International Prognostic Score Predicts Time to First Treatment in Patients With Early-Stage CLL

An international prognostic score (IPS-E) consisting of a sum score for three markers for consistently predicted time to first treatment (TTFT) in patients with early-stage chronic lymphocytic leukemia (CLL), according to a study published in Blood. The three markers are unmutated immunoglobulin heavy chain (IGHV) genes, absolute lymphocyte count >15×109/L, and the presence of palpable lymph nodes.

Study lead author Davide Rossi, MD, of the Oncology Institute of Southern Switzerland, said that the IPS-E may be helpful in counseling patients with early-stage CLL. It also could help define the population that should be treated, as the individual course of the disease is heterogenous and the probability of requiring treatment other than active surveillance is difficult to anticipate at time of diagnosis. “Moreover,” Dr. Rossi added, “the IPS-E could help the treating physician better allocate medical resources, such as deciding on the amplitude of the interval between clinical assessments according to the risk group.”

To develop the IPS-E, researchers from Europe, the U.K., and the U.S. performed a retrospective analysis of individual patient datasets from 11 cohorts that included patients with:

  • diagnosis after 1996, confirmed by flow cytometry
  • Binet stage A CLL
  • active surveillance as initial management

In total, 4,933 patients with early-stage CLL from the 11 international cohorts were included in this analysis. The study endpoint was TTFT, defined as the duration between presentation and the initiation of first treatment for CLL because of progression to symptomatic disease.

The investigators considered 19 baseline biomarkers as covariates for development of the IPS-E prognostic index, including:

  • clinical characteristics (age, sex, >1 palpable lymph nodes with a diameter of >1 cm, and palpable spleen)
  • laboratory values (hemoglobin level, platelet count, absolute lymphocyte count, and beta-2-microglobulin)
  • cytogenetic abnormalities as assessed by FISH [del(17p), del(11q), trisomy 12, del(13q)]
  • gene mutations (IGHV, ATM, MYD88, NOTCH1, SF3B1, and TP53)

In a multivariable analysis, four of the variables were independently associated with TTFT:

  • unmutated IGHV genes
  • absolute lymphocyte count >15×109/L
  • palpable lymph nodes
  • trisomy 12

The researchers then repeated the multivariable analysis in each single validation Binet A cohort. In these analyses, trisomy 12 fell out, so only unmutated IGHV genes, absolute lymphocyte count >15 x109/L, and palpable lymph nodes were the most stable biomarkers associated with TTFT. These variables consistently maintained the highest percentage of selection (>50%) across validation cohorts.

Using these three biomarkers, the researchers built the score to be the sum of the covariates, with one point attributed to each variable. The score classified patients by risk status:

  • IPS-E score 0: low risk
  • IPS-E score 1: intermediate risk
  • IPS-E score 2 to 3: high-risk patients

The IPS-E was effective for discriminating the three risk groups in terms of TTFT, according to a sensitivity analysis that accounted for pretreatment mortality as competing risk. The ability of the score to predict TTFT was represented by a concordance statistic (C-index) of 0.74 in the training series and a C-index of 0.70 in the aggregate of validation series. According to a meta-analysis of both the training and validation cohorts, the 5-year cumulative risk of treatment initiation was 8.4% among the low-risk group, 28.4% among the intermediate-risk group, and 61.2% among the high-risk group.

According to Dr. Rossi, the IPS-E represents a prognostic tool that adds additional information to other available scores, most of which aim at predicting overall survival of patients with CLL in need of therapy. “Compared with other scores, IPS-E is simple, being the sum of only three variables,” he said. Dr. Rossi added that the calculation of the IPS-E requires the assessment of a single molecular variable – IGHV mutation status – for which testing is widely available and standardized. “The current approach with patients with early-stage CLL is based on the clinical and the blood cell count assessment, leaving the molecular study at the timepoint of progression to an active disease requiring treatment,” he said. “Since IGHV status never changes during the course of disease, it might be evaluated at the time of first diagnosis to provide an estimate of TTFT to the patient and to the treating physician.”

Dr. Rossi suggested that the IPS-E will require prospective evaluation in other patient cohorts, but the current instrument “can be regarded as a building block to which newly discovered independent outcome predictors for patients with early-stage CLL could be added. A prospective study could be used to further examine and potentially strengthen the IPS-E.”

The authors report no relevant conflicts of interest.


Condoluci A, Terzi di Bergamo L, Langerbeins P, et al. International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia. Blood. 2020;135:1859-1869.