Malignant inflammation in cutaneous T-cell lymphoma: a hostile takeover

Cutaneous T-cell lymphomas (CTCL) are characterized by the presence of chronically inflamed skin lesions containing malignant T cells. Early disease presents as limited skin patches or plaques and exhibits an indolent behavior. For many patients, the disease never progresses beyond this stage, but in approximately one third of patients, the disease becomes progressive, and the skin lesions start to expand and evolve. Eventually, overt tumors develop and the malignant T cells may disseminate to the blood, lymph nodes, bone marrow, and visceral organs, often with a fatal outcome. The transition from early indolent to progressive and advanced disease is accompanied by a significant shift in the nature of the tumor-associated inflammation. This shift does not appear to be an epiphenomenon but rather a critical step in disease progression. Emerging evidence supports that the malignant T cells take control of the inflammatory environment, suppressing cellular immunity and anti-tumor responses while promoting a chronic inflammatory milieu that fuels their own expansion. Here, we review the inflammatory changes associated with disease progression in CTCL and point to their wider relevance in other cancer contexts. We further define the term "malignant inflammation" as a pro-tumorigenic inflammatory environment orchestrated by the tumor cells and discuss some of the mechanisms driving the development of malignant inflammation in CTCL

Targeting histone deacetyalses in the treatment of B- and T-cell malignancies

HDAC inhibitors (HDACI) are now emerging as one of the most promising new classes of drugs for the treatment of select forms of non-Hodgkin’s lymphoma (NHL). They are particularly active in T-cell lymphomas, possibly hodgkin’s lymphoma and indolent B cell lymphomas. Presently, two of these agents, vorinostat and romidepsin, have been approved in the US for the treatment of relapsed and refractory cutaneous T cell lymphomas (CTCL). Initially, these agents were developed with the idea that they affected transcriptional activation and thus gene expression, by modulating chromatin condensation and decondensation. It is now clear that their effects go beyond chromatin and by affecting the acetylation status of histones and other intra-cellular proteins, they modify gene expression and cellular function via multiple pathways. Gene expression profiles and functional genetic analysis has led to further understanding of the various molecular pathways that are affected by these agents including cell cycle regulation, pathways of cellular proliferation, apoptosis and angiogenesis all important in lymphomagenesis. There is also increasing data to support the effects of these agents on T cell receptor and immune function which may explain the high level of activity of these agents in T cell lymphomas and hodgkin’s lymphoma. There is ample evidence of epigenetic dysregulation in lymphomas which may underlie the mechanisms of action of these agents but how these agents work is still not clear. Current HDAC inhibitors can be divided into at least four classes based on their chemical structure. At present several of these HDAC inhibitors are in clinical trials both as single agents and in combination with chemotherapy or other biological agents. They are easy to administer and are generally well tolerated with minimal side effects. Different dosing levels and schedules and the use of isospecific HDAC inhibitors are some of the strategies that are being employed to increase the therapeutic effect of these agents in the treatment of lymphomas. There may also be class differences that translate into specific activity against different lymphoma. HDAC inhibitors will likely be incorporated into combinations of targeted therapies both in the upfront and relapsed setting for lymphomas

Centre effect on treatment outcome for patients with untreated acute myelogenous leukaemia? An analysis of the AML 8A study of the Leukemia Cooperative Group of the EORTC and GIMEMA

In the AML 8A study patients were treated with remission-induction therapy followed by one consolidation course. Patients in complete remission (CR) were randomised between autologous bone marrow transplantation (ABMT) and a second intensive consolidation course, except for those with a histocompatible sibling donor, who received allogeneic bone marrow transplantation (alloBMT). This analysis was performed to determine whether centres which only performed induction and consolidation therapy, achieved similar results as centres who also performed transplantation. 542/676 (80%) from transplantation centres and 150/194 (77%) from referring centres achieved CR, with an early death rate of 5% and 11%, respectively (P = 0.01). 66% of patients with a donor from transplantation centres received alloBMT in first CR compared with 57% from referring centres (P = 0.2), Transplantation centres randomised 64% of patients without a donor, referring centres 47% (P = 0.04). The full protocol treatment was completed by 275/542 (51%) and 61/150 (41%) patients, respectively (P = 0.04). The overall survival rate at 6 years from diagnosis was 34% and 36%, respectively (P = 0.9). In conclusion, the type of centre did not appear to have an influence on overall survival. The feasibility of the study was acceptable for both types of centres. The referring centres applied more selection for transplantation. Despite a more intensive second-line treatment at transplantation centres, the overall outcome remained similar to that of referring centres. (C) 1999 Elsevier Science Ltd. All rights reserved

The influence of HLA-matched sibling donor availability on treatment outcome for patients with AML: an analysis of the AML 8A study of the EORTC Leukaemia Cooperative Group and GIMEMA

To determine whether patients with a HLA-identical sibling donor have a better outcome than patients without a donor, an analysis on the basis of intention-to-treat principles was performed within the framework of the EORTC-GIMEMA randomized phase III AML 8A trial. Patients in complete remission (CR) received one intensive consolidation course. Patients with a histocompatible sibling donor were then allocated allogeneic bone marrow transplantation (alloBMT). the patients without a donor were randomized between autologous BMT (ABMT) and a second intensive consolidation (IC2). 831 patients 8 weeks from diagnosis were included. HLA typing was performed in 672 patients. AlloBMT was performed during CR1 in 180 (61%) out of 295 patients with a donor. Another 38 patients were allografted: ave in resistant disease, 14 during relapse and 19 in CR2, ABMT was performed in 130 (34%) out of 377 patients without a donor in CR1, in six: (2%) patients during relapse and in 38 (10%) patients during CR2. The disease-free survival (DFS) from CR for patients with a donor was significantly longer than for patients without a donor (46% v 33% at 6 years; P = 0.01, RR 0.78, 95% confidence interval 0.63-0.96). The overall survival from diagnosis for patients with a donor was longer, but not statistically significant, than for patients without a donor (48% v 40% at 6 years; logrank P= 0.24). When patients were stratified according to prognostic risk groups, the same trend in favour of patients with a donor was seen for survival duration and the DFS remained significantly longer for this group of patients

Second Primary Malignancies in CTCL Patients from 1992 to 2011: A SEER-Based, Population-Based Study Evaluating Time from CTCL Diagnosis, Age, Sex, Stage, and CD30+ Subtype

Cutaneous T-cell lymphoma (CTCL) is a diverse group of extranodal non-Hodgkin lymphomas with malignant T lymphocytes localizing in the skin. CTCL can mainly be classified as mycosis fungoides, Sézary syndrome, or primary cutaneous CD30+ lymphoma. Patients with CTCL have an increased risk of developing second primary malignancies. Our objective was to analyze the overall incidence of second primary malignancies in patients with CTCL by age, sex, stage, and the primary cutaneous CD30+ lymphoproliferative subtype of CTCL, as this group has usually been excluded from previous analyses. We used the Surveillance, Epidemiology, and End Results (SEER) database to evaluate CTCL cases diagnosed between 1992 and 2011. We calculated the multiple primary standardized incidence ratio, comparing the observed incidence of second primary malignant neoplasms in the CTCL patient population versus the general population. CTCL is associated with an overall increased risk of cancers. This incidence is greatest within the first year of diagnosis. The risk of secondary Hodgkin disease is greatest in patients aged ≥60 years; the risk of secondary non-Hodgkin lymphoma is greatest in patients aged 20-39. Males demonstrated a significantly increased risk of developing Hodgkin lymphoma, while females showed a significantly increased risk of developing bronchopulmonary malignancy. Overall, secondary malignancy incidence was significantly elevated for stage I and IV CTCL. Patients with CD30+ CTCL had a significantly higher incidence of Hodgkin lymphoma, non-Hodgkin lymphoma, and urinary cancers than the general population. Occult secondary malignancies, particularly lymphomas, should be considered in adult CTCL patients, including those with the CD30+ subtype