Current Multidisciplinary Lymphoma and Myeloma Management for Surgeons.

Although there are more than 100 clinically distinct lymphoid neoplasms with varied prognoses and treatment approaches, they generally share high sensitivity to glucocorticoids, cytotoxic chemotherapy, and radiation. The disease control rates for lymphoid malignancies are higher than many solid tumors, and many are curable even when presenting with extensive involvement. Novel targeted therapies have improved disease control and cure rates for nearly all subtypes of lymphoid neoplasms. Surgical oncologists will primarily be involved in obtaining biopsies of sufficient quality to allow accurate diagnosis. However, there are scenarios in which surgical intervention may be necessary to address an oncologic emergency.

Brentuximab vedotin with AVD for stage II-IV HIV-related Hodgkin lymphoma (AMC 085): phase 2 results from an open-label, single arm, multicentre phase 1/2 trial.

BACKGROUND: Brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is approved in the upfront setting for advanced stage classical Hodgkin lymphoma (cHL). People living with HIV have been excluded from these studies. We aimed to understand the activity and safety of brentuximab vedotin-AVD in people living with HIV diagnosed with Hodgkin lymphoma, while focusing on HIV disease parameters and antiretroviral therapy (ART) interactions. METHODS: We present the phase 2 portion of a multicentre phase 1/2 study. Eligible patients were 18 years or older, had untreated stage II-IV HIV-associated cHL (HIV-cHL), a Karnofsky performance status of more than 30%, a CD4+ T-cell count of 50 cells per µL or more, were required to take ART, and were not on strong CYP3A4 or P-glycoprotein inhibitors. Patients were treated intravenously with 1·2 mg/kg of brentuximab vedotin (recommended phase 2 dose) with standard doses of AVD for six cycles on days 1 and 15 of a 28-day cycle. The primary endpoint of the phase 2 portion was 2-year progression-free survival (PFS), assessed in all eligible participants who began treatment. Accrual has been completed. This trial is registered at ClinicalTrials.gov, NCT01771107. FINDINGS: Between March 8, 2013, and March 7, 2019, 41 patients received study therapy with a median follow up of 29 months (IQR 16-38). 34 (83%) of 41 patients presented with stage III-IV and seven (17%) with stage II unfavourable HIV-cHL. 37 (90%) of 41 patients completed therapy, all 37 of whom achieved complete response. The 2-year PFS was 87% (95% CI 71-94) and the overall survival was 92% (78-97). The most common grade 3 or worse adverse events were peripheral sensory neuropathy (four [10%] of 41 patients), neutropenia (18 [44%]), and febrile neutropenia (five [12%]). One treatment-related death was reported, due to infection. INTERPRETATION: Brentuximab vedotin-AVD was highly active and had a tolerable adverse event rate in HIV-cHL and is an important therapeutic option for people with HIV-cHL. The complete reponse rate is encouraging and is possibly related to a unique aspect of HIV-cHL biology. Upcoming 5-year data will evaluate the sustainability of the outcomes obtained. FUNDING: National Institutes of Health and National Cancer Institute.

Consensus recommendations on peripheral blood smear review: defining curricular standards and fellow competency.

Graduate medical education training in hematology in North America is accredited by the Accreditation Council for Graduate Medical Education (ACGME). Trainees routinely review peripheral blood smears (PBS) in providing clinical care. Competency in PBS review at graduation is required by the ACGME. However, there are no consensus guidelines on best practices surrounding PBS review, education, or competency. We describe the generation of proposed theory and the consensus recommendations developed through a multi-institutional focus group, developed using constructivist grounded theory and a modified nominal group technique. Eight academic hematologists, spanning classical and malignant hematology, enrolled and participated in 2 one-hour focus groups. All routinely worked with fellows and half had formally instructed trainees on PBS interpretation. Focus group data were analyzed using mixed-methods techniques. Tenets of emerging theory were identified through inductive coding. Consensus recommendations (CR) were generated. Participants reviewed CR in an iterative fashion until consensus was reached. Strong consensus was reached on multiple aspects of PBS education. All agreed that trainees should learn PBS review through a systematic approach. Group discussion focused on disorders of red and white blood cells. The diagnoses of acute leukemia and thrombotic microangiopathies were most commonly discussed, with specific emphasis on disorders in which prompt recognition was required to avert significant patient morbidity. These CR offer external validity to future research and curricular development for both PBS review and other visuospatial tasks in medical education.

AMC-070: Lenalidomide Is Safe and Effective in HIV-Associated Kaposi Sarcoma.

PURPOSE: Kaposi sarcoma (KS), an endothelial cell tumor associated with KS herpesvirus (KSHV), remains among the most common malignancies occurring with HIV infection (HIV-KS). As an oral anti-inflammatory, antiangiogenic, and immunomodulatory agent, lenalidomide is potentially an attractive alternative to standard chemotherapy for KS. EXPERIMENTAL DESIGN: The primary objectives of this phase I/II trial were to determine the maximum tolerated dose (MTD) and response rates for lenalidomide in HIV-KS. Secondary objectives included correlating response with natural killer (NK) and T-cell subsets, plasma cytokines, viral copy number, and KSHV gene expression in biopsies. Four dose levels of oral lenalidomide taken 21 consecutive days of 28-day cycles were evaluated in adults with HIV-KS on antiretroviral therapy with controlled viremia. RESULTS: Fifteen and 23 participants enrolled in phases I and II, respectively, 76% of whom had received prior KS therapy. The MTD was not reached, declaring 25 mg as the recommended phase II dose (RP2D). The most frequent adverse events were neutropenia, fatigue, leukopenia, and diarrhea. Of the 25 evaluable participants receiving RP2D, 60% responded. Correlative studies performed in a subset of participants demonstrated a significant increase in proportions of blood T cells with T-regulatory phenotype, and plasma cytokines trended toward a less inflammatory pattern. Clinical response was associated with loss of KSHV transcription. CONCLUSIONS: Lenalidomide is active in HIV-KS. The most common adverse events were manageable. With 60% of participants receiving RP2D obtaining a partial response and <10% discontinuing due to adverse events, the response and tolerability to lenalidomide support its use in HIV-KS. See related commentary by Henry and Maki, p. 2485.

Impact of Myc in HIV-associated non-Hodgkin lymphomas treated with EPOCH and outcomes with vorinostat (AMC-075 trial).

EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is a preferred regimen for HIV-non-Hodgkin lymphomas (HIV-NHLs), which are frequently Epstein-Barr virus (EBV) positive or human herpesvirus type-8 (HHV-8) positive. The histone deacetylase (HDAC) inhibitor vorinostat disrupts EBV/HHV-8 latency, enhances chemotherapy-induced cell death, and may clear HIV reservoirs. We performed a randomized phase 2 study in 90 patients (45 per study arm) with aggressive HIV-NHLs, using dose-adjusted EPOCH (plus rituximab if CD20+), alone or with 300 mg vorinostat, administered on days 1 to 5 of each cycle. Up to 1 prior cycle of systemic chemotherapy was allowed. The primary end point was complete response (CR). In 86 evaluable patients with diffuse large B-cell lymphoma (DLBCL; n = 61), plasmablastic lymphoma (n = 15), primary effusion lymphoma (n = 7), unclassifiable B-cell NHL (n = 2), and Burkitt lymphoma (n = 1), CR rates were 74% vs 68% for EPOCH vs EPOCH-vorinostat (P = .72). Patients with a CD4+ count <200 cells/mm3 had a lower CR rate. EPOCH-vorinostat did not eliminate HIV reservoirs, resulted in more frequent grade 4 neutropenia and thrombocytopenia, and did not affect survival. Overall, patients with Myc+ DLBCL had a significantly lower EFS. A low diagnosis-to-treatment interval (DTI) was also associated with inferior outcomes, whereas preprotocol therapy had no negative impact. In summary, EPOCH had broad efficacy against highly aggressive HIV-NHLs, whereas vorinostat had no benefit; patients with Myc-driven DLBCL, low CD4, and low DTI had less favorable outcomes. Permitting preprotocol therapy facilitated accruals without compromising outcomes. This trial was registered at www.clinicaltrials.gov as #NCT0119384.

Pilot Trial AMC-063: Safety and Efficacy of Bortezomib in AIDS-associated Kaposi Sarcoma.

PURPOSE: AIDS-related Kaposi sarcoma is often incompletely controlled, requiring serial therapies. Kaposi sarcoma herpesvirus (KSHV) induces transformation of endothelial cells, where it resides in a predominately latent state. We hypothesized proteasome inhibition would have direct antitumor activity, induce lytic activation of KSHV, and inhibit HIV infectivity, improving control of both Kaposi sarcoma and HIV. The primary objective was determining the MTD of bortezomib in AIDS-Kaposi sarcoma. Secondary objectives included estimating the impact of bortezomib on Kaposi sarcoma response, KSHV plasma DNA copy number (PDCN), and HIV viral loads (VL). PATIENTS AND METHODS: A 3+3 dose escalation design was employed evaluating four dose levels of bortezomib (0.75, 1, 1.2, or 1.6 mg/m2) administered intravenously on days 1, 8, and 15 of 28-day cycles in patients with relapsed/refractory (r/r) AIDS-Kaposi sarcoma taking antiretroviral therapy. RESULTS: Seventeen patients enrolled. No dose-limiting toxicities occurred and the MTD was not reached. The most common adverse events included diarrhea, fatigue and nausea. Among 15 evaluable patients, partial response (PR) occurred in nine (60%), with a PR rate of 83% in the 1.6 mg/m2 cohort; the remainder had stable disease (SD). Median time to response was 2.1 months. Median change in KSHV PDCN was significantly different between those with PR versus SD. During cycle 1, seven of 11 evaluable patients had decreases in HIV VL. CONCLUSIONS: Bortezomib is well-tolerated and active in AIDS-Kaposi sarcoma. The 60% PR rate is notable given the dose-finding nature of the study in a r/r population. Changes in KSHV PDCN and HIV VL trended as hypothesized.

Safety and efficacy of an oncolytic viral strategy using bortezomib with ICE/R in relapsed/refractory HIV-positive lymphomas.

HIV-associated lymphomas (HALs) have high rates of latent infection by gammaherpesviruses (GHVs). We hypothesized that proteasome inhibition would induce lytic activation of GHVs and inhibit HIV infectivity via preservation of cytidine deaminase APOBEC3G, improving lymphoma control. We tested this oncolytic and antiviral strategy by using bortezomib combined with ifosfamide, carboplatin, and etoposide (ICE) alone or with rituximab (ICE/R) in relapsed/refractory HAL. A 3+3 dose-escalation design was used with a 7-day lead-in period of single-agent bortezomib. Bortezomib was administered intravenously on days 1 and 8 of each cycle at 1 of 4 dose levels: 0.7, 1.0, 1.3, or 1.5 mg/m2 ICE began day 8 of cycle 1 and day 1 of subsequent cycles. Rituximab was included on day 1 of cycles 2 to 6 for CD20+ lymphomas. Twenty-three patients were enrolled. The maximum tolerated dose of bortezomib was not reached. Grade 4 toxicities attributable to bortezomib were limited to myelosuppression. Responses occurred in 17 (77%) of 22 patients receiving any protocol therapy. The 1-year overall survival was 57%. After bortezomib alone, both patients with Kaposi sarcoma herpesvirus (KSHV)-positive lymphoma had more than a 1-log increase in KSHV viral load. In 12 patients with Epstein-Barr virus (EBV)-positive lymphoma, median values of EBV viral load increased. Undetectable HIV viremia at baseline in the majority of patients limited evaluation of HIV inhibition. APOBEC3G levels increased in 75% of evaluable patients. Bortezomib combined with ICE/R in patients with relapsed/refractory HAL is feasible with response and survival comparing favorably against previously reported second-line therapies. Changes in GHV viral loads and APOBEC3G levels trended as hypothesized. This trial was registered at www.clinicaltrials.gov as #NCT00598169.

Safety and Preliminary Efficacy of Vorinostat With R-EPOCH in High-risk HIV-associated Non-Hodgkin's Lymphoma (AMC-075).

INTRODUCTION: Vorinostat (VOR), a histone deacetylase inhibitor, enhances the anti-tumor effects of rituximab (R) and cytotoxic chemotherapy, induces viral lytic expression and cell killing in Epstein-Barr virus-positive (EBV+) or human herpesvirus-8-positive (HHV-8+) tumors, and reactivates latent human immunodeficiency virus (HIV) for possible eradication by combination antiretroviral therapy (cART). PATIENTS AND METHODS: We performed a phase I trial of VOR given with R-based infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) (n = 12) and cART in aggressive HIV-associated B-cell non-Hodgkin lymphoma (NHL) in order to identify safe dosing and schedule. VOR (300 or 400 mg) was given orally on days 1 to 5 with each cycle of R-EPOCH for 10 high-risk patients with diffuse large B-cell lymphoma (1 EBV+), 1 EBV+/HHV-8+ primary effusion lymphoma, and 1 unclassifiable NHL. VOR was escalated from 300 to 400 mg using a standard 3 + 3 design based on dose-limiting toxicity observed in cycle 1 of R-EPOCH. RESULTS: The recommended phase II dose of VOR was 300 mg, with dose-limiting toxicity in 2 of 6 patients at 400 mg (grade 4 thrombocytopenia, grade 4 neutropenia), and 1 of 6 treated at 300 mg (grade 4 sepsis from tooth abscess). Neither VOR, nor cART regimen, significantly altered chemotherapy steady-state concentrations. VOR chemotherapy did not negatively impact CD4+ cell counts or HIV viral loads, which decreased or remained undetectable in most patients during treatment. The response rate in high-risk patients with NHL treated with VOR(R)-EPOCH was 100% (complete 83% and partial 17%) with a 1-year event-free survival of 83% (95% confidence interval, 51.6%-97.9%). CONCLUSION: VOR combined with R-EPOCH was tolerable and seemingly efficacious in patients with aggressive HIV-NHL.

mTOR activity in AIDS-related diffuse large B-cell lymphoma.

BACKGROUND: Patients infected with HIV have a significantly increased risk of developing non-Hodgkin lymphomas despite the widespread use of HAART. To investigate mTOR pathway activity in acquired immunodeficiency syndrome (AIDS) related diffuse large B-cell lymphoma AR-DLBCL, we used immunohistochemistry to examine the presence of the phosphorylated 70 ribosomal S6 protein-kinase (p70S6K), an extensively studied effector of mTOR Complex 1 (mTORC1) and the phosphorylated phosphatase and tensin homolog (pPTEN), a negative regulator of mTORC1 pathway. MATERIALS AND METHODS: We evaluated tissue samples from 126 patients with AR-DLBCL. Among them, 98 samples were from tissue microarrays (TMAs) supplied by the Aids and Cancer Specimen Resource (ACSR), the remaining 28 samples were from cases diagnosed and treated at the University of California, San Diego (UCSD). The presence of p70S6K was evaluated with two antibodies directed against the combined epitopes Ser235/236 and Ser240/244, respectively; and additional monoclonal anti-bodies were used to identify pPTEN and phosphorylated proline-rich Akt substrate of 40kDa (pPRAS40). The degree of intensity and percentage of cells positive for p70S6K and pPTEN were assessed in all the samples. In addition, a subgroup of 28 patients from UCSD was studied to assess the presence of pPRAS40, an insulin-regulated activator of the mTORC1. The expression of each of these markers was correlated with clinical and histopathologic features. RESULTS: The majority of the patients evaluated were males (88%); only two cases (1.6%) were older than 65 years of age. We found high levels of both p70S6K-paired epitopes studied, 48% positivity against Ser235/236 (44% in ACSR and 64% in UCSD group), and 86% positivity against Ser240/244 (82% in ACSR and 100% in UCSD group). We observed more positive cells and stronger intensity with epitope Ser240/244 in comparison to Ser235/236 (p<0.0001). The degree of intensity and percentage of cells positive for pPTEN was positively correlated with p70S6K levels (p = 0.016 for 235/236 and p = 0.007 for 240/244). High levels of pPRAS40 were observed in the majority of the cases evaluated (64.3%), but no correlation was found with either pPTEN (p = 0.9) or p70S6K (p = 0.9) levels. CONCLUSION: AR-DLBCL frequently contain p70S6K, a main downstream effector of the mTOR pathway. The presence of p70S6K is positively correlated with pPTEN, an inactive form of PTEN, which makes mTORC1 activated. The presence of p70S6K was independent of HIV viral load or CD4 (+) counts. These results suggest that the mTOR pathway is active in the majority of AR-DLBCL, and p70S6K, particularly the Ser240/244 epitope immunohistochemistry is an excellent surrogate biomarker, which could be used to identify cases expected to be responsive to mTOR inhibitors.

Long-term survival in AIDS-related primary central nervous system lymphoma.

BACKGROUND: The optimal therapeutic approach for patients with AIDS-related primary central nervous system lymphoma (AR-PCNSL) remains undefined. While its incidence declined substantially with combination antiretroviral therapy (cART), AR-PCNSL remains a highly aggressive neoplasm for which whole brain radiotherapy (WBRT) is considered a standard first-line intervention. METHODS: To identify therapy-related factors associated with favorable survival, we first retrospectively analyzed outcomes of AR-PCNSL patients treated at San Francisco General Hospital, a public hospital with a long history of dedicated care for patients with HIV and AIDS-related malignancies. Results were validated in a retrospective, multicenter analysis that evaluated all newly diagnosed patients with AR-PCNSL treated with cART plus high-dose methotrexate (HD-MTX). RESULTS: We provide evidence that CD4+ reconstitution with cART administered during HD-MTX correlates with long-term survival among patients with CD4 <100. This was confirmed in a multicenter analysis which demonstrated that integration of cART regimens with HD-MTX was generally well tolerated and resulted in longer progression-free survival than other treatments. No profound differences in immunophenotype were identified in an analysis of AR-PCNSL tumors that arose in the pre- versus post-cART eras. However, we detected evidence for a demographic shift, as the proportion of minority patients with AR-PCNSL increased since advent of cART. CONCLUSION: Long-term disease-free survival can be achieved in AR-PCNSL, even among those with histories of opportunistic infections, limited access to health care, and medical non-adherence. Given this, as well as the long-term toxicities of WBRT, we recommend that integration of cART plus first-line HD-MTX be considered for all patients with AR-PCNSL.

What is the Incidence of Kidney Stones after Chemotherapy in Patients with Lymphoproliferative or Myeloproliferative Disorders?

Introduction This study describes the incidence and risk factors of de novo nephrolithiasis among patients with lymphoproliferative or myeloproliferative diseases who have undergone chemotherapy. Materials and Methods From 2001 to 2011, patients with lymphoproliferative or myeloproliferative disorders treated with chemotherapy were retrospectively identified. The incidence of image proven nephrolithiasis after chemotherapy was determined. Demographic and clinical variables were recorded. Patients with a history of nephrolithiasis prior to chemotherapy were excluded. The primary outcome was incidence of nephrolithiasis, and secondary outcomes were risk factors predictive of de novo stone. Comparative statistics were used to compare demographic and disease specific variables for patients who developed de novo stones versus those who did not. Results A total of 1,316 patients were identified and the incidence of de novo nephrolithiasis was 5.5% (72/1316; symptomatic stones 1.8% 24/1316). Among patients with nephrolithiasis, 72.2% had lymphoproliferative disorders, 27.8% had myeloproliferative disorders, and 25% utilized allopurinol. The median urinary pH was 5.5, and the mean serum uric acid, calcium, potassium and phosphorus levels were 7.5, 9.6, 4.3, and 3.8 mg/dL, respectively. In univariate analysis, mean uric acid (p=0.013), calcium (p<0.001)), and potassium (p=0.039) levels were higher in stone formers. Diabetes mellitus (p<0.001), hypertension (p=0.003), and hyperlipidemia (p<0.001) were more common in stone formers. In multivariate analysis, diabetes mellitus, hyperuricemia, and hypercalcemia predicted stone. Conclusions We report the incidence of de novo nephrolithiasis in patients who have undergone chemotherapy. Diabetes mellitus, hyperuricemia, and hypercalcemia are patient-specific risk factors that increase the odds of developing an upper tract stone following chemotherapy. .

Phase II trial of imatinib in AIDS-associated Kaposi's sarcoma: AIDS Malignancy Consortium Protocol 042.

PURPOSE: Kaposi's sarcoma (KS) is a disease of multifocal vascular proliferation that requires infection with KS herpes virus (KSHV/HHV-8). Activation of the c-kit and platelet-derived growth factor (PDGF) receptors by autocrine/paracrine mechanisms follows endothelial cell KSHV infection. In a pilot study, imatinib, a c-kit/PDGF-receptor inhibitor, induced partial regression of AIDS-associated KS (AIDS-KS) in five of 10 patients. PATIENTS AND METHODS: This multicenter phase II study was designed to estimate the response rate to imatinib in AIDS-KS. Secondary objectives included investigation of predictors of response and imatinib pharmacokinetics in patients on antiretrovirals. Patients received imatinib 400 mg/day by mouth for up to 12 months with dose escalation up to 600 mg/day at 3 months if their disease was stable. RESULTS: Thirty patients were treated at 12 AIDS Malignancy Consortium sites. Ten patients (33.3%) achieved partial response, six (20%) had stable disease, and seven (23.3%) exhibited KS progression. Nine patients completed 52 weeks of imatinib therapy. The median treatment duration was 22.5 weeks. Only five patients (16.7%) discontinued therapy owing to adverse events. Antiretroviral regimens did not significantly alter imatinib metabolism. Activating mutations in PDGF-R and c-kit were not found at baseline or at disease progression. We found no correlation with response with changes in any of the candidate cytokines. CONCLUSION: Imatinib has activity in AIDS-KS. Pharmacokinetic interactions with antiretroviral drugs did not correlate with toxicity. Thirty percent of patients showed long-term clinical benefit and remained on imatinib for the entire year. These results suggest imatinib is well tolerated and may be an alternative therapy for some patients with AIDS-KS.

What is the incidence of kidney stones after chemotherapy in patients with lymphoproliferative or myeloproliferative disorders?

INTRODUCTION: This study describes the incidence and risk factors of de novo nephrolithiasis among patients with lymphoproliferative or myeloproliferative diseases who have undergone chemotherapy. MATERIALS AND METHODS: From 2001 to 2011, patients with lymphoproliferative or myeloproliferative disorders treated with chemotherapy were retrospectively identified. The incidence of image proven nephrolithiasis after chemotherapy was determined. Demographic and clinical variables were recorded. Patients with a history of nephrolithiasis prior to chemotherapy were excluded. The primary outcome was incidence of nephrolithiasis, and secondary outcomes were risk factors predictive of de novo stone. Comparative statistics were used to compare demographic and disease specific variables for patients who developed de novo stones versus those who did not. RESULTS: A total of 1,316 patients were identified and the incidence of de novo nephrolithiasis was 5.5% (72/1316; symptomatic stones 1.8% 24/1316). Among patients with nephrolithiasis, 72.2% had lymphoproliferative disorders, 27.8% had myeloproliferative disorders, and 25% utilized allopurinol. The median urinary pH was 5.5, and the mean serum uric acid, calcium, potassium and phosphorus levels were 7.5, 9.6, 4.3, and 3.8 mg/dL, respectively. In univariate analysis, mean uric acid (p=0.013), calcium (p<0.001)), and potassium (p=0.039) levels were higher in stone formers. Diabetes mellitus (p<0.001), hypertension (p=0.003), and hyperlipidemia (p<0.001) were more common in stone formers. In multivariate analysis, diabetes mellitus, hyperuricemia, and hypercalcemia predicted stone. CONCLUSIONS: We report the incidence of de novo nephrolithiasis in patients who have undergone chemotherapy. Diabetes mellitus, hyperuricemia, and hypercalcemia are patient-specific risk factors that increase the odds of developing an upper tract stone following chemotherapy.

Whole transcriptome sequencing enables discovery and analysis of viruses in archived primary central nervous system lymphomas.

Primary central nervous system lymphomas (PCNSL) have a dramatically increased prevalence among persons living with AIDS and are known to be associated with human Epstein Barr virus (EBV) infection. Previous work suggests that in some cases, co-infection with other viruses may be important for PCNSL pathogenesis. Viral transcription in tumor samples can be measured using next generation transcriptome sequencing. We demonstrate the ability of transcriptome sequencing to identify viruses, characterize viral expression, and identify viral variants by sequencing four archived AIDS-related PCNSL tissue samples and analyzing raw sequencing reads. EBV was detected in all four PCNSL samples and cytomegalovirus (CMV), JC polyomavirus (JCV), and HIV were also discovered, consistent with clinical diagnoses. CMV was found to express three long non-coding RNAs recently reported as expressed during active infection. Single nucleotide variants were observed in each of the viruses observed and three indels were found in CMV. No viruses were found in several control tumor types including 32 diffuse large B-cell lymphoma samples. This study demonstrates the ability of next generation transcriptome sequencing to accurately identify viruses, including DNA viruses, in solid human cancer tissue samples.

Retinal vein occlusion during flare of multicentric Castleman's disease.

We report a case of successive bilateral retinal vein occlusion in a human immunodeficiency virus (HIV)-positive male with multicentric Castleman's disease treated successfully with a single injection of intravitreal bevacizumab. Castleman's disease should be a differential diagnosis of occlusive retinovascular disease and, occasionally, ocular manifestation can lead to systemic diagnosis.

Temporal trends in presentation and survival for HIV-associated lymphoma in the antiretroviral therapy era.

BACKGROUND: Lymphoma is the leading cause of cancer-related death among HIV-infected patients in the antiretroviral therapy (ART) era. METHODS: We studied lymphoma patients in the Centers for AIDS Research Network of Integrated Clinical Systems from 1996 until 2010. We examined differences stratified by histology and diagnosis year. Mortality and predictors of death were analyzed using Kaplan-Meier curves and Cox proportional hazards. RESULTS: Of 23 050 HIV-infected individuals, 476 (2.1%) developed lymphoma (79 [16.6%] Hodgkin lymphoma [HL]; 201 [42.2%] diffuse large B-cell lymphoma [DLBCL]; 56 [11.8%] Burkitt lymphoma [BL]; 54 [11.3%] primary central nervous system lymphoma [PCNSL]; and 86 [18.1%] other non-Hodgkin lymphoma [NHL]). At diagnosis, HL patients had higher CD4 counts and lower HIV RNA than NHL patients. PCNSL patients had the lowest and BL patients had the highest CD4 counts among NHL categories. During the study period, CD4 count at lymphoma diagnosis progressively increased and HIV RNA decreased. Five-year survival was 61.6% for HL, 50.0% for BL, 44.1% for DLBCL, 43.3% for other NHL, and 22.8% for PCNSL. Mortality was associated with age (adjusted hazard ratio [AHR] = 1.28 per decade increase, 95% confidence interval [CI] = 1.06 to 1.54), lymphoma occurrence on ART (AHR = 2.21, 95% CI = 1.53 to 3.20), CD4 count (AHR = 0.81 per 100 cell/µL increase, 95% CI = 0.72 to 0.90), HIV RNA (AHR = 1.13 per log10copies/mL, 95% CI = 1.00 to 1.27), and histology but not earlier diagnosis year. CONCLUSIONS: HIV-associated lymphoma is heterogeneous and changing, with less immunosuppression and greater HIV control at diagnosis. Stable survival and increased mortality for lymphoma occurring on ART call for greater biologic insights to improve outcomes.

Association of early HIV viremia with mortality after HIV-associated lymphoma.

OBJECTIVE: To examine the association between early HIV viremia and mortality after HIV-associated lymphoma. DESIGN: Multicenter observational cohort study. SETTING: Center for AIDS Research Network of Integrated Clinical Systems cohort. PARTICIPANTS: HIV-infected patients with lymphoma diagnosed between 1996 and 2011, who were alive 6 months after lymphoma diagnosis and with at least two HIV RNA values during the 6 months after lymphoma diagnosis. EXPOSURE: Cumulative HIV viremia during the 6 months after lymphoma diagnosis, expressed as viremia copy-6-months. MAIN OUTCOME MEASURE: All-cause mortality between 6 months and 5 years after lymphoma diagnosis. RESULTS: Of 224 included patients, 183 (82%) had non-Hodgkin lymphoma (NHL) and 41 (18%) had Hodgkin lymphoma. At lymphoma diagnosis, 105 (47%) patients were on antiretroviral therapy (ART), median CD4⁺ cell count was 148 cells/µl (interquartile range 54-322), and 33% had suppressed HIV RNA (<400 copies/ml). In adjusted analyses, mortality was associated with older age [adjusted hazard ratio (AHR) 1.37 per decade increase, 95% CI 1.03-1.83], lymphoma occurrence on ART (AHR 1.63, 95% CI 1.02-2.63), lower CD4⁺ cell count (AHR 0.75 per 100 cells/µl increase, 95% CI 0.64-0.89), and higher early cumulative viremia (AHR 1.35 per log10 copies × 6-months/ml, 95% CI 1.11-1.65). The detrimental effect of early cumulative viremia was consistent across patient groups defined by ART status, CD4⁺ cell count, and histology. CONCLUSION: Exposure to each additional 1-unit log10 in HIV RNA throughout the 6 months after lymphoma diagnosis was associated with a 35% increase in subsequent mortality. These results suggest that early and effective ART during chemotherapy may improve survival.

Pegylated liposomal doxorubicin, rituximab, cyclophosphamide, vincristine, and prednisone in AIDS-related lymphoma: AIDS Malignancy Consortium Study 047.

PURPOSE: Infusional chemotherapy is efficacious in patients with AIDS-related lymphoma, but it may be difficult to administer. We studied standard agents with rituximab plus pegylated liposomal doxorubicin (DR-COP) in an attempt to provide a more practical approach to therapy while ascertaining rates of response, potential infectious complications, and prognostic role of biologic markers. PATIENTS AND METHODS: We conducted a prospective, multi-institutional phase II trial, employing (day 1) pegylated liposomal doxorubicin 40 mg/m(2), rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2), vincristine 1.4 mg/m(2) (not > 2 mg), and prednisone 100 mg orally on days 1 through 5, with concomitant antiretroviral therapy. RESULTS: In 40 evaluable patients, median CD4 cells was 114/µL (range, 5 to 1,026/µL), and median HIV-1 viral load (VL) was 25,000 copies/mL. High or intermediate/high age-adjusted International Prognostic Index was present in 28%. Overall response was 67.5%, with complete remission in 47.5% (95% CI, 31.5 to 63.9). Of 19 complete responders, 84% had extranodal disease, 47% had CD4 < 100/µL, and 47% had VL > 50,000 copies/mL; one relapsed. With 25.5-month median follow-up, 62% (95% CI, 44 to 75) of patients remain alive. Sixteen patients (40%) experienced 22 infections, with grade 4 in only two (5%). No patient died as a result of infection during treatment; one had opportunistic infection. CONCLUSION: Profound immunodeficiency and high HIV-1 viral load do not preclude attainment of complete response after DR-COP with highly active antiretroviral therapy. The regimen is tolerable, and use of rituximab was not associated with death as a result of infection during treatment. This approach may be useful in patients in whom the more intensive infusional regimens are impractical.

Outcome of patients with relapsed/refractory acquired immune deficiency syndrome-related lymphoma diagnosed 1999-2008 and treated with curative intent in the AIDS Malignancy Consortium.

No comparative studies exist for relapsed/refractory (rel/rfr) acquired immune deficiency syndrome (AIDS)-related lymphoma (ARL). To determine practices over the last decade and to assess the outcomes of salvage chemotherapy with curative intent and autologous stem cell transplant (ASCT), we retrospectively evaluated treatment outcomes in patients with rel/rfr ARL who were treated in 13 national AIDS Malignancy Consortium (AMC) sites between 1999 and 2008 (n = 88). The most commonly used second-line therapies were ICE (ifosfamide/carboplatin/etoposide, n = 34), dose adjusted EPOCH (etoposide/prednisone/vincristine/cyclophosphamide/doxorubicin, n = 17) and ESHAP (etoposide/methylprednisolone/cytarabine/cisplatin, n = 11). The odds of achieving a response were lower for those with non-Hodgkin lymphoma (NHL) than for those with HL and for those with primary refractory disease than for those with relapse. Overall survival (OS) was significantly longer for those with relapsed disease compared to those with refractory disease and for those with non-Burkitt NHL compared to those with Burkitt. OS was longer in patients who underwent ASCT compared to those who did not (1-year OS: 63.2% vs. 37.2%). However, among 32 patients (36%) who achieved a complete or partial response (CR/PR) after second-line therapy, 1-year OS was not different between the two groups (87.5% for ASCT vs. 81.8% for non-ASCT). Long-term survival in some patients with rel/rfr ARL may be possible without transplant, although transplant remains the standard of care for chemotherapy sensitive disease.