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Prognostic Indices in Chronic Lymphocytic Leukemia (CLL)

Jan 7, 2021 11:00:00 AM / by Champions Oncology

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The management and treatment of patients with chronic lymphocytic leukemia (CLL) has improved greatly in recent years due to new insights in genetic and molecular factors that contribute to disease progression. Clinical staging systems were first developed more than 40 years ago and include the Rai system[1], which is based on the presence of lymphocytosis (at least 5,000 mm3 monoclonal lymphocytes), enlargement of lymph nodes, spleen or liver, and changes in red blood cells and platelets. The Binet staging system is an alternative method based on the number of affect lymphoid tissue groups and the occurrence of thrombocytopenia and anemia. The Rai system is more common used in the United States, whereas the Binet system is used more frequently in Europe[2].

ChecklistThese systems have been used by clinicians to determine if asymptomatic patients should just be monitored and not treated, or if symptomatic patients should be treated with chemotherapy or immune-oncology-based treatments. 

More recently, several studies identified genetic mutations associated with CLL. The mutational status of the immunoglobulin heavy chain IGHV genes was shown to be particularly informative as patients with unmutated IGHVgenes typically have a more aggressive form of CLL compared with patients with mutated IGHV genes. Other prognostic markers include mutations in TP53, NOTCH1, and SF3B1, elevated expression of ZAP-70 and CD8, and elevated serum levels of lactate dehydrogenase, thymidine kinase and β2-microglobulin[3].  These newly identified markers have been incorporated into alternative prognostic indices (PIs) were first developed to predict overall survival in different CLL clinical studies and have been developed into PIs to determine time to first treatment. The CLL-International Prognostic Index (CLL-IPI) is one example of a PI that uses TP53 status, IGHV mutational status, serum β2-microglobulin concentration, clinical stage (Binet or Rai) and age (≤65 years vs. >65 years). These variables are assigned different weights to stratify patients into four different overall survival risk groups that can be also applied toward treatment recommendations.

Several different CLL PIs exist currently, and meta-analyses of large clinical trials studies and clinical data are being used to compare the prognostic value of these different PIs. For early stage CLL, comparison of these different PIs has shown discordant results, although the PIs appear to show similar results for time to first treatment and risk groups[4]. These PIs may be more helpful in identifying patients better suited to investigational immunotherapy treatments now that molecular and genetic diagnostics can be used to evaluate CLL patients.  Advances in genomics, proteomics and data analysis are identifying new markers associated with CLL progression and are likely to further enhance the value of CLL PIs in the future.

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[1] Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975; 46: 219–3.

[2] Binet JL, Auquier A, Dighiero G, et al. A new prognostic classifi cation of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981; 48: 198–206

[3] International CLL-IPI Working Group. "An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data." The Lancet Oncology 17.6 (2016): 779-790.

[4] González-Gascón-Y-Marín I, Muñoz-Novas C, Figueroa I, Hernández-Sánchez M, Rodríguez-Vicente AE, Quijada-Álamo M, Pérez-Carretero C, Moreno C, Collado R, Espinet B, Puiggros A, Heras NL, Bosch F, Hernández JÁ; Grupo Español de Leucemia Linfática Crónica and Grupo Cooperativo Español de Citogenética Hematológica. Prognosis Assessment of Early-Stage Chronic Lymphocytic Leukemia: Are We Ready to Predict Clinical Evolution Without a Crystal Ball? Clin Lymphoma Myeloma Leuk. 2020 Aug;20(8):548-555.e4.

 

Tags: Hematological Malignancies