Chronic lymphocytic leukemia and prognostic models: A bridge between clinical and biological markers
Authors: Gianluigi Reda, Ramona Cassin, Bruno Fattizzo, Diana Giannarelli, Veronica Mattiello, Wilma Barcellini, Agostino Cortelezzi
Journal: American Journal of Hematology (2017)

Prognostic chronic lymphocytic leukemia (CLL) scores have been focusing mainly on clinical features for a long time (ie, Rai and Binet). Their prognostic value, especially in predicting treatment response, progressively weakened along with advances in biological insight. Immunoglobulin heavy chain variable region (IGHV) and fluorescence in situ hybridization (FISH), two widespread and reproducible prognostic markers, provide information about overall response rate (ORR) and progression-free survival (PFS); moreover in the BCRi (B-cell Receptor inhibitors) era they can address therapeutic choices.1 Despite recent advances in therapy, CLL is still an incurable disease. Although 80% of patients are currently diagnosed in early clinical stage, only a third will never require treatment.2 Individual course of disease is extremely variable and prognostication is a burning tool in the management of CLL patients. To improve discriminatory power, an expanding list of CLL novel prognostic markers has emerged. In the previous years, many models have been developed and validated in retrospective and heterogeneously treated cohorts.2 A new prognostic model, CLL-IPI,3 developed on 3472 patients selected from 13 clinical trials, aimed to evaluate and combine age with clinical (Binet/Rai stage), biochemical (beta2microglobulin), and genetic (17p and/or TP53 deletion, IGHV mutational status) parameters. CLL-IPI would allow a more targeted management of CLL patients in both clinical practice and in trials testing novel drugs. In a recent issue, Delgado et al.4 described a simplified CLL-IPI based on two biomarkers (FISH and IGHV) to identify different outcome in CLL patients. To validate this model, both a retrospective cohort and newly diagnosed patients in Binet A stage were used.4 We applied this model to our CLL cohort in order to assess whether simplified CLL-IPI could be reproducible in a "real life" population. We retrospectively collected clinical, biochemical, and biological parameters of 698 consecutive patients with CLL from medical records. Patients had been re-classified on the basis of iwCLL 2008 criteria and followed at the Department of Hematology of our Hospital from 1983 to 2016. Median follow-up time was 12 years (range 0-30). Four hundred one (57%) patients were male and 297 (43%) female. Regarding clinical evaluation, 517 (74%) patients presented Rai 0-I and 567 (82%) Binet A stage at diagnosis. Three hundred three (43%) patients required therapy and were treated according to available iwCLL criteria with different regimens. Therapy choice was performed following international guidelines, patient age, comorbidities, clinical judgment, and available clinical trials. Chlorambucil (CHL) for 190 patients (27.3%), fludarabine-cyclophosphamide-rituximab (FCR) for 108 (15.5%), ofatumumab-bendamustine (O-Benda) for 12 (1.7%), bendamustine-rituximab (BR) for 44 (6.3%), alemtuzumab for 65 (9.3%) and, in the last years, small molecules (Ibrutinib and Idelalisib) for 29 cases (4.1%) were used. Time To First Treatment (TTFT) was evaluated from the time of diagnosis to first-line therapy start and overall survival (OS) from CLL diagnosis to death. Data about both FISH and IGHV were available for 329 patients. Our cohort was representative of real life population on the basis of CLL-IPI. In fact, we identified four risk groups with different TTFT and OS (Figure 1A,B): 186 patients (56.5%) presented IPI 0-1, 99 (30.1%) IPI 2-3, 32 (9.7%) IPI 4-6, and 12 (3.7%) IPI 7-10. The percentage of high and very-high risk patients was similar to that observed in original CLL-IPI study (17%). Overall survival (OS) and time to first treatment (TTFT) in CLL patients. OS and TTFT are estimated by Kaplan–Meyer method and divided according to CLL-international prognostic index (IPI, panel A and B) and simplified IPI (panel C and D). pts = patients By comparing our population with Delgado's series, we observed comparable clinical stage, beta2microglobulin median values (2.3 mg/dL range 0.1-5.8 mg/dL vs 2.2 mg/dL, range 0.2-16.5 mg/dL), and 11q or 17p deletions (34 cases, 7.9% and 27 cases, 6.3%, respectively). At variance, our population was older (65 years range 32-91 years vs 62 years range 22-93) and displayed lower IGHV unmutated status (122, 36%) than that generally observed in CLL (45%)5 and in Delgado series (57%). Simplified CLL-IPI maintains its predictive value both on TTFT and OS in our cohort. In fact, three prognostic classes were identified based on the presence/absence of the two negative risk factors IGHV unmutated and 11q or 17p deletion: 193 (60%) patients were low risk (no negative factors), 92 (29%) intermediate-risk (one negative factor, IGHV umutated or del17p/11q), and 36 (11%) high-risk (both negative factors). Of note, all low-risk patients that underwent therapy had been treated with standard immunochemotherapy. Projected OS at 15 years was 80% for low risk, 50% for intermediate-risk, and 30% for high risk patients (Figure 1C). Simplified CLL IPI also allowed patients stratification with respect to TTFT (Figure 1D). Our analysis confirms the predictive value of simplified IPI in decision making. In the era of small molecules, that can mitigate the negative impact of biological factors, simplified IPI helps in identifying poor risk cases that may benefit of novel drugs as well as a subgroup of non-high risk patients that may be still treated with standard immunochemotherapy. Authors have no affiliations that they consider to be relevant and important with any organization that to any author's knowledge has a direct interest, particularly a financial interest, in the subject matter discussed.