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Background: Outcomes for patients with peripheral T-cell lymphoma (PTCL) who fail to achieve complete response (CR) or relapse after front-line therapy are poor with lack of prospective outcomes data. Objectives: COMPLETE is a prospective registry of 499 patients enrolled at academic and community sites in the United States detailing patient demographics, treatment and outcomes for patients with aggressive T cell lymphomas. We report results for patients with primary refractory and relapsed disease. Methods: Primary refractory disease was defined as an evaluable best response to initial treatment (induction ± maintenance or consolidation/transplant) other than CR, and included a partial response, progressive disease, or no response/stable disease. Relapsed disease was defined as an evaluable best response to initial treatment of CR, followed by disease progression at a later date, irrespective of time to progression. Patients were included in the analysis if initial treatment began within 30 days of enrollment and treatment duration was ≥4 days. Results: Of 420 evaluable patients, 97 met the definition for primary refractory and 58 with relapsed disease. In the second-line setting, relapsed patients received single-agent therapies more often than refractory patients (52 vs. 28%; p = 0.01) and were more likely to receive single-agent regimens (74 vs. 53%; p = 0.03). The objective response rate to second-line therapy was higher in relapsed patients (61 vs. 40%; p = 0.04) as was the proportion achieving a CR (41 vs. 14%; p = 0.002). Further, relapsed patients had longer overall survival (OS) compared to refractory patients, with a median OS of 29.1 versus 12.3 months. Conclusions: Despite the availability of newer active single agents, refractory patients were less likely to receive these therapies and continue to have inferior outcomes compared to those with relapsed disease. PTCL in the real world remains an unmet medical need, and improvements in front-line therapies are needed.

Preclinical animal studies have demonstrated an association between maternal use of tyrosine kinase inhibitors and embryofetal toxicity; yet, multiple clinical case series have reported normal pregnancy outcomes and healthy infants in women on these medications during the course of their pregnancy. We describe a case of a woman with chronic myeloid leukemia who had taken the second-generation tyrosine kinase inhibitor dasatinib during the first 12 weeks of her dichorionic diamniotic twin pregnancy and subsequently delivered two low-birth weight infants, one with severe cardiac malformations and the other without apparent birth abnormalities. To our knowledge, this is the first reported case of fetal cardiovascular defects in an infant born to a woman on dasatinib during a twin pregnancy and supports current recommendations to avoid this medication during pregnancy. We also review relevant preclinical and clinical studies of tyrosine kinase inhibitor use during pregnancy and explore alternative therapeutic options for patients with chronic myeloid leukemia during pregnancy to aid clinicians in the appropriate management of these patients so as to minimize both maternal and fetal risks.

PurposeTo evaluate the impact of the addition of bortezomib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on outcomes in previously untreated patients with non–germinal center B-cell–like (non-GCB) diffuse large B-cell lymphoma (DLBCL).Patients and MethodsAfter real-time determination of non-GCB DLBCL using the Hans immunohistochemistry algorithm, 206 patients were randomly assigned (1:1; stratified by International Prognostic Index [IPI] score) to six 21-day cycles of standard R-CHOP alone or R-CHOP plus bortezomib 1.3 mg/m2intravenously on days 1 and 4 (VR-CHOP). The primary end point, progression-free survival (PFS), was evaluated in 183 patients with centrally confirmed non-GCB DLBCL who received one or more doses of study drug (91 R-CHOP, 92 VR-CHOP).ResultsAfter a median follow-up of 34 months, with 25% (R-CHOP) and 18% (VR-CHOP) of patients having had PFS events, the hazard ratio (HR) for PFS was 0.73 (90% CI, 0.43 to 1.24) with VR-CHOP ( P = .611). Two-year PFS rates were 77.6% with R-CHOP and 82.0% with VR-CHOP; they were 65.1% versus 72.4% in patients with high-intermediate/high IPI (HR, 0.67; 90% CI, 0.34 to 1.29), and 90.0% versus 88.9% (HR, 0.85; 90% CI, 0.35 to 2.10) in patients with low/low-intermediate IPI. Overall response rate with R-CHOP and VR-CHOP was 98% and 96%, respectively. The overall survival HR was 0.75 (90% CI, 0.38 to 1.45); 2-year survival rates were 88.4% and 93.0%, respectively. In the safety population (100 R-CHOP and 101 VR-CHOP patients), grade ≥ 3 adverse events included neutropenia (53% v 49%), thrombocytopenia (13% v 29%), anemia (7% v 15%), leukopenia (26% v 25%), and neuropathy (1% v 5%).ConclusionOutcomes for newly diagnosed, prospectively enrolled patients with non-GCB DLBCL were more favorable than expected with R-CHOP and were not significantly improved by adding bortezomib.

Background With increased understanding of the unique entities, subtype-specific approaches for peripheral T-cell lymphoma (PTCL) are emerging, and more precise diagnoses are becoming increasingly important. Patients and Methods We analyzed the approach to the histopathologic diagnosis of PTCL using data from the comprehensive oncology measures of peripheral T-cell lymphoma (COMPLETE) study. The COMPLETE trial is a large prospective cohort study of patients with newly diagnosed PTCL in the United States. Results A total of 499 patients were enrolled from 40 academic and 15 community-based centers. Baseline assessment forms were collected for 493 patients, of which 435 (88%) were available for analysis. The most common diagnoses were PTCL, not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, and angioimmunoblastic T-cell lymphoma (AITL). A mean of 10 markers (range, 0-21) was assessed per patient. CD30 was assessed frequently but not uniformly in cases that were not anaplastic large cell lymphoma. Only 17% of PTCL-NOS cases were assessed for PD1. CXCL13 was a relatively sensitive marker in AITL, expressed in 84% of tested cases; however, only 3% of PTCL-NOS cases were tested. T follicular helper cell marker assessment differed between academic and community practices, with PD1 more often evaluated by academic centers in cases of AITL (62% vs. 12%; P = .01). Conclusion The diagnostic workup for PTCL in the United States varies widely and often lacks important phenotypic information to fully characterize the lymphoma. Gaps in testing of selected markers should be filled, given the impending revision to the World Health Organization classification. The accuracy of diagnosis will become increasingly important as we enter the era of targeted treatment for PTCL.

BACKGROUND Long-term survival in patients with aggressive peripheral T-cell lymphoma (PTCL) is generally poor, and there currently is no clear consensus regarding the initial therapy used for these diseases. Herein, the authors analyzed treatment patterns and outcomes in a prospectively collected cohort of patients with a new diagnosis of nodal PTCL in the United States. METHODS Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) is a prospective multicenter cohort study designed to identify the most common prevailing treatment patterns used for patients newly diagnosed with PTCL in the United States. Patients with nodal PTCL and completed records regarding baseline characteristics and initial therapy were included in this analysis. All statistical tests were 2-sided. RESULTS Of a total of 499 patients enrolled, 256 (51.3%) had nodal PTCL and completed treatment records. As initial therapy, patients received doxorubicin-containing regimens (41.8%), regimens containing doxorubicin plus etoposide (20.9%), other etoposide regimens (15.8%), other single-agent or combination regimens (19.2%), and gemcitabine-containing regimens (2.1%). Survival was found to be statistically significantly longer for patients who received doxorubicin (log-rank P = .03). After controlling for disease histology and International Prognostic Index, results demonstrated a trend toward significance in mortality reduction in patients who received doxorubicin compared with those who did not (hazard ratio, 0.71; 95% confidence interval, 0.48-1.05 [P = .09]). CONCLUSIONS To the authors' knowledge, there is no clear standard of care in the treatment of patients with PTCL in the United States. Although efforts to improve frontline treatments are necessary, anthracyclines remain an important component of initial therapy for curative intent. Cancer 2017;123:1174–1183. © 2016 American Cancer Society.

Background The role of autologous stem cell transplantation (ASCT) in the first complete remission (CR1) of peripheral T-cell lymphomas (PTCLs) is not well defined. This study analyzed the impact of ASCT on the clinical outcomes of patients with newly diagnosed PTCL in CR1. Methods Patients with newly diagnosed, histologically confirmed, aggressive PTCL were prospectively enrolled into the Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE) study, and those in CR1 were included in this analysis. Results Two hundred thirteen patients with PTCL achieved CR1, and 119 patients with nodal PTCL, defined as anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified, were identified. Eighty-three patients did not undergo ASCT, whereas 36 underwent consolidative ASCT in CR1. At the median follow-up of 2.8 years, the median overall survival was not reached for the entire cohort of patients who underwent ASCT, whereas it was 57.6 months for those not receiving ASCT (P = .06). ASCT was associated with superior survival for patients with advanced-stage disease or intermediate-to-high International Prognostic Index scores. ASCT significantly improved overall and progression-free survival for patients with AITL but not for patients with other PTCL subtypes. In a multivariable analysis, ASCT was independently associated with improved survival (hazard ratio, 0.37; 95% confidence interval, 0.15-0.89). Conclusions This is the first large prospective cohort study directly comparing the survival outcomes of patients with nodal PTCL in CR1 with or without consolidative ASCT. ASCT may provide a benefit in specific clinical scenarios, but the broader applicability of this strategy should be determined in prospective, randomized trials. These results provide a platform for designing future studies of previously untreated PTCL.

Long-term survival in patients with aggressive peripheral T-cell lymphoma (PTCL) is generally poor, and there currently is no clear consensus regarding the initial therapy used for these diseases. Herein, the authors analyzed treatment patterns and outcomes in a prospectively collected cohort of patients with a new diagnosis of nodal PTCL in the United States.Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) is a prospective multicenter cohort study designed to identify the most common prevailing treatment patterns used for patients newly diagnosed with PTCL in the United States. Patients with nodal PTCL and completed records regarding baseline characteristics and initial therapy were included in this analysis. All statistical tests were 2-sided.Of a total of 499 patients enrolled, 256 (51.3%) had nodal PTCL and completed treatment records. As initial therapy, patients received doxorubicin-containing regimens (41.8%), regimens containing doxorubicin plus etoposide (20.9%), other etoposide regimens (15.8%), other single-agent or combination regimens (19.2%), and gemcitabine-containing regimens (2.1%). Survival was found to be statistically significantly longer for patients who received doxorubicin (log-rank P = .03). After controlling for disease histology and International Prognostic Index, results demonstrated a trend toward significance in mortality reduction in patients who received doxorubicin compared with those who did not (hazard ratio, 0.71; 95% confidence interval, 0.48-1.05 [P = .09]).To the authors' knowledge, there is no clear standard of care in the treatment of patients with PTCL in the United States. Although efforts to improve frontline treatments are necessary, anthracyclines remain an important component of initial therapy for curative intent. Cancer 2017;123:1174-1183. © 2016 American Cancer Society.

Objectives: To examine interactions among clinical factors and pathologic biomarkers in predicting the outcome of patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab-based immunochemotherapy. Methods: In 85 patients treated at a single institution, clinicopathologic variables were analyzed, including the International Prognostic Index (IPI); germinal/nongerminal center phenotype; MYC, p53, BCL2, Ki-67, and Epstein-Barr virus (EBV) expression; and MYC translocation status. Results: In univariate analysis, overall survival (OS) was worse for patients with high IPI scores, nongerminal center phenotype, high MYC and p53 expression by immunohistochemistry, and EBV positivity. In multivariable analysis, p53 expression was the strongest prognostic factor (P < .05) independent of IPI and cell of origin. A significant positive association between p53 and MYC expression was found. Moreover, coexpression of p53/MYC had an enhanced negative effect on OS independent of BCL2 expression. Conclusions: Immunohistochemical assessment of p53, particularly in combination with MYC, could be useful in identifying a high-risk subgroup of DLBCL.

Background: EBV-positive (EBV+) cells are detectable in a variable but significant fraction of lymphomas of all lineages and histologic type by in situ hybridization for EBV-encoded RNA (EBER-ISH). EBV positivity generally confers a worse prognosis in lymphoma but, with the exception of adoptive T-cell therapies, no EBV-targeting mechanism-based anti-lymphoma therapeutics are in development. EBV's DNA genome encodes a viral thymidine kinase (vTK, BXLF1) and a serine/threonine protein kinase (PK, BGLF4), which are expressed only during lytic cycle, and can activate anti-viral nucleoside analogues via mono-phosphorylation, leading to inhibition of EBV DNA synthesis. Nstat is able to induce the expression of PK/BGLF4 and vTK/BXLF1. This effect supports the mechanism-based strategy of leveraging EBV's presence in lymphoma by combining Nstat with VGCV, the oral prodrug for ganciclovir (GCV). EBV's PK phosphorylates GCV, which inhibits both viral and cellular DNA synthesis in EBV+ tumor cells and potentially in surrounding EBV- tumor cells (bystander effect). Based on this targeted approach, a phase 1b/2a trial was launched to determine the safety and activity of this combination in R/R EBV+ lymphomas of various lineages and histology. Here we report the phase 1b results. Methods: Eligible patients had biopsy-proven R/R EBV+ lymphoma by EBER-ISH (any positive cell) and had failed ≥1 prior systemic therapy. Phase 1b followed a 3+3 design over 5 dose ranging cohorts. The phase 1b primary objectives were safety/tolerability of Nstat/VGCV and recommended phase 2 dose (RP2D). In cohorts 1-4, variable doses of Nstat and VGCV were administered orally continuously on 28-day cycles. In cohort 5 Nstat was administered for the first 4 days of each week with daily VGCV. Toxicity was assessed by CTCAE 5.0. Efficacy was assessed by local and central radiology every 2 cycles by PET/CT (Lugano 2014 Classification). Correlative studies for phase 1b include PK/PD and other exploratory biomarkers. Results: Phase 1b enrolled 25 patients. The median age was 58 (19-84) with 72% males. Thirteen patients had either EBV+ T/NK-cell lymphoma (N=8; 5 TCL, 3 NKL), or Hodgkin lymphoma (HL) (N=5). Twelve patients had EBV+ B-cell lymphoma (BCL) (Table 1), of which 4 were HIV+ and 3 had a history of PTLD. Median number of prior therapies was 2 (1-9). Two patients with TCL had failed prior HDACi therapy. In cohorts 1-4, the most frequent treatment related hematologic grade 3-4 (G3-4) adverse events (AE) were thrombocytopenia (35%), neutropenia (25%), and lymphopenia (15%), none of which occurred at G3-4 in cohort 5. No non-hematologic G3-G4 AE were observed in >10% of patients in any cohort and no patient discontinued therapy due to AE. The RP2D was declared to be Nstat 20 mg days 1-4 each week and VGCV 900 mg daily on a 28-day cycle. At the RP2D there have been no G3-4AE. Seventeen patients are evaluable for response (8 BCL 5 T/NK, 4 HL). ORR was 53% (9/17), with 29% CRR (5/17). The Clinical Benefit Rate (CBR; CR/PR/Stable Disease) was 76% (13/17). Responses were seen across histologic subtypes and in heavily pre-treated patients. Durable responses were observed (one >12 months and one >10 months). For the 14 evaluable HIV-negative patients (5 BCL, 5 T/NK, 4 HL) ORR, CRR, and CBR were 64%, 36%, and 93%, respectively, with CRs and PRs in all histologic subtypes. The ORR was 3/5 for BCL (2 CR, 1 PR); 5/5 for T/NK (2 CR, 3 PR); and 1/4 in HL (1 CR). One BCL patient with combined variable immunodeficiency (CVID) achieved a CR. Only 1 of 3 BCL patients with a history of PTLD was evaluable and achieved a CR. All three evaluable HIV+ BCL patients progressed. Of 8 patients with detectable baseline plasma EBV DNA, 7 demonstrated a reduction (-17% to -83%). Other biomarker studies are in progress. Conclusion: In this phase 1b study, the combination of oral Nstat and VGCV was well tolerated in patients with EBV+ lymphomas, with no unexpected G3-G4 AE, and showed a very encouraging signal of efficacy, especially in HIV-negative patients, with CRs in BCL, TCL, and HL. The combination of Nstat and VGCV is a compelling targeted oral therapy for R/R EBV+ lymphomas of different lineage and histologic type and should be explored in other EBV+ malignancies. The phase 2a portion of this study is actively recruiting (NCT03397706). Disclosures Porcu: Viracta: Honoraria, Other: Scientific Board, Research Funding; Innate Pharma: Honoraria, Other: Scientific Board, Research Funding; BeiGene: Other: Scientific Board, Research Funding; Incyte: Research Funding; Daiichi: Research Funding; Kyowa: Honoraria, Other: Scientific Board, Research Funding; ADCT: Research Funding; Spectrum: Consultancy. Feldman:Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Trillium: Research Funding; Viracta: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau. Brem:Celgene: Honoraria, Speakers Bureau; BMS/Pfizer: Honoraria; Janssen: Honoraria, Speakers Bureau; Bayer: Honoraria; Genetech: Honoraria; Pharmacyclics: Honoraria, Speakers Bureau. Brammer:Celgene: Research Funding; Seatlle Genetics: Honoraria, Speakers Bureau. Barta:Celgene: Research Funding; Merck: Research Funding; Mundipharma: Honoraria; Bayer: Consultancy, Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees. Trauger:Viracta: Employment. Gutheil:Viracta Therapeutics: Consultancy. Katkov:Viracta: Employment. McRae:Viracta: Employment. Royston:Viracta: Employment.

Summary Background Proteins of the BCL-2 family regulate clonal selection and survival of lymphocytes, and are frequently overexpressed in lymphomas. Navitoclax is a targeted high-affinity small molecule that inhibits the anti-apoptotic activity of BCL-2 and BCL-XL. We aimed to assess the safety and antitumour activity of navitoclax in patients with lymphoid tumours, and establish the drug's pharmacokinetic and pharmacodynamic profiles. Methods In this phase 1 dose-escalation study, patients (aged ≥18 years) with relapsed or refractory lymphoid malignancies were enrolled and treated at seven sites in the USA between November, 2006, and November, 2009. A modified Fibonacci 3+3 design was used to assign patients to receive oral navitoclax once daily by one of two dosing schedules: intermittently for the first 14 days of a 21-day cycle (14/21) at doses of 10, 20, 40, 80, 110, 160, 225, 315, or 440 mg/day; or continuously for 21 days of a 21-day cycle (21/21) at doses of 200, 275, 325, or 425 mg/day. Study endpoints were safety, maximum tolerated dose, pharmacokinetic profile, pharmacodynamic effects on platelets and T cells, and antitumour activity. This trial is registered with ClinicalTrials.gov, number NCT00406809. Findings 55 patients were enrolled (median age 59 years, IQR 51–67), 38 to receive the 14/21 dosing schedule, and 17 to receive the 21/21 dosing schedule. Common toxic effects included grade 1 or 2 anaemia (41 patients), infection (39), diarrhoea (31), nausea (29), and fatigue (21); and grade 3 or 4 thrombocytopenia (29), lymphocytopenia (18), and neutropenia (18). On the intermittent 14/21 schedule, dose-limiting toxic effects were hospital admissions for bronchitis (one) and pleural effusion (one), grade 3 increase in aminotransferases (one), grade 4 thrombocytopenia (one), and grade 3 cardiac arrhythmia (one). To reduce platelet nadir associated with intermittent 14/21 dosing, we assessed a 150 mg/day lead-in dose followed by a continuous 21/21 dosing schedule. On the 21/21 dosing schedule, two patients did not complete the first cycle and were excluded from assessment of dose-limiting toxic effects; dose-limiting toxic effects were grade 4 thrombocytopenia (one), grade 3 increase in aminotransferases (one), and grade 3 gastrointestinal bleeding (one). Navitoclax showed a pharmacodynamic effect on circulating platelets and T cells. Clinical responses occurred across the range of doses and in several tumour types. Ten of 46 patients with assessable disease had a partial response, and these responders had median progression-free survival of 455 days (IQR 40–218). Interpretation Navitoclax has a novel mechanism of peripheral thrombocytopenia and T-cell lymphopenia, attributable to high-affinity inhibition of BCL-XL and BCL-2, respectively. On the basis of these findings, a 150 mg 7-day lead-in dose followed by a 325 mg dose administered on a continuous 21/21 dosing schedule was selected for phase 2 study. Funding Abbott Laboratories, Genentech, and National Cancer Institute, National Institutes of Health.

Kaposi sarcoma–associated herpesvirus (KSHV) infection is essential to the development of Kaposi sarcoma (KS). Notch signaling is also known to play a pivotal role in KS cell survival and lytic phase entrance of KSHV. In the current study, we sought to determine whether KSHV regulates Notch components. KSHV-infected lymphatic endothelial cells showed induction of receptors Notch3 and Notch4, Notch ligands Dll4 and Jagged1, and activated Notch receptors in contrast to uninfected lymphatic endothelial cells. In addition, KSHV induced the expression of endothelial precursor cell marker (CD133) and mural cell markers (calponin, desmin, and smooth muscle alpha actin), suggesting dedifferentiation and trans-differentiation. Overexpression of latency proteins (LANA, vFLIP) and lytic phase proteins (RTA, vGPCR, viral interleukin-6) further supported the direct regulatory capacity of KSHV viral proteins to induce Notch receptors (Notch2, Notch3), ligands (Dll1, Dll4, Jagged1), downstream targets (Hey, Hes), and endothelial precursor CD133. Targeting Notch pathway with γ-secretase inhibitor and a decoy protein in the form of soluble Dll4 inhibited growth of KSHV-transformed endothelial cell line. Soluble Dll4 was also highly active in vivo against KS tumor xenograft. It inhibited tumor cell growth, induced tumor cell death, and reduced vessel perfusion. Soluble Dll4 is thus a candidate for clinical investigation.

Purpose To evaluate the safety and efficacy of liposomal doxorubicin (Myocet; Medeus Pharma Ltd, Herts,UK) when substituted for doxorubicin in the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) in patients with newly diagnosed AIDS-related non-Hodgkin's lymphoma (AIDS-NHL). Secondary objectives were to assess the impact of HIV viral control on response and survival, and to correlate MDR-1 expression with outcome. Patients and Methods Liposomal doxorubicin at doses of 40, 50, 60, and 80 mg/m2 was given with fixed doses of cyclophosphamide, vincristine, and prednisone every 21 days. All patients received concurrent highly active antiretroviral therapy. NHL tissues were evaluated for multidrug resistance (MDR-1) expression. Results Twenty-four patients were accrued. 67% had high or high-intermediate International Prognostic Index scores; the median CD4 lymphocyte count was 112/mm3 (range, 19/mm3 to 791/mm3). No dose-limiting toxicities were observed at any level, with myelosuppression being the most frequent toxicity. Overall response rate was 88%, with 75% complete responses (CRs), and 13% partial responses. The median duration of CR was 15.6+ months (range, 1.7 to 43.5+ months). Effective HIV viral control during chemotherapy was associated with significantly improved survival (P = .027), but CRs were attained independent of HIV viral control. MDR-1 expression did not correlate with response, suggesting that the liposomal doxorubicin may evade this resistance mechanism. Conclusion Liposomal doxorubicin in combination with cyclophosphamide, vincristine, and prednisone is active in AIDS-NHL, with complete remissions achieved in 75% independent of HIV viral control or tissue MDR-1 expression. HIV viral control is associated with a significant improvement in survival. Additional studies are warranted.

Purpose: To evaluate the response and side effects of combination therapy with low dose CHOP chemotherapy and mitoguazone dihydrochloride in patients with non-Hodgkin's lymphoma associated with the acquired immunodeficiency syndrome (AIDS-NHL). Methods: Eighteen patients newly diagnosed with intermediate or high-grade AIDS-NHL were treated with low dose CHOP as follows: day 1, cyclophosphamide 350mg/m2, intravenously (IV); doxorubicin 25mg/m2 IV; vincristine 2mg IV; and prednisone 100mg given orally on days 1 through 5. In addition, mitoguazone dihydrochloride was given at a dose of 600mg/m2 IV on days 1 and 15 of each 28-day treatment cycle. Results: Seventeen males and one female patient were accrued. Twelve patients had high-grade pathologies while the remainder had an intermediate grade pathology (diffuse large cell). The median CD4+ lymphocyte count was 98/dl (range 1–924). Three patients (17%) reported an AIDS-defining illness prior to lymphoma diagnosis. Of 14 evaluable patients, 6 (43%) achieved a complete remission and 5 (35%) a partial remission. The median failure free and overall survival times were 6.5 and 8.4 months, respectively. Major toxicity was hematologic with grade 3 or 4 neutropenia in 72%; two patients died of neutropenic sepsis. Conclusions: Mitoguazone in combination with low dose CHOP is a safe regimen, associated with a response rate of 79% (CR 43%, PR 36%, 95% CI=49–95%). These preliminary results suggest no major improvement in terms of response over use of CHOP without mitoguazone.

To examine interactions among clinical factors and pathologic biomarkers in predicting the outcome of patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab-based immunochemotherapy.In 85 patients treated at a single institution, clinicopathologic variables were analyzed, including the International Prognostic Index (IPI); germinal/nongerminal center phenotype; MYC, p53, BCL2, Ki-67, and Epstein-Barr virus (EBV) expression; and MYC translocation status.In univariate analysis, overall survival (OS) was worse for patients with high IPI scores, nongerminal center phenotype, high MYC and p53 expression by immunohistochemistry, and EBV positivity. In multivariable analysis, p53 expression was the strongest prognostic factor (P.05) independent of IPI and cell of origin. A significant positive association between p53 and MYC expression was found. Moreover, coexpression of p53/MYC had an enhanced negative effect on OS independent of BCL2 expression.Immunohistochemical assessment of p53, particularly in combination with MYC, could be useful in identifying a high-risk subgroup of DLBCL.

No effective salvage regimen has been defined for patients with AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) who do not respond to first-line chemotherapy that contains anthracycline. Combined dexamethasone, cytosine arabinoside, and cisplatin (DHAP) and etoposide, methylprednisolone, cytosine arabinoside, and cisplatin (ESHAP) have shown good response rates in HIV-negative patients with relapsed lymphomas. We retrospectively analyzed patients with refractory or relapsed AIDS-NHL who had been treated with either DHAP or ESHAP to evaluate the feasibility and efficacy of these regimens. Twenty-six patients with refractory or relapsed AIDS-NHL were treated between 1990 and 1999 either with DHAP ( n = 13) or with ESHAP ( n = 13). Only 1 patient from each group (8%) had achieved complete remission with any previous therapy, and most had progressive disease after the regimen immediately preceding DHAP or ESHAP. In the ESHAP group, 4 patients (31%) achieved complete remission (CR) and 3 patients (23%) attained partial remission (PR) for an overall response rate of 54%. The median survival was 7.1 months (range, 1-58.9+ months) from the time ESHAP was begun. Among the 3 patients with primary refractory lymphoma, there was 1 CR, 1 PR, and one patient with stable disease. In contrast, only 1 PR (7%) was observed with DHAP; the median survival was 3 months. Myelosuppression was the most significant toxicity with grade 4 neutropenia occurring in all who received ESHAP and in 54% of patients treated with DHAP. Neutropenic fever occurred in 8 (62%) ESHAP-treated and 6 (46%) DHAP-treated patients. Although hematologic toxicity is profound, ESHAP appears to be an active salvage regimen for patients with relapsed or refractory AIDS-NHL.

AIDS-related Kaposi's sarcoma (KS) is a tumour of vascular endothelium, which is seen predominantly in men who have sex with men. The majority of affected individuals have advanced immunosuppression at the time of the initial KS diagnosis. The disease may present with cutaneous lesions, or with involvement of visceral organs, of which the gastrointestinal tract is most common. KS may also present with lymphoadenopathy or with isolated lymphoedema, even in the absence of cutaneous lesions. Affected individuals are uniformly co-infected with HIV and with Human Herpesvirus type 8 (HHV8). HHV8 is present within KS tissues, and is aetiological in the pathogenesis of disease, along with aberrant cytokine expression, production of multiple angiogenic peptides, and immune dysregulation. While not presently curable, multiple treatment options exist and must be evaluated in terms of the specific needs of the individual patient. Various local therapies are aimed at eradicating small lesions, while acknowledging that the KS in general, or its likelihood of recurring will be unaffected. Systemic chemotherapy is used to treat extensive visceral involvement. Knowledge of the pathogenesis of disease has led to the development of novel treatment strategies, aimed at HHV8 as the target of therapy, or at the inflammatory cytokine or angiogenic milieu necessary for KS growth. Use of highly active anti-retroviral therapy, aimed at controlling the underlying HIV infection, has been associated with a dramatic decrease in the incidence of KS, and may also be useful in the treatment of existing KS disease.

Summary Purpose To assess the efficacy and toxicity of liposomal daunorubicin administered as a two-hour intravenous infusion to patients with relapsed or refractory non-Hodgkin’s lymphoma (NHL) Patients and methods Eligible patients had relapsed or refractory NHL with measurable or evaluable disease, and low grade, select intermediate grade, or mantle cell pathologic types. Prior exposure to an anthracycline or anthracenedione was allowed. Liposomal daunorubicin at a dose of 100 mg/m2 was given intravenously over a minimum of 120 minutes every 3 weeks, as a single agent Results Thirty-three patients were accrued twenty-three (70%) had low-grade histologies, six (18%) had intermediate-grade histologies (follicular large-cell and diffuse small cleaved), and four (12%) patients had mantle-cell lymphoma Eighteen (55%) had received two or more prior regimens, fourteen (42%) received a prior anthracycline A median of six cycles of liposomal daunorubicin were administered (range 1–15) Of 31 patients evaluable for response, 2 complete and 10 partial remissions were documented for a major response rate of 39% (95% confidence interval (CI) 22%–58%). The median duration of response was 195 months (range 4.3–41.1 +) Six responders (50%) had received a prior anthracycline, one responder had mantle-cell histology The major toxicities were grade 3 or 4 neutropenia in 26 patients (79%), mild to moderate nausea in 22 (67%), and fatigue in 16 (48%) Conclusions Liposomal daunorubicin at 100 mg/m2 every three weeks has activity in patients with relapsed or refractory NHL, including patients with prior exposure to an anthracycline Further studies of liposomal daunorubicin in combination with other agents are warranted

Diffuse large B-cell lymphomas (DLBCLs) are aggressive tumors and the most common form of non-Hodgkin lymphoma (NHL). DLBCLs arise from germinal center (GC) or post-GC B cells and display marked heterogeneity in genetic features and clinical outcomes DLBCLs, similar to other NHL and to solid tumors, are known to evade host immune response by usurping immune checkpoint pathways such as CTLA4 and PD-1. The initial Phase I and Phase II trials of checkpoint inhibitors in NHL revealed promising results, but rational and reliable biomarkers for selecting patients that benefit from such therapies is missing. Even in the case of the better-studied PD1-PD-L1 pathway, the characterization of expression of those proteins in DLBCLs is not standardized, and their relationship with molecular and clinical features in DLBCLs are still largely unknown. We set out to study PD-L1 expression using three commonly used anti-PD-L1 antibodies in a well-characterized single-institutional cohort of 52 primary DLBCLs from Keck School of Medicine of USC treated with R-CHOP or R-CHOP-like therapy with clinical follow up. All cases were characterized by aCGH; Focus::Lymphoma NGS test (Cancer Genetics Inc), which includes 220 most commonly mutated genes in B NHL; FISH including bcl2 and c-myc; and immunohistochemical staining to define cell of origin (Hans classification) and with three anti-PD-L1 antibodies (Abcam EPR1161, Abcam 28-8 and Ventana SP263 clones). We observed variable sensitivity, specificity and dynamic range of three anti-PD-L1 antibodies. EPR1161 and SP263 clones had highest correlation (Pearson correlation=0.69) and similar staining characteristics demonstrating robust linear membranous staining on neoplastic cells and on reactive infiltrating Immune Cells (IC). PD-1 expression on IC had inverse correlation with PD-L1 expression on neoplastic cells, suggesting immunosuppressive effect of PD-L1 positive neoplastic cells on tumor microenvironment. Non-GCB DLBCLs had higher PD-L1 positivity than GCB DLBCLs (p=0.0001, 0.01 and 0.06 respectively for EPR1161, DAKO 28-8 and Ventana SP263 Abs, t-test). Using molecular characterization, we observed that PD-L1 expression marked high risk aggressive DLBCLs, which also had higher TP53 expression, TP53 mutation and/or del 17p13 (Pearson correlation= 0.176). Moreover, higher expression of PD-L1 had negative correlation with mutations associated with GCB-like DLBCLs including BCL2, FOXO1, KMT2D, EZH2 (p=0.003, 0.01, 0.06, 0.08; t-test) and positive correlation with mutations associated with ABC-like DLBCLs including FAT2 (p=0.04, t-test). Interestingly, while PD-L1 expression correlated with high risk molecular and cytogenetic groups of DLBCL, it did not show correlation with BCL2 or C-MYC expression nor with BCL2/C-MYC double expressors. Most importantly, Kaplan Meyer analysis showed that even in the settings of chemotherapy, higher PD-L1 expression correlated with more aggressive disease, using all three antibodies ( p=0.03, 0.01, 0.04 respectively for Abcam EPR1161, Abcam 28-8 and Ventana SP263 clones). We conclude that PD-L1 expression reflects the biology of aggressive subsets of DLBCLs, which are also characterized by high risk cytogenetic and molecular biomarkers. PD-L1 expression can be measured by several antibody clones, which have different performance characteristics but show positive correlation. Disclosures No relevant conflicts of interest to declare.

Background: NK/T cell non-Hodgkin lymphomas (NK/T NHL) are rare high-grade lymphomas that are diagnostically challenging and carry a poor prognosis. Incidence is notably higher in Asian countries as compared to North America and Europe. South Americans have an incidence similar to Asian countries though less well described. In this study we reviewed the incidence and outcomes of NK/T NHL in the US with a specific focus on patient race/ethnicity. Methods: Surveillance, Epidemiology and End Results (SEER) database was used to examine the standardized incidence rates (SIR) of NK/T cell NHL among adult (≥18 yrs) patients diagnosed between 1992-2013. Mutually exclusive race/ethnicity categories were: African-Americans (AA), Asians/Pacific Islanders (API), Hispanic whites (HW) and Non-Hispanic whites (NHW). Cases that received a diagnosis at death certificate/autopsy, no follow-up records, or lacking age at diagnosis, sex, or race/ethnicity documentation were excluded. Age adjusted incidence rates (AAIR) were calculated by race. Cox proportional hazards models, adjusted for confounding variables, were used to evaluate association between patient demographics and overall survival (OS). Results: A total of 706 cases met inclusion criteria. Of these, 64% were males and 36% females. AAIR was higher in males irrespective of race/ethnicity. Among different race/ethnic subgroups, API and HW had a higher AAIR than NHW and AA (0.2, 0.18, 0.05 and 0.04, respectively) (Figure 1). Median OS for males and females was similar (1.8 yr and 2 yr, respectively; p=0.76) There was a statistically significant difference in median OS by age for all patients with 4.3 yr for age 18-44 as compared with 0.8 yr for age >75 yr (p Conclusions: Significant disparities exist in the US for NK/T NHL incidence by race and gender, with highest AAIR among the racial minorities of API and HW, which are fastest and second fastest growing minority groups in the US respectively. Increasing age, advanced disease stage and site outside of the nasal cavity or sinus are independent predictors of poor prognosis. Some differences do exist in survival by race. These factors need to be considered for better resource allocation and utilization for this rare, often incurable and aggressive disease. Figure 1 Figure 1. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Kelly:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau.

Over time, the epidemiologic and demographic characteristics of AIDS have changed in the United States, while the use of highly active antiretroviral therapy has changed the natural history of the disease. The goal of the study was to ascertain any changes in the epidemiologic, immunologic, pathologic, or clinical characteristics of AIDS-related lymphoma (ARL) over the course of the AIDS epidemic. Records of 369 patients with ARL diagnosed or treated at a single institution from 1982 through 1998 were reviewed. Single institutional data were compared to population-based data from the County of Los Angeles. Significant changes in the demographic profile of patients with newly diagnosed ARL have occurred, with the later time intervals associated with a higher prevalence in women (P = .25), in Latino/Hispanic individuals (P

Over time, the epidemiologic and demographic characteristics of AIDS have changed in the United States, while the use of highly active antiretroviral therapy has changed the natural history of the disease. The goal of the study was to ascertain any changes in the epidemiologic, immunologic, pathologic, or clinical characteristics of AIDS-related lymphoma (ARL) over the course of the AIDS epidemic. Records of 369 patients with ARL diagnosed or treated at a single institution from 1982 through 1998 were reviewed. Single institutional data were compared to population-based data from the County of Los Angeles. Significant changes in the demographic profile of patients with newly diagnosed ARL have occurred, with the later time intervals associated with a higher prevalence in women (P = .25), in Latino/Hispanic individuals (P

Kaposi sarcoma (KS) is responsive to a number of different steroid hormones, such as glucocorticoids and retinoids. An active metabolite of vitamin D, 1α,25 dihydroxyvitamin D3, was used to study the effect of this steroid hormone in KS. Steroid hormones exert their effect through their cognate nuclear receptors, which for vitamin D metabolites is the vitamin D receptor (VDR). It was first shown that KS cell lines and primary tumor tissue express high levels of VDR, whereas endothelial cells had minimal expression and fibroblasts had no expression. Second, KS cell growth was inhibited by VDR agonist 1α,25 dihydroxyvitamin D3 with a 50% inhibitory concentration of 5 × 10 −8 mol/L, whereas endothelial cells and fibroblast cells showed no response. Studies on the mechanism of KS tumor growth inhibition by 1α,25 dihydroxyvitamin D3 showed that production of autocrine growth factors interleukin (IL)-6 and IL-8 was reduced in a dose-dependent manner, whereas no effect was observed on vascular endothelial growth factor and basic fibroblast growth factor. Transcription initiated at the IL-6 promoter was repressed by VDR agonist. The DNA sequences required to mediate this repression were localized to nucleotides −225/−110 in the 5′-flanking region. The antitumor activity of VDR agonists was also confirmed in KS tumor xenograft and after topical application in patients with KS. 1α,25 Dihydroxyvitamin D3 and its analogs may thus be candidates for clinical development in KS.

To ascertain the results of standard ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine) in HIV-infected patients with newly diagnosed Hodgkin's disease (HD), a nonrandomized, prospective, multiinstitutional clinical trial was conducted by the AIDS Clinical Trials Group (ACTG), in HIV-infected patients with Hodgkin's disease. All patients received the standard ABVD regimen, with granulocyte-colony-stimulating factor (G-CSF). Antiretroviral therapy was not used. Between May, 1992 and August, 1996, 21 patients were added to the study and treated. The median CD4 count was 113 cells/mm 3 , and 29% had a history of a clinical AIDS-defining condition before diagnosis of HD. Systemic B symptoms were present in 90% at diagnosis. Stage IV HD was present in 67%, with bone marrow involvement in 12 (57%). Nodular sclerosis HD was present in 38%, with mixed cellular disease in 31%. Among all patients entered and treated, complete remission (CR) was attained in 9 (43%; 90% confidence interval [CI], 24%-63%), whereas partial response occurred in 4 (19%), leading to an overall objective response rate of 62% (90% Cl, 42%-79%). Despite routine use of G-CSF, 10 patients (47.6%) experienced life-threatening neutropenia, with absolute neutrophil counts

The incidence of intermediate and high grade B-cell non-Hodgkin's lymphomas in HIV-infected individuals is approximately 60 times greater than in the general population. These AIDS-related lymphomas (AIDS-NHL) are a late manifestation of HIV infection and may increase in frequency as patients live longer with highly active antiretroviral therapy and effective prophylaxis of opportunistic infections. AIDS-NHL have unique clinical and pathological features that are different from non-Hodgkin's lymphomas in the general population. Histologically AIDS-NHL are either high (2/3) or intermediate (1/3) grade lymphomas. Clinically AIDS-NHL have a preponderance for extranodal involvement with central nervous system being the most common site for this. In addition to the clinical and pathological features of AIDS-NHL, a current knowledge of their pathogenesis and treatment options are presented in this review.

BACKGROUND The objective of this study was to develop and test a combined therapeutic approach for patients with AIDS-related lymphoma (ARL), employing agents with independent mechanisms of action and nonoverlapping toxicity. This study was designed to test the feasibility and tolerance of combining low dose chemotherapy with infusional immunotoxin in the treatment of ARL patients. METHODS Previously untreated patients received low dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, and vincristine (m-BACOD) on a 21- to 28-day schedule. Patients who did not have progressive disease by Cycle 3 received anti-B4-blocked ricin (anti-B4bR), a murine monoclonal antibody linked to modified ricin, 20 μg/kg/day for 7 days administered by continuous infusion on an outpatient basis. A repeat cycle of anti-B4-bR was administered during Cycle 4 of chemotherapy based on tolerance. Patients received two cycles of chemotherapy beyond complete remission up to eight cycles. Study endpoints were toxicity, development of human antimurine antibody (HAMA) and human antiricin (HARA), tumor response, and survival. RESULTS Twenty-six of 44 patients received the immunotoxin therapy. Anti-B4-bR infusion was associated with transaminase elevation (Grade 3) in 14 of 26 patients (58%), and flulike symptoms were common. HAMA or HARA was observed in 8 patients (31%). The overall response rate was 57% (13 complete responses and 12 partial responses). The median survival for all patients was 8.9 months. CONCLUSIONS This study demonstrates the safety and feasibility of using chemotherapy and immunotoxin therapies in combination and supports their further evaluation to improve the outcomes of patients with ARL. Cancer 1998;83:2580-2587. © 1998 American Cancer Society.

BACKGROUND Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analog with cytotoxic activity against both resting and proliferating cells. Clinical studies with cladribine have reported antitumor activity against various hematologic malignancies. METHODS The authors studied responses to cladribine among patients with low and intermediate grade non-Hodgkin's lymphoma that had been refractory to or relapsed after prior chemotherapy. Cladribine was given intravenously over 2 hours at a dose of 0.14 mg/kg daily for 5 consecutive days, repeated every 4 weeks. RESULTS Twenty-eight patients (16 males, 12 females) with a median age of 58 years (range, 41-75 years) were accrued. Twenty-three patients had low grade and 5 had intermediate grade lymphoma. Stage IV disease was present in 22 (79%), and 17 (61%) had systemic B-symptoms. The majority (57%) had received 2 or more prior chemotherapy regimens (median, 2; range, 1-5); 6 had had prior fludarabine therapy. Major responses were documented in 32% (9 of 28 patients), with 4 complete remissions (CR) and 5 partial remissions (PR) after a median of 4 cycles (range, 1-9). One CR occurred in one patient with intermediate grade diffuse large cell lymphoma, and three of six patients who had had prior fludarabine therapy experienced CR or PR with cladribine. Severe hematologic toxicities included reversible neutropenia, protracted thrombocytopenia, and lymphopenia. Other reported adverse effects included mild-to-moderate fatigue, nausea, and diarrhea. CONCLUSIONS Cladribine is an active single agent in the treatment of patients with refractory or relapsed advanced stage indolent lymphoma, with major responses in one third of patients. Cancer 1998;83:2370-2376. © 1998 American Cancer Society.

Chromosomal microarray (CMA) is widely used to detect and refine chromosome abnormalities in both congenital and neoplastic cases. Recently, a blood sample from a newborn male with no apparent dysmorphic features was sent to the Mayo Clinic Cytogenetics laboratory for G-banded karyotype analysis to clarify prenatal findings of a positive trisomy 21 noninvasive prenatal screening (NIPS) result. Chromosome analysis of 20 metaphases revealed 13 were normal (46,XY) and 7 had a satellited supernumerary marker chromosome (47,XY,+mar). To further characterize the marker chromosome, CMA studies were performed, which revealed an 8.6 megabase mosaic duplication from 21q11.2 to 21q21.1. Subsequent metaphase FISH studies demonstrated that the duplicated region was present on the supernumerary marker chromosome, indicating that the marker chromosome is derived from chromosome 21. Interphase FISH studies showed that the marker was present in 68% of interphase nuclei. Despite its large size, the duplicated region contains only 30 known genes. In addition, similar duplications involving this region have not been previously described, making the clinical significance of this duplication uncertain. Importantly, the duplicated interval does not include the Down syndrome critical region (21q22.1 to 22q22.3), consistent with this patient’s lack of dysmorphic features. This report highlights the importance of diagnostic follow-up testing and the clinical utility of conventional and molecular cytogenetic techniques in the setting of abnormal NIPS results.

PURPOSE Kaposi's sarcoma (KS) is the most common tumor in patients with AIDS and can be fatal in patients with lung involvement. Systemic chemotherapy is the most effective treatment for pulmonary KS. We thus conducted this study to determine the efficacy of liposomal daunorubicin in the treatment of patients with pulmonary KS. METHODS Patients with biopsy-proven, symptomatic pulmonary KS were accrued. Liposomal daunorubicin was given at a dose of 60 mg/m2 intravenously every 2 weeks. Response was monitored by chest radiographs, pulmonary function tests, arterial blood gases, and grading of pulmonary symptoms. RESULTS Fifty-three male patients were accrued. The median CD4+ lymphocyte count was 13/microL (range, 0 to 200); 70% reported a prior AIDS-defining opportunistic infection. All patients were symptomatic, with cough reported in all patients, shortness of breath in 94%, and hemoptysis in 55%. The mean study entry diffusing capacity of carbon monoxide (DLCO) was 58.5% (percent of predicted). The median dose of liposomal daunorubicin delivered was 360 mg/m2 (range, 60 to 1,380). More than 75% of patients had complete or partial resolution of baseline pulmonary symptoms. Complete or partial improvement in DLCO was observed in 22%; complete or partial resolution of radiographic abnormalities was reported in 32%. The most common treatment-related toxicity was neutropenia, which occurred in 85%. There were no instances of cardiac toxicity observed, even at high cumulative doses. CONCLUSION Liposomal daunorubicin at 60 mg/m2 is safe and active in patients with pulmonary KS. Trials combining liposomal daunorubicin with other active agents in KS should be considered.

Within the past decade, HIV disease has become one of the most significant epidemics the world has seen. An estimated 29.4 million people have been infected world-wide, with 604,176 cases diagnosed in the United States as of June 1997. In the United States, HIV infection primarily is acquired by male to male sexual transmission and the sharing of needles among intravenous (IV) drug users, although a significant proportion of cases have occurred as a result of heterosexual transmission. The AIDS epidemic has been increasing disproportionately in black and Hispanic populations, and rates of infected women also are rising. Although there are many different manifestations of HIV disease, neoplasms occur frequently among the more severely compromised patients. As many as one in six HIV-infected people will develop an HIV-related neoplasm. It is not uncommon for patients to be unaware of their HIV-infected status and to have developed to advanced stages of infection where neoplasms are more commonly associated. The primary physician should be aware of symptoms of both the initial and advanced stages of HIV infection, and should attempt to identify patients at-risk as early in the infectious period as possible. Two neoplasms, Kaposi's sarcoma and non-Hodgkin's lymphoma, account for the greatest number of malignancies in HIV-infected patients.

Kaposi's sarcoma (KS) is the most common tumor seen in patients with HIV-1 infection. KS causes significant morbidity and mortality through involvement of the skin and visceral organs. The optimal treatment for KS depends on the extent of the disease and immunologic status. However, with knowledge gained on the pathogenesis of disease, newer therapies and compounds are being developed. Early disease patients are best treated with either local therapy or agents that have low toxicity and can be delivered long term. Advanced disease, such as in patients with widespread mucocutaneous disease, lymphedema, and visceral disease, are treated most effectively with cytotoxic agents such as liposomal anthracyclines, vinca alkaloids, or paclitaxel. Future treatment developments are focusing on the role of effective anti-HIV therapy and anti-human herpesvirus (HHV)-8 therapy in an effort to interfere with key steps in the etiology of KS to control the disease. Secondly, agents that focus on the interruption of autocrine and paracrine growth factors such as vascular endothelial cell growth factor and basic fibroblast growth factor, interleukin-6, and interleukin-8 are of therapeutic interest. Some of these compounds currently under evaluation include antiangiogenesis inhibitors and retinoids.

Background Reduced doses of cytotoxic chemotherapy or standard-dose therapy plus a myeloid colony-stimulating factor decreases hematologic toxicity and its complications in patients with non-Hodgkin's lymphoma associated with infection with the human immunodeficiency virus (HIV). However, the effect of reducing the doses of cytotoxic chemotherapeutic agents on clinical outcome is not known. Methods We randomly assigned 198 HIV-seropositive patients with previously untreated, aggressive non-Hodgkin's lymphoma to receive standard-dose therapy with methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) along with granulocyte–macrophage colony-stimulating factor (GM-CSF; n = 94) or reduced-dose m-BACOD with GM-CSF administered only as indicated (n = 98). Results A complete response was achieved in 39 of the 94 assessable patients assigned to low-dose therapy (41 percent) and in 42 of the 81 assessable patients assigned to standard-dose therapy (52 percent, P = 0.56). ...

Purpose: To define the safety and toxicity of interleukin-4 (IL-4) when administered subcutaneously in patients with AIDS-related Kaposi's sarcoma (AIDS-KS); to evaluate the effect of IL-4 on immunologic and virologic parameters; and to preliminarily assess the response rate of IL-4 in AIDS-KS. Patients and methods: Eighteen patients with mucocutaneous, non-visceral AIDS-KS were treated with IL-4 at a dose of 1 mcg/kg subcutaneously, daily until unacceptable toxicity or for a maximum period of six months. Twelve (66%) patients had extensive mucocutaneous disease with over 25 lesions. Ten patients had received prior systemic chemotherapy. Seventeen had CD4+ lymphocyte counts less than 200/mm 3 . Results: The most common adverse effects included headache in 78%, fever in 56%, chills in 44%, and edema in 44%. Hematologic toxicities consisted of grade 4 neutropenia (less than 500/mm 3 ) in 33%, mild anemia in 22%. Transient elevation of liver enzymes was noted in 17%. A transient elevation in CD4+ lymphocyte counts occurred during the first two weeks of therapy. Four of eleven patients tested showed marked decline in plasma HIV RNA after four weeks. Partial remission was observed in one patient, lasting six months. Three other patients (17%) had stable disease: 7 weeks in one patient, and 10 weeks in each of the two other patients. Conclusion. Grade 4 neutropenia (absolute neutrophil count < 500/mm 3 ) was the most common hematologic adverse effect with IL-4 in patients with AIDS-KS. In contrast to in vitro findings, there was a decrease in plasma HIV RNA after four weeks of IL-4 therapy in the majority of patients tested. IL-4 produced minimal anti-tumor effects in AIDS-KS with one partial remission in a patient with CD4 lymphocyte counts over 200/mm 3 . Further studies of IL-4 in AIDS-KS may be considered in patients with better immune status.

BACKGROUND Use of multiagent chemotherapy has been associated with complete remission (CR) in approximately 50% of patients with newly diagnosed acquired immunodeficiency syndrome (AIDS)-lymphoma, although additional AIDS-related complications may occur. Both chemotherapy and antiretroviral therapy were employed in an attempt to ascertain if the combination was safe, and associated with changes in human immunodeficiency virus (HIV) p24 antigen levels during the course of treatment. METHODS Low dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone(M-BACOD) chemotherapy and zalcitabine (ddC) were employed in 28 patients. Since both vincristine and zalcitabine may cause peripheral neuropathy, a Phase I/II study design was employed. Serum was analyzed for immune complex dissociated (ICD) HIV p24 antigen and interleukin (IL)-6 levels during therapy. RESULTS CR was achieved in 14 of 25 patients (56%), with partial response (PR) in 5 (20%). CRs were equivalent in patients with good or poor prognostic indicators, including a history of AIDS prior to lymphoma (CR = 60%); and/or CD4 lymphocytes < 200/mm3 (CR = 53%). Five patients with a CR subsequently relapsed (36%); median survival of CR patients was 29.2 months (4.1–61+), whereas that of all of the treated patients was 8.1 months. No significant peripheral neuropathy or other toxicity was observed. Serum ICD p24 antigen levels either fell (7/14) or remained consistently negative (2/14) in 9 of 14 patients (64%), whereas 36% experienced an increase. Elevated serum IL-6 levels at diagnosis were associated with systemic “B” symptoms (P = 0.023), whereas changes in IL-6 correlated with response to therapy over time (P = 0.006). CONCLUSIONS Combination antineoplastic and zalcitabine antiretroviral therapy may be safely administered to patients with AIDS-related lymphoma, resulting in CR in 56%, lack of significant neurotoxicity, and favorable effect on HIV p24 antigen in 50%. Elevation of serum IL-6 is associated with systemic “B” symptoms, whereas changes in serum IL-6 may correlate with response. Cancer 1996;78:517-26.

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/m2, rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2 (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.

Background Addition of bortezomib to R-CHOP (VR-CHOP) may overcome the less favorable prognosis of non-GCB subtype lymphoma (Ruan et al. JCO 2011). We report results of a prospective open-label, randomized, phase 2 study evaluating the efficacy and safety of frontline R-CHOP vs VR-CHOP in pts with non-GCB DLBCL. Methods Adult pts with previously untreated non-GCB DLBCL who had ≥1 site of measurable disease, ECOG performance status 0-2, and adequate hematologic, hepatic, and renal function were eligible. Confirmation of non-GCB subtype using the Hans immunohistochemical (IHC) algorithm was required. Hans IHC non-GCB testing was performed in real time at a central US laboratory (48-72 hr turnaround from arrival of FFPE sample). Several centers demonstrated consistent scoring with the central laboratory and were permitted to enroll pts based on local non-GCB subtyping, with retrospective central laboratory confirmation. All pts received 6 cycles of standard R-CHOP in 21-d cycles (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 [max 2 mg], all IV on d 1, and prednisone 100 mg PO on d 1-5). In the VR-CHOP arm, pts also received bortezomib 1.3 mg/m2 IV on d 1 and 4 of each cycle. Follow-up was every 3 mos for up to 2 yrs after enrollment of the last pt. The primary endpoint was progression-free survival (PFS). Secondary endpoints included: overall survival (OS), overall response rate (ORR) and complete response (CR) rate after cycles 2 and 6, and safety. Response/disease progression were investigator-assessed by CT and FDG-PET scan at the end of cycles 2 and 6, and in follow up per 2007 Revised Response Criteria for Malignant Lymphoma. Adverse events (AEs) were graded by NCI-CTCAE v3.0. Sample size (n=~190) was determined to provide 80% power to detect an improvement in 2-yr PFS from 62% with R-CHOP (Fu et al. JCO 2008) to 77% (1-sided log rank; significance level 0.05). Here we present preliminary findings (data cut-off: Jun 2015). Results 206 pts were randomized at 69 sites; of these, 183 (91 R-CHOP, 92 VR-CHOP) had centrally confirmed non-GCB DLBCL and received ≥1 dose of study drug (modified intent-to-treat population). 86% (R-CHOP) and 85% (VR-CHOP) of pts completed study treatment per protocol. 60% of pts received study drug within 4 wks after tumor sample collection. Baseline characteristics were (R-CHOP vs VR-CHOP): male 58% vs 49%; median age 62 vs 65 yrs (>65 yrs 44% vs 46%); AJCC stage III/IV disease 73% vs 72%; extranodal disease 46% vs 52%; bone marrow involvement 11% vs 14%; IPI low/low-int/high-int/high 24/25/38/12% vs 26/28/33/13%. After a median follow-up of 31.5 mos, 2-yr PFS was 77% vs 82% (HR 0.77; 90% CI: 0.45, 1.30; p=0.70). In pts with high-int/high IPI, 2 yr PFS was 64% vs 72% (HR 0.66; 90% CI: 0.34, 1.28; p=0.294), whereas in pts with low/low-int IPI the HR was 1.13 (90% CI: 0.46, 2.75; p=0.821). At data cut-off, 15% and 11% of pts in the R-CHOP and VR-CHOP arms had died (HR: 0.65; 90% CI: 0.32, 1.29); median OS was not estimable in either arm and 2 yr OS rates were 80% vs 82%. In pts with high-int/high IPI, 2 yr OS rates were 79% (R-CHOP) vs 92% (VR-CHOP); in pts with low/low-int IPI, 2-yr OS rates were 98% in both arms. In 86 R-CHOP and 90 VR-CHOP response-evaluable pts, ORRs were 98% vs 92% (52% vs 54% CR). After 2 yrs, 73% of R-CHOP pts and 76% of VR-CHOP pts had not yet received a subsequent anti-lymphoma therapy. The safety population comprised 100 R-CHOP and 101 VR-CHOP pts. In both arms, pts received a median of 6 cycles of therapy (range 1-6). In the R-CHOP and VR-CHOP arms, 71% and 79% of pts had a G≥3 AE, and 31% and 34% had serious AEs, and 55% and 68% reported drug-related G≥3 AEs, the most common of which were neutropenia (34% vs 28%) and thrombocytopenia (8% vs 20%).G≥3 peripheral neuropathy rates were 1% (R-CHOP) and 5% (VR-CHOP). Conclusions These preliminary data suggest no significant efficacy advantage with the addition of bortezomib to R-CHOP in pts with previously untreated non-GCB DLBCL. This may be due to lack of bortezomib effect, time required for Hans IHC testing, IHC missclassification, or pt selection (R-CHOP alone pts had better outcomes/lower event rate than expected). These results have important implications for upcoming studies of new therapeutic strategies in DLBCL that target pt subsets based on cell of origin. Disclosures Kolibaba: Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; TG Therapeutics: Research Funding; Cell Therapeutics: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Amgen: Research Funding; Acerta: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Novartis: Research Funding; GSK: Research Funding; Janssen: Research Funding. Tulpule:Millennium Pharmaceuticals Inc.: Research Funding. Flinn:Cephalon, Inc; Teva Pharmaceutical Industries Ltd; Genentech, inc; Gilead: Research Funding. Flowers:Janssen: Research Funding; Infinity Pharmaceuticals: Research Funding; Janssen: Research Funding; Onyx Pharmaceuticals: Research Funding; Acerta: Research Funding; Millennium/Takeda: Research Funding; Spectrum: Research Funding; Onyx Pharmaceuticals: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics: Research Funding; Gilead Sciences: Research Funding; Acerta: Research Funding; Seattle Genetics: Consultancy; Pharmacyclics: Research Funding; Millennium/Takeda: Research Funding; AbbVie: Research Funding; Infinity Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy; OptumRx: Consultancy; AbbVie: Research Funding; Genentech: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; OptumRx: Consultancy; Genentech: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Spectrum: Research Funding. Papish:Genentech: Speakers Bureau; Pfizer: Speakers Bureau; Genomic Health: Speakers Bureau; Novartis: Speakers Bureau. Venugopal:Genentech: Research Funding; Celgene: Research Funding. Hajdenberg:Gilead: Speakers Bureau; AbbVie: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Mulligan:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Neuwirth:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Suryanarayan:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Esseltine:Takeda Pharmaceuticals, Inc.: Equity Ownership; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Johnson & Johnson: Equity Ownership.

Axl is an oncogenic receptor tyrosine kinase that plays multiple roles in tumorigenesis and metastasis of many cancers. This study is the first to demonstrate that Axl is induced in Kaposi sarcoma and Kaposi sarcoma herpesvirus (KSHV) transformed endothelial cells. Conditionally, expression of one KSHV latency protein vFLIP induces Axl expression in endothelial cells. This induction can be blocked by nuclear factor-κB inhibitor, consistent with the known vFLIP mechanism of action. KS cell lines lacking KSHV also have elevated Axl expression, which probably resulted from hypomethylation of AXL promoter. Axl activation activates downstream phosphoinositol-3 kinase signaling, and Axl knockdown by siRNA impairs phosphoinositol-3 kinase signaling. Furthermore, Axl knockdown inhibits KS cell growth and invasion. To explore the potential for translation of these findings, we generated monoclonal antibodies to block the biologic functions of Axl. MAb173, which induces receptor degradation, showed activity in vitro to inhibit KS cell invasion. Moreover, in vivo xenograft studies with KS cells with or without KSHV infection showed that MAb173 reduced tumor growth, increased tumor cell apoptosis, and markedly decreased Axl protein level in tumors. Axl thus has a potential role in KS pathogenesis and is a candidate for prognostic and therapeutic investigations.

Purpose Bendamustine HCl is a bifunctional mechlorethamine derivative with clinical activity in the treatment of non-Hodgkin's lymphoma. This study evaluated bendamustine plus rituximab in 67 adults with relapsed, indolent B-cell or mantle cell lymphoma without documented resistance to prior rituximab. Patients and Methods Patients received rituximab 375 mg/m2 intravenously on day 1 and bendamustine 90 mg/m2 intravenously on days 2 and 3 of each 28-day cycle for four to six cycles. An additional dose of rituximab was administered 1 week before the first cycle and 4 weeks after the last cycle. Sixty-six patients (median age, 60 years) received at least one dose of both drugs. Results Overall response rate was 92% (41% complete response, 14% unconfirmed complete response, and 38% partial response). Median duration of response was 21 months (95% CI, 18 to 24 months). Median progression-free survival time was 23 months (95% CI, 20 to 26 months). Outcomes were similar for patients with indolent or mantle cell histologies. The combination was generally well tolerated; the primary toxicity was myelosuppression (grade 3 or 4 neutropenia, 36%; grade 3 or 4 thrombocytopenia, 9%). Conclusion Bendamustine plus rituximab is an active combination in patients with relapsed indolent and mantle cell lymphoma.

Anthracyclines are valuable cytotoxic agents in cancer treatment. However, their usefulness is limited by cumulative dose-dependent cardiotoxicity that may manifest as life-threatening congestive heart failure. To avoid cardiotoxicity, the use of doxorubicin is typically capped at a safe cumulative dose. Liposomal formulations may reduce cardiac risks whilst maintaining anti-cancer efficacy. Efficacy and safety studies of non-pegylated liposomal doxorubicin (NPLD) in metastatic breast cancer (MBC) are reviewed, along with studies that examine efficacy and cardiac tolerability in combination with newer agents such as paclitaxel and trastuzumab. These show that cardiac safety of liposomal doxorubicin is similar to that of epirubicin in cumulative dose, but that the formulation, unlike epirubicin, has similar anti-cancer efficacy to doxorubicin at equimolar doses. Liposomal doxorubicin may have a better therapeutic index than non-liposomal anthracyclines. This justifies further studies in patients where cumulative cardiotoxicity is a concern, as does study of its use with other potentially cardiotoxic agents.

The purpose of the study was to evaluate the safety, efficacy, and pharmacokinetics of pixantrone (BBR2778) when substituted for etoposide in the ESHAP regimen in patients with aggressive relapsed or refractory non-Hodgkin's lymphoma. Nineteen patients received protocol therapy, consisting of pixantrone 80 mg/m2 over 1 h on day 1, methylprednisolone 500 mg on days 1 - 5, cisplatin 25 mg/m2 on days 1 - 4, and cytarabine 2000 mg/m2 on day 5. Cycles were repeated every 21 days, in the outpatient setting. Dose limiting toxicity, consisting of bone marrow suppression, occurred at the first dose level (80 mg/m2), which was defined as the recommended dose. Grade 3 and 4 toxicities were mainly hematologic. Only one patient had grade 4 febrile neutropenia. No significant decreases in ejection fraction greater than 20% occurred. Overall response rate was 58%, with 37% complete and 21% partial responses. Six of the 11 responders (55%) underwent stem cell transplant. Median time to progression and overall median survival were 5.7 months and 14.5 months, respectively. There is no significant interaction between pixantrone and the combined drugs. The recommended dose of pixantrone in combination with methylprednisolone, cytarabine, and cisplatin (PSHAP) is 80 mg/m2. PSHAP is an active salvage regimen and should be further evaluated as a pretransplant cytoreductive regimen.

Chemotherapy-related anemia is prevalent among patients with hematologic malignancies. A randomized, open-label, multicenter trial of early versus late epoetin alfa in this population was conducted, focusing on quality of life (QOL).Patients with non-Hodgkin lymphoma, Hodgkin lymphoma, chronic lymphocytic leukemia, or multiple myeloma and baseline hemoglobin of 10 to 12 g/dL who were scheduled foror = 4 months of myelosuppressive chemotherapy were randomized to receiveor = 16 weeks of epoetin alfa at a dose of 40,000 U once weekly immediately (early) or to wait and only receive epoetin alfa if hemoglobin decreased to9 g/dL (late). Those patients with a hemoglobin level12 g/dL after 3 chemotherapy cycles were not randomized. The primary endpoint was a mean change in the Functional Assessment of Cancer Therapy-Anemia (FACT-An) total.In all, 269 patients with a hemoglobin levelor = 12 g/dL were randomized. The mean total FACT-An increased 3.84 (95% confidence interval [95% CI], 0.21-7.46) in early patients and decreased 4.37 (95% CI, -7.99 to -0.74) in late patients (P = .003). Early patients had significantly (P.05) higher mean scores for total FACT-General; FACT-General physical and functional well-being subscales, total anemia scale, and fatigue subscale; and daily activity, energy, and important activity Linear Analog Scale Assessment scales, as well as reduced bedrest days and restricted activity days. The mean hemoglobin increased 1.2 g/dL (95% CI, 0.98-1.46) in early patients but decreased 0.2 g/dL (95% CI, -0.32-0.12) in late patients (P.0001). Adverse events were similar between groups (with fatigue being the most prevalent); clinically relevant thromboembolic events were more common in early patients.Treating mild anemia immediately with epoetin alfa during chemotherapy for hematologic malignancy significantly improved QOL, productivity, and hemoglobin compared with delaying treatment until the hemoglobin level decreases to9.0 g/dL.

Background The toxicity and efficacy of nonpegylated liposomal doxorubicin (TLC D-99) when substituted for conventional doxorubicin in the CHOP (doxorubicin/cyclophosphamide/vincristine/prednisone) regimen were evaluated in the treatment of newly diagnosed patients with aggressive non-Hodgkin's lymphoma. Liposomal doxorubicin at doses of 40 mg/m 2 , 50 mg/m 2 , 60 mg/m 2 , and 80 mg/m 2 was given with fixed doses of cyclophosphamide, vincristine, and prednisone. Chemotherapy cycles were repeated every 21 days. Patients and Methods Forty-seven patients with a median age of 55 years (range, 25-83 years) were studied. Results No dose-limiting toxicities were observed at any level. Reversible grade 3/4 neutropenia was the most common toxicity (95.8%). Most nonhematologic side effects were grade 1/2 in severity. Complete remissions were documented in 31 of 46 evaluable patients (67.4%) and partial remissions in 7 (15.2%), for an overall major response rate of 82.6%. The median duration of complete remission is ≥ 27.7 months (range, 2.4 months to ≥ 59.8 months). An exploratory objective was to correlate multidrug resistance–1 (MDR-1) expression with outcome. Immunohistochemistry for MDR-1-related p-glycoprotein was assessed in lymphoma tissues from 27 patients. Of the 27 lymphoma tissues studied, 8 (30%) were MDR-1 positive at diagnosis. The complete response rate was 63% in MDR-1–positive lymphomas and 74% in the MDR-1–negative cases ( P = 0.66). Conclusion Nonpegylated liposomal doxorubicin in combination with cyclophosphamide, vincristine, and prednisone is an active regimen for patients with newly diagnosed, aggressive non-Hodgkin's lymphoma. The regimen is relatively well tolerated, with hematologic suppression as the major toxicity. Liposomal encapsulation might evade resistance caused by MDR-1 expression.

Purpose Vascular endothelial growth factor antisense (VEGF-AS) is an antisense oligonucleotide that targets VEGF, inhibiting angiogenesis and tumor cell proliferation. This study established the safety, biologic effects, and pharmacokinetics of VEGF-AS in 51 patients with advanced malignancies. Methods VEGF-AS was administered as a 2-hour infusion daily for 5 consecutive days for only one cycle on the first four dose levels, and then administered daily for 5 days every other week for up to 4 months on subsequent levels. Pharmacokinetics, tumor response, and the effect on plasma VEGF levels were determined. Results The maximum-tolerated dose was 200 mg/m2. Dose-limiting toxicities included grade 4 fever, and pulmonary embolism in one patient each at 250 mg/m2. Mild anemia, fever, fatigue, and gastrointestinal complaints were the most common adverse events. VEGF-AS t1/2β (beta-phase terminal half-life of drug concentration) was 2.25 hours (range, 1.97 to 2.95 hours). Mean plasma VEGF-A (P = .002) and VEGF-C (P = .01) levels decreased 24 hours postinfusion, with a trend towards greater decreases at higher dose levels. At the maximum-tolerated dose, five of six patients demonstrated reductions in plasma VEGF. Clinical responses included complete remission in one patient with AIDS-Kaposi's sarcoma, a mixed but dramatic response in one patient with cutaneous T-cell lymphoma, and prolongation of progression-free survival compared with that obtained on the immediate prior regimen in six patients (12%) with renal cell, bronchoalveolar, small cell lung, thyroid, and ovarian carcinomas, and chondrosarcoma, respectively. Conclusion VEGF-AS was well tolerated, with biologic effects and preliminary evidence of clinical efficacy.

Genomic complexity in diffuse large-B-cell lymphoma has recently been reported to have strong prognostic value in patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab-based immunochemotherapy (PMID:22975378). In that study, the presence of the respective gain/loss of at least one of nine genomic markers along the CDKN2A-TP53-RB-E2F axis was used to define cases with “complex” genomes. Genomic imbalance at these specific loci were suggested to functionally contribute toward cell cycle deregulation resulting in increased overall genomic instability. Other clinicopathologic studies have clearly demonstrated that inferior survival is also associated with elevated expression of p53, which serves as a surrogate for TP53 mutation. To date, there have been very few studies, if any, that have examined the relationship between genomic imbalance and complexity, and clinicopathologic features in DLBCL, in particular with relevance to TP53. To this end, DNA was extracted from either sections of formalin-fixed paraffin-embedded biopsies with greater than 70% tumor burden or tumor-enriched cores of 85 DLBCL specimens from patients treated at a single institution (with IRB approval). DNAs from 39 specimens have been blindly submitted to array-CGH to date, using a targeted array (Agilent Technologies). The design permitted assessment at 50 loci commonly gained/lost in DLBCL (arising within 36 minimal common regions [MCRs]) using well defined scoring criteria. Specimens were classified as “complex” if any one of the following aberrations were detected: gain of 1q23, 6p21, 7q22, 12q15, or 19p13, or loss of 9p21, 13q14, 16q12, or 17p13. For all cases, expression of p53, MYC, BCL2, Ki-67, and Epstein-Barr virus (EBV) had previously been examined and reported (PMID:24619762) as was the COO subtype. Correlative analyses with overall survival (OS) were tested using the Kaplan Meier method and log rank statistic. Significance of pathogenomic correlations were examined using the Fisher’s exact t-test (P For the preliminary analysis comprising 39 cases, genomic complexity (observed for 22 cases) did not significantly correlate with IPI, consistent with the prior report where genomic complexity associated with inferior survival independent of IPI (PMID:22975378). However, genomic complexity did portend shortened survival within the preliminary 39 patients studied to date (P1), did not exhibit significant association with outcome. Fourteen of 18 cases with p53 expression (>30%) had complex genomes, which was significantly enriched compared with cases with low or no p53 expression (P 70%) and MYC (45%) expression, nor with COO subtype. Specifically for TP53, loss of 17p13 was detected in 7/39 cases, and positively correlated with adverse outcome both for the entire dataset (P=0.05) and for RCHOP-treated patients (P=0.02). Interestingly, of those with loss, 3 were not positive for p53 expression and overall, p53 expression did not correlate with 17p loss. Previous analyses in this dataset had also revealed that co-expression of p53 and MYC, but not BCL2 had an enhanced negative effect on outcome. Only one of 5 cases with co-expression of p53 and MYC also displayed 17p loss. Overall then, p53 expression was associated with underlying genomic complexity but specific loss of the TP53 locus appeared to mark another smaller subset of DLBCL patients with inferior survival, independent of p53 expression. Expansion of the study to include the additional 46 cases is currently ongoing to confirm these emerging correlative patterns, as is determination of the TP53 mutation status of each specimen. Additional correlative pathogenomic studies will also be afforded with the larger dataset, examining the role of the 8 other loci of genomic gain/loss suggested to underlie genomic complexity in DLBCL. Disclosures Ma: Cancer Genetics, Inc.: Employment, Stock option holder Other. Houldsworth:Cancer Genetics, Inc: Employment, Stock and stock option holder Other.

Background: Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE) is the largest registry of prospectively treated PTCL patients in the United States. Patients are enrolled at the initial diagnosis of PTCL and within 30 days of starting treatment. Data on demographics, clinical characteristics, diagnosis, therapy delivered as induction or salvage, and outcomes are collected. Methods: For this report, we examined baseline characteristics and induction treatment patterns for patients with the 3 most common subtypes of PTCL: PTCL not otherwise specified (NOS), anaplastic large cell lymphoma (ALCL) and angioimmunoblastic T-cell lymphoma (AITL). Only data from locked records are reported. Locked records are those that have been reviewed and digitally signed by the treating investigator. Results: Five hundred patients were enrolled from February 2010 until January 2014. As of July 2014, there were 257 locked baseline records and 188 locked treatment records for patients with a diagnosis of PTCL-NOS, ALCL or AITL. The mean age of these patients was 60 (range: 51-70). Most were male (66%) and white (78%). At study entry, 234 (91%) had an ECOG performance status of 0-1, 190 (74%) had Ann Arbor stage of III/IV, and 120 (47%) had one or more B symptoms. Half of the patients had extranodal disease. Mean international prognostic index (IPI) score was 2 (range 0-5). For staging, a PET/CT was the most common radiographic method used (58% of patients), and for pathologic diagnosis, on average, 10 phenotypic and ~1 genetic markers were assessed. For baseline characteristics reported here, patients treated at academic centers had more extranodal disease, a higher IPI score and tended to have more advanced disease compared to patients treated in the community. The primary intent of initial therapy was a cure for 89% of patients and 60% received an anthracycline or anthracycline plus etoposide-containing regimen. A minority of patients (21%) participated in a clinical trial for PTCL. Further details on induction therapy can be found in the table below. Table Initial Treatment Characteristics Total Academic Community Initial Treatment Approach* N=188 n=158 n=30 Induction chemotherapy (CT) alone 125 (66%) 102 (65%) 23 (77%) Induction CT + consolidation or maintenance 11 (6%) 10 (6%) 1 (3%) Stem cell transplant 36 (19%) 33 (21%) 3 (10%) Local radiotherapy +/- chemotherapy 10 (5%) 7 (4%) 3 (10%) Observation/best supportive care 6 (3%) 6 (4%) 0 (0%) Induction Regimens N=186 n=154 n=32 CHOP/CHOP-like 76 (41%) 56 (36%) 20 (63%) CHOP/CHOP-like + etoposide 37 (20%) 30 (20%) 7 (22%) Gemcitabine-based regimen 6 (3%) 6 (4%) 0 (0%) Platinum-based regimen 5 (3%) 5 (3%) 0 (0%) Other 62 (33%) 57 (37%) 5 (15%) Number of Cycles of Induction CT Median, Inter-Quartile Range (Cycles) 5 (2-6) 5 (2-6) 5 (1-6) Type of Transplant Performed N=36 n=33 n=3 Autologous 34 (94%) 31 (94%) 3 (100%) Allogeneic 2 (6%) 2 (6%) 0 (0%) *5 patients received CNS prophylaxis with selected treatments shown above CHOP=cyclophosphamide, doxorubicin, prednisone, and vincristine Conclusions: Early results from the first prospective US-based registry of newly diagnosed patients with PTCL-NOS, ALCL and AITL show that beyond CHOP-based therapy, there is little consensus on initial management of these patients. These data strongly support the need to develop evidence-based approaches for this rare and heterogeneous group of patients. Disclosures Pinter-Brown: Spectrum: Consultancy, Membership on an entity's Board of Directors or advisory committees. Foss:spectrum: Research Funding; seattle genetics: Research Funding; Merck: Research Funding; Celgene: Honoraria, Research Funding; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Carson:Spectrum: Consultancy; Celgene: Consultancy, Speakers Bureau. Horwitz:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Research Funding; Infinity: Research Funding; Kiowa-Kirin: Research Funding; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy. Rosen:Allos: Consultancy, Honoraria. Gisselbrecht:Spectrum: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hsi:Daiichi-Sankyo: Consultancy; Allos: Research Funding; Seattle Genetics: Speakers Bureau; Eli Lilly: Research Funding; Abbott: Research Funding; Cellerant Therapeutics: Research Funding; BD Biosciences: Research Funding; Millennium: Research Funding. Advani:Seattle Genetics: Research Funding. Lechowicz:Spectrum: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy; Millennium: Consultancy. Smith:Allos/Spectrum: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kahl:Allos : Research Funding. Park:Teva: Research Funding; Seattle Genetics: Research Funding; Janssen: Travel funding, Travel funding Other.

Purpose To compare the prognostic factors for survival and the validity of the International Prognostic Index (IPI) in patients with HIV-related diffuse large-cell lymphoma (HIV-DLCL) treated with curative intent in the pre–highly active antiretroviral therapy (HAART) era versus the HAART era. Patients and Methods We retrospectively reviewed 192 patients with HIV-DLCL diagnosed from 1982 to 2003. Pre-HAART era included 120 patients who did not receive HAART, whereas the HAART era included 72 patients diagnosed after January 1997 who received HAART. Results There were no statistically significant differences in terms of either lymphoma or HIV-related characteristics in the two time periods. The complete response rate improved from 32% in the pre-HAART to 57% in the HAART era (P = .0006), and median survival time improved from 8.3 to 43.2 months (P = .0005). In groups with low-, low-intermediate–, and high-intermediate–risk IPI disease, 3-year overall survival rates were 20%, 22%, and 5% in the pre-HAART era and 64%, 64%, and 50% in the HAART era, respectively. On multivariate analysis, factors independently associated with decreased survival in both periods were increasing IPI scores and failure to attain complete remission, whereas CD4 less than 100 cells/μL predicted shorter survival in only the pre-HAART era. Conclusion Prognostic factors and overall survival of patients with HIV-DLCC have changed. Clinical outcomes in patients with HIV-DLCL are now approaching the outcomes of patients with de novo lymphoma.

Purpose of review AIDS-related lymphoma has a decreased response rate and poorer prognosis to standard chemotherapy when compared with lymphoma in the non-HIV population. In addition to the known HIV-related and lymphoma-related poor prognostic factors, this review discusses another factor, MDR-1 expression and its impact on response to therapy in patients with AIDS-related lymphoma. Recent findings There is an increased incidence of de-novo MDR-1 expression in AIDS-related lymphoma compared with lymphoma in the non-HIV settings. MDR-1 expression in AIDS-related lymphoma is associated with poor response to conventional combination chemotherapy. Liposomal encapsulation of doxorubicin when substituted for doxorubicin in the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) seems to overcome P-glycoprotein-mediated drug resistance in AIDS-related lymphoma. Summary The overexpression of MDR-1 gene product P-glycoprotein is an adverse prognostic factor in AIDS-related lymphoma. Treatment with liposomal encapsulated doxorubicin seems to overcome the P-glycoprotein-related drug resistance. This and other strategies to modulate MDR-1 should be further explored in order to improve success rates in the treatment of AIDS-related lymphoma.

Purpose To compare outcomes of patients with HIV-Burkitt's lymphoma (HIV-BL) and HIV-diffuse large-cell lymphoma (HIV-DLCL) after treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or M-BACOD (methotrexate, bleomycin, cyclophosphamide, etoposide) in pre–highly active antiretroviral therapy (HAART) versus HAART eras. Patients and Methods Three hundred sixty-three patients with AIDS-related lymphoma diagnosed from 1982 to 2003 were reviewed retrospectively, including 262 in the pre-HAART (HIV-BL, 117; HIV-DLCL, 145) and 101 in the HAART era (HIV-BL, 18; HIV-DLCL, 83). Pre-HAART included those who did not receive HAART, and HAART era included those diagnosed after January 1997 who received HAART. Results There were no significant differences between groups in terms of age, sex, history of injection drug use, prior AIDS, lactate dehydrogenase level, and disease stage at diagnosis. Compared with HIV-BL, HIV-DLCL was associated with significantly lower CD4 counts in the pre-HAART but not the HAART era. Although the overall median survival was similar for both groups in the pre-HAART era (HIV-BL, 6.4 months v HIV-DLCL, 8.3 months; P = .43), survival was significantly worse in patients with HIV-BL in the HAART era (HIV-BL, 5.7 months v HIV-DLCL, 43.2 months; P = .0003). Failure to attain complete remission and CD4 count less than 100 cells/mm3 independently predicted for poor survival in the pre-HAART era. In comparison, histology of HIV-BL and no attainment of complete remission were independent poor prognostic factors in the HAART era. Conclusion Survival of patients with HIV-DLCL has improved in the HAART era, along with CD4 count, whereas survival of similarly treated patients with HIV-BL remained poor. The current practice of using the same regimen for both groups of patients should be re-evaluated.

Purpose IM862 is a synthetic dipeptide (l-glutamine l-tryptophan) with in vitro and in vivo antiangiogenic properties. Phase I/II studies showed minimal toxicity and a response rate of 36% in AIDS-Kaposi's sarcoma. We report a 24-week, randomized, double-blinded, placebo-controlled phase III trial with the phase II dose, 5 mg intranasally every other day. Patients and Methods Two hundred two HIV-positive patients were enrolled, 104 on IM862 and 98 on placebo. Results Baseline characteristics were comparable except current antiretroviral therapy: 88% versus 96% (IM862 v placebo group; P = .042). The median treatment durations were 19.5 versus 24 weeks (IM862 v placebo). No significant difference was detected in response rate (IM862, 23%; 95% CI, 15% to 32% v placebo, 21%; 95% CI, 14% to 31%; P = .46), time to response (8.5 weeks v 14 weeks; P = .024), or duration of response. However, IM862 was associated with both a shorter time to response (8.5 weeks v 14 weeks; P = .024) and shorter median time to progression (16 weeks, 95% CI, 13 to 27 weeks v 35 weeks, 95% CI, 26 to 114 weeks; P = .012). Conclusion Despite promising phase I and phase II studies, IM862 5 mg every other day was not superior to placebo and may accelerate time to progression. Highly active antiretroviral therapy alone was associated with a substantial rate of sustained tumor response and may have contributed to prior estimates of IM862 response. Therapeutic trials for AIDS-Kaposi's sarcoma must account for ongoing immune reconstitution in the setting of concurrent highly active antiretroviral therapy that may confound estimates of therapeutic activity.