Genetic Risk Classification Research Articles

A cluster-randomised, parallel group, controlled intervention study of genetic prostate cancer risk assessment and use of PSA tests in general practice—the ProCaRis study: study protocol

IntroductionUnsystematic screening for prostate cancer (PCa) is common, causing a high number of false-positive results. Valid instruments for assessment of individual risk of PCa have been called for. A DNA-based...

Prognostic Utility of the European LeukemiaNet (ELN) Genetic-Risk Classification in Adults with De Novo Acute Myeloid Leukemia (AML): A Study of 1,550 Patients (Pts)

Abstract 414▪▪This icon denotes a clinically relevant abstractThe ELN standardized system for reporting cytogenetic and select molecular findings was created to enable comparisons of studies correlating treatment outcome with genetic data in AML (Döhner et al. Blood 2010;115:453). The ELN classification is based on published reports on prognostic import of cytogenetic and molecular alterations, but has not been tested in large cohorts of similarly treated AML pts, except for 1 study comprising ∼20% secondary AML pts (Röllig et al. JCO 2011;29:2758). Thus our goal was to assess the prognostic utility of the ELN classification in a relatively large cohort lacking the confounding effects of AML type (de novo v secondary) or different therapies [chemotherapy v allogeneic stem cell transplant (SCT)]. We analyzed 1,550 de novo AML pts (excluding AML M3, which is not part of the ELN classification) treated with cytarabine-daunorubicin-based chemotherapy on Cancer and Leukemia Group B frontline protocols; no pt received SCT in 1st complete remission (CR). Since consolidation therapy of younger [<60 years (y)] and older (’60 y) pts differed in intensity, we analyzed younger (n=818; median age 44 y, range 17–59) and older (n=732, median age 69 y, range 60–86) pts separately.The pts were classified into the 4 ELN Genetic Groups: Favorable (Fav), Intermediate I (Int I), Intermediate II (Int II) or Adverse (Adv). Younger pts were classified in the Fav Group twice as often and in the Int II and Adv Groups ∼30% less often than older pts (Table 1). Within the Fav Group, core binding factor AML [t(8;21), inv(16) or t(16;16)] was twice as common (P<.001) and NPM1-mut/FLT3-ITD– half as common in younger than in older pts. In the Int I Group, NPM1-mut/FLT3-ITD+ was more common in younger and NPM1-wt/FLT3-ITD– in older pts, whereas in the Int II Group, t(9;11) was twice more common in younger pts. In the Adv Group, pts with balanced cytogenetic abnormalities (abns), ie, inv(3) or t(3;3), t(6;9) and t(v;11)(v;q23), were mainly younger, and pts with –7 mainly older (Table 1).Table 1Distribution of ELN Groups and subsets in 818 younger and 732 older ptsGenetic Group SubsetYounger Pts %*Older Pts %*PFav4120<.001t(8;21)2213.01inv(16) or t(16;16)3312<.001NPM1-mut, no FLT3-ITD†2854<.001CEBPA-mut†1720.44Int I1819.64NPM1-mut &FLT3-ITD†5538.006NPM1-wt &FLT3-ITD†1012.85NPM1-wt, no FLT3-ITD†3550.01Int II1930<.001t(9;11)115.05Cytogenetic abns not classified as Fav or Adv8995.05Adv2231<.001inv(3) or t(3;3)83.03t(6;9)41.02t(v;11)(v;q23)156.01−5 or del(5q)33.78−7512.02abn(17p)00—Complex karyotype (≥3 abns)6575.04*For genetic subsets, % are calculated within each Genetic Group†Pts with cytogenetically normal AMLAfter a median follow-up for younger and older pts alive of, respectively, 7.6 y (range, 0.6–19.1) and 6.1 y (range, 2.3–16.4), CR rates, disease-free (DFS) and overall (OS) survival differed significantly across the ELN Groups in both age groups (Table 2, Fig. 1). Pairwise comparisons between individual ELN Groups also yielded significant differences for all of them, except for the comparison between the Int I and Int II Groups, which did not show significant differences for any outcome endpoint in older pts nor for CR rates or DFS in younger pts; OS of younger Int II pts was longer than OS of Int I pts (P=.02; Fig. 2). For each ELN Group, the outcome of older pts was worse than that of younger pts. We conclude that despite differences in frequencies of younger and older pts classified into Fav, Int II and Adv ELN Groups and subsets within these Groups, the ELN classification allows prognostic grouping of both younger and older de novo AML pts. It is hoped that new markers (eg, TET2, ASXL1 mut) will improve pt classification to ELN Int I and Fav Groups.Table 2Outcomes according to the ELN GroupsOutcomeFavInt IInt IIAdvPYounger pts, n=818n=339n=144n=156n=179CR rate, %96767950<.001DFS, median, y5.50.81.20.6.001OS, median, y11.51.22.10.8<.001Older pts, n=732n=145n=136n=222n=229CR rate, %83616339<.001DFS, median, y1.10.60.70.5<.001OS, median, y1.60.90.90.5<.001 [Display omitted] [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Evaluation of the New Genetic Risk Classification of the European LeukemiaNet Recommendations in 1,110 Patients with De Novo AML and Proposal of a Refined Version

Abstract 413 Background:The recently published recommendations for prognostication in AML (Döhner et al. for ELN, Blood 2010;115,453–474) were based on a review of the literature and included cytogenetics as well as NPM1, CEBPA and FLT3-ITD mutation status for risk stratification. We here aimed to evaluate the prognostic impact of this approach in an independent cohort. Patients: We started with a cohort of 1,428 adults with newly diagnosed AML, which were investigated by cytomorphology, immunophenotyping, cytogenetics, and molecular genetics. We first excluded patients with t(15;17) (n=59), therapy-associated AML (n=111) and secondary AML (n=148). Thus, 1,110 patients with de novo AML and cytogenetics available in all cases were further evaluated according to ELN criteria. The following molecular markers were investigated: NPM1 (1,064/1,110), FLT3-ITD (1,066/1,110), CEBPA (880/1,110), MLL-PTD (1,064/1,110) and RUNX1 (454/1,110). Results: Male/female ratio was 1.2 (598/512), median age was 66.6 years (range 18.3 – 100.4). According to the ELN proposal 297 (26.8%) pts were assigned to the favorable group (CBF leukemias, NPM1mut/without FLT3-ITD in normal karyotype (NK), or CEBPAmut in NK), 363 (32.7%) pts were classified as intermediate I (NPM1mut/FLT3-ITD+, or NPM1wt/FLT3-ITD+, or NPM1wt without FLT3-ITD; all NK), 249 (22.4%) as intermediate II (t(9;11) or cytogenetic abnormalities not classified as favorable or adverse), and 201 (18.1%) as adverse (inv(3)/t(3;3); t(6;9); t(v;11)(v;q23); −5 or del(5q); −7; abn(17p); complex karyotype, i.e. ≥ 3 chromosome abnormalities)). Evaluation according to these criteria revealed significant differences in overall survival between the favorable subgroup and all other subgroups (inter I p<0.001; inter II 0.008, adv <0.001). Also adverse vs all other subgroups (all p<0.001) differed significantly with respect to OS. However, no significant differences were observed between both large cohorts of inter I and inter II (together 55.1% of all pts). We therefore intended to revise the ELN criteria for better discrimination of the intermediate groups. In addition to ELN recommendations we considered a threshold of 0.5 for the FLT3-ITD ratio (mut/wt) which had been suggested more valid for prognostication than the mutation status per se. For the revised classification molecular markers were mandatory for all cases with intermediate risk cytogenetics. Therefore, 100 cases had to be excluded due to missing data. Thus, 1,010 pts were reclassified into our new subgroups defined as: favorable I: CBF leukemias; favorable II:NPM1mut or biallelic CEBPAmut (without any other molecular marker and no fav or adv cytogenetics); intermediate I:FLT3-ITD ratio <0.5 (without RUNX1 or MLL-PTD and no fav or adv cytogenetics); intermediate II:FLT3-ITD ratio ≥0.5 and/or RUNX1mut and/or MLL-PTD+ (and no fav or adv cytogenetics); adverse: as defined by ELN. Patients were distributed as follows: fav I: 68 (6.7%), fav II: 286 (28.3%), inter I: 157 (15.5%), inter II: 298 (29.5%), adv: 201 (19.9%). Fav I and fav II had no significant differences in OS (median n.r. vs 62.2 mo, n.s.) and therefore were grouped together as “favorable”. This finally leads to four different prognostic subgroups: favorable: CBF leukemias; NPM1mut or biallelic CEBPAmut, intermediate I:FLT3-ITD ratio <0.5, intermediate II:FLT3-ITD ratio ≥0.5 and/or RUNX1mut and/or MLL-PTD+, adverse. Patients were distributed as follows: fav: 354 (35.0%), inter I 157 (15.5%), inter II: 298 (29.5%), adv: 201 (19.9%). Median OS differed between all subgroups: fav 62.2, inter I 24.3, inter II 12.4, adv 8.7 mo. (fav vs inter I p=0.058, vs inter II <0.001, vs adv <0.001; inter I vs inter II 0.004, vs adv <0.001; inter II vs adv 0.039). Conclusion: The new ELN proposal for prognostication in de novo AML is based on cytogenetic and molecular genetic data. Based on this proposal we further improved prognostication in a series of 1,010 pts by integrating the following molecular markers besides cytogenetics: NPM1mut, biallelic CEBPAmut and FLT3-ITD ratio <0.5 for the favorable group and FLT3-ITD ratio ≥0.5, other CEBPAmut, MLL-PTD+, or RUNX1mut for the intermediate group, and adverse based on cytogenetics only. This refined version may contribute to a better risk assessment in de novo AML patients allowing to separate 4 subgroups with striking differences in OS. Disclosures:Alpermann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Long-Term Prognosis of Acute Myeloid Leukemia According to the New Genetic Risk Classification of the European LeukemiaNet Recommendations: Evaluation of the Proposed Reporting System

The current European LeukemiaNet (ELN) recommendations for acute myeloid leukemia (AML) propose a new risk reporting system, integrating molecular and cytogenetic factors and subdividing the large heterogenous group of intermediate-risk patients into intermediate-I (IR-I) and intermediate-II (IR-II). We assessed the prognostic value of the new risk classification in a large cohort of patients. Complete data for classification were available for 1,557 of 1,862 patients treated in the AML96 trial. Patients were assigned to the proposed genetic groups from the ELN recommendations, and survival analyses were performed using the Kaplan-Meier method and log-rank test for significance testing. The median age of all patients was 67 years. With a median follow-up of 8.3 years, significant differences between all risk categories were observed in patients age ≤ 60 years regarding the time to relapse, relapse-free survival, and overall survival (OS). Patients in the IR-II group had a better prognosis than patients in the IR-I group. The median OS times in young patients with favorable risk (FR), IR-I, IR-II, and adverse risk (AR) were 5.3, 1.1, 1.6, and 0.5 years, respectively. Separate analyses in the age group older than 60 years revealed significant differences between FR, AR, and IR as a whole, but not between IR-I and IR-II. In younger patients with AML, the ELN classification seems to be the best available framework for prognostic estimations to date. Caution is advised concerning its use for prospective treatment allocation before it has been prospectively validated. In elderly patients, alternative prognostic factors are desirable for further risk stratification of IR.

Genetics of chronic lymphocytic leukemia: genomic aberrations and V(H) gene mutation status in pathogenesis and clinical course.

The genetic characterization of chronic lymphocytic leukemia (CLL) has made significant progress over the past few years. While conventional cytogenetic analyses only detected chromosome aberrations in 40-50% of cases, new molecular cytogenetic methods, such as fluorescence in situ hybridization (FISH), have greatly enhanced our ability to detect chromosomal abnormalities in CLL. Today, genomic aberrations are detected in over 80% of CLL cases. Genes potentially involved in the pathogenesis were identified with ATM in a subset of cases with 11q deletion and p53 in cases with 17p13 deletion. For the most frequent aberration, the deletion 13q14, candidate genes have been isolated. Genetic subgroups with distinct clinical features have been identified. 11q deletion is associated with marked lymphadenopathy and rapid disease progression. 17p deletion predicts for treatment failure with alkylating agents, as well as fludarabine and short survival times. In multivariate analysis 11q and 17p deletions provided independent prognostic information. Recently, another important issue of genetic risk classification in CLL was identified with the mutation status of the immunoglobulin variable heavy chain genes (V(H)). CLL cases with unmutated V(H) show more rapid disease progression and shorter survival times. Whether CD38 expression can serve as a surrogate marker for V(H) mutation status is currently discussed controversially. V(H) mutation status and genomic abnormalities, such as 17p and 11q deletion, have recently been shown to be related to each other, but were of independent prognostic information in multivariate analysis. Moreover, genomic aberrations and V(H) mutation status appear to give prognostic information irrespective of the clinical stage and may therefore allow a risk assessment for individual patients early in the course of their disease.