HIV-related Lymphoma Research Articles

Rituximab in Lymphoma and Chronic Lymphocytic Leukaemia: A Practice Guideline

Rituximab is the first monoclonal antibody to be approved for use by the US Food and Drug Administration in cancer. Its role in the treatment of non-Hodgkin lymphoma, including chronic lymphocytic leukaemia (CLL), has evolved significantly. We aimed to systematically review and update the literature on rituximab in lymphoma and CLL, and provide evidence-based consensus guidelines for its rational use. Validated methodology from the Cancer Care Ontario Program in Evidence-based Care was used. A comprehensive literature search was completed by a methodologist from the Hematology Disease Site Group of Cancer Care Ontario. Data were extracted from randomised controlled trials of rituximab-containing chemotherapy regimens for patients with lymphoma or CLL. Fifty-six primary randomised controlled trials were retrievable and met all inclusion criteria. Clinically important benefits in progression-free survival or overall survival were seen in the following settings: (i) addition of rituximab to combination chemotherapy for initial treatment of aggressive B-cell lymphomas, including diffuse large B-cell lymphoma, Burkitt lymphoma and HIV-related lymphoma with CD4 count ≥50/mm3; (ii) addition of rituximab to combination chemotherapy for initial and subsequent treatment of follicular lymphoma and other indolent B-cell lymphomas; (iii) use of rituximab maintenance in patients with indolent B-cell lymphomas who have responded to chemoimmunotherapy; (iv) addition of rituximab to fludarabine-based chemotherapy or chlorambucil for initial treatment of CLL. The consensus opinion of the Hematology Disease Site Group is that rituximab is recommended for these indications.

Autologous hematopoietic cell transplantation for HIV-related lymphoma: results of the BMT CTN 0803/AMC 071 trial

AbstractAutologous hematopoietic cell transplant (AHCT) for HIV-infected patients is largely limited to centers with HIV-specific expertise. The Blood and Marrow Transplant Clinical Trials Network 0803/AIDS Malignancy Consortium 071 trial is a multicenter phase 2 study of AHCT for patients with HIV-related lymphoma (HRL). Eligible patients had chemotherapy-sensitive relapsed/persistent HRL, were >15 years of age, and had treatable HIV infection. Patients were prepared using carmustine, etoposide, cytarabine, and melphalan and received consistent management of peritransplant antiretroviral treatment. The primary endpoint was 1-year overall survival. Forty-three patients were enrolled; 40 underwent AHCT. Pretransplant HIV viral load was undetectable (<50 copies/mL) in 32 patients (80%); the median CD4 count was 249/μL (range, 39-797). At a median follow-up of 24.8 months, 1-year and 2-year overall survival probabilities were 87.3% (95% confidence interval [CI], 72.1-94.5) and 82% (95% CI, 65.9-91), respectively. The probability of 2-year progression-free survival was 79.8% (95% CI, 63.7-89.4). One-year transplant-related mortality was 5.2%. Median time to neutrophil and platelet recovery was 11 days and 18 days, respectively. Nine patients experienced a total of 13 unexpected grade 3-5 adverse events posttransplant (10 grade 3 and 3 grade 4 events). Twenty-two patients had at least 1 infectious episode posttransplant. At 1 year post-AHCT, median CD4+ T-cell count was 280.3 (range, 28.8-1148.0); 82.6% had an undetectable HIV viral load. Trial patients were compared with 151 matched Center for International Bone Marrow Transplant Research controls. Outcomes between HIV-infected patients and controls were not statistically significantly different. HRL patients should be considered candidates for AHCT if they meet standard transplant criteria. The trial was registered at www.clinicaltrials.gov as #NCT01141712.

Stromal immune infiltration in HIV-related diffuse large B-cell lymphoma is associated with HIV disease history and patient survival.

Understanding tumor microenvironment and its impact on prognosis of HIV-related lymphomas may provide insight into novel therapeutic strategies. We characterized the relationship between infiltrating immune cells with tumor characteristics, HIV disease history and survival in 80 patients with HIV-related diffuse large B-cell lymphoma (DLBCL) diagnosed in the era of combined antiretroviral therapy (1996-2007) at Kaiser Permanente California. Eighty patients with HIV-unrelated DLBCL were included for comparison. Data on patients' clinical history were obtained from Kaiser Permanente's electronic health records. The density of stromal CD4, CD8 and FOXP3 T cells and CD68 macrophages, as well as tumor molecular characteristics were examined using immunohistochemistry. The associations between stromal immune infiltration and patient's clinical history or tumor characteristics were examined using Kruskal-Wallis tests or Pearson's correlation coefficient. The effect of stromal immune infiltration on 2-year mortality was evaluated in multivariable logistic regression. Compared with HIV-unrelated DLBCL, patients with HIV-related DLBCL had significantly reduced stromal CD4 and FOXP3 T cells, but increased density of macrophages. Increased density of stromal macrophages was correlated with lower circulating CD4 cell count at DLBCL diagnosis. Tumor molecular characteristics, including BCL6, p53 and cMYC expression, but not Epstein-Barr virus infection status, were significantly correlated with stromal immune infiltration, particularly FOXP3 T cells. A higher density of infiltrating CD8 T cell was significantly associated with reduced mortality in patients with HIV-related DLBCL (odds ratio = 0.30 [0.09-0.97] for ≥25 vs. <10%). These data provide evidence for the prognostic significance of cytotoxic T cells in determining outcomes of HIV-related lymphoma.

Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells

The highly active antiretroviral therapy reduces HIV-1 RNA in plasma to undetectable levels. However, the virus continues to persist in the long-lived resting CD4+ T cells, macrophages and astrocytes which form a viral reservoir in infected individuals. Reactivation of viral transcription is critical since the host immune response in combination with antiretroviral therapy may eradicate the virus. Using the chronically HIV-1 infected T lymphoblastoid and monocytic cell lines, primary quiescent CD4+ T cells and humanized mice infected with dual-tropic HIV-1 89.6, we examined the effect of various X-ray irradiation (IR) doses (used for HIV-related lymphoma treatment and lower doses) on HIV-1 transcription and viability of infected cells. Treatment of both T cells and monocytes with IR, a well-defined stress signal, led to increase of HIV-1 transcription, as evidenced by the presence of RNA polymerase II and reduction of HDAC1 and methyl transferase SUV39H1 on the HIV-1 promoter. This correlated with the increased GFP signal and elevated level of intracellular HIV-1 RNA in the IR-treated quiescent CD4+ T cells infected with GFP-encoding HIV-1. Exposition of latently HIV-1infected monocytes treated with PKC agonist bryostatin 1 to IR enhanced transcription activation effect of this latency-reversing agent. Increased HIV-1 replication after IR correlated with higher cell death: the level of phosphorylated Ser46 in p53, responsible for apoptosis induction, was markedly higher in the HIV-1 infected cells following IR treatment. Exposure of HIV-1 infected humanized mice with undetectable viral RNA level to IR resulted in a significant increase of HIV-1 RNA in plasma, lung and brain tissues. Collectively, these data point to the use of low to moderate dose of IR alone or in combination with HIV-1 transcription activators as a potential application for the “Shock and Kill” strategy for latently HIV-1 infected cells.

Epidemiology and management of HIV-related non-Hodgkin lymphoma (NHL) in the United States (US): Analysis of the National Cancer Data Base (NCDB).

1521 Background: Antiviral therapy has altered the incidence and prognosis of NHL associated with human immunodeficiency virus infection (HIV+NHL). We analyzed recent trends in HIV+NHL presentation...

The Role of the Tumor Microenvironment in HIV-Associated Lymphomas

There has been considerable interest in the role of the lymphoma microenvironment. Despite the use of highly active antiretroviral therapy (HAART), AIDS-related diffuse large-B-cell lymphoma remains common and HIV-relatedHIV-associated classical Hodgkin's lymphoma is increasing in incidence. Less is known about the impact HIV and HAART have on the lymphoma microenvironment. AIDS-related diffuse large B-cell lymphoma is highly angiogenic, demonstrates increased lymphoblastic histology, proliferation, increased activated cytotoxic T cells, reduced CD4(+) and FOXP3(+) T cells, but no differences in tumor-associated macrophages. Early initiation of HAART improves immunosurveillance, but cases without viral antigens appear able to avoid immunologic reaction. Increased T cell infiltrates seen with HAART treatment in HIV-related classical Hodgkin's lymphoma may contribute to malignant cell growth.

MYCing progress against immunosuppression-associated cancers

Molecular profiling provides insights into HIV-related lymphoma pathogenesis.

Research progress on epstein-barr virus and its related lymphoma

Epstein-Barr virus (EBV) belongs to r-DNA herpes virus family and the first discovered virus associated with human tumors. Numerous studies have found that EBV infection is related to the occurrence of a variety of lymphomas, such as Hodgkin's lymphoma, Burkitt's lymphoma, NK/T-cell lymphoma, HIV-related lymphoma and diffuse large B-cell lymphoma. Recent studies indicated that the gene expression products of EBV latent infections play an important role in the lymphoma, and these findings provide the theoretical basis for the treatment of EBV-related lymphoma. This review mainly discusses the progress in the mechanism and the therapy of EBV-related lymphoma.

Autologous stem cell transplantation in HIV-related lymphoma in the rituximab era - a feasibility study in a monocentric cohort.

IntroductionSince the introduction of highly active antiretroviral therapy (HAART) [1] and later on the availability of anti-CD20 monoclonal antibody treatment [2], the therapeutic options as well as the prognosis of AIDS related lymphoma (ARL) have been improved. There is however no uniform agreement on how to treat patients who do not achieve a partial remission, who experience a relapse or who have very aggressive subtypes. Autologous hematopoietic stem cell transplantation (ASCT) has become an option for those patients. We retrospectively examined ARL patients to elucidate the feasibility of high-dose chemotherapy and autologous stem cell transplantation.Patients and methodsData of seven male and one female HIV+ patients with ARL was collected and informed consent was obtained. Age, HIV disease characteristics (CD4 count, HIV-RNA-PCR, ART) and transplantation-related details (histopathology, myeloablative therapy, neutrophil engraftment and NCI-CTCAE during/after transplantation as well as follow up and survival) were obtained from the patients’ medical records. ResultsEight patients were treated with the intent of ASCT. The median age was at 64 years. Four patients had experienced prior AIDS. The median CD4 NADIR was at 157/µl, the median CD4 count at diagnosis of lymphoma at 81/µl. Five patients were receiving combination antiretroviral therapy (cART) at the time of lymphoma diagnosis, four of which had achieved a viral load of less than 50/µl. Two patients have died, due to (Nr. 8) a transplant-related complication (non-infectious leukoencephalophathy). The other patient died of an unknown reason (351 days after transplantation). The median survival is at 345 days to date. The time until engraftment was well at 11 days. Grade 3/4 haematological toxicity was present in all patients. Five out of three patients developed infectious complications, but there were no infection-related deaths. One patients (Nr. 4) developed a Kaposi Sarcoma reactivation that necessitated further chemotherapy.ConclusionsASCT is feasible in high risk ARL with good engraftment. Toxicity was substantial and studies are needed to define which patients have an unduly high risk of toxicity.

HIV-related NK/T-cell lymphoma in the brain relapsed during intensive chemotherapy but regressed after chemotherapy discontinuation: the importance of maintaining cellular immunity.

This study reports a case of human immunodeficiency virus (HIV)-related natural killer/T-cell lymphoma with an unexpected clinical course. The lymphoma cells were positive for Epstein-Barr virus and the primary nodal lesions regressed after chemotherapy and combined antiretroviral therapy (c-ART); however, brain metastasis progressed along with a reduction in the CD8+ T-cell count. Chemotherapy was discontinued and the patient was treated with c-ART alone, resulting in regression of the brain lesions and recovery of the CD8+ T-cell count. This case highlights the importance of maintaining anti-tumor immunity in patients with HIV-related lymphoma.

Unique Clinical Implications of HIV-Related Lymphoma

Since the introduction of combination antiretroviral therapy (cART) almost two decades ago, a number of changes have taken place in the spectrum of cancer affecting HIV-infected individuals. Although the incidence and proportion of deaths related to non-AIDS-defining malignancies, mostly infection-related cancers, are increasing, lymphoma is still a major complication of HIV-infection and is the most frequent neoplastic cause of death among HIV-infected individuals [1,2]. A decline in the incidence of lymphoma has been observed in the cART era, along with a concomitant increase in CD4 counts and a decrease of HIV RNA at lymphoma diagnosis. In general, the incidence of non-Hodgkin lymphoma (NHL) initially declined but has eventually stabilized. Nevertheless, the changes in the incidence of AIDS-related lymphoma (ARL) have been heterogeneous among the different lymphoma types. Cases of diffuse large B-cell lymphoma (DLBCL), especially primary CNS lymphoma, have decreased, while the proportion of Burkitt’s lymphoma (BL) cases have increased [3–5]. The incidence of Hodgkin’s lymphoma (HL) has remained stable and even increased in some cohorts [6,7]. This heterogeneity could be explained by the fact that the use of cART has decreased the proportion of HIV-infected individuals with low CD4 counts and, as a consequence, lymphomas that typically presented in severe immunosuppressed patients have diminished as well. This is the case of primary effusion lymphomas, plasmablastic lymphomas and primary CNS lymphoma, all having a higher incidence among patients with severe immunosuppression and poor HIV control. On the other hand, cART would act by increasing CD4 counts thereby facilitating the development of lymphomas with favorable biology and more likely to be cured, such as BL and HL [8]. Some changes have been observed in the presentation of HIV-associated lymphoma in the cART era. Regarding the transmission risk factor, there seems to have been an increase in the proportion of men who have sex with men and a decrease of intravenous drug users [5], probably due to the changes in the spectrum of HIV infection transmission in the population. Patients are older at lymphoma diagnosis, with higher

British HIV Association guidelines for HIV‐associated malignancies 2014

<scp>B</scp>ritish <scp>HIV</scp> Association guidelines for <scp>HIV</scp>‐associated malignancies 2014

Comparative Outcomes of Chemotherapy with and without HAART for HIV-Related B-Cell Lymphoma: A Meta-Analysis

BackgroundHuman immunodeficiency virus (HIV) infected individuals have an increased incidence of malignancies, including B-cell lymphomas. The use of highly active antiretroviral therapy (HAART) during antineoplastic therapy for HIV related lymphoma remains controversial. The current meta-analysis investigates the impact of the upfront addition of HAART to chemotherapy on overall survival (OS) compared to chemotherapy alone. MethodsWe searched MEDLINE (January 1996 to May 2013), the Cochrane Central Register of Controlled Trials (May 2013), and the references of retrieved articles. Published clinical trials were included that both clearly defined the patients treated with and without HAART and provided the respective outcomes for each group. Two authors independently assessed the quality of studies and abstracted data. Primary outcomes were complete remission (CR) and overall survival (OS). Hazard ratios were pooled using random effects methods. Heterogeneity was assessed with I2 and by visual inspection of the Galbraith plots. Sources of heterogeneity were explored using stratified analysis and random-effects meta-regression. ResultsFour retrospective chart reviews, one retrospective case control, two cohort studies, one randomized trial, and two prospective trials were eligible for review, providing 1070 subjects with an average age of 41.3 years. The mean CD4 count was 223/μl and HIV viral load 192,452 copies/ml. There was significant heterogeneity between studies.Individuals receiving HAART were more likely to achieve CR compared to those not receiving HAART (RR 1.47, CI: 1.04-2.06, I2=75.0%). Among those receiving HAART, 56% (95% CI: 45%-67%, I2=67.8%) achieved CR compared to 37% (95% CI: 28%-45%, I2=75.1) not receiving HAART. The addition of HAART to chemotherapy improves OS when compared to those receiving chemotherapy alone (HR: 0.58, 95% CI: 0.49-0.68, I2=91.4%, Figure 1), representing an increased median OS time of 20.5 months (95% CI: 2.6-38.4, I2=93.6%). Calculation of a pooled HR using survival curve data from studies with extractable data yielded similar results (HR: 0.50, 95% CI: 0.41-0.61, Figure 2). Higher CD4 counts were associated with improved survival (p<0.0005). Conversely, older age (p=0.017), higher viral load (p<0.0005), higher stage lymphoma (p=0.023), the presence of B-symptoms (p<0.0005), and worse functional status (p<0.0005) were associated with decreased survival. Following adjustment for these predictors, concurrent HAART and chemotherapy resulted in improved OS (HR: 0.46, 95% CI: 0.38-0.57). There was no evidence of publication bias for any of our outcomes (CR: p=0.39, median survival: p=0.47, HR: p=0.07). There was also no relationship between quality and any of our outcomes (CR: p=0.77, median survival: p=0.32, HR: p=0.33). [Display omitted] [Display omitted] ConclusionOverall survival and complete remission are improved with the upfront addition of HAART to chemotherapy when compared to chemotherapy alone for patients with HIV related B-cell lymphoma. Disclosures:No relevant conflicts of interest to declare.

Lack Of Clinical Benefit For Routine Surveillance Imaging For Diffuse Large B-Cell Lymphoma In First Complete Remission

BackgroundThe use of routine surveillance imaging (RSI) for patients in first complete remission (CR1) following front-line rituximab (R) based anthracycline therapy remains controversial. We compared patients with diffuse large B-cell lymphoma (DLBCL) who received an R-CHOP or a similar regimen, obtained a CR and then were followed by either RSI or clinical surveillance (CS) in which scans were only performed for signs or symptoms. MethodsPatients from three tertiary care center from 2001-2011, who achieved a CR1 with frontline R-CHOP or similar therapy for DLBCL, and had a minimum follow up of 1 year were analyzed. Patients with HIV-related lymphoma, transformed lymphoma, and post-transplant lymphoproliferative disorders were excluded. Patients with composite lymphoma were included only if the DLBCL component was >50%. Patients were stratified into two groups based on the surveillance strategy employed. Baseline patient characteristics, prognostic features, treatment type, and outcomes were compared. Results391 patients with DLBCL treated with R-CHOP or similar regimens who obtained CR1 were analyzed. There were 129 patients in the CS group and 262 in the RSI group. Patient characteristics (age, gender, stage, and IPI) were similar in the two groups. The median follow up is 5 years (range 1 – 12). Relapse after CR1 was detected in 26 (20%) of patients in the CS group and 46 (18%) of the RSI group. The median number of images in the CS group was 0 (range 0-14) and 4 (range 1-27) in the RSI group, p<0.0001. The median average number of images per year of follow up in the CS group was 0 (range 0-6) and 1 (range 1-13) in the RSI group, p<0.0001. Relapses were detected through clinical manifestations in 100 % of CS cases versus 43% in RSI cases, p=0.01. The 5 year progression-free survival (PFS) was 76% in the CS group and 82 % in the RSI group (p = 0.31). The 5 year overall survival (OS) was 87% in the CS group and 92 % in the RSI group (p=0.15). The table shows an analysis of OS by IPI and type of surveillance. ConclusionsThe majority of relapses in patients with DLBCL after achieving CR1 to an R-CHOP or similar regimen occur when signs or symptoms of the disease lead to evaluation and are not detected by RSI. Although asymptomatic relapses are occasionally detected by RSI, in this large cohort of patients neither a PFS nor OS benefit could be demonstrated in favor of RSI. Given the additional cost, radiation exposure and risk of additional procedures, we conclude that the use of RSI in patients with DLBCL in CR1 has limited clinical utility. Disclosures:No relevant conflicts of interest to declare.5 year Overall SurvivalCS GroupRSI Groupp-valueLow IPI (n=174)94 (84-98)97 (90-99)0.53Low-Int IPI (n=86)84 (57-95)88 (74-94)0.71High-Int IPI (n=93)78 (29-93)90 (68-97)0.25High IPI (n=38)74 (29-93)78 (53-91)0.83

Microenvironment Assessment, Disease Characteristics and Prognosis In HIV-Associated (HIV-cHL) and HIV-Negative Classical Hodgkin Lymphoma: The Influence Of Epstein Barr Virus (EBV)

IntroductionStudies of EBV positive (+) and negative (-) classical Hodgkin lymphoma (cHL) have shown the importance of the immune microenvironment in affecting Reed-Sternberg (hRS) cell survival, proliferation, and biologic behavior. For example, macrophage infiltrates may correlate with inferior disease outcome and survival and proliferation of the hRS cells depends on trophic signals from various inflammatory cells, including CD4+ T cells. The latter finding may explain why HIV-cHL patients (pts) usually present with higher circulating CD4+ T-cell counts (cCD4) compared to HIV-related non-Hodgkin lymphoma. Pathobiologically, HIV-cHL differs from HIV negative cHL (cHL) in that it is nearly always EBV+, has higher numbers of hRS cells, presents with more advanced median stage, exhibits more commonly the mixed cellularity (MC) pattern, and some studies suggest it is more clinically aggressive. To investigate the microenvironment of HIV-cHL and its influence on cHL biology, we assessed the immune cell composition and clinical characteristics of HIV-cHL and compared the findings to those of EBV+ and EBV- cHLs. Methods31 HIV-cHL and 40 cHL (8 EBV+/32 EBV-) cases were identified and corresponding tissue microarrays (TMAs) created. TMAs were evaluated for EBV (EBER), CD30, and microenvironment-associated antigens: PAX5, CD3, CD4, CD8, CD68, CD163 (% positive), TIA1, FOXP3 (relative number 0-4+); the hRS-macrophage microenvironment was evaluated by assessing the number of hRS where >50% of the circumference of the neoplastic cell was associated with CD68+ cells. Results were compared based on HIV status, EBV status (in HIV negative pts), demographics, cCD4 and histology; each was correlated with overall survival. Analyses were performed using non-parametric Fisher's exact test, Kaplan-Meier method and Cox Proportional Hazards model. ResultsM F ratio was 9:1 in the HIV group vs. 1.3:1 in the HIV negative pts (p <0.001). The median cCD4 in the HIV+ pts at HIV-cHL diagnosis was 248 cells/mm3. No differences in age, stage, B symptoms, bulky disease, IPS score, and hRS concentration were found between HIV+ and HIV negative cHLs pts. 7% of cHLs and 33% of HIV-cHLs were classified as MC (p<0.01). 90% of HIV-cHLs were EBV+ compared to 20% of the cHL cases. Statistically significant differences were seen in the number of CD4+ and CD8+ cells between the EBV+ and EBV- cHLs irrespective of HIV status. The only difference among all the immune microenvironment markers observed between EBV+ HIV-cHL and EBV+ cHL cases was that of peri-hRS CD68 cells, which were more abundant in the EBV+ HIV-cHL (Table 1; 51% vs. 30% p<0.005). Similar differences in peri-hRS CD68 staining were observed between the HIV-cHL and all cHL pts. The only deaths in HIV-cHL pts occurred when CD68 was >15% (p<0.05). No statistical differences were noted for OS with respect to cCD4, histologic subtype, race, gender, or HIV status. ConclusionsNo significant differences were observed between HIV-cHL and cHL pts with respect to stage, B symptoms, bulky disease, IPS score, or overall survival, but there were more MC cases in the HIV-cHL cohort. The microenvironment of HIV-cHL and EBV+ cHL is similar, but different from EBV- cHL with respect to percentages of CD163+, PAX5+, CD4+ and CD8+ cells. The location of CD68+ macrophages was the only discordant result between the EBV+ HIV-cHL and EBV+ cHL cohorts. The differences in location of the CD68+ cells, which may be dependent on HIV status, suggests greater influence of these cells on the biologic behavior of the neoplastic process, correlating with poor survival. However, the similarity in the microenvironments in HIV-cHL and EBV+ cHL with respect to CD4, CD8, and CD163 staining implies an important role for EBV on disease biology, as well. Thus, these data suggest that EBV as well as HIV, play prominent roles in determining the immune response and disease behavior in HIV-cHL, warranting further study Disclosures:No relevant conflicts of interest to declare.

Correction: Effect of Immune Reconstitution on the Incidence of HIV-Related Hodgkin Lymphoma

Correction: Effect of Immune Reconstitution on the Incidence of HIV-Related Hodgkin Lymphoma

Effect of Immune Reconstitution on the Incidence of HIV-Related Hodgkin Lymphoma

BackgroundThe incidence of Hodgkin lymphoma (HL) has increased since introduction of combined antiretroviral therapy (cART). While HIV-related HL is highly associated with EBV, the causes underlying the rising incidence remain unclear. The aim of this study was to evaluate the effect of immune reconstitution on HL incidence among a cohort of HIV-infected male veterans ever receiving cART.MethodsWe performed a retrospective cohort study utilizing data from the Veterans Affairs HIV Clinical Case Registry from 1985-2010. HL cases were identified using ICD-9 codes (201.4-9). Poisson regression was conducted to evaluate relationships between cART-related immunologic measures (e.g., nadir CD4 before cART, time-updated CD4, % time undetectable HIV RNA) and HL incidence. Additionally, we examined CD4 change after cART initiation.Results31,056 cART users contributed 287,256 person-years and 196 HL cases (IR=6.8/10,000 person-years). Rate of CD4 increase after cART was worse among HL cases than non-cases (p<0.05). In multivariate regression, HL risk was elevated among veterans with recent CD4 200-350 cells/µL (IRR=1.67, 95%CI=1.16-2.40) and <200 cells/µL (IRR=1.61, 95%CI=1.09-2.39), compared to >350 cells/µL. HL risk was lower among veterans with >80% time undetectable HIV RNA (IRR=0.57, 95%CI=0.35-0.92) and 40-80% undetectable (IRR=0.68, 95%CI=0.47-0.99), compared to <40% undetectable. HL risk was higher in the first 12 months (IRR=2.02, 95%CI=1.32-3.10) and 12-24 months (IRR=1.75, 95%CI=1.16-2.64) after cART initiation, compared to >36 months.ConclusionThese data highlight immunosuppression and poor viral control may increase HL risk, specifically during immune reconstitution in the interval post cART initiation. Findings suggest an immune reconstitution type mechanism in HIV-related HL development.

Plasma Viremia and Cellular HIV-1 DNA Persist Despite Autologous Hematopoietic Stem Cell Transplantation for HIV-Related Lymphoma

A cure of HIV-1 has been achieved in one individual through allogeneic stem cell transplantation with a CCR5[INCREMENT]32 homozygous donor. Whether myeloablation and autologous stem cell transplantation for lymphoma in patients on suppressive antiretroviral therapy can eliminate HIV-1 reservoirs is unknown. Low-level plasma viremia and total HIV-1 DNA and 2-LTR circles in blood mononuclear cells were quantified after autologous transplantation in 10 patients on suppressive antiretroviral therapy using quantitative polymerase chain reaction assays capable of single-copy nucleic acid detection. Plasma viremia was detectable in 9 patients, whereas HIV-1 DNA was detectable in all 10 patients, indicating that HIV-1 had not been eliminated.

Follow-up of patients receiving rituximab for diffuse large B cell lymphoma: an overview of systematic reviews

The advent of rituximab has significantly improved the clinical outcomes of patients with diffuse large B cell lymphoma (DLBCL). Although rituximab is considered safe and effective, data on its long-term use are limited, which suggests that patients should undergo systematic, long-term follow-up aiming to identify delayed or yet undescribed adverse reactions and optimize treatment effectiveness. This study presents an overview of systematic reviews of strategies for follow-up of DLBCL patients receiving rituximab and documents the current state of knowledge on efficacy and safety in this population. A highly sensitive strategy was used to identify systematic reviews of randomized clinical trials (RCTs) in the Cochrane Library, Embase, Lilacs, MEDLINE, and Scirus databases. A handsearch of medical and government agency websites was also conducted. Seven studies were included, among them there were RCTs of patients who used CHOP/CHOP-like chemotherapy plus rituximab for three to eight cycles every 14 to 21days as induction therapy, whereas some studies used maintenance therapy for 3 to 24months. Only one study described a follow-up model for management of adverse drug reactions. The benefits of rituximab for induction therapy of DLBCL were demonstrated, although there is no evidence of significant improvement in the overall survival of high-risk patients or those with HIV-related lymphoma. Rituximab therapy was associated with increased rates of fever, infection, and grade 3/4 hematological toxicity, as well as higher infection-related mortality in HIV-positive patients. Although one study addressed the management of adverse reactions to rituximab, our search did not yield any publications on systematic follow-up strategies for these patients. This finding suggests that such instruments should be developed and validated to optimize the effectiveness and long-term safety of novel therapies.

Spindle-shaped CD163+ rosetting macrophages replace CD4+ T-cells in HIV-related classical Hodgkin lymphoma

Combination antiretroviral therapy is highly effective in HIV infection, leading to decreased incidences of AIDS-defining neoplasms. However, HIV patients still have a 10-fold increased risk of developing classical Hodgkin lymphoma compared with the general population. As Hodgkin- and Reed–Sternberg cells represent only a minority in the tumor infiltrate, the aim of the present study was to characterize the microenvironment of HIV-related classical Hodgkin lymphoma and compare it with classical Hodgkin lymphoma cases of immunocompetent individuals. The major morphologic differences were the presence of necrotic foci and the absence of epithelioid cell formation in HIV-related Hodgkin lymphoma. We observed a significantly decreased number of CD4+ T-cells and a significantly increased number of CD163+ macrophages in HIV-related Hodgkin lymphoma. Cases exhibiting a ‘sarcomatoid' pattern of the reactive infiltrate exhibited significantly greater numbers of macrophages, associating the ‘sarcomatoid' pattern to the presence of spindle-shaped macrophages. Whereas, rosetting of CD4+ T-cells around Hodgkin- and Reed–Sternberg cells was frequently observed in classical Hodgkin lymphoma in immunocompetent persons; rosetting in a subset of HIV-related Hodgkin lymphoma cases appeared to involve cytoplasmic protrusions of spindle-shaped macrophages. HIV-related Hodgkin lymphoma, therefore, is characterized by unique morphologic features, which should be recognized by pathologists.