HIV-associated Hodgkin Lymphoma Research Articles

Stage-adapted treatment of HIV-associated Hodgkin lymphoma: Long-term results of a prospective, multicenter study.

Results of a prospective study of stage-adapted treatment of humanimmunodeficiency virus (HIV)-associated Hodgkin lymphoma (HIV-HL) showed a 2-year overall survival (OS) of 90.7% with no significant difference between early favorable (EF), early unfavorable (EU), and advanced HL. Patients with EF HIV-HL received two to four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy involved field (IF) radiation, those with EU HIV-HL received four cycles of ABVD or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) baseline + 30 Gy IF, and six to eight cycles of BEACOPP baseline were administered in advanced disease. The objective of the present analysis is to determine long-term outcomes of HIV-HL. Of 108 patients, 23 (21%) had EF HL, 14 (13%) had EU HL, and 71 (66%) had advanced-stage HL. After a median follow-up of 9.14 (range, 0-12.9) years, there were five primary refractory HL patients (5%) and 11 relapses (10%), of which seven were late relapses (>2 years). A second primary malignancy (SPM) occurred in 10 patients after a median of 7.3 years (range, 1.5-10.7) from HL diagnosis. The 10-year OS for patients with EF, EU, and advanced HL was 95.7%, 84.6%, and 76.1%, respectively. By multivariate analysis, Center for Disease Control and Prevention category C (hazard ratio [HR]3.00, 95% confidence interval [CI]:1.16-7.74, p = 0.023) and achievement of complete remission were significant for OS (HR 0.03, 95% CI: 0.01-0.08, p = 2.45 × 10-9). In conclusion, a stage-adapted treatment approach for HIV-HL is highly effective with long-term survival rates similar to those reported in HIV-uninfected HL. However, the risk for late relapse and SPM is significant.

Outcome in patients with HIV-associated Hodgkin lymphoma treated with chemotherapy using Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine in the combination antiretroviral therapy (cART) era: results of a multicenter study from China

Little is known about the outcome for HIV-associated Hodgkin lymphoma (HIV-HL) as this is less common than HIV-negative lymphoma. Therefore, we performed a multi-center study to analyze the clinical characteristics and outcomes of HIV-HL patients in China. Nineteen cases of HIV-HL were diagnosed and treated at three center and including the sixth people’s hospital of Zhengzhou, Peking union medical college hospital, and Chongqing university cancer hospital, between December 2013 and June 2022. Data on the clinical features, laboratory results, response, and prognosis were collected and analyzed. The median age at diagnosis was 43(22–74) years. All patients were infected with HIV through sexual transmission, with ten cases transmitted through man having sex with man (MSM) and nine cases transmitted through heterosexual transmission. Seven patients were diagnosed with lymphoma and found to be infected with HIV. Four cases were in stage III, and fifteen cases were in stage IV. After a median follow up of 46.8(4.0-112.9) months, 17 cases were alive after ABVD regimen chemotherapy combined with combination antiretroviral therapy (cART). The 5-year progression-free survival (PFS) and overall survival (OS) rate were 83.9% and 89.5%,respectively. HIV-HL exhibits an invasive process in clinical practice, and cART combined with ABVD regimen chemotherapy can achieve long-term survival for patients.

Real-World Multicenter Study of PD-1 Blockade in HIV-Associated Hodgkin Lymphoma across the United States

Background: Despite a 5 to 20-fold higher risk of Hodgkin lymphoma (HL) in people with HIV (PWH) than the general population, PWH were excluded from clinical trials that led to the approval of anti-PD-1 agents (PD-1) in HL. PD-1 have overall response rates (ORR) of 65-70% in the general population and are used in all lines of HL therapy. Several prospective and retrospective studies have shown PD-1 are safe in PWH, but they remain underutilized in HIV-associated HL (HIV-HL) where data are limited. Methods: Patients (pts) with HIV-HL were identified from the retrospective, international database, “Cancer Therapy using Checkpoint inhibitors in PWH-International (CATCH-IT)” consortium, that is maintained at the Dana-Farber Cancer Institute (DFCI) and approved by DFCI and local institutional review boards. Pts who received either nivolumab or pembrolizumab, alone or in combination with other agents were included. Records were reviewed for demographics, HL and HIV characteristics, and treatment data. Safety was evaluated by the occurrence of immune-related adverse events (irAEs) per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Response to treatment was evaluated using descriptive statistics, and immune reconstitution was measured by changes in CD4 + T cell counts (CD4) from prior to end of PD-1 therapy via paired t-tests. ORR was defined as the proportion of pts with partial or complete response (PR/CR) per the 2014 Lugano classification for HL. Duration of response (DOR) was defined as the time from the date of the first CR or PR to the date of progressive disease (PD) or death. Progression-free survival (PFS) was defined as the time from PD-1 initiation to disease progression, death, or censored on the date of the last follow-up. Overall survival (OS) was defined as the time from PD-1 initiation to death or censored at the last follow-up. DOR, PFS, and OS were evaluated by Kaplan-Meier methodology. Results: We identified 23 pts with HIV-HL from 12 institutions in the United States: 20 cisgender men, 3 cisgender women; 10 Black,10 White, and 10 Hispanic; median age 48 years [interquartile range (IQR): 36-58]. At HL diagnosis, 19 (83%) pts had advanced stage disease, and in 20 pts where EBV status of the tumor was known, all were positive. Nine (39%) pts had primary refractory disease. The median number of prior systemic therapies was 2 (IQR: 1-3). One pt had PD-1 as 1 st-line therapy, 6 had PD-1 as 2 nd-line therapy, and 16 had PD-1 as ≥3 rd-line therapy. Fourteen (61%) pts received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as 1 st-line therapy. Two pts had prior autologous stem cell transplant (ASCT). At the time of PD-1 initiation, 22 pts (96%) had advanced stage disease, 17 (46%) had extranodal disease, and the median ECOG performance status was 1 (IQR: 0-2). Seventeen (74%) pts received PD-1 monotherapy, 5 (22%) received nivolumab + brentuximab vedotin, and 1 received nivolumab + ifosfamide, carboplatin, and etoposide. Four pts had uncontrolled HIV at the time of PD-1 initiation (HIV viral load range=10,000-2,000,000 copies/mL). All pts received antiretroviral therapy during treatment. Median baseline CD4 was 155 cells/µL (IQR: 66-297) and CD8 was 429 cells/µL (IQR: 158-716). Median CD4 and CD8 increased to 310 and 653 cells/µL at the end of PD-1 treatment (P=0.0084, P=0.32). The median number of PD-1 cycles was 6 (IQR: 4-21). Three (13%) pts had irAEs (all grade 3): hypothyroidism, autoimmune pancreatitis, and pneumonitis. None required PD-1 discontinuation. The ORR was 83% in the overall cohort. Sixteen pts (70%) had CR, 3 (13%) PR, and 4 (17%) PD as best response. Among the 19 pts with CR or PR, the median DOR was 19.7 months; 8 had PD after initial response and 11 had ongoing CR at data cut-off. Ten pts received consolidation with ASCT after PD-1, 6 of whom had received PD-1 at ≥3 rd line treatment. All pts who received ASCT had ongoing CR at data cut-off. Median PFS was 21.2 months in the overall cohort. Among pts with CD4 <200 and >200 cells/µL, PFS was not statistically different (17.3 vs 29 months; P=0.95). At data cut-off, 17 pts (74%) were alive and 6 (26%) had died due to HIV-HL. Median OS was 23.6 months in the overall cohort. Conclusion: In HIV-HL, PD-1 blockade was safe, had a high ORR and CR rate, and allowed for immune reconstitution in pts across a wide range of CD4 counts and HIV viral loads. These data add to the evidence that anti-PD-1 agents are effective in PWH and should be used in HIV-HL.

Clinical Analysis of 22 Cases of HIV-Associated Hodgkin Lymphoma in China

Introduction: Knowledge of HIV associated Hodgkin lymphoma mainly comes from case series or retrospective studies. Further,these criteria and guidelines have not been systematically evaluated. To investigate the clinical characteristics, response, and prognosis of HIV associated Hodgkin lymphoma in China. Methods:A total of twenty-two cases of human immunodeficiency virus infection-related Hodgkin lymphoma patients from 5 Chinese hospitals were enrolled in this study, between December 2013 and June 2022. Data on the clinical features, laboratory results, response, and prognosis were collected and analyzed. Results : The median age at diagnosis was 44(22-60) years. All patients were infected with HIV through sexual transmission, with ten cases transmitted through man sex with man and twelve cases transmitted through heterosexual transmission. Nine patients were diagnosed with lymphoma and found to be infected with HIV. Five cases were in stage III,and seventeen cases were in stage Ⅳ.After a median follow up of 30.6（4.0～112.9) months, 17 cases were alive after ABVD regimen chemotherapy combined with antiretroviral therapy. The 3-year PFS and OS rate were 80.8% and 85.9%,respectively. Conclusion : HIV associated Hodgkin lymphoma exhibit an invasive process in clinical practice, and standardized treatment can achieve long-term survival. 【Key words】HIV; Hodgkin lymphoma; Therapeutics;Prognostic

Optimising treatment of HIV-associated Hodgkin lymphoma

Optimising treatment of HIV-associated Hodgkin lymphoma

Long-term efficacy and safety of programmed death-1 (PD-1) antibody alone in relapsed/refractory human immunodeficiency virus-associated Hodgkin lymphoma.

We report a young patient initially diagnosed with human immunodeficiency virus (HIV)‐associated Hodgkin lymphoma (HL), and received six cycles of ABVD chemotherapy regimens and involvement field irradiation therapy. However, the disease progressed after two months later, and then received second line GDP regimen. Unfortunately, after five cycles of GDP, the patient progression disease (PD) again. The patient was then offered sintilimab alone. After 8 cycles, the patient received complete response (CR) and no 3/4 grade toxicity. Currently, at a follow‐up period of four years, he is still alive with CR and no lymphoma‐related symptoms. This case demonstrates the feasibility of sintilimab antibody in relapsed/refractory HIV‐associated Hodgkin lymphoma.

First Extensive Analysis of 18F-Labeled Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography in a Large Cohort of Patients With HIV-Associated Hodgkin Lymphoma: Baseline Total Metabolic Tumor Volume Affects Prognosis.

18F-labeled fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET-CT) data in HIV-associated Hodgkin lymphoma (HIV-HL) are scarcely reported. In addition to the description of the characteristics of both baseline and interim 18F-FDG PET-CT examinations (PET1 and iPET, respectively), the aim of this study was to assess the prognostic value of PET1 and previously identified clinical parameters in this population. PET1 of 109 patients with HIV-HL, treated with doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy regimen since 2007, and 104 iPET were centrally reviewed. All the patients were enrolled in an ongoing prospective single-center cohort of HIV-associated lymphoma. Most patients had a disseminated disease according to the Ann Arbor classification (30% stage III and 43% stage IV), with especially bone marrow and liver as extranodal localizations. After a median follow-up of 6.7 years, 12 patients relapsed (11%) and 13 died (12%). Five-year progression-free survival (PFS) was 75.1%, and 5-year overall survival was 86.1%. Median total metabolic tumor volume (TMTV) was 121.4 cm3. The optimal TMTV cutoff identified for prognostic analysis was 527 cm3, with a 2-year PFS of 71% in the 20 patients with TMTV > 527 cm3, compared with 91% in the 89 patients with TMTV ≤ 527 cm3 (P = .004). On multivariate analysis, a high TMTV was the only parameter independently associated with PFS. In this large series of HIV-HL patients with a homogeneous management, high TMTV on PET1 examination was associated with a poor prognosis.

Increased Production of B-Cell Activating Cytokines and Altered Peripheral B-Cell Subset Distribution during HIV-Related Classical Hodgkin Lymphoma.

Simple SummaryPatients with HIV are at high risk of developing Hodgkin’s lymphoma. This is potentially due to alterations in blood circulating B-lymphocytes and their activating cytokines. We analyzed the distribution of circulating B-lymphocytes and the level of the activating cytokines IL6, IL10 and BAFF in 38 patients with HIV-related Hodgkin’s lymphoma during a 2-year follow-up. We also compared their characteristics at diagnosis with (1) pre-diagnosis serum samples and (2) samples from control HIV-infected subjects without lymphoma. We found an increase in activating cytokines in cases compared to controls. The level of activating cytokines increased in advanced lymphoma. It decreased over time during follow-up. B-lymphocytic count was similar between patients and controls, but their subset distribution differed. There was an overrepresentation of naive B-lymphocytes over memory B-lymphocytes in HIV-associated Hodgkin lymphoma patients, more pronounced in those with advanced lymphoma. Follow-up showed an increase in B-lymphocytic count with an even greater proportion of naive B-cells. Together this suggests that in HIV-infected patients, Hodgkin lymphoma is associated with an altered blood distribution of B-lymphocytic subsets and an increased production of activating cytokines. This environment may contribute to the process of tumorigenesis.Classical Hodgkin Lymphoma incidence increases in HIV-1-infected patients (HIV-cHL). HIV infection is associated with higher B-cell activation. Here, in 38 HIV-cHL patients from the French cohort ANRS-CO16 Lymphovir, we examined longitudinally over 24 months the serum levels of the B-cell activating cytokines IL10, IL6, and BAFF, and blood distribution of B-cell subsets. Fourteen HIV-cHL patients were also compared to matched HIV-infected controls without cHL. IL10, IL6, and BAFF levels were higher in HIV-cHL patients than in controls (p < 0.0001, p = 0.002, and p < 0.0001, respectively). Cytokine levels increased in patients with advanced-stage lymphoma compared to those with limited-stage (p = 0.002, p = 0.03, and p = 0.01, respectively). Cytokine levels significantly decreased following HIV-cHL diagnosis and treatment. Blood counts of whole B-cells were similar in HIV-cHL patients and controls, but the distribution of B-cell subsets was different with higher ratios of naive B-cells over memory B-cells in HIV-cHL patients. Blood accumulation of naive B-cells was more marked in patients with advanced cHL stages (p = 0.06). During the follow-up, total B-cell counts increased (p < 0.0001), and the proportion of naive B-cells increased further (p = 0.04). Together the results suggest that in HIV-infected patients, cHL is associated with a particular B-cell-related environment that includes increased production of B-cell-activating cytokines and altered peripheral distribution of B-cell subsets. This B-cell-related environment may fuel the process of tumorigenesis.

Immunodeficiency-associated Hodgkin lymphoma

Introduction Hodgkin lymphoma (HL) can occur in different host conditions, i.e. in the general population and immunocompromised individuals, either during HIV infection or solid organ/hematopoietic transplantation and immunosuppressive drug treatment. Areas covered Areas covered include multidimensional characteristics of tumor cells and cellular composition of tumor microenvironment of HL. Current conventional treatments and new treatment strategies for HL in immunosuppressed patients, especially in persons living with HIV (PLWH), are also discussed. PubMed and MEDLINE were used for database searches to identify articles published from 1989 to 2020. Only articles or abstracts in English were considered for this Review Expert opinion In 2012, the International Agency for Research on Cancer -IARC- has considered the epidemiological and biological scientific evidence sufficient to establish that HIV induced immune deficiency is a cause of HL. Moreover, the risk of HL is substantially increased in people with iatrogenically acquired immune depression following organ transplantation. For people with post-transplant HL or for those with HIV/AIDS-associated HL, standard treatments mirror those in the general population. In the last decade, the combination of cART with anti neoplastic treatments, alongside with current anti-rejection therapies, has increased long-term survival of people with HL and acquired immune deficiencies. High dose chemotherapy and autologous stem cell transplantation have been favourably proven as salvage therapy in PLWH with relapsed and refractory HL. Immune checkpoint inhibitors emerged as an area of clinical investigation for relapsed and refractory HL in the general population. Pembrolizumab, an anti-programmed cell death protein 1 (PD-1) drug, resulted safe in PLWH indicating that PD-1 ligand assessment should be advisable in HIV-associated HL. In post-transplant-associated HL management is challenging because it must balance disease eradication with graft rejection, increased immunosuppression and life-threatening infections.

Clinical Characteristics and Histopathological Patterns of Hodgkin Lymphoma and Treatment Outcomes at a Tertiary Cancer Center in Ethiopia.

PURPOSEIn developing countries, Hodgkin lymphoma (HL) affects the young population. In Ethiopia, nearly 70% of the population are < 35 years of age. Therefore, this study aimed to elucidate the age distribution, histopathologic patterns, clinical characteristics and treatment outcomes of HL in Ethiopia.MATERIALS AND METHODSData from clinical records of 133 consecutive patients with HL between 2014 and 2019 were reviewed and collected. Formalin-fixed paraffin-embedded tissue blocks of HL cases were collected and used for subtype classification.RESULTSA total of 68.4% (91) of the patients were male; male-to-female ratio was 2.2:1. The median age was 22 years. The age distribution was 57.1% (76), 30.8% (41), and 2.3% (3) for the age groups (10-29), (30-59), and (60-69) years, respectively. Thirteen percent (12) were associated with HIV. The majority of the cases, 50.4% (67), were of the mixed-cellularity (MCCHL) subtypes and 30% (40) nodular-sclerosis (NSCCHL). Most HIV-associated cases (60%, 6) were of the MCHL subtype. The 4-year overall survival (OS) was 83.1%. The 4-year OS of early-stage patients was 100% and advanced-stage patients with low-risk (International Prognostic Score [IPS] ≤ 2) and high-risk (IPS ≥ 3) were 94.1% and 62.9%, respectively. All patients who received combined-therapy survived, whereas those who received doxorubicin, bleomycin, vinblastine, and dacarbazine only showed a 4-year OS rate of 77.9%.CONCLUSIONHL affects the youngest and most productive population in Ethiopia. The treatment outcome is favorable in both HIV-associated and non–HIV-associated HL. However, the study population was likely a highly selected group as the majority of the Ethiopian population do not have access to specialized care.

HIV-associated Hodgkin Lymphoma with a Granulomatous Bone Marrow Biopsy: A Case Report.

The incidence of HIV-associated Hodgkin lymphoma has risen during the era of combined antiretroviral therapy (ART) despite the proven, protective effects of ART as treatment for HIV. The clinical presentation of Hodgkin Lymphoma may also resemble disseminated mycobacterial infection - in symptoms, laboratory findings, and even bone marrow biopsy. This is a case report of a patient with HIV who was suspected to have disseminated mycobacterial infection after a first bone marrow biopsy showed granulomatous inflammation and was later found to have HIV-associated Hodgkin lymphoma on a repeat biopsy.

Brief Report: HIV-Associated Hodgkin Lymphoma Involving the Bone Marrow Identifies a Very High-Risk Subpopulation in the Era of Widescale Antiretroviral Therapy Use in Johannesburg, South Africa

Background: The incidence of HIV-associated Hodgkin lymphoma (HIV-HL) has not dropped in the era of widespread antiretroviral therapy (ART), and there have reportedly been shifts in the most prevalent variants encountered. In this study, factors of interest in cases of HIV-HL diagnosed before and after the widespread availability of ART in Johannesburg, South Africa, were compared. Methods: All cases of HIV-HL diagnosed in 2007 and 2017 were extracted from the laboratory information system, and pertinent factors compared. Results: The number of cases of HL increased significantly over the period assessed, but without a clear increase in the incidence of HIV-HL. As has been reported previously, the proportion of HIV-HL subclassified as the Nodular Sclerosis and Mixed Cellularity subtypes increased and decreased respectively over the period. The number of unclassifiable cases also increased significantly largely because of more frequent diagnosis in bone marrow (BM). BM involvement was highly prevalent at both timepoints (51.7% in 2007 vs 66.2% in 2017; P = 0.18), but was more frequently associated with multiple cytopenias in 2017. Despite significant ART upscaling, the median CD4 count was significantly lower in 2017 (242.5 cells/μL in 2007 vs 85.5 in 2017; P = 0.002). This particularly affected patients with BM involvement, and the median survival time was significantly shorter among BM+ patients diagnosed in 2017 as compared to those diagnosed in 2007. Notably, 40.8% of the patients with BM involvement diagnosed in 2017 died before the diagnosis was established. Conclusion: HIV-HL with BM involvement identifies a very high-risk subpopulation in the post-ART era.

Hodgkin lymphoma at Groote Schuur Hospital, South Africa: the effect of HIV and bone marrow infiltration

Human immunodeficiency virus (HIV) is associated with an increased risk of developing Hodgkin lymphoma (HL). South Africa (SA) has the highest HIV prevalence rate in the world. There is currently no outcome-based data for HIV-associated HL from SA. A bone marrow database was compiled of all bone marrow biopsies (BMB) reported at National Health Laboratory Service (NHLS) Groote Schuur Hospital (GSH) between January 2005 and December 2012. Patients who had a BMB performed for staging of HL or where HL was diagnosed on the BMB were included for further analysis. Clinical and laboratory data was extracted from medical and laboratory records. Primary outcome measures included histological subtype, bone marrow infiltration (BMI) by HL, CD4 count, HIV-viral load (HIV-VL), tuberculosis (TB) data, treatment with chemotherapy and 5-year overall survival (OS). The database included 6569 BMB and 219 patients of these had HL and were included for analysis. The median age at presentation (32years) was similar in the HIV+ and HIV- populations. While males predominated in the HIV- group, females predominated in the HIV+ group (male:female ratio of 1.5:1 vs 0.7:1, respectively). The majority of patients (71%) were HIV negative (HIV-) and 29% were HIV positive (HIV+). The diagnosis of HL was made on BMB in 17% of cases. BMI was seen in 37% (82/219) overall, and was found in more HIV+ patients (61%; 39/64) than HIV- patients (28%; 43/155; p = 0.03). The histological subtype varied according to HIV status with nodular sclerosis classical Hodgkin lymphoma (NSCHL) being most frequent in the HIV- group and classical Hodgkin lymphoma (CHL)-unclassifiable the most frequent in the HIV+ group. HIV+ patients had a median CD4 count of 149 × 106/L and 39% were anti-retroviral therapy (cART) naive at HL diagnosis. HIV+ patients had received anti-TB therapy more frequently than HIV- patients (72% vs 17%; p = 0.007). More HIV+ patients did not receive chemotherapy than HIV- patients (31% vs 3%; p = 0.001). The 5-year OS was 56%. HIV+ patients with BMI had a 5-year OS of 18%. BMI, HIV status, low CD4 count, histological subtype and TB therapy had a statistical significant impact on 5-year OS (p < 0.01). The 5-year OS was 56%, with both BMI and HIV+ status being associated with poor survival. BMB provided the diagnosis of HL in 17% of cases, confirming its diagnostic utility in our setting. Our cohort showed similar survival outcomes to other countries in Africa, Asia and Central America with comparable socio-economic constraints to SA.

AIDS malignancy consortium (AMC) 095: A phase I study of ipilimumab (IPI) and nivolumab (NIVO) in advanced HIV-associated solid tumors (ST) with expansion cohorts in HIV-associated solid tumors and classical Hodgkin lymphoma (cHL).

TPS44 Background: Immune checkpoint blockade (ICB) using agents that target the priming phase (i.e. CTLA-4) and effector phase (e.g. PD-1) of host immunity, used individually or in combination, has emerged as a therapeutic strategy for cancers. However, little is known about the safety, tolerability and efficacy of ICB in patients (pts) with HIV infection and cancer. Methods: AMC 095 (NCT02408861) is a multicenter, international phase I study of the PD-1 inhibitor, nivo alone or in combination with a CTLA-4 inhibitor, ipi, in 2 cohorts stratified by CD4 counts (Stratum 1: CD4 counts≥200/uL and Stratum 2: CD4 count 100-200/uL) with additional expansion cohorts at the recommended phase II dose in pts with ST and cHL. The primary study objective is to determine the safety and feasibility of nivo alone and the nivo+ipi combination. Secondary objectives are to evaluate the effects of single agent nivo, and ipi+ nivo, on HIV replication and immune function (HIV viral load in plasma using conventional assay, CD4+, and CD8+ cells), and to obtain preliminary information regarding response. The trial was initiated in 8/15, as of 9/30/17, the study is ongoing, and 14 pts have been enrolled. Updated information on the safety and responses will be presented. Clinical trial information: NCT02408861. Funded by the NCI Grant #UM1CA121947.[Table: see text]

Characterization of Epstein–Barr Virus LMP1 deletion variants by Next-Generation Sequencing in HIV-associated Hodgkin Lymphoma (French ANRS CO16 LYMPHOVIR cohort)

Characterization of Epstein–Barr Virus LMP1 deletion variants by Next-Generation Sequencing in HIV-associated Hodgkin Lymphoma (French ANRS CO16 LYMPHOVIR cohort)

Outcomes of HIV-associated Hodgkin lymphoma in the era of antiretroviral therapy.

Clinical series suggest favorable outcomes of HIV-associated Hodgkin lymphoma, in conflict with population-based statistics. Our objective was to investigate the proportion of Americans who received curative chemotherapy for this disease, and compare their survival with HIV-negative cases using population data. We selected cases of HIV-associated Hodgkin lymphoma diagnosed in 2004-2012 from the National Cancer Data Base. Factors associated with receipt of chemotherapy were analyzed by logistic regression. Overall survival was compared in proportional hazard models adjusting for available confounding factors. Among 2090 HIV-positive patients, 81% received chemotherapy, but 16% received no treatment. Advanced age, male sex, nonwhite race, poor socioeconomic status, and undetermined histologic subtype were associated with higher risk of nontreatment. In 2012, 49% of HIV-positive patients were black, and 15% were Hispanic. Unadjusted 5-year overall survival was significantly lower for HIV-positive (66%) than for HIV-negative (80%) populations. However, among patients who received chemotherapy, HIV-positive status was not significantly associated with higher mortality in classical histologic subtypes, including nodular sclerosis (hazard ratio, HR, 1.08; 95% confidence interval, CI, 0.88-1.33) and mixed cellularity (HR, 1.06; 95% CI, 0.80-1.40). In contrast, prognosis remained significantly worse for cases with undetermined histology (HR, 1.56; 95% CI, 1.31-1.85), suggesting a more aggressive biology or other high-risk characteristics in this subgroup. Worse survival statistics for HIV-associated Hodgkin lymphoma are driven by lower rates of chemotherapy administration. The disparity in treatment delivery needs attention because a majority of HIV-positive Americans with Hodgkin lymphoma are now black or Hispanic, and this proportion is increasing.

AMC-085: A Pilot Trial of AVD and Brentuximab Vedotin in the Upfront Treatment of Stage II-IV HIV-Associated Hodgkin Lymphoma. A Trial of the AIDS Malignancy Consortium

Introduction: Patients (pts) infected with HIV have a 6-8 fold increased risk of classic Hodgkin lymphoma (cHL). Incidence may have increased with the implementation of combined anti-retroviral therapy (cART) in the mid 1990s. Frontline therapy for HIV-associated cHL (HIV-cHL) using, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in the pre-cART era showed a 2 year overall survival (OS) of 48%, but outcomes are currently similar to the non-HIV population. Pts with advanced disease have a 30% chance of relapse with ABVD. Brentuximab vedotin (BV), an anti-CD30 an antibody drug conjugate that selectively induces apoptosis of CD30+ cells with a complete response of 34% in patients with relapsed/refractory cHL. An international trial of BV with doxorubicin, vinblastine, and dacarbazine (AVD) vs. ABVD is ongoing. Here we present the phase I portion of the first trial using BV with AVD in the upfront treatment of HIV-cHL. The Phase II portion is actively accruing in both the United States and France as part of an AIDS Malignancy Consortium (AMC)/Lymphoma Study Association (LYSA) collaboration.Methods: The Phase I was a 3+3 dose de-escalation design evaluating 3 dose levels of BV (1.2 mg/kg, 0.9 mg/kg, and 0.6 mg/kg) every 2 weeks combined with standard, fixed doses of doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2 (AVD) in a 28 day cycle. Eligibility: HIV+ pts diagnosed with untreated cHL stage II-IV with CD4 counts ≥50 cells/mm3 were required to take cART regimens for at least 1 week before treatment. Ritonavir, zidovidine, and cobisistat were excluded. Baseline, cycle 2, and post treatment PET/CT scans were required. Dose limiting toxicities (DLTs) were defined during cycle 1.Results: Sixpts (5 men and 1 woman) were treated in the phase I portion from 3/2013-5/2015. Staging: II (n=1), III (n=1) IV (n=4). Pathology: mixed cellularity (n=2), nodular sclerosis (n=3), and lymphocyte depleted/mixed cellularity (n=1) HIV-cHL. The median CD4 T cell count at lymphoma diagnosis was 499 cells/mm3 (range 86-784) and the median viral load was 44 copies/ml (range 20-77). No cycle 1 DLTs were identified in the first 6 eligible patients and only 3 grade 3 adverse events in later cycles were noted, pneumonia, n=1, and neuropathy n=2, and neutropenia, n=1. In 2 pts, toxicity required delays in therapy of over 3 weeks (after c5d1 and after c6d1) resulting in subject removal from further protocol therapy. One pt had a decrease in the diffusion lung capacity for carbon monoxide (DLCO) to 65% after cycle 2, and BV was withheld while AVD continued as per protocol. Two pts were later deemed ineligible, and excluded from any analysis, due to the concomitant use of ritonavir-based cART at enrollment. Both developed febrile neutropenia and one developed a grade 3 pancreatitis during cycle 1, emphasizing the importance of not treating patients with BV + AVD with concurrent CYP3A4 inhibitors. Five of the 6 pts achieved cycle 2 PET/CT negativity as defined by a Deauville score 1-3. The PET/CT positive patient ultimately had a negative post-therapy scan. The 5 pts who completed therapy achieved CR post-therapy, and one patient has yet to complete treatment. Phase II is enrolling at BV 1.2 mg/kg in combination with AVD.Conclusions: AVD-BV in stage II-IV HIV-cHL was well-tolerated therapy as no DLT were identified. Five of the 6 patients achieved a negative C2 PET/CT and 5/5 of the patients who completed therapy thus far achieved a CR. The recommended Phase II dose is 1.2 mg/kg +AVD every other week. The phase II portion (51 subjects) is actively accruing in both the USA and France, in an AMC/LYSA collaboration, clinicaltrials.gov NCT01771107. DisclosuresNo relevant conflicts of interest to declare.

Prognosis of HIV-Associated Hodgkin Lymphoma in the Antiretroviral Therapy Era: Analysis of the National Cancer Data Base (NCDB)

▪Background: The incidence of Hodgkin lymphoma (HL) among HIV-positive (HIV+) patients remains high despite the use of antiretroviral therapy. HIV+HL is characterized by a higher prevalence of the mixed cellularity (MC) subtype and by expression of Epstein-Barr virus-encoded genes. Despite poor historical outcomes, recent studies show similar overall survival (OS) among HIV+ and HIV-negative HL patients who receive standard therapy. We examined the actual proportions of HIV+HL patients receiving chemotherapy in the United States (US), and their OS, using the NCDB-a clinical oncology database capturing >70% of incident cancer cases in the US.Methods: We analyzed classical HL cases reported to the NCDB between 2004 and 2012, with recorded HIV status. Factors associated with non-receipt of chemotherapy were studied in a mixed-effects logistic model clustered on hospital. OS was compared in Cox models adjusting for age, sex, race, stage, B symptoms and socioeconomic status, reporting adjusted hazard ratio (HR) and 95% confidence intervals (CI). CD4 counts, chemotherapy details or HL recurrences were not available in the NCDB.Results: We identified 2,090 HIV+HL and 24,889 HIV-negative patients. HIV+ patients were on average older (median age 43 vs. 39 years in HIV-negative), more often male (80% vs. 53%), black (37% vs. 12%) or Hispanic (17% vs. 8%%, all P <.00001). The proportion of black patients increased from 31% in 2004 to 49% in 2012. HIV+HL patients had also more often advanced-stage (III/IV) disease (66% vs. 40%), B symptoms (64% vs. 41%), extranodal HL (5% vs. 3%), MC (22% vs. 12%), lymphocyte-depleted (LD, 3% vs. 1%) or undetermined histology (HL-NOS, 40% vs. 26%), and less nodular sclerosis (NS) subtype (32% vs. 57%, all P<.00001).Early (I/II) stage HIV+HL patients were more often treated with chemotherapy alone (51% vs. 46% of HIV-negative), less frequently with combined modality (28% vs. 42%), and 18% received no treatment (vs. 9%, P<.0001). Similarly, in advanced stage they were less likely to receive chemotherapy than HIV-negative patients (84% vs. 91%, P<.0001). The proportion of all HIV+HL cases receiving any chemotherapy was 81%, unchanged between 2004 and 2012 (P =.29). Their risk of not receiving chemotherapy increased with age, and was significantly higher for patients who were black (odds ratio, OR, vs. white, 1.55, CI, 1.14-2.09), uninsured (OR, 1.65, CI, 1.08-2.51), or with HL-NOS (OR vs. NS, 1.73, CI, 1.27-2.35). It varied significantly by hospital (intraclass correlation, 9%, CI, 4-20%), but without difference between community and academic centers (P =.47).OS at 5 years for HIV+HL patients was 66.1% overall (95% CI, 63.7-68.4%), 78.7% in stage I/II, and 59.9% in stage III/IV. Among patients who received chemotherapy, these estimates were 73.0%, 83.5% and 68.0%, respectively. OS did not improve between 2004 and 2011 (P =.18). When HIV+ and HIV-negative HL patients were compared in models adjusting for confounders (Table), OS was not significantly different in the classic NS or MC subtypes as long as patients received chemotherapy. In contrast, HIV+ HL-NOS had significantly worse OS even with chemotherapy, similar to OS of HIV-negative patients with the unfavorable LD subtype.Conclusions: This large contemporary analysis confirms similar survival of HIV- and HIV+HL patients with the classical NS/MC histologies as long as they receive chemotherapy. HL of undetermined histologic subtype (possibly because of atypical, aggressive morphology or difficulty in obtaining an excisional nodal specimen) identifies HIV+ patients with poor prognosis despite standard therapy, who might benefit from novel, alternative approaches. As of 2012, half of HIV+HL patients in the US are black, and they are at high risk of not receiving curative chemotherapy, although it is unclear whether this is because of health care-related factors or worse immune deficiency status.Table 1HistologyAll patientsPatients receiving chemotherapy5-year OS (%)Cox model5-year OS (%)Cox modelHIV+HIV-HRPHIV+HIV-HRPNS74.585.31.42.000180.287.11.14.23MC73.073.11.31.02677.676.81.14.37Lymphocyte-rich74.181.81.25.5971.183.71.49.38LD57.555.41.09.7669.062.90.95.89HL-NOS55.172.01.85<.000163.577.31.57<.0001 DisclosuresOlszewski:Genentech, Inc.: Research Funding; Bristol-Myers Squibb, Inc.: Consultancy.

High Risk Features Contrast With Favorable Outcomes in HIV-associated Hodgkin Lymphoma in the Modern cART Era, ANRS CO16 LYMPHOVIR Cohort.

Human immunodeficiency virus (HIV) infection is associated with a high risk of classical Hodgkin's lymphoma (cHL) in the combined antiretroviral therapy (cART) era. We analyzed the characteristics and outcome of HIV-associated cHL diagnosed in the modern cART era. The French ANRS-CO16 Lymphovir cohort enrolled 159 HIV-positive patients with lymphoma, including 68 (43%) with cHL. HIV-HL patients were compared with a series of non-HV-infected patients consecutively diagnosed with HL. Most patients (76%) had Ann-Arbor stages III-IV and 96% of patients were treated with ABVD. At diagnosis, median CD4 T-cell count was 387/µL and 94% of patients were treated with cART. All patients received cART after diagnosis. Five patients died from early progression (n = 2), sepsis (1) or after relapse (2). Two additional patients relapsed during follow-up. Two-year overall and progression free survivals (PFS) were 94% [95% CI, 89%, 100%] and 89% [82%, 97%], respectively. The only factor associated with progression or death was age with a relative risk of 8.1 [1.0; 67.0] above 45 years. The PFS of Lymphovir patients appeared similar to PFS of HIV-negative patients, 86% [82%, 90%], but patients with HIV infection displayed higher risk features than HIV-negative patients. Although high-risk features still predominate in HIV-HL, the prognosis of these patients, treated with cART and mainly ABVD, has markedly improved in the modern cART era and is now similar to non-HIV-infected patients.

HAART and lungs: do HIV protease inhibitors impact cancer risk?

HAART and lungs: do HIV protease inhibitors impact cancer risk?