Prevalence and Prognostic Impact of CEBPA mutations in Children with AML Treated with the AIEOP-LAM 2002/01 Protocol.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2643-2643
Author(s):  
Giovanni Cazzaniga ◽  
Riccardo Masetti ◽  
Giulia Ferrari ◽  
Tiziana Coliva ◽  
Carmelo Rizzari ◽  
...  
Keyword(s):  
Overall Survival ◽  
Risk Group ◽  
Prognostic Impact ◽  
Granulocytic Differentiation ◽  
Free Survival ◽  
Cebpa Mutations ◽  
The Impact ◽  
Standard Risk ◽  
Improved Outcome

Abstract Abstract 2643 Poster Board II-619 C/EBP is a transcription factor that regulates terminal granulocytic differentiation. CEBPA mutations have been associated with improved outcome in both adult and pediatric patients with acute myeloid leukemia (AML). However, the impact in different treatment protocols, as well as the different outcome between single and double mutants, is still to be definitively established. We evaluated the prevalence and prognostic significance of CEBPA mutations in children with de novo non promyelocitic AML treated in Italy with the AIEOP-LAM 2002/01 pediatric protocol. Among 205 patients enrolled in the protocol between December 2002 and December 2007, 103 were successfully analyzed for CEBPA mutations by PCR amplification of TAD and bZIP domains of the gene, and through sequencing of positive cases after DHPLC analysis. Characteristics of analyzed and non analyzed patients were not statistically different. Two types of CEBPA mutations, N-terminal (TAD) truncating mutations and in-frame bZip domain mutations, were detected in 13/103 (12.6%) patients tested; 8 of them (61.5%) harboured both mutation types. Laboratory, clinical characteristics and outcomes for patients with CEBPA mutations were compared to those of patients with wild-type CEBPA. CEBPA mutations were significantly more common in older patients (8/13 vs 30/90 children were older than 10 years), in patients with FAB M1 (7/13 vs 4/90), and in patients with normal cytogenetics (13/13). None of the CEBPA mutated cases carried either FLT3 or NPM1 mutations. Only 1 mutated case was found in Standard Risk patients (defined as children carrying isolated CBF abnormality and achieving complete remission after 1 cycle of induction therapy), while the other 12 patients belonged to the High Risk group. Although the values did not reach statistical significance because of the low prevalence of CEBPA mutations, with a median follow up of 39 months (range 4–86) the event-free survival probability at 5 years was 76.9% vs. 59.6% for children with or without CEBPA mutations, respectively. The values for Disease-Free Survival were 83.3% vs. 65.4% and those for Overall Survival were 90.0%. 66.4%, respectively. No difference in terms of outcome was found between patient with a single and those with double mutants, neither between those with TAD- and bZIP- mutations. Therefore, patients in the AIEOP-LAM 2002/01 pediatric trial carrying CEBPA mutations seem to have a lower relapse rate and improved outcome, their overall survival approaching that of children belonging to the Standard Risk group (90% vs. 97%). If confirmed in a larger cohort of patients and with longer follow-up, these data suggest that CEBPA mutation analysis could be usefully employed to identify patients at lower risk of treatment failure and for allocating them into different classes of risk. Disclosures: No relevant conflicts of interest to declare.

High Dose Daunorubicin Improves Survival in AML up to Age 60, Across All Cytogenetic Risk Groups Including Patients with Unfavorable Cytogenetic Risk, and FLT3-ITD Mutant AML: Updated Analyses from Eastern Cooperative Oncology Trial E1900

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 373-373 ◽  
Author(s):  
Marlise R. Luskin ◽  
Ju-Whei Lee ◽  
Hugo F Fernandez ◽  
Hillard M. Lazarus ◽  
Jacob M. Rowe ◽  
...  
Keyword(s):  
Overall Survival ◽  
Induction Therapy ◽  
Risk Group ◽  
Multivariable Analysis ◽  
Risk Groups ◽  
Prognostic Impact ◽  
Npm1 Mutation ◽  
Mutation Status ◽  
The Impact

Abstract Background: Eastern Cooperative Oncology Group trial E1900 (E1900) showed that induction therapy with a high daily dose of daunorubicin (90 mg/m2) (DNR 90) improves survival in younger patients (pts) (<50 yrs) and intermediate (int) cytogenetic risk AML, but at 2 years of follow-up no benefit was seen in older pts (50-60 yrs), or in those with unfavorable cytogenetic risk or FLT3-ITD mutant AML (Fernandez et al. N Engl J Med 2009). Here we update results of E1900 with longer follow-up, focusing on the benefit of DNR 90 in cytogenetic and common molecular subgroups. Methods: Overall survival (OS) was measured from randomization for induction therapy to death from any cause (censored at last contact). Hazard ratios (HR) for death were computed using univariate and multivariable Cox proportional hazards models; multivariable Cox models were adjusted for sex, age, hemoglobin level, leukocyte count, platelet count, and cytogenetic profile. All conclusions regarding the impact of DNR 90, unless noted, are similar based on univariate and multivariable analysis. Results: Overall, 657 pts were enrolled with a median follow-up of 80.1 months. The HR for death in the DNR 90 group as compared with the standard-dose daunorubicin (45 mg/m2) (DNR 45) group was 0.74 (p=0.001). Pts <50 yrs benefited from DNR 90 (p = 0.002) while those >=50 yrs were not proven to benefit (p = 0.12). Pts with favorable (fav) and int. cytogenetic risk benefited from DNR 90 (p = 0.03 and p = 0.02, respectively). A benefit for pts with unfavorable cytogenetic risk was seen on multivariable analysis (p = 0.04). Impact of DNR 90 by mutation status: The 3 most common mutations were FLT3-ITD (24%), NPM1 (26%), and DNMT3A (24%). AML pts with any of these 3 mutations benefited from DNR 90 (p = 0.009, p = 0.002, and p = 0.02, respectively). FLT3-ITD pts who received DNR 90 had a 4-yr OS of 31%. Benefit was seen in pts age 50-60 with FLT3-ITD or NPM1 mutation (p = 0.02 and p = 0.04, respectively). No benefit of DNR 90 was seen in a small cohort of pts with MLL-PTD (p = 0.06). Benefit of DNR 90 in FLT3-ITD, NPM1, and DNMT3A mutant AML was confirmed in the int. cytogenetic risk group. Impact of DNR 90 on prognostic impact of NPM1: The presence of an NPM1 mutation conferred an improvement in OS in the DNR 90 group which was not seen in the DNR 45 group (p = 0.01 vs p = 0.3). This finding was confirmed in the int. cytogenetic risk group. Conclusion: With median follow-up of over 6 years on E1900, we confirm that DNR 90 improves outcome in pts with fav/int cytogenetic risk, DNMT3A or NPM1 mutant AML, or age < 50 (Patel et al. N Engl J Med 2012). Additionally, we now demonstrate that DNR 90 additionally benefits pts with FLT3-ITD AML, and pts with unfavorable cytogenetic risk, regardless of age. Moreover, we show that the favorable prognostic impact of the NPM1 mutation is only present when pts receive DNR 90. Given the benefit of DNR 90 across all cytogenetic risk groups as well as common molecularly defined subgroups of AML, DNR 90 should be the standard for all pts up to age 60 who are candidates for induction chemotherapy. Table HR for death by AML cohort. Subgroup N Univariate Model DNR 45 DNR 90 HR (DNR 90/DNR 45) & 95% CI Wald P All patients (n=657) Overall 330 327 0.74 (0.61, 0.89) 0.001 Age < 50 yrs³ 50 yrs 188 142 172 155 0.66 (0.50, 0.85) 0.81 (0.62, 1.06) 0.002 0.12 Cytogenetic Favorable Intermediate Unfavorable 38 232 59 51 212 63 0.51 (0.28, 0.93) 0.76 (0.61, 0.96) 0.79 (0.54, 1.16) 0.03 0.02 0.22 FLT3-ITD WT MUT 215 83 241 64 0.74 (0.59, 0.92) 0.61 (0.42, 0.89) 0.008 0.009 MLL-PTD WT MUT 290 16 296 15 0.70 (0.58, 0.86) 0.46 (0.21, 1.04) 0.0004 0.06 NPM1* WT MUT 180 65 192 65 0.70 (0.55, 0.89) 0.50 (0.32, 0.78) 0.003 0.002 DNMT3A WT MUT 177 61 194 58 0.66 (0.52, 0.85) 0.62 (0.41, 0.94) 0.001 0.02 * Statistically significant test of interaction (p<0.2) Figure 1A: Overall Survival by NPM1 Mutation Status and Treatment Arm Figure 1A:. Overall Survival by NPM1 Mutation Status and Treatment Arm Figure 1B: Overall Survival of FLT-ITD Mutant AML Patients by Treatment Arm Figure 1B:. Overall Survival of FLT-ITD Mutant AML Patients by Treatment Arm Disclosures No relevant conflicts of interest to declare.

scholarly journals Pharmacogenetic score predicts overall survival, progression-free survival and platinum sensitivity in ovarian cancer

2020 ◽  
Vol 21 (14) ◽  
pp. 995-1010
Author(s):  
Sara Gagno ◽  
Michele Bartoletti ◽  
Chiara Romualdi ◽  
Elena Poletto ◽  
Simona Scalone ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Germ Line ◽  
Risk Group ◽  
Prognostic Score ◽  
Progression Free Survival ◽  
High Risk Group ◽  
Free Survival ◽  
Estrogen Activity ◽  
The Impact

Aim: To define the impact of polymorphisms in genes involved in platinum-taxane and estrogen activity in the outcome of platinum-based treated ovarian cancer patients (OCP). Patients & Methods: Two hundred and thirty OCP were analyzed for 124 germ-line polymorphisms to generate a prognostic score for overall survival (OS), progression-free survival (PFS) and platinum-free interval (PFI). Results: ABCG2 rs3219191D>I, UGT1A rs10929302G>A and UGT1A rs2741045T>C polymorphisms were significantly associated with all three parameters (OS, PFS and PFI) and were used to generate a score. Patients in high-risk group had a poorer OS (hazard ratio [HR]: 1.8; 95% CI: 1.3–2.7; p = 0.0019), PFS (HR: 2.0; 95% CI: 1.4–2.9; p < 0.0001) and PFI (HR: 1.9; 95% CI: 1.4–2.8; p = 0.0002) compared with those in low-risk group. Conclusion: The prognostic-score including polymorphisms involved in drug and estrogen pathways stratifies OCP according to OS, PFS and PFI.

Increased Expression of Macrophage Migration Inhibitory Factor (MIF) Receptor CD74 Is Associated with Inferior Outcome in Younger Patients (Pts) with Cytogenetically Normal Acute Myeloid Leukemia (CN-AML): a Cancer and Leukemia Group B (CALGB) Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1616-1616 ◽  
Author(s):  
Eyal C. Attar ◽  
Kati Maharry ◽  
Krzysztof Mrózek ◽  
Michael D. Radmacher ◽  
Susan P. Whitman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cellular Proliferation ◽  
Conflicts Of Interest ◽  
Advanced Pancreatic Cancer ◽  
Disease Free Survival ◽  
Prognostic Impact ◽  
Free Survival ◽  
Expression Levels ◽  
The Impact ◽  
Disease Free

Abstract Abstract 1616 Poster Board I-642 CD74 is a type II integral membrane protein receptor that binds its ligand MIF to induce phosphorylation of the extracellular signal-regulated kinase-1/2 (ERK-1/2) and drive cellular proliferation via nuclear factor-kappa B (NF-kB) activation. CD74 expression has been identified in human solid tumors, and its expression is associated with adverse prognosis in advanced pancreatic cancer. As CD74 is expressed and NF-kB constitutively activated in myeloblasts, we hypothesized that CD74 expression might also be associated with adverse outcome in AML. To investigate the prognostic impact of CD74 expression in the context of other predictive molecular markers in CN-AML, we assessed CD74 expression levels by Affymetrix HG-U133 Plus 2.0 microarray in 102 younger [<60 years (y)] adults with primary CN-AML, treated on the front-line CALGB 19808 trial with an induction regimen containing daunorubicin, cytarabine, etoposide and, in some cases, the inhibitor of multidrug resistance valspodar, and consolidation with autologous stem cell transplantation. Microarray data were analyzed using the Robust Multichip Average method, making use of a GeneAnnot chip definition file, which resulted in a single probe-set measurement for CD74. At diagnosis, CD74 expression, when assessed as a continuous variable, was significantly associated only with extramedullary disease involvement (P=.006) among clinical features, and with none of the molecular prognostic variables tested, including NPM1, WT1, CEBPA, FLT3 (FLT3-ITD and FLT3-TKD) mutations, MLL partial tandem duplication, or differential BAALC and ERG expression levels. Although CD74 expression levels were not associated with achievement of complete remission (CR; 83% vs 81%), higher levels of CD74 were associated with shorter disease-free survival [DFS; P=.046, hazard ratio (HR) 1.85, 95% confidence interval (CI) 1.12-3.08] and with shorter overall survival (OS; P=.02, HR 1.32, CI 1.04-1.67). In multivariable analyses, higher CD74 expression was independently associated with shorter DFS (P=.045, HR 1.98, CI 1.16-3.40), after adjusting for WT1 mutations (P<.001) and FLT3-TKD (P=.04), and shorter OS (P=.01, HR 1.58, CI 1.11-2.25) after adjusting for FLT3-TKD (P=.02), WT1 mutations (P=.007), BAALC expression levels (P=.02), white blood counts (P=.007), and extramedullary involvement (P=.04). As quartiles 2-4 had similar expression levels distinct from the lowest quartile, to display the impact of CD74 expression levels on clinical outcome only, pts were dichotomized into low (the lowest quartile) and high (the top three quartiles) CD74 expressers. The Kaplan-Meier curves for DFS and OS (Figures 1 and 2) are shown below. In conclusion, our study identifies elevated CD74 expression as associated with adverse prognosis in younger CN-AML pts. Since we previously reported that higher CD74 expression was favorably associated with achievement of CR in AML patients receiving chemotherapy plus bortezomib, an inhibitor of the proteasome and NF-kB (Attar et al., Clin Cancer Res, 2008;14:1446-54), it is possible that in future studies elevated CD74 levels can be used not only for prognostication, but also to stratify CN-AML pts to study of bortezomib-containing chemotherapy regimens. Figure 1 Disease free survival Figure 1. Disease free survival Figure 2 Overall survival Figure 2. Overall survival Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of Early Switching to Nilotinib As Second Line TKI in Patients with Chronic Myeloid Leukemia Who Were Intolerant to, Suboptimal to and Failed Imatinib: The Thai Multi-Centered Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4267-4267
Author(s):  
Pongtep Viboonjuntra ◽  
Arnuparp Lekhakula ◽  
Kanchana Chansung ◽  
Chittima Sirijerachai ◽  
Pimjai Niparuck ◽  
...  
Keyword(s):  
Overall Survival ◽  
Adverse Events ◽  
Real Life ◽  
Progression Free Survival ◽  
Second Line ◽  
Free Survival ◽  
Kaplan Meier ◽  
Grade 3 ◽  
The Impact

Abstract Introduction : To date, the ELN recommendation and NCCN guidelines are the principle mile stones to follow up the treatment response and to make the decision of TKIs switching. However, in real life practice, many factors influence changing the real switching date from the date had an indication. This study aims to analyze the impact of early switching to second line TKI, nilotinib, in real life practice, for the CML patients who failed, had sub-optimal response or were intolerant to imatinib. Methods : This prospective study was conducted through 7 medical centers in Thailand between 1st of September 2009 and 31st of August 2011. Adult CML patients of age ≥ 18 years old, in chronic and accelerated phase, who had failure, suboptimal response or intolerance to imatinib, based on ELN 2009 guideline, were included and were eligible with nilotinib 400 mg twice daily. Prospective data collection for 24 months of each patient was performed. The main objective was to identify the impact of early switching to nilotinib on major molecular response (MMR). The other objectives were to observe the efficacy of nilotinib including overall survival, progression free survival and the safety. The survival results were presented as Kaplan-Meier survival curves. For the comparison of the treatment groups, the Kaplan-Meier estimator with the corresponding log-rank test for equality of survivor functions across treatment group was applied. Results : The final 108 cases were analysed. The median age was 47 (17-79) years with the proportion of male to female of 1.4:1 respectively. The median duration of the prior imatinib treatment was 18 months (2-142 months). The median duration between the date of indication and the date of real switching was 3.1 months (0-62.8 months) with 50% changing less than 3 months, 26.9% between 3 months and 12 months, and 23.1% changing longer than 12 months. The indication of switching included 63.6% failure to imatinib, 29% intolerance to imatinib and 7.4% suboptimal to imatinib. On the nilotinib switching, 70.4% completed 24 months follow-up, and 29.6% discontinued treatment mostly because of unsatisfactory results or adverse events. Evaluation was made every 3 months based on 2009 ELN recommendation. At 3 months, 57%, 20%, and 8% of the patients achieved CHR, CCyR and MMR, respectively. Those who did not achieve CHR at 3 months never achieved MMR, while 86 % of those who achieved CCyR at 3 months achieved MMR. All CML achieving MMR at 3 months had sustained MMR throughout the study period (24 months). Imatinib suboptimal response had better outcome than imatinib failure and imatinib intolerance groups. A preliminary analysis of BCR-ABL mutation was performed on 90 cases, and mutations were found on 21 cases. Two of them were T315I which were excluded from the study. The cases with mutation had poorer response to treatment than those without mutation. There was one case with initial G250E mutation developing T315I mutation after treatment with nilotinib. At 24 months, one case progressed to accelerated phase and 3 cases progressed to blastic transformation. The 2-year overall survival and 2-year progression-free survival and were 98.9% and 96.9% (figure 1 and 2), respectively. The interquatile analysis was done to identify the groups of cumulative MMR according to the duration between the date of indication and the date of real switching to nilotinib. The patients who switched to nilotinib within 12 months after date of indication could have a greater chance to achieved MMR than those who switched treatment later than 12 months (p(log-rank) = 0.002) (figure 3). Skin rash, musculoskeletal pain, and infection were the three most common non-hematologic adverse events, However, most of them were grade 1-2, except for 4 cases with grade 3-4 infections. Grade 3-4 hematologic adverse events included thrombocytopenia (12%), neutropenia (11%), anemia (5%) and leucopenia (4%), and most of them were manageable. Although biochemical abnormalities were commonly found, most of them were mild. Conclusions : Nilotinib, as a second line treatment showed excellent efficacy and tolerability. Indication for nilotinib treatment, initial mutation status and depth of response at 3 months after treatment can predict outcomes of the patients. However, the patients will have a greater chance to achieve MMR if they switched to nilotinib within 12 months after the date of indication for changing. Disclosures No relevant conflicts of interest to declare.

MicroRNA 181a (miR-181a) expression as a prognosticator in cytogenetically normal acute myeloid leukemia (CN AML)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7001-7001
Author(s):  
S. Schwind ◽  
G. Marcucci ◽  
K. Maharry ◽  
M. D. Radmacher ◽  
S. P. Whitman ◽  
...  
Keyword(s):  
High Risk ◽  
De Novo ◽  
Risk Group ◽  
Continuous Variable ◽  
High Risk Group ◽  
Prognostic Impact ◽  
Multivariable Analyses ◽  
The Mean ◽  
Cebpa Mutations

7001 Background: We showed recently that CEBPA mutations (mut) in CN AML are associated with better outcome and a unique microRNA expression profile, including miR-181a upregulation. Here we tested if miR-181a expression can predict outcome independently. Methods: We analyzed 187 de novo CN AML adult patients (pts) aged <60 years (y; median 45) similarly treated on CALGB 9621 and 19808. Of these, 122 had molecular high risk [FLT3-ITD or NPM1 wild type (wt)] and 65 low risk (no FLT3-ITD, NPM1 mut) CN AML. FLT3, NPM1, CEBPA, MLL, and WT1 mutations, and ERG and BAALC expression were analyzed centrally. miR-181a expression was measured in pretherapy marrow using OSUCCC v3.0 arrays. The mean of 2 miR-181a probe log intensities was used as a continuous variable for analyses. Results: Higher miR-181a levels (miR-181a↑) were associated with CEBPA mut, NPM1 wt, no FLT3-TKD, lower ERG expression, higher %FAB M1/M2, lower WBC and age, higher blood blasts, and lower % gum hypertrophy. miR-181a↑ tended to associate with more complete remissions (CRs; p = .07) and significantly associated with longer disease-free (DFS; p = .05) and overall (OS; p = .01) survival (median follow-up 6.5 y for pts alive). A stronger prognostic impact of miR-181a was observed in the molecular high risk group, where miR-181a↑ predicted more CRs (p = .03), and longer DFS (p = .0002) and OS (p = .0001). In multivariable analyses of the molecular high risk group, miR-181a↑independently predicted CR, and longer DFS and OS (Table). For descriptive purposes, we dichotomized pts at the median miR-181a expression value. For high v low miR-181a expressers, CR rates were 84% vs 72% and 5 y DFS and OS rates 43% vs 18% and 48% vs 19%, respectively. Conclusions: miR-181a expression is a prognostic marker in CN AML, mainly in the molecular high risk group, where it predicts outcome independently of other variables including CEBPA mutations. As miR-181a↑ confer better treatment response, novel approaches increasing miR-181a levels might benefit not only CN but also other AML pts. [Table: see text] No significant financial relationships to disclose.

Assessment of the treatment results in patients with breast cancer coexisting with pregnancy: A single-center observational study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e12566-e12566
Author(s):  
Anna Skrzypczyk-Ostaszewicz ◽  
Agnieszka I. Jagiello-Gruszfeld ◽  
Jerzy Giermek ◽  
Zbigniew Nowecki
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Cancer Diagnosis ◽  
Disease Free Survival ◽  
Breast Cancer Diagnosis ◽  
Diagnosis And Treatment ◽  
Free Survival ◽  
The Impact ◽  
Disease Free

e12566 Background: This study discusses the analysis of the prospectively collected material on pregnant patients treated for breast cancer at the Department of Breast Cancer and Reconstructive Surgery of the Maria Skłodowska-Curie National Oncology Institute - National Research Institute (until 2020: Oncology Center - Institute) in Warsaw, in the years 1995 - 2020. 84 patients were included into the final analysis and 72 children were assessed simultaneously. Methods: The paper summarizes information on the diagnosis and treatment of breast cancer during pregnancy, the course of pregnancy and childbirth and the birth parameters of children i.e. weight, length and Apgar score, as well as the dependencies between them, mainly the impact of some breast cancer, diagnosis and treatment process features on the newborns. The patietnt’s survavial - DFS ( disease free survival) and OS ( overall survival) - was also analyzed. The course of breast cancer diagnosis and treatment data were obtained from the patients’ medical documentation (medical records) and from information provided by the mothers during follow-up visits and read in the children's health books. In order to answer the research questions, statistical analyzes were conducted using the IBM SPSS Statistics 26 package. Results: In the analyzed period, the disease recurrence was recognized in 34 (40.5%) patients, and 24 (28.6%) patients died. The median disease-free survival (DFS) was 12.3 years (147.5 months), and the median overall survival (OS) was not reached during the follow-up period. The estimated 5-year survival rates for DFS and OS were 57.9% and 74.5% respectively, and for 10-year survival - 51.4% and 64.5%. The study showed a statistically significant relationship between the baseline clinical advancement and DFS. It has been also analyzed how the diagnosis, treatment and method of pregnancy termination changed in two time periods (1995-2012 and 2013-2020). There were no statistically significant differences in survival - both DFS and OS - between the group of patients treated before and after 2012. In the assessment of the impact of some factors on the birth children parameters (weight and length), statistically significant results were obtained for: pregnancy advancement at diagnosis, breast cancer stage at diagnosis, pregnancy advancement at the start of chemotherapy, the chemotherapy regimen (classic or dose-dense), the number of cycles of chemotherapy given during pregnancy, and the number of drugs used in supportive treatment. Conclusions: The entire analysis has become not only an insightful characteristic of the studied group, but also these results may be important in everyday clinical practice and may help to optimize the management of an extremely complex and difficult situation, which is the coexistence of pregnancy with a malignant disease that threatens the mother’s life.

Low Expression Of BCL11B Predicts Poor Overall Survival In Adult Standard Risk T-ALL

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1362-1362
Author(s):  
Isabelle Bartram ◽  
Nicola Gökbuget ◽  
Cornelia Schlee ◽  
Sandra Heesch ◽  
Lars Fransecky ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Poor Prognosis ◽  
Clinical Characteristics ◽  
Risk Group ◽  
High Expression ◽  
Prognostic Impact ◽  
Expression Levels ◽  
Standard Risk ◽  
Low Expression

Abstract Introduction Although risk stratification, detection of minimal residual disease (MRD) and implementation of novel therapeutic agents have improved outcome in acute lymphoblastic leukemia (ALL), survival in adult T-ALL patients still remains unsatisfactory. Therefore, new prognostic markers and potential therapeutic targets are warranted. BCL11B, a key player in normal T-cell development, has recently gained interest due to its high mutation rate (9-16%) in T-ALL. We investigated the frequency of BCL11B mutations, expression levels and the prognostic value in a large uniformly treated cohort of adult T-ALL. Patients and methods We analyzed bone marrow (BM) samples of 201 adult T-ALL patients sent to the reference laboratory of the German Multicenter Study Group for Adult ALL (GMALL). BCL11B expression was determined in 195 patients by qRT-PCR, BCL11B mutations were assessed in 178 patients by Sanger sequencing of exon 4 (including all 6 zink finger [ZF] domains). Low expression of BCL11B was defined by expression levels in the lowest quartile (BCL11Blow), high expression by levels in the three remaining quartiles (BCL11Bhigh). Samples had previously been characterized for expression of BAALC, IGFBP7, MN1, WT1, GATA3, ERG as well as for the mutations status of NOTCH1, WT1, and TCR rearrangements. Clinical data were available for 169 patients enrolled on the GMALL trials. We generated BCL11B associated gene expression profiles (GEP) derived from an independent set of 86 T-ALL patients enrolled in the Microarrays Innovations in LEukemia multicenter study. Results BCL11B was aberrantly expressed in adult T-ALL with significantly higher expression levels in thymic compared to early T-ALL (0.6 vs. 0.3, P=0.01). Expression of genes associated with a prognostic impact (BAALC, IGFBP7, ERG) or/and T-cell stage dependent expression profile (GATA3, IGFBP7) showed that BCL11Blow (n=49) had higher MN1 (1.6 vs, 0.3, P=0.01), IGFBP7 (1.3 vs. 0.5, P=0.02), and lower GATA3 expression (2.1 vs. 5.7, P<0.01) compared to BCL11Bhigh patients (n=146). This maturation stage specific expression of BCL11B was stressed by a higher rate of TCR rearrangement in BCL11Bhigh patients (73% vs. 27%, P=0.005) and further underlined by the BCL11B derived GEP linking low BCL11B to an immature molecular signature characterized by high expression of BAALC, IGFBP7, FLT3, CD34. Regarding clinical characteristics, low BCL11B expression was associated with a poor prognosis (5-year overall survival (OS): low 35% (n=40) vs. high 53% (n=129), P=0.02) in the overall T-ALL cohort. In the standard risk group of thymic T-ALL (n=102), BCL11Blow identified patients with an unexpected poor outcome (5-year OS: 20%, n=18) compared to BCL11Bhigh (62%, n=84, P<0.001). In addition, BCL11Blow thymic T-ALL patients showed a lower remission rate (5 years: 38% vs. 72%, P=0.02). BCL11B mutations were found in 24 of the 178 (13.5 %) T-ALL patients. In 9 patients, mutations resulted in frame shifts, whereas the remaining, except for a single one, missense mutations were located in the ZF domains: three resulting in introduction of a stop codon. BCL11B mutations were enriched in the mature immunophenotype (thymic: 20%, mature: 8%, early: 3%, P=0.03). No differences were observed in mRNA levels for BAALC, IGFBP7, MN1, WT1, GATA3, ERG, but patients with BCL11B mutations were less frequently assigned to the BCL11Blow group compared to those with high expression (5% vs. 95%, P=0.02). Regarding the clinical characteristics, BCL11B mutations had no prognostic impact regarding OS, neither in the total T-ALL cohort (5-year OS: 56% vs. 48%, n.s.) nor in the thymic T-ALL subgroup (5-year OS: 65% vs. 51%, n.s). Conclusion Our data confirmingly show a high frequency of BCL11B mutations (13.5%) in the so far largest cohort of adult T-ALL patients. As loss of function mutations were restricted to functional ZF domains and recurrently occurred in thymic T-ALL, these data stress a potential pathogenetic role of BCL11B as T-cell specific transcription factor. Importantly, low expression was associated with poor prognosis; in particular in the standard risk group of thymic T-ALL, BCL11Blow is a novel marker that identifies patients with an unacceptable poor prognosis. These findings might help to improve risk stratification in a significant proportion of adult T-ALL patients, which fail to standard therapy despite the favourable immunophenotypic characteristics. Disclosures: No relevant conflicts of interest to declare.

Results of the ECOG E1900 Trial in Younger Adults with AML Using an Event Free Survival Endpoint Are Concordant with Results Based on Overall Survival: Potential for a Surrogate Endpoint to Facilitate Rapid Approval of Therapies in AML

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2599-2599 ◽  
Author(s):  
Marlise R. Luskin ◽  
Ju-Whei Lee ◽  
Hugo F. Fernandez ◽  
Hillard M. Lazarus ◽  
Jacob M. Rowe ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Treatment Failure ◽  
Induction Treatment ◽  
High Dose ◽  
Event Free Survival ◽  
Npm1 Mutation ◽  
Free Survival ◽  
The Impact

Abstract Background: Novel therapies are required to improve the outcome of patients with AML. New agents are asked to demonstrate an overall survival (OS) benefit before qualifying for FDA approval. The long duration of clinical trials required in order to achieve this endpoint hampers quick evaluation of candidate therapies, including novel agents. Identification of reliable surrogate endpoints for OS in AML is needed. Here we compare the results of therapy for patients with untreated AML ages 16-60 years on the Eastern Cooperative Oncology Group 1900 trial (E1900) of induction chemotherapy followed by consolidation and autologous transplant in order to evaluate the validity of an event free survival (EFS) endpoint as a surrogate for OS. Methods:OS was measured from randomization for induction therapy to death from any cause (censored at last contact). EFS was measured from randomization to induction treatment failure, relapse after compete response (CR), or death in remission (censored at last contact). Hazard ratios (HR) were computed using Cox proportional hazards models. The association between EFS and OS was evaluated using the Kendall tau-a rank correlation for censored data. Results:There were657 patients enrolled of which 426 patients relapsed or had induction treatment failure before death or date of last contact. Median EFS and OS were 8.0 months (95% CI, 6.3 to 9.7 months) and 23.6 months (95% CI, 16.9 to 23.6 months), respectively. With a median follow-up of 80.1 months, there is a statistically significant correlation between EFS and OS (Kendall tau-a = 0.467, 95% confidence interval (CI) = (0.425, 0.510), p<0.001). This correlation was similarly significant at a median follow-up of 25.2 months (Kendall tau-a = 0.361, 95% CI (0.323, 0.400), p <0.001) when the E1900 trial was originally reported (Fernandez et al. NEJM 2009). Key findings reported based on the original OS endpoint are similar when analyzed with an EFS endpoint (Table 1). High-dose daunorubicin (90 mg/m2) (DNR 90) confers both an EFS and OS benefit in patients aged < 50 years and patients with intermediate cytogenetic risk, and does not confer an EFS or OS benefit in older patients and patients with unfavorable cytogenetic risk, on univariate analysis. Divergent results are only seen in the small subset of favorable cytogenetic risk patients, where DNR 90 conferred an OS benefit (p=0.027) without an EFS benefit (p=0.32). Both EFS and OS endpoints consistently reflect the impact of mutation status on survival. The presence of a FLT3-ITD or DNMT3A mutation has a negative impact on both EFS and OS while an IDH2 mutation has a favorable impact on EFS and OS. The presence of a NPM1 mutation confers a favorable impact on EFS and OS in patients who received DNR 90 and did not impact EFS or OS in patients receiving standard-dose daunorubicin (45 mg/m2) (DNR 45). The presence of an IDH1 mutation does not impact EFS or OS. Conclusions:The results of E1900 demonstrating superiority of DNR 90 in AML induction in patients up to age 60 are concordant when using an EFS or OS endpoint. This is true for the group as a whole as well as for subgroups for which targeted agents are in development (FLT3/IDH2 inhibitors). Further investigation of whether EFS is a reliable surrogate for OS is warranted in AML. If confirmed, its use as a primary endpoint could be adopted by regulatory agencies in order to allow more rapid completion of clinical trials in AML and bring new therapies to AML patients in a timely fashion. Table 1. Results of E1900 based on an EFS endpoint versus an OS endpoint. Subgroup N OS HR (DNR 90/DNR 45) & 95% CI Wald P EFS HR (DNR 90/DNR 45) & 95% CI Wald P DNR 45 DNR 90 Age < 50 yrs ³ 50 yrs 188 142 172 155 0.66 (0.50, 0.85) 0.81 (0.62, 1.06) 0.002 0.118 0.64 (0.50, 0.82) 0.86 (0.67, 1.10) 0.0004 0.23 Cytogenetic Favorable Intermediate Unfavorable 38 141 59 51 127 63 0.51 (0.28, 0.93) 0.68 (0.50, 0.92) 0.79 (0.54, 1.16) 0.027 0.012 0.225 0.76 (0.44, 1.31) 0.63 (0.47, 0.83) 0.72 (0.49, 1.05) 0.32 0.001 0.09 Subgroup N OS HR (MUT/WT) & 95% CI Wald P EFS HR (MUT/WT) & 95% CI Wald P FLT3-ITD WT MUT 456 147 1.62 (1.31, 2.01) <.0001 1.48 (1.21, 1.82) 0.0002 DNMT3A WT MUT 371 119 1.30 (1.03, 1.65) 0.03 1.23 (0.98, 1.54) 0.07 IDH1 WT MUT 465 36 0.88 (0.59, 1.33) 0.55 0.91 (0.62, 1.34) 0.64 IDH2 WT MUT 451 50 0.63 (0.43, 0.93) 0.02 0.68 (0.48, 0.97) 0.03 NPM1 DNR 45 DNR 90 245 257 0.84 (0.61, 1.16) 0.60 (0.41, 0.89) 0.30 0.01 0.90 (0.66, 1.22) 0.59 (0.41, 0.84) 0.49 0.004 Disclosures No relevant conflicts of interest to declare.

Cytogenetic Evolution in Patients with IPSS Low and Intermediate-1 Risk. Study from the Spanish Group of Myelodysplastic Syndrome

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4649-4649
Author(s):  
Brayan Marcel Merchán ◽  
Margarita Ortega ◽  
María José Llamas-Poyato ◽  
Montserrat Cortés ◽  
Montserrat Arnan ◽  
...  
Keyword(s):  
Overall Survival ◽  
Population Distribution ◽  
Risk Group ◽  
Univariate Analysis ◽  
Normal Karyotype ◽  
Molecular Diagnostic ◽  
Kaplan Meier ◽  
Cytogenetic Analyses ◽  
The Impact

Abstract Cytogenetic abnormalities (CA) are the most important prognostic factor in MDS patients, nevertheless the incidence of CA at diagnosis is not higher than 50% and even less in lower risk patients. The acquisition of CA (ACA) has recently been reported as a frequent and poor prognostic event in patients with normal karyotype at diagnosis (Jabbour et al 2013). The aim of our study was to analyze in a large cohort of patients the incidence, characteristics, and prognosis of the ACA in patients with low and intermediate-1 IPSS risk at diagnosis. We retrospectively reviewed 254 adult patients from the Spanish Registry of MDS with IPSS low or intermediate-1 risk diagnosed between 1995 and 2013. In total 121 patients had at least two consecutive cytogenetic analyses during the follow up. The main end points were overall survival (OS) and AML evolution (TFS). Cytogenetic analyses were conducted on unstimulated bone marrow cells after culture (24–72 hours). The ISCN 2005 criteria were used for identification of abnormal clones. ACA was defined by structural change or gain in at least 2 metaphases and loss in 3 metaphases as proposed in previous reports. Differences among variables were evaluated by non-parametric tests. OS and TFS were analyzed by Kaplan-Meier curve. The median follow-up was 25 months (0-155). The median age at diagnosis was 71 years (26-87) and 28% of the patients were female. The IPSS risk group was low in 43% and intermediate-1 in 57% of the population. Distribution as the IPSS-R was very low 20%, low 42%, Intermediate-1 30%, poor 6%, and there were no cases with very poor risk. At diagnosis, 34.7% of patients had abnormal karyotype. ACA was detected in 16 patients (13,2%) after a median of 30 months (range, 5-165). The most common ACA identified were trisomy 8 as sole abnormality followed by chromosome 7 abnormalities in in 25% and 12.5% of patients, respectively. Of the 42 patients with CA at diagnosis, 12% developed new ACA while among 79 patients with normal karyotype at diagnosis, 14% developed ACA (p=0,7). The presence of ACA changed the IPSS-R risk group in 14 out 16 patients. Compared with patients without ACA, the presence of ACA was significantly associated with a lower hemoglobin level (Table 1). In univariate analysis, ACA was not apparently associated with a higher incidence of AML evolution as there were 2 out of 16 patients (12,5%) with ACA that developed AML while between the 105 patients without ACA, 11 developed AML (11,5%) (P=NS). At last follow-up, 34 (28%) patients died and the median OS for the entire cohort was 67 months (IC 95% 34-99). In Kaplan-Meier curve, the presence of ACA was associated with lower overall survival (median 67 months (95% CI: 34-99) than patients without ACA (median 140 months (95% CI 36,9.243) (P =0.01). In summary, the present analysis shows that, the ACA occurs in around 13% of cases, which is a lower frequency than previously reported in other series, and it may have impact in overall survival. Future studies should address the impact molecular alterations and somatic point mutations; molecular diagnostic may allow identified patients with higher risk to transformation. Table 1. Hematologic parameters at the time for the cytogenetic control. ACA (n= 16) NO ACA (n=105) P Hb g/dL 9,1 (5.8-11.9) 10,3 (5.6-17.7) 0.04 WBC × 109/L 3,15 (0.7-24.1) 4,1 (0.9-32) 0.85 Pla × 109/L 71 (16-127) 93,5 (4-574) 0.38 Blast × 109/L 6 (1-15) 2.4 (0-19) 0.09 Disclosures Valcárcel: Celgene: Honoraria, Speakers Bureau.

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