The time to first treatment is an independent predictor of overall survival in chronic lymphocytic leukemia

To the Editor: Approximately, 80% of chronic lymphocytic leukemia (CLL) patients are diagnosed in the asymptomatic phase and/or at an early stage of the disease. Although the majority of these patients show a low-risk profile and are managed with active observation, the time to the first treatment (TTFT) in these CLL patients appears quite heterogeneous. Historical clinical observations suggested that CLL patients experiencing early progression develop a persistent risk of short overall survival (OS). Similar findings indicating a correlation between early progression after therapy and short OS have been reported in other hematological malignancies. Here, we hypothesized that an early need for treatment could inform OS also in the CLL setting. Therefore, we investigated the inclusion of the duration of the therapy-free interval following diagnosis as additional prognosticator to refine the OS prediction of well-recognized risk factors in a wide multicenter cohort of newly diagnosed CLL patients on a watch-andwait strategy. The REporting recommendations for tumor MARKer prognostic studies (REMARK) criteria were followed throughout this study. Further details in Supplementary Appendix. Distribution in the whole cohort of 3860 CLL cases of the clinical and biological variables validated in CLL-IPI and Brno-Barcelona score systems, including age, Rai staging, β2-microglobulin, immunoglobulin heavy-chain variable (IGHV) gene mutational status, del(11q) and del(17p), all tested at diagnosis/first presentation, are reported in Supplementary Table 1. Distribution of variables is as expected in a cohort of early-stage CLL. Sufficient information for evaluation of the CLL-IPI and Brno-Barcelona score systems were available in 2573 cases, which were included in the final analysis (Supplementary Figure 1). The median follow-up time was 6.8 years (interquartile range: 4.2–9.9 years). At univariate analyses, age ≥65 years, Rai stages I–II, abnormal β2M serum levels, del(11q), IGHVunmut status and del(17p) were all OS predictors both in univariable and multivariable analysis; this basic model provided an explained variation in mortality (R) and a Harrell's C index of 37.7% and 72.6%, respectively (Supplementary Table 2). Patients experiencing therapy need within 6, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months from diagnosis were defined as TTFT6-60 failures (TTFT6-60Fail). Cases remaining therapy-free within 6–60 months were categorized as TTFT6-60 achievers (TTFT6-60Achieve). OS for TTFT6-60Fail cases was defined as the time from TTFT6-60 failure to death or last follow-up. OS for patients with TTFT6-60Achieve was defined as the survival time from achieving TTFT6-60 until death or last follow-up. In each TTFT6-60 category, patients died before 6–60 months or with <6–60 months of follow-up were excluded from the analysis (Supplementary Figure 1). Cases requiring therapy within 6–60 months (TTFT6-60Fail) experienced a roughly three-time higher risk of dying (Hazard ratios (HRs) ranging from 2.6 to 3.2) as compared to patients with a longer therapy-free interval (TTFT6-60Achieve; reference group, HR = 1) in univariate Cox analyses (Supplementary Table 3). All the investigated cut-offs of TTFT, except the TTFT6 (p = .083), independently predicted the mortality incidence rate (HR ranging from 1.45 to 2.04) in a sequence of multivariable models including all the variables of the CLL-IPI and the Brno-Barcelona scores as potential confounders (Supplementary Table 4). In addition, the inclusion of the biomarker TTFT in the range from TTFT12 to TTFT42 significantly improved the prognostic accuracy of this risk stratification model compared to a model including the CLL-IPI and Brno-Barcelona scores variables alone (Supplementary Table 2), as witnessed by higher values for both R and Harrell's indices (values ranging from 38.6% to 40.4%, and from 72.9% to 73.8%, respectively; Supplementary Table 4) in models that include TTFT values. Conversely, TTFT at time points ranging from 48 to 60 months failed to add prognostic accuracy to the same model in terms of R and Harrel's indices (Supplementary Table 4). Remarkably, the zenith of the prognostic accuracy of TTFT was found at a cut-off value of 18 months (TTFT18; HR 2.04, 95% CI 1.52–2.75; R 40.4%; Harrell's C index 73.8%), while at values of TTFT ranging from 24 to 60 months, a gradual reduction of both R (from 39.8% to 36.3%) and Harrell's C index (from 73.3% to 70.9%) was observed (Supplementary Figure 2). To establish whether the prognostic power of TTFT18Fail was dependent not only on the time of the therapy (i.e., less than 18 months) but also on treatment (i.e., treated/untreated), we performed univariate and multivariable Cox analyses by splitting cases of our cohort in those never-treated (never-treated TTFT18Achieve) from those treated but after 18 months (TTFT18Achieve) and comparing them with TTFT18Fail cases. A significantly shorter OS was accounted for in cases with TTFT18Fail (median 8 years) compared with treated TTFT18Achieve (median 13 years) and with never-treated TTFT18Achieve cases (median 22 years; Supplementary Figure 3). In this context, however, when tested by multivariable analysis (n = 2336), the treated TTFT18Achieve group lost its independent prognostic role with respect to the never-treated TTFT18Achieve group, while TTFT18Fail remained an independent prognostic factor of OS together with del(17p), del(11q), abnormal β2M serum level, IGHVunmut status, and age, but not Rai stage (Supplementary Table 5; R2, 42%; C index, 75%). Received: 6 February 2023 Revised: 15 March 2023 Accepted: 3 April 2023