International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia

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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Calreticulin Mutation Does Not Modify the International Prognostic Score for Predicting the Risk of Thrombosis Among 1,150 Patients with Essential Thrombocythemia

Blood ◽

10.1182/blood.v124.21.404.404 ◽

2014 ◽

Vol 124 (21) ◽

pp. 404-404

Author(s):

Guido Finazzi ◽

Alessandra Carobbio ◽

Paola Guglielmelli ◽

Elisa Rumi ◽

Silvia Salmoiraghi ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Prognostic Score ◽

Low Risk ◽

Intermediate Risk ◽

Thrombotic Risk ◽

Exon 9 ◽

International Prognostic Score ◽

Risk Categories ◽

Calr Mutation

Abstract Background An International Prognostic Score for the risk of thrombosis (IPSET-thrombosis) in Essential Thrombocythemia (ET) was developed (Barbui et al. Blood, 2012;120:5128). Risk factors included: age >60 years (1 point), cardiovascular (CV) risk factors (1 point), previous thrombosis (2 points) and the presence of JAK2V617F mutation (2 points). Low, intermediate and high risk categories were identified by scores 0-1; 2; and ≥ 3, respectively. Mutations in the exon 9 of CALreticulin (CALR) gene were recently identified in about 50-60% of patients with JAK2V617F negative ET and associated with a reduced thrombotic risk as compared with JAK2V617F positive patients. Aim To evaluate whether the identification of CALRmutation in patients with ET has any impact on the IPSET-thrombosis score Patients and Methods Under the auspices of AGIMM (AIRC Gruppo Italiano Malattie Mieloproliferative), four Italian centers with recognized experience in myeloproliferative neoplasms participated in the current study. Overall, 1,150 patients who met the 2008 WHO criteria for ET and were molecularly characterized for JAK2V617F, MPLW515L/K and CALR exon 9 mutations were included. The JAK2 and MPL mutations were assessed by real-time quantitative polymerase chain reaction and by high-resolution melting analysis followed by bidirectional Sanger sequencing. Mutations in exon 9 of CALRwere assessed by bidirectional sequencing or next generation sequencing. Results Presenting features of the study population were: median age 58 years (range 5th-95th percentile 27-82 years; 65% females), median hemoglobin 14.1 g/dL (range 5th-95th percentile 11.8-16.3), median leukocyte count 8.7x109/L (range 5th-95th percentile 5.4-14.7), median platelet count 718x109/L (range 5th-95th percentile 486-1313). CV risk factors (at least one among smoke, diabetes and hypertension) were present in 568 (49%) patients. Arterial or venous thrombosis history before or at diagnosis was documented in 167 (15%) patients. JAK2V17F, MPLW515L/K and CALRmutations were detected in 744 (65%), 44 (4%) and 164 (14%) patients respectively. The remaining 198 patients (17%) were wild-type for all three mutations. During a median follow-up of 4.1 years (range 0-29), 104 patients developed an arterial or venous thrombotic event, with a total incidence rate of 1.59% patients/year (pt-ys). The IPSET-thrombosis ability to discriminate the thrombotic risk was confirmed. In fact, in the low risk (reference category), the rate was 0.57% pt-ys; in the intermediate risk was 1.60% pt-ys (Hazard Ratio (HR) 3.10, 95% Confidence Interval (CI) 1.55-6.18, p=0.001) and in the high risk group was 2.34% pts-yr (HR 4.59, 95% CI 2.41-8.77 p<0.0001). As to the impact of CALR mutation in the three categories of the IPSET-thrombosis score, we observed that CALR mutated patients were more frequently distributed in the low risk (48%) and intermediate risk (46%) than in the high risk IPSET groups (6%). In univariate analysis, patients carrying CALR mutation had a lower incidence of thrombosis than those with JAK2V617F (HR 0.61, 95% CI 0.34-1.09, p=0.093). However, CALR mutated patients were significantly younger (median age 53.5 versus 60.8 years, p=0.001) and presented with less previous thrombosis (8% versus 17%, p=0.005) than JAK2V617F mutated patients. This could explain why in multivariable models, CALR mutation did not retain the association with the risk of thrombosis. This was demonstrated in the whole population (HR 0.81, 95% CI 0.30-2.17, p=0.674), as well as in the low risk (HR 1.01, range 0.27-3.81, p=0.987) and intermediate risk categories (HR 1.80, range 0.57-5.72, p=0.317); the high risk category was not evaluable for the low proportion of CALRmutated patients in this group. Conclusions CALR mutation does not have a significant impact on the IPSET-thrombosis prognostic score. The score can be used as it is to predict the risk of thrombosis in molecularly-annotated, WHO-2008 diagnosed ET patients. Disclosures Vannucchi: Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding.

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

Blood ◽

10.1182/blood-2021-152717 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4691-4691

Author(s):

Ramadevi Prathapam ◽

Najuma Maharjan ◽

Sheila B Powers ◽

Tracey Allen K Freitas ◽

Guoli Sun ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Prognostic Model ◽

Lymphocytic Leukemia ◽

Low Risk ◽

Intermediate Risk ◽

Clinical Value ◽

Trisomy 12 ◽

Biomarker Testing ◽

Testing Approach

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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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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Early Ofatumumab Treatment For High-Risk, Treatment-Naive Patients With Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v122.21.5307.5307 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5307-5307

Author(s):

Nitin Jain ◽

Michael J. Keating ◽

Alessandra Ferrajoli ◽

Marina Konopleva ◽

Deborah A. Thomas ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Delay Time ◽

Early Stage ◽

Lymphocytic Leukemia ◽

Early Stage Disease ◽

Tumor Lysis ◽

Ighv Gene ◽

Grade 3

Background Ofatumumab is a human IgG1-kappa monoclonal antibody that binds to CD20 on normal B cells and on B chronic lymphocytic leukemia cells, resulting in B cell lysis. Ofatumumab has single-agent activity in patients (pts) with refractory CLL (Wierda, JCO 2010). Pts with CLL who have early stage disease (Rai 0-II) but have high-risk prognostic markers such as deletion 17p or deletion 11q have an increased risk of disease progression. Currently, these pts are offered watch-and-wait approach. The objective of this Phase II study is to evaluate the efficacy of ofatumumab in treating these pts with the goal to delay time to first chemoimmunotherapy treatment. Methods Pts with CLL/SLL were eligible provided they had high-risk for progression based on the presence of at least one of the following features: Rai stage II, serum beta-2 microglobulin (β2M) ≥3 mg/L, absolute lymphocyte count ≥25,000/µL, unmutated (≤2%) IGHV gene or mutated IGHV3-21, ZAP70 positive, CD38 positive (≥ 30%), or 11q or 17p deletion by FISH. Pts having a 2008 IWCLL/NCI-WG indication for CLL treatment were not eligible. Pts with Rai stage III-IV CLL were not eligible. Ofatumumab 300 mg dose 1, then 1000 mg weekly for 7 additional weeks (8 doses) was administered. Response assessment, including bone marrow evaluation, was done at least 2 months after last dose of ofatumumab and pts were followed for progression-free survival and time to first chemoimmunotherapy. Results Twenty-five pts (9 women, 16 men) were enrolled so far. The median age was 59 yrs (range, 40-81). The baseline characteristics are listed in the Table. Fifty percent of pts had unmutated IGHV gene. Thirty-four percent of pts had high-risk cytogenetic by FISH analysis. The median follow-up on the study is 4.7 months (range, 0.5-26). Grade 3-4 adverse events included infusion reaction in 6 pts. Autoimmune hepatitis with grade 4 ALT, grade 4 AST, and grade 4 alkaline phosphatase elevations was seen in 1 pt. Other grade 3-4 toxicities included rash (1 pt), shingles (1 pt), and tumor lysis (1 pt). Tumor lysis was seen in the pt with the WBC count of 207 K/µL. Eighteen pts (7 too early) are evaluable for response. Responses are as follows: 6 CR, 3 nPR, 3 PR, and 6 with stable disease. Three pts have progressed at 18.8, 14.1 and 3.2 months after starting the study treatment; 2 pts had unmutated IGHV gene (FISH negative) and one pt had trisomy 12 (IGHV mutation status unknown). None of the pts with deletion 17p or deletion 11q have progressed. All pts are alive at this time. The median overall follow up time is 7.6 months (range, 1-28). Conclusions Ofatumumab is well tolerated in pts with early stage CLL and may delay time to first chemoimmunotherapy. Disclosures: Ferrajoli: GlaxoSmithKline: Research Funding.

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International Prognostic Score (IPS-A) for Patients with Early Stage Chronic Lymphocytic Leukemia

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2019.07.212 ◽

2019 ◽

Vol 19 ◽

pp. S278 ◽

Cited By ~ 1

Author(s):

Adalgisa Condoluci ◽

Lodovico Terzi di Bergamo ◽

Petra Langerbeins ◽

Manuela Hoechstetter ◽

Carmen Herling ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Early Stage ◽

Prognostic Score ◽

Lymphocytic Leukemia ◽

International Prognostic Score

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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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INTERNATIONAL PROGNOSTIC SCORE FOR EARLY STAGE CHRONIC LYMPHOCYTIC LEUKEMIA (IPS-A)

Hematological Oncology ◽

10.1002/hon.51_2629 ◽

2019 ◽

Vol 37 ◽

pp. 81-82

Author(s):

A. Condoluci ◽

L. Terzi di Bergamo ◽

P. Langerbeins ◽

M. Hoechstetter ◽

C. Herling ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Early Stage ◽

Prognostic Score ◽

Lymphocytic Leukemia ◽

International Prognostic Score

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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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Value of clinical treatment score post-5 years (CTS5) for late relapse risk assessment in patients with early-stage HER2+ breast cancer (BC) in the north central cancer treatment group (NCCTG) N9831 (Alliance) trial.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.529 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 529-529

Author(s):

Tanmayi Pai ◽

Angelica Gil ◽

Yaohua Ma ◽

Zhuo Li ◽

Pooja Advani ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Tumor Size ◽

Cox Regression ◽

Early Stage ◽

Low Risk ◽

Late Relapse ◽

Intermediate Risk ◽

Relapse Risk ◽

Significant Difference

529 Background: Multiple prognostic models exist to predict late relapse risk in early stage hormone receptor-positive (HR+) breast cancer (BC). The CTS5 is one such model that has been validated in HR+ HER2-negative BC. The value of this model in HR+ HER2+ has not been established. Here, we assessed CTS5 in patients (pts) with early stage HER2+ BC treated in the NCCTG N9831 (Alliance) trial. Methods: Pts with stage I-III HER2+ HR+ BC who survived ≥ 5 years were included. The online CTS5 calculator was used to determine CTS5 score and risk group (low, intermediate, and high) based on age, tumor size, grade, and number of involved nodes. Kaplan-Meier (KM) estimates, Cox regression models, and C index were used for analysis. Results: From 3,130 pts, 1,204 pts met the criteria and were included. Median age was 49 (22-79) years and median tumor size was 2.4 (0.1-12) cm. 63.6% had grade 3 tumors, 33.6% grade 2, and 2.8% grade 1. Median follow up was 10.89 (5.01-15.32) years. Based on CTS5, 821 (68.2%) pts were classified as high risk, 289 (24%) as intermediate risk, and 94 (7.8%) as low risk. Overall, using univariate Cox regression analysis, there was no statistically significant difference in recurrence free survival (RFS) among pts with intermediate vs. low (HR 0.47 95%CI 0.18-1.22, p = 0.12) and high vs. low (HR1.23 95%CI0.57-2.67, p = 0.6) with the C index of 0.58. Among pts who received concurrent trastuzumab (H) with HR+ BC, there was also no statistical difference in RFS between high vs. low (HR 0.68 95%CI0.24-1.97, p = 0.48) with the C index of 0.55. Paradoxically, pts with intermediate risk had better RFS than low risk (HR 0.18 95%CI0.03-0.97, p = 0.05). As a continuous variable, there is also no significant improvement in RFS per 1 unit increase in CTS5 score (HR 1.19 95%CI 0.73-1.96, p = 0.49) with the C index of 0.54. After 5 years, 7.06% (n = 30/425) of HR+ pts treated with concurrent H recurred. Conclusions: The CTS5 model is not prognostic in pts with early stage HR+ HER2+ BC receiving adjuvant H. While most HR+ HER2+ pts are classified as high risk by CTS5, the recurrence between years 5-10 was low in pts who received adjuvant H. This study highlights the need to develop a new predictive model for risk of late relapse in this specific group of pts to enable clinicians to determine which pts would benefit from extended adjuvant endocrine therapy. Support: BCRF-19-161, U10CA180821, Genentech. https://acknowledgments.alliancefound.org Clinical trial information: NCT00005970 .

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Validation of the Plasmic Score for Predicting ADAMTS13 Activity < 10% in Patients Admitted to Hospitals in Alberta with Suspected Thrombotic Thrombocytopenic Purpura

Blood ◽

10.1182/blood-2019-126354 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2379-2379 ◽

Cited By ~ 1

Author(s):

Chris Wynick ◽

Joanne Britto ◽

Daniel Sawler ◽

Arabesque Parker ◽

Mohammad Karkhaneh ◽

...

Keyword(s):

High Risk ◽

Plasma Exchange ◽

Thrombotic Thrombocytopenic Purpura ◽

Risk Score ◽

Predictive Value ◽

Clinical Pathways ◽

Low Risk ◽

Intermediate Risk ◽

Thrombocytopenic Purpura ◽

Adamts13 Deficiency

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy (TMA), characterized by widespread intravascular thrombosis. Diagnosis of TTP is confirmed by a deficiency in ADAMTS13. However, given the urgency of prompt diagnosis and delayed turnaround time of ADAMTS13 assay in most labs, initial diagnosis is based on clinical acumen. Suspected TTP is empirically treated with plasma exchange (PLEX), which, while beneficial in TTP, may delay appropriate treatment for similar disorders. The PLASMIC score was developed by Bendapudi et al. (Lancet Hematology 2017) to utilize clinical signs and investigations to predict which patients had an ADAMTS13 score < 10%, and therefore TTP, who require PLEX. Validation studies have shown a very high sensitivity (90-98%) and high specificity (46-92%), although these studies included an enriched population with available ADAMTS13 assay results (Jajosky et al. Transfusion and Apheresis Science, 2017, Li et al. Journal of Thrombosis and Hemostasis 2018). The purpose of this study is to validate the PLASMIC score using a Canadian population of suspected TTP regardless if ADAMTS13 was ordered, and compare it to clinical gestalt. This is a retrospective cohort study of all adults aged 18 years or older who presented or were transferred to any of the two apheresis centres in Alberta, Canada with a suspected diagnosis of TTP from January 1, 2008 - December 31, 2018. A confirmed diagnosis of TTP was defined as an ADAMTS13 level prior to PLEX < 10%, or ADAMTS13 level between 10-20% if drawn after plasma infusion or PLEX. ADAMTS13 testing was done in accordance with the procedures at these institutions. The PLASMIC score was used to stratify patients into low (0-4), intermediate (5) and high (6-7) risk of TTP (Table 1). Descriptive analyses was performed to examine the proportion of patients with low-, intermediate-, and high-risk PLASMIC score who had ADAMTS13 testing done and who received PLEX. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of PLASMIC score were calculated. Two PLASMIC score cutoffs were used for the analysis, 1) high risk vs low to intermediate risk, and 2) intermediate to high risk vs low risk. Receiver operator curve (ROC) analysis was used to test the association between severe ADAMTS13 deficiency and the PLASMIC score. PLASMIC scores were also compared to clinical gestalt, defined as initiation of PLEX within 48 hours of presentation. The C statistic was calculated from the area under the ROC and compared using the Z-test. As some patients who may have died from TTP did not have ADAMTS13 level sent, sensitivity analysis was performed to assess the ROC curve for the PLASMIC score in detecting both definite and probable TTP. A P-value of <0.05 was considered statistically significant. Of the 162 cases of suspected TTP, 61 (38%) had severe ADAMTS13 <10%. ADAMTS13 was sent prior to plasma exchange in 103 (64%) cases and shortly after PLEX initiation in 15 (9%). Using a high-risk PLASMIC score cut-off (6-7) vs low to intermediate-risk score (0-5), the sensitivity was 83.6%, specificity 67.3%, PPV 60.7% and NPV 87.2%. In contrast, using a cut-off of medium to high-risk PLASMIC score (5-7) vs low-risk score (0-4), the sensitivity improved to 96.7%, whereas the specificity was reduced to 30.7% (PPV 45.7% and NPV 93.9%). The C-statistics were 0.75 (95% CI 0.69-0.82) and 0.64 (95% CI 0.59-0.69) using the high PLASMIC score and medium-high PLASMIC score cut-offs, respectively (Figure 1). In contrast to PLASMIC score-based risk stratification, clinical gestalt has a comparable sensitivity of 83.6%, but a much lower specificity of 38.9%. There was very low correlation between PLASMIC score and clinical gestalt (kappa 0.0883 (95% CI -0.03-0.21). In our cohort, a high-risk PLASMIC score successfully predicted patients with severe ADAMTS13 deficiency in a Canadian TMA population, with similar sensitivity and improved specificity compared to clinical gestalt. Integration of this scoring system into institutional clinical pathways should be considered to supplement clinician judgment and reduce costs. Disclosures No relevant conflicts of interest to declare.

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