Key Points: CLL patients harboring mutated IGHV genes but neither 11q or 17p deletion experience durable remission after frontline FCR.

Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early stage disease and managed with active surveillance. The individual course of subjects 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 CLL patients with early, asymptomatic disease (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 IGHV genes, absolute lymphocyte count >15 x10⁹/l, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (one point each), and separated low-risk (score 0), intermediate-risk (score 1) and high-risk patients (score 2-3) 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 of 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.

PURPOSE: High levels of circulating tumor plasma cells (CTC-high) in patients with multiple myeloma are a marker of aggressive disease. We aimed to confirm the prognostic impact and identify a possible cutoff value of CTC-high for the prediction of progression-free survival (PFS) and overall survival (OS), in the context of concomitant risk features and minimal residual disease (MRD) achievement.METHODS: CTC were analyzed at diagnosis with two-tube single-platform flow cytometry (sensitivity 4 × 10^–5) in patients enrolled in the multicenter randomized FORTE clinical trial (ClinicalTrials.gov identifier: NCT02203643 ). MRD was assessed by second-generation multiparameter flow cytometry (sensitivity 10^–5). We tested different cutoff values in series of multivariate (MV) Cox proportional hazards regression analyses on PFS outcome and selected the value that maximized the Harrell's C-statistic. We analyzed the impact of CTC on PFS and OS in a MV analysis including baseline features and MRD negativity.RESULTS: CTC analysis was performed in 401 patients; the median follow-up was 50 months (interquartile range, 45-54 months). There was a modest correlation between the percentage of CTC and bone marrow plasma cells ( r = 0.38). We identified an optimal CTC cutoff of 0.07% (approximately 5 cells/µL, C-index 0.64). In MV analysis, CTC-high versus CTC-low patients had significantly shorter PFS (hazard ratio, 2.61; 95% CI, 1.49 to 2.97, P < .001; 4-year PFS 38% v 69%) and OS (hazard ratio, 2.61; 95% CI, 1.49 to 4.56; P < .001; 4-year OS 68% v 92%). The CTC levels, but not the bone marrow plasma cell levels, affected the outcome. The only factor that reduced the negative impact of CTC-high was the achievement of MRD negativity (interaction P = .039).CONCLUSION: In multiple myeloma, increasing levels of CTC above an optimal cutoff represent an easy-to-assess, robust, and independent high-risk factor. The achievement of MRD negativity is the most important factor that modulates their negative prognostic impact.

Background: Small nucleolar RNAs (snoRNAs) and small Cajal body-specific RNAs are non-coding RNAs involved in the maturation of other RNA molecules. Alterations of sno/scaRNA expression may play a role in cancerogenesis. This study elucidates the patterns of sno/scaRNA expression in 211 chronic lymphocytic leukemia (CLL) patients (Binet stage A) also in comparison with those of different normal B-cell subsets. Methods: The patterns of sno/scaRNA expression in highly purified CD19⁺ B-cells of 211 CLL patients and in 18 normal B-cell samples - 6 from peripheral blood, and 12 from tonsils (4 germinal center, 2 marginal zone, 3 switched memory and 3 naïve B-cells) - were analyzed on the Affymetrix GeneChip® Human Gene 1.0 ST array. Results: CLLs display a sno/scaRNAs expression profile similar to normal memory, naïve and marginal-zone B-cells, with the exception of a few down-regulated transcripts (SNORA31, -6, -62, and -71C). Our analyses also suggest some heterogeneity in the pattern of sno/scaRNAs expression which is apparently unrelated to the major biological (ZAP-70 and CD38), molecular (IGHV mutation) and cytogenetic markers. Moreover, we found that SNORA70F was significantly down-regulated in poor prognostic subgroups and this phenomenon was associated with the down-regulation of its host gene COBLL1. Finally, we generated an independent model based on SNORA74A and SNORD116-18 expression, which appears to distinguish two different prognostic CLL groups. Conclusions: These data extend the view of sno/scaRNAs deregulation in cancer and may contribute to discover novel biomarkers associated with the disease and potentially useful to predict the clinical outcome of early stage CLL patients.