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Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3–9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.

Translocation t(4;12)(q11‐13;p13) is a recurrent but very rare chromosomal aberration in acute myeloid leukaemia (AML) resulting in the non‐constant expression of a CHIC2/ETV6 fusion transcript. We report clinico‐biological features, molecular characteristics and outcomes of 21 cases of t(4;12) including 19 AML and two myelodysplastic syndromes (MDS). Median age at the time of t(4;12) was 78 years (range, 56–88). Multilineage dysplasia was described in 10 of 19 (53%) AML cases and CD7 and/or CD56 expression in 90%. FISH analyses identified ETV6 and CHIC2 region rearrangements in respectively 18 of 18 and 15 of 17 studied cases. The t(4;12) was the sole cytogenetic abnormality in 48% of cases. The most frequent associated mutated genes were ASXL1 (n = 8/16, 50%), IDH1/2 (n = 7/16, 44%), SRSF2 (n = 5/16, 31%) and RUNX1 (n = 4/16, 25%). Interestingly, concurrent FISH and molecular analyses showed that t(4;12) can be, but not always, a founding oncogenic event. Median OS was 7.8 months for the entire cohort. In the 16 of 21 patients (76%) who received antitumoral treatment, overall response and first complete remission rates were 37% and 31%, respectively. Median progression‐free survival in responders was 13.7 months. Finally, t(4;12) cases harboured many characteristics of AML with myelodysplasia‐related changes (multilineage dysplasia, MDS‐related cytogenetic abnormalities, frequent ASXL1 mutations) and a poor prognosis.

Erdheim‐Chester disease (ECD) is frequently associated with clonal hematopoiesis and myeloid neoplasms (MN), but clinical phenotype and response to kinase inhibitors (KI) in this setting remain unclear. We analyzed 67 patients with ECD associated with MN (ECD‐MN) from a French national cohort and assessed ECD treatment response, MN progression, and leukemic transformation. Outcomes were compared with those of 348 patients with ECD without MN. ECD‐MN were characterized by low blast counts and favorable MN prognostic scores. Compared with ECD patients without MN, those with MN were older (median 65 vs. 59 years, P < 0.0001) and had more frequent cardiac (54% vs. 37%, P < 0.01), pulmonary (48% vs. 31%, P < 0.01), gastrointestinal (34% vs. 11%, P < 0.0001), and lymph node involvement (31% vs. 8%, P < 0.0001). KI therapy led to higher ECD response rates at 6 and 12 months compared with pegylated‐interferon α (Peg‐IFN) (96% vs. 58%, P = 0.02). MN progression and leukemic transformation at 6 months occurred, respectively, in 25% and 3% of KI‐treated patients versus 25% and 18% of those treated with Peg‐IFN. After a median follow‐up of 25 (12–38) months on KI, the mutational landscape remained unchanged. Median overall survival was shorter in patients with MN (76 vs. 163 months, P < 0.001). In conclusion, ECD associated with MN represents a distinct clinical entity, marked by broader organ involvement and poorer prognosis. KI therapy provides a superior response without increasing the risk of MN progression or leukemic transformation, supporting its use as a frontline treatment in this population.

Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) into aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). We characterize 58 primary human RS samples by genome-wide DNA methylation and whole-transcriptome profiling. Our comprehensive approach determines RS DNA methylation profile and unravels a CLL epigenetic imprint, allowing CLL-RS clonal relationship assessment without the need of the initial CLL tumor DNA. DNA methylation- and transcriptomic-based classifiers were developed, and testing on landmark DLBCL datasets identifies a poor-prognosis, activated B-cell-like DLBCL subset in 111/1772 samples. The classification robustly identifies phenotypes very similar to RS with a specific genomic profile, accounting for 4.3-8.3% of de novo DLBCLs. In this work, RS multi-omics characterization determines oncogenic mechanisms, establishes a surrogate marker for CLL-RS clonal relationship, and provides a clinically relevant classifier for a subset of primary “RS-type DLBCL” with unfavorable prognosis. Richter syndrome (RS) is the transformation of chronic lymphocytic leukaemia (CLL) into aggressive lymphoma, in most cases diffuse large B-cell lymphoma (DLBCL). Here, the authors characterize the DNA methylation and transcriptomic profiles of RS samples, find a clonally-related CLL epigenetic imprint, and develop classifiers for “RS-type” de novo DLBCLs.

Waldenström Macroglobulinaemia (WM) is sometimes difficult to differentiate from marginal zone lymphoma (MZL), two entities with overlapping features for which no single marker assessed by multiparameter flow cytometry (MFC) is specific. The aim of this work was to establish a diagnostic phenotypic score for bone marrow (BM) and peripheral blood (PB) WM samples, to differentiate it from MZL and to improve the detection of small circulating WM clones. This study revealed a distinct phenotypic profile between WM and MZL B‐cells. WM B‐cells showed decreased expression of CD19, FMC7, CD22, CD27 and increased expression of CD79b and CD13. Supervised and unsupervised MFC analyses were used to define a phenotypic scoring system: a score of 3/6 or greater in BM or 4/7 or greater in PB samples supported the diagnosis of WM (sensitivity of 97.9% and 94.1% and specificity of 80.0% and 93.5%, respectively). These results were validated in a prospective cohort with very high sensitivity and specificity for the two scoring systems. Clinico‐biological correlations showed that the absence or low expression of CD38 on BM WM B‐cells was significantly associated with increased BM and PB infiltration (p < 0.0001 and p = 0.0024 respectively) and CXCR4 mutation (p < 0.0001). These results demonstrate that MFC can be used to differentiate WM from MZL with a scoring system that can be easily implemented in routine practice.

The different types of drug resistance encountered in chronic lymphocytic leukemia (CLL) cannot be fully accounted for by the 17p deletion (and/or TP53 mutation), a complex karyotype (CK), immunoglobulin heavy‐chain variable region genes (IGHV) status and gene mutations. Hence, we sought to assess the associations between recurrent genomic abnormalities in CLL and the disease's development and outcome. To this end, we analyzed 64 samples from patients with CLL and gain of the short arm of chromosome 2 (2p+), which is frequent in late‐stage and relapsed/refractory CLL. We found that fludarabine/cyclophosphamide/rituximab (a common first‐line treatment in CLL) is not effective in removing the 2p+ clone ‐ even in samples lacking a CK, the 17p deletion or unmutated IGHV. Our results suggest strongly that patients with CLL should be screened for 2p+ (using karyotyping and fluorescence in situ hybridization) before a treatment option is chosen. Longer follow‐up is now required to evaluate bendamustine‐rituximab, ibrutinib, and idelalisib‐rituximab treatments. We report on a series of 64 chronic lymphocytic leukemia (CLL) patients harboring a 2p gain. To the best of our knowledge, this is the largest yet studied cohort of patients with 2p+ CLL. We performed a detailed longitudinal analysis of samples collected before and after standard CLL treatments.