AIDS-related Diffuse Large B-cell Lymphoma Research Articles

Physician Perceptions and Preferences in the Treatment of Acquired Immunodeficiency Syndrome (AIDS)-Related Lymphoma (ARL).

The treatment of ARL is complicated by the numerous immuno-chemotherapy, antiretroviral, and prophylactic options available to lymphoma specialists. The optimal management in the era of combination antiretroviral therapy (cART) is unclear. We administered a survey instrument to determine physician preferences and perceptions in the management of ARL and to assess the variability in treatment in Canada. The survey was developed with items grouped into key domains of ARL management (physician demographics, attitudes, and treatment preferences) and piloted for content validity and clarity. The final questionnaire was administered to lymphoma physicians with valid contact information in the provinces of Ontario (ON; n=155) and British Columbia (BC; n=48). The Dillman Tailored Design Method was followed for multi-modality (internet and standard mail) survey administration. Of 196 physicians, 131 either responded by completing the questionnaire (n=117; 60% response rate) or declining to participate (n=14; 7%). Most responders were male (63%), white (70%), practicing in an academic setting (63%), and belonged to a median age group range of 41–50 years. The majority (98%) had a positive attitude towards the treatment of ARL, as measured by a previously validated 2-item attitude scale. However, barriers to adequate care were still identified; 84% of physicians agreed that uncontrolled human immunodeficiency virus infection represented a major barrier to ARL care and 54% agreed that a patient's concurrent intravenous drug abuse impaired care. Most physicians recommended the concomitant use of cART in the care of their patients with ARL (n=72 of 109 responses; 66%). Similarly, a majority of respondents recommended CHOP-like regimens (cyclophosphamide, doxorubicin, vincristine, and prednisone; n=92 of 108 responses; 85%) to form the backbone of chemotherapy. The addition of the rituximab was preferred by 41% physicians but not by 40% others, with remaining respondents unsure of the agent's role. In logistic regression analysis, use of rituximab was predicted only by location of practice (province), after adjusting for other potential predictors including physician age, race, gender, practice environment (academic vs. community), years of experience, ARL patient volume, and modality of survey response. Physicians from BC were much more likely to administer rituximab than ON practitioners (OR 44.5; 95% CI: 7.76–255.0, p<0.0001). We explored the reasons that physicians did not recommend rituximab; most cited a concern for additional toxicity with rituximab in ARL. Eight physicians in ON highlighted the lack of formulary funding for rituximab in the province as the primary reason they did not treat patients with this agent. In the current cART era, Canadian physicians have a positive attitude towards ARL treatment. The majority prefer to use cART in combination with CHOP for AIDS-related diffuse large B-cell lymphoma. The use and perceived benefit of rituximab may be influenced by inter-provincial formulary differences and by regional variation in policy and guideline recommendations.

AIDS and non-AIDS diffuse large B-cell lymphomas express different antigen profiles

Based on gene expression profiling, diffuse large B-cell lymphomas arising in immunocompetent patients can be divided into germinal center and activated B-cell types. Since little is known about acquired immunodeficiency syndrome associated diffuse large B-cell lymphomas, we tested whether the protein expression of germinal center and activated B-cell markers differed between acquired immunodeficiency syndrome (AIDS) vs non-AIDS diffuse large B-cell lymphomas. We immunohistochemically stained tissue microarrays of 39 de novo diffuse large B-cell lymphomas: 12 AIDS associated and 27 non-AIDS, with germinal center (BCL6, CD10, CyclinH) and activated B-cell markers (MUM1, CD138, PAK1, CD44, BCL2). We scored each case for percent positive cells (0–19%=0; 20–49%=1; 50–100%=2). The activated B-cell and germinal center summation scores of each case were used as (x, y) coordinate data points to construct two-dimensional contour-frequency plots. The contour plot of non-AIDS diffuse large B-cell lymphomas showed two distinct clusters: a cluster with a high germinal center phenotype (cluster 1) and a cluster with a high activated B-cell phenotype (cluster 3). In contrast, the AIDS-related diffuse large B-cell lymphomas formed a single aggregate (cluster 2) (P=0.02, Fisher exact test). When the contour plots of the AIDS-related and the non-AIDS cases were superimposed, cluster 2 of the AIDS cases expressed an intermediate germinal center/activated B-cell phenotype compared to clusters 1 and 3 of the non-AIDS diffuse large B-cell lymphomas. Our results confirm that non-AIDS diffuse large B-cell lymphomas segregate into two groups with either germinal center or activated B-cell phenotype. We report the new finding that the AIDS status of the patient predicts the immunophenotype of the diffuse large B-cell lymphomas.

Treatment with Rituximab, CHOP and Highly Active Antiretroviral Therapy (HAART) in AIDS-Related Diffuse Large B-Cell Lymphomas (DLBCL). Study of 60 Patients.

Background and objective. Rituximab and CHOP (R-CHOP) is the most employed treatment for DLBCL, but pts with AIDS-related lymphomas are usually excluded from clinical trials. The objective of this open, prospective multicenter trial is to evaluate the feasibility, efficacy and toxicity R-CHOP and HAART in AIDS-related DLBCL.Patients and methods. Between April 2001 and July 2005, 60 consecutive HIV-infected pts with newly diagnosed DLBCL were included in 20 Spanish hospitals. HAART was given to all patients from diagnosis if they were not already receiving it. Six cycles of R-CHOP were administered, IT CNS prophylaxis (MTX, ARA-C and hydrocortisone) was given in every cycle to all patients. G-CSF support was recommended Response to chemotherapy, toxicity, OS and DFS for complete responders were recorded.Results. Median age 42 yr (range 26–64), 49 (82%) males, 30 (50%) with previous known diagnosis of HIV infection (median from dx HIV to NHL 10 yr, range 0.5–19). Median CD4 lymphocyte count 152/mL (range 0–905), median HIV load 19x103 copies/mL (range 0–2x106). 36 pts were receiving HAART at the time of NHL dx (median 3.5 yr, range 0.5–9). Extranodal involvement 43 (72%), stage III-IV 38 (63%) and 36/56 had intermediate-high or high age-adjusted IPI score. 10 patients are under treatment, 1 (2%) withdrawal, 6 (12%) induction death (infection 3, hepatic failure 2, multiorgan failure 1), 10 (20%) resistant, CR 33 (66%). After a median follow-up of 2 yr, 2-yr survival probability was 63% (95%CI 50–76). The probability of remaining alive and in first CR at 2 yr for complete responders was 89% (95%CI 77–100). Three patients died in first CR (opportunistic infection, sudden death and violent death) and no relapses have occurred to date. Virologic and immunologic responses to HAART at 6 months after the completion of treatment were maintained or achieved in 17/21 (81%) and 14/22 (64%) of patients, respectively. Out of 245 R-CHOP cycles analysed the most frequent grade II-IV toxicities were infections (30, 12%), gastrointestinal (21, 9%) and neurologic (5, 2%).Conclusion. In patients with AIDS-related DLBCL the combination of HAART and R-CHOP is feasible and effective. In this trial the response rate and survival are comparable to those obtained in immunocompetent patients treated with R-CHOP.

Expression of the BAFF-R (BR3) Is Positive in a Minority of Diffuse Large B Cell Lymphomas and Does Not Correlate with the Germinal Center or Non Germinal Center Origin of Lymphomatous Cells.

BAFF, a member of the TNF family, has been shown to be implicated in B cell maturation and survival through an interaction with its three receptors, BCMA, TACI and BAFF-R. Recent data revealed that it also plays a role in B cell malignancies. For exemple, an autocrine activation of the BAFF receptors could participate to oncogenesis during multiple myeloma or chronic lymphocytic leukemia. BAFF-R, the sole BAFF specific receptor, is expressed in a subset of Diffuse Large B Cell Lymphomas (DLBCL). Since BAFF-R activation in B cells leads to cell proliferation and survival, expression of this receptor in DLBCL could correlate with more aggressive lymphomas. DLBCL can be divided into prognostically important subgroups with germinal center B cell-like (GCB), activated B cell-like (ABC) and type 3 gene expression profiles using a cDNA microarray. The germinal center origin of malignant B cells in DLBCL can also be characterized by immunohistochemistry (IHC) according to CD10, Bcl6 CD138 and MUM1 expression. In this work, we investigated whether expression of BAFF-R in DLBCL correlate or not with the GCB vs non GCB phenotype of lymphomatous cells. Lymph nodes biopsies from 23 DLBCL (among whom 3 post-transplantation lymphomas and 1 AIDS-related DLBCL) were analyzed. In a first step, we characterized by IHC the precise phenotype of each DLBCL: CD10+/Bcl6+ DLBCL were classified into the germinal center (GCB) group (n=9), whereas CD10-/BCL6-/MUM1+ lymphomas defined the non germinal center (NGCB) one (n=14). Each DLBCL was then analyzed for BAFF-R expression by IHC. In agreement with a recent report, most of the DLBCL were found to be negative for BAFF-R expression (16 out of 23). Interestingly, 4 of the 9 GCB DLBCL were found to be BAFF-R positive (44%), whereas only 3 out of 14 (21%) in the NGCB group. Although the difference did not reach statistical significance, we concluded from this observation that a consequent percentage of GCB DLBCL express the specific receptor BAFF-R. Thus, we actually analyze the clinical and biological characteristics of BAFF-R positive DLBCL and investigate whether expression of BAFF-R could represent a bad prognosis factor in term of clinical outcome and response to treatment.