferation and activation, representing a possible therapeutic pathway for anti-tumor immunity. However, LAG-3 has yet to be evaluated in pediatric cancers. The purpose of this study is to characterize the expression pattern and clinical significance of LAG-3 in pediatric HL using immunohistochemistry. Methods: Patient tumor samples from prior Children’s Oncology Group clinical trials (AHOD0031) with matched patient outcome data containing 200 patient samples were obtained. 95% confidence intervals were calculated based on a range of observed prevalence of immune checkpoint expression. Using immunohistochemistry, paraffin embedded samples were tested for the expression of LAG-3 and PD-L1. Samples were stained for CD30 to better delineate Reed Sternberg cells from the remainder of the tumor microenvironment. Immune checkpoint staining was compared to positive controls of normal tonsil tissue, and negative controls of 3T3 cells. Expression intensity was scored by a Pediatric Pathologist. Results: 115 unique HL patient cases with evaluable HL tissue and correlating clinical outcome data were analyzed. Samples from 73/115 patients (63%) demonstrated positive LAG-3 staining, defined as over 10% of TILs expressing LAG-3. No demographic data including gender, race/ethnicity, age, or stage were significantly associated with LAG-3 expression. While not statistically significant there was a numerical difference in event free survival (EFS) and patients with LAG-3 expression demonstrated worse EFS. In terms of degree of LAG-3 expression, patients with the lowest positive expression were found to have the worst EFS, and those with highest expression demonstrated the best EFS. 97% of patient cases were found to be PD-L1 positive. 71/73 (97%) of patients who expressed LAG3 were also PDL1+, and 71/106 (67%) of PDL1+ cases were also LAG3+. LAG-3 and PD-L1 were found to be independent (p = 0.09). Conclusions: This project is innovative in its characterization of LAG-3 as an immune checkpoint target in pediatric HL. We hope that the information from this project will be used to support new clinical trials for pediatric patients with Hodgkin lymphoma.

Autoimmune disease in patients with diffuse large B-cell lymphoma: occurrence and impact on outcome

Background: Patients with certain autoimmune diseases (AID) have an increased risk of developing diffuse large B-cell lymphoma (DLBCL). However, the occurrence of AID in patients with DLBCL as well as the impact of AID on outcome has not been extensively studied. The main purpose of this study was to establish the occurrence of AIDs in a population-based cohort of DLBCL patients and to compare outcomes in patients with or without AID treated with rituximab(R)-CHOP/CHOP-like treatment. We also aimed to analyse gender differences and the potential role of different AIDs on outcome and the frequency of treatment-associated neutropenic fever.Patients and methods: All adult patients treated 2000–2013 with R-CHOP/CHOP-like treatment for DLBCL in four counties of Sweden were included (n = 612). Lymphoma characteristics, outcome and the presence of AID were obtained through medical records.Results: The number of patients with AID was 106 (17.3%). Thyroid disease dominated (n = 33, 31.1%) followed by rheumatoid arthritis (RA) (n = 24, 22.6%). The proportion of AID was significantly higher in females (59/254, 23.2%) vs. in males (47/358, 13.1%) (p = .001). In the whole cohort there was no difference in event free survival (EFS) or overall survival (OS) between patients with or without AID. However, patients with an AID primarily mediated by B-cell responses (thyroid disorders excluded) had a worse OS (p = .037), which seemed to affect only women. The AID group more often had neutropenic fever after first treatment (16.0% vs 8.7%, p = .034) and those with neutropenic fever had a worse OS (p = .026) in Kaplan-Meier analyses.Conclusion: There is a high prevalence of AID among patients with DLBCL. AIDs categorized as primarily B-cell mediated (in this study mainly RA, systemic lupus erythematosus and Sjögren’s syndrome) may be associated with inferior OS. AID patients may be more prone to neutropenic fever compared to patients without concomitant AID.

Spirit 2: Final 5 Year Analysis of the UK National Cancer Research Institute Randomized Study Comparing Imatinib with Dasatinib in Patients with Newly Diagnosed Chronic Phase CML

▪Objective. SPIRIT 2 is the largest phase 3 prospective randomized open-label trial comparing imatinib (I) 400mg with dasatinib (D) 100mg daily in newly diagnosed chronic phase CML. The primary endpoint was 5 year event-free survival. Methods. 812 (406 in each arm) of 814 patients recruited started study medication (median age 53.2, 275/812 (33.8%) were over 60 years old). Patients were recruited at 144 hospitals between August 2008 and March 2013 and randomized to receive either imatinib 400mg or dasatinib 100mg daily. Secondary endpoints included overall survival, rates of treatment failure, cytogenetic/molecular response - RT-PCR BCR-ABL/ABL ratio of <0.1%IS(major molecular response (MMR), 3 log reduction, MR3) and deeper. To address the potential confounding effect on the primary endpoint of patients switching from randomized treatment to an alternative TKI or other treatment, exploratory per-protocol analyses were performed using the inverse probability of censoring weighting (IPCW) method.Results. All patients have now completed 5 years of follow-up. 424/812 (52.2%) patients completed the study whilst still taking first line medication: 230/406 (56.7%) on dasatinib, 194/406 (47.8%) on imatinib. Of the patients who discontinued first line therapy, more patients on the imatinib arm switched due to suboptimal PCR response (as decided by the local investigator) than on dasatinib (D7/406, 1.7%; I71/406, 17.4%) but more patients on the dasatinib arm discontinued due to intolerance (D123/406, 30.3%; I68/406, 16.7%). More patients went on to transplant in the imatinib arm than in the dasatinib arm (D 6/406, 1.5%; I 30/406 7.6%) and in the imatinib patients undergoing transplant the reason for first line treatment failure was disease progression in 5/30 and suboptimal molecular response in 11/30. Using an intention to treat analysis cumulative incidence of MR3 and MR4 on first line therapy within 5 years was higher in the dasatinib arm than the imatinib arm (MR3: D 83.0%, I 63.0% - difference 20.0%, p<0.0001; MR4: D 77.5%, I 57.2% - difference 20.3%, p<0.0001).At 24 months the complete cytogenetic response rate was D 42.6%, I 31.8% - difference 10.8%, Chi-square test p=0.001.At 5 years the probability of treatment failure-free survival was higher with dasatinib than imatinib(D60.9%, I52.9% - HR: 0.73 (95%-CI:0.59-0.90), p=0.004) but there were no significant differences in event free survival (D91.0%, I89.0% - HR:0.80 (95%-CI:0.51-1.25), p=0.319) or overall survival (D91.9%, I91.2% - HR: 0.90 (95%-CI:0.56-1.47), p=0.690). IPCW modelling results will be presented at the meeting.The overall rate of pleural effusion over 5 years in the dasatinib arm was 36.0% with a higher incidence in older patients. 13 patients developed their first pleural effusion after 3 years on study. Conclusions. In SPIRIT 2 we observed a higher molecular and cytogenetic response rate and also a higher pleural effusion rate with dasatinib but a higher treatment failure rate with imatinib often because investigators were concerned about sub-optimal PCR responses. More imatinib-treated patients proceeded to transplant. There were no statistically significant differences in event free survival (the primary endpoint) or overall survival. Imatinib remains a highly effective first line therapy though subgroup analyses are planned to explore whether dasatinib may have advantages in particular clinical scenarios. DisclosuresO'Brien:Bristol Myers Squibb: Research Funding; CTI: Other: Chair of Independent Data Monitoring Committee; National Institute for Health and Care Excellence (NICE): Other: Chair of Technology Appraisal Committee. Osborne:Servier: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; MSD: Honoraria; Roche: Honoraria; Novartis: Honoraria. Bell-Gorrod:Bristol-Myers Squibb: Consultancy; Merck EDM Serono: Consultancy; PharmaMar: Consultancy; Novartis: Consultancy; GlaxoSmithKline: Consultancy. Latimer:Pfizer: Consultancy; BMS: Consultancy; Merck: Consultancy; Astra Zeneca: Consultancy; Bluebirdbio: Consultancy; Janssen: Consultancy. Apperley:Incyte: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Byrne:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Pocock:Kent & Canterbury Hospital: Employment. Copland:Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Clark:Ariad/Incyte: Consultancy; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

B Cell Precursor Lymphoblastic Leukemia Patients with Good Treatment Response Have Low Levels of Erythroid Precursors

Acute lymphoblastic leukemia treatment leads to elimination of blasts and stepwise regeneration of normal hematopoiesis. Several studies identified prognostic relevance of minimal residual disease (MRD) in bone marrow (BM) before achieving complete remission (Giuseppe Basso et al., J Clin Oncol, 2009). Crucial question is how to assess BM quality at day 15 (d15) of ALL BFM protocols. In ALL BFM 2009 protocol good quality sample is defined as containing more than 2% erythroid precursors (EP) of nucleated cells. EP were defined as CD19neg(orCD7neg)CD45neg.Two pt cohorts were included in the study. First cohort (Coh2000) consisted of pts treated by AIEOP BFM ALL 2000, n=196 (177 BCP ALL, 19 T ALL, median follow-up 5.4 yrs, range 0.025-10). AIEOP BFM ALL 2000 study was a PCR MRD based protocol (assessment at day d33 and d78) and flow cytometric MRD (FC MRD) was assessed only on research basis at d15. Second cohort (Coh2009) consisted of pts treated by AIEOP BFM ALL 2009, n=331 (292 BCP ALL, 39 T ALL, median follow up 4.8 yrs; range 0.0027-7.6). In Coh2009, both PCR MRD (d33, d78) and FC MRD d15 were used for risk stratification.We asked following questions:What is the specificity and viability of EP defined by CD45 negativity? Is a definition based on bright expression CD71 more specific?Is the amount of EP different between B and T ALLs and between risk groups defined by FC at d15? What is the overall frequency of low EP at d15?What is the relationship between amount of EP and FC MRD at d15?Is there any prognostic relevance of low EP?Results:Population of EP was selected based on negativity of CD45 and a lineage marker (CD19 or CD7) among nucleated cells, which were defined as positive by a SYTO nucleic fluorescent dye. We found a high amount of non-viable cells defined by 4′,6-diamidino-2-phenylindole (DAPI) positivity (6.5-96%, median 55%). When we added bright CD71 into the EP definition (EP CD71++), the percentage of DAPI positivity was significantly lower (0-66%, median 9%) (p<0.0001 in both cohorts).There is no difference in amount of EP at d15 between B and T ALL in either of the cohorts. The treatment reduction in SR pts (FC MRD d15<0.1%) was in Coh2009 used only in BCP ALL and we focused in further analyses on BCP ALLs. Overall, the EP were below 2% in 16% and 18% in Coh2000 and Coh2009, respectively. Within risk groups, EP below 2% at d15 occurred more frequently in Standard Risk (SR; 27%) than in non-SR (non-SR; 12%) in both cohorts (p=0.0002). The frequency of low EP appears higher than the expected frequency of technically poor samples. Moreover, it is unlikely that quality of BM aspiration would depend on the risk group of the pt. This further supports the role of normal BM response to presence of leukemic cells on one hand and to therapy on the other one.In both cohorts we found significant positive correlation between amount of EP and FC MRD at day 15 (Coh2000 p-value= 0.0016 (R 0.23); Coh2009 p value <0.0001 (R 0.33)). The correlation was significant in BCP ALLs only (Coh2000 p value=0.008 (R 0.26); Coh2009 p value<0.0001 (R 0.39)). The same significant correlation is observed in BCP ALLs with more precisely defined population EP CD71++DAPIneg (Coh2000 p value=0.04 (R0.18); Coh2009 p<0.0001 (R 0.35)). Part of the Coh2000 was treated with prednisone and part of the pts with dexamethasone between d8 and d28, whereas the entire Coh2009 received prednisone only. However, the frequency of low EP was not different between dexamethasone and prednisone-treated pts, the correlation between FC MRD and EP was significant only in prednisone treated pts (p=0.0003, R=0.33).We focused on SR BCP ALL pts (FC MRD d15<0.1%). We did not find difference in event free survival (EFS) between pts with amount of EP below and above 2%. This result indicates that the pts with low MRD and low EP are not just pts with hemodiluted BM samples.Conclusion: Sample quality is essential question in the assessment of MRD in BM. Although low EP may indicate poor BM aspiration quality, it may also result from other biological factors. At d15 BCP ALL, these factors include the interaction of normal BM cells with leukemia, patient's risk group, and type of corticosteroid used. EPs should be detected using an erythroid marker, such as CD71. However, new markers of BM quality, less influenced by leukemia treatment, are needed.Supported by Ministry of Health of CR, grant nr. 15-28525A, NV18-07-00430 and NV18-03-00343; Czech Science Foundation nr. P302/12/G101. DisclosuresBrüggemann:PRMA: Consultancy; Incyte: Consultancy; Pfizer: Speakers Bureau; Roche: Speakers Bureau; Affimed: Research Funding; Regeneron: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau.

Association of baseline big endothelin-1 level with long-term prognosis among cardiac resynchronization therapy recipients

BackgroundSerum concentration of big endothelin-1 (ET-1) has prognostic significance in heart failure. However, its prognostic value in cardiac resynchronization therapy (CRT) recipients has not been well-characterized. MethodsA cohort of 367 consecutive patients who received CRT between January 2010 and December 2015 were enrolled, and categorized into three groups according to baseline big ET-1 tertiles: big ET-1 ≤ 0.34 pmol/L (N = 119), big ET-1 between 0.34–0.56 pmol/L (N = 127) and big ET-1 > 0.56 pmol/L (N = 121). The primary endpoints included mortality rate (all-cause) and heart transplantation. ResultsOver a median follow-up of 21 months, 48 (13.08%) patients died, 6 (1.63%) underwent heart transplantation and 100 (27.25%) had heart failure hospitalization (HFH). We found a significant difference in event free survival between the three groups, with high levels of big ET-1 correlating with worse survival (Log-rank test, P < .001). After adjusting for multiple factors in the multivariate model, big ET-1 > 0.56 pmol/L was an independent predictor for primary endpoint event [hazard ratio (HR): 2.005, 95% confidence interval(CI) 1.045–6.2621, P = .040] and HFH (HR = 2.126, 95%CI 1.182–3.827, P = .012). ConclusionBaseline big ET-1 > 0.56 pmol/L was independently associated with higher all-cause mortality and HFH among CRT recipients, and therefore can be added to the marker panel used for stratifying high risk CRT patients for priority treatment.

Abstract LB-B14: Pediatric Preclinical Testing Consortium evaluation of the second-generation selective inhibitor of nuclear export (SINE) compound KPT-8602

Abstract Introduction: KPT-8602 is a second-generation SINE compound that specifically blocks exportin-1 (XPO1) cargo interactions. XPO1 is a nuclear export receptor, a critical regulator of cell proliferation and survival, that is characterized as the sole transporter of several tumor suppressor and growth regulatory proteins, including p53, p21, p27, BCR-ABL, FOXO and STAT3. Overexpression of XPO1 has been correlated with high-risk disease and poor survival in multiple pediatric cancers, including leukemia and neuroblastoma (NB). Our prior work demonstrated that selinexor, a closely-related SINE compound, induced complete remission (CR) or maintained CR (MCR) in 2 of 8 ALL patient-derived xenografts (PDXs) tested while it did not induce tumor regressions in 6 neuroblastoma models (Attiyeh EF, et al. Pediatr Blood Cancer. 2016;63:276-86). While selinexor has shown activity in a variety of adult malignancies and is being tested in pediatric phase 1 trials, KPT-8602 shows similar pharmacokinetic properties to selinexor and improved tolerability in preclinical models, and thus it was tested against ALL and NB models by the PPTC. Methods: KPT-8602 was tested against 6 NB and 12 ALL pediatric PDX models using 10 and 8 mice/arm, respectively. Based on tolerability, a dose of 12.5 mg/kg was selected and administered once daily via oral gavage 5 days per week for 4 weeks. Events were defined as quadrupling of tumor volume from day 0 (for NB) or as the proportion of human CD45+ cells in the peripheral blood (%huCD45+) ≥25% (for ALL). The Kaplan-Meier method was used to compare time-to-event between treated and control groups. Objective response categories were assigned as progressive disease (PD, which is subdivided into progressive disease without or with growth delay, PD1 or PD2, respectively), stable disease (SD), partial response (PR), CR, and MCR [Houghton PJ, et al. Pediatr Blood Cancer, 2007]. KPT-8602 was developed and provided for testing by Karyopharm Therapeutics, Inc. Results: KPT-8602 was generally well tolerated, but with weight loss during treatment of approximately 15% and 2% for the neuroblastoma and ALL models, respectively. KPT-8602 induced significant differences in event free survival (EFS) distribution compared to control in 16 of the 18 (88.9%) evaluable xenograft lines studied. Four NB and 10 ALL PDX models showed a &amp;gt;2-fold extension in median EFS for treated compared to control animals. For the 6 NB PDX models, 3 had a minimum relative tumor volume (minRTV) of &amp;lt;1, and 2 achieved PR while 1 was PD2. For the ALL panel, 3 achieved a CR and 3 more achieved a MCR. Among the ALL PDXs achieving CR/MCR were 4 B-cell ALL (including 2 Ph-like ALL) and 2 T-ALL. The neuroblastoma PDX showing the most favorable response to selinexor showed a PR to KPT-8602, and the 2 ALL PDXs with CR/MCR responses to selinexor showed MCR responses to KPT-8602. Conclusions: These data indicate that KPT-8602 demonstrates significant anti-cancer efficacy and tolerability in preclinical models of childhood ALL and NB. Our results support further preclinical testing of KPT-8602 in combination with other targeted therapies for ALL and NB, as well as testing against additional pediatric cancer models in the PPTC. (Supported by NCI Grants: CA199222; CA199000; CA199287) Citation Format: Kateryna Krytska, Kathryn Evans, Tara Pritchard, Matthew Tsang, Raymond Yung, Yael P. Mosse, Stephen W. Erickson, Yuelong Guo, Erkan Baloglu, Yosef Landesman, Kyle A. Jensen, William Senapedis, Beverly A. Teicher, Malcolm A. Smith, Richard B. Lock, John M. Maris. Pediatric Preclinical Testing Consortium evaluation of the second-generation selective inhibitor of nuclear export (SINE) compound KPT-8602 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B14.

Intracranial plaque enhancement from high resolution vessel wall magnetic resonance imaging predicts stroke recurrence.

Intracranial atherosclerosis is associated with frequent stroke recurrence. High resolution vessel wall magnetic resonance imaging (HRMRI) can provide atheroma information related to its vulnerability. We performed HRMRI in stroke patients with intracranial atherosclerosis to determine whether plaque characteristics from vessel wall imaging can predict future stroke recurrence. Between July 2011 and June 2013, acute stroke patients with symptomatic intracranial atherosclerosis were prospectively enrolled and 3-tesla HRMRI was performed on the relevant artery. The plaque enhancement was visually determined from T1 post-gadolinium enhancement image. Stroke recurrence was monitored after index event and multivariate Cox proportional hazards model was constructed to identify factors related to future stroke recurrence. A total of 138 patients were included with a median follow-up of 18 months. There were 39 stroke recurrences. Plaque enhancement was detected in 108 patients (78.3%), and 37 of them experienced stroke recurrence. Among 30 stroke patients without plaque enhancement, two patients experienced stroke recurrence. Kaplan-Meier curves demonstrated a significant difference in event free survival between the patients with plaque enhancement and those patients without plaque enhancement (event rates at year 1: 30.3% vs. 6.8%, log-rank test, p = 0.004). Multivariate Cox-regression analysis showed that the plaque enhancement from HRMRI was independently associated with stroke recurrence (hazard ratio: 7.42, 95% confidence interval: 1.74-31.75, p = 0.007). Intracranial plaque enhancement from HRMRI is associated with stroke recurrence among the patients with symptomatic intracranial atherosclerosis.

The Utility and Applicability of Chronic Myeloid Leukemia Scoring Systems for Predicting the Prognosis of Egyptian Patients on Imatinib: Retrospective Study

Background: Chronic myeloid leukemia (CML) is myeloproliferative clonal neoplasm. Imatinib has greatly improved CML prognosis. Many prognostic scoring systems have been developed for CML risk stratification. In clinical practice, 3 systems are widely used: Sokal, Hasford and European Treatment Outcome Study (EUTOS). Recently, EUTOS long-term survival (ELTS) score is the first long-term scoring system that considered specifically CML-related death. Therefore, the aim of the present study was to validate the effectiveness of Sokal, Hasford, EUTOS and ELTS scoring systems in predicting the outcome in Egyptian CML-chronic phase (CML-CP) patients treated with imatinib. Patients and methods: Retrospective study performed on 167 patients with CML-CP who were treated with imatinib. Using the Sokal, Hasford, EUTOS and ELTS scores, we divided the patients into each risk groups. Results: Significant differences in event free survival (EFS), time without progression (TWP) and overall survival (OS) prediction between the Sokal, Hasford and ELTS risk groups, but no significant difference among the EUTOS score risk groups. Conclusion: Our study indicates that Sokal, Hasford and ELTS scoring systems but not the EUTOS score are effective in predicting early treatment response, EFS, TWP and OS for Egyptian CML patients treated with imatinib

Impact of Different In Vivo T Cell Depletion Strategies on Outcomes Following Hematopoietic Stem Cell Transplantation for Idiopathic Aplastic Anaemia: A Study on Behalf of the EBMT SAA Working Party

To determine the optimal serotherapy regimen in idiopathic aplastic anaemia stem cell transplantation, we analysed 1837 patients who underwent either in vivo T cell depletion with either ATG (n=1283) or Alemtuzumab (n=261) or no serotherapy (n=293) as part of their conditioning regimen. All patients had either undergone a matched sibling or matched unrelated donor stem cell transplant (at least 6 out of 6). Data was obtained retrospectively from the EBMT SAA database, between the periods 2000-2013. The major endpoints were graft versus host disease, overall survival and event free survival. Events were classified as graft failure, secondary malignancy, relapse and requirement for second transplant. The median follow up was 34 months in the ATG group, 30.9 months in the Alemtuzumab group and 47.9 months in the no serotherapy group. Rate of grade 2-4 acute GVHD was 19.1% without serotherapy; this was higher than that observed with both ATG (13.3%, p<0.001) and Alemtuzumab (6.7%, p<0.001; ATG vs Alemtuzumab: p=0.012). Cumulative incidence of chronic GVHD at 36 months was 30.4% without serotherapy; this was higher than that observed with both ATG (20.8%, p=0.021) and Alemtuzumab (14.7%, p=0.003; ATG vs Alemtuzumab: p=0.083). In multivariate analysis, grade 2-4 acute and chronic GVHD rates were significantly lower with Alemtuzumab compared to no serotherapy (Odds Ratio ratio (OR) = 0.16, p< 0.001 95%CI 0.08-0.31 and HR= 0.38, 95% CI 0.24-0.62, p< 0.001 respectively). Similarly, acute and chronic GVHD were lower with Alemtuzumab compared to ATG (OR = 0.26;p<0.001 95%CI 0.14-0.47 and HR = 0.58; 95%CI 0.38-0.89, p=0.012 , respectively). Acute and chronic GVHD were higher without serotherapy compared to ATG (OR = 1.65; p =0.01 95%CI 1.12-2.41 and HR = 1.51; 95%CI 1.12-2.04, p=0.008 , respectively). There was no difference in event free survival between the three groups. However, overall survival at 36 months was 73.3%, 81.3% and 81.5 in no serotherapy, ATG and alemtuzumab, respectively (ATG vs no serotherapy p=0.01; Alemtuzumab vs no serotherapy p=0.025; Alentuzumab vs ATG p=0.604). In multivariate analysis overall survival favoured in vivo T cell depletion compared to no serotherapy; (Alemtuzumab vs no serotherapy, HR=0.44; 95%CI 0.29-0.67, p<0.001); (no serotherapy vs. ATG HR=1.55; 95%CI 1.19-2.01, p=0.001). Among serotherapy, Alemtuzumab was associated with better OS as compared with ATG (OR=0.68; 95%CI 0.48-0.98, p=0.037). Our results suggest that use of in vivo T cell depletion in sibling and unrelated matched stem cell transplantation in idiopathic aplastic anaemia leads to a survival advantage. Alemtuzumab is associated with less GVHD than ATG without affecting event free survival. [Display omitted] DisclosuresSnowden:Celgene: Other: Educational support, Speakers Bureau; Janssen: Other: Educational support, Speakers Bureau; MSD: Consultancy, Other: Educational support, Speakers Bureau; Sanofi: Consultancy. Dufour:Pfizer: Consultancy. Risitano:Pfizer: Consultancy; Novartis: Research Funding; Rapharma: Consultancy, Research Funding; Alnylam: Consultancy, Research Funding; Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: this paper includes discussion of the use of alentuzumab for GVHD prophylaxis, which is currently off-label.

Atypical Presentation of Childhood Leukemia.

To, The Editor, Leukemia is the most common childhood cancer worldwide [1]. Acute lymphoblastic leukemia (ALL) usually manifests with pallor, hepatosplenomegaly, lymphadenopathy, fever, bone pain, and bleeding [2]. Presence of frank osteolytic lesions with hypercalcemia is infrequent [3].We describes here a case of paediatric ALL who presented with multiple lytic lesions, hypercalcemia and absence of blasts in the peripheral blood film. A 10-year-old boy presents with generalised weakness, pain in right hypochondriac region which was non radiating, aggravated by coughing, associated with vomiting which was non bilious and non projectile for last 15 days. On examination, mild pallor was present with no icterus and lymphadenopathy. Liver was palpable 2 cm below the right costal margin. On investigations, complete hemogram showed Hb of 9.2g/ dl, WBC count of 8.0×109 /L with neutrophils 54%, lymphocyte 36%, monocyte 7%, eosinophil 2%, myelocyte 1% and platelet count 271 ×109 /L. Peripheral blood film showed mild anisocytosis with microcytes and hypochromia. His serum biochemistry studies were as follows: sodium: 134.8 mmol/L, potassium: 4.2 mmol/L, Crealinium: 0.93mg/dl, Calcium: 14.2 mg/dl, Phosphorous 6.4 mg/dl, uric acid: 7.6 mg/dl, LDH: 654 IU/L, Alkaline phosphatase: 110U/L, Albumin: 3.6g/dl. His ESR was 100 mm/h. Serum vitamin D3 level was 16.3 (15-30ng/ml). His serum parathyroid hormone (PTH) level was 7.2 (13.7-77.2 pg/ml). His abdominal ultrasound was normal except for hepatomegaly. The skeletal survey showed multiple lytic lesions in skull [Table/Fig-1] and ill defined translucent areas in pelvic bone. In view of anemia and multiple lytic lesions, bone marrow examination was done. Bone marrow examination revealed hypercellular marrow with 55% blasts which were positive for CD 10, CD 19, CD 22 and negative for myeloperoxidase confirming to diagnosis of precursor B acute lymphoblastic leukemia. Cytogenetic analysis of bone marrow showed 46XY karyotype. Molecular analysis for t (9; 22), t (12; 21), t (1; 19), and t (4; 11) using PCR method were negative. Patient was started on aggressive hydration, bisphosphonate and frusemide with monitoring of tumour lysis markers. For ALL, he was started with chemotherapy as per BFM 2002 protocol. His serum calcium levels decreased to 11.0 mg/dl after 48 hrs. Currently he is undergoing chemotherapy and his Day +15 marrow was hypocellular with 3% blasts (M1 marrow). Hypercalcemia is a rare finding in paediatric ALL ranging in frequency from 0.6- 4.8% [4]. Hypercalcemia of malignancy can occur due to two mechanisms. First is localized bone destruction by invasive cancer cells and second mechanism involves osteoclastic bone resorption after the release of humoral derived factors from tumour cells. Although hypercalcemia is assumed to be linked with high tumour bulk, a series of 22 patients showed no difference in event free survival in children with hypercalcemia at presentation. It has been reported that t (17;19), which is associated with poor prognosis, is frequently seen in patients with hypercalcemia due to humoral factors [5]. In our patient, hypercalcemia was due to direct bone invasion and cytogenetics was normal. The presence of multiple lytic lesions and hypercalcemia with no blasts in the peripheral blood are uncommon findings in ALL, which has prompted us to report this case. [Table/Fig-1]: X-ray Skull showing multiple lytic lesions

Spirit 2: An NCRI Randomised Study Comparing Dasatinib with Imatinib in Patients with Newly Diagnosed CML

▪Objective. SPIRIT 2 is the largest phase 3 prospective randomized open-label trial comparing imatinib 400mg with dasatinib 100mg daily: this is the first presentation of data comparing the two arms.Methods. 814 patients were recruited at 144 hospitals between August 2008 and March 2013. 812 started study medication (406 in each arm). The primary endpoint is event-free survival at 5 years. A key secondary endpoint is the rate of achievement of a BCR-ABL/ABL ratio of <0.1%IS (major molecular response (MMR), 3 log reduction or MR3).Results. Discontinuations. With a median follow up of 34 months a total of 289/812 (35.6%) patients have discontinued study medication. 118/812 (14.5%) patients have discontinued due to non-haematological toxicity: imatinib 47/406 (11.6%); dasatinib 71/406 (17.5%). 40 patients discontinued due to sub optimal response as assessed by the treating physician: imatinib 37/406 (9.1%); dasatinib 3/406 (0.7%). Side effects. Patients receiving imatinib experienced GI toxicity more often than patients receiving dasatinib; fatigue, rash and headache were more common with dasatinib. A higher rate of grade 3/4 thrombocytopenia was observed in the dasatinib arm: imatinib 17/406 (4.2%); dasatinib 52/406 (12.8%). Pleural effusions occurred in 78/406 (19.2%) patients on dasatinib; 13 of 78 (16.7%) patients required drainage. Arterial cardiovascular events (excluding hypertension) were experienced by 10/812 (1.2%) patients: imatinib 2/406 (0.5%; myocardial infarction (MI) x2); dasatinib 8/406 (2.0%; MI x1; angina/acute coronary syndrome x5; peripheral arterial disease x2). Hypertension was observed in 10/812 (1.2%) patients: imatinib 3/406 (0.7%); dasatinib 7/406 (1.7%). Venous CV events occurred in 7/812 (0.9%) patients: imatinib 3/406 (0.7%); dasatinib 4/406 (1.0%). Efficacy. For both PCR and cytogenetic analyses patients that had discontinued their allocated therapy or that did not have a 12 month sample were analysed as not having achieved MR3/CCR. The MR3 (PCR <0.1%IS) rate at 12 months in all treated patients is significantly different (p<0.001) between the two treatment arms: imatinib 173/406 (42.6%); dasatinib 236/406 (58.1%). The MR3 rate at 12 months in patients treated with dasatinib is 51/78 (65.4%) in those with a pleural effusion and 185/328 (56.4%) in those without (p=0.148, NS).The complete cytogenetic response (CCR) rate at 12 months is: imatinib 163/406 (40.1%); dasatinib 207/406 (51.0%). The difference between the two treatment arms is statistically significant (p=0.002) but caution is required in interpreting these data as there were missing analyses in 367 of 812 (45.2%) patients: imatinib 191 of 406 (47.0%), dasatinib 176 of 406 (43.3%). The difference in major cytogenetic response (MCR) rate between the two treatment arms at 12 months is not statistically significant: imatinib 200/406 (49.3%); dasatinib 218/406 (53.7%), p=0.206. Disease progression and deaths. 16 patients have progressed to either accelerated phase or blast crisis and 13 of those progressions were within the first year. Accelerated phase: imatinib 3/406 (0.7%); dasatinib 2/406 (0.5%). Blast crisis: imatinib 7/406 (1.7%); dasatinib 4/406 (1.0%).Conclusions. Dasatinib-treated patients have a higher rate of molecular response at 1 year but, with a median of 34 months follow up, there is no significant difference in rates of disease progression or overall survival. More patients abandoned imatinib than dasatinib due to investigator concerns about sub optimal responses. Further follow up is required to evaluate whether there will be differences in event free survival at five years. DisclosuresO’Brien:Ariad: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Hedgley:BMS: Research Funding; ARIAD: Research Funding. Adams:BMS: Research Funding. Apperley:Ariad Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Holyoake:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Byrne:BMS: Honoraria; Novartis: Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy. Osborne:ARIAD: Research Funding. Copland:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria. Clark:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Honoraria, Research Funding.

Cancer incidence, morbidity, and survival in Canadian first nation children: A Manitoba population‐based study from the cancer in young people in Canada (CYP‐C) registry

Health disparities between Canadian First Nation (FN) people and the rest of the national population exist. No studies have specifically documented cancer-related health outcomes in Canadian FN children. The purpose of this study was to describe the incidence of pediatric malignancies in Manitoba FN children, and to compare morbidity patterns and survival between FN and non-FN children with cancer in the Canadian province of Manitoba. A retrospective, population-based review of all children (0-14.99 years) diagnosed with malignancy (2001-2008) in Manitoba, Canada was undertaken using the Cancer in Young People in Canada registry. FN children were compared to the non-FN population for markers of morbidity and survival. The average annual age-standardized incidence rate for all childhood cancers in FN children was 132 per 1,000,000 per year. 240 children were included in the morbidity and survival analyses (38 FN; 202 non-FN). No differences were found between FN and non-FN children in time from first presentation of symptoms to consultation with an oncology specialist or diagnosis, or number of hospital admissions / total days of admission for treatment complications. Overall survival was inferior for FN children in univariable analysis (P = 0.048) but not when risk group was included in a multivariable analysis (P = 0.15). No difference in event free survival or cumulative incidence of relapse was identified. The estimated incidence of childhood cancers in the Manitoba FN population is similar to provincial incidence rates. No differences in morbidity patterns or survival were found between Manitoba FN and non-FN children with cancer.

Abstract 18308: Prognostic Value of Stress Echocardiography Appropriateness Criteria for Evaluation of Coronary Artery Disease

Background: Appropriateness criteria for stress echocardiography (SE) have been published to reduce the rate of inappropriate testing. There are limited data validating the prognostic value of these criteria in clinical practice. Methods: 250 consecutive patients undergoing SE for evaluation of known or suspected coronary artery disease were classified into appropriate, uncertain and inappropriate categories according to appropriateness criteria guidelines. A positive SE was defined as the development of new wall motion abnormalities or a biphasic response. The primary end-point was the composite of myocardial infarction and death. Results: Of the 250 SE, 120 (48%) were dobutamine studies and 130 (52%) were exercise studies. Of the 250 patients, 156 (62.4%), 71 (28.4%) and 23 (9.2%) were classified as appropriate, inappropriate and uncertain, respectively. A significantly greater proportion of studies classified as appropriate 71(45.5%) demonstrated inducible ischaemia compared to inappropriate studies 9(12.7%) or uncertain studies 4(17.4%), p&lt;0.0001. During a median follow-up of 12.4 months (inter-quartile range 10.6 - 16.3 months), events occurred in 18 (11.5%), 2 (2.8%) and 0 patients classified as appropriate, inappropriate and uncertain respectively. Event-free survival was significantly reduced in patients with a SE demonstrating ischaemia compared to patients without inducible ischaemia, p &lt;0.0001. Kaplan Meier curves demonstrated reduced event-free survival in patients with whose studies were classified as appropriate compared to inappropriate (p=0.01) or uncertain (p=0.05). There was no difference in event free survival between those classified as uncertain or inappropriate (p=0.48). The only independent predictors of mortality or myocardial infarction were a positive SE (hazard ratio 5.39) and left ventricular ejection fraction (hazard ratio 0.95). Conclusion: Appropriateness criteria for evaluation of coronary artery disease have the ability to both determine the need for stress testing and identify patients at high risk of ischaemia, subsequent revascularisation and cardiac events.

Evaluating oncogenic pathway dysregulation in adolescents and young adults with acute myeloid leukemia.

7107 Background: Adolescent and young adults (AYAs) with Acute Myeloid Leukemia (AML) have been shown to have better outcomes with induction chemotherapy when compared to older young adults (OYAs). Multiple psychosocial, treatment, and host-related factors unique to AYAs have been identified but the contribution of disease biology to these outcomes has not yet been fully characterized. The purpose of this study was to evaluate disease biology as it relates to age-specific differences in outcomes for AYAs with AML. Methods: Clinically annotated, microarray data from 425 patients with newly diagnosed AML from two publicly available datasets: GSE1159; and GSE12417 were analyzed. Age-specific cohorts (AYAs ≤ 30 years; n = 58 and OYAs &gt;30 but ≤ 60 years; n=276) were prospectively identified. Patients in GSE1159 were treated according to protocols of the Dutch–Belgian Hematology–Oncology Cooperative group and included 111 patients who ultimately underwent stem-cell transplantation. Patients in GSE12417 were treated per the AMLCG-1999 protocol. Gene expression analysis was conducted by applying previously defined and tested signature profiles reflecting deregulation of oncogenic signaling pathways and altered tumor environment. All statistical analysis was performed using S-plus and survival analysis by Cox proportional-hazards regression was used to assess differences in overall survival (OS) between age-specified study cohorts and a one-sided p-value ≤ 0.05 was considered statistically significant. Results: AYA patients had a significantly better OS (median survival 24.1 months vs. 13.0 months in OYAs; p=0.0285), but there was no difference in Event Free Survival (p=0.23). Analysis of oncogenic pathways revealed that AYA patients likely had better OS because of lower TNF (p=0.03) and higher myc (p=0.02) pathway activation. Conclusions: AML arising in AYAs may represent a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that contributes to OS. We hope these findings will enable clinically meaningful adjustments of treatment strategies in the AYA AML patient population.

The usefulness of the consensus clinical diagnostic criteria in Brugada syndrome

BackgroundConsensus statements were proposed for the diagnosis of Brugada syndrome (BS). The clinical diagnostic criteria were defined as documented ventricular fibrillation or ventricular tachycardia (VT), family history of sudden cardiac death at <45years, diagnostic ECGs of family members, inducibility of VT during electrophysiological study, syncope or nocturnal agonal respiration. The clinical validation of these criteria is still missing.Methods and results280 patients (41±18years, male: 168 pts) with diagnostic coved type I ECG were included. Consensus clinical diagnostic criteria were present in 244 (87%) patients (40±18y, 142 males). In 36 pts (13% of the 280 pts, 51±12years, 27 males) consensus clinical diagnostic criteria were not met. Nine patients (25%) presented with spontaneous type I ECG. Ten of the 36 patients (28%) had a history of atrial fibrillation and 13 (36%) had conduction disease on the baseline ECG. In 23 patients (64%) family screening was not performed. Two of the 36 patients had undocumented syncope during follow-up. Univariate analysis showed no significant difference in event free survival between patients with or without consensus clinical diagnostic criteria. ConclusionsIn a significant number of patients with diagnostic ECG pattern the current diagnostic criteria for BS are not met. These patients have frequently spontaneous type I ECG and clinical signs of Brugada syndrome as paroxysmal atrial fibrillation or conduction disturbances. Our results suggest that in patients with a diagnostic type I ECG pattern the current clinical consensus diagnostic criteria have limited added diagnostic value.