Detection Rate of Integrated Molecular and Cytogenetic Biomarker Testing for Chronic Lymphocytic Leukemia

Abstract Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in western countries and typically occurs in elderly individuals. There will be an estimated 21,250 newly diagnosed cases in the United States this year and 4,320 deaths. Due to the highly variable clinical course of this disease, prognostication and risk stratification methods are necessary for guiding decisions on clinical management. Integrated prognostic models incorporating laboratory testing for multiple molecular, cytogenetic, and other biomarkers have recently been proposed by major clinical guidelines to classify patients into risk subgroups. The current NCCN Guidelines for Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia describe such an integrated prognostic model known as the Rossi model that includes TP53, NOTCH1, SF3B1, and BIRC3 mutations along with the cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) to classify CLL patients into 4 distinct prognostic subgroups: high-risk (TP53 and/or BIRC3 abnormalities), intermediate-risk (NOTCH1 and/or SF3B1 mutations and/or deletion 11q), low-risk (trisomy 12 and wild-type for all genetic lesions), and very low-risk (deletion 13q only). The 10-year survival rates for these subgroups are 29%, 37%, 57%, and 69%, respectively. To assess the clinical value of an integrated biomarker testing approach, we analyzed results of 651 consecutive cases submitted to our clinical diagnostic laboratory for testing on our integrated panel of molecular and cytogenetic biomarkers for CLL. Our panel includes detection of genomic alterations by FISH (deletion 6q, 13q, 11q, 17p, trisomy 12, IGH rearrangement, and IGH/CCND1 translocation) and detection of sequence variants in BIRC3, BTK, MYD88, NOTCH1, PCLG2, SF3B1, and TP53 by next-generation sequencing (NGS). In total, 472 cases had positive findings by either FISH (90%) or NGS (46%) for a detection rate of 72.5%. Using the Rossi integrated prognostic model, 17.5% of cases fell into the high-risk subgroup, 20% of cases fell into the intermediate-risk subgroup, 43.5% of cases fell into the low-risk subgroup, and 19% of cases fell into the very low-risk subgroup. Importantly, among cases with positive FISH findings, 40.1% of cases also had positive molecular findings. In approximately 84% of cases belonging to the low-risk cytogenetic subgroups by FISH assessment alone, the incorporation of molecular findings resulted in reclassification into a higher-risk subgroup. Among the FISH-negative cases, 17% were classified as high-risk or intermediate-risk based on the molecular findings. Together, these findings support the clinical value of an integrative biomarker testing approach that includes both molecular and cytogenetic biomarkers to stratify CLL patients into risk subgroups to help guide decisions on clinical management. Disclosures Prathapam: Quest Diagnostics: Current Employment. Maharjan: Quest Diagnostics: Current Employment. Powers: Quest Diagnostics: Current Employment. Freitas: Quest Diagnostics: Current Employment. Sun: Quest Diagnostics: Current Employment. Tan: Quest Diagnostics: Current Employment. Gupta: Quest Diagnostics: Current Employment. Hucthagowder: Quest Diagnostics: Current Employment. Graham: Quest Diagnostics: Current Employment. Whitman: Quest Diagnostics: Current Employment. Khadgi: Quest Diagnostics: Current Employment. Daniel: Quest Diagnostics: Current Employment. Racke: Quest Diagnostics: Current Employment. Champion: Quest Diagnostics: Current Employment.

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Association of Insurance Status and Marital Status with Outcomes of Patients with Chronic Lymphocytic Leukemia: A Population-Based Study

Blood ◽

10.1182/blood-2019-127756 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5459-5459

Author(s):

Yi Miao ◽

Wei Xu ◽

Lei Fan ◽

Jianyong Li

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Marital Status ◽

Survival Data ◽

Conflicts Of Interest ◽

Prognostic Index ◽

Lymphocytic Leukemia ◽

Low Risk ◽

Insurance Status ◽

Intermediate Risk

Introduction: Socioeconomic factors including insurance and marital status have impacts on the outcomes of cancer patients. Until now, there are few data regarding whether insurance status and marital status have effects on the outcomes of patients with chronic lymphocytic leukemia (CLL). In this study, the Surveillance, Epidemiology, and End Results (SEER) database was used to evaluate the prognostic roles of insurance and marital status in patients with CLL. Methods: Data from the SEER 18 Registries were used to conduct this study. Cases with newly-diagnosed CLL/small lymphocytic lymphoma (CLL/SLL) (International Classification of Diseases for Oncology, 3rd Edition [ICDO-3] codes 9823) in the time period between 2008 and 2015 were included. Exclusion criteria included history of cancer, unknown insurance status, unknown marital status, unknown survival data, unknown cause of death and survival months documented as 0. For each case we included age at the time of diagnosis, sex, marital status (married, divorced, single, widowed, unmarried or domestic partner, or separated), insurance status (Medicaid, insured, or uninsured), SEER cause-specific death classification, survival months and vital status. Survival curves were plotted by the Kaplan-Meier method and the log-rank test was used for comparison. P value was 2-sided and P<0.05 was considered to be statistically significant. All analyses were conducted using Graphpad Prism 6. Results: Atotal of 23,611 patients with CLL/SLL were included into the current analysis. The median follow-up was 34 months. We found that insurance status (uninsured or Medicaid) was significantly associated with decreased cancer-specific survival (CSS) (hazards ratio[HR]: 1.378, 95% confidence interval [CI]:1.251-1.664, P<0.0001) and overall survival (OS) (HR: 1.413, 95%CI:1.357-1.645, P<0.0001) (Figure 1A-B). Marital status (other than married) was also associated with decreased CSS (HR: 1.692, 95%CI:1.604-1.898, P<0.0001) and OS (HR: 1.791, 95%CI:1.757-1.968, P<0.0001) (Figure 1C-D). We then developed a prognostic index incorporating insurance status, marital status, and the well-known prognostic factor age (age≥65), with each risk factor being assigned 1 point. Four risk groups were generated: low (0), low-intermediate (1), high-intermediate (2), and high (3). The 5-year CSS rates for patients in low-risk, low-intermediate-risk, high-intermediate-risk, and high-risk subgroups were 94.2%, 85.8%, 77.7%, and 67.0%, respectively (P<0.0001) (Figure 1E). And the 5-year OS rates for patients in low-risk, low-intermediate-risk, high-intermediate-risk, and high-risk subgroups were 90.8%, 71.3 %, 55.7%, and 41.5%, respectively (Figure 1F) (P<0.0001). Conclusion: Insurance status and marital status have significant impacts on survival outcomes of patients with CLL/SLL. A 3-points prognostic index comprising insurance status, marital status and age could be used for risk stratification for patients with CLL/SLL. Figure 1 Disclosures No relevant conflicts of interest to declare.

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Prediction of Outcome in Patients With Chronic Lymphocytic Leukemia Treated With Ibrutinib: Development and Validation of a Four-Factor Prognostic Model

Journal of Clinical Oncology ◽

10.1200/jco.20.00979 ◽

2020 ◽

pp. JCO.20.00979 ◽

Cited By ~ 3

Author(s):

Inhye E. Ahn ◽

Xin Tian ◽

David Ipe ◽

Mei Cheng ◽

Maher Albitar ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Phase Ii ◽

Prognostic Model ◽

Risk Group ◽

Machine Learning Algorithms ◽

Lymphocytic Leukemia ◽

Low Risk ◽

Data Set ◽

Increased Risk

PURPOSE Randomized trials established the superiority of ibrutinib-based therapy over chemoimmunotherapy in chronic lymphocytic leukemia. Durability of progression-free survival (PFS) with ibrutinib can vary by patient subgroup. Clinical tools for prognostication and risk-stratification are needed. PATIENTS AND METHODS Patients treated with ibrutinib in phase II and III trials provided the discovery data set and were subdivided into discovery and internal validation cohorts. An external validation cohort included 84 patients enrolled in our investigator-initiated phase II trial. Univariable analysis of 18 pretreatment parameters was performed using PFS and overall survival (OS) end-points. Multivariable analysis and machine-learning algorithms identified four factors for a prognostic model that was validated in internal and external cohorts. RESULTS Factors independently associated with inferior PFS and OS were as follows: TP53 aberration, prior treatment, β-2 microglobulin ≥ 5 mg/L, and lactate dehydrogenase > 250 U/L. Each of these four factors contributed one point to a prognostic model that stratified patients into three risk groups: three to four points, high risk; two points, intermediate risk; zero to one point, low risk. The 3-year PFS rates for all 804 patients combined were 47%, 74%, and 87% for the high-, the intermediate-, and the low-risk group, respectively ( P < .0001). The 3-year OS rates were 63%, 83%, and 93%, respectively ( P < .0001). The model remained significant when applied to treatment-naïve and relapsed/refractory cohorts individually. For 84 patients in the external cohort, BTK and PLCG2 mutations were tested cross-sectionally and at progression. The cumulative incidences of mutations were strongly correlated with the model. In the external cohort, Richter’s transformation occurred in 17% of the high-risk group, and in no patient in the low-risk group. CONCLUSION Patients at increased risk of ibrutinib failure can be identified at treatment initiation and considered for clinical trials.

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International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia

Blood ◽

10.1182/blood.2019003453 ◽

2020 ◽

Vol 135 (21) ◽

pp. 1859-1869 ◽

Cited By ~ 7

Author(s):

Adalgisa Condoluci ◽

Lodovico Terzi di Bergamo ◽

Petra Langerbeins ◽

Manuela A. Hoechstetter ◽

Carmen D. Herling ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Risk Score ◽

Early Stage ◽

Prognostic Score ◽

Lymphocytic Leukemia ◽

Low Risk ◽

Intermediate Risk ◽

Early Stage Disease ◽

International Prognostic Score

Abstract Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials.

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Chronic Lymphocytic Leukemia: Evaluation of Cytogenetic Markers as Prognostic Factors

Blood ◽

10.1182/blood.v116.21.4860.4860 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4860-4860

Author(s):

Jose Carda ◽

Patricia Sousa ◽

Patricia Olim ◽

Emília Magalhães ◽

Luis Rito ◽

...

Keyword(s):

Overall Survival ◽

Prognostic Factors ◽

Retrospective Study ◽

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Progressive Disease ◽

Risk Group ◽

Staging System ◽

Lymphocytic Leukemia ◽

Intermediate Risk

Abstract Abstract 4860 Backgroud: Chronic lymphocytic leukemia (CLL) is one of the most frequent chronic lymphoproliferative disorders in Europe. It is characterized by persistent monoclonal lymphocitosis with localized or generalized lymphadenopathy. Despite the initial clinical presentation, it has a heterogeneous natural history, with the majority of patients living 10–12 years, but with some patients dying rapidly, within 2–3 years of diagnosis. Beside clinical prognostic factors, novel cytogenetic markers are recognized to be useful in predicting disease free and overall survival in CLL. AIMS: In a retrospective study throughout 10 years (1999-2009), we analyzed the clinical and biological presentation and compared the evolution and survival of patients with B-CLL using different cytogenetic markers. METHODS: We identified 112 cases (63 males and 49 females) of B-CLL with cytogenetic study by fluorescence in situ hybridization (FISH). RESULTS: Amongst 112 patients, the male to female (M/F) ratio was 1.3:1 and the median age was 70 (43-96) years. At diagnosis, the median lymphocyte count was 15.5 G/L (5.4-173). Fifty five patients (49%) had lymphadenopathies and seventeen (15%) had splenomegaly and/or hepatomegaly at presentation. By the revised Rai staging system seventy (63%) patients were included in low risk group, thirty (27%) in intermediate risk group and twelve (10%) in high risk group. The expression of ZAP-70 and CD38 by flow citometry was performed in 75 patients and revealed 13 (17%) patients CD38+ and 12 (16%) ZAP70+. The study of chromosomal aberrations with FISH showed thirty six patients (32%) with no abnormality, thirty six (32%) with isolated 13q deletion, fifteen (14%) with 12 trisomy, twelve (11%) with 11q deletion and thirteen (11%) with 17p deletion. Forty (36%) patients showed progressive disease in a median time of sixteen months (0-120), thirteen with 13qdel, seven with 17pdel and five with 12 trisomy. After treatment two patients showed progressive disease, six maintain a stable disease and thirty two obtain a remission, nine in complete remission. The Overall Survival (OS) at ten years was 70%. By the revised Rai staging system the OS at ten years was 80% for low risk, 70% for intermediate risk and all the high risk patients died during follow up. The OS at five years for the del13q-, 12 trisomy, del11q- and del17p- was 90%, 88%, 58% and 60%, respectively. SUMMARY: Chronic lymphocytic leukemia is currently considered a chronic disorder with a favourable outcome, but with a variable evolution to progressive disease. This retrospective study allowed the characterization of patient with CLL in our department and the acknowledgement that our results are quite similar to the published data. Disclosures: No relevant conflicts of interest to declare.

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Integrated Mutational and Cytogenetic Analysis Identifies New Prognostic Subgroups in Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v120.21.712.712 ◽

2012 ◽

Vol 120 (21) ◽

pp. 712-712

Author(s):

Davide Rossi ◽

Silvia Rasi ◽

Valeria Spina ◽

Alessio Bruscaggin ◽

Sara Monti ◽

...

Keyword(s):

High Risk ◽

General Population ◽

Life Expectancy ◽

Clonal Evolution ◽

Lymphocytic Leukemia ◽

Low Risk ◽

Risk Category ◽

Intermediate Risk ◽

Newly Diagnosed ◽

Risk Patients

Abstract Abstract 712 The identification of NOTCH1, SF3B1, MYD88 and BIRC3 genetic lesions in chronic lymphocytic leukemia (CLL) prompts a comprehensive and dynamic prognostic algorithm including gene mutations, chromosomal abnormalities, and their changes during clonal evolution. The study utilized both time-fixed (637 newly diagnosed CLL) and time-dependent (257 CLL provided with 524 sequential samples) approaches. Each sample was investigated for TP53, NOTCH1, SF3B1, MYD88, and BIRC3 mutations by Sanger sequencing and for 17p13, 11q22-q23, 13q14 and BIRC3 deletions and +12 by FISH. Del13q14 and +12 distributed in a mutually exclusive fashion (p<0.0001), and identified three main genetic subgroups: cases harboring del13q14, cases harboring +12 and cases lacking both del13q14 and +12. With the sole exception of the expected association between NOTCH1 mutations and +12 CLL (p=0.0014), the prevalence of the other genetic lesions did not differ among molecular subgroups. FISH abnormalities segregated patients in distinct prognostic groups according to Döhner (Fig 1A). Among new genetic lesions, survival analysis confirmed the independent prognostic value of NOTCH1, SF3B1 and BIRC3 lesions in this study cohort. MYD88 mutations had no prognostic effect (p=0.1728). Recursive partitioning analysis followed by random survival forest validation established the hierarchical order of relevance of the genetic lesions, and created an integrated mutational and cytogenetic (MUCY) model that classified newly diagnosed CLL into four prognostic subgroups (Fig 1B). High risk patients harbored TP53 disruption and/or BIRC3 disruption independent of co-occurring lesions (10-year survival: 29.1%). When the demographic effects of age, sex and year of diagnosis were compensated, the 10-year life expectancy of high risk patients was only 37.7% of that expected in the matched general population (p<0.0001). Intermediate risk patients harbored NOTCH1 and/or SF3B1 mutations and/or del11q22-q23 in the absence of TP53 and BIRC3 abnormalities (10-year OS: 37.1%). The 10-year life expectancy of intermediate risk patients was reduced to 48.5% compared to the matched general population (p<0.0001). The low risk category comprised both patients harboring +12 and patients wild type for all genetic lesions (i.e. normal) (10-year OS: 57.3%), with a 10-year life expectancy of 70.7% compared to the matched general population (p<0.0001). Very low risk patients harbored del13q14 as the sole genetic lesion (10-year OS: 69.3%), with a 10-year life expectancy only slightly (84.2%) and not significantly (p=0.1455) lower than that expected in the matched general population. Multivariate analysis selected the MUCY model as one of the most important independent risk factor of CLL OS (HR: 1.38; 95% CI: 1.18–1.60; p<0.0001; 99% bootstrap selection), along with age (HR: 1.06; 95% CI: 1.04–1.07; p<0.0001; 100% bootstrap selection), Rai stage (HR: 1.36; 95% CI: 1.23-1-51; p<0.0001; 100% bootstrap selection) and unmutated IGHV genes (HR: 1.63; 95% CI: 1.17–2.26; p=0.0039; 92% bootstrap selection). Overall, 21.5% (105/488) low risk patients according to the FISH model (del13q14, normal and +12) were reclassified into high risk genetic subgroups by the MUCY model because of the co-occurrence of NOTCH1 (64/488, 13.1%), SF3B1 (35/488, 7.1%), and TP53 (17/488, 3.4%) mutations or BIRC3 disruption (14/488, 2.8%). Consistently, the inclusion of NOTCH1, SF3B1 and BIRC3 lesions in addition to FISH abnormalities significantly improved the model accuracy of OS prediction (c-index: 0.617 vs c-index: 0.642 p<0.0001). At 10 years from diagnosis, 24.5% CLL of the very low and low risk genetic subgroups developed new TP53, NOTCH1, SF3B1, BIRC3 or del11q22-q23 lesions due to clonal evolution, and therefore switched to a higher risk category of the MUCY model. By time-dependent and landmark analysis, the MUCY model retained a statistically significant impact on CLL OS (HR: 1.52; 95% CI: 1.21–1.90; p=0.0003) at any time from diagnosis and independent of its dynamic changes due to clonal evolution. The MUCY model classifies CLL patients into more precise subgroups, advances our understanding of CLL biology, and improves current prognostic algorithms. These findings have relevant implications for the design of clinical trials aimed at assessing the use of mutational profiling to inform therapeutic decisions based on risk stratification. Disclosures: No relevant conflicts of interest to declare.

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External Validation On Biological Basis of New Prognostic Index in Early Asymptomatic Chronic Lymphocytic Leukemia (CLL) Patients: The Gruppo Italiano Studio Linfomi (GISL) Experience.

Blood ◽

10.1182/blood.v114.22.2375.2375 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2375-2375

Author(s):

Stefano Molica ◽

Sonia Fabris ◽

Giovanna Cutrona ◽

Massimo Gentile ◽

Emanuela Anna Pesce ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Risk Score ◽

Prognostic Index ◽

Lymphocytic Leukemia ◽

Low Risk ◽

Biological Parameters ◽

Cytogenetic Abnormalities ◽

Prognostic Relevance ◽

Binet Stage

Abstract Abstract 2375 Poster Board II-352 A prognostic index based on widely available clinical and laboratory features was recently proposed to predict survival in patients with previously untreated patients with chronic lymphocytic leukemia (CLL) by MD Anderson investigators. However, whether proposed clinical risk categories may surrogate new biological variables of prognostic relevance (i.e., mutational status of the IgVH gene regions, ZAP-70 or CD-38 expression, cytogenetic abnormalities) is unclear thus far. In a series of 160 asymptomatic Binet stage A patients enrolled in a Gruppo Italiano Studio Linfomi (GISL) multicentre trial designed to validate prospectively biological parameters in early CLL as well as to assess the impact on clinical outcome of an early versus delayed policy of treatment with subcutaneous alemtuzumab in the high biological risk, we evaluated whether clinical categories derived from newly proposed prognostic index reflected biological risk. Since the original prognostic index was derived from a database including cases with more advanced disease we used an optimal cutoff search to determine how to best split Binet stage A patients in different prognostic groups. To this purpose an independent patient cohort consisting of 310 Binet stage A patients included in a GIMEMA (Gruppo Italiano Malattie EMatologiche Maligne dell'Adulto) database was used. According to recursive partitioning (RPART) model, a classification tree was built that identified two subsets of patients who scored respectively: 0-3 (low risk) and 4-7 (high risk). Therefore, by prognostic index, 48.7% and 51.2% of 160 asymptomatic stage A patients, respectively, met criteria of low risk and high risk disease. In our prospective series high- risk score was more frequently associated with both unmutated IgVH status (P=0.009) and higher CD38-expression (P=0.002); in contrast only a trend towards an increased ZAP-70 expression could be found (P=0.06). As far as cytogenetic abnormalities are concerned, we observed that 11q deletion occurred more frequently among patients belonging to high-risk score (P=0.005), while cases with 13q deletion or trisomy 12 were homogeneously distributed among low- and high-risk patient category(P=0.151 and P=0.452, respectively). We did not consider suitable for correlation analysis 17p deletion since observed only in 2 out of 160 Binet stage A patients. In conclusion, our results demonstrate in a prospective cohort of patients with early CLL that clinical categories of a revised score index may surrogate biological parameters of prognostic relevance. The observation reinforces the revised IWCLL guidelines recommendations to assess the risk of CLL patients on clinical basis and to deserve biological studies to patients eligible for clinical trials. Disclosures: No relevant conflicts of interest to declare.

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Inclusion of Total BODY Computed Tomography (TB-CT) SCANS In the INITIAL WORK-up of Binet STAGE A CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS On CLINICAL Grounds: PRELIMINARY RESULTS of the Prospective, MULTICENTER O-CLL1- GISL STUDY

Blood ◽

10.1182/blood.v118.21.2837.2837 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2837-2837

Author(s):

Massimo Gentile ◽

Giovanna Cutrona ◽

Sonia Fabris ◽

Emanuela Anna Pesce ◽

Francesco Maura ◽

...

Keyword(s):

High Risk ◽

Ct Scan ◽

Disease Progression ◽

Low Risk ◽

Ct Scans ◽

Intermediate Risk ◽

Trisomy 12 ◽

Initial Work ◽

Binet Stage

Abstract Abstract 2837 Rai and Binet staging systems are not devoid of some limitations, including the lack of evaluation of thoracic and abdominal lymphadenopathies. The widely-used IWCLL guidelines do not incorporate use of TB-CT scan in the diagnostic algorithm. In the present study, we investigated whether TB-CT scans could up-stage Binet stage A CLL patients included in the prospective multicenter O-CLL01 GISL study (clinicaltrial.gov ID: NCT00917549), and whether this subgroup presented differences in prognostic markers and in progression-free survival (PFS). To date, 454 patients have been enrolled and TB-CT scans were available in 238 patients. The median age was 60 years (range, 33–71) and 136 (57%) were male. According to Rai, 180 patients were at low risk (stage 0) and 58 at intermediate risk (stages I-II). b2-microglobulin was elevated in 35.5% of cases. Seventy-eight patients (32%) were IgVH unmutated, 108 patients (45%) had a high ZAP-70 expression, 45 patients (19%) were CD38 positive (>30%). FISH data were available in 226/238 cases; the most frequent abnormality was del(13)(q14) (105 pts, 46.5%), followed by trisomy 12 (24 pts, 10.6%), del(11q22.3) (13 pts 5.5%), del(17p13) (4 pts 1.8%) while 80 cases (35.4%) cytogenetics were normal. Cytogenetic abnormalities were clustered in 3 risk groups [i.e. low (del(13q14) and normal), intermediate (trisomy 12) and high risk (del(11q22) and del(17p13)]. Two hundred six out of 238 patients had a minimum follow-up of 6 months and were evaluable for PFS. Considering TB-CT scan, 54 out of 238 analyzed (22.7%) patients converted into Binet stage B. Notably, 63% were male, b2-microglobulin was elevated in 50% of cases, 42.6% were IgVH unmutated, 48.1% had a high ZAP-70 expression, 27.8% were CD38 positive, and 17.6% showed a high-risk FISH. Binet B patients showed a statistically higher rate of cases with high risk cytogenetic abnormalities than Binet A patients (17.6% vs 4.6%; p=0.032). While, no statistically different distribution of gender, age, B2-microglobulin, IgVH mutational status, CD38 or ZAP-70 expression were observed between the two subgroups. After a median follow-up of 24 months 46/206 (22%) evaluable cases showed disease progression. Binet B patients showed a PFS significantly shorter than those with a normal TB-CT (2-years PFS probability, 85.6% vs 68.5%; p<0.0001). According to the Rai classification 102/180 (56.7%) low risk patients were re-defined as intermediate risk with the integration of TB-CT scan. This subset of patients showed a statistically higher rate of cases with elevated ZAP-70 (51.5% vs 35.9%; p=0.049) and CD38 (22.5% vs 10.3%; p=0.045) than patients at low risk. After a median follow-up of 25 months, 23/154 (15%) of evaluable cases showed disease progression. Patients with an intermediate risk Rai stage showed a PFS significantly shorter than those with a low risk (2-years PFS probability, 82% vs 96%; p=0.002). In this setting 70 cases met the diagnostic criteria of monoclonal B-lymphocytosis (<5 × 109/L B- lymphocytes in the blood). With the integration of TB-CT scan 30/70 (42.9%) monoclonal B-lymphocytosis patients were re-defined as intermediate risk according the Rai classification. No statistically different distribution of clinical and biological parameters were observed between cases who remained in the low risk stage and those who became at intermediate risk. After a median follow-up of 28 months 4/57 cases evaluable for PFS showed a disease progression (2 cases for each subgroup). Considering low risk Rai stage, no statistical difference in PFS was observed among nonCT-upstaged MBL, CT-upstaged MBL, nonCT-upstaged Rai 0, while CT-upstaged Rai 0 cases showed a statistically shorter PFS (p<.0001) than the other groups (Figure 1). Finally, TB-CT scan allowed the early identification of a second neoplasia in 2 cases (lung cancer 1 pt, renal cell carcinoma 1 pt). Our preliminary data indicate that the integration of TB-CT scans in the clinical staging allows for an effective clinical discrimination of Binet A CLL cases in approximately 23% of cases at more advanced stages, predicting a worse clinical outcome. However, the use of TB-CT scanning for upstaging is not beneficial for predicting PFS in MBL cases. A longer follow-up will demonstrate whether the inclusion of TB-CT scan in the initial work-up of patients with early-stage CLL will provide clinically relevant prognostic information.Figure 1.PFS in Rai 0 cases.Figure 1. PFS in Rai 0 cases. Disclosures: Di Raimondo: celgene: Honoraria. Foà:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽

10.1182/blood.v118.21.283.283 ◽

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.

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Prognostic stratification of pulmonary embolism: what does it change from 2014 European Society of Cardiology guidelines?

Reviews in Health Care ◽

10.7175/rhc.v5i4.952 ◽

2014 ◽

Vol 5 (4) ◽

pp. 153-160

Author(s):

Luca Masotti ◽

Giancarlo Landini ◽

Gianni Lorenzini ◽

Irene Chiti ◽

Grazia Panigada

Keyword(s):

Pulmonary Embolism ◽

High Risk ◽

Mortality Risk ◽

Prognostic Model ◽

Early Mortality ◽

Low Risk ◽

Intermediate Risk ◽

Prognostic Stratification ◽

European Society Of Cardiology ◽

Acute Pe

Prognostic stratification is of utmost importance for clinical management of acute pulmonary embolism (PE). Clinical presentation, echocardiography and biomarkers represented the key points on which recommendations of European Society of Cardiology (ESC) released in 2008 were based. In fact, in 2008 the ESC prognostic model suggested to divide acute PE in high risk, heamodynamically unstable, based on presentation with shock or hypotension, and non high risk, haemodynamically stable. The non high risk PE was divided in intermediate rand low risk PE based on echocardiographicand biomarkers signs of right heart dysfunction (RHD) and myocardial damage. This approach was not an academic speculation but permitted to define the early mortality risk (>15% in high risk, 3-15% in intermediate risk, <1% in low risk) and bring the most appropriate treatment. Over the years it became clear that co-morbidity influenced the early mortality risk and may define better the low mortality risk. Practical clinical scores, such as the Pulmonary Embolism Severity Index, PESI, in its original or simplified version, demonstrated to have high prognostic power to identify high (early mortality risk over 10%) and low risk (early mortality risk ≤ 1%) patients. Furthermore, it has become clear that the combination of ESC prognostic model, based on haemodynamics, and clinical prognostic scores may improve the prognostic stratification of acute PE, especially for patients with intermediate risk in whom the range of early mortality risk is wide The latest version of ESC recommendations on management of acute PE released in August 2014 go toward this direction and suggest to divide the non high risk PE in low or intermediate risk taking in account the PESI score. In this review we describe the prognostic strategy of acute PE suggested from the latest version of ESC recommendations.

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55例血管免疫母细胞性T细胞淋巴瘤的临床特征和预后模型

Blood ◽

10.1182/blood-2020-141699 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 37-38

Author(s):

Xiaohong Tan ◽

Jie Sun ◽

Sha He ◽

Chao Rong ◽

Hong Cen

Keyword(s):

High Risk ◽

Prognostic Model ◽

Risk Group ◽

Prognostic Index ◽

Risk Groups ◽

High Risk Group ◽

Low Risk ◽

Intermediate Risk ◽

Ecog Ps ◽

Medical University

Angioimmunoblastic T-cell lymphoma (AITL) is a distinct subtype of peripheral T-cell lymphoma with unique clinical and pathological features. This study aim to analyze the characteristics of AITL and to design a prognostic model specifically for AITL, providing risk stratification in affected patients. We retrospectively analyzed 55 newly diagnosed AITL patients at the Affiliated Tumor Hospital of Guangxi Medical University from January 2007 to June 2016 and was permitted by the Ethics Committee of the Affiliated Tumor Hospital of Guangxi Medical University. Among these patients, the median age at diagnosis was 61 (27-85) and 54.55% (30/55) of the patients were older than 60 years. 43 patients were male, accounting for 78.18% of the whole. Among these, 92.73% (51/55) of the diagnoses were estimated at advanced stage. A total of 20 (36.36%) patients were scored >1 by the ECOG performance status. Systemic B symptoms were described in 16 (29.09%) patients. In nearly half of the patients (27/55; 49.09%) had extranodal involved sites. The most common extranodal site involved was BM (11/55; 20.00%). 38.18% (21/55) and 27.27% (15/55) patients had fever with body temperature ≥37.4℃ and pneumonia, respectively. 40% (22/55) patients had cavity effusion or edema. Laboratory investigations showed the presence of anemia (hemoglobin <120 g/L) in 60% (33/55), thrombocytopenia (platelet counts <150×109/L) in 29.09% (16/55), and elevated serum LDH level in 85.45% (47/55) of patients. Serum C-reactive protein and β2-microglobulin levels were found to be elevated in 60.98% (25/41) and 75.00% (36/48)of the patients, respectively. All patients had complete information for stratification into 4 risk subgroups by IPI score, in which scores of 0-1 point were low risk (9/55;16.36%), two points were low-intermediate risk (17/55; 30.92%), three points were high-intermediate risk (20/55; 36.36%), and four to five points were high risk (9/55; 16.36%). 55 patients were stratified by PIT score with 7.27% (4/55) of patients classified as low risk, 32.73% (18/55) as low-intermediate risk, 34.55% (19/55) as high-intermediate risk, and 25.45% (14/55) as high risk depending on the numbers of adverse prognostic factors.The estimated two-year and five-year overall survival (OS) rate for all patients were 50.50% and 21.70%. Univariate analysis suggested that ECOG PS (p= 0.000), Systemic B symptoms (p= 0.006), fever with body temperature ≥ 37.4℃ (p= 0.000), pneumonia (p= 0.001), cavity effusion or edema (p= 0.000), anemia (p= 0.013), and serum LDH (p= 0.007) might be prognostic factors (p< 0.05) for OS. Multivariate analysis found prognostic factors for OS were ECOG PS (p= 0.026), pneumonia (p= 0.045), and cavity effusion or edema(p= 0.003). We categorized three risk groups: low-risk group, no adverse factor; intermediate-risk group, one factor; and high-risk group, two or three factors. Five-year OS was 41.8% for low-risk group, 15.2% for intermediate-risk group, and 0.0% for high-risk group (p< 0.000). Patients with AITL had a poor outcome. This novel prognostic model balanced the distribution of patients into different risk groups with better predictive discrimination as compared to the International Prognostic Index and Prognostic Index for PTCL. Disclosures No relevant conflicts of interest to declare.

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