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Approximately 8% of all non-Hodgkin lymphomas are extranodal marginal zone B cell lymphomas of mucosa-associated lymphoid tissue (MALT), also known as MALT lymphomas. These arise at a wide range of different extranodal sites, with most cases affecting the stomach, the lung, the ocular adnexa and the thyroid. The small intestine is involved in a lower percentage of cases. Lymphoma growth in the early stages is associated with long-lasting chronic inflammation provoked by bacterial infections (e.g., Helicobacter pylori or Chlamydia psittaci infections) or autoimmune conditions (e.g., Sjögren’s syndrome or Hashimoto thyroiditis). While these inflammatory processes trigger lymphoma cell proliferation and/or survival, they also shape the microenvironment. Thus, activated immune cells are actively recruited to the lymphoma, resulting in either direct lymphoma cell stimulation via surface receptor interactions and/or indirect lymphoma cell stimulation via secretion of soluble factors like cytokines. In addition, chronic inflammatory conditions cause the acquisition of genetic alterations resulting in autonomous lymphoma cell growth. Recently, novel agents targeting the microenvironment have been developed and clinically tested in MALT lymphomas as well as other lymphoid malignancies. In this review, we aim to describe the composition of the microenvironment of MALT lymphoma, the interaction of activated immune cells with lymphoma cells and novel therapeutic approaches in MALT lymphomas using immunomodulatory and/or microenvironment-targeting agents.

SummaryIn recent years, treatment of patients exhibiting chronic lymphocytic leukemia has changed extensively due to advances in the development of targeted therapies. The Bcl‑2 inhibitor venetoclax demonstrated outstanding results when used in mono- as well as combination therapy. Minimal residual disease (MRD) measurement has become an important endpoint in most studies and shows high prognostic potential. With upcoming combination strategies, the role of MRD measurement has also increased and is likely to become a routine marker in future clinical practice.

Overexpression of bcl‐2 and c‐myc are defining features of double‐expressor‐lymphoma (DEL) but may also occur separately in patients with primary central nervous system lymphoma (PCNSL). Despite all progress in optimizing treatment regimen, there is lack of sufficient risk stratification models. Here, we first describe the relationship between DEL biology, the National Comprehensive Cancer Network International Prognostic Index (NCCN‐IPI), treatment response, disease progression, and mortality in PCNSL. In this study, we determined c‐myc and bcl‐2 status immunohistochemically in samples of 48 patients with newly diagnosed PCNSL and followed these patients for a median interval of 6.2 years. Twelve, 18, and 17 patients harbored none, one, or both DEL features. Corresponding overall response rates after first‐line therapy were strongly associated with DEL biology (100%, 42%, and 44% in patients with 0, 1, or 2 DEL features). Patients with one or both DEL features had a 5‐fold and 13‐fold higher 5‐year risk of progression and/or death than patients without DEL features. These associations prevailed after adjusting for the NCCN‐IPI. DEL improved the discriminatory capability of the NCCN‐IPI (P = .0001). Furthermore, we could show that addition of DEL biology to the NCCN‐IPI significantly improved the score's discriminatory potential both toward progression‐free survival (increase in Harell's c = 0.15, P = .005) and overall survival (increase in Harell's c = 0.11, P = .029). In conclusion, DEL biology is a strong and simple‐to‐use predictor of adverse outcome in PCNSL. Addition of DEL to the NCCN‐IPI improves its prognostic potential. Disease progression from PCNSL harboring both DEL features is invariably fatal. This defines a novel PCNSL patient subset with a great unmet need for improved therapy.

Background A combination of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard first-line therapy for diffuse large B cell lymphoma (DLBCL), the most common aggressive lymphoma in adults. One of the major adverse effects of this regimen is vincristine-induced polyneuropathy which leads to discontinuation of vincristine in up to 30% of DLBCL-patients. Dose reduction of vincristine might worsen treatment outcomes of DLBCL but identification of treatment alternatives for patients exhibiting peripheral neuropathy during R-CHOP is an unmet need in hematology. Methods In this retrospective cohort study, comprising 987 patients with de novo DLBCL, we delineated the role of vinorelbine as a substitute for vincristine in R-CHOP by measuring improvements in neuropathy and outcome variables. Results Five-year overall survival (OS) and progression-free survival (PFS) were 72.6% and 63.1% in patients who received regular doses of vincristine, as compared to 60.6% and 51.7% in patients who received reduced doses of vincristine (p = 0.022 and p = 0.003, respectively). Of 199 patients who switched to vinorelbine, the majority experienced an improvement of neuropathy Furthermore, vinorelbine-switched patients showed favorable oncologic outcomes. Conclusion Replacement of vincristine by vinorelbine due to neuropathy is effective and safe, and results in a significant improvement in neuropathy as compared to treatment with R-CHOP.

In tumor cells of more than 20 different cancer types, the CXCR4-CXCL12-axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher CXCR4 expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of CXCL12 expression and lymphoma infiltration rate as well as a reduction of CXCR4 expression in remission of bone marrow involvement after treatment. Additionally, we investigated the effects of three CXCR4 antagonists in vitro. Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. WK1 demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of pro-apoptotic genes of the BCL2-family in CXCR4-positive lymphoma cell lines. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-&kappa, B/BCR-target genes. These data indicate that the CXCR4-CXCL12-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.

Background: Blood-based parameters are gaining increasing interest as potential prognostic biomarkers in patients with diffuse large B-cell lymphoma (DLBCL). The aim of this study was to comprehensively evaluate the prognostic significance of pretreatment plasma uric acid levels in patients with newly diagnosed DLBCL. Methods: The clinical course of 539 DLBCL patients, diagnosed and treated between 2004 and 2013 at two Austrian high-volume centres with rituximab-based immunochemotherapy was evaluated retrospectively. The prognostic influence of uric acid on overall survival (OS) and progression-free survival (PFS) were studied including multi-state modelling, and analysis of conditional survival. Results: Five-year OS and PFS were 50.4% (95% CI: 39.2–60.6) and 44.0% (33.4–54.0) in patients with uric acid levels above the 75th percentile of the uric acid distribution (Q3, cut-off: 6.8 mg dl−1), and 66.2% (60.4–71.5) and 59.6% (53.7–65.0%) in patients with lower levels (log-rank P=0.002 and P=0.0045, respectively). In univariable time-to-event analysis, elevated uric acid levels were associated with a worse PFS (hazard ratio (HR) per 1 log increase in uric acid 1.47, 95% CI: 1.10–1.97, P=0.009) and a worse OS (HR=1.60, 95% CI: 1.16–2.19, P=0.004). These associations prevailed upon multivariable adjustment for the NCCN-IPI score. Uric acid levels significantly improved the predictive performance of the R-IPI and NCCN-IPI scores, and in multi-state analysis, it emerged as a highly significant predictor of an increased risk of death without developing recurrence (transition-HR=4.47, 95% CI: 2.17–9.23, P

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The role of subclonal TP53 mutations, defined by a variant allele frequency of 40%, 20%-40% and 40%, 19 had variant allele frequencies between 20%-40% and 18 had frequencies

Introduction: The interaction of the chemokine receptor CXCR4 and its ligand CXCL12 appears to be implicated in many important biological processes such as proliferation, survival, migration, and/or invasion. Furthermore, it is important for normal leukocyte trafficking. Deregulation of this axis is frequently observed in several hematologic malignancies. In diffuse large B cell lymphomas (DLBCL), the CXCR4-CXCL12 axis is still largely unexplored and published data are contradictive. Hence, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. Methods: We determined the CXCR4 and CXCL12 expression levels in NGCB- and GCB-DLBCL consisting of primary and transformed follicular lymphomas (n=77 in total), the corresponding bone marrow samples (n=63) and non-neoplastic germinal center-B cells (GC-B, n=5) serving as non-malignant control. To investigate the effects of CXCR4 antagonists in vitro and their function in regulation of important pathways (JNK, ERK1/2 and NF-κB) known to be involved in lymphomagenesis, we treated lymphoma cell lines with three different CXCR4 antagonists, AMD070, AMD3100 and WK1 (a novel nicotinic acid derivative of AMD070 - synthesized by us), followed by functional assays and gene expression profile. Results: CXCR4 was 140-fold higher expressed in DLBCL compared to non-neoplastic GC-B cells. Interestingly, higher CXCR4 expression correlated to a clinically advanced stage, to bone marrow infiltration and worse cancer-specific survival in DLBCL. Further expression analysis by using the corresponding bone marrow biopsies demonstrated that CXCL12 expression correlated to the lymphoma infiltration rate and that CXCR4 expression was reduced in remission under therapy. Moreover, two CXCR4 antagonists - AMD070 and especially WK1 - exerted pro-apoptotic effects on CXCR4 positive lymphoma cells in vitro and induced the expression of certain pro-apoptotic genes in CXCR4 positive cell lines. Remarkably, these effects were more pronounced for the WK1. Finally, WK1 treatment resulted in reduced expression of JNK-, ERK1/2- and NFκB/BCR-target genes. Conclusion: Our data demonstrate that the CXCR4-CXCL12 axis is involved in the pathogenesis of DLBCL. Since CXCR4 antagonists exert pro-apoptotic effects and impact lymphoma relevant pathways, they represent interesting molecules to develop novel therapeutic agents. Disclosures No relevant conflicts of interest to declare.

Nuclear orphan receptor NR4A1 exerts an essential tumor suppressor function in aggressive lymphomas. In this study, we investigated the hypothesized contribution of the related NR4A family member NR4A3 to lymphomagenesis. In aggressive lymphoma patients, low expression of NR4A3 was associated with poor survival. Ectopic expression or pharmacological activation of NR4A3 in lymphoma cell lines led to a significantly higher proportion of apoptotic cells. In a mouse NSG xenograft model of lymphoma (stably transduced SuDHL4 cells), NR4A3 expression abrogated tumor growth, compared with vector control and uninduced cells that formed massive tumors. Transcript analysis of four different aggressive lymphoma cell lines overexpressing either NR4A3 or NR4A1 revealed that apoptosis was driven similarly by induction of BAK, Puma, BIK, BIM, BID, and Trail. Overall, our results showed that NR4A3 possesses robust tumor suppressor functions of similar impact to NR4A1 in aggressive lymphomas. Cancer Res; 77(9); 2375–86. ©2017 AACR.

Introduction Acute myeloid leukemia (AML) with "TP53 mutation, chromosomal aneuploidy or both" has recently been described as a distinct AML subgroup exhibiting an exceedingly adverse prognosis. Therefore, testing for TP53 mutations has become an essential part of the European LeukemiaNet 2017 recommendations for risk classification. However, the incidence and pathogenic role of subclonal TP53 mutations defined by a variant allele frequency (VAF) Methods We evaluated the prognostic value of TP53 VAFs in a cohort of 1537 patients with newly diagnosed AML, prospectively treated within 3 trials of the "German-Austrian AML Study Group". Mutation testing was performed by targeted deep sequencing and patients with TP53 mutations were categorized into 3 groups defined by VAFs 40%, respectively. Results A total of 108 TP53 mutations were identified in 98 patients (6.4%). Amongst those, 61 patients showed a VAF >40%, 19 a VAF between 20% and 40% and 18 a VAF 40%, 49/61 [80%]; 20%-40%, 17/19 [89%]; 40%, 49/61 [80%]; 20%-40%, 16/19 [84%]; 40%, 42.6%; 20%-40%, 57.9%; 40%, 5.8 months; 20%-40%, 6.9 months; 40%, 5.2 months; 20%-40%, 6.9 months; Conclusion In our study on a large cohort of AML patients, TP53 mutated subclones defined by VAF Disclosures No relevant conflicts of interest to declare.