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Validation of a new prognostic index for patients with chronic lymphocytic leukemia.

ABSTRACT: The clinical course of chronic lymphocytic leukemia (CLL) is highly variable. A prognostic index based on widely available clinical and laboratory features was recently developed to predict survival among patients with previously untreated CLL. This index requires validation in an independent series of patients before widespread use can be recommended.The Mayo Clinic CLL database was used to evaluate the validity and reproducibility of the new prognostic index.A total of 440 patients with newly diagnosed CLL who were seen at the Mayo Clinic within 12 months of diagnosis and for whom data were available with which to calculate index score were identified. Patients were classified as low, intermediate, or high risk using the prognostic index. The estimated median survival times were: not reached for low risk, 10.1 years for intermediate risk, and 7.2 years for high risk. The estimated median and 5-year survival by prognostic index risk category were similar to those originally reported. The prognostic index risk category added predictive value beyond that of Rai risk alone (P=.004). The prognostic index risk category remained a predictor of survival when analysis was limited to Rai stage 0 (P=.03) and nonreferred patients (P<.0001) and also predicted time to treatment (P<.0001).The results of the current study confirm the ability of a newly developed prognostic index to predict survival among patients with previously untreated CLL. The study also extended the utility of the index by demonstrating that it is useful at diagnosis, retains prognostic value when applied exclusively to Rai stage 0 patients, is effective in nonreferred patients, and predicts time to treatment.

SUBMITTER: Shanafelt TD

PROVIDER: S-EPMC2629134 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Validation of a new prognostic index for patients with chronic lymphocytic leukemia.

Shanafelt Tait D TD Jenkins Greg G Call Timothy G TG Zent Clive S CS Slager Susan S Bowen Deborah A DA Schwager Susan S Hanson Curtis A CA Jelinek Diane F DF Kay Neil E NE

Cancer 20090101 2

<h4>Background</h4>The clinical course of chronic lymphocytic leukemia (CLL) is highly variable. A prognostic index based on widely available clinical and laboratory features was recently developed to predict survival among patients with previously untreated CLL. This index requires validation in an independent series of patients before widespread use can be recommended.<h4>Methods</h4>The Mayo Clinic CLL database was used to evaluate the validity and reproducibility of the new prognostic index. ...[more]

PMID: 19090008

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Project description:BackgroundThe established clinical staging systems (Rai/Binet) of chronic lymphocytic leukemia (CLL) cannot accurately predict the appropriate treatment of patients in the earlier stages. In the past two decades, several prognostic factors have been identified to predict the outcome of patients with CLL, but only a few studies investigated more markers together. To predict the time to first treatment (TTFT) in patients of early stages, we evaluated the prognostic role of conventional markers as well as cytogenetic abnormalities and combined them together in a new prognostic scoring system, the CLL prognostic index (CLL-PI).MethodsTaking advantage of a population of 406 untreated Chinese patients with CLL at early and advanced stage of disease, we identified the strongest prognostic markers of TTFT and, subsequently, in a cohort of 173 patients who had complete data for all 3 variables, we integrated the data of traditional staging system, cytogenetic aberrations, and mutational status of immunoglobulin heavy chain variable region (IGHV) in CLL-PI. The median follow-up time was 45 months and the end point was TTFT.ResultsThe median TTFT was 38 months and the 5-year overall survival was 80%. According to univariate analysis, patients of advanced Rai stages (P < 0.001) or with 11q- (P = 0.002), 17p- (P < 0.001), unmutated IGHV (P < 0.001), negative 13q- (P = 0.007) and elevated lactate dehydrogenase levels (P = 0.001) tended to have a significantly shorter TTFT. And subsequently, based on multivariate Cox regression analysis, three independent factors for TTFT were identified: advanced clinical stage (P = 0.002), 17p- (P = 0.050) and unmutated IGHV (P = 0.049). Applying weighted grading of these independent factors, a CLL-PI was constructed based on regression parameters, which could categorize four different risk groups (low risk [score 0], intermediate low [score 1], intermediate high [score 2] and high risk [score 3-6]) with significantly different TTFT (median TTFT of not reached (NR), 65.0 months, 36.0 months and 19.0 months, respectively, P < 0.001).ConclusionsThis study developed a weighted, integrated CLL-PI prognostic system of CLL patients which combines the critical genetic prognostic markers with traditional clinical stage. This novel modified PI system could be used to discriminate among groups and may help predict the TTFT and prognosis of patients with CLL.

Project description:PurposeRandomized 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 methodsPatients 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.ResultsFactors 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.ConclusionPatients at increased risk of ibrutinib failure can be identified at treatment initiation and considered for clinical trials.

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Validation of a new prognostic index for patients with chronic lymphocytic leukemia.

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Validation of a new prognostic index for patients with chronic lymphocytic leukemia.

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