Comprehensive Genetic Screening of Chronic Myelomonocytic Leukemias (CMML)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3811-3811
Author(s):  
Raphael Itzykson ◽  
Olivier Kosmider ◽  
Aline Renneville ◽  
Margot Morabito ◽  
Céline Berthon ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Conflicts Of Interest ◽  
Gene Dosage ◽  
Univariate Analysis ◽  
Continuous Variable ◽  
Prognostic Impact ◽  
Gene Dosage Effect ◽  
Disease Evolution ◽  
Mutational Status

Abstract Abstract 3811 Background: A large number of genes have been found mutated in CMML including 18 encoding signaling molecules (CBL, N/KRAS, JAK2, FLT3, KIT), epigenetic regulators (TET2, IDH1/2, DNMT3A, ASXL1, EZH2) transcription (RUNX1, NPM1) and splicing (SRSF2, SF3B1, U2AF1, ZRSR2) factors. We report the genotypic patterns, clinical correlates and prognostic impact of mutations in those 18 genes in a large cohort of CMML patients (pts). Methods: Bone marrow or peripheral CD14+ cells from 224 CMML pts from a non interventional study (n=186) or a phase II decitabine trial (n=38; Braun Blood 2011) were genotyped by mutation specific techniques and Sanger sequencing for up to 18 genes (depending on available material): TET2, IDH1, IDH2, DNMT3A, CBL, NRAS, KRAS, JAK2V617F, FLT3, KIT, NPM1, RUNX1, ASXL1, EZH2, SF3B1, SRSF2, U2AF1 and ZRSR2. The number of TET2 alleles with a functional Cystein Rich (CysR) domain (Delhommeau NEJM 2009) was predicted based on mutation type and zygosity, assuming that double mutations affect independent alleles. Overall (OS) and AML-free (AMLFS) survival were analyzed from the date of genotyping. Results: 224 CMML pts (152M/72F, median age 75y) were genotyped at diagnosis (37%) or after a median of 7.2 months of evolution (none had received hypomethylating agents [HMA] before genotyping); WHO diagnosis was CMML-1/2 in 78%/22%, 70% pts had normal karyotype, 22% had extramedullary disease (EMD); 13 pts had autoimmune manifestations (AIM). The most frequently mutated genes were TET2 (58%), SRSF2 (47%) and ASXL1 (38%). Mutations in RUNX1, CBL and NRAS were found in 14%, 11% and 10% of pts, respectively (resp). All other genes were mutated in <10% of pts. Only 5% pts lacked any mutation, and 70% had ≥2 mutated genes; TET2, IDH1 and IDH2 mutations, present in 64% of pts, were mutually exclusive. Mutations in splice and signaling genes were present in 63% and 35% of pts, with 2 mutated genes within each group in 3% and 2% pts, resp. ASXL1 mutations were less frequent in the presence of TET2 mutations (P<.0001). Significant mutual associations included ASXL1/RUNX1, ASXL1/NRAS, TET2/SRSF2, RUNX1/SRSF2 and U2AF1/IDH2. In multivariate analysis accounting for those interactions, TET2 status was the only independent predictor of hemoglobin values (median 10.2 vs 11.9 g/dL in wildtype [wt] vs mutated pts, P<.0001) with a gene dosage effect (P=.0003). Platelet counts were higher in JAK2V617F pts, and lower in pts with RUNX1, TET2 or SRSF2 mutations. WBC and monocyte counts were higher in pts with ASXL1 and NRAS mutations. EMD was associated to ASXL1, CBL, KRAS and JAK2 mutations. EMD, CMML-2 and abnormal karyotype were less frequent in TET2 mutated pts. All 13 pts with AIM had at least one mutated gene, with no specific genotype spectrum. With a median follow-up of 25.4 months, median OS and AMLFS were 32.2 and 28.0 months resp. In univariate analysis, OS was decreased in pts with IDH2 mutations (P=.04), and AMLFS was shorter in pts with NRAS (P=.04), RUNX1 (P=.03) and SRSF2 (P=.04) mutations. ASXL1 mutations markedly reduced OS (median 18.5 vs 35.7 months in wt pts) and AMLFS (median 12.5 vs 34.7 months, both P<.0001), with similar results in the 74 pts who received HMA during follow-up. In the 224 pts, there was no significant effect of overall TET2 status (wt vs mutated) on OS or AMLFS (both P=.09) but median OS was 29.3, 35.7 months and not reached in pts with 2 (57%), 1 (30%) and 0 (13%) TET2 alleles with a putatively functional CysR domain (P=.01). Similar differences were noted for AMLFS (P=.008). In multivariate analysis including peripheral blood counts, WHO classification, cytogenetics, disease evolution and therapy, ASXL1 was the only gene whose mutations independently predicted inferior OS (HR: 2.44, 95% CI: 1.36–4.37, P=.003)and AMLFS (HR: 2.54, 95% CI: 1.46–4.42, P=.001); SRSF2 mutations only predicted inferior AMLFS (HR: 2.05, 95% CI: 1.15–3.65, P=.02). The total number of mutated genes as a continuous variable, which was higher in ASXL1 mutated pts (mean 3.0 vs 1.8, P<.0001), was the only genetic variable to retain prognostic value when added to those models (OS and AMLFS both P<.0001). Conclusion: TET2, SRSF2 and ASXL1 are the most frequent mutated genes in CMML. The number and location of TET2 mutations may impact CMML presentation and outcome. The total number of mutated genes has the strongest prognostic relevance, but ASXL1 mutational status provides a robust surrogate prognostic marker for daily practice. Disclosures: No relevant conflicts of interest to declare.

ID1 Expression Correlates with CEBPA Mutational Status and Is Not An Independent Risk Factor in Cytogenetically Normal AML,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3554-3554
Author(s):  
Katharina Wagner ◽  
Frederik Damm ◽  
Michael A Morgan ◽  
Felicitas Thol ◽  
Haiyang Yun ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Prognostic Factor ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
High Expression ◽  
Prognostic Impact ◽  
Mutational Status ◽  
Negative Prognostic Factor ◽  
Cebpa Mutations

Abstract Abstract 3554 Background: Acute myeloid leukemia with normal karyotype (CN-AML) is a heterogenous disease. During the last years, mutations in several genes (e.g. NPM1, FLT3, CEBPA, WT1, IDH1, IDH2) have been identified which are involved in the pathogenesis of AML and affect the prognosis of these patients. Moreover, deregulated expression of genes such as MN1, BAALC, ERG and WT1 was demonstrated to be predictive of outcome in CN-AML. Recently, high expression of the ID1 gene was described as a negative prognostic factor in AML (Tang et al. Blood 2009, 114:2993–3000). Aims: We have shown that C/EBPα, a transcription factor encoded by the CEBPA gene, binds to a regulatory element in the promoter region of the ID1 gene and regulates ID1 expression in leukemic cells (Wagner et al. Proc Natl Acad Sci USA 2006, 103:6338–6343). Therefore, we wanted to analyze the prognostic impact of ID1 expression in CN-AML in the context of other molecular markers, in particular CEBPA mutations. Methods: ID1 expression was quantified normalized to ABL by real time RT-PCR in 269 patients (age 16–60 years) with CN-AML treated with intensive double induction and consolidation therapy within the AMLSG 295 and 0199 trials (NCT00209833). The patients were also analyzed for mutations in the genes NPM1, FLT3, CEBPA, WT1, IDH1 and IDH2. Median follow up was 79 months. Results: Expression of ID1 varied over a 3-log range. High expression of ID1 (ID1high, defined as > median expression level) was significantly associated with the presence of a FLT3 -ITD or an IDH2 mutation and WT1 wildtype. Moreover, ID1 expression was closely associated with CEBPA mutational status. Altogether, 41 patients (15%) harboured a CEBPA mutation (24 monoallelic and 17 biallelic mutations). ID1 expression in the CEBPA wildtype patients was significantly higher than in patients with monoallelic CEBPA mutations and these patients had a significantly higher ID1 expression compared to patients with biallelic CEBPA mutations (p = 0.001). ID1high patients had a trend to a lower complete remission (CR) rate (74% vs. 84%; p = 0.07), but in multivariate analysis only blast clearance on day 15 after induction 1, age and WT1 SNP rs16754 were independent predictors for the achievement of CR. In univariate analysis, ID1high patients had an inferior overall survival (OS) compared to patients with low expression (median OS 29 vs. 78 months, 5 year OS 39% vs. 53%, p = 0.026). ID1high status was an independent negative prognostic factor in multivariate analysis when analyzed together with NPM1, FLT3 -ITD, WT1, IDH1, IDH2, extramedullary disease and platelet counts (HR 1.51; 95% CI 1.06–2.19). However, when also CEBPA mutational status was entered into the model, ID1 expression lost its prognostic impact and the only independent prognostic factors were age, platelets, CEBPA mutations, NPM1 /FLT3 -ITD risk group and WT1 SNP rs16754. Likewise, ID1high patients had a trend to an inferior relapse-free survival (RFS; HR 1.36, 95% CI 0.96–1.93, p = 0.086) in univariate analysis. However, in multivariate analysis including CEBPA mutational status, ID1 expression had no impact on RFS and the only prognostic factors for RFS were NPM1 and CEBPA mutations and WT1 SNP rs16754. In CEBPA wildtype patients, ID1 expression had no impact on CR-rate, OS or RFS in univariate or multivariate analysis. Conclusions: CEBPA mutations seem to deregulate ID1 expression in CN-AML. Therefore, ID1 expression is not an independent prognostic factor in CN-AML. Disclosures: No relevant conflicts of interest to declare.

Evaluation of Exercise Capacity In Children with SCD by Six Minute Walk Test

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2664-2664
Author(s):  
Caterina Minniti ◽  
Shoaib Alam ◽  
Gregory J. Kato ◽  
Mehdi Nouraie ◽  
Craig Sable ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Exercise Capacity ◽  
Conflicts Of Interest ◽  
Strong Predictor ◽  
Univariate Analysis ◽  
History Of ◽  
Rate Of Decline ◽  
Changes Over Time ◽  
Minute Walk

Abstract Abstract 2664 Background: The six-minute walk (6MW) test is used in pediatrics in clinical practice and research to determine cardiopulmonary functional status. A change in 6MW may be affected by factors not strictly related to cardiopulmonary function, which may be different in different patient populations. In children and adolescents, age and height has been found to be a strong predictor of 6MW distance. We set out to study the effects of hematological and echocardiographic variables on 6MW distance in children with sickle cell disease (SCD) and its changes over time. Methods: We reviewed prospectively collected hematological, 6MW distance, and echocardiographic data from four hundred children with SCD (including 311 Hb SS or β0) and 69 controls (including 21 Hb AS) enrolled in PUSH (Pulmonary Hypertension and the Hypoxic Response in SCD). Subjects were evaluated at baseline and after 18–24 months, as per protocol. An un-encouraged 6MW was performed in children 5 years or older by trained personnel as per the guidelines of the American Thoracic Society. Subjects were studied at steady state, at least three weeks after any acute exacerbation of SCD. We used ANOVA for univariate analysis and stepwise linear regression for multivariate analysis. Results: Median (interquartile range) 6MW in severe SCD genotype (SS and S-β0) was 444 (399-508) and in controls was 495 meters (435-539) (P = 0.0002), while it was 461 meters (408-518) in milder SCD genotypes (P=0.2 for comparison with severe genotypes) (Table 1). In multivariate analysis, Hb, WBC and history of frequent pain episodes were significantly associated to distance of 6MW. Follow up 6MW obtained in 174 SCD subjects revealed a decline of 10% or more in distance in 22% of subjects with severe genotypes and 33% of other genotypes. The decline was more frequent in the subset of SS subjects with TRV>2.59 (40% vs 19%). CONCLUSION: Six minute walk distance is significantly shorter in children with SCD, even as young as 5 years of age, when compared to age and race appropriate controls, indicating early compromise of exercise capacity. SS and S-β-0 genotype subjects have more impairment of exercise capacity compared to milder genotypes. Predictors of 6MW distance are similar in SCD and non SCD subjects, which validates the use of this test in this patient population. Longitudinal changes in subjects with SCD are similar, with declines in about a quarter of the subjects. Patients with SS who have an elevated TRV have the highest rate of decline in 6MW. These results validate the use of 6MW as a tool for assessing exercise capacity in children with SCD. Disclosures: No relevant conflicts of interest to declare.

Analysis of Transfusion Dependency Development and Disease Evolution in Patients with MDS with 5q- and without Transfusion Needs at Diagnosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3180-3180
Author(s):  
Felix Lopez-Cadenas ◽  
Blanca Xicoy ◽  
Silvia Rojas P ◽  
Kaivers Jennifer ◽  
Ulrich Germing ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Board Of Directors ◽  
Research Funding ◽  
Statistical Significance ◽  
Univariate Analysis ◽  
Rank Test ◽  
Advisory Committees ◽  
Disease Evolution ◽  
Free Survival

Abstract Introduction: Myelodysplastic syndrome with del5q (MDSdel5q) is the only cytogenetically defined MDS category recognized by WHO in 2001, 2008 and 2016 and is defined as a MDS with deletion on the long arm of chromosome 5 and less than 5% of blast cells in bone marrow. It is known that for patients with MDSdel5q and transfusion dependence (TD), Len (LEN) is the first choice of treatment. However, data regarding factors that may impact on the development of TD or disease evolution in patients diagnosed without TD are scanty. In our study a retrospective multicenter analysis on patients with low-int 1 MDSdel5q without TD at diagnosis has been performed in order to answer these questions. Patients and methods: We performed a multicenter collaborative research from the Spanish (RESMD) and German MDS registries. Data from 153 low risk MDSdel5q without TD at diagnosis were retrospectively analyzed. Statistical analysis: Data were summarized using median, range, and percentage. The event of TD was defined as the development of TD according to the IWG criteria (2006) and/or the beginning of a treatment which could modify disease course (LEN or ESA). Transfusion or treatment free survival (TFS), overall survival (OS) and leukemia free survival (LFS) were measured from diagnosis to TD or treatment, the first occurred (or to last follow up if none), last follow up or death from any cause and evolution to AML, respectively. TFS, OS and LFS were analyzed using the Kaplan Ð Meier method. The Log-rank test was used to compare variables and their impact on survival for univariate analysis.Multivariate analysis was performed using Cox's proportional hazards regression model. For comparison of Kaplan Meier curves the long rank test was used, with statistical significance with p<0.05. Statistical analysis was performed using SPSS 20.0. Results: Main clinical and biological characteristics were summarizing in table 1. From the total of 153 patients, finally 121 were evaluable. During the study 56 patients (46.2%) became in TD and 47 (38.8%) did not develop TD but received a modified disease course treatment. In this sense, most of the patients developed relevant anemia regarding those data (103 out of 121 patients, 85%). Median time to TD or treatment (TFS) was 20 months (1-132) from diagnosis. Secondary MDS (p=0.02), thrombocytosis (>350 109/L) (p=0.007), and neutropenia (<1.5 x 109/L) (p=0.02) were associated with poorer TFS. Thrombocytosis and neutropenia retained statistical significance in the multivariate analysis (Table 2). Among the TD patients (N=56), 42 (75%) received treatment: 28 LEN, 7 ESA and 7 other treatments. Among patients that did not develop TD (N=65), 47 (72.3%) received treatment before TD development: 16 LEN, 28 ESA and 3 other treatments. In order to know the evolution of these patients, survival analysis was performed. Median follow up was 58.9 months among alive patients and 57% of them were alive at the time of the last follow up. Estimated OS at 2 and 5 years was 94% and 64%. Regarding Univariate analysis, platelet <100 x 109/L (p=0.03), patients older than 71 years (p=0.001), and progression into AML (p=0.02) were associated with poorer OS. On the contrary, patients who had received treatment showed better OS (p<0.0001). This benefit is more evident among patients receiving LEN, median OS for patients receiving LEN, ESA/other treatments and not treated group was 137 months (CI 95%: 59,4 -215,5), 99,3 months (CI 95%: 46,6 -152) and 57,9 months (CI 95%: 38,2 -77,6), respectively, p<0.0001 (Figure 1). In the multivariate analysis, patients older than 71 years and LEN treatment retained the statistical significant impact on OS (Table 2). Twenty-eight patients (23%) progressed into AML, median time to AML was 35 months (5-122). When univariate analysis was performed, variables with adverse impact on LFS were platelets <100 x 109/L(p=0.019), neutropenia < 0.8 x 109/L (p=0.026), an additional cytogenetic abnormality (p=0.013) while treatment with LEN had a favorable impact (p=0.035). In the multivariate analysis only the presence of additional cytogenetic abnormalities retained statistical significance (Table 2). CONCLUSIONS: Most of the patients with low risk del(5q) MDS and no TD at diagnosis developed symptomatic anemia very early after diagnosis (20 months). Carefully monitoring should be stablished in order to detect this time point. Outcome of this subset of patients could improve after target therapy. Figure 1 Figure 1. Disclosures Del Cañizo: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees. Díez Campelo:celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees.

Transfusion Need at Diagnosis or Its Development During the First Year of Diagnosis in Primary Myelofibrosis: Effect On Survival and Correlation with JAK2 and TET2 Mutational Status.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1909-1909
Author(s):  
Ayalew Tefferi ◽  
Sergio Siragusa ◽  
Rakhee Vaidya ◽  
Susan Schwager ◽  
Kebede Hussein ◽  
...  
Keyword(s):  
Median Survival ◽  
Conflicts Of Interest ◽  
Multivariable Analysis ◽  
Primary Myelofibrosis ◽  
First Year ◽  
Prognostic Impact ◽  
Mutational Status ◽  
Risk Patients ◽  
One Year

Abstract Abstract 1909 Poster Board I-932 Background: The International Prognostic Scoring System (IPSS) for primary myelofibrosis (PMF) utilizes five independent predictors of inferior survival; of these, a hemoglobin level <10 g/dL has the highest impact on survival (Cervantes et al. Blood 2009;113:2895). In the current study, we examined the additional prognostic impact of transfusion need at diagnosis or becoming transfusion-dependent in the first year of diagnosis. These events were also correlated with JAK2 or TET2 mutational status. Methods: Patients were selected from the Mayo Clinic PMF database based on availability of bone marrow histology and IPSS-relevant information at diagnosis and follow-up transfusion history at one year from diagnosis. WHO criteria were used for PMF diagnosis. Patients who underwent allogeneic hematopoietic cell transplantation were censored at time of transplant. Patient records were updated in July, 2009. Survival curves were constructed using the Kaplan-Meier method and compared by the log-rank test. Multivariable survival was analysed using Cox regression model. Results: A consecutive cohort of 254 patients was studied (median age 59 years; range 28-87; 159 males). IPSS risk category was low, intermediate (int)-1, int-2 and high in 75, 71, 62 and 46 patients, respectively. JAK2V617F was present in 118 (62%) of 192 patients and TET2 mutations in 6 (13%) of 45 patients evaluated. Transfusion need at diagnosis was documented in 62 patients whereas an additional 22 patients became transfusion-dependent during the first year of their diagnosis. The remaining 170 patients remained transfusion-independent for at least one year post-diagnosis. To date, 139 patients have died. In patients who are alive, median follow-up was 5.3 years. Median survivals in IPSS high, Int-2, Int-1 and low risk patients were, 3, 3.9, 6.8 and 12.8 years, respectively (p<0.0001). Median survival for patients requiring transfusions at diagnosis was similar to that of patients who became transfusion-dependent in their first year of diagnosis, and both were significantly shorter than the median survival seen in patients who remained transfusion-free during the first year post-diagnosis: 2.9, 2.2 and 9.7 years, respectively (p<0.0001; figure). Multivariable analysis confirmed the IPSS-independent prognostic value of transfusion status-based risk stratification. Neither JAK2 nor TET2 mutational status correlated with transfusion need. Conclusions: In PMF, becoming transfusion-dependent in the first year of diagnosis is prognostically as detrimental as requiring transfusions at initial presentation. These events are not affected by JAK2 or TET2 mutational status and confer an IPSS-independent adverse prognosis. The ability to identify Int-1 risk patients with shortened survival (Figure) holds major treatment implications. Disclosures: No relevant conflicts of interest to declare.

MicroRNAs in Intermediate Risk Cytogenetic Acute Myeloid Leukemia Add Relevant Prognostic Information to Molecular Categorization

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 235-235
Author(s):  
Marina Díaz-Beyá ◽  
Alfons Navarro ◽  
Tania Díaz ◽  
Marta Pratcorona ◽  
Maria Rozman ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Mirna Expression ◽  
Conflicts Of Interest ◽  
Detection System ◽  
Intensive Therapy ◽  
Molecular Characteristics ◽  
Prognostic Impact ◽  
Intermediate Risk ◽  
Prognostic Information ◽  
Mutational Status

Abstract Abstract 235 The prognosis of AML patients within the intermediate cytogenetics category is mainly determined by the mutational status of some relevant genes, such as NPM1 mutations (NPMmut), or biallelic CEBPA mutations (CEBPAmut), associated with a favorable outcome, and with the presence of FLT3 internal tandem duplication (FLT3-ITD), which correlates with an adverse prognosis. Nonetheless, additional biological features such as microRNA (miRNA) expression pattern might contribute to refine prognosis and guide therapy in this setting. The aim of the present study is to investigate whether miRNA expression is associated with molecular characteristics and clinical outcome in intermediate-risk AML patients (IR-AML). We have analyzed samples from 85 IR-AML patients (median age, 52 [range, 18–71]; 52% males) who received intensive therapy from 1994 to 2009. Forty-three patients (51%) harbored NPMmut, 37 (44%) harbored FLT3-ITD (including 23 with NPMmut), and 11 (13%) harbored CEBPAmut, including 7 with biallelic mutations. The expression of 670 mature miRNAs was analyzed by multiplex Real Time PCR using TaqMan Human MicroRNA Arrays (Applied Biosystems). All PCR reactions were performed using an ABI 7900 HT sequence detection system. miRNA expression data was analyzed by the 2−DDCt method, using RNU48 as endogenous control. Statistical analysis was performed with BRB Array Tools, SPSS version 15.0.1 and R software version 2.9.0. Supervised analysis by means of t-test based on multiplex permutations (class comparisons analysis, p<0.001) revealed a distinctive miRNA signature in patients with NPMmut, with overexpression of miR-10a, miR-10a*, miR-10b and miR-196b, and downregulation of miR-126, miR126*, miR-424, miR-424* and miR-335, as well as patients with biallelic CEBPAmut, characterized by downregulation of miR-196b and upregulation of miR-181a. Response rate in this series of patients was 84%, with 5-year survival of 43±11% and relapse incidence (RI) of 55±14%. Multivariate analysis for overall survival(OS) including NPM status, FLT3-ITD status, age, WBC, and Log Rank OS significant miRNAs (miR-632, miR-23b, miR-409-3p, let-7a*, miR-565 and miR-196b) identified age, absence of NPMmut, and FLT3-ITD as unfavorable variables together with low expression of miR-409-3p (p<0.001; HR=3.3, 95% CI: 1.7–6.4), and increased level of let-7a* (p=0.026; HR=5.1, 95% CI: 1.21–21.5) and miR-196b (p=0.056; HR=7.27, CI: 0.95–55.6). Concerning risk of relapse (RR), multivariate analysis including NPM status, age, FLT3-ITD, WBC, and Log Rank RR significant miRNAs (miR-632, miR-155*, miR-135a, miR-409-3p, miR-150, miR-23a* and miR-363) the absence of NPMmut, FLT3-ITD and increasing leukocyte count were associated with a higher RI. Remarkably, decreased miR-409-3p expression (p=0.011; HR=3.3, 95% CI: 1.3–8.2) and miR-135a (p=0.02; HR=4.2, 95% CI: 1.2–14.2), together with higher levels of miR-23a* (p<0.001; HR=6.2, 95% CI: 2.61–14.7) were independently associated with a higher relapse risk. Of note, a decreased miR-409-3p level retained its adverse prognosis value in the subgroup of patients without favorable molecular markers (i.e., wild-type NPM1 and CEBPA and/or FLT3-ITD;p=0.001) together with low miR-361-3p (p=0.013, HR= 2.4, CI: 1.2–5.1). On the contrary, let-7a* levels segregated subgroups of patients in the category of favorable genotype (i.e., mutated NPM1 without FLT3-ITD p=0.027). In this series of patients of intermediate-risk cytogenetic AML, measurement of expression levels of several miRNAs such as miR-409-3p, miR-135a, let-7a* or miR-23a* showed independent prognostic value, and contribute to predict the outcome within specific molecular subgroups. Nonetheless, confirmation of the prognostic impact of these miRNAs and investigation of possible underlying mechanisms account for this effect require future studies. Disclosures: No relevant conflicts of interest to declare.

What Is the Appropriate Dose Attenuation System of RCHOP for Elderly DLBCL Patients? - A Single Institutional Analysis in 115 Cosecutive Patients From Japan -

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3639-3639
Author(s):  
Akira Tanimura ◽  
Risen Hirai ◽  
Atsushi Sato ◽  
Miki Nakamura ◽  
Masataka Takeshita ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Elderly Patients ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Age Related

Abstract Abstract 3639 Background: The combination therapy of RCHOP [rituximab (R), cyclophosphamide (CY), doxorubicin (DOX), vincristine (VCR), and prednisone (PSL)] is a standardized treatment for diffuse large B-cell lymphoma (DLBCL). However, its clinical outcome is worse in elderly patients because of comorbidities, age-related decrease in organ function, and impaired drug metabolism. If possible, the dose of RCHOP in elderly patients and patients with comorbidities should be adjusted appropriately. Since 2005, we have used a unified dose attenuation system for RCHOP according to the age and comorbidities of patients. This study retrospectively verified this system. Patients/Methods: We analyzed 115 consecutive DLBCL patients treated at our institute from September 2001, when rituximab was approved in Japan, to December 2010. From September 2001 to August 2005, 33 patients received dose adjustment of RCHOP according to the physician's discretion (PHY group). From September 2005, 82 patients received RCHOP according to the unified dose attenuation system (UNI group). In the UNI group, patients younger than 60 years received the standard RCHOP dose [R, 375 mg/m2; CY, 750 mg/m2; DOX, 50 mg/m2; VCR, 1.4 mg/m2 (max 2.0 mg/body); PSL, 100 mg/m2]. In patients older than 60 years, the doses of CY, DOX, VCR, PSL, and R were attenuated as shown in Table 1. In addition to age, the doses of CY, DOX, and VCR were adjusted according to organ functions (Table 2). The two groups were compared statistically. Results: The median age of patients was 70 years (range, 38–91), with 70.4% of patients classified as stage III or IV DLBCL, 40.4% with an international prognostic index (IPI) score of 0–2, and 70.2% with a ECOG performance status (PS) of 0 or 1. Low serum albumin levels (under normal range) were observed in 50.5% patients, and a high Charlson comorbidity index (CCI) score of >1 was found in 58.3%. The characteristics of the patients in the two groups were almost similar. The UNI system was completed in 94% of patients. The complete response (CR) rate was 63% in all patients (UNI group, 73%; PHY group, 39%; P = 0.0006). Univariate analysis revealed that better prognostic factors for CR were a low IPI score, better PS, and the UNI group. In the multivariate analysis, only the UNI group was a significantly better prognostic factor for CR. With a median follow-up of 26 months, the 5-year event-free survival (EFS) and overall survival (OS) were 39.3% and 68% in all patients, 43% and 72% in the UNI group, and 27% and 59% (5-year EFS; P = 0.0083, 5-year OS; P = 0.16) in the PHY group, respectively. Multivariate analysis showed that better prognostic factors for EFS were a low IPI score, a low CCI score, and the UNI group, and that for OS were low IPI and low CCI scores. In elderly patients aged >70 years (N = 59), the CR rates were 81% and 13% in the UNI and PHY groups, respectively (P = 0.0004), with OS in the UNI group being longer than that in the PHY group (72% vs. 59%; P = 0.02; Fig.1). In the UNI group, patient age did not affect the CR rate (<70, 71% vs. 70–79, 83% vs. >79, 79%; P = 0.56) or 5-year OS (<70, 76% vs. 70–79, 70% vs. >79, 66%; P = 0.58). The actual dose of CY, DOX, and VCR compared with the standard RCHOP dose was 64% and 26%, 63% and 16%, and 63% and 21% in the UNI and PHY groups, respectively. Disease progression during treatment, discontinuation of therapy, and death during treatment were observed in 10% and 15%, 5% and 24%, and 5% and 3% in the UNI and PHY groups, respectively. Nineteen patients (23%) from the UNI group died over a median follow-up of 15 months, while 15 patients (45%) of the PHY group died over a median follow-up period of 29 months. Lymphoma-related deaths were 12 (14%) in the UNI group and 8 (24%) in the PHY group. Five secondary primary malignancies (SPM) were observed (1 colon cancer and 1 breast cancer in the PHY group, and 1 lung cancer and 2 myelodysplastic syndrome in the UNI group). Four deaths were related to SPM. Conclusion: The unified dose attenuation system determined by the patients' age and comorbidities may achieve an effective dose level and better prognosis in elderly DLBCL patients. Disclosures: No relevant conflicts of interest to declare.

Genomic Aberrations Dramatically Improve The Strong Prognostic Impact Of IGHV Mutational Status In Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1370-1370
Author(s):  
Giovanni Del Poeta ◽  
Dario Ragusa ◽  
Francesco Buccisano ◽  
Michele Dal Bo ◽  
Luca Maurillo ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Sanger Sequencing ◽  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
Univariate Analysis ◽  
Intermediate Stage ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Mutational Status ◽  
Genomic Aberrations

Abstract CLL is a heterogeneous disease with patients (pts) experiencing rapid disease progression and others living for years without requiring treatment. Recently, next generation sequencing has revealed new molecular alterations, targeting the NOTCH1 and BIRC3 genes which occur in about 10% CLL at diagnosis and correlate with poor outcome. Given the possibility of targeting NOTCH1 and BIRC3 with drugs currently under development, the primary endpoints of our research were: 1) to determine overall survival (OS) upon IGHV, NOTCH1, TP53 and BIRC3 in univariate analysis; 2) to correlate these genomic aberrations with other biological or clinical prognostic factors, and finally 3) to confirm NOTCH1, BIRC3 and TP53 as independent prognostic factors. We investigated 475 pts with a median age of 65 years (range 33-89), whose 160 had low Rai stage, 301 intermediate stage and 14 high stage. NOTCH1 mutations (mut) were studied by ARMS PCR for c.7544-7545delCT and by Sanger sequencing of NOTCH1 exon 34. Mutations of TP53 were analysed by DNA direct sequencing, while BIRC3 disruption (disr) was studied by Sanger sequencing for mutations and by interphase FISH for deletions. All these alterations were studied at diagnosis or before any chemotherapeutic approach. NOTCH1mut and TP53mut pts were 52 (10.9%) and 36/475 (7.6%), respectively. Thirty four patients were BIRC3mut (7.2%) and 26 BIRC3 deleted (5.5%) for a total of 46 cases (9.7%) BIRC3disr. NOTCH1, TP53 and BIRC3 alterations were mutually exclusive. There were significant correlations between NOTCH1 (P<0.00001), TP53 (P=0.004), BIRC3 status (P=0.00004) and IGHV mutations. Concerning FISH cytogenetics (460 patients), a significant correlation (P<0.0001) was found between NOTCH1mut and trisomy 12 (20/62; 32%). TP53mut were strictly associated with del17p (15/25; 60%; P<0.0001), while BIRC3disr was found mainly within 11q22-q23 deletions subset (22/46;49%; P<0.0001). With regard to clinical outcome, 30 (83%) of 36 TP53mut pts (P=0.00009), 47 (90%) of 52 NOTCH1mut (P<0.00001) and 40 (87%) of 46 BIRC3disr pts had received chemotherapy at the time of analysis. Twenty nine NOTCH1mut (56%), 15 TP53mut (42%) and 18 BIRC3disr (39%) pts underwent at least two lines of treatment (P<0.0001). Noteworthy, shorter OS was observed in IGHV unmutated (UM) patients (12% vs 80% at 18 years, P<0.00001), in NOTCH1mut pts (12% vs 71% at 16 years, P<0.00001), in TP53mut pts (9% vs 76% at 14 years, P<0.00001) and in BIRC3disr pts (29% vs 65% at 16 years, P=0.00001). To further explore the prognostic impact of NOTCH1mut, TP53mut and BIRC3disr, we investigated them within the UM (153 pts) IGHV subset, notoriously at worst prognosis. As a matter of fact, NOTCH1mut (16% vs 45% at 14 years, P=0.012), TP53mut (0% vs 43% at 13 years, P=0.002) and BIRC3disr (0% vs 57% at 11 years, P=0.011) pts showed significant shorter OS [Figure]. Within the mutated IGHV subgroup we obtained similar results. In multivariate analysis of OS, TP53mut (HR 5.2, P<0.00001), age >60 years (HR 3.8, P=0.00002), IGHV UM status (HR 0.30, P=0.0001), intermediate/high Rai stages (HR 2.8, P=0.0002), NOTCH1mut (HR 2.6, P=0.001), and BIRC3disr (HR 2.5, P=0.005) were confirmed to be independent adverse prognostic factors. Noteworthy, here, we demonstrated that genomic aberrations are able to improve the historical prognostic ability of the IgHV mutational status. In conclusion, genomic aberrations, particularly TP53mut, NOTCH1mut and BIRC3disr should be considered as novel important prognostic parameters in CLL and therefore they have to be necessarily considered in updated scoring prognostic systems. Disclosures: No relevant conflicts of interest to declare.

Mutations of NOTCH1 Are An Independent Predictor of Survival in Chronic Lymphocytic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 283-283
Author(s):  
Davide Rossi ◽  
Silvia Rasi ◽  
Giulia Fabbri ◽  
Valeria Spina ◽  
Marco Fangazio ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Univariate Analysis ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Prognostic Role ◽  
Trisomy 12 ◽  
Notch1 Mutations

Abstract Abstract 283 The clinical course of chronic lymphocytic leukemia (CLL) ranges from very indolent, with a nearly normal life expectancy, to rapidly progressive leading to death and occasionally undergoing transformation to Richter syndrome (RS). TP53 disruption identifies a fraction of high risk CLL destined to experience a very short survival. High risk CLL, however, cannot be fully recapitulated by TP53 disruption and other lesions of cancer genes may be implicated in this aggressive phenotype. Analysis of the CLL coding genome has recently disclosed that the NOTCH1 proto-oncogene is recurrently mutated at CLL presentation. Here we assessed the prognostic role of NOTCH1 mutations in CLL. Two series of previously untreated CLL were utilized as training (n=309, median follow-up 6 years) and validation (n=230, median follow-up 7 years) cohorts. NOTCH1 mutations were analyzed by DNA Sanger sequencing in blind with respect to clinical data. In the training series, NOTCH1 mutations occurred in 34/309 (11.0%) patients, being mostly represented (26/34, 76.5%) by a recurrent two bp frameshift deletion (c.7544_7545delCT). The remaining NOTCH1 mutations (8/34, 23.5%) were frameshift deletions other than c.7544_7545delCT (n=7) and frameshift insertions (n=1). All mutations were predicted to disrupt the NOTCH1 PEST domain. CLL with NOTCH1 mutations preferentially carried unmutated IGHV genes (76.5%, p<.001). Other characteristics at presentation associated with NOTCH1 mutations were advanced Rai stage (26.5%, p=.006) and trisomy 12 (44.1%, p<.001). By univariate analysis, NOTCH1 mutations associated with an increase in the hazard of death (HR: 3.77; 95% CI: 2.14–6.66) and a significant overall survival OS shortening (p<.001) (Fig. 1A). Multivariate analysis selected NOTCH1 mutations as an independent risk factor of OS (HR: 4.22; 95% CI: 2.15–8.28; p<.001), after adjusting for age (p<.001), Rai stage (p=.005), IGHV mutation status (p=.465), 11q22-q23 deletion (p=.128), trisomy 12 (p=.183) and TP53 disruption (p<.001). The poor prognosis conferred by NOTCH1 mutations was attributable, at least in part, to a shorter time to progression requiring treatment (p<.001), and a higher cumulative probability of RS development (p=.026). Although NOTCH1 mutated patients were devoid of TP53 disruption in 31/34 (91.2%) cases, the OS predicted by NOTCH1 mutations was similar to that of TP53 mutated/deleted CLL (Fig. 1C). Analysis of the validation series confirmed: i) the prevalence of NOTCH1 mutations at CLL presentation (26/230, 11.3%); ii) the spectrum of NOTCH1 mutations at CLL presentation (c.7544_7545delCT: 21/26, 80.7%; other mutations: 5/26, 19.3%) iii) the adverse prognostic impact of NOTCH1 mutations in CLL both by univariate analysis (Fig. 1B) and by multivariate analysis (HR: 2.08; 95% CI: 1.10–3.93; p=.023); iv) the preferential mutually exclusive distribution of NOTCH1 mutations and TP53 disruption (25/26, 96.2%); v) that OS of NOTCH1 mutated CLL is similarly poor as that of TP53 disrupted CLL (Fig. 1D). The current study on 539 CLL documents that NOTCH1 mutations: i) represent one of the most frequent cancer gene mutations known to be involved at CLL presentation; ii) identify a subgroup of patients showing poor OS similar to that of TP53 disrupted cases; iii) exert a prognostic role independent of widely accepted clinical and genetic risk factors; iv) predict OS in series from different institutions, as documented by the training-validation approach chosen for the design of this study. Disclosures: No relevant conflicts of interest to declare.

Prognostic Significance of DNA/Cig Flow Cytometry Assay in the ‘'era” of Novel Therapies in Multiple Myeloma (MM).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2918-2918
Author(s):  
Xenofon Papanikolaou ◽  
Jackie Szymonifka ◽  
Susann Szmania ◽  
Katie Stone ◽  
Sarah Waheed ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Multivariate Analysis ◽  
Dna Content ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Flow Cytometric Analysis ◽  
Prognostic Impact ◽  
Prognostic Groups

Abstract Abstract 2918 Background: Genetic heterogeneity is a well-known characteristic of MM. Two broad subtypes, Hyperdiploid MM (>46) and Non Hyperdiploid MM (≤46), are defined by chromosome number and are each associated with a distinct prognosis. However, karyotype in MM is informative in no more than one-third of newly diagnosed cases. DNA flow cytometry has given excellent results in the quantification of the cell DNA content. Furthermore, the combined DNA and cytoplasmic Immunoglobulin (DNA/cIg) flow cytometric analysis offers a number of distinct advantages in the study of MM compared to other assays. The relative quantification of cIg is feasible even for cases of non-secreting MM, the characterization of the ploidy of that clone, or even the identification of more than one abnormal clone in the same monoclonal population based on differential DNA content. Methods: 480 patients that met the criteria for symptomatic or progressive MM were enrolled to the Total Therapy (TT) 3A & B protocols as previously published. The number of distinct DNA ploidy clones (NC) found on DNA/cIg analysis, their percentages and their respective DNA Index (DI) and cIg Index (cIgI), and percentage of cells in S phase, were evaluated alone and in relevance with known powerful prognostic parameters as previously published (Table 1). A DI between 0.99 and 1.01 referred to diploidy, lesser than 0.99 to hypodiploidy and more than 1.01 to hyperdiploidy. Cox proportional hazards regression was used to perform univariate and multivariate analysis of the various prognostic factors for overall survival (OS) and progression-free survival (PFS). Results: Of the total cohort of TT3 patients, 98% had DNA/cIg flow cytometry done on initial diagnosis. In 28%, no clone was identified; in 22% one clone, in 37% two clones, in 13% three clones and in 0.5% four clones were identified. Of 342 patients with at least one cell clone, hyperdiploidy was the feature of the dominant clone in 49% (169/342), diploidy in 42% (147/342) and hypodiploidy in 8% (26/342). The median values for DI and cIgI were 1.01 (0.72–2.02) and 3.4 (1.0–22), respectively. In the univariate analysis for OS, NC was highly significant (p<0.001, HR=1.32). The characterization of the ploidy of the dominant clone by DNA/cIg did not achieve statistical significance (p=0.172, HR=1.29). Nevertheless, when the DI of this clone was evaluated as a continuous numerical variable, DI>1 was statistically significant (p=0.021, HR=0.65). The same was also true for the cIgI of the dominant clone (p=0.019, HR=0.74). Regarding PFS, NC (p=0.005, HR=1.23), diploidy of the dominant clone (p=0.042, HR=1.40), the DI>1 of the dominant (p=0.006, HR=0.63) and the secondary (p=0.031, HR=1.58) clone as well as the cIgI of the dominant clone (p=0.037, HR=0.81) were statistically significant. In the multivariate analysis regarding OS, the NC was able to enter both models with and without GEP (p=0.007, HR=1.26 and p=0.002, HR=1.29 respectively). Regarding PFS, NC yielded similar results (p=0.054, HR=1.15 and p=0.013, HR=1.19 for the GEP including and non-including model respectively). Implementation of GEP and DNA/cIg was able to identify 3 distinct prognostic groups in hyperdiploidy both for OS and PFS (Figure 1). Conclusion: Hyperdiploidy is the most common ploidy status in MM. The level of cIg production has a prognostic impact in MM. Clonal heterogeneity as portrayed by the NC in DNA/cIg is a major prognostic factor in MM. When DNA/cIg is combined with GEP in hyperdiploid cases, it is able to stratify them into three distinct prognostic groups. Disclosures: No relevant conflicts of interest to declare.

Analysis Of Transfusion Dependence Development and Disease Evolution In Patients With MDS and Del(5q) and Without Transfusion Needs At Diagnosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1542-1542
Author(s):  
Silvia M Rojas ◽  
María Díez-Campelo ◽  
Elisa Luño ◽  
Teresa Bernal ◽  
Monica Cabrero ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Statistical Analysis ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Statistical Significance ◽  
Univariate Analysis ◽  
Disease Evolution ◽  
Free Survival ◽  
Kaplan Meier

Abstract Myelodysplastic syndrome with 5q- (MDS 5q-) is the only cytogenetically defined MDS category recognized by the world Health Organization (WHO) in 2001 and 2008 and is defined as a MDS with isolated deletion on the long arm of chromosome 5 and less than 5% of blast cells in bone marrow (BM). It is well known that for patients with MDS 5q- and transfusion dependence (TD), Lenalidomide is the first choice treatment. However, as far as we know there are no data regarding factors that may impact on the development of TD in these patients or the disease evolution in patients diagnosed without TD. In the present study a retrospective multicenter analysis on patients with low-int 1 MDS 5q- without TD at diagnosis has been performed in order to answer these questions. Patients and methods Data from eighty-four low-Int 1 risk MDS 5q- patients diagnosed between 1980 and 2012 were retrospectively analyzed. Ninety percent of patients had a single 5q deletion and according to IPSS-R 99% were in low and very low risk. Statistical analysis The event of TD was defined as the development of TD according to the IWG criteria (2006) and/or the beginning of a treatment which could modify disease course (Lenalidomide or ESA). Patients follow up was updated on March 30, 2013, and all follow up data were censored at that point. Transfusion free survival (TFS), Overall survival (OS) and AML were analyzed using the Kaplan – Meier method. TFS, OS, and Leukemia free survival (LFS) were measured from diagnosis to TD or to last follow up if transfusion free (TFS), death from any cause or last follow up (OS) and evolution to AML or last follow up (LFS). Multivariate analysis was performed using Cox’s proportional hazards regression model. Incidence of progression to AML was analyzed with cumulative incidence competing risk method. For comparison of Kaplan Meier curves the long rank test was used, with statistical significance with p<0.05 statistical analysis was performed using SPSS 15.0 and NCSS V.8, 2010. Results During the study 61 (73%) became TD at a median of 1.7 years from diagnosis. The unique factor associated with poorer TFS was Hb level <9 g/dl (p=0.007) and this impact retained statistical significance in the multivariate analysis (table.1) Among the 61 TD patients, 49 received treatment: 19 lenalidomide, 24 ESA and 6 other treatments. Fifteen patients were treated (7 with lenalidomide and 8 with ESA) previous to TD development. In order to know the evolution of this very good prognostic subgroup of patients, OS and LFS analysis were performed. Median follow up was 48 months, 46% of patients are alive at the time of the last follow up and 31% developed secondary AML (sAML). Estimated OS at 2 and 5 y was 92% and 50% respectively. Regarding Univariate analysis, platelet <100.000 x109/L, and IPSS-R intermediate risk group were associated with poorer OS (p=0.001 and 0.019 respectively). On the contrary, patients who had received treatment showed better OS. This benefit is more evident among patients receiving Lenalidomide (p=0.015). In the multivariate analysis platelets <100.000 x109/L and Lenalidomide treatment retained the statistical significant impact on OS (table1). When LFS was analyzed the cumulative incidence of progression into AML was 4,4% after 2 y. and 12,7% after 5 y from diagnosis with median time to sAML of 8.16 years (CI 95%: 6.05-10.27). LFS at 2 and 5 y was 86% and 73% respectively. When univariate analysis was performed variables with impact on sAML were platelet <100.000 x109/L (p=<0,001), and to have received treatment (p=0,02). In the multivariate analysis only thrombocytopenia retained statistical significance (table1).In summary, the present analysis shows that Hb is the only parameter that conditions the TD development in MDS-5q- patients. In this very good prognostic subgroup beginning treatment with lenalidomide improves survival. Disclosures: Díez-Campelo: Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen-Cilag: Research Funding. Off Label Use: In the present study we describe Lenalidomide treatment among patients with MDS and del(5q-) receiving this drug, not approval for this use in Europe, patients with anemia and transfusional requirements. Solé:Celgene: Consultancy, Honoraria; Celgene: Consultancy. Consuelo:Celgene Jansen-Cilag Arry Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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