Number Of Cytogenetic Abnormalities Research Articles

P770: A COMPARATIVE STUDY OF LEUKEMIC TRANSFORMATION IN THERAPY-RELATED AND DE NOVO MYELODYSPLASTIC SYNDROME AFTER HYPOMETHYLATING AGENT FAILURE

Background: Therapy-related myelodysplastic syndrome (t-MDS) is subset of myelodysplastic syndrome (MDS), known for having dismal survival outcomes. The majority of patients (pts) with t-MDS have similar clinical courses with de novo MDS patients after hypomethylating agent failure (HMA-F) that often results in transformation to acute myeloid leukemia (AML). Aims: We conducted a study to identify unique clinicopathologic features of t-AML from t-MDS compared to secondary AML (sAML) from de novo MDS after HMA-F. Methods: We identified sAML patients after HMA-F from all untreated MDS pts in a tertiary cancer center registry from 2017-2021. Clinical characteristics and pathologic data including cytogenetic (CG) and next generation sequencing (NGS) information were collected at the time of MDS diagnosis (dx), HMA-F, and AML dx. Results: 71 (48%) MDS pts with AML transformation after HMA-F were included in the study with a median follow-up time of 15.4 months (mo). At the time of MDS dx, 31 (43%) pts had t-MDS: 97%, 58% and 29% had a history of chemotherapy, radiation, and prior stem cell transplant (SCT), respectively. t-MDS patients were more likely to present with age<65 (48% vs. 28%, p=0.070) and thrombocytopenia (33,000 vs. 75,500, p=0.004) when compared to de novo MDS pts. The majority of t-MDS pts had very high risk disease by IPSS-R (67% vs. 39%, p=0.031), while de novo MDS pts frequently had high risk disease (50% vs. 20%, p=0.013). 90% of t-MDS pts had adverse CG (IPSS-R CG score 3-4) at MDS dx, compared to 46% in de novo MDS pts (p=0.004). NGS at MDS dx showed more frequent TP53 mutations in t-MDS than in de novo MDS (73% vs 36%, p=0.003). Interestingly, ASXL1 (36% vs. 1%, p=0.001), RUNX1 (9% vs. 0%, p=0.004), STAG2 (21% vs. 0%, p=0.013), TET2 (13% vs. 0%, p<0.001), and SRSF2 (18% vs. 0%, p=0.027) were more frequently found in de novo MDS (Table). t-MDS had worse overall survival (OS) from MDS dx (HR 1.82, p=0.026). The median OS from MDS dx was 19.4 mo and 14.3 mo in de novo MDS and t-MDS, respectively. The number of HMA cycles received before HMA-F was 6 (range: 1-13) in t-MDS and 5 (range: 1-23) in de novo MDS. At the time of HMA-F, t-MDS pts presented with more anemia (p=0.005) and thrombocytopenia (p=0.064). The number of CG clones were similar, but the number of CG abnormalities were higher in t-MDS pts (p=0.025). Among pts with subsequent AML transformation after HMA-F, the median time from HMA-F to AML was 1.5 mo in t-MDS to AML, compared to 4.6 mo in de novo MDS to AML. At time of AML dx, 48 (68%) pts had mutation panels available. All TP53 mutation status stayed the same in t-MDS pts at the time of MDS and AML dx. Other changes in mutations were shown in Table. Though the median OS from AML transformation was short in all pts, t-MDS pts had inferior outcomes (2.4 mo vs. 5.0 mo, HR 1.70, p=0.043). The initial response rate to salvage therapy was comparable between t-MDS and de novo MDS after AML transformation (50% and 56%, p=0.761), but more pts underwent SCT with de novo MDS compared to t-MDS (10% vs. 3%, p=0.383). Image:Summary/Conclusion: Transformation to AML after HMA-F results in poor outcomes, but pts with t-MDS have worse survival with distinct CG and mutation profiles. Further understanding of the pathogenesis of AML transformation in both t-MDS and de novo MDS after HMA-F is warranted with improved therapy options an area of unmet need.

Characteristics and clinical outcome of high-risk multiple myeloma patients in Korea (KMM 1805).

Optimal treatments for multiple myeloma (MM) patients with high-risk cytogenetics must be determined, but subgroup features are not well-defined. We used real-world data from the Korean Myeloma Registry (KMR) to analyze the characteristics and clinical outcomes of newly diagnosed MM patients with ≥ 1 high-risk cytogenetic abnormality: Group 1: t(4;14) or t(14;16); Group 2: del(17p); Group 3: t(4;14)/del(17p) or t(14;16)/del(17p). Overall, 347 high-risk patients were identified (males, 48.7%; median age, 63years). Median progression-free survival (PFS) and overall survival (OS) were 19.0months (95% CI 17.0-20.0) and 50.0months (95% CI 37.0-61.0), respectively. PFS (p = 0.047) and OS (p = 0.020) differed significantly between groups. After stratification by transplant eligibility, PFS and OS were significantly poorer in Group 3 among transplant-eligible patients, and even poorer in those with gain(1q). Patients stratified by cytogenetic abnormality and revised International Staging System (R-ISS) had significantly different PFS (p < 0.001) and OS (p = 0.003), with the worst survival in R-ISS III/Group 3 (median OS 21.0months). Higher number of high-risk cytogenetic abnormalities was a negative prognostic marker for PFS and OS (p < 0.001). Real-world KMR data showed that risk factors for poor prognosis of MM patients included del(17p), R-ISS stage, and number of cytogenetic abnormalities.

Progression-Free Survival (PFS) According to the Presence of Adverse Cytogenetic Abnormalities in Patients (pts) with Multiple Myeloma (MM) Receiving Ixazomib (ixa)-Based vs Placebo (pbo)-Based Therapy: A Pooled Analysis of the TOURMALINE-MM1, MM2, MM3, and MM4 Phase 3 Studies

Progression-Free Survival (PFS) According to the Presence of Adverse Cytogenetic Abnormalities in Patients (pts) with Multiple Myeloma (MM) Receiving Ixazomib (ixa)-Based vs Placebo (pbo)-Based Therapy: A Pooled Analysis of the TOURMALINE-MM1, MM2, MM3, and MM4 Phase 3 Studies

Clinicopathologic Features, Mutation Spectrum and Clinical Outcome of Complex/Monosomy Karyotype AML in Young Adult Patients in Hong Kong

Objectives: Acute myeloid leukemia (AML) with complex/monosomal karyotype (CK/MK) is associated with poor response to conventional chemotherapy and clinical outcome. This study examined the clinicopathologic features, mutation spectrum and clinical outcome of young adult patients with CK/MK AML treated with a uniform protocol in Hong Kong.Methods: Young adult patients (18-60 year old) with CK/MK-AML treated in 7 regional hospitals in Hong Kong from January 2003 to July 2016, were analyzed retrospectively. CK-AML was defined as those with ≥ 3 clonal abnormalities. MK-AML was defined as those with ≥ 2 autosomal monosomies or single autosomal monosomy and at least one structural abnormality. Treatment comprised induction (7+3 regimen or equivalent) and consolidation (high-dose cytarabine). Relapsed or refractory patients received salvage chemotherapy. All patients who achieved complete remission (CR) were referred to allogeneic hematopoietic stem cell transplantation (HSCT) from HLA identical sibling or matched unrelated donors. Mutation spectra of their diagnostic bone marrow samples were analyzed by MiSeq NGS with the TruSight Myeloid sequencing panel targeting 54 genes covering full coding sequence of 15 genes and exonic hot spot for 39 genes. Leukemia-free survival (LFS) and overall survival (OS) were evaluated by Kaplan-Meier curves and compared by log-rank test. Cox proportional hazard model was used in univariate and multivariate analyses.Results: Seventy-six patients (41 men and 35 women) with CK/MK-AML were analyzed. Their clinicopathologic features as well as mutation spectra of 45 patients whose diagnostic marrow were examined by NGS were shown in Table 1. A total of 116 genetic mutations were found (median 2 mutations, range 1-7 mutations per patient). Five patients died before induction and 2 refused treatment. Of the 69 patients who received induction chemotherapy, CR was achieved in 48 of them (70%) after one (N=33) or two (N=15) courses. After 1, 2 and 5 years, LFS was 41%, 26% and 18% and OS was 49%, 20% and 12% respectively. There was no significant association between CR and clinicopathologic features including age, gender, presenting WCC, percentage of marrow and circulating blasts, specific subtypes and number of cytogenetic abnormalities, number of gene mutations and presence of TP53 mutations. In univariate analysis, HSCT at CR1 was significantly associated with longer LFS with a hazard ratio (HR) of 6.1 (range, 2.4-15.7, p <0.001). Achievement of CR1, absence of -17/17p- and HSCT at CR1 were significantly associated with OS with HRs of 8.3 (range 4.4-15.8, p <0.001), 3.2 (range, 1.7-3.2, p<0.001) and 5.7 (range, 2.4-13.5, p <0.001) respectively. TP53 mutations, number of karyotypic abnormalities and mutations were not predictive of CR, LFS or OS in this cohort. In multivariate analysis, achievement of CR1 (HR 4.3, 2.2-8.2, p <0.001), absence of -17/17p- (HR 3.0, 1.5-5.9, p=0.002) and HSCT at CR1(HR 5.8, 2.4-13.7, p <0.001) were associated with superior OS.Conclusion: Karyotypic abnormalities particularly the presence of -17/17p-, the achievement of initial remission upon induction and timely HSCT are important factors associated with disease control and survival in CK/MK AML. The role of gene mutations, particularly TP53, RUNX1 and DMNT3A as well as the best maintenance strategies post HSCT would have to be further evaluated. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The factors influencing clinical outcomes after leukapheresis in acute leukaemia

Leukapheresis is used for the mechanical removal of leukaemic cells in hyperleukocytosis. However, the effectiveness of leukapheresis remains unclear due to selection and confounding factors in the cohorts. We compared the effectiveness of leukapheresis among the subgroups according to either the 2016 World Health Organization classification or the number of cytogenetic abnormalities with a retrospective, single-centre study from January 2009 to December 2018. Acute myeloid leukaemia (AML, n = 212) and acute lymphoblastic leukaemia (ALL, n = 97) were included. The 30-day survival rates (95% confidence interval, 95% CI) for AML and ALL were 86.3% (81.6–90.9%) and 94.8% (90.3–99.2%), respectively. For AML, ‘primary AML with myelodysplasia-related changes’ and ‘AML with biallelic mutation of CEBPA’ showed better 30-day survival outcomes (P = 0.026) than the other subgroups. A higher platelet count after leukapheresis was associated with better 30-day survival in AML patients (P = 0.029). A decrease in blast percentage count after leukapheresis was associated with better 30-day survival in ALL patients (P = 0.034). Our study suggested that prophylactic platelet transfusion to raise the platelet count to 50 × 109/L or greater might improve clinical outcome in AML patients undergoing leukapheresis.

Clinical Course of High-Risk Multiple Myeloma Patients in Korea: A Multicenter Retrospective Study

Introduction: Increased understanding of the pathophysiology of multiple myeloma (MM) and the introduction of new drugs has led to considerable survival improvements in recent years. The International Myeloma Working Group consensus recently updated the definition for high-risk MM based on cytogenetic abnormalities. Moreover, the recent introduction of new therapeutic agents and the revision of insurance reimbursement policies have changed the clinical characteristics of MM patients in Korea. Yet, current epidemiology and the clinical characteristics of MM patients in Korea have not been fully investigated. Therefore, we aimed to understand the characteristics and management of Korean MM patients in a real-world setting by analyzing patients with high-risk cytogenetic abnormalities in the Korean Myeloma Registry. Methods: This is a retrospective observational study using the Korean Myeloma Registry, the web-based multicenter patient registry system established by the Korean Multiple Myeloma Working Party. Patients who are newly diagnosed with MM from 2010 to 2017 with at least one high-risk cytogenetic abnormality [t(4;14), t(14;16), or del(17p)] were included. Primarily, patients were classified by cytogenetic abnormality into three groups: Group 1, t(4;14) or t(14;16); Group 2, del(17p); and Group 3, t(4;14)/del(17p) or t(14;16)/del(17p). These patients were also stratified by the revised International Scoring System (R-ISS) and transplantation history for detailed analysis. We also used the number of cytogenetic abnormalities in an explanatory analysis; in this case, we included gain(1q). Progression-free survival (PFS) and overall survival (OS) were estimated, and the Hazard Ratio with the log-rank test was used for statistical comparison. Results: 391 out of 2170 MM patients from seven hospitals were identified as high-risk patients (men, 49.6%; median age, 63 years old). Median PFS for all patients was 18.9 months (95% CI 17.27-20.33), and the median OS was 44.6 months (95% CI 36.5-60.1). PFS (P&amp;lt;0.001) and OS (P=0.012) between the cytogenetic abnormality groups were significantly different after stratification by transplant history. Patients with t(4;14)/del(17p) or t(14;16)/del(17p) amongst transplant recipients showed the worst outcome, with median PFS 15.5 (95% CI 8.7-20.5) months and median OS 35.6 (95% CI 14.9-N/A) months. Without stratification, there were no significant between-group differences in PFS and OS. OS was also significantly different between cytogenetic abnormality groups stratified by the revised International Staging System (R-ISS) (P=0.003). The lowest median OS durations were 16.9 months (95% CI 6.5-33.6) for del(17p) with R-ISS III, and 21.7 months (95% CI 9.3-N/A) for t(4;14)/del(17p) or t(14;16)/del(17p) with R-ISS III. Patients with higher R-ISS staging in the presence of del(17p) showed worse survival outcomes. Finally, PFS and OS were significantly inversely correlated with the number of cytogenetic abnormalities (P&amp;lt;0.001). Conclusion: In real-world data from the Korean Myeloma Registry, we were able to observe the association of poor prognosis of MM patients with the number of cytogenetic abnormalities (PFS and OS) and R-ISS (OS). Moreover, we were also able to find the association of cytogenetic abnormality del(17p) and poor prognosis in MM patients. Lastly, we believe that this study provides the characteristics and management of MM patients needed to understand the real-world clinical course of high-risk MM patients in South Korea. Disclosures Kim: Amgen, BMS, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Yoon:Novartis: Consultancy, Honoraria; Janssen: Consultancy; F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding; YuhanPharma: Research Funding; Kyowahako Kirin: Research Funding; Amgen: Consultancy, Honoraria. Yoon:Celltrion: Honoraria; Samyang: Research Funding; Amgen, Chongkundang, Celgene, Astrazeneca: Consultancy. Lee:AMGEN: Current Employment.

Clinical Relevance of Driver Mutations and Number of Driver Mutations in Patients with Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

▪INTRODUCTION: Clinical outcomes of patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are very heterogeneous. Although next generation sequencing has identified a number of somatic mutations in MDS and CMML the analysis of their prognostic impact has resulted in contradictory results. Although the number of cytogenetic abnormalities is a well-known prognostic factor in MDS, there is limited information evaluating the prognostic relevance of the number of mutations in this disease. Correlation of mutation data with patient outcomes and integration into clinical practice is still lacking.METHODS: We conducted whole exome sequencing of 88 previously untreated patients with MDS and 26 with CMML. Exome capture hybrid was performed using Agilent SureSelect All Exon V4. Sequencing was performed with Illumina HiSeq 2000 and aligned to the hg19 human genome reference. Common virtual normal in house pool was used for somatic variant calling. Variant allele frequency (VAF) estimates were used to evaluate clonal and subclonal relationships within each individual sample. Clonal relationships were tested using Pearson chi-squared tests. Clinical and demographic data was obtained from clinical records. As a validation cohort, we studied 413 patients with untreated MDS and CMML with sequencing data obtained by use of a 28-gene next generation sequencing platform. The Kaplan-Meier produce limit methods were used to estimate the median overall survival (OS) and leukemia-free survival (LFS).RESULTS: A total of 218 high-confidence driver mutations in 32 genes in 98 (86%) patients were identified. Patient characteristics are shown in Table 1. Median age was 66 (19-85). Median number of driver mutations was 2 (range 0-7). Most frequently detected mutations included TET2, SRSF2, ASXL1 and RUNX1 in >10% patients (Figure 1A). Median number of altered pathways was 2 (range 0-6) with mutations in TP53, splicing and DNA methylation tending to have higher VAF. Fifty-seven (50%) patients had at least 2 mutations and were evaluable for clonal heterogeneity testing. Among these patients, 32 (56%) were clonaly heterogeneous. The most frequent subclonal mutations included ASXL1 (31%), TET2 (25%) and RUNX1 (19%). Median follow up was 21.6 months (range 1-102 months). By univariate analysis, mutations in BCOR (HR 2.85, 95% CI 1.12-7.29, p=0.029), STAG2 (HR 2.45, 95% CI 1.04-5.80, p=0.041) and TP53 (HR 5.25, 95% CI 2.37-11.63, p<0.001) affected OS unfavorably and SF3B1 mutation affected OS favorably (median survival NR vs 28.7 months, p=0.023). Overall survival negatively correlated with increased number of mutations (p=0.02) with patients with 3 or more mutations having significantly worse outcomes (HR 1.94, 95% CI 1.10-3.41, p=0.022). Mutations in EZH2 (HR 8.49, 95% CI 1.85-39.02, p=0.006) and TP53 (HR 6.24, 1.63-23.86, p=0.007) as well as number of mutations predicted for shorter LFS (HR 1.50, 95% CI 1.06-2.12, p=0.021). Clonal heterogeneity was not associated with significant differences in OS or LFS. By multivariate analysis IPSS-R group (Intermediate: HR 1.45, 95% CI 0.56-3.77, p=0.448; High/Very High; HR 4.66, 95% CI 2.01-10.84, p<0.001), TP53 mutation (HR 3.12, 95% CI 1.30-7.49, p=0.011), and ³3 mutations (HR 2.51, 95% CI 1.32-4.76, p=0.005) retained their adverse impact on outcome. A new prognostic model integrating these variables separated patients into three risk groups (low, intermediate and high) with 3-year survival of 76, 62 and 0%, respectively (p<0.001) (Figure 1B), restaged 54 (47%) patients from IPSS-R and had increased stratification potential compared to IPSS-R (Dxy 0.46 vs 0.43; c-index 0.73 vs 0.71). Application of this model to the validation cohort rendered similar results (Figure 1C) with the new molecular model exhibiting higher discrimination potential for survival compared to IPSS-R (Dxy values 0.54 vs 0.51; c-index 0.77 vs 0.75).CONCLUSIONS: Incorporation of mutation data into existing risk models improves prognostication of patients with MDS. Like cytogenetic abnormalities, the number of driver mutations have independent prognostic impact in MDS which seems almost equivalent to that of TP53mut. We believe that our study sets the basis for future multicenter studies aimed at developing a new prognostic model incorporating molecular data generated by use of a uniform sequencing technology. [Display omitted] [Display omitted] DisclosuresKonopleva:Cellectis: Research Funding; Calithera: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:Sunesis: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding; Ariad: Research Funding; BMS: Research Funding; Kiromic: Research Funding; Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria. DiNardo:Celgene: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Agios: Research Funding; Daiichi Sankyo: Research Funding.

Monosomal karyotype of chromosome 5/7 was an independent poor prognostic factor for Chinese myelodysplastic syndrome patients

Monosomal karyotype (MK) was defined as the presence of at least 2 autosomal monosomies or of a single monosomy associated with at least one additional structural abnormality. 6.4-16.3% myelodysplastic syndrome (MDS) patients were reported to fulfill the criteria for MK and associated with poor prognosis in the majority of patients with MDS. In order to further clarify the prognostic significance of MK in Chinese MDS patients, 2080 primary patients were retrospectively analyzed in our center. MK was observed in 8.1% patients (168/2080), and monosomies of chromosome 5/7 were the most frequent types of MK. We further found that MK was significantly associated with elderly patients, higher bone marrow blasts and relatively poor cytogenetics. In addition, MDS patients with MK (n = 59) had poor survival than those without MK (n = 491) in total cohort (P < 0.001), and there was significant difference in the OS between the patients with MK (n = 56) and without MK (n = 53) in the relatively poor cytogenetics group (P = 0.0025). Incorporation of MK into IPSS-R could further stratify MDS patients into different prognostic groups (P < 0.001). Interestingly, monosomies of chromosome 5/7 rather than MK were significantly related to shorter OS (HR = 2.709, P < 0.001) by multivariate analysis. In conclusion, our results suggested that 8.1% MDS patients were presented with MK, and the incidence of MK increased with the number of cytogenetic abnormalities. Monosomies of chromosome 5/7 were the most frequent MK as well as an independent poor risk factor for OS in Chinese MDS patients.

TP53 Mutation Status Divides MDS Patients with Complex Karyotypes into Distinct Prognostic Risk Groups: Analysis of Combined Datasets from the International Working Group for MDS-Molecular Prognosis Committee

Background:Complex karyotypes in patients with myelodysplastic syndromes (MDS) are defined by the presence of 3 or more cytogenetic abnormalities and are considered indicators of a poor prognosis by nearly all models in clinical use. There is evidence that the prognostic significance of complex karyotypes in MDS can be refined by considering the number of cytogenetic abnormalities or the presence of specific lesions, the presence of monosomy, and the mutation status of the TP53 gene. Mutations of TP53 are strongly associated with adverse clinical features including complex karyotypes, yet still have independent prognostic significance. Whether these mutations or other elements associated with complex karyotypes carry the greatest prognostic significance is unknown and has been the subject of recent contradictory findings. Here we examine the relationship between TP53 mutations, the number and type of chromosomal abnormalities, and clinical features including overall survival in a combined analysis of MDS patients with complex karyotypes.Methods:Data on 258 complex karyotype MDS patients from the US and Europe gathered by members of the International Working Group for Prognosis in MDS-Molecular Committee were combined for this analysis. Patients gave informed consent to have their data and clinical samples collected at their respective institutions in accordance with the Declaration of Helsinki. Tumor samples were examined for TP53 mutations primarily with next generation sequencing techniques. Categorical variables were compared using a Fisher exact test or Kruskal-Wallis test as appropriate, while continuous variables were compared using a Wilcoxon rank-sum test. All p-values reported are two-sided, unadjusted for multiple testing, and considered significant at the 0.05 level.Results:Of the 258 complex karyotype MDS samples examined, TP53 mutation status was determined in 223, of which 133 (60%) carried a TP53 mutation. Patients with TP53 mutations were slightly older than unmutated patients (median age 70.8 vs. 65.5 years, p=0.055), were more thrombocytopenic (median platelet count 42 vs. 78 x109/L, p=0.002), and had a greater percentage of bone marrow blasts (7.75% vs 4%, p=0.03). Mutated patients were also more likely to have a monosomal karyotype (85% vs. 59%, p<0.0001), have 5 or more chromosomal abnormalities (85% vs. 51%, p<0.0001), and have abnormalities of chromosome 17 (38% vs. 23%, p=0.03).Patients with TP53 mutation had a significantly shorter median overall survival of 7.7 months compared to 23.4 months for patients with unmutated TP53 (p<0.0001, see figure). Multivariate analysis that considered potential confounders such as monosomal karyotypes, number of abnormalities, blast proportions and platelet count identified TP53 mutation status as the most significant prognostic marker for overall survival (hazard ration [HR] 2.12, p<0.0001). The presence of only 3 or only 4 karyotype abnormalities was protective compared with 5 or more such lesions (HR 0.385, p=0.0005 for 3 lesions and HR 0.505, p=0.0083 for 4 lesions).Discussion:Despite strong associations with adverse clinical and cytogenetic abnormalities incorporated into existing prognostic scoring systems, TP53 mutations carry significant independent prognostic value for patients with MDS. In our multivariable analyses, TP53 mutation appears to dominate over monosomal karyotype as an adverse prognostic marker in MDS patients with complex cytogenetics. Many of the TP53 mutations identified had a small variant allele fraction suggesting that they were present in a disease subclone. The small number of mutant cells in these cases may be insufficient to alter clinical measures, but could still indicate a poor prognosis if they represent a clone capable of treatment resistance and rapid disease progression.This combined analysis is a work in progress that will include data from additional groups and explore mutation status of other MDS-related genes, TP53 variant allele fraction, clinical risk scores, and data from patients without complex karyotypes.Conclusions:Somatic TP53 mutations are highly enriched in MDS patients with complex karyotypes and identify a group with significantly shortened overall survival. Sequencing of TP53 can improve the prediction of prognosis in MDS patients with 3 or more chromosomal abnormalities. [Display omitted] DisclosuresBejar:Genoptix Medical Laboratory: Consultancy, Honoraria, Licensed IP, no royalties Patents & Royalties, Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees. Haferlach:MLL Munich Leukemia Laboratory: Other. Garcia-Manero:Celgene: Research Funding. Sekeres:Celgene: Membership on an entity’s Board of Directors or advisory committees; Amgen Corp: Membership on an entity’s Board of Directors or advisory committees; Boehringer-Ingelheim Corp: Membership on an entity’s Board of Directors or advisory committees. Campbell:14M Genomics Limited: Consultancy, Equity Ownership.

P-168 Familial myelodysplastic syndrome/acute leukemia in adult setting – Experience from a single Brazilian center

Introduction: Myelodysplastic syndromes (MDS) are a group of heterogenous clonal stem cell disorders characterized by inefficient haematopoiesis with one or more cytopenias and increased risk of transformation to acute leukemia. Purpose: The current diagnosis includes peripheral blood morphology, bone marrow biopsy and cytogenetic exam. Clonal cytogenetic abnormalities are described in 40-60% of cases. In 1997, the established System of International Prognostic Score was based on the number of cytopenias on the peripheral blood, precentage bone marrow blasts and karyotype abnomalities. In this system are described a limited number of cytogenetic abnormalities and the importance of their forecast is underestimated. This score classify patients into four risk groups, allow overall survival and estimate the risk of progression to acute leukemia. Materials and Methods: In September 2012 the Revised International Prognostic Scoring System (R-IPSS) was developed in the framework of a project of the International Working Group for Prognosis in MDS (IWG-PM) peak. For scoring according to IPSS-R, it was taken into account: severity of cytopenias (Hb level, the number of platelets, the absolute number of neutrophils), the percentage of bone marrow blasts and cytogenetic exam. It was found that this system prognostic allows a better classification of patients with MDS into risk groups. We analyzed 25 patients diagnosed with MDS, according to theWHO classification 2001, with low risk and intermediate-1 during the period 2008-2012. These patients have been hospitalized in three centers of Hematology Departments from Romania. Results: The lot of patients was evaluated according to R-IPSS (2012) and it was found that the new system allows a better prognosis estimation and more accurate patient risk group classification. Conclusions: Although according to IPSS (1997), all patients included in this studywere low risk (0-1) but applying the new scoring system has allowed a better classification of patients, six of them were with intermediate and high risk (3,5-6).

Treatment Outcomes with Pomalidomide (POM) in Combination with Low-Dose Dexamethasone (LoDex) in Patients with Relapsed and Refractory Multiple Myeloma (RRMM) and Del(17p13) and/or t(4;14)(p16;q32) Cytogenetic Abnormalities Who Have Received Prior Therapy with Lenalidomide (LEN) and Bortezomib (BORT)

Treatment Outcomes with Pomalidomide (POM) in Combination with Low-Dose Dexamethasone (LoDex) in Patients with Relapsed and Refractory Multiple Myeloma (RRMM) and Del(17p13) and/or t(4;14)(p16;q32) Cytogenetic Abnormalities Who Have Received Prior Therapy with Lenalidomide (LEN) and Bortezomib (BORT)

Molecular Aspects ofH. pylori-Related MALT Lymphoma

Helicobacter pylori-related extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue is a paradigm for malignancy arising in an inflammatory background. While the diagnosis of H. pylori gastritis is often straightforward, distinction between severe gastritis and early lymphoma can be difficult and requires careful assessment of clinical findings in addition to histological features and immunohistochemical results. A number of cytogenetic abnormalities have been discovered in H. pylori-related lymphomas and several have clinical importance, related to the responsiveness of lymphoma to H. pylori eradication therapy, but routine molecular studies are not widely utilized. While molecular methods may be used in equivocal cases, a trial of conservative therapy is warranted given the propensity for these lymphomas to regress with eradication of the organism. Once therapy is initiated, care must be taken to avoid a premature assignment of disease refractoriness because complete response can take several months to more than a year. Cases truly refractory to H. pylori eradication therapy may be treated with adjuvant chemoradiation with a high response rate.

C-MYC translocation in t(14;18) positive follicular lymphoma at presentation: An adverse prognostic indicator?

Follicular lymphoma (FL) is a common subtype of low grade B-cell non-Hodgkin lymphoma (NHL). Although this form of lymphoma often pursues an indolent course, in some cases it may behave in a more aggressive manner. Clinical and histological parameters have been shown to correlate with an adverse prognosis but a number of cytogenetic abnormalities may also be associated with aggressive disease. Although, the t(14;18) in itself does not affect outcome in cases of FL, secondary abnormalities that occur in a complex polyploid karyotype may identify cases with a poor prognosis. It is unusual to find both t(14;18) and C-MYC translocation in the same tumour; those cases in which it has been described include examples of high-grade B-cell NHL (either de novo or transformed FL) or B-cell acute lymphoblastic lymphoma. In this report, three cases of FL are described in which both t(14;18) and a C-MYC translocation were identified at presentation. We also summarize four further cases from the literature. This is a small series but one which raises the possibility that the presence of a C-MYC translocations at presentation may identify a particularly aggressive subtype of FL. Further studies are required to investigate the true incidence of this aberration, the impact on C-MYC regulation, clinical course and response to treatment.

The Occurrence of Mutations in PTPN11 and KRAS Is Not Dissimilar in Patients with Indolent Juvenile Myelomonocytic Leukemia (JMML) from Those with Clinically More Aggressive Disease.

Patients with JMML have a variable clinical course. Many have relentless myeloproliferation, irrespective of the initial therapy, and die rapidly if not successfully given a bone marrow transplant (BMT). Others partially respond to therapy with reduction in their leukocytosis and organomegaly, but with continued cytopenias. Finally, some children have a much more indolent clinical course, requiring little or even no therapy. A number of cytogenetic abnormalities are found in JMML, particularly monosomy 7. Molecular abnormalities have also been described including mutations in PTPN11, NRAS and KRAS, but it is not clear whether the karyotype and genotype are related to the phenotype. To address this issue, we studied 33 cases diagnosed between 1992 to 2007. All fulfilled the minimal diagnostic criteria for JMML. Three had Noonan syndrome (NS), and 1 a constitutional trisomy 8 mosaicism (CT8M). The remaining 29 had no known genetic syndrome. The median age at presentation was 15 months (0–96 months) and 22 (69%) were under 2 years of age. Patients were retrospectively allocated to 1 of 3 clinical groups. Group I (18 patients, 55%) had aggressive disease with minimal or no response to initial therapy. Group II (8 patients, 24%) had a partial response to therapy but persistent severe cytopenias or persistence of a monosomy 7 clone. All patients in Group I and II were scheduled to receive a BMT; this was carried out in 16 of 18 Group I patients and 7 of 8 Group II patients. A further 7 cases (Group III, 21%) had indolent disease with a median follow-up of 5 years (1–12 years). It is noteworthy that 2 of the 3 patients with NS were in this category. There was no difference at presentation in the clinical or diagnostic parameters between the 3 clinical groups. Cytogenetic analysis was available in 32 patients with 20 (63%) having a normal karyotype, 9 (28%) monosomy 7, 2 complex abnormalities and 1 CT8M. The presence of monosomy 7 was restricted to Groups I and II, but as this cytogenetic finding was used as an indication for BMT, limited conclusions can be drawn about the natural history of this subset. All Group III patients had a normal karyotype. Mutation screening using WAVE DHPLC analysis revealed 12 patients (36%), including the 3 NS patients, with PTPN11 mutations, 6 (18%) with NRAS and 8 (24%) with KRAS mutations. The total incidence of mutations was similar in the 3 clinical groups being 78%, 88% and 71% in Groups I, II and III respectively. KRAS mutations were not present in Group III patients, but this was not significant. Six of the 33 patients in this series, all in Group I, have transformed to an acute leukemia. Two had cytogenetic abnormalities although none had monosomy 7, 1 had a PTPN11 mutation, 2 an NRAS and 2 a KRAS mutation. Four out of 14 patients with a RAS mutation underwent transformation compared to 1 out of 12 of those with a PTPN11 mutation (p = 0.18). Of note, 1 patient with a KRAS G12S mutation was in Group II, which differs from the indolent course reported for this mutation by others. These results indicate that neither cytogenetic abnormalities nor specific mutations in PTPN11, NRAS or KRAS predict the clinical course of JMML. This study also raises the possibility that the clinical course is determined, in part, by cooperating mutations or polymorphisms that have not yet been identified.

Aflatoxin exposure and cytogenetic alterations in individuals from The Gambia, West Africa

Aflatoxin-albumin adducts in peripheral blood provide a measure of exposure to aflatoxin over the previous 2–3 months. In the present study, the levels of these adducts were determined in a group of individuals from The Gambia, West Africa and were compared in a cross-sectional study to the levels of various cytogenetic alterations (chromosomal aberrations, micronuclei, sister chromatid exchanges) in the same individuals to test whether an increase in genetic damage is associated with an increased exposure in this population. Of 35 subjects tested for aflatoxin-albumin adducts, all but 3 were positive. There were no correlations between the adduct level and the number of cytogenetic abnormalities at the individual level. A comparison of the cytogenetic alterations was made between Gambian individuals and a group of 22 healthy people from Italy where aflatoxin exposure is expected to be low. The levels of structural chromosomal aberrations, sister chromatid exchanges and micronuclei were all higher in the former group. Overall, these data are indicative of a higher exposure to genotoxins in Gambian subjects, one of which are aflatoxins, but suggest that more specific genetic markers of aflatoxin exposure are required to further examine the link between aflatoxin exposure and genetic alterations.