Successful treatment of primary cutaneous diffuse large B cell lymphoma leg type with single agent venetoclax

Successful treatment of primary cutaneous diffuse large B cell lymphoma leg type with single agent venetocla

CUDC-907 blocks multiple pro-survival signals and abrogates microenvironment protection in CLL.

CUDC-907, a dual PI3K/HDAC inhibitor, has been proposed to have therapeutic potential in hematopoietic malignancies. However, the molecular mechanisms of its effects in chronic lymphocytic leukaemia (CLL) remain elusive. We show that CLL cells are sensitive to CUDC-907, even under conditions similar to the protective microenvironment of proliferation centres. CUDC-907 inhibited PI3K/AKT and HDAC activity, as expected, but also suppressed RAF/MEK/ERK and STAT3 signalling and reduced the expression of anti-apoptotic BCL-2 family proteins BCL-2, BCL-xL, and MCL-1. Moreover, CUDC-907 downregulated cytokines BAFF and APRIL and their receptors BAFFR, TACI, and BCMA, thus blocking BAFF-induced NF-κB signalling. T cell chemokines CCL3/4/17/22 and phosphorylation of CXCR4 were also reduced by CUDC-907. These data indicated that CUDC-907 abrogates different protective signals and suggested that it might sensitize CLL cells to other drugs. Indeed, combinations of low concentrations of CUDC-907 with inhibitors of BCL2, BTK, or the NF-κB pathway showed a potent synergistic effect. Our data indicate that, apart from its known functions, CUDC-907 blocks multiple pro-survival pathways to overcome microenvironment protection in CLL cells. This provides a rationale to evaluate the clinical relevance of CUDC-907 in combination therapies with other targeted inhibitors

Long-term follow-up of patients with CLL treated with the selective Bruton's tyrosine kinase inhibitor ONO/GS-4059.

[First paragraph] The inhibitor of Bruton’s tyrosine kinase (BTK) ibrutinib has transformed the treatment of chronic lymphocytic leukemia (CLL); many patients with previously untreatable disease may now enter durable remissions.1,2 Nevertheless, the kinome of ibrutinib is broad, resulting in toxicities including bleeding, arthralgia, diarrhea, hypertension, and atrial fibrillation.3-6 Up to 20% of patients discontinue ibrutinib due to toxicity.7-9 More selective BTK inhibitors (BTKis) include ONO/GS-4059, acalabrutinib, and BGB-3111. Preliminary data indicate that these drugs have comparable activity to ibrutinib, but with reduced toxicities.10-12 However, long-term follow-up and response data have not yet been reported. We provide an updated, 3-year follow-up of treatment efficacy, safety, and laboratory correlates, including baseline mutational profiling of CLL patients in the phase 1 ONO/GS-4059 extension study

DNA methylation profiling of hepatosplenic T-cell lymphoma.

[First paragraph] Hepatosplenic T–cell lymphoma (HSTL) is a malignancy with an unfavorable outcome mainly affecting young adults. To discover genes showing altered DNA-methylation in HSTL we performed array-based DNA methylation profiling of HSTL cells from 11 patients and compared the findings to those obtained from purified non-neoplastic ab-positive and gd-positive T cells. The procedure identified 1,339 hypermethylated and 2,774 hypomethylated CpG-loci in HSTL compared to controls. DNA methylation changes in HSTL were enriched for regulatory elements, like enhancers. Considering the top 100 differentially-methylated CpGs from various subset comparisons, we identified eight consistently hypermethylated genes (BCL11B, CD5, CXCR6, GIMAP7, LTA, SEPT9, UBAC2, UXS1) and four consistently hypomethylated genes (ADARB1, NFIC, NR1H3, ST3GAL3) in HSTL

Improved classification of leukemic B-cell lymphoproliferative disorders using a transcriptional and genetic classifier.

B-cell chronic lymphoproliferative disorders (B-CLPD) encompass a group of hematologic tumors that often present with leukemic involvement.1 Their heterogeneity and the lack of relatively specific diagnostic markers for most of these diseases make their diagnosis challenging, especially in cases that only have blood involvement or when histology is not available. With the currently used immunophenotypic and molecular markers, around 10% of B-CLPD cases remain unclassifiable and are categorized as B-CLPD, not otherwise specified (B-CLPD, NOS). Few recurrent gene mutations and chromosomal abnormalities have been documented in some entities: BRAF and MYD88 mutations in hairy cell leukemia (HCL) and lymphoplasmacytic lymphoma (LPL), respectively,2,3 in addition to the recurrent 7q31–q32 deletion in splenic marginal zone lymphoma (SMZL).1 However, none of them are diagnostic hallmarks of any particular entity. Gene expression profiling studies have recognized specific signatures that identify most common hematological neoplasms.4,5 Based on these results we postulated that the analysis of the gene expression profiling (GEP) of a large series of leukemic B-CLPD could identify specific signatures for each leukemic disease entity. These signatures could be useful for the classification of cases with undetermined diagnosis (B-CLPD, NOS). In this study, we have investigated the GEP of a large series of leukemic lymphoid neoplasms and identified specific gene signatures for most entities that were validated in an independent cohort. We have also derived and validated a simplified quantitative polymerase chain reaction (qPCR)-based 8-gene assay that reliably recognized these entities and could assist in the diagnosis in routine practice, particularly in atypical cases and B-CLPD, NOS

Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology.

The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies