Aggressive Lymphoma Subtypes Research Articles

Survival after cancer in Italian persons with AIDS, 1986-2005: a population-based estimation.

Cancer survival in persons with AIDS (PWA) after introduction of antiretroviral therapies remains poorly characterized. The aim is to provide population-based estimates of cancer survival, overall and for the most important cancer types in PWA, and a comparison with persons without AIDS (non-PWA) affected by the same cancer. PWA with cancer at AIDS diagnosis or thereafter were individually matched with non-PWA by type of cancer, sex, age, year of diagnosis, area of living, and, for lymphomas, histological subtype. Five-year observed survival and hazard ratios (HRs) of death in PWA versus non-PWA with 95% confidence intervals (CIs) were estimated. We included 2262 Italian PWA and 4602 non-PWA with cancer diagnosed during 1986-2005. Between 1986 and 1995, and 1996 and 2005, 5-year survival for all cancers in PWA improved from 12% to 41% and the corresponding HR versus non-PWA decreased from 5.1 (95% CI: 4.3 to 6.1) to 2.9 (95% CI: 2.6 to 3.3). During 1996-2005, HRs were 2.0 (95% CI: 1.4 to 2.9) for Kaposi sarcoma, 3.4 (95% CI: 2.9 to 4.1) for non-Hodgkin lymphoma, and 2.4 (95% CI: 1.4 to 4.0) for cervical cancer. HRs were 2.5 (95% CI: 2.1 to 3.1) for all non-AIDS-defining cancers, 5.9 (95% CI: 3.1 to 11.2) for Hodgkin lymphoma, and 7.3 (95% CI: 2.8 to 19.2) for nonmelanoma skin cancer. A ≤3-fold survival difference was found for cancers of the stomach, liver, anus, lung, brain, and the most aggressive lymphoma subtypes. The persisting, although narrowing, gap in cancer survival between PWA and non-PWA indicates the necessity of enhancing therapeutic approaches, so that PWA can be provided the same chances of survival observed in the general population, and improving cancer prevention and screening.

Clinicopathologic comparison of plasmablastic lymphoma in HIV-positive, immunocompetent, and posttransplant patients: single-center series of 25 cases and meta-analysis of 277 reported cases.

Plasmablastic lymphoma (PBL) is a rare B-cell non-Hodgkin lymphoma often associated with Epstein-Barr virus (EBV) infection. To gain insight in this aggressive lymphoma subtype, the clinicopathologic characteristics of 25 unpublished single-center PBLs (2 in acquired immunodeficiency syndrome patients, 11 in immunocompetent individuals [IC-PBL], 12 in transplant recipients [PT-PBL]) and of 277 reported PBLs were summarized. In the reported series, PBL patients were predominantly male (77%) with a median age at diagnosis of 46 years (range, 1.2 to 87 y). The majority of the biopsies (66%) was EBV positive. Extranodal presentation was most frequent (88%, of which 35% were oral, 18% gastrointestinal, 12% cutaneous). PBL was diagnosed in acquired immunodeficiency syndrome patients (50%), immunocompetent individuals (35%), and transplant recipients (14%). These subgroups differed in age at diagnosis (median: 41, 64, 47 y, respectively), primary localization (oral, oral, cutaneous, respectively), EBV positivity (75%, 50%, 67%, respectively), CD45 expression (31%, 33%, 70%, respectively), and C-MYC aberrations (78%, 44%, 38%, respectively). Ann Arbor stage I, EBV positivity, CD45 expression, and lack of C-MYC aberrations were associated with better outcome (P<0.05). Our series of IC-PBL and PT-PBL cases revealed differential expression of CD10 (0% vs. 42%, respectively), CD56 (22% vs. 42%, respectively), TP53 (67% vs. 8%, respectively), and BCL2 (88% vs. 25%, respectively). Gene expression analysis of 5 of our PT-PBLs revealed upregulation of DNMT3B, PTP4A3, and CD320 in EBV-positive PT-PBL and suggested a role for cancer/testis antigens. The results of this retrospective study suggest different pathogenic mechanisms of PBL in different immunologic settings and a potentially important impact of EBV and CD45 on prognosis.

Treatment of HIV-associated plasmablastic lymphoma: A single-center experience with 25 patients.

8583 Background: Plasmablastic lymphoma (PBL) is a rare and aggressive subtype of B-cell lymphoma with a predominant occurrence in patients with HIV and other immune compromised states. It commonly...

Efficacy of anti-CD47 antibody-mediated phagocytosis with macrophages against primary effusion lymphoma

BackgroundRecently, the critical role of CD47 on the surface of resistant cancer cells has been proposed in their evasion of immunosurveillance. Primary effusion lymphoma (PEL) is a subtype of aggressive non-Hodgkin lymphoma that shows serous lymphomatous effusion in body cavities, especially in advanced acquired immunodeficiency syndrome (AIDS). PEL is resistant to conventional chemotherapy and has a poor prognosis. In this study, we evaluated the effect of anti-CD47 antibody (Ab) on PEL in vitro and in vivo. MethodsSurface CD47 of PEL cell lines was examined by flow cytometry. Efficacy of knocking down CD47 or anti-CD47 Ab-mediated phagocytosis against PEL was evaluated using mouse peritoneal macrophages and human macrophages in vitro. Primary PEL cells were injected intraperitoneally into NOD/Rag-2/Jak3 double-deficient (NRJ) mice to establish a direct xenograft mouse model. ResultsSurface CD47 of PEL cell lines was highly expressed. Knocking down CD47 and anti-CD47 Ab promoted phagocytic activities of macrophages in a CD47 expression-dependent manner in vitro. Treatment with anti-CD47 Ab inhibited ascite formation and organ invasion completely in vivo compared with control IgG-treated mice. ConclusionCD47 plays the pivotal role in the immune evasion of PEL cells in body cavities. Therapeutic antibody targeting of CD47 could be an effective therapy for PEL.

Chronic myeloid leukemia as a secondary malignancy after diffuse large B-cell lymphoma

Chronic myeloid leukemia as a secondary malignancy after diffuse large B-cell lymphoma

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Introduction: Lymphoproliferative disorders (LPD) are common in immunosuppressed patients and in patients with connective tissue disorders (CTD). There is increased risk in Sjögren's syndrome (SS) with moderate risk in systemic lupus erythematosis (SLE). Methods: We present a case of 50-year-old African-American female with SLE diagnosed in 1982. She underwent open lung biopsy in 2007 for evaluation of bilateral lower lobe interstitial infiltrates and dyspnea, which showed findings of follicular bronchiolitis. Over the years she was treated with prednisone, methotrexate, mycophenolate mofetil, plaquenil and azathioprine. In December 2012, she presented with dyspnea, chest tightness, low-grade fever, night sweats and productive cough. CT scan of chest showed bilateral patchy ground glass opacities (stable) and new bulky mediastinal, hilar and axillary lymphadenopathy. Sputum was positive for MRSA but negative for AFB and PCP. QuantiFERON-TB Gold test, HIV test, hepatitis B antigen and hepatitis C antibody were negative. Serology for EBV IGM was negative but IgG antibody was positive. ANA was positive. C4 complement level was low. Anti-Ro and Anti-La antibodies were negative. She underwent CT guided FNA of left axillary lymph node, which was inconclusive. She then underwent mediastinoscopy with excisional biopsy of pre-tracheal lymph node which showed atypical lymphoid infiltrate but was non diagnostic of lymphoma. Two months later patient presented with worsening dyspnea and increasing lymphadenopathy on CT chest and abdomen. Excisional biopsy of the left axillary lymph node was performed. Results: The pathology was positive for diffuse large B-cell lymphoma, an aggressive sub-type of non-Hodgkin's lymphoma. The patient was started on chemotherapy with R-CHOP. Conclusions: The continuum of LPD in patients with SLE can vary from follicular bronchiolitis to aggressive lymphoma. Understanding the spectrum of LPD and the various clinical and radiological manifestations in patients with CTD is essential for diagnosis. The time to progression from follicular bronchiolitis to lymphoma is unknown. Patients developing benign LPD like follicular bronchiolitis may have a higher chance of progression to lymphoma. Several mechanisms like chronic immunosuppressive therapy, abnormal immune-regulatory process and autoimmunity has been postulated. CLINICAL IMPLICATIONS: Our case highlights that lymphoma should be high in the differential diagnoses in patients with SLE and lymphadenopathy. The patients who develop benign lymphoproliferative disorder like follicular bronchiolitis should be closely monitored, for their progression to lymphoma.

Preliminary Results Of a Phase II Study Of Single Agent Bay 80-6946, a Novel PI3K Inhibitor, In Patients With Relapsed/Refractory, Indolent Or Aggressive Lymphoma

IntroductionBAY 80–6946 is a potent and reversible Class I phosphatidylinositol-3-kinase (PI3K) inhibitor with significant activity against both PI3K-δ and PI3K-α isoforms. The PI3K-α inhibitory activity may overcome a PI3K-mediated mechanism of resistance triggered by PI3K-δ inhibition. A phase I dose-escalation study (Patnaik et al, ASH 2012) established the maximum tolerated dose of BAY 80-6946 (0.8 mg/kg) and reported promising activity (6/6 PR) in follicular lymphoma. In the present study we further investigated the activity and safety of BAY 80-6946 in patients with indolent or aggressive lymphoma subtypes that have progressed after standard therapy. MethodsPatients with histologically confirmed indolent or aggressive lymphoma relapsed or refractory to ≥2 prior lines of treatment were eligible. Patients received BAY 80-6946 at a dose of 0.8 mg/kg as a 1 hour infusion on days 1, 8 and 15 of a 28-day cycle. Patients continued on therapy until disease progression or unacceptable toxicity. Responses were assessed every two cycles according to the response criteria for lymphoma (Cheson et al., JCO 17:1244,1999) or the guidelines for diagnosis and treatment of chronic lymphocytic leukemia (CLL; Hallek et al., Blood111:5446-56, 2008). ResultsAs of July 31, 2013, a total of 61 lymphoma patients (27 indolent and 34 aggressive) were enrolled and 56 started study treatment. Patients were similarly distributed among indolent and aggressive cohorts with respect to gender (52% female), median age (68 yr, range 22-90) and ethnicity (76% Caucasian) and were heavily pretreated (median number of prior therapies: 3; prior Rituximab: 84%; prior ASCT: 20%). Other characteristics included advanced stage III-IV in 85% and B symptoms in 17%. The following entities were represented: follicular (FL; n=13); CLL (n= 11); marginal zone (MZL; n=3; none staged to date); diffuse large B-cell (DLBCL; n=18); mantle cell (MCL; n=7); transformed (n=5); and peripheral T-cell (PTCL; n=4). At the time of analysis patients had received between 1 and 5 cycles of treatment. Objective responses were seen across histologic subtypes (Table 1). At the time of this interim analysis, the overall response rate (RR) and complete RR were 40% and 20% in FL, 67% and 0% in CLL, 83% and 17% in MCL, and 50% and 0% in PTCL, respectively.Table 1Best response by lymphoma subtype in staged patientsFL (n=10)CLL (n=9)DLBCL(n=17)MCL(n=6)Transformed(n=5)PTCL(n=4)CR/CRu201100PR261412SD627020PD018122CR – complete response; CRu – CR unconfirmed; PR – partial response; SD – stable disease; PD – progressive diseaseGrade 3 adverse events (AE) were reported in 49% of patients, and grade 4 AE (all neutropenia) occurred in 15% of patients. Grade 3/4 AEs occurring in ≥5% of patients included hypertension (31%), neutropenia (16%), hyperglycemia (13%), diarrhea (5%) and fatigue (5%). Hyperglycemia of any grade occurred in 47%. Four patients required insulin therapy, but no grade 4 hyperglycemia was observed. Hypertension of any grade occurred in 46% of patients. Eight patients required antihypertensive treatment, but no grade 4 hypertension was reported. Diarrhea of any grade occurred in 25% of cases. No case of colitis was reported. There were two cases of interstitial pneumonitis, with both cases resolved following corticosteroid administration. Withdrawal of study drug due to AEs occurred in 10 patients (16%), and 4 patients required a dose reduction. Four deaths occurred; 1 due to progressive disease, 1 due to acute respiratory insufficiency, 1 due to Cryptococcal meningitis and 1 due to sepsis after start of a salvage chemotherapy regimen. ConclusionsThe novel PI3K inhibitor BAY 80-6946 is clinically active as a single agent and appears to have an acceptable toxicity profile in relapsed/refractory lymphoma. Preliminary efficacy results are encouraging, as promising activity has been observed in FL, CLL, MCL, and PTCL. The safety profile was consistent with prior studies. Further studies of this compound in patients with lymphoma are warranted. Disclosures:Vitolo:Roche: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau. Mappa:Bayer S.p.A.: Employment. Giurescu:Bayer Pharma AG: Employment. Childs:Bayer HealthCare Pharmaceuticals: Employment.

Plasmablastic Lymphoma: 28 Patient Single Institution Experience

IntroductionPlasmablastic lymphoma (PBL) is a rare, aggressive subtype of non-Hodgkin lymphoma. Published data are predominantly in the form of case reports and small retrospective case series. Initial reports of PBL were described in HIV positive patients (pts) with disease in the oral cavity, and in pts after organ transplantation on immunosuppressive therapy. The natural history may have evolved recently, with case reports of PBL in immunocompetent patients. There is no established standard of care therapy, though HIV positive pts benefit from initiation of anti-retroviral therapy, tend to respond to chemotherapy, have historically been associated with CD20 expression, and have increased overall survival rates compared with HIV negative pts with PBL. We now describe our experience in pts with PBL who received treatment at the University of Texas MD Anderson Cancer Center (UTMDACC). MethodsWe conducted a retrospective analysis of pts diagnosed with PBL between August 2000 and August 2012. We evaluated the baseline demographics, stage, therapy, response rate, progression-free survival (PFS) and overall survival (OS). Results28 pts (males n=23) with PBL were identified, with a median age of 51 (range 26-81). 10 patients had a diagnosis of HIV, and 15 were EBV positive. 7 pts had stage I disease, 2 had stage II, 1 had stage III and 18 had stage IV disease. The primary site of disease in the 7 pts with stage I disease was: 2 in the maxillary sinus, 2 in the nasal cavity, and 1 each in the colon, testicle, and lower jaw. 2 pts with stage II disease had primary sites in bowel and tonsils. 7/17 (41%) of HIV negative pts and 2/10 (20%) of HIV positive pts had stage I/II disease.The median LDH was 492 IU/L (313-618), median Ki-67 proliferation index was 85%, and all pathological samples were CD20 negative. Median follow up was 16 months (1-120). 27 pts received systemic therapy (1 pt elected hospice care). PBL was an initial cancer diagnosis for 25 pts who received the following as first line therapy: Hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, dexamethasone alternating with methotrexate and cytarabine) (n=10), CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) (n=7), modified CVAD, 2 with EPOCH (etoposide, vincristine, cyclophosphamide, Adriamycin, prednisone) (n=4), bortezomib/dexamethasone (n=1), and the DeAngelis protocol (methotrexate, vincristine, procarbazine, with intrathecal methotrexate) (n=1) for CNS involvement. 2 pts had prior therapy for diagnosis of diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) prior to diagnosis of PBL. The first pt with DLBCL was treated with Rituximab-hyper-CVAD 6 years earlier, and gemcitabine/oxaliplatin for the diagnosis of PBL. The second pt had CLL which underwent Richter's transformation to PBL, and was treated with hyper-CVXD (cyclophosphamide, vincristine, liposomal daunorubicin and dexamethasone). 1 pt underwent auto-stem cell transplant, while 8 pts received localized radiation (5 for consolidation and 3 for palliative therapy); 5/7 pts with stage I disease received consolidation with involved field radiation. After first line therapy, 20/27 patients (74%) achieved complete response, 5/27 (19%) partial response, and 2/27 (7%) stable disease. Median PFS and OS were 24.1 and 28.8 months, respectively. 5 year PFS and OS were 40% and 38%, respectively. Early stage disease (stage I or II) and younger age at diagnosis (less than 40 years old) were associated with improved survival. 5 year PFS for stage I/II pts was 90%. Conclusion41% of HIV negative pts had stage I/II disease. Early stage PBL pts who received combined chemotherapy followed by radiotherapy achieved a good PFS of 90% at 5 years. PBL consistently lacked CD20 expression irrespective of HIV status. PBL can be seen in both HIV+ and HIV– patients with overall 40% long term survival. [Display omitted] [Display omitted] Disclosures:Qazilbash:Otsuka Pharmaceuticals: Research Funding. Fanale:Seattle Genetics, Inc.: Advisory/scientific board membership and travel expenses Other, Consultancy, Honoraria, Research Funding. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees.

Three-Year Survival Results From An Ongoing Phase 2 Study Of Brentuximab Vedotin In Patients With Relapsed Or Refractory Systemic Anaplastic Large Cell Lymphoma

BackgroundSystemic anaplastic large cell lymphoma (sALCL) is a CD30-positive aggressive subtype of mature T-cell lymphoma. Approximately 40–65% of patients (pts) with sALCL develop recurrent disease after frontline treatment. Outcomes are poor for pts with relapsed T cell lymphomas, including sALCL, with a median overall survival (OS) of 7.0 mos (Mak et al, 2013). Few effective therapies are available to address this unmet need. Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate comprising a CD30-directed antibody attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. A phase 2 study evaluated the efficacy and safety of brentuximab vedotin in 58 pts with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047). Long-term follow-up data from this ongoing trial are presented. MethodsPts received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). ResultsIn this heavily pre-treated pt population with poor prognosis, 62% had primary refractory disease (defined as no complete remission [CR] or relapse within 3 mos of frontline therapy), 26% had failed a prior autologous stem cell transplant (SCT), and 72% had ALK-negative disease. As previously reported, the ORR with brentuximab vedotin was 86% (50 of 58 pts) and the CR rate was 59% (34 of 58 pts). At the time of this analysis (datacut June 2013), all pts had discontinued treatment and the median observation time from first dose was 33.4 mos (range, 0.8-45.6). The median duration of objective response for all pts was 13.2 mos (95% CI: 5.7, 26.3) and the median duration of response for pts who obtained a CR was 26.3 mos (95% CI: 13.2, -). Of the 34 pts who achieved a CR, 16 (47%) remained in remission at the time of this analysis. Thirty-seven of 58 pts (64%) were alive at the time of last follow up. The median progression-free survival (PFS) for all pts was 14.6 mos and the median OS has not yet been reached. The estimated 3-year survival rate was 63% (95% CI: 51%, 76%). Median OS for pts who obtained a CR has not yet been reached while median OS for pts who did not obtain a CR was 7.7 mos (95% CI: 4.5, 13.7). Median OS for pts with PET-negative disease at Cycle 4 has not yet been reached while median OS for pts with PET-positive disease at Cycle 4 was 14.6 mos. After discontinuing treatment in the study, 17 pts (29%) received a hematopoietic SCT (9 allogeneic, 8 autologous). The median PFS has not yet been met for the group of pts who achieved a CR and received a subsequent SCT (95% CI: 14.6, -), while the median PFS for the group who achieved a CR and did not receive post-treatment SCT was 18.4 mos (95% CI: 8.4, 33.7). As previously reported, adverse events (AEs) in ≥20% of pts were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). The majority of AEs were Grade 1 or 2 in severity. ConclusionsAfter a median observation time of 33.4 mos from first dose of brentuximab vedotin, 64% of pts with relapsed or refractory sALCL were alive at the time of last follow up and the median OS has not yet been reached. Pts who achieved a CR with brentuximab vedotin experienced longer OS than pts who did not achieve a CR and early PET-negative status appeared to be important for long-term survival. These long-term follow-up results further underscore the durability of clinical benefit obtained with brentuximab vedotin. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-positive mature T-cell lymphomas, including sALCL (ClinicalTrials.gov #NCT01777152). [Display omitted] Disclosures:Pro:Seattle Genetics, Inc.: Advisory/Scientific board membership and travel expenses Other, Consultancy, Research Funding. Advani:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Research Funding. Brice:Seattle Genetics, Inc.: Honoraria, Research Funding. Bartlett:Seattle Genetics, Inc.: Advisory/Scientific Board Membership and Travel Expenses Other, Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding. Matous:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Fanale:Seattle Genetics, Inc.: Advisory/Scientific Board Membership and Travel Expenses Other, Consultancy, Honoraria, Research Funding. Connors:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Huebner:Takeda: Equity Ownership; Takeda Cambridge US: Employment. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Honoraria, Research Funding, Speakers Bureau.

Evaluation Of Targeting CD47-SIRPα Using Primary Effusion Lymphoma Xenograft Mouse Model

IntroductionRecently, the critical roles of CD47 on the surface of resistant cancer cells and its ligand, signal regulatory protein alpha (SIRPα), have been proposed in their evasion of immunosurveillance. Primary effusion lymphoma (PEL) is a subtype of aggressive non-Hodgkin lymphoma that shows serous lymphomatous effusion without tumor masses in body cavities especially in advanced advanced acquired immunodeficiency syndrome (AIDS). The lack of optimal therapy combined with the aggressive nature of PEL results in a short median survival of less than 6 months. There is therefore a need for the development of new therapies. In this study, we transplanted PEL cells intraperitoneally into immunodeficient mice and evaluated the effect of targeting CD47-SIRPα signal with anti-CD47 antibody (Ab) and NOD-specific SIRPα on PEL. MethodsSurface CD47 expressions of six PEL cell lines and peripheral blood mononuclear cells (PBMC) from six different donors were examined by flow cytometry. The antiproliferative activities of anti-CD47Ab against PEL cell lines were measured by the methylthiotetrazole (MTT) method. Efficacy of anti-CD47 Ab-mediated phagocytosis against PEL was evaluated using mouse peritoneal macrophages and human macrophages in vitro. In a direct xenograft mouse model, primary PEL cells were injected intraperitoneally into NOD/Rag-2/Jak3 double-deficient mice to assess the in vivo efficacy of anti-CD47 Ab. To clarify the effect of NOD-specific SIRPα on PEL, we compared the phagocytic activities of peritoneal macrophages against PEL and the in vivo engraftment of PEL among Rag-2/Jak3 double-deficient mice with NOD and non-NOD (Balb/c and C57/BL6) genetic backgrounds. Organ invasion by PEL cells was evaluated by immunohistochemistry and flow cytometry. ResultsSurface CD47 of PEL cell lines was highly expressed compared with that of PBMC. Anti-CD47 Ab did not have a direct antitumor effect against PEL cell lines. Treatment with anti-CD47 Ab promoted phagocytic activities of mouse peritoneal macrophages and human macrophages in vitro. In addition, the expression of CD47 was significantly correlated with the fold increase of phagocytic activity. Treatment with anti-CD47 Ab inhibited the ascites formation and organ invasion completely in vivo compared with control IgG-treated mice. Anti-CD47 Ab-treated mice seemed to stay in healthy and show no apparent change. Although the numbers of peritoneal macrophages were not different among Rag-2/Jak3 double-deficient mice with NOD and non-NOD genetic backgrounds, the phagocytic activity in NOD mice was significantly decreased compared with non-NOD mice. Consistent with the data of phagocytosis assay, the development of PEL cells in NOD mice was superior to those in non-NOD mice. ConclusionsCD47 and SIRPα play the pivotal role in the immune evasion of PEL. NOD-specific SIRPα polymorphism has been reported to produce signals for macrophages not to engulf human cells. Thus, NOD-specific SIRPα is considered to contribute to the attenuation of macrophage phagocytosis and enable the development of PEL. CD47-SIRPα signal could be a therapeutic target for the immunotherapy of PEL. Disclosures:No relevant conflicts of interest to declare.

Combination Of Ibrutinib With ABT-199, a BCL-2 Pathway Inhibitor: Effective Therapeutic Strategy In a Novel Mantle Cell Lymphoma Cell Line Model

BackgroundMantle cell lymphoma (MCL) is an aggressive subtype of Non-Hodgkin Lymphoma associated with poor prognosis. Constitutive activation of B-cell receptor (BCR) signaling plays an essential role for the survival and proliferation of malignant B-cells. Targeting Bruton's tyrosine kinase (BTK), a component of BCR signaling pathway, with ibrutinib is a promising strategy. As a single agent, complete and partial response rates of 21% and 47%, respectively, were observed in a phase 2 study for relapsed or refractory MCL. Simultaneous inhibition of multiple biologic pathways has the potential to result in a synergism. We combined ibrutinib with ABT-199, a BH3 mimetic that selectively targets the BCL-2 pathway, and tested their in vitroefficacy against MCL. Experimental designA novel MCL cell line, CCMCL1, and four other MCL cell lines (Jeko-1, Mino, JVM2, Rec-1) were used for flow cytometry-based apoptosis and cell cycle analyses to evaluate the combinational effect of ibrutinib with ABT-199 (ChemieTek. Indianpolis. IN). The interaction between drugs was examined with Calcusyn software and combination index values served to determine the combined effect as synergistic (<1), additive (=1), or antagonistic (>1). Immunoblotting was performed to investigate signaling pathways of MCL cells exposed to these agents. ResultsCCMCL1 was derived from primary leukemic MCL cells. Cells were initially directly injected via tail vein into an NSG mouse. Engrafted cells were then isolated at 10 weeks from spleen and placed into routine cell culture. Immunophenotyping showed CCMCL1 cells have similar characteristics as the primary patient MCL cells, which expressed CD5, CD19, CD20, FMC7 and monotypic kappa light chain. Immunohistochemical staining of engrafted mouse spleen tissue showed expression of cyclin D1 and SOX11. The karyotype is highly complex with an IGH@/CCND1 fusion by metaphase FISH. In addition to spleen, MCL cell infiltration was observed in mouse liver, bone marrow, blood, brain, lung, kidney and intestine. In vitro cultured CCMCL1 cells underwent apoptosis upon expose to ibrutinib and ABT-199 as single agents. Combination of these two drugs resulted in synergistic induction of apoptosis (Table 1). Synergism was also observed with Jeko-1, Mino, JVM-2 and Rec-1 cells. Immunoblotting showed CCMCL1 cells have constitutive expression of cyclin D1, SOX11, PAX5 and MCL1. Ibrutinib as a single agent induced a rapid down-regulation of SOX11 and MCL1, while combination of ibrutinib with ABT-199 further enhanced down regulation of SOX11, followed by down-regulation of PAX5 at a later time point. We are currently testing the in vivo efficacy of combining these two drugs in a CCMCL1 NSG mouse model. [Display omitted] ConclusionOur CCMCL1/NSG mouse model is a new model for pre-clinical assessment of MCL treatment approaches. Combination of ibrutinib with ABT-199 has synergistic effect of apoptotic induction in CCMCL1 as well as four other MCL cell lines tested. Ibrutinib or ibruitnib/ABT-199 combination induced apoptosis of MCL is associated with down-regulation of SOX11 and PAX5. Simultaneous down regulation of MCL1 via ibrutinib and targeting of BCL2 may contribute to the in vitrosynergism observed. These data support further investigation of this novel therapeutic strategy. Disclosures:No relevant conflicts of interest to declare.

Clinical and Economic Burden Of Peripheral T-Cell Lymphoma In The United States

BackgroundPeripheral T-cell lymphoma (PTCL) is an aggressive and heterogeneous subtype of non-Hodgkin lymphoma (NHL). PTCL has a poor prognosis due to advanced stage at presentation, and generally poor response to standard chemotherapy. According to recent SEER estimates, PTCL accounts for about 4% of all NHL cases in the United States each year. To date, few studies have assessed the clinical and economic burden of PTCL. MethodsMarketScan data for commercially insured and Medicare supplemental patients were used to retrospectively identify unique PTCL patients. Patients were identified by ICD-9-CM diagnosis codes between October 1, 2007 and June 30, 2011. The time of first PTCL diagnosis code served as the index date, and a second PTCL diagnosis date was used for confirmation. All patients were required to have at least 6 months of continuous enrollment before and 12 months of continuous enrollment after their index date. Patients were excluded if aged <18 years, date of birth or gender were missing, or if they had received a stem cell transplant (SCT) prior to PTCL diagnosis. The control group includes patients that may have any other malignant (excluding PTCL) or non-malignant condition and are considered to represent an average insured patient population from the payer perspective. The control group was matched based on age, sex, region, plan type, payer type, and length of enrollment. Mean cost per month was measured and annualized to provide average yearly costs. Healthcare costs included hospitalizations, pharmacy services, office visits, emergency room visits, hospice stays, SCT, and other patient-related costs (lab procedures, radiology procedures, blood transfusions, and other ancillary procedures). ResultsOf 2820 patients with ≥1 PTCL diagnosis, 1000 patients were identified that met all inclusion criteria (mean age 56 years, 58% male), and were matched to the control group. On an average annual basis, PTCL patients were hospitalized more often (0.9 vs 0.1 hospitalizations), and experienced a longer length of stay (6.4 vs 4 days) compared with matched controls. In addition, PTCL patients had a higher utilization of office visits (16.2 vs 4.1 visits), pharmacy services (34.2 vs 11.6 prescriptions), emergency room visits (0.8 vs 0.2 visits), and hospice care (0.6 vs 0.1 stays). PTCL patients also experienced higher comorbidities (mean Charlson Comorbidity Index of 1.72 vs 0.39, as determined at index date). Overall, PTCL patients incurred much higher average annual costs compared with matched patients ($75,934.08 vs $4660.64; Table), driven mainly by hospitalizations (32.2% of overall costs) and pharmacy services (19.6% of overall costs). ConclusionsPTCL is associated with high resource utilization rates and high overall costs. The development of efficacious treatments for PTCL may offer better disease management and may reduce the clinical and economic burden of PTCL. Disclosures:Potashman:Millennium: The Takeda Oncology Company: Employment. Burudpakdee:Millennium: The Takeda Oncology Company: Consulting researcher Other. Wang:Millennium: The Takeda Oncology Company: Consulting researcher Other, Research Funding. Zhu:Millennium: The Takeda Oncology Company: Employment. Carson:Millennium: The Takeda Oncology Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin Pharma, Inc.: Research Funding.

CD30 targeting with brentuximab vedotin: a novel therapeutic approach to primary effusion lymphoma

AbstractPrimary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma characterized by short survival with current therapies, emphasizing the urgent need to develop new therapeutic approaches. Brentuximab vedotin (SGN-35) is an anti-CD30 monoclonal antibody (cAC10) conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. Brentuximab vedotin is an effective treatment of relapsed CD30-expressing Classical Hodgkin and systemic anaplastic large cell lymphomas. Herein, we demonstrated that PEL cell lines and primary tumors express CD30 and thus may serve as potential targets for brentuximab vedotin therapy. In vitro treatment with brentuximab vedotin decreased cell proliferation, induced cell cycle arrest, and triggered apoptosis of PEL cell lines. Furthermore, in vivo brentuximab vedotin promoted tumor regression and prolonged survival of mice bearing previously reported UM-PEL-1 tumors as well as UM-PEL-3 tumors derived from a newly established and characterized Kaposi's sarcoma-associated herpesvirus- and Epstein-Barr virus-positive PEL cell line. Overall, our results demonstrate for the first time that brentuximab vedotin may serve as an effective therapy for PEL and provide strong preclinical indications for evaluation of brentuximab vedotin in clinical studies of PEL patients.

Central nervous system and head and neck imaging findings of MYC/BCL2 “double hit” B cell lymphoma

MYC/BCL2 double hit lymphoma (DHL) is a rare, recently recognised and highly aggressive subtype of non-Hodgkin lymphoma, with an affinity to involve the central nervous system and the head and neck either at initial presentation or during relapse. We present a case of 43-year-old woman with MYC/BCL2 DHL relapse in the nasopharynx with extensive spread to the neck, skull base, and the central nervous system. To our knowledge, this is the first reported case in the literature describing the MRI and CT scan findings and the profound pattern of disease involvement of this rare neoplasm.

Targeting CD47-sirpa for the controlling malignant effusion in primary effusion lymphoma

Recently, the critical roles of CD47 on the surface of resistant cancer cells and its ligand, signal regulatory protein alpha (SIRPA), have been proposed in their evasion of immunosurveillance. Primary effusion lymphoma (PEL) is a subtype of aggressive non-Hodgkin lymphoma that shows serous lymphomatous effusion in body cavities especially in advanced AIDS. PEL is resistant to conventional chemotherapy and has a poor prognosis. In this study, we evaluated the effect targeting CD47-SIRPA signal on PEL using xenograft mouse model.

Histone deacetylase inhibitor potentiated the ability of MTOR inhibitor to induce autophagic cell death in Burkitt leukemia/lymphoma

BackgroundBurkitt leukemia/lymphoma is a major subtype of aggressive B-cell lymphoma. Biological targeted therapies on this disease need to be further investigated and may help to improve the clinical outcome of the patients.MethodsThis study examined the anti-tumor activity of the histone deacetylases (HDAC) inhibitor valproic acid (VPA) combined with the mammalian target of rapamycin (MTOR) inhibitor temsirolimus in Burkitt leukemia/lymphoma cell lines, as well as in primary tumor cells and a murine xenograft model.ResultsCo-treatment of VPA and temsirolimus synergistically inhibited the tumor cell growth and triggered the autophagic cell death, with a significant inhibition of MTOR signaling and MYC oncoprotein. Functioned as a class I HDAC inhibitor, VPA potentiated the effect of temsirolimus on autophagy through inhibiting HDAC1. Molecular silencing of HDAC1 using small interfering RNA (siRNA) attenuated VPA-mediated regulation of CDKN1A, CDKN1B and LC3-I/II, regression of tumor cell growth and induction of autophagy. Meanwhile, VPA counteracted temsirolimus-induced AKT activation via HDAC3 inhibition. HDAC3 siRNA abrogated the ability of VPA to modulate AKT phosphorylation, to suppress tumor cell growth and to induce autophagy. Strong antitumor effect was also observed on primary tumor cells while sparing normal hematopoiesis ex vivo. In a murine xenograft model established with subcutaneous injection of Namalwa cells, dual treatment efficiently blocked tumor growth, inhibited MYC and induced in situ autophagy.ConclusionsThese findings confirmed the synergistic effect of the HDAC and MTOR inhibitors on Burkitt leukemia/lymphoma, and provided an insight into clinical application of targeting autophagy in treating MYC-associated lymphoid malignancies.

MicroRNA dysregulation in B-cell non-Hodgkin lymphoma

MicroRNA dysregulation in B-cell non-Hodgkin lymphoma Emilia L Lim,1 Marco A Marra1,21Canada&rsquo;s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada; 2Department of Medical Genetics, University of British Columbia, Vancouver, BC, CanadaAbstract: B-cell non-Hodgkin lymphomas (NHLs) are lymphoproliferative disorders that can arise at different stages of B-cell development. Even though molecular classification of NHL has allowed for more accurate recognition of distinct aggressive lymphoma subtypes, many patients still fail to respond to standard therapy. As such, there is a need to identify biomarkers and therapeutic targets that can lead to more specific treatments for each NHL patient&#39;s disease. MicroRNAs (miRNAs) are small, 17&ndash;25 nt RNA molecules that regulate gene expression at the posttranscriptional level. miRNA expression and function is often coordinately dysregulated in NHL, and consequently results in each NHL disease type harboring a distinct miRNA expression signature. miRNA dysregulation may be a consequence of several mechanisms, ranging from dysregulation of the DNA sequences encoding the miRNA to transcriptional regulation of miRNA loci, to dysregulation of the miRNA biogenesis pathway or dysregulation of messenger RNA (mRNA) targets. This coordinated dysregulation of miRNA expression systematically results in the activation of several oncogenic pathways, and consequently the reprogramming of B-cell NHL transcriptomes. The widespread dysregulation of miRNAs suggests that miRNAs may be used as a diagnostic and prognostic tool, and also as actionable drug targets. In this review, we summarize the miRNA profiles of the most common B-cell NHLs, discuss the causes and consequences of miRNA dysregulation, and consider the prospects of miRNA-based biomarkers and therapeutic targets in NHL.Keywords: miRNA, non-Hodgkin lymphoma, dysregulation, therapy

Potent antitumor activity of zoledronic acid-induced Vγ9Vδ2 T cells against primary effusion lymphoma

Primary effusion lymphoma (PEL) is a subtype of aggressive and resistant non-Hodgkin lymphoma that occurs predominantly in patients with advanced AIDS. In this study, we examined the antitumor activity of zoledronic acid (Zol)-induced Vγ9Vδ2 T cells against PEL cells in vitro and in vivo. Vγ9Vδ2 T cells recognized endogenous mevalonate metabolites and MICA/B of PEL cell lines, inducing cytotoxicity via granule exocytosis and TRAIL-mediated pathway. Vγ9Vδ2 T cells suppressed the development of PEL cells and existed in a PEL xenograft mouse model. These results show that immunotherapy with Zol-induced Vγ9Vδ2 T cells could demonstrate an efficient strategy for PEL.

Assault on MALT1

Two new studies identify inhibitors of MALT1 that show anticancer activity in vitro and in vivo for an aggressive subtype of lymphoma.

In Vivo Growth of Mantle Cell Lymphoma Xenografts in Immunodeficient Mice Is Positively Regulated by VEGF and Associated with Significant Up-regulation of CD31/PECAM1

Mantle cell lymphoma (MCL) is an aggressive lymphoma subtype with dismal prognosis. New treatments are needed to improve outcome of relapsed/refractory disease. Recently, several drugs targeting at least partially the process of angiogenesis have been successfully tested in the therapy of MCL. Molecular mechanisms that regulate MCL-induced angiogenesis and that might represent potential new druggable targets remain, however, incompletely understood. We established two mouse models of human MCL by subcutaneous xenotransplantation of JEKO-1 and HBL-2 cell lines into immunodeficient mice. Histological analyses of xenografts confirmed their neovascularization. The growth of xenografts was significantly suppressed by single-agent therapy with bevacizumab, monoclonal antibody targeting vascular endothelial growth factor (VEGF). Subsequently, we analysed expression of 94 angiogenesis-related genes in ex vivo isolated JEKO-1 and HBL-2 cells compared to in vitro growing cells using TaqMan low-density arrays. The most up-regulated genes in both JEKO-1 and HBL-2 xenografts were genes encoding platelet/endothelial cell-adhesion molecule (CD31/PECAM1), VEGF receptor 1 (FLT1), hepatocyte growth factor (HGF), angiogenin (ANG) and transcription factor PROX1. The most downregulated genes in both JEKO-1 and HBL-2 xenografts were midkine (MDK) and ephrine B2 (EPHB2). In summary, our results demonstrate an important role of angiogenesis in the biology of MCL and provide preclinical evidence of potent anti-MCL activity of bevacizumab. In addition, gene expression profiling of 94 angiogenesis-related targets revealed several in vivo up-regulated and down-regulated transcripts. The most differentially expressed target in both MCL tumours was CD31/PECAM1. Whether any of these molecules might represent a potential druggable target in MCL patients remains to be elucidated.