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The Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is the causal agent of Kaposi sarcoma (KS), but is also pathogenetically related to several lymphoproliferative disorders, including primary effusion lymphoma (PEL)/extra-cavitary (EC)-PEL, KSHV-associated multicentric Castleman disease (MCD), KSHV-positive diffuse large cell lymphoma (DLBCL) and germinotropic lymphoproliferative disorder (GLPD). These different KSHV-associated diseases may co-occur and can have overlapping features. KSHV, similar to the Epstein-Barr virus (EBV), is a lymphotropic gamma herpesvirus which is preferentially present in abnormal lymphoid proliferations occurring in immune compromised individuals. Notably, both KSHV and EBV can infect and transform the same B cell, which is frequently seen in the KSHV-positive, EBV-positive PEL/EC-PELs. The mechanisms by which KSHV leads to lymphoproliferative disorders is thought to be related to the expression of a few transforming viral genes that can affect cellular proliferation and survival. There are critical differences between KSHV-MCD and PEL/EC-PEL, the two most common KSHV-associated lymphoid proliferations, including the viral associations, the patterns of viral gene expression and the cellular differentiation stage reflected by the phenotype and genotype of the infected abnormal B cells. Advances in treatment have improved outcomes, but mortality rates remain high. Our deepening understanding KSHV biology, the clinical features of KSHV-associated diseases, and newer clinical interventions should lead to improved and increasingly targeted therapeutic interventions.

Burkitt lymphoma (BL) accounts for most pediatric non-Hodgkin lymphomas, being less common but significantly more lethal when diagnosed in adults. Much of the knowledge of the genetics of BL thus far has originated from the study of pediatric BL (pBL), leaving its relationship to adult BL (aBL) and other adult lymphomas not fully explored. We sought to more thoroughly identify the somatic changes that underlie lymphomagenesis in aBL and any molecular features that associate with clinical disparities within and between pBL and aBL. Through comprehensive whole-genome sequencing of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumors, we identified additional significantly mutated genes, including more genetic features that associate with tumor Epstein-Barr virus status, and unraveled new distinct subgroupings within BL and DLBCL with 3 predominantly comprising BLs: DGG-BL (DDX3X, GNA13, and GNAI2), IC-BL (ID3 and CCND3), and Q53-BL (quiet TP53). Each BL subgroup is characterized by combinations of common driver and noncoding mutations caused by aberrant somatic hypermutation. The largest subgroups of BL cases, IC-BL and DGG-BL, are further characterized by distinct biological and gene expression differences. IC-BL and DGG-BL and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among aBL and pBL cohorts. These findings highlight shared pathogenesis between aBL and pBL, and establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiologic, diagnostic, and therapeutic strategies.

Mast cell sarcoma is a rare disease associated with a dismal prognosis. We report a unique case of mast cell sarcoma arising in a patient with a history of T-lymphoblastic leukemia/lymphoma (T-ALL)...

Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia (CLL), typically to an aggressive lymphoma. Treatment options for RS are limited and the disease is often fatal. Receptor tyrosine kinase–like orphan receptor 1 (ROR1) is expressed on CLL cells and other cancers but not on healthy adult tissues, making it an attractive, tumor-specific therapeutic target. VLS-101 is being developed as an antibody-drug conjugate (ADC) for therapy of ROR1-expressing (ROR1+) cancers. VLS-101 comprises UC-961 (a humanized immunoglobulin G1 monoclonal antibody that binds an extracellular epitope of human ROR1), a maleimidocaproyl-valine-citrulline-para-aminobenzoate linker, and the antimicrotubule cytotoxin monomethyl auristatin E (MMAE). VLS-101 binding to ROR1 results in rapid cellular internalization and delivery of MMAE to induce tumor cell death. We studied 4 RS patient-derived xenografts (RS-PDXs) with varying levels of ROR1 expression (11%, 32%, 85%, and 99% of cells). VLS-101 showed no efficacy in the lowest-expressing RS-PDX but induced complete remissions in those with higher levels of ROR1 expression. Responses were maintained during the posttherapy period, particularly after higher VLS-101 doses. In systemic ROR1+ RS-PDXs, VLS-101 dramatically decreased tumor burden in all RS-colonized tissues and significantly prolonged survival. Animals showed no adverse effects or weight loss. Our results confirm ROR1 as a target in RS and demonstrate the therapeutic potential of using an ADC directed toward ROR1 for the treatment of hematological cancers. A phase 1 clinical trial of VLS-101 (NCT03833180) is ongoing in patients with RS and other hematological malignancies.

Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)–associated MCD, POEMS-associated MCD, and HHV-8−/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti–interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.

Pseudo-Gaucher cells can be found in multiple hematologic malignancies, hemoglobinopathies, infections, and multiple storage disorders upon bone marrow aspirate and biopsy; however, Gaucher disease (GD) should be ruled out, particularly when the cytoplasmic inclusions cannot be adequately characterized. It is well known that GD may be associated with monoclonal gammopathies; however, although enzyme replacement therapy (ERT) may result in an improvement in polyclonal gammopathies, its effect on the progression of monoclonal gammopathy of undetermined significance to multiple myeloma (MM) remains uncertain. ERT may improve patient’s cytopenias and facilitate administration of anti-myeloma therapy in patients with concurrent GD and MM; however, the current paucity of data makes it challenging to determine its effect on response to anti-myeloma therapy or the risk of relapse. Hematologists should be familiar with the clinical presentation and diagnosis of GD and its association with monoclonal gammopathies. Here we present a case of synchronous smoldering MM and GD. Keywords: Gaucher disease, Multiple myeloma

Introduction: Six cycles of rituximab plus infusional EPOCH is considered a preferred regimen for first-line treatment of HIV-associated diffuse large B-cell lymphoma (DLBCL), HHV8-positive DLBCL, and primary effusion lymphoma, and is among the preferred regimens for HIV-associated Burkitt's lymphoma in the 2019 NCCN guidelines. A phase III trial demonstrated non-inferiority of 4 cycles of R-CHOP (followed by 2 additional doses of rituximab) compared with 6 cycles of R-CHOP in immunocompetent patients with low-risk DLBCL (stage I-II, age 18-60 years, and an age-adjusted International Prognostic Index score of 0), indicating that de-escalation of treatment duration may be safely achieved without compromising curability in an appropriately selected patient population. Here we report the outcomes for patients with HIV-associated DLBCL and high-grade non-Hodgkin lymphoma (NHL) treated with 4-6 cycles of EPOCH plus rituximab based a response-adapted treatment strategy under a completed prospective clinical trial (AMC-034). Methods: One hundred-six patients with HIV-associated DLBCL or high-grade CD20-positive NHL enrolled at multiple centers across the U.S. were randomized to receive rituximab (375 mg/m2) given either concurrently prior to each infusional EPOCH cycle, or sequentially (weekly for 6 weeks) following completion of dose-adjusted EPOCH regimen tailored for HIV+ patients. EPOCH consisted of a 96-hour IV infusion of etoposide, doxorubicin, and vincristine plus oral prednisone followed by IV bolus cyclophosphamide every 21 days for 4 to 6 cycles. Patients received 2 additional cycles of therapy after documentation of a complete response (CR) by computerized tomography after cycles 2 and 4. Results: Sixty-four of 106 patients (60%, 95% CI 50%, 70%) had a CR in both treatment arms; characteristics of entire population and CR proportions stratified by number of EPOCH treatment cycles were similar (Table 1).The 2-year event-free survival (EFS) rates were similar in the 24 patients with CR who received 4 or fewer EPOCH cycles (78%, 95% confidence intervals [55%, 90%]) due to achieving a CR after 2 cycles, compared with those who received 5-6 cycles of EPOCH (85%, 95% CI 70%, 93%) due to failure to achieve a CR after 2 cycles (Table 2 and Figure 1). Time to disease progression and overall survival wer also similar for those treated with 4 or fewer cycles compared with 5-6 cycles (91% vs. 87%, and 78% vs. 90%, respectively) (Table 2 and Figure 1). Conclusion: A response-adapted strategy may permit a shorter treatment duration without compromising therapeutic efficacy in an appropriately selected population of patients with HIV-associated NHL, which merits further evaluation in additional prospective trials. Disclosures Noy: Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding.

Idiopathic multicentric Castleman disease (iMCD) is a rare immunologic disorder characterized by systemic inflammation, multicentric lymphadenopathy, and organ dysfunction. Enlarged lymph nodes demonstrate a spectrum of characteristic but variable histopathologic features historically categorized into hyaline vascular (HV) (or hypervascular (HyperV) more recently), plasmacytic, or "mixed." Though the etiology is unknown, a pro-inflammatory cytokine storm, often involving interleukin-6 (IL-6), contributes to pathogenesis. Anti-IL-6 therapy with siltuximab is the only FDA- or EMA-approved treatment based on efficacy and safety in multiple studies. Importantly, no patients considered to have HV histopathology achieved the primary endpoint in the Phase II study. NCCN currently recommends siltuximab first-line for iMCD except for patients considered to have HV histopathology. We investigated whether histopathologic subtype should guide siltuximab treatment decisions. Secondary analyses of clinical trial and real-world data revealed similar clinical benefit across histopathologic subtypes. Notably, only 18/79 patients in the Phase II study were consistently classified into histopathologic subtype by three independent review panels, demonstrating limited reliability to guide treatment decisions. Real-world data further demonstrate siltuximab's effectiveness in patients considered to have HV (or HyperV). Though histopathology is a critical component for diagnosis, there is insufficient evidence to guide treatment based solely on lymph node histopathologic subtype. This article is protected by copyright. All rights reserved.

Background Primary CNS lymphoma (PCNSL) is a rare non-Hodgkin lymphoma that is often associated with immunosuppressed states. The Epstein-Barr Virus (EBV) may play a role in tumor pathogenicity in some cases. The objective of this study was to examine the patient characteristics, tumor pathology, and survival outcomes associated with EBV tumor status in patients with PCNSL. Methods This was a retrospective subset analysis from 17 academic medical centers that included 439 patients of ages 60 years and above with PCNSL (David K et al. ASH 2020). The associations between EBV status and clinical or demographical variables were tested by Fisher's exact test, Wilcoxon rank-sum test, or CMH trend test. Kaplan-Meier estimator was used to estimate survival probability. Survival difference between groups was tested by log-rank test for statistical significance. Confidence interval of survival rate was calculated using Greenwood's formula. Results A total of 247 patients with available EBV status were included in this analysis. Median age was 71 (range 60-84) and 44.5% were male. Notably, none of the patients were HIV-positive. Twenty-five patients (10.1%) had EBV positive tumors as detected by EBER (EBV-encoded RNA) in-situ hybridization or LMP1 immunohistochemistry (IHC), 17 of which were solid organ transplant (SOT)-related post-transplant lymphoproliferative disorders (PTLD) and 8 of which were not PTLD. All EBV-positive non-PTLDs were diffuse large B-cell lymphoma. Three (15%) SOT-related PTLDs were EBV-negative. Patient characteristics analyzed included age at diagnosis, sex, ECOG performance status, history of prior or concurrent malignancies, history of solid organ transplant or autoimmune disease, history of allogeneic stem cell transplant, and immunosuppressive treatment. Of these, only a history of solid organ transplant or autoimmune disease (P Tumor characteristics analyzed included expression of C-MYC, BCL2, CD5, cell of origin markers (BCL6, MUM1, CD10), and CD20 through IHC, C-MYC and BCL2 translocation through FISH, histology, and involvement of brain parenchyma, CSF, spinal cord, and eyes. EBV-positive tumors were associated with low C-MYC (p=0.047) and BCL6 (p=0.0006) expression on immunohistochemistry, but not other factors. There were no significant differences in tumor characteristics between those with EBV-positive PTLD and EBV-positive non-PTLD. Among patients with PTLD, 30% (n=6) did not receive primary chemotherapy, and the most common treatment regimens were high-dose methotrexate (HD-MTX) with or without rituximab (n=5) and rituximab alone (n=3). However, there was no significant difference in outcomes among PTLD patients who received chemotherapy or those who did not. Among EBV-positive non-PTLD patients, only 12.5% (n=1) did not receive primary chemotherapy and the most common treatment regimens were methotrexate/rituximab/temozolomide (n=3) and HD-MTX with or without rituximab (n=3). There was no difference in overall or progression free survival between patients with EBV-positive and EBV-negative tumors, or in outcomes among SOT-related PTLD patients regardless of EBV status. However, patients with EBV-positive non-PTLD PCNSL had better overall survival compared to patients with EBV-positive PTLD and EBV-negative tumors (p=0.033, Figure). Conclusions In this large observational study of older patients with PCNSL, the incidence of EBV positive tumors was overall low and was most commonly associated with SOT-related PTLD. Mycophenolate mofetil was the most common immunosuppressive medication. In those without PTLD, there were no patient or tumor factors that were associated with EBV status. Unexpectedly, non-PTLD EBV-positive PCNSL had superior outcomes to EBV-positive PTLD and EBV-negative PCNSL. Future studies of EBV-positive non-PTLDs are warranted to further evaluate the potential impact of EBV latency and the immune response on the tumor microenvironment. Disclosures Reddy: BMS: Consultancy, Research Funding; Celgene: Consultancy; Abbvie: Consultancy; Genentech: Research Funding; KITE Pharma: Consultancy. Bachanova:Karyopharma: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; FATE: Research Funding; Incyte: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bond:Seattle Genetics: Honoraria. Goldlust:Tocagen: Membership on an entity's Board of Directors or advisory committees, Other: travel; BMS: Membership on an entity's Board of Directors or advisory committees, Other: travel; WEX: Consultancy, Other: travel; Cortice Bio: Consultancy, Other: travel; Boston Biomedical: Consultancy; COTA: Other; Novocure: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel, Research Funding, Speakers Bureau. Spurgeon:Gilead: Research Funding; Genentech: Research Funding; Cardinal Health: Honoraria; Bristol-Myers Squibb: Research Funding; VelosBio: Consultancy, Research Funding; Acerta: Research Funding; Janssen: Consultancy, Research Funding; AstraZeneca: Research Funding; Pharmacyclics: Consultancy; Beigene: Research Funding; Verastem: Research Funding; Genmab: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Karmali:AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; Takeda: Research Funding; BeiGene: Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Smith:Janssen: Consultancy; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; BMS: Consultancy; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; TG Therapeutics: Consultancy, Research Funding. Rubenstein:Kymera: Research Funding. Kahl:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy. Evens:Abbvie: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; MorphoSys: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Martin:Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; Cellectar: Consultancy; Beigene: Consultancy; Bayer: Consultancy; I-MAB: Consultancy; Sandoz: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Celgene: Consultancy.

A small subset of cases of chronic lymphocytic leukemia undergoes transformation to diffuse large B-cell lymphoma, Richter syndrome (RS), which is associated with a poor prognosis. Conventional chemotherapy results in limited responses, underlining the need for novel therapeutic strategies. Here, we investigate the ex vivo and in vivo efficacy of the dual phosphatidylinositol 3-kinase-δ/γ (PI3K-δ/γ) inhibitor duvelisib (Duv) and the Bcl-2 inhibitor venetoclax (Ven) using 4 different RS patient-derived xenograft (PDX) models. Ex vivo exposure of RS cells to Duv, Ven, or their combination results in variable apoptotic responses, in line with the expression levels of target proteins. Although RS1316, IP867/17, and RS9737 cells express PI3K-δ, PI3K-γ, and Bcl-2 and respond to the drugs, RS1050 cells, expressing very low levels of PI3K-γ and lacking Bcl-2, are fully resistant. Moreover, the combination of these drugs is more effective than each agent alone. When tested in vivo, RS1316 and IP867/17 show the best tumor growth inhibition responses, with the Duv/Ven combination leading to complete remission at the end of treatment. The synergistic effect of Duv and Ven relies on the crosstalk between PI3K and apoptotic pathways occurring at the GSK3β level. Indeed, inhibition of PI3K signaling by Duv results in GSK3β activation, leading to ubiquitination and subsequent degradation of both c-Myc and Mcl-1, making RS cells more sensitive to Bcl-2 inhibition by Ven. This work provides, for the first time, a proof of concept of the efficacy of dual targeting of PI3K-δ/γ and Bcl-2 in RS and providing an opening for a Duv/Ven combination for these patients. Clinical studies in aggressive lymphomas, including RS, are under way. This trial was registered at www.clinicaltrials.gov as #NCT03892044.

Somatic missense mutations of BTG1 are exclusive to germinal center (GC)-derived B cell lymphomas (~12% of DLBCLs) and are most prevalent in ABC-DLBCL (p=0.0184 vs GCB-DLBCL), particularly in the MCD/cluster 5 subtype, which features extranodal dissemination and unfavorable outcome. However, the relevance, mechanism of action and biological contribution of BTG1 mutations have not been studied. Using a rigorous genomic covariate analysis, we identified BTG1 mutations as a top genetic driver in DLBCL. Furthermore, molecular dynamics simulations indicated that BTG1 recurrent mutations, including the most frequent Q36H, disrupted the protein structure, with likely deleterious functional consequences. To investigate the effect of BTG1 mutation in GC B cells, we generated a conditional Btg1Q36H knock in mouse crossed to the B cell specific Cd19Cre line. Surprisingly, there was no apparent phenotype in GC B cells or other B cell populations. However, placing Btg1 Q36H and WT GC B cells in competition within the same mouse through adoptive transfer revealed a dramatic competitive advantage of Btg1 Q36H cells, virtually taking over the GC reaction. To gain further insight into this striking fitness advantage, we performed RNAseq in Btg1 Q36H GCs, which showed marked enrichment for genes induced in positively selected GC B cells, including MYC targets and biosynthetic pathways. The same genes were also enriched in BTG1 mutant DLBCL patients in 2 independent cohorts. Furthermore, Btg1 Q36H GC B cells displayed greater RNA content and cell size, reflecting increased fitness. Positive selection normally triggers a brief Myc pulse in GC B cells. We therefore crossed our Btg1Q36H mice to the MycGFPprotein fusion reporter and observed higher proportion of Myc GFP+ cells in Btg1 Q36H GCs. For mechanistic studies, we generated isogenic BTG1 Q36H or BTG1 WT human DLBCL cell lines. BTG1 Q36H cells exhibited enrichment for the same positively selected GC B and MYC target genes, as well as greater RNA content and cell size. BTG1 family members were suggested to interact with RNA. Performing RNA-immunoprecipitation, we discovered that ~800 transcripts associated with BTG1 WT, but not BTG1 Q36H. Notably, these corresponded to the same positively selected GC B and MYC target genes, including MYC itself. BTG1 was shown to regulate mRNA stability in other cell types. However, BTG1 Q36H did not alter MYC mRNA stability and instead facilitated MYC protein synthesis, thus disrupting a novel GC context-specific checkpoint mechanism, whereby BTG1 normally attenuates spurious MYC translation to tightly restrict fitness potential. In GC B cells, Myc induction coincides with S phase entry, but G2/M progression requires re-entry into the proliferative dark zone. To characterize GC dynamics in vivo, we performed targeted single cell RNAseq in competing Btg1 Q36H and WT GC B cells and noted earlier and higher proportion of positively selected Btg1 Q36H GC B cells having committed to G2/M and the proliferative program. We confirmed faster S phase completion in competing Btg1 Q36H GC B cells by in vivo EdU/BrdU labelling and greater re-entry into the proliferative dark zone by in vivo antigen delivery to synchronize GC B cells at the time of positive selection. Given that MCD-DLBCLs express high levels of BCL2, we crossed our Btg1Q36H mice to the VavP-Bcl2 model. As compared to VavP-Bcl2, VavP-Bcl2+Btg1 Q36H mice displayed shorter survival (p=0.0005), earlier onset of lymphoma, dysplastic B cell infiltration into non lymphoid organs and they contained highly mutated, selected and clonal tumor B cells. Moribund VavP-Bcl2+Btg1 Q36H mice uniquely featured sheets of large, immunoblastic lymphoma cells, characteristic of ABC-DLBCLs. Most notably, examining ABC-DLBCLs from 5 independent cohorts showed inferior clinical outcome for BTG1 mutant patients (p=0.0011) and independent association of BTG1 mutation with inferior overall survival by multivariable Cox regression (p=0.0190). Collectively, we find that BTG1 mutations mediate lymphomagenesis through an entirely novel mechanism of action that recapitulates the embryonic MYC-dependent "super-competitive" phenotype originally described in Drosophila imaginal disc cells. In the GC, "super-competition" is provided by BTG1 mutation via a subtle acceleration of MYC induction and GC dynamics, conferring dramatic fitness and the potential to transform into aggressive lymphomas. Disclosures Hoehn: Prellis Biologics: Consultancy. Elemento: Janssen: Research Funding; Freenome: Consultancy, Other: Current equity holder in a privately-held company; Volastra Therapeutics: Consultancy, Other: Current equity holder, Research Funding; Owkin: Consultancy, Other: Current equity holder; Champions Oncology: Consultancy; One Three Biotech: Consultancy, Other: Current equity holder; Eli Lilly: Research Funding; AstraZeneca: Research Funding; Johnson and Johnson: Research Funding. Scott: NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling.; BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling--licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling. ; AstraZeneca: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Research Funding; Rich/Genentech: Research Funding. Melnick: Constellation: Consultancy; Epizyme: Consultancy; Daiichi Sankyo: Research Funding; Sanofi: Research Funding; Janssen Pharmaceuticals: Research Funding; KDAC Pharma: Membership on an entity's Board of Directors or advisory committees.

Introduction: AIDS-related Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, with a variable response to chemotherapy depending on, and not limited to, cell of origin, double/triple hit, or MYC/BCL-2 co-expression status. Similar to DLBCL, AIDS-related DLBCL (ARL) with non-germinal center histology or MYC expression reports poorer response to treatment. In the immunocompetent population CD30+ DLBCL defines a histology with improved survival, however, the characteristics and outcomes of ARL expressing CD30 are not well studied. Methods: We assessed 3 cohorts of ARL. The first cohort, consisted of of an immunohistochemistry tissue microarray (TMA) of 30 ARL patients, followed by two validation cohorts. The first validation was a TMA of 80 ARL, from the AIDS Cancer Specimen Resource. Both TMAs were stained for CD10, BCL6, MUM1, CD20, Ki67, EBER, MYC (by IHC) cut off at 40%, BCL2 (by IHC) cut off 50%, and CD30 (considered positive if any CD30 was expressed on the malignant cells). The third validation cohort was from the County Hospital AIDS Malignancy Project (CHAMP), a prospective database of patients with hematological malignancies and HIV. Of the 100 cases with ARL, only 25 cases were found to have CD30 staining performed, thus only those cases were included. In total, 135 patients diagnosed with ARL were assessed. Cell of origin and germinal (GCB) vs. non-germinal center (NGC) was determined by the Hans algorithm. Statistical differences between groups were analyzed by the fisher exact test. Survival data, when available, was estimated using the Kaplan-Meier method and compared using the log-rank test. Results: Of the 135 ARL, 30% (n=41) were CD30+. Ninety-one% of the cohort was male. EBER was 23% positive in the entire cohort (n=29/126). EBER was positive in the CD30+ vs. CD30- population, 59% (N=17) vs 26% (p 80% was also higher in the CD30- vs the CD30+ cohort 75 vs.60%, (p=0.052). Myc, BCL2, and double expressor lymphomas were identified 59 vs. 57%, 59 vs. 57%, and 31 vs. 28%, respectively, in the CD30+ ARL vs. the CD30- population, none were statistically significant. Survival data was only obtained for 56 of the patients. In the patients treated in the combined anti-retroviral era (ART), there was no difference in survival in the CD30+ vs. CD30- population, 74% (n=18) vs. 84% (n=12) at 5 years (p=0.8). In the 15 patients treated in the early ART era, the OS at 5 years was 48% for the CD30+ vs. 52% (p=0.4), the rest were treated in the pre-ART era. Conclusion: CD30+ ARL in this cohort represents 30% of all ARL evaluated, and presents almost exclusively as a non-germinal center phenotype and has a strong correlation with EBV. While no differences in survival were identified in this study, possible due to the small numbers of patients assessed with survival data, historically, NGC ARL have been shown to have poorer outcomes, by 20-30% in studies with da-EPOCH. As such, the need for better therapies, potentially to overcome these poor prognostic factors, should be studied further. Figure 1 Figure 1. Disclosures Reid: ADC Therapeutics: Other: Serves as Principle Investigator, Research Funding; Aptose Biosciences: Other: Serves as Principle Investigator, Research Funding; Millennium Pharmaceuticals: Other: Serves as Principle Investigator, Research Funding; Xencor: Other: Serves as Principle Investigator.

Introduction ALK-negative anaplastic large cell lymphoma (ALK- ALCL) is an uncommon type of T-cell non-Hodgkin lymphoma (T-NHL) with worse prognosis compared to ALK-positive (ALK+) ALCLs. Most published studies on the genomics of T-NHL have focused on peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and previous studies of ALCL described rearrangements in DUSP22 and TP63 and mutations in genes comprising the JAK/STAT pathway as common genetic drivers in ALK- ALCL. The degree to which these drivers affect survival or other molecular features of ALK- ALCL remains unknown. Here, we describe novel subgroups of ALK- ALCL that exhibit distinct survival. One subgroup appears molecularly similar to ALK+ALCLs and is associated with favorable survival while the second subgroup is quite distinct from ALK- ALCLs and associated with poor outcomes. Methods and Results Eighty-two ALK- ALCL patients were recruited to the Atlas of Blood Cancer (ABC) genomes project, a worldwide consortium established to define the molecular origins of blood cancers. Tumor biopsies from these patients, as well as 10 ALK+ ALCL samples for comparison were obtained from participating institutions. Each case was subjected to centralized pathology review by an experienced panel of hematopathologists to ensure the accuracy of the diagnosis. All cases, along with paired normal tissues, were subjected to DNA and RNA (whole exome-level) sequencing on the Illumina platform to identify mutations and expression changes for each of these cases using methods well established in our group and described previously. We first examined the genetic alterations in ALK- ALCLs. In addition to frequently described genetic alterations such as TP63 and DUSP22 rearrangements, as well as mutations in JAK1, STAT3 and TP53, we also detected mutations in ERBB4, SETD2 and KMT2D, which may serve as potential novel drivers and have not been described previously to our knowledge. We next performed comparative gene expression analysis of the ALK- and ALK+ ALCLs. Surprisingly, a proportion of ALK- ALCL cases (38%) clustered together with ALK+ ALCLs and had a signature resembling ALK+ cases, which we designated as "ALK-like ALCL" here. Both the ALK-like ALCLs and the other ALK- ALCL cases showed decreased ALK expression compared to the ALK+ ALCLs by gene expression analysis. These results point to downstream pathways that are common among ALK+ALCLs and ALK-like ALCLs, but different from the other ALK- ALCLs. Gene set enrichment analysis revealed that the ALK-like ALCLs overexpressed genes in pathways related to monocyte and fibroblast activation, whereas the remaining ALK- ALCLs overexpressed genes in the T follicular helper cells, memory T cells and adaptive immune response-related pathways (P Conclusion Our data indicate that ALK- ALCLs represent a heterogeneous group of diseases and comprise at least two distinct subgroups that can be identified based on their similarity to the ALK+ ALCLs. The ALK-like ALCLs demonstrated distinct molecular features and favorable outcomes. Our results provide a potentially new approach to patient risk-stratification and pathological classification of this disease. Disclosures Kwong: Celgene: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Jaye: Stemline Therapeutics: Honoraria. Behdad: Roche/Foundation Medicine: Speakers Bureau; Thermo Fisher: Speakers Bureau; Lilly: Speakers Bureau. Hsi: AbbVie Inc, Eli Lilly: Research Funding. Dave: Data Driven Bioscience: Current equity holder in publicly-traded company.

Introduction Blood cancers are collectively common and strikingly heterogeneous diseases both clinically and molecularly. According to the WHO taxonomy, there are over 100 distinct myeloid and lymphoid neoplasms. Genomic profiling of blood cancers has been applied in a somewhat ad hoc fashion using diverse sequencing approaches including the use of targeted panels, whole exome sequencing, whole genome sequencing, RNA sequencing, etc. The lack of data uniformity has made it difficult to comprehensively understand the clinical and molecular spectrum within and across diseases. Systematic genomic approaches can address the central challenges in the diagnosis and treatment of blood cancers. For the diagnosis of blood cancers, the incorporation of genomics could greatly enhance the accuracy and speed of clinical diagnostics. Genomics could also inform their pathology classification. However, these applications must be preceded by a clear understanding of the particular genetic aberrations and expression profiles that unite and distinguish different leukemias and lymphomas. Therapeutic development can also be aided by genomic approaches through identification of new targets and establishing the relevance of existing targets and treatments. Targeted therapies including those directed at specific surface markers (e.g. CD19, CD30 and CD123) or molecular targets (e.g. BCR-ABL fusions, IDH1 mutations and EZH2 mutations) are rarely restricted to a single disease, with most occurring in multiple blood cancers. A systematic understanding of the presence or overlap of these targets within or across blood cancers would significantly expand the therapeutic possibilities and better enable the use of existing therapies in both common and rare cancers. However, such therapeutic possibilities need to be established through a rigorous, data-driven approach. We initiated the Atlas of Blood Cancers Genomes (ABCG) project to systematically elucidate the molecular basis of all leukemias and lymphomas by building upon advances in genomic technologies, our capabilities for data analysis and economies of scale. Using a uniform approach to systematically profile all blood cancers through DNA and RNA sequencing at the whole exome/whole transcriptome level, we aim to link genomic events with clinical outcomes, disease categories and subcategories, thereby providing a complete molecular blueprint of blood cancers. Methods/Results The ABCG project consists of collaborators from 25 institutions around the world who have collectively contributed samples from 10,481 patients comprising every type of blood cancer in the current WHO classification. The samples include thousands of myeloid leukemias and mature B cell lymphomas, hundreds of Hodgkin lymphoma and plasma cell myeloma, as well as every rare type of hematologic malignancy (along with case-matched normal tissue). All cases were de-identified and their associated pathology and detailed clinical information entered into a purpose-built web-based system that included disease-specific data templates. All cases were subjected to centralized pathology review and clinical data review by experienced hematopathologists and oncologists. All 10,481cases are being sequenced at the DNA and RNA level, and are being profiled to define the genetic alterations and expression changes that are characteristic of each disease. Analysis will include translocations, copy number alterations, and viral status. These molecular features will be examined in conjunction with genetic events, pathologic factors, and the clinical features. We have already generated results for ALK-negative anaplastic large B cell lymphoma and primary mediastinal B cell lymphomas (N=210). These data demonstrate novel subgroup and molecular discoveries that are enabled by integrative DNA and RNA sequencing analysis and the examination of molecular features across different diseases as well as within individual entities. In addition, other disease entities and the collective data will be presented in the meeting. Conclusion The ABCG project will comprehensively study the genetic and clinicopathological features of all blood cancers using systematic genomic approaches. We anticipate our data, approaches and results will serve as a lasting resource for the molecular classification and therapeutic development for leukemias and lymphomas. Disclosures McKinney: Novartis: Research Funding; Nordic Nanovector: Research Funding; Molecular Templates: Consultancy, Research Funding; Kite/Gilead: Honoraria, Speakers Bureau; Incyte: Research Funding; Genetech: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy; Celgene: Consultancy, Research Funding; BTG: Consultancy; Beigene: Research Funding; ADC Therapeutics: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy; Verastem: Consultancy. Behdad: Lilly: Speakers Bureau; Roche/Foundation Medicine: Speakers Bureau; Thermo Fisher: Speakers Bureau.

Introduction: Primary mediastinal large B-cell lymphoma (PMBL) is a rare non-Hodgkin lymphoma subtype that occurs predominantly in young adults, with an overall favorable prognosis. The cell of origin is presumed to be thymic medullary B-cells and the gene expression profile of PMBL is similar to classic Hodgkin lymphoma. Recent studies have begun unravelling the genomic alterations underlying PMBL. Frequent, recurrent mutations (e.g. B2M, TNFAIP3, SOCS1, STAT6, GNA13) have been reported, but most of the studies have analyzed a small number of cases. To gain further insights into disease biology, we recruited 63 cases of PMBL as part of the Atlas of Blood Cancer Genomes (ABC-G) initiative, a consortium consisting of 25 institutions. Methods: Formalin-fixed paraffin-embedded (FFPE) biopsies and clinical data were collected. All cases were subjected to centralized review by an experienced panel of hematopathologists to ensure accurate diagnosis. Whole-exome DNA and RNA sequencing was performed using the Illumina platform and the DNA and RNA reads aligned to the GRCh38 genome and transcriptome respectively. Exonic variants were filtered using a set of paired normal samples and population-based databases to identify putative driver mutations, which were then aggregated at the gene level. Mutational analysis was performed on 56 samples that passed quality filtering and expression analysis on 45 samples. RNAseq data was normalized using DESeq2. Results: The cohort included samples from 16 males and 24 females, with a median age of 33 years (range 16 - 72) at the time of diagnosis. The majority of patients were treated with R-CHOP (47%) or R-EPOCH (43%), with 93% of patients surviving through the end of follow-up (median follow-up: 60.1 months). Besides the known recurrent mutations involving the JAK-STAT (STAT6 -21%, SOCS1 - 26%), NFKB (TNFAIP3 - 27%, NFKB1A - 7%), immune escape (B2M - 20%, LTB - 11%, IRF8 - 9%, IRF4 -9%), and chromatin modification (ZNF217 - 16%, CREBBP - 11%, KMT2D -11%) pathways , we discovered recurrent somatic variants in novel candidate driver genes in this disease, including NOTCH4 (7%), DICER1 (11%), MCL1 (7%), amongst others. EZH2, EP300, and XPO1 mutations were not detected. CIITA mutations and fusions were observed in 14% and 11% of cases, respectively, with novel partner genes (IGHA2, IGHG1, CDC6) detected in 67% of the fusion positive cases. Copy number alterations included gains at 2p16.1 (REL - 20%) and 9p24.2 (JAK2/PDL1/PDL2 - 24%), as well as loci not previously implicated in PMBL, 8q24.3 and 9q34.3 (each in 20%). Of note, CIITA alterations and 9p24 gains were virtually mutually exclusive, highlighting diverse mechanisms of immune escape in this entity. The transcriptomes of cases harboring CIITA alterations demonstrated differential enrichment of genes involved in protein glycosylation. The PMBLs in our series showed significant enrichment of the reported PMBL genetic classifier score, compared to nodal diffuse large B cell lymphoma (DLBCL) (p=0.0003). Finally, the gene expression profile of thymic B cells was more similar to that of PMBL than nodal DLBCL (p=0.0144). Conclusions: Our study, representing one of the largest comprehensive genomic and transcriptomic analyses of PMBL, expands the mutational landscape of PMBL, provides evidence for biologically distinct disease subsets and suggests an origin of PMBLs from thymic B-cells. Disclosures Hsi: AbbVie: Research Funding; Eli Lilly: Research Funding; Cytomx: Honoraria; Seattle Genetics: Honoraria. McKinney: BTG: Consultancy; Celgene: Consultancy, Research Funding; Epizyme: Consultancy; Genetech: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria, Speakers Bureau; Molecular Templates: Consultancy, Research Funding; Nordic Nanovector: Research Funding; Novartis: Research Funding; Pharmacyclics: Consultancy; Verastem: Consultancy; Beigene: Research Funding; ADC Therapeutics: Consultancy, Speakers Bureau. Jaye: Stemline Therapeutics: Honoraria. Cohen: Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding; Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy. Behdad: Lilly: Speakers Bureau; Roche/Foundation Medicine: Speakers Bureau; Thermo Fisher: Speakers Bureau. Dave: Data Driven Bioscience: Current equity holder in publicly-traded company.

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8–negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti–interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

Human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.

EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is a preferred regimen for HIV-non-Hodgkin lymphomas (HIV-NHLs), which are frequently Epstein-Barr virus (EBV) positive or human herpesvirus type-8 (HHV-8) positive. The histone deacetylase (HDAC) inhibitor vorinostat disrupts EBV/HHV-8 latency, enhances chemotherapy-induced cell death, and may clear HIV reservoirs. We performed a randomized phase 2 study in 90 patients (45 per study arm) with aggressive HIV-NHLs, using dose-adjusted EPOCH (plus rituximab if CD20+), alone or with 300 mg vorinostat, administered on days 1 to 5 of each cycle. Up to 1 prior cycle of systemic chemotherapy was allowed. The primary end point was complete response (CR). In 86 evaluable patients with diffuse large B-cell lymphoma (DLBCL; n = 61), plasmablastic lymphoma (n = 15), primary effusion lymphoma (n = 7), unclassifiable B-cell NHL (n = 2), and Burkitt lymphoma (n = 1), CR rates were 74% vs 68% for EPOCH vs EPOCH-vorinostat (P = .72). Patients with a CD4+ count

Castleman disease (CD) describes a spectrum of heterogeneous disorders defined by characteristic lymph node histopathology. Enlarged lymph nodes demonstrating CD histopathology can occur in isolation (unicentric CD; UCD) sometimes accompanied by mild symptoms, or at multiple sites (multicentric CD, MCD) with systemic inflammation and cytokine-driven multi-organ dysfunction. The discovery that Kaposi sarcoma herpesvirus/human herpesvirus (HHV)-8 drives MCD in a subset of patients has led to the hypotheses that UCD and MCD patients with negative HHV-8 testing by conventional methods may represent false negatives, or that these cases are driven by another virus, known or unknown. To investigate these hypotheses, the virome capture sequencing for vertebrate viruses (VirCapSeq-VERT) platform was employed to detect RNA transcripts from known and novel viruses in fresh frozen lymph node tissue from CD patients (12 UCD, 11 HHV-8-negative MCD [idiopathic MCD; iMCD], and two HHV-8-positive MCD) and related diseases (three T cell lymphoma and three Hodgkin lymphoma). This assay detected HHV-8 in both HHV-8-positive cases; however, HHV-8 was not found in clinically HHV-8-negative iMCD or UCD cases. Additionally, no novel viruses were discovered, and no single known virus was detected with apparent association to HHV-8-negative CD cases. Herpesviridae family members, notably including Epstein-Barr virus (EBV), were detected in 7 out of 12 UCD and 5 of 11 iMCD cases with apparent correlations with markers of disease severity in iMCD. Analysis of a separate cohort of archival formalin-fixed, paraffin-embedded lymph node tissue by In situ hybridization revealed significantly fewer EBV-positive cells in UCD and iMCD compared to tissue from HHV-8-positive MCD and EBV-associated lymphoproliferative disorder. In an additional cohort, quantitative testing for EBV by PCR in peripheral blood during disease flare did not detect systemic EBV viremia, suggesting detection lymph node tissue is due to occult, local reactivation in UCD and iMCD. This study confirms that HHV-8 is not present in UCD and iMCD patients. Further, it fails to establish a clear association between any single virus, novel or known, and CD in HHV-8-negative cases. Given that distinct forms of CD exist with viral and non-viral etiological drivers, CD should be considered a group of distinct and separate diseases with heterogeneous causes worthy of further study.

Immunodeficiency-associated lymphoproliferative disorders (IA-LPDs) are pathologically and clinically heterogeneous. In many instances, similar features are shared by a spectrum of IA-LPDs in clinically diverse settings. However, the World Health Organization (WHO) classifies IA-LPDs by their immunodeficiency setting largely according to the paradigm of posttransplant lymphoproliferative disorders but with inconsistent terminology and disease definitions. The field currently lacks standardization and would greatly benefit from thinking across immunodeficiency categories by adopting a common working vocabulary to better understand these disorders and guide clinical management. We propose a 3-part unifying nomenclature that includes the name of the lesion, associated virus, and the specific immunodeficiency setting for all IA-LPDs. B-cell lymphoproliferative disorders (LPDs) are usually Epstein-Barr virus (EBV)+ and show a spectrum of lesions, including hyperplasias, polymorphic LPDs, aggressive lymphomas, and, rarely, indolent lymphomas. Human herpes virus 8–associated LPDs also include polyclonal and monoclonal proliferations. EBV− B-cell LPDs and T- and NK-cell LPDs are rare and less well characterized. Recognition of any immunodeficiency is important because it impacts the choice of treatment options. There is an urgent need for reappraisal of IA-LPDs because a common framework will facilitate meaningful biological insights and pave the way for future work in the field.

Classical Hodgkin lymphoma (cHL) is characterized by sparsely distributed Hodgkin and Reed-Sternberg (HRS) cells amid reactive host background, complicating the acquisition of neoplastic DNA without extensive background contamination. We overcame this limitation by using flow-sorted HRS and intratumor T cells and optimized low-input exome sequencing of 10 patient samples to reveal alterations in genes involved in antigen presentation, chromosome integrity, transcriptional regulation, and ubiquitination. β-2-microglobulin (B2M) is the most commonly altered gene in HRS cells, with 7 of 10 cases having inactivating mutations that lead to loss of major histocompatibility complex class I (MHC-I) expression. Enforced wild-type B2M expression in a cHL cell line restored MHC-I expression. In an extended cohort of 145 patients, the absence of B2M protein in the HRS cells was associated with lower stage of disease, younger age at diagnosis, and better overall and progression-free survival. B2M-deficient cases encompassed most of the nodular sclerosis subtype cases and only a minority of mixed cellularity cases, suggesting that B2M deficiency determines the tumor microenvironment and may define a major subset of cHL that has more uniform clinical and morphologic features. In addition, we report previously unknown genetic alterations that may render selected patients sensitive to specific targeted therapies.

Ribavirin, an antiviral drug used to treat infections including respiratory syncytial virus (RSV), interferes with the function of the eukaryotic translation initiation factor 4E (eIF4E) [1]. EIF4E...

In β-thalassemia, the mechanism driving ineffective erythropoiesis (IE) is insufficiently understood. We analyzed mice affected by β-thalassemia and observed, unexpectedly, a relatively small increase in apoptosis of their erythroid cells compared with healthy mice. Therefore, we sought to determine whether IE could also be characterized by limited erythroid cell differentiation. In thalassemic mice, we observed that a greater than normal percentage of erythroid cells was in S-phase, exhibiting an erythroblast-like morphology. Thalassemic cells were associated with expression of cell cycle–promoting genes such as EpoR, Jak2, Cyclin-A, Cdk2, and Ki-67 and the antiapoptotic protein Bcl-XL. The cells also differentiated less than normal erythroid ones in vitro. To investigate whether Jak2 could be responsible for the limited cell differentiation, we administered a Jak2 inhibitor, TG101209, to healthy and thalassemic mice. Exposure to TG101209 dramatically decreased the spleen size but also affected anemia. Although our data do not exclude a role for apoptosis in IE, we propose that expansion of the erythroid pool followed by limited cell differentiation exacerbates IE in thalassemia. In addition, these results suggest that use of Jak2 inhibitors has the potential to profoundly change the management of this disorder.

ROR1 is a transmembrane receptor with tightly controlled expression during development. It is present on multiple tumor types but not on normal adult tissues. Hematological malignancies are often ROR1-positive, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and diffuse large B cell lymphoma (DLBCL). Given its unique pattern of expression, ROR1 represents a tumor-specific therapeutic target. The anti-ROR1 antibody, UC-961, is ahumanized IgG1 monoclonal antibody (mAb) that binds with high affinity to a specific extracellular epitope of human ROR1 receptor and can block Wnt5a-induced ROR1 signaling. Nonclinical studies document that UC-961 does not react with normal adult human tissues and selectively binds to tumor cells. Because of the antibody high specificity, rapid internalization, and trafficking to lysosomes, UC-961 appears ideally suited to serve as the targeting moiety for an anti-ROR1 ADC. Accordingly, we have developed VLS-101, a UC-961-linker-monomethyl auristatin E (MMAE) ADC that preserves the high-affinity binding and specificity of UC-961 and allows for ROR1-targeted intracellular release of MMAE. RS is an aggressive lymphoma, typically of DLBCL type, arising as transformation of CLL. Despite, progressive improvements in the therapy of CLL, very few effective treatment options exist for patients with RS. Using our recently established RS patient-derived xenografts (RS-PDXs), we explored the expression and signaling properties of ROR1 in RS and investigated the ex-vivo and in vivo effects of VLS-101. When assessed by flow cytometry (FACS), immunohistochemistry (IHC), and reverse-transcriptase-polymerase chain reaction (RT-PCR), 3 of 4 RS-PDXs showed ROR1 positivity (2 highly positive: 99% and 80% of cells; 1 medium/low positive: 25% of cells by FACS). The extent of ROR1 expression correlated among the 3 assays methods and was consistent with ROR1 expression data reported for non-RS DLBCL samples. When engaged by its ligand Wnt-5a, ROR1 activated downstream targets, Rac1 and RhoA, and induced phosphorylation of the p65 subunit of NF-kB and Jnk in RS cells. When cells purified from RS-PDX tumor masses were exposed to VLS-101 ex-vivo, the drug induced time- and dose-dependent apoptosis, as shown by increases in annexin V/propidium iodide and by Caspase-3 and PARP cleavage. VLS-101 efficacy was then assessed in vivo in both subcutaneous and systemic RS-PDX models. When palpable masses had formed in subcutaneous models, mice were randomly assigned to vehicle or VLS-101, bi-weekly treated for 3 consecutive weeks, and then compared for tumor growth and survival. In the 3 ROR1-expressing RS-PDX models, VLS-101 caused highly significant disease regressions. Complete regressions were observed even in RS-PDXs without universal ROR1 expression, suggesting a MMAE bystander effect. After treatment discontinuation, VLS-101-treated animals showed no tumor regrowth for several months and had significantly extended survival. Data were confirmed in systemic ROR1-expressing RS models in which tumor cells were intravenously injected and allowed to engraft for ~14 days before starting treatment. VLS-101 was administered with the same schedule adopted for the subcutaneous model. VLS-101 eliminated RS cells in bone marrow, peripheral blood, and spleen, increasing survival in VLS-101-treated animals relative to controls (approximately 20-50 days, depending on the RS-PDX model). Of note, no in vivo VLS-101 efficacy was observed in the ROR1-negative RS-PDX, confirming the specificity of VLS-101 targeting. VLS-101 showed no adverse effects on animal well-being or body weight. Collectively, these results indicate that ROR1 is expressed on RS cells where it can transduce pro-survival signals and can be diagnostically evaluated for selective targeting. Nonclinical data document that the MMAE-containing ADC, VLS-101, can cause RS-PDX apoptosis in vitro and can safely and selectively induce complete tumor regressions in in vivo models of RS derived from patient tumors with heavy prior clinical treatment and variable levels of ROR1 expression. Building on these types of results, a Phase 1 clinical trial of VLS-101 (NCT03833180) is ongoing in patients with lymphoid cancers. Disclosures Vaisitti: VelosBio Inc.: Research Funding; Verastem Inc: Research Funding. Jessen:VelosBio Inc.: Employment. Vo:VelosBio Inc: Employment. Ko:VelosBio Inc: Employment. Allan:Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Acerta Pharma: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Bayer: Consultancy. Furman:Acerta Pharma: Consultancy; Pharmacyclics: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy; Incyte: Consultancy; Oncotracker: Consultancy; Verastem: Consultancy; Abbvie: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy. Miller:VelosBio Inc.: Employment. Lanutti:VelosBio Inc.: Employment. Deaglio:iTeos Therapeutics: Research Funding; Verastem Inc: Research Funding; VelosBio Inc.: Research Funding. OffLabel Disclosure: The drug used in this project is an anti-ROR1-toxin-conjugated antibody

Background The B cell receptor (BCR) is a signaling complex composed of surface immunoglobulin and heterodimer subunits, Igα (CD79a) and Igβ (CD79b) (Sanchez, et al. 1993). Chronic lymphocytic leukemia (CLL) demonstrates dim surface staining of CD79b compared to normal B cells or other B cell malignancies, in part due to overexpression of a splice variant that lacks coding for the extracellular domain (Alfarano, et al. 1999; Cabezudo, et al. 1999). Aggressive lymphomas, like diffuse large B cell lymphomas of non-germinal center origin (DLBCL-ABC), overexpress surface CD79b and can harbor gain of function mutations (Schmitz, et al. 2018). Richter's transformation (RT), a complication of CLL is defined by transformation to a DLBCL-ABC subtype most commonly. Upon transformation outcomes are poor and survival is short with standard therapeutic approaches. Polatuzumab vedotin (Pv), an antibody drug conjugate, targets CD79b on the surface and has obtained FDA approval for relapsed DLBCL in combination with bendamustine and rituximab. Targeting CD79b may represent an attractive therapeutic strategy for patients (pts) with RT. To this end we sought to characterize CD79b expression in RT. Methods Pts with CLL or RT and available paraffin embedded tissue blocks were identified in coordination with Weill Cornell Medicine's (WCM) pathology department. Clone AT107-2 (Bio-Rad, USA) which targets an intracellular epitope was used to stain for CD79b in formalin fixed paraffin embedded (FFPE) tissue sections after optimization following institutional staining procedures. CD79b was classified as either positive (pos) or negative (neg) based on staining pattern and intensity as deemed by a board certified hematopathologist. RT pt derived xenografts (RT-PDXs) were assessed for surface expression of CD79b via flow cytometry. Nonpermabilized cells derived from RT-PDXs were stained using an anti-human CD79b-FITC conjugated antibody (clone CD3-1, Southern Biotech, USA). Mean fluorescence intensity (MFI) was established. RNA seq data was obtained from 2 of 3 RT-PDX models and has been reported previously (Vaisitti, et al. 2018). CD79b transcripts per million (TPM) were analyzed and compared to that of normal lymph node (LN) tissue deposited in the Human Protein Atlas RNA Seq database (HPA-RNA Seq). GraphPad Prism 8.0 was used to perform statistical analysis. Results Nineteen pts with RT and 5 pts with CLL were identified for the study. Median age at diagnosis of the 19 RT pts was 71 years compared to 67 years for the 5 CLL pts. Five RT pts (26%) were treatment naïve (TN) at time of RT. Ten (53%) RT pts transformed on targeted therapy, 6 on BTK inhibitors, 2 on IMiD based therapy, 2 on venetoclax. CD79b stained pos for 16 RT pts (84%) and all 5 (100%) CLL pts. We were not able to identify any correlations between CD79b expression due to low numbers of neg cases. Surface expression of CD79b was evaluated on RT-PDX models from different passages and found to be pos in all 3 models with a median percentage of CD79b+ cells of 45.9% (range 34.6-76%). The median MFI was 2028.5 (range MFI 860-4289). Two of the 3 three models had bimodal populations of cells (pos and neg) whereas the third model was more uniformly pos. RNA seq data from 2 RT-PDX models was available and compared to RNA-seq data from normal LN tissue deposited in the HPA-RNA Seq database. The mean TPM of CD79b for RT-PDX cases was 837.5 compared to 311.5 for normal LN tissue, p=0.028. Conclusion CD79b expression was pos in 84% of FFPE primary RT specimens evaluated. We were able to confirm extracellular CD79b expression with flow cytometry in all 3 RT-PDX models with a median MFI of 2028.5. Surface expression was found to be bimodal in 2 models and uniformly pos in 1 model suggesting tumor heterogeneity. Rna-seq data from RT-PDX models demonstrated higher TPM values in RT-PDX samples compared to normal LN tissue. We conclude that RT expresses CD79b at sufficient levels despite deriving from a CLL cell that historically has demonstrated low surface CD79b expression. Further studies will be undertaken characterizing pos and neg cellular populations focusing on mechanisms of expression and potential differences in splice variant expression. Disclosures Allan: Pharmacyclics LLC, an AbbVie company: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Consultancy; Janssen: Consultancy, Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vaisitti:Verastem Inc: Research Funding; VelosBio Inc.: Research Funding. Joyce:Genentech: Employment. Schulz:Genentech, Inc.: Employment; Roche: Equity Ownership. Deaglio:Verastem Inc: Research Funding; iTeos Therapeutics: Research Funding; VelosBio Inc.: Research Funding. Furman:Genentech: Consultancy.

Follicular Lymphoma (FL) is the most common indolent lymphoma derived from light zone germinal center B cells and characterized by a t(14;18) translocation resulting in upregulation of BCL2 in over 80% of cases. This translocation alone is not sufficient for tumorogenesis, and must be combined with additional genetic mutations to transform B cells. FL is incurable and the disease course can be highly varied, with survival ranging from a few months to decades following diagnosis and treatment with standard chemoimmunotherapy. The heterogeneity of FL poses major challenges to identifying the association of genetic alterations and clinical outcome. Current WHO guidelines recommend establishing grade for each FL case with grade 3 thought to be more aggressive than 1 and 2. The genetic basis and clinical implications of grade in FL are unclear. Recent sequencing studies have identified many genes found to be recurrently mutated in FL including KMT2D and CREBBP. However, the degree to which genetic alterations cooperate with each other or contribute to clinical outcome is unclear. Based on the observed mutational rates in follicular lymphoma, we estimated 900 cases were needed to comprehensively delineate the genetic alterations that underlie histologic grade and clinical outcome. Accordingly, we enrolled a cohort of 1042 patients with newly diagnosed FL. All treated patients received rituximab-containing standard regimens. To go beyond the identification of gene-coding events, we developed a very large panel of 110 Mbp covering exonic (~40Mbp) and non-exonic regions (~70Mbp) of interest to enable a wide range of genomic analysis including mutation calling in both coding and non-coding regions, rearrangement detection, viral identification, and copy number analysis. In addition to the whole exome, we extended coverage to include introns, promoters, and untranslated regions of all known driver genes in cancer. We included the entirety of the immunoglobulin loci, T-cell receptor loci and CD3 loci to detect clonotypes and rearrangements. We also included lymphoma-relevant long non-coding RNAs, microRNAs, enhancers, and breakpoint-prone regions. For viral detection, we targeted the genomes of eight cancer-related viruses: Epstein-Barr virus, human papillomavirus, human immunodeficiency virus, hepatitis B, hepatitis C, Kaposi's sarcoma-associated herpesvirus, human T-lymphotropic virus, and Merkel cell polyomavirus. In addition, to enable high resolution identification of copy number variation (CNV) calls, the entire genome was tiled with probes spaced 10kb apart. DNA and RNA were extracted from all tumors and their paired normal samples, prepared into DNA and RNA sequencing libraries and subjected to sequencing on the Illumina platform to a targeted coverage of 150X. Somatic events were identified and further filtered to identify driver events in both coding and non-coding regions. FLs demonstrated a significant degree of genetic heterogeneity with over 100 genes mutated with a frequency of at least 2%. Nearly 100% of FL cases had a mutation in at least one chromatin-modifying gene. The most frequently mutated genes in follicular lymphoma were KMT2D, BCL2, IGLL5 and CREBBP. In addition, we identified frequent mutations in SPEN, BIRC6 and SETD2. To our knowledge, this is the first description of alterations in these genes in FL. Transcriptome analysis indicated a strong correlation between BIRC6 mutations and the previously described immune response 2 signature that is associated with a poor prognosis. We further performed unbiased clustering of genetic alterations in these FL cases. We identified a cluster that was specifically enriched in BCL6 and TP53 alterations and was strongly associated with grade 3 FLs which are predicted to have poorer outcomes with low intensity therapies. We further examined the genetic profiles of 1001 DLBCLs in comparison to this cohort of FLs. Our data indicate a continuum of highly overlapping genetic alterations with DLBCL displaying more complex patterns that included alterations in MYC, TP53 and CDKN2A (mainly copy number losses), indicating shared pathogenetic mechanisms underlying FL and DLBCL, particularly those germinal center B cell origin. Disclosures Koff: Burroughs Wellcome Fund: Research Funding; V Foundation: Research Funding; Lymphoma Research Foundation: Research Funding; American Association for Cancer Research: Research Funding. Leppä:Roche: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Gang:ROCHE: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hsi:Abbvie: Research Funding; Eli Lilly: Research Funding; Cleveland Clinic&Abbvie Biotherapeutics Inc: Patents & Royalties: US8,603,477 B2; Jazz: Consultancy. Flowers:AbbVie: Consultancy, Research Funding; Denovo Biopharma: Consultancy; BeiGene: Consultancy, Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Optimum Rx: Consultancy; Millenium/Takeda: Research Funding; TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Spectrum: Consultancy; Bayer: Consultancy; Acerta: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Neff:Enzyvant: Consultancy; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fedoriw:Alexion Pharmaceuticals: Other: Consultant and Speaker. Reddy:Genentech: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy; KITE Pharma: Consultancy; Abbvie: Consultancy. Mason:Sysmex: Honoraria. Behdad:Loxo-Bayer: Membership on an entity's Board of Directors or advisory committees; Thermo Fisher: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Speaker. Burton:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dave:Data Driven Bioscience: Equity Ownership.

Introduction: EPOCH-based chemotherapy is considered a preferred first-line treatment for HIV-associated diffuse large B-cell lymphoma (DLBCL) and primary effusion lymphoma in the 2019 NCCN guidelines. We previously reported that adding the HDAC inhibitor vorinostat (VOR) to EPOCH had no impact on complete response (CR) rate, the primary trial endpoint, and similar 1-year survival rates (ASCO 2018, abstract 7573). Here, we report updated results from AMC075 and evaluate the impact of a DTI ≥15 days on clinical outcomes. A DTI ≥15 days has been shown to be associated with a better prognosis in an HIV-negative population treated with R-CHOP (Maurer et al. J Clin Oncol 2018; 36:1603-1610). We also look at the impact of allowing 1 cycle of systemic therapy given prior to study enrollment in order to circumvent logistical challenges in recruiting otherwise eligible trial subjects. Methods: Between 2012 and 2017 we conducted a randomized phase II study of EPOCH (with rituximab in CD20+ tumors) ± VOR 300 mg administered on days 1-5 of each cycle with HIV antiretroviral therapy in 90 participants with aggressive HIV-NHLs. Eligible patients had at least one of the following high-risk features or tumor characteristics: Age-adjusted International Prognostic Index (aa-IPI) of 2-3, Ki-67 ≥ 80%; activated B-cell (ABC) diffuse large B-cell lymphoma(DLBCL); or any other aggressive non-germinal center (non-GCB), non-Burkitt B-cell NHL. Patients who received 1 prior cycle of chemotherapy (CHOP-like or EPOCH) +/- rituximab were allowed to register. The primary endpoint was CR rate. Secondary objectives included determining adverse events, survival rates, and the effect of EPOCH +/- VOR on HIV viral reservoirs. We performed a post-hoc analysis evaluating the impact of time from DTI ≥15 days vs. Results: Of 86 evaluable patients, 64 had DLBCL (34 GCB-type and 27 ABC-type), 15 plasmablastic lymphoma (PBL), and 7 primary effusion lymphoma (PEL) [Table 1]. Fifty-one (59%) patients were treatment naïve, whereas 35 (41%) had been pre-treated with one cycle of CHOP-like or EPOCH prior to enrollment. Grade 4 neutropenia was more frequent for VOR-EPOCH than for EPOCH (47% vs. 20%), and also grade 4 thrombocytopenia more frequent for VOR-EPOCH (29% vs 2%). The two regimens had similar rates of febrile neutropenia (18% vs. 16%). CR rates were also comparable for the two regimens (68% vs. 74%) [1-sided P=0.72] (Table 1). Median HIV plasma RNA generally decreased in both arms. No significant differences were observed in T-cell subsets or size of the latent HIV reservoir between arms. Treatment outcomes did not differ significantly across NHL subtypes or EBV status (Table 1), nor with pre-protocol systemic therapy (Table 2). Overall CR rates were 45% in patients with CD4+ counts of 50-100 cells/mm3, 63% with 100-199 cells/mm3, and 85% in patients with >200 cells/mm3(Table 1). The 3-year overall survival rates for VOR-EPOCH was 70% and for EPOCH 77% (log-rank P=0.39), and 3-year event-free survival rates were 63% vs. 69%, respectively (log-rank P=0.32) [Figure 1]. Thirty-six patients (86% of n=42) with long DTI (≥15 days) had CR, compared to only 25 (57% of n=44) with short ( Conclusion: This prospective trial demonstrated that EPOCH-based chemotherapy was broadly efficacious against aggressive HIV-NHLs, including high risk subtypes (ABC DLBCL, PBL, and PEL). However, a 5-day course of VOR given with each chemotherapy cycle failed to improve outcomes. Consistent with prior reports in HIV-uninfected patients with DLBCL, a DTI of ≥15 days was associated with better clinical outcomes than a shorter DTI. A strategy of permitting pre-protocol therapy was useful in facilitating accrual and was used in about 40% of study participants without compromising clinical outcomes. Disclosures Baiocchi: Prelude: Consultancy. Noy:Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. OffLabel Disclosure: Vorinostat is being tested in combination with chemotherapy for HIV-associated B-cell lymphoma

Background Human herpes-virus 8-negative/idiopathic multicentric Castleman disease (iMCD) is a rare inflammatory disorder involving multicentric lymphadenopathy with characteristic histopathology. Clinical presentation is heterogenous and includes cytokine-driven constitutional symptoms, cytopenias, systemic inflammation, and multi-organ dysfunction. International consensus treatment guidelines are based on a large cohort of case studies and a few clinical trials, but the available evidence is limited. Siltuximab, an anti-IL-6 therapy, is the only FDA-approved treatment for iMCD; 34% of patients achieved durable symptomatic and tumor response in the phase II trial. Tocilizumab, an anti-IL-6 receptor therapy, is frequently used off label and demonstrated promising results in an open-label study in Japan. The treatment guidelines recommend siltuximab ± corticosteroids (CS) as first-line therapy for all iMCD patients and tocilizumab as a substitute when siltuximab is not available. Rituximab, a CD20 antibody, is recommended as an alternate first-line therapy in patients who are non-severe and do not exhibit marked cytokine-driven symptoms. In all other patients, rituximab is recommended second-line; however, it has never been systematically evaluated in iMCD. Chemotherapies, immunosuppressants, and immunomodulators are recommended second- or third-line, but again, effectiveness is not well described. Better understanding of treatment effectiveness is urgently needed. Herein, we describe treatment and response in a real-world cohort of iMCD patients. Methods Data were collected and abstracted for 68 patients enrolled in an on-going IRB-approved natural history study of Castleman disease. Diagnosis is graded by an expert panel of clinicians and pathologists on an on-going basis; patients unlikely to have iMCD were excluded from analysis (N=12). Of the 56 patients included, 37 (66%) are expert panel-confirmed and 19 (34%) are awaiting confirmation. Durable response is defined as achieving ≥50% improvement in the proportion of abnormal iMCD minor clinical and laboratory diagnostic criteria sustained for ≥1 year. Small sample size prevented statistical comparisons. Results Median age at diagnosis is 33 years (range: 1-65 years). The cohort is 52.9% female, 63% white, and 4 (7%) patients died. Thirty-three unique drugs, including anti-IL-6 therapies, CS, chemotherapies, immunosuppressants, and others have been administered across the 56 patients. Rituximab is the most frequently used drug, administered to 39 (70%) patients. Siltuximab (29 patients, 52%) and tocilizumab (19 patients, 34%) are the next two most frequently used targeted therapies. There was a 52% response (15/29) to regimens inclusive of siltuximab, 50% response (9/18) to those inclusive of tocilizumab, and 25% response (9/26) to those inclusive of rituximab. Siltuximab±CS induced response in 15/24 (63%) patients, tocilizumab±CS in 4/7 (57%), and rituximab±CS in 2/13 (15%). Among the 37 expert-confirmed iMCD patients, we found a 58% response (11/19) to regimens inclusive of siltuximab, 47% (8/17) to those inclusive of tocilizumab, and 27% (7/26) to those inclusive of rituximab. Further, in these patients, siltuximab±CS induced response in 11/16 (69%), tocilizumab±CS in 3/6 (50%), and rituximab±CS in 1/6 (17%) patients. Of note, 3 of 4 deceased patients received both anti-IL-6 therapy and rituximab and all 4 received chemotherapies and immunosuppressants but did not respond to any drug. Discussion These data reveal that despite there being one FDA-approved treatment, iMCD is treated with a variety of agents. Among the full cohort, siltuximab±CS demonstrated a 63% durable response, which was higher than the response reported in the clinical trial (not statistically compared). This may reflect differences in response criteria and/or disease activity of patients in clinical trials versus real world settings. Siltuximab and tocilizumab have never been systematically compared; in this cohort they demonstrated similar response. Considering the morbidity and mortality of iMCD, these data suggest that current therapies demonstrate important activity. However, additional agents are needed for refractory patients, who have few options and are at risk of death due to disease progression. Further data are needed to compare groups and identify optimal treatment protocols. Disclosures Liu: BridgeBio Pharma: Employment, Equity Ownership. Gibson:EUSA Pharma: Employment. Kanhai:EUSA Pharma: Employment. Martin:EUSA Pharma: Employment. Srkalovic:Takeda: Speakers Bureau; Janssen: Speakers Bureau; Foundation Medicine: Speakers Bureau; EUSA Pharma: Speakers Bureau. Uldrick:Patent: Patents & Royalties: co-inventor on US Patent 10,001,483 entitled ; Celgene: Other: research support from Celgene through a CRADA at the NCI; Roche: Other: commercial research support through a CTA with Fred Hutchinson Cancer Research Center; Merck: Other: drug for a clinical trial from Merck through a CRADA with the NCI. van Rhee:Takeda: Consultancy; Sanofi Genzyme: Consultancy; Karyopharm Therapeutics: Consultancy; EUSA: Consultancy; Adicet Bio: Consultancy; Kite Pharma: Consultancy; Castleman Disease Collaborative Network: Consultancy. Fajgenbaum:Janssen Pharmaceuticals: Research Funding. OffLabel Disclosure: Tocilizumab, a monoclonal antibody directed against IL-6-receptor, is approved for use in rheumatoid arthritis in the US. It is frequently used off-label in idiopathic multicentric Castleman disease (iMCD) and is recommended as a substitute first-line therapy in the International Consensus iMCD treatment guidelines. Rituximab, a monoclonal antibody directed against CD20, is used in rheumatoid arthritis and other autoimmune and cancerous disorders. It is frequently used off-label in iMCD and is recommended as an alternate first-line or a second-line therapy in the International Consensus iMCD treatment guidelines. Corticosteroids are used broadly in iMCD and are recommended as needed as useful adjunctive therapy in the International Consensus iMCD treatment guidelines.

Introduction: Patients (pts) with HIV have a 6-fold increased risk of developing classic Hodgkin lymphoma (cHL) over the general population. The outcome of frontline therapy for HIV-associated cHL (HIV-cHL) using doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is similar to the non-HIV population. However, pts with advanced stage cHL continue to have a 30% chance of refractory/relapsed disease with ABVD. Brentuximab vedotin (BV) is an anti-CD30 antibody drug conjugate that selectively induces apoptosis of CD30+ cells. The FDA approved BV with AVD (BV-AVD) after the Echelon-1 (E1) study for advanced stage disease demonstrated improved modified progression free survival (mPFS) at 2 years compared with standard ABVD: 82% vs. 77%. Pts with HIV were excluded from both relapsed/refractory and frontline BV trials. Here we present the final results of the phase 2 trial of BV-AVD in previously untreated HIV-associated cHL, an AIDS Malignancy Consortium/LYSA collaboration (ClinicalTrials.gov ID: NCT01771107). Methods: Forty-one pts were treated on days 1 and 15 of 6, 28 day cycles, with 1.2mgs/kg of BV in combination with doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2 (AVD). Eligibility criteria included untreated cHL stage II-IV, CD4 + T-cell counts ≥50 cells/mm3, and initiation of combined antiretroviral therapy (cART) at least 1 week prior to therapy. Ritonavir, zidovidine, cobisistat, and other strong CYP3A4 or P-glycoprotein inhibitors were excluded with a washout of at least 1 week being required. Hematopoietic growth factor was mandated. The primary objective was 2 year PFS. The sample size was based on providing an estimate of the PFS with a 95% CI +/- 10% under the assumption of a 2 year progression free survival (PFS) estimate of 85%. Secondary objectives included toxicity, effects on CD4/CD8 + T-cells, HIV-1 viral load, prognostic significance of post C2 and end of treatment PET-CT. Results: Forty-one pts (93% men) were treated with a median age of 48y (range 24-67). Pts presented with stage II (17%), III (27%), and IV (56%) disease. Two year PFS estimate in the overall population (N=41) was 86% (95% CI: .74, .98). The 2-year overall survival (OS) estimate was 92% (95% CI: 0.83, 1.0) with 3 deaths at the time of analysis, including 1 which was a treatment related death (Figure 1A). For pts with advanced disease (N=34), the 2-year PFS estimate was 87% (95% CI: 0.76, 0.99) with an OS estimate of 90% (95% CI: 0.8, 1.00) (Figure 1B). Safety profiles were quite similar to the BV-AVD arm in the E1 study of the pts who received growth factor. Neuropathy was higher in our study compared to E1, (49% vs. 29% for any grade, P=0.01; 9.8% vs. 5% for G3/4, p=0.06). G3 Neutropenia was greater in AMC 085 compared to E1 BV-AVD arm with growth factor: 57% vs. 29% (p Conclusions: BV-AVD in stage II-IV HIV-cHL was efficacious although neutropenia and neuropathy were increased compared to the non-HIV population. The 2-year PFS estimate was 86% for the entire cohort and 87% for advanced stage HIV-cHL. Major interactions with strong CYP3A4 inhibitors lead to toxicity and must be avoided. The etiology of the CD4 increase is under investigation and may have implications for future therapy. Disclosures Rudek: Cullinan Apollo: Research Funding; Taiho: Research Funding; RenovoRX: Research Funding; Celgene: Research Funding. Barta:Mundipharma: Honoraria; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Noy:Medscape: Honoraria; Janssen: Consultancy; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. OffLabel Disclosure: Brentuximab Vedotin has been approved for the upfront treatment of advanced stage cHL in combination with AVD though not specifically approved for use in patients infected with HIV or stage 2 cHL.

Background: Post-transplant lymphoproliferative disorders (PTLD) are a diverse group of lymphoid neoplasms arising after solid organ (SOT) or hematopoietic stem cell transplant (HSCT). They may resemble lymphomas in immunocompetent patients (monomorphic); present as destructive, heterogeneous lesions (polymorphic); or be non-destructive but mass-forming (non-destructive, previously known as 'early lesions'). PTLDs are often associated with Epstein-Barr virus (EBV) infection or reactivation, which likely functions as a driver in these cases. Non-destructive lesions may be challenging to diagnose in the absence of EBV. However, a significant fraction of PTLDs are EBV(-), including a subset of non-destructive lesions. The pathogenesis of these remains to be fully elucidated. Human herpesvirus 6 (HHV-6) reactivation is common during transplantation, occurring in up to 70% of HSCT and 80% of SOT patients. While it has been hypothesized that HHV-6 may play a role in PTLD, particularly in EBV(-) cases, the role of HHV-6 in the pathogenesis of PTLD remains underexplored. Methods: Following IRB approval, pathology archives at Weill Cornell/New York Presbyterian Hospital were searched to identify patients with a tissue diagnosis of PTLD and correlated with clinical information. A tissue microarray was constructed from blocks with sufficient tissue. Standard immunohistochemistry (IHC) and in situ hybridization for EBV-encoded RNA (EBER) were performed, and IHC conditions were optimized for antibodies against HHV-6 gp60/110 (Millipore Sigma, MAB853) and p41 (Santa Cruz Biotechnologies, 9A5D12). Statistical comparisons utilized Student's t-test and Fisher's exact test. Results: We identified 79 patients from 6/23/94-6/6/19 with a tissue diagnosis of PTLD. Morphologic subtype could be determined in 74, including 8 patients with non-destructive lesions. Compared to monomorphic or polymorphic, patients with non-destructive PTLDs were significantly younger (median age 9, p While tissue testing failed on blocks > 20 years old, 13 PTLD cases from 12 patients had sufficient evaluable material for HHV-6 testing (Table 2). 9/12 patients had a SOT (8 renal, 1 heart) and 3 had HSCT. HHV-6 was identified in 5/13 lesions (38%), all of which were in SOT patients (Figure 1). EBER was detected in 8/13 lesions (62%). When stratified by PTLD subtype, 3/3 non-destructive PTLDs were HHV-6+ (100%). Two were EBER(-) and the remaining case only showed scattered EBER+ cells. Unfortunately, material was not available for testing the EBER+ non-destructive lesions. 2/9 of the monomorphic lesions tested (22%) were positive for both HHV-6 and EBER. While the series is limited, the association between HHV-6 and non-destructive lesions, compared to other types of PTLD, appears significant (p Conclusions: Non-destructive, monomorphic and polymorphic PTLDs show significant differences in timing, patient demographics and transplant type, suggesting that they may differ in associated risk factors affecting their pathogenesis. Confirming prior studies, we find non-destructive lesions tend to occur in younger patients, often following SOT as compared to HSCT and with a median time from transplantation of ~50 months. In addition, the presence of HHV-6 in the absence of (or with limited) EBV in the 3 non-destructive lesions tested raises the possibility that HHV-6 may play a role in the pathogenesis of this PTLD subtype that has yet to be defined. These findings are intriguing given the frequent reactivation of HHV-6 seen in transplant populations. HHV-6 has been variably associated with post-transplant complications including pneumonitis, delayed hematopoietic engraftment and graft versus host disease and thus received relatively more attention in the HSCT population. A causative role for HHV-6 in PTLD remains speculative, but these findings raise the possibility that clinicians treating the SOT population should also consider aggressively identifying and treating HHV-6 reactivation. Disclosures Rutherford: AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Heron: Consultancy, Honoraria; Janssen Scientific Affairs: Consultancy, Honoraria; Juno Therapeutics Inc: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Hepatosplenic T-cell lymphoma (HSTL) is an aggressive non-Hodgkin lymphoma, that usually presents with marked hepatosplenomegaly, systemic symptoms, and often marked thrombocytopenia. HSTL can also be associated with hemophagocytic lymphohistiocytosis. Hepatosplenic T-cell lymphoma has been called “a great clinical imitator,” because its clinical features can closely mimic other hematological and/or nonhematological disorders (acute leukemia, autoimmune disorders, systemic infections). In patients with an unusual clinical presentation, the diagnosis of HSTL can only be made by the pathologist who logically integrates the available morphological, immunohistochemical, molecular, and cytogenetic data. The treatment of HSTL is still challenging. Because of its aggressive clinical course, systemic chemotherapy and hematopoietic stem cell transplantation represent the best therapeutic approaches.

Plasmablastic lymphoma (PBL) is an aggressive CD20 negative diffuse large B cell lymphoma over-represented in patients with HIV infection. CD45 expression is weak, but immunoglobulin genes are rearranged and plasma cell markers are expressed.[1] In 1997, 95% of the cases were reported to be from HIV + patients, all with oral cavity involvement, 68% stage I. In this pre-HAART era report, 9//11 patients with follow-up died within a year of diagnosis. Most other case reports and case series have typically described poor survival for patients with PBL, particularly those infected with HIV,[2] while others were more optimistic.[3] We sought to characterize patients with PBL diagnosed and treated solely in the HAART era. We identified 12 patients with newly diagnosed PBL treated at the AIDS Malignancy Consortium (AMC) sites from 1999 to 2008. This retrospective analysis suggests these patients had better outcomes than those identified pre-HAART, perhaps due to use of aggressive chemotherapy made possible because of better supportive care and antiretroviral therapy. All AMC sites, which participated in this retrospective review were queried for cases of PBL diagnosed from 1998–2008. Two of the authors (AC and AN) reviewed the pathology reports for the criteria for plasmablastic lymphoma described in the 2008 WHO Classification.[4] Twelve cases from 9 AMC sites were included in this study. Descriptive statistics were computed for demographic and clinical characteristics. Overall survival (OS) was calculated from date of initial diagnosis to death or last follow-up. Kaplan-Meier estimates of 1-year survival were computed. All AMC sites had an Institutional Review Board waiver of authorization. Baseline clinical characteristics at study entry are presented in Table 1. The median CD4 + count at HIV diagnosis was 256 cells/uL (range 45–750) and was lower at initial PBL diagnosis with a median of 136 cells/uL (range of 2–514). Sixty-seven percent of the patients had had a prior opportunistic infection. Most (58%) of patients were not on HAART at lymphoma diagnosis, however, they had all previously taken HAART at some point. Of 7 patients not on HAART, 6 started HAART, typically at diagnosis or chemoimmunotherapy initiation. Stage at initial diagnosis was I (25%), II (25%), III (0%) and IV (50%). Four of 7 patients with extranodal disease had more than one site of involvement. Extranodal sites of disease at initial diagnosis included bone without bone marrow (4), bone marrow (1), liver (2), kidney (2), sinus (1), cerebrospinal fluid (1), colon (1), skin (1), adrenal (1), nasopharynx (1) and stomach (1). Table 1 Clinical characteristics at study entry of 12 HIV-positive patients with initial diagnosis of plasmablastic lymphoma. Surprisingly, no patients had oral involvement. LDH was elevated in 5/8 where the value was known. The International Prognostic Index could not be calculated for the group as a whole as performance status assessment data was not available in one third of the patients. Not all cases had uniform immunophenotypic data available [Table 1]. As per the definition of plasmablastic lymphoma, all 12 cases tested were negative for the B cell marker CD20. Similarly, markers of terminal B cell differentiation, CD138 and MUM-1/IFR4, were positive in 6/6 cases and in 4/4 cases tested, respectively Epstein-Barr virus (EBV) was present in 8/8 cases based on in situ hybridization (EBER). At initial diagnosis, 10/12 patients received chemotherapy, although HAART alone was attempted without success in one patient. Treatment was CHOP on a 14 day cycle (n=1) [5] or 21 day cycle (n=3), [6] (cyclophosphamide, doxorubicin, vincristine, prednisone), infusional CDE (n=1), (cyclophosphamide, doxorubicin, etoposide); [7] infusional EPOCH (n=2) (cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone),[8,9] or other (n=5). The other therapies included EPOCH with high dose methotrexate and zidovudine, either alternating (n=2), or sequential (n=2). Three patients with stage I/II disease received radiation in combination with chemotherapy. Two of the ten treated patients experienced grade 3/4 toxicity. No patient died of treatment. One patient experienced grade 3/4 fatigue, anemia, thrombocytopenia, febrile neutropenia, nausea, vomiting, diarrhea, and weight loss, and the other patient experienced renal insufficiency. Responses were complete (CR) in 7, partial (PR) in 2 and refractory in 1. CRs were seen with CHOP (n=4), EPOCH (n=2), and EPOCH alternating with high dose methotrexate and zidovudine (n=1). PRs were seen after EPOCH alternating with high dose methotrexate and zidovudine (n=2). The one patient treated with CDE had refractory disease. Overall survival is shown in Fig. 1. At a median follow up of 73 weeks (range, 40–165), the median survival was not reached. The one-year survival was 66.7% (SE, 13.6). No patients died in the follow up period after year one. Figure 1 Survival of plasmablastic lymphoma patients. We report the first case series of plasmablastic lymphoma patients, under the care of dedicated HIV malignancy oncologists in a consortium setting, diagnosed and treated exclusively in the HAART era. In this study we demonstrate relatively long disease free survival despite earlier reports showing nearly all HIV + patients with PBL were destined to die from progressive lymphoma. In the initial, pre-HAART study of PBL by Delecluse, et al.[1] 9 of the 11 patients died within 16 months of diagnosis including 3 patients with stage I disease treated with external beam radiation, poly-chemotherapy or a combination of both. In the HAART era, intensive treatment of aggressive lymphomas, such as Burkitt and diffuse large B cell lymphoma, can result in CR and long-term survival for HIV infected patients.[9–11] Cohort studies suggest that plasmablastic lymphoma has an inferior survival to Burkitt and DLBCL.[12] We demonstrate that PBL may be curable, even in patients with higher stage disease and more extranodal involvement compared to the cases described by Delecluse, et al. where the disease was primarily localized to the jaw in the majority of patients. Recently, Ibrahim et al. reported in abstract form, their single institution experience with 25 patients during the HAART era.[13] Similar to our study, only 32% were on HAART and the median CD4 + cell count was 87cells/uL. Only 76% received chemotherapy, with EPOCH being the most common treatment choice (56%), and 28% received radiotherapy. The response rate was 84% and the median OS observed in all patients who received chemotherapy was 11.6 months (range, 2–63 months). Those who were treated with EPOCH demonstrated a better median overall survival (17 months) compared to those treated with CHOP and CHOP-like regimens (7 months, p=0.04). Castillo et al. reviewed 112 cases in the literature and noted a median overall survival of 15 months with a 3 year OS of only 25%. In contrast, Cattaneo et al. reported their single institution experience of 13 patients treated during the HAART era with a 67% 3 year OS.[14] 15 patients were treated, all with CHOP or CHOP-like regiments, with involved field consolidation in seven. Five received high dose therapy with autologus stem cell transplant as first CR consolidation. The initial goal of this AMC retrospective study was to identify which first line therapy might be the most promising for HIV positive patients with plasmablastic lymphoma. The rarity of this lymphoma resulted in a very small cohort, possibly as a result of incomplete retrieval from institutional databases. In this regard, we were unable to draw specific conclusions due to the sample size, the disparate number of lymphoma regimens, and the retrospective nature of the study. However, it is notable that CR was achieved with CHOP or EPOCH based regimens. The literature on regimens more intensive than CHOP is inconsistent. Two earlier retrospective studies did not demonstrate an advantage of therapies more intensive than CHOP for PBL.[15,16] Loghavi et al. noted a series of 50 patients (20 HIV+) tended to have a better OS with CHOP than hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) (p=0.078).[17] Nonetheless, many experts do consider CHOP inadequate and favor intensive therapies including EPOCH.[18] As an aside, we cannot comment on the efficacy of HAART therapy alone, as only one patient was treated with this strategy with disease progression. In addition to intensive chemotherapy, it is probable that our patients fared better than those in the pre- HAART era due in part to better supportive care and more robust immune status. However, we cannot be certain, as the median CD4 + cell count of 256 cells/uL at initial PBL diagnosis was relatively low. Moreover, 59% had had a prior opportunistic infection and only 29% were on HAART at PBL diagnosis. Currently Clinical Trials Support Unit (CTSU) 9177 is prospectively studying EPOCH therapy for patients diagnosed with PBL irrespective of HIV status. Given the biologic similarity to multiple myeloma, drug classes like immune modulatory agents (IMiDs) and protease inhibitors [19] might also be promising agents for future study. The nearly ubiquitous finding of Epstein Barr in tumor tissue (11of 12 evaluable cases in our study) may provide a rationale for viral-based strategies. Finally, the role for autologous stem cell transplant in the setting of relapsed/refractory disease is also worthy of exploration.

Background A phase II trial of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) from the National Cancer Institute showed promising activity in untreated diffuse large B-cell lymphoma. The Cancer and Leukemia Group B conducted a study to determine if these results could be reproduced in a multi-institutional setting.Design and Methods The study included 69 patients with untreated diffuse large B-cell lymphoma at least 18 years of age and at least stage II. Radiaton therapy was not permitted on study. Median age was 58 years (range 23–83) and 40% had high-intermediate or high International Prognostic Index risk. Immunohistochemical biomarkers for cell of origin and proliferation were performed.Results With a median follow up of 62 months, time to progression and overall survival were 81% and 84%, respectively, and time to progression was 87%, 92% and 54% for low/low-intermediate, high-intermediate and high International Prognostic Index risk groups, respectively, at 5-years and beyond. The time to progression and event-free survival of germinal center B-cell lymphoma were 100% and 94%, respectively, and non-germinal center B-cell GCB diffuse large B-cell lymphoma were 67% and 58%, respectively, at 62 months (germinal center vs. non-germinal center B cell P=0.008). DA-EPOCH-R was tolerated without significant grade 4 non-hematologic toxicities.Conclusions These results provide the first confirmation by a multi-institutional group that DA-EPOCH-R provides high durable remissions in diffuse large B-cell lymphoma and is effective in both germinal center and non-germinal center B-cell subtypes. The trial was registered at ClinicalTrials.Gov (NCT00032019).

NK/T lymphomas have rarely been reported in HIV/AIDS patients. Here we report a case of a 37-year-old woman, with AIDS and a recent diagnosis of Kaposi sarcoma in a mesenteric lymph node, who presented with extra-ocular nerve palsies and gastrointestinal bleeding. A small intestine resection specimen revealed an extra-nodal NK/T cell lymphoma, nasal type. The unique presentation of this rare and aggressive lymphoma in the setting of AIDS and Kaposi sarcoma underscores the importance of maintaining a broad differential diagnosis when evaluating a malignant neoplasm from a HIV-positive patient.

Reported median overall survival (OS) in patients with mantle cell lymphoma (MCL) has been reported to be just 3-4 years. As a consequence, first-line treatment has become more aggressive. Single-center studies with R-Hyper-CVAD and/or autologous stem-cell transplant (ASCT) have produced 3-year OS rates80%, prompting many to adopt their use. We evaluated outcomes from a single-center cohort managed in a more traditional fashion.We identified patients with MCL evaluated at Weill Cornell Medical Center since 1997, and included those with known date of diagnosis. An online social security database was used to verify survival.We identified 181 patients with MCL, and date of diagnosis could be determined in 111. Three-year OS from diagnosis was 86% [95% confidence interval (CI) 78% to 92%]. Median OS was 7.1 years (95% CI 63-98 months). Adequate information on therapy was available for 75 patients. Only five were treated upfront with (R)-Hyper-CVAD or ASCT while an additional four patients received one of these regimens subsequently. Treatment type had no significant effect on OS.Outcomes with standard approaches can yield similar survival to that achieved with more intensive approaches. Biases may account for the perceived superiority of aggressive strategies.

Signaling through the transforming growth factor–β (TGF-β) pathway results in growth inhibition and induction of apoptosis in various cell types. We show that this pathway is blocked in Kaposi sarcoma herpesvirus (KSHV)–infected primary effusion lymphoma through down-regulation of the TGF-β type II receptor (TβRII) by epigenetic mechanisms. Our data also suggest that KSHV infection may result in lower expression of TβRII in Kaposi sarcoma and multicentric Castleman disease. KSHV-encoded LANA associates with the promoter of TβRII and leads to its methylation and to the deacetylation of proximal histones. Reestablishment of signaling through this pathway reduces viability of these cells, inferring that KSHV-mediated blockage of TGF-β signaling plays a role in the establishment and progression of KSHV-associated neoplasia. These data suggest a mechanism whereby KSHV evades both the antiproliferative effects of TGF-β signaling by silencing TβRII gene expression and immune recognition by suppressing TGF-β–responsive immune cells through the elevated secretion of TGF-β1.

Progressive iron overload is the most salient and ultimately fatal complication of β-thalassemia. However, little is known about the relationship among ineffective erythropoiesis (IE), the role of iron-regulatory genes, and tissue iron distribution in β-thalassemia. We analyzed tissue iron content and iron-regulatory gene expression in the liver, duodenum, spleen, bone marrow, kidney, and heart of mice up to 1 year old that exhibit levels of iron overload and anemia consistent with both β-thalassemia intermedia (th3/+) and major (th3/th3). Here we show, for the first time, that tissue and cellular iron distribution are abnormal and different in th3/+ and th3/th3 mice, and that transfusion therapy can rescue mice affected by β-thalassemia major and modify both the absorption and distribution of iron. Our study reveals that the degree of IE dictates tissue iron distribution and that IE and iron content regulate hepcidin (Hamp1) and other iron-regulatory genes such as Hfe and Cebpa. In young th3/+ and th3/th3 mice, low Hamp1 levels are responsible for increased iron absorption. However, in 1-year-old th3/+ animals, Hamp1 levels rise and it is rather the increase of ferroportin (Fpn1) that sustains iron accumulation, thus revealing a fundamental role of this iron transporter in the iron overload of β-thalassemia.

Radioimmunotherapy (RIT) with tositumomab and iodine 131 tositumomab can produce durable and complete responses in relapsed/refractory low-grade Non-Hodgkin's lymphoma. Patients with bone marrow involvement (BMI) with tumor25% of the intertrabecular space are generally excluded from RIT because of risk of excessive hematologic toxicity. The authors conducted a dose-escalation study of tositumomab and iodine 131 tositumomab to determine whether RIT is feasible in this population. Patients had baseline BMI of25% and platelet count ofor=150,000/mm3. In contrast to the usual 75 cGy total body dose of radiation, dose escalation of Iodine I 131 tositumomab began at a total body dose of 45 cGy, and increased to 55 cGy in a second cohort. Dose-limiting toxicity (DLT) was defined as absolute neutrophil count500 cells/mm3 or platelets25,000/mm3 for17 days, or absolute neutrophil count750/mm3 or platelets50,000/mm3 for24 days. Eleven subjects were enrolled (8 at 45 cGy and 3 at 55 cGy). Estimated BMI ranged from 30 to 65% (median approximately 40%). Patients had received a median of three prior chemotherapies (range 1 - 6). One of the six evaluable patients treated at 45 cGy experienced DLT. Three patients received 55 cGy, one had hematologic DLT concurrent with lymphoma progression and extensive BMI at relapse. Three of 11 (27%) patients received hematologic supportive care. Two patients had objective responses of 1 and 42.4+ months, respectively. RIT with attenuated dose iodine 131 tositumomab for patients with25% BMI has acceptable toxicity and can result in lymphoma responses.

Immunodeficiency dramatically increases susceptibility to cancer as a result of reduced immune surveillance and enhanced opportunities for virus-mediated oncogenesis. Although AIDS-related lymphomas (ARLs) are frequently associated with known oncogenic viruses, many cases contain no known transforming virus. To discover novel transforming viruses, we profiled a set of ARL samples using whole transcriptome sequencing. We determined that Epstein-Barr virus (EBV) was the only virus detected in the tumor samples of this cohort, suggesting that if unidentified pathogens exist in this disease, they are present in

Hodgkin lymphoma (HL) originates from the clonal expansion of malignant Hodgkin and Reed-Sternberg (HRS) cells. These B-cell–derived elements constitute less than 10% of the tumoral mass. The remaining tissue is comprised of an inflammatory infiltrate that includes myeloid cells. Myeloid cells activate B cells by producing BAFF and APRIL, which engage TACI, BCMA, and BAFF-R receptors on the B cells. Here, we studied the role of BAFF and APRIL in HL. Inflammatory and HRS cells from HL tumors expressed BAFF and APRIL. Unlike their putative germinal center B-cell precursors, HRS cells lacked BAFF-R, but expressed TACI and BCMA, a phenotype similar to that of plasmacytoid B cells. BAFF and APRIL enhanced HRS cell survival and proliferation by delivering nonredundant signals via TACI and BCMA receptors through both autocrine and paracrine pathways. These signals caused NF-κB activation; Bcl-2, Bcl-xL, and c-Myc up-regulation; and Bax down-regulation, and were amplified by APRIL-binding proteoglycans on HRS cells. Interruption of BAFF and APRIL signaling by TACI-Ig decoy receptor, which binds to and neutralizes BAFF and APRIL, or by small-interfering RNAs targeting BAFF, APRIL, TACI, and BCMA inhibited HRS cell accumulation in vitro and might attenuate HL expansion in vivo.