The role of subclonal
mutations, defined by a variant allele frequency of <20%, has not been addressed in acute myeloid leukemia yet. We, therefore, analyzed their prognostic value in a cohort of ...1,537 patients with newly diagnosed disease, prospectively treated within three trials of the "German-Austrian Acute Myeloid Leukemia Study Group". Mutational analysis was performed by targeted deep sequencing and patients with
mutations were categorized by their variant allele frequency into groups with frequencies >40%, 20%-40% and <20%. A total of 108
mutations were found in 98 patients (6.4%). Among these, 61 patients had variant allele frequencies >40%, 19 had variant allele frequencies between 20%-40% and 18 had frequencies <20%. Compared to specimens with clonal
mutations, those with subclonal ones showed significantly fewer complex karyotypes and chromosomal losses. In either
-mutated group, patients experienced significantly fewer complete responses (
<0.001) and had worse overall and event-free survival rates (
<0.0001). In Cox regression analyses adjusting for age, white blood cell count, cytogenetic risk and type of acute myeloid leukemia, the adverse prognostic effect of
mutations remained significant for all
-mutated subgroups. These data suggest that subclonal
mutations are a novel prognostic parameter in acute myeloid leukemia and emphasize the usefulness of next-generation sequencing technologies for risk stratification in this disorder. The study was registered at ClinicalTrials.gov with number NCT00146120.
The tumor microenvironment (TME) is a critical regulator of tumor growth, progression, and metastasis. Since immune cells represent a large fraction of the TME, they play a key role in mediating pro- ...and anti-tumor immune responses. Immune escape, which suppresses anti-tumor immunity, enables tumor cells to maintain their proliferation and growth. Numerous mechanisms, which have been intensively studied in recent years, are involved in this process and based on these findings, novel immunotherapies have been successfully developed. Here, we review the composition of the TME and the mechanisms by which immune evasive processes are regulated. In detail, we describe membrane-bound and soluble factors, their regulation, and their impact on immune cell activation in the TME. Furthermore, we give an overview of the tumor/antigen presentation and how it is influenced under malignant conditions. Finally, we summarize novel TME-targeting agents, which are already in clinical trials for different tumor entities.
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.
Summary
In the last few years, treatment of patients exhibiting chronic lymphocytic leukaemia has changed extensively due to advances in the development of targeted therapies. The role of ...immunochemotherapy has been for the most part replace and the guidelines have been modified accordingly. Herein, we give an overview on updated onkopedia guidelines, studded with updates of the landmark studies of the latest American Society of Hematology (ASH) meeting. In addition, since still crucial, recommendations concerning coronavirus disease 2019 (COVID-19) in chronic lymphocytic leukaemia patients will be covered.
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.
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.
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
), 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<0.0001).
We demonstrate that elevated uric acid levels predict poor long-term outcomes in DLBCL patients beyond the NCCN-IPI risk index.
Chemokine receptors and their ligands have been identified as playing an important role in the development of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and Richter syndrome (RS). ...Our aim was to investigate the different expression profiles in de novo DLBCL, transformed follicular lymphoma (tFL), and RS. Here, we profiled the mRNA expression levels of 18 chemokine receptors (
-
,
-
,
and
) using RQ-PCR, as well as immunohistochemistry of seven chemokine receptors (CCR1, CCR4-CCR8 and CXCR2) in RS, de novo DLBCL, and tFL biopsy-derived tissues. Tonsil-derived germinal center B-cells (GC-B) served as non-neoplastic controls. The chemokine receptor expression profiles of de novo DLBCL and tFL substantially differed from those of GC-B, with at least 5-fold higher expression of 15 out of the 18 investigated chemokine receptors (
-
,
,
,
,
,
and
) in these lymphoma subtypes. Interestingly, the de novo DLBCL and tFL exhibited at least 22-fold higher expression of
,
,
, and
compared with RS, whereas no significant difference in chemokine receptor expression profile was detected when comparing de novo DLBCL with tFL. Furthermore, in de novo DLBCL and tFLs, a high expression of CCR7 was associated with a poor overall survival in our study cohort, as well as in an independent patient cohort. Our data indicate that the chemokine receptor expression profile of RS differs substantially from that of de novo DLBCL and tFL. Thus, these multiple dysregulated chemokine receptors could represent novel clinical markers as diagnostic and prognostic tools. Moreover, this study highlights the relevance of chemokine signaling crosstalk in the tumor microenvironment of aggressive lymphomas.
In tumor cells of more than 20 different cancer types, the
-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
-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
expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of
expression and lymphoma infiltration rate as well as a reduction of
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-κB/BCR-target genes. These data indicate that the
-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.
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.
Many of the world’s around 6,000 languages are in danger of disappearing as people give up use of a minority language in favor of the majority language in a process called language shift. Language ...shift can be monitored on a large scale through the use of mathematical models by way of differential equations, for example, reaction–diffusion equations. Here, we use a different approach: we propose a model for language dynamics based on the principles of cellular automata/agent-based modeling and combine it with very detailed empirical data. Our model makes it possible to follow language dynamics over space and time, whereas existing models based on differential equations average over space and consequently provide no information on local changes in language use. Additionally, cellular automata models can be used even in cases where models based on differential equations are not applicable, for example, in situations where one language has become dispersed and retreated to language islands. Using data from a bilingual region in Austria, we show that the most important factor in determining the spread and retreat of a language is the interaction with speakers of the same language. External factors like bilingual schools or parish language have only a minor influence.
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