Cutrona, Giovanna

AbstractMost 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.

Abstract Background: Over the last two decades several phenotypic, molecular, and chromosomal markers have been identified that are significantly associated with the prognosis of CLL patients. Therefore, clinicians managing CLL patients would benefit from a simplified prognostic index. Methods: We analyzed prospectively collected data from 337 Binet A CLL patients enrolled in Italian the O-CLL1-GISL protocol with the aim of developing scores capable of predicting treatment free survival (TFS). Factors independently associated with TFS were included in the prognostic indexes. To account for differences in the magnitude of the association between the individual independent factors and TFS, we assigned a weighted risk score to each factor based on ranges of their corresponding hazard ratios (HRs) (i.e., 1 point for HR 1.1-1.9; 2 points for HR 2.0-2.9, etc.). The total risk score was then calculated by the sum of the ratings of each factor on individual basis. Risk groups were identified combining risk categories with a non-statistically different TFS. Results: We developed two scores based on weighted multivariable models: the first included clinical and laboratory parameters [clinical score (c-score)], while the second was based on biological markers [biological score (b-score)] (Table 1). The c-score allowed to predict the TFS of patients through the combination of Rai stage, b2-microglobulin and absolute lymphocyte count (ALC), while the b-score predicted TFS by IGHV mutational status and CD38 expression. The c-score showed a C-statistic of 0.72, while the b-score was 0.67, although cases stratified according to the b-score showed a more specific mRNA/microRNA profile. When the two scores were forced in a multivariate analysis, both showed an independent predictive value on TFS with a similar HR, demonstrating their complementarity. Thus, we attempted to integrate the two scores performing a further multivariate analysis in which all parameters, significantly associated with TFS at univariate analysis, were tested (Table 1). ALC, Rai stage, b2-microglobulin together with IGHV mutational status, resulted independently associated with TFS. We constructed a weighted score [comprehensive score (co-score)], including all the above 4 variables, which allowed the identification of 3 different risk groups with significantly different TFS (Figure 1). The C-statistic of the g-score was 0.75, showing a better concordance than the other two scores. Moreover, its validity was externally validated in a series of 297 newly diagnosed Binet A CLL patients from the Mayo Clinic, USA. Conclusions: Using this multistep process and external validation, we developed a score with high discriminatory power and predictive significance on the individual patient level. Table 1. Univariate and multivariate Cox proportional Hazards Models Variable Univariate analysis Multivariate analysis Clinical model Biological model Comprehensive model HR (95% CI) P HR (95% CI) P score HR (95% CI) P score HR (95% CI) P score Age (years) <60/>60 1.12 (0.73-1.74) 0.59 - - - - - - - - - Sex Male/Female 0.93 (0.6-1.44) 0.93 - - - - - - - - - Rai stage 0/I-II 2.30 (1.47-3.50) <0.0001 2.13 (1.24-3.03) 0.004 0/2 - - - 1.76 (1.11-2.78) 0.015 0/1 ALC (109/L) <10/>10 3.43 (1.99-5.92) <0.0001 2.91 (1.85-5.20) <0.0001 0/2 - - - 2.70 (1.54-4.72) 0.001 0/2 b-2 microglobulin normal/elevated 3.04 (1.96-4.70) <0.0001 2.78 (1.79-4.30) <0.0001 0/2 - - - 2.65 (1.66-4.21) <0.0001 0/2 LDH normal/elevated 1.25 (0.57-2.71) 0.57 - - - - - - - - - CD38 negative/positive 3.22 (2.06-5.02) <0.0001 - - - 2.11 (1.15-3.16) 0.02 0/2 1.40 (0.80-2.42) 0.24 - ZAP-70 negative/positive 2.34 (1.51-3.61) <0.0001 - - - 1.21 (0.70-2.16) 0.485 - 1.0 (0.98-1.01) 0.72 - IGHV mutated/unmutated 3.57 (2.32-5.50) <0.0001 - - - 2.10 (1.12-3.90) 0.019 0/2 2.39 (1.27-4.50) 0.007 0/2 FISH risk low+int/high 2.93 (1.46-5.90) 0.002 - - - 1.65 (0.76-3.34) 0.216 - 1.80 (0.84-3.88) 0.13 - Abbreviations: ALC: absolute lymphocyte count; CI: confidential interval; HR: hazard ratio. Figure 1. TFS according to comprehensive progression risk score. Figure 1. TFS according to comprehensive progression risk score. Disclosures Shanafelt: Cephalon: Research Funding; Glaxo-Smith-Kline: Research Funding; Genentech: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Jannsen: Research Funding; Polyphenon E International: Research Funding; Pharmacyclics: Research Funding. Kay:Genentech: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Tolero Pharma: Research Funding; Pharmacyclics: Research Funding.

Abstract BACKGROUND: Consistent with the advanced age at diagnosis (median age ~70 years), most patients with CLL have co-existent health problems. These co-morbidities influence the ability of many CLL patients to tolerate aggressive chemotherapy-based treatment and can also contribute to treatment-related side effects. The recent development of novel signaling inhibitors, particularly the Bruton's tyrosine kinase inhibitor ibrutinib, has been a major treatment advance for patients with CLL. While these agents generally have favorable toxicity profiles relative to standard chemotherapy-based treatments, they are chronic therapies which patients typically stay on for an extended period. Preliminary data suggests ibrutinib may be associated with an increased risk of atrial fibrillation (Afib). In one randomized trial comparing ibrutinib to ofatumumab in patient with relapsed CLL, incident grade 3+ Afib occurred in 3% of ibrutinib treated patients compared to 0% of ofatumumab treated patients (NEJM 371:213). Despite these observations, the baseline frequency of Afib in patients with CLL is not well described - particularly incident atrial fibrillation acquired during the course of the disease. METHODS: We used the Mayo Clinic CLL database to evaluate the prevalence of Afib at the time of CLL diagnosis as well as the incidence of Afib during follow-up. All patients with a new diagnosis of CLL after January 1995 who were seen at Mayo within 12 months of diagnosis were included in the analysis. Afib was identified by chart review and by billing search using ICD9 codes. Data on co-morbid conditions associated with risk of Afib was also abstracted (e.g. hypertension, coronary artery disease [CAD], valvular heart disease, cardiomyopathy, diabetes mellitus, pulmonary disease). RESULTS: A total of 2444 patients with newly diagnosed and previously untreated CLL were seen at Mayo Clinic within 12 months of diagnosis between 1/1995 and 4/2015.Median age at diagnosis was 65 years and 1626 (66.5%) patients were men. A history of Afib was present at the time of CLL diagnosis in 148 (6.1%) patients. Four additional patients had Afib documented in the record but the precise date of onset (e.g. prior to or after CLL diagnosis date) could not be determined. Age, male sex and history of CAD, valvular heart disease, cardiomyopathy, hypertension, and diabetes were associated with a greater likelihood of having a history of Afib at the time of CLL diagnosis (all p&lt;0.01). Among the 2292 patients without a history of Afib at CLL diagnosis, 139 (6.1%) had incident Afib during the course of follow-up for their CLL. The incidence of Afib among patients without a history of Afib at diagnosis was approximately 1%/year (Figure 1A). Considering both Afib present at the time of CLL diagnosis or acquired during the course of the disease, 291 (11.9%) of the 2444 patients in this cohort experienced Afib (median follow-up: 59 months). Among patients without Afib at the time of CLL diagnosis, the following characteristics at the time of CLL diagnosis were associated with an increased risk of incident Afib on multivariate analysis: older age (age 65-74 HR=2.4, p&lt;0.001; age ≥75 HR=3.6, p&lt;0.001), male sex (HR=1.8, p=0.004); valvular heart disease (HR=2.4, p=0.007), and hypertension (HR=1.5; p=0.02). A predictive model for acquired Afib was subsequently constructed based on the independent factors in the Cox regression model. An individual weighted risk score was assigned to each independent factor based on the regression coefficients of the HRs. The Afib risk score (range 0-7) was defined as the sum of the scores of these independent factors. The risk of incident Afib among patients with risk scores of 0-1, 2-3, 4, and 5+ is shown in Figure 1B. Rates for these 4 groups were significantly different (p&lt;0.001), with the 10-year Afib rates (95% C.I.) for those with a score of 0-1, 2-3, 4, and 5+: 4% (2-6%), 9% (6-13%), 17% (11-23%), and 33% (20-43%), respectively. CONCLUSIONS: A history of Afib is present in approximately 1 out of every 16 patients with newly diagnosed CLL. Among patients without Afib at diagnosis, the incidence rate of Afib is ~1%/year. The risk of incident Afib in newly diagnosed CLL patients can be predicted based on age, sex, and co-morbid health conditions present at diagnosis. These data provide context to help interpret data on the frequency of Afib in CLL patients treated with ibrutinib and other novel agents. Disclosures Shanafelt: Janssen: Research Funding; Polyphenon E Int'l: Research Funding; Glaxo-Smith_Kline: Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Pharmactckucs: Research Funding. Ding:Merek: Research Funding. Kay:Tolero Pharm: Research Funding; Hospira: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

The chronic lymphocytic leukemia International Prognostic Index (CLL‐IPI) combines 5 parameters (age, clinical stage, TP53 status [normal vs. del(17p) and/or TP53 mutation], IGHV mutational status, serum β2‐microglobulin) to predict survival and time‐to‐first‐treatment (TTFT) in CLL patients. We performed an observational study in 337 prospectively collected, Binet stage A patients to validate the ability of the CLL‐IPI to predict TTFT in an independent cohort of early stage CLL patients. The CLL‐IPI score stratified Binet stage A patients into three subgroups with different outcome. Since the CLL‐IPI was originally developed to predict survival, we next investigated the optimal cut‐off score to predict TTFT in Binet stage A patients. Recursive partitioning analysis identified three subsets with scores of 0 (n = 139), 1 (n = 90), and ≥ 2(n = 108). The probability of remaining free from therapy 5 years after diagnosis was 85%, 67% and 46% in these three categories (P < 0.0001.; C‐statistic:c = 0.72; 95% CI:0.58‐0.81). This optimized CLL‐IPI scoring for TTFT was subsequently validated in an independent cohort of Binet A patients from the Mayo Clinic (n = 525). The ability of either original or optimized CLL‐IPI to predict TTFT was equivalent to other prognostic models specifically designed for this endpoint (2011 MDACC score and O‐CLL1 score). Although originally developed to predict suvival, the CLL‐IPI is useful for predicting TTFT in early stage CLL patients. Am. J. Hematol. 91:1090–1095, 2016. © 2016 Wiley Periodicals, Inc.