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We present long-term combined results of two clinical trials implementing R-MACLO-IVAM induction followed by thalidomide or rituximab maintenance in 44 patients with untreated mantle cell lymphoma (MCL). The first 22 patients (UM-MCL1 ClinicalTrials.gov identifier NCT00450801) received maintenance with thalidomide (200 mg daily until relapse/intolerable toxicity) and a subsequent cohort of 22 patients (UM-MCL2 ClinicalTrials.gov identifier NCT00878254) received rituximab (375 mg/m2 IV weekly × 4, repeated every 6 months for 3 years). Considering all 44 patients, 41 (93.2%) achieved complete response (CR), two (4.5%) partial response (PR), and one (2.3%) was not evaluated for response. With a median follow up of 7.2 years (range < 1 month to 16 years), the 5-year progression-free survival (PFS) was 55.6% (95% CI: 38.9%-69.4%) and median PFS 7.9 years (95% CI: 3.7-11 years). The 5-year OS was 83.3% (95% CI: 68.1%-91.7%) and median OS was not reached. Patients with blastic variant (n = 6) had a 5-year PFS and OS of 20.8% and 60%, respectively. Myelosuppression was the most common adverse event during immunochemotherapy. Long-term treatment-related mortality was 6.8%. Note, R-MACLO-IVAM followed by maintenance therapy is an effective regimen to induce long-term remission in MCL without need for consolidation with ASCT.

The best upfront therapy for patients with non-gastric extranodal marginal zone lymphoma (EMZL) remains unclear. Patients with localized disease are usually treated with radiation therapy resulting...

Purpose Given the paucity of data on higher-grade transformation (HGT) to aggressive lymphoma in patients with marginal zone lymphoma (MZL), we report on a large cohort of patients, identify risk factors, and determine HGT impact on overall survival (OS). Methods We analyzed 453 patients with biopsy-proven MZL seen at our institution between 1995 and 2016. Kaplan-Meier, Cox proportional hazards regression, and competing risk methods were used in analyses of time-to-event outcomes. Results Thirty-four patients (7.5%) had biopsy-proven HGT to diffuse large B-cell lymphoma, including seven (21%) diagnosed at the time of initial MZL diagnosis. Among 27 incident patients, median time to HGT was 29 months (range, 1.3 to 135 months). Higher risk of HGT was observed in those with nodal/splenic MZL (subdistribution hazard ratio [SHR], 2.60; P = .023). On multivariable competing risk analysis, elevated lactate dehydrogenase (SHR, 2.71), more than four nodal sites (SHR, 2.97), and failure to achieve complete remission (CR) after initial treatment (SHR, 3.76) conveyed significantly higher risk for HGT ( P < .02). International Prognostic Index (IPI), Follicular Lymphoma IPI, and Mucosa-Associated Lymphoid Tissue Lymphoma IPI were only significant predictors of HGT univariably. Patients with HGT had shorter OS (5-year rate, 65% v 86%; P < .001). Patients who presented with HGT within 12 months since MZL diagnosis had shorter OS than those with HGT at MZL diagnosis combined with those with HGT more than 12 months later (4-year rate, 43% v 81%, P < .001). Non-CR and higher scores of IPI, Follicular Lymphoma IPI, and Mucosa-Associated Lymphoid Tissue Lymphoma IPI were the main significant predictors for shorter progression-free survival and OS. Conclusion Failure to achieve CR after initial treatment, elevated lactate dehydrogenase, and more than four nodal sites at the time of MZL diagnosis are the main predictors of increased risk of HGT. Patients with HGT have shorter OS.

Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of R/R large B-cell lymphoma and follicular lymphoma (FL), both after ≥2 lines of systemic therapy. ZUMA-5 is a Phase 2, multicenter, single-arm study evaluating axi-cel in patients with R/R iNHL (including FL and marginal zone lymphoma [MZL]). In the primary analysis of ZUMA-5 (N=104; 17.5 months median follow-up), the overall response rate (ORR) was 92% (76% complete response [CR] rate), and median peak CAR T-cell levels were numerically greater in patients with FL who were in ongoing response at data cutoff than in those who relapsed (Jacobson et al. ASH 2020. Abstract 700). Here, we report updated clinical and pharmacologic outcomes from ZUMA-5. Methods: Adult patients with R/R FL or MZL after ≥2 lines of therapy (including an anti-CD20 mAb plus an alkylating agent) underwent leukapheresis and conditioning chemotherapy followed by a single axi-cel infusion at 2×10 6 CAR T cells/kg. The primary endpoint was centrally assessed ORR per Lugano classification. The updated efficacy analysis occurred when ≥80 consecutively treated patients with FL had ≥2 years of follow-up post-infusion and included patients with MZL who had ≥4 weeks of follow-up post-infusion. Results: As of March 31, 2021, 149 patients with iNHL (124 FL; 25 MZL) were treated with axi-cel. Of those, 110 patients (86 FL; 24 MZL) were eligible for efficacy analyses. Among eligible patients with FL, median follow-up was 30.9 months (range, 24.7-44.3). Centrally assessed ORR was 94% in patients with FL (79% CR rate). At data cutoff, 57% of eligible patients with FL had ongoing responses; 68% of patients who achieved a CR had ongoing responses. The estimated duration of response (DOR) and progression-free survival (PFS) medians were 38.6 months and 39.6 months in patients with FL, respectively. Among patients with FL who progressed Among eligible patients with MZL, median follow-up was 23.8 months (range, 7.4-39.4). The ORR was 83% in patients with MZL (63% CR rate), with 50% of eligible patients in ongoing response and 73% of patients with a CR in ongoing response at data cutoff. Medians for DOR and TTNT were not reached in patients with MZL; 24-month rates were not estimable and 51%, respectively. Median PFS was 17.3 months in patients with MZL and median OS was not reached (70% OS rate at 24 months). Common Grade ≥3 AEs in all treated patients with iNHL were consistent with prior reporting: neutropenia (33%), decreased neutrophil count (28%), and anemia (25%). Grade ≥3 cytopenias present ≥30 days post-infusion were reported in 34% of patients with iNHL (33% FL; 36% MZL). Consistent with previous reports, Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 7% of patients (6% FL; 8% MZL) and 19% of patients (15% FL; 36% MZL), respectively. Most CRS cases (120/121) and NEs (82/87) of any grade resolved by data cutoff. Among patients with FL who had evaluable samples, 76% (65/86) had detectable CAR gene-marked cells at low levels by 12 months post-infusion; 53% (23/43) had detectable cells 24 months post-infusion. Among evaluable patients with MZL, 67% (8/12) had detectable CAR gene-marked cells 12 months post-infusion; 60% (3/5) had detectable cells 24 months post-infusion. B-cell reconstitution was detectable in 59% of evaluable patients with FL (49/83) and 42% of those with MZL (5/12) by 12 months post-infusion. By 24 months, B cells were detectable in 61% of evaluable patients with FL (25/41) and 50% of those with MZL (2/4). Conclusions: With long-term follow-up in ZUMA-5, axi-cel demonstrated substantial and continued benefit in patients with iNHL. In FL, high response rates translated to durability, with a median DOR of 38.6 months and 57% of eligible patients in ongoing response at data cutoff. In MZL, efficacy outcomes appeared to improve with longer follow-up, with the median DOR and OS not yet reached. Axi-cel maintained a manageable safety profile, with no new safety signals . Disclosures Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees. Chavez: Merk: Research Funding; MorphoSys, Bayer, Karyopharm, Kite, a Gilead Company, Novartis, Janssen, AbbVie, TeneoBio, and Pfizer: Consultancy; MorphoSys, AstraZeneca, BeiGene, Genentech, Kite, a Gilead Company, and Epizyme: Speakers Bureau; AstraZeneca: Research Funding; ADC Therapeutics: Consultancy, Research Funding; BMS: Speakers Bureau. Sehgal: Juno/Celgene: Research Funding; Kite/Gilead: Research Funding. Epperla: Genzyme: Honoraria; Karyopharm: Other: Ad Board; Beigene: Speakers Bureau; Verastem: Speakers Bureau. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Munshi: Kite, a Gilead Company, and Incyte: Honoraria; Kite, a Gilead Company, and Incyte: Speakers Bureau. Casulo: Genentech: Research Funding; BMS: Research Funding; Verastem: Research Funding; Gilead: Research Funding. Maloney: Kite, a Gilead Company, Juno, and Celgene: Research Funding; A2 Biotherapeutics: Consultancy; BioLineRx, Juno, Celgene, Kite, a Gilead Company, Gilead, Novartis, and Pharmacyclics: Honoraria; A2 Biotherapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Juno: Patents & Royalties. Reshef: Bayer: Consultancy; BMS, Regeneron, TScan, Synthekine, Atara, Jasper, Bayer: Consultancy; ilead, BMS, Precision, Immatics, Atara, Takeda, Shire, Pharmacyclics, Incyte: Research Funding; Gilead and Novartis: Honoraria. Leslie: Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy; Abbvie: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy. Oluwole: Pfizer: Consultancy; Curio Science: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Rosenblatt: Synergys: Patents & Royalties; BioGraph 55: Research Funding. Sherman: Kite, a Gilead Company: Current Employment; Gilead: Current equity holder in publicly-traded company. Dong: Kite, a Gilead Company: Current Employment; Gilead: Current equity holder in publicly-traded company; GliaCure/Tufts: Consultancy, Patents & Royalties. Giovanetti: Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company. Yang: Kite, a Gilead Company: Current Employment. Lui: Gilead Sciences: Other: stock or other ownership; Kite, a Gilead Company: Current Employment, Other: travel support. Bashir: Kite, a Gilead Company: Ended employment in the past 24 months; OmniacPharmConsult Ltd: Other: stock or other ownership. Jung: Amgen, Kura, Gilead, and Turning Point: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Jacobson: Lonza: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Nkarta: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau.

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited therapeutic options. Metastasis is the major cause of TNBC mortality. Angiogenesis facilitates TNBC metastases. Many TNBCs also form vascular channels lined by tumor cells rather than endothelial cells, known as ‘vasculogenic mimicry’ (VM). VM has been linked to metastatic TNBC behavior and resistance to anti-angiogenic agents. Epidermal growth factor receptor (EGFR) is frequently expressed on TNBC, but anti-EGFR antibodies have limited efficacy. We synthesized an anti-EGFR antibody–endostatin fusion protein, αEGFR IgG1-huEndo-P125A (αEGFR-E-P125A), designed to deliver a mutant endostatin, huEndo-P125A (E-P125A), to EGFR expressing tumors, and tested its effects on angiogenesis, TNBC VM, and motility in vitro, and on the growth and metastasis of two independent human TNBC xenograft models in vivo. αEGFR-E-P125A completely inhibited the ability of human umbilical vein endothelial cells to form capillary-like structures (CLS) and of TNBC cells to engage in VM and form tubes in vitro. αEGFR-E-P125A treatment reduced endothelial and TNBC motility in vitro more effectively than E-P125A or cetuximab, delivered alone or in combination. Treatment of TNBC with αEGFR-E-P125A was associated with a reduction in cytoplasmic and nuclear β-catenin and reduced phosphorylation of vimentin. αEGFR-E-P125A treatment of TNBC xenografts in vivo inhibited angiogenesis and VM, reduced primary tumor growth and lung metastasis of orthotopically implanted MDA-MB-468 TNBC cells, and markedly decreased lung metastases following intravenous injection of MDA-MB-231-4175 lung-tropic TNBC cells. Combined inhibition of angiogenesis, VM, and TNBC motility mediated by αEGFR-E-P125A is a promising strategy for the prevention of TNBC metastases.

Background: Patients with advanced-stage iNHL, including follicular lymphoma (FL) and marginal zone lymphoma (MZL), frequently relapse with standard treatment, underscoring a need for novel therapies. Axi-cel autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy is approved for the treatment of R/R large B cell lymphoma after ≥ 2 lines of systemic therapy. Here, we present the primary analysis of ZUMA-5, a Phase 2, multicenter, single-arm study of axi-cel in patients with R/R iNHL. Methods: Adults with FL (Grades 1-3a) or MZL (nodal or extranodal) had R/R disease after ≥ 2 lines of therapy (must include an anti-CD20 mAb plus an alkylating agent), and ECOG 0 - 1. Patients underwent leukapheresis followed by conditioning therapy (cyclophosphamide/fludarabine) and a single infusion of axi-cel at 2 × 106 CAR T cells/kg. The primary endpoint was objective response rate (ORR) by central review (per Lugano classification; Cheson, et al. J Clin Oncol. 2014). Secondary endpoints included complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and levels of CAR T cells in blood and cytokines in serum. The primary efficacy analysis occurred when ≥ 80 treated patients with FL had ≥ 12-months follow-up. Results: As of 3/12/2020, 146 patients with iNHL (124 FL; 22 MZL) received axi-cel; 84 patients with FL had ≥ 12-months follow-up. The median age was 61 years (range, 34 - 79); 57% of patients were male. Thirty-eight percent of patients had ECOG 1, 86% had stage III/IV disease, 47% had ≥ 3 FLIPI, and 49% had high tumor bulk (GELF). Patients had a median 3 prior lines of therapy (range, 1 - 10); 64% had ≥ 3 prior lines. Progression < 2 years after initial chemoimmunotherapy (POD24) occurred in 55% of patients, and 68% were refractory to last prior treatment. Axi-cel was successfully manufactured for all enrolled patients. With a median follow-up of 17.5 months (range, 1.4 - 31.6), the ORR was 92% among efficacy-evaluable patients with iNHL (n = 104), with a 76% CR rate. In patients with FL (n = 84), the ORR was 94% (80% CR rate); in those with MZL (n = 20), the ORR was 85% (60% CR rate). ORR was comparable across key risk groups analyzed by FLIPI, POD24, GELF, refractory status, and prior lines of therapy. As of the data cutoff, 62% of all treated patients had ongoing responses (64% for FL). The medians for DOR, PFS, and OS were not reached; 12-month estimated rates were 72% (95% CI, 61 - 80), 74% (95% CI, 63 - 82), and 93% (95% CI, 86 - 97), respectively. AEs of any grade occurred in 99% of all treated patients. Grade ≥ 3 AEs occurred in 86% of patients with iNHL (85% in FL; 95% in MZL), most commonly neutropenia (33%), decreased neutrophil count (27%), and anemia (23%). Grade ≥ 3 cytokine release syndrome (CRS; per Lee, et al, Blood. 2014) occurred in 7% of patients with iNHL (6% in FL; 9% in MZL). Grade ≥ 3 neurologic events (NEs; per CTCAE v4.03) occurred in 19% of patients with iNHL (15% in FL; 41% in MZL). Most CRS (118/119) and NEs (81/87) of any grade resolved by data cutoff. Grade 5 AEs occurred in 3 patients: multisystem organ failure in the context of CRS (Day 7; related to axi-cel; n = 1 FL), aortic dissection (Day 399; unrelated to axi-cel; n = 1 FL), and coccidioidomycosis infection (Day 327; unrelated to axi-cel; n = 1 MZL). The median peak CAR T cell level was 38 cells/µL (range, 0 - 1415) in all treated patients with iNHL, with 36 cells/µL (range, 0 - 1415) in those with FL and 53 cells/µL (range, 2 - 453) in those with MZL. The AUC0 - 28 was 448 cells/µL × days (range, 6 - 19,900) in all treated patients with iNHL, with 422 cells/µL × days (range, 6 - 19,900) and 552 cells/µL × days (range, 13 - 6468) in those with FL and MZL, respectively. The median time to peak was 9 days (range, 8 - 371) in all patients, 8 days (range, 8 - 371) in patients with FL, and 15 days (range, 8 - 29) in patients with MZL. In efficacy-evaluable patients with FL, median peak CAR T cell levels were numerically greater in those with ongoing response at 12 months than in those who relapsed (P = .057). In all treated patients with FL, CAR T cell peak was associated with Grade ≥ 3 CRS (P = .031) and NEs (P = .005). Conclusions: Axi-cel had considerable and durable clinical benefit in patients with iNHL, with high ORR and CR rates. Axi-cel had a manageable safety profile, with lower rates of Grade ≥ 3 NEs observed in patients with FL vs those in patients with MZL and those previously reported in aggressive NHL (Locke, et al. Lancet Oncol. 2019). Disclosures Chavez: Genentech: Speakers Bureau; Epizyme: Speakers Bureau; Gilead: Consultancy; Verastem: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Pfizer: Consultancy; Celgene: Consultancy; AstraZeneca: Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Merck: Research Funding; Bayer: Consultancy; BeiGene: Speakers Bureau; Karyopharm: Consultancy; AbbVie: Consultancy. Sehgal:Juno Therapeutics: Research Funding; TP Therapeutics: Research Funding; Prothena: Research Funding; Gilead Sciences: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding. William:Celgene: Consultancy, Honoraria; Incyte: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Dova: Research Funding; Guidepoint Global: Consultancy; Kyowa Kirin: Consultancy, Honoraria. Munoz:Incyte: Research Funding; Fosunkite: Consultancy; Innovent: Consultancy; Acrotech/Aurobindo: Speakers Bureau; Verastem: Speakers Bureau; AstraZeneca: Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy; Beigene: Consultancy, Speakers Bureau; Merck: Research Funding; Portola: Research Funding; Millenium: Research Funding. Salles:BMS/Celgene: Honoraria, Other: consultancy or advisory role; Kite, a Gilead Company: Honoraria, Other: consultancy or advisory role ; Epizyme: Honoraria, Other: consultancy or advisory role; Janssen: Honoraria, Other: consultancy or advisory role; MorphoSys: Honoraria, Other: consultancy or advisory role; Novartis: Honoraria, Other: consultancy or advisory role; Roche: Honoraria, Other: consultancy or advisory role; Abbvie: Other: consultancy or advisory role; Autolos: Other: consultancy or advisory role; Debiopharm: Consultancy, Honoraria, Other: consultancy or advisory role; Genmab: Honoraria, Other; Karyopharm: Honoraria; Takeda: Honoraria. Munshi:Kite, a Gilead Company: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau. Maloney:Celgene: Consultancy, Honoraria, Research Funding; Bioline Rx: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties, Research Funding; Gilead Science: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Genentech: Consultancy, Honoraria. de Vos:Bayer: Consultancy; Verastem: Consultancy. Reshef:Kiadis: Research Funding; Monsanto: Consultancy; Novartis: Honoraria; Magenta: Consultancy; Atara: Consultancy, Research Funding; Celgene: Consultancy; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Immatics: Research Funding; Shire: Research Funding; Bluebird: Research Funding; Gilead: Consultancy, Honoraria, Other: Travel support, Research Funding. Leslie:Epizyme: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; BMS: Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yakoub-Agha:Celgene: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Oluwole:Bayer: Consultancy; Spectrum Pharmaceuticals: Consultancy; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Fung:AstraZeneca: Honoraria, Other: speakers' bureau, travel support; Genentech: Honoraria, Other: speakers' bureau, travel support; AbbVie: Honoraria, Other: speakers' bureau, travel support; Kite, a Gilead Company: Honoraria, Other: speakers' bureau, travel support; Sanotif: Honoraria, Other: speakers' bureau, travel support; Takeda: Honoraria, Other: speakers' bureau, travel support; Janssen Oncology: Honoraria, Other: speakers' bureau, travel support. Rosenblatt:Merck: Other: consultancy or advisory role ; Biograph55: Other: consultancy or advisory role, Research Funding; Synergy: Patents & Royalties; University of Miami: Other: Leadership. Rossi:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Goyal:Kite, a Gilead Company: Current Employment. Plaks:Kite, a Gilead Company: Current Employment, Other: travel support; Gilead Sciences: Other: stock or other ownership . Yang:Kite, a Gilead Company: Current Employment. Lee:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Godfrey:IGM Biosciences: Current Employment, Current equity holder in publicly-traded company. Vezan:Kite, a Gilead Company: Current Employment, Honoraria, Other: Travel support; Abbvie: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company. Avanzi:Kite, a Gilead Company: Current Employment, Other: travel support; Gilead Sciences: Other: stock or other ownership ; MSKCC: Patents & Royalties. Neelapu:N/A: Other; Calibr: Other; Poseida: Research Funding; Cellectis: Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Adicet Bio: Other; Legend Biotech: Other; Precision Biosciences: Other: personal fees, Research Funding; Incyte: Other: personal fees; Cell Medica/Kuur: Other: personal fees; Allogene Therapeutics: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Celgene: Other: personal fees, Research Funding; Novartis: Other: personal fees; Bristol-Myers Squibb: Other: personal fees, Research Funding; Unum Therapeutics: Other, Research Funding; Karus Therapeutics: Research Funding; Acerta: Research Funding; Takeda Pharmaceuticals: Patents & Royalties.

In spite of newly emerging therapies and the improved survival of patients with non-Hodgkin lymphoma (NHL), relapses or primary refractory disease are commonly observed and associated with dismal prognosis. Although discovery of the anti-CD20 antibody rituximab has markedly improved outcomes in B-cell NHL, rituximab resistance remains an important obstacle to successful treatment of these tumors. To improve the efficacy of CD20-targeted therapy, we fused interleukin 21 (IL-21), which induces direct lymphoma cytotoxicity and activates immune effector cells, to the anti-CD20 antibody (αCD20-IL-21 fusokine). We observed substantially enhanced IL-21R-mediated signaling by the fusokine compared with native IL-21 at equimolar concentrations. Fusokine treatment led to direct apoptosis of lymphoma cell lines and primary tumors that otherwise were resistant to native IL-21 treatment. In addition to direct cytotoxicity, the fusokine enhanced NK cell activation, effector functions, and interferon γ production, resulting in greater antibody-dependent cell-mediated cytotoxicity compared with IL-21 and/or anti-CD20 antibody treatments. Further, the αCD20-IL-21 fusokine stabilizes IL-21 and prolongs its half-life. In vivo αCD20-IL-21 therapy resulted in a significant tumor control in the rituximab-resistant A20-huCD20 tumors. Collectively, the dual functional ability of the αCD20-IL-21 fusokine to induce direct apoptosis and activate immune effector cells may provide benefit over existing treatments for NHL.

Between 11 and 37% of extranodal marginal zone lymphoma (EMZL) patients present with disease involvement in multiple mucosal sites (MMS). We analyzed 405 EMZL patients seen between 1995 and 2017: 265 (65.4%) patients presented with stage I disease, 49 of 309 (15.8%) patients with bone marrow involvement, and 35 of 328 (10.7%) patients with monoclonal gammopathy (MG). Forty-three (10.6%) patients had MMS presentation, which was more frequently seen in patients aged >60 years (55.8%). Five (17.9%) of 28 MMS patients had MG. MMS patients commonly exhibited the International Prognostic Index (IPI) >2 (79.1%), Follicular Lymphoma International Prognostic Index (FLIPI) >2 (39.5%), and Mucosa-Associated Lymphoid Tissue Lymphoma International Prognostic Index (MALT-IPI) 2-3 (60.5%). Both MMS presentation and MG were associated with shorter survival univariately. In multivariable Cox regression models, shorter progression-free survival (PFS) and overall survival (OS) were observed in patients with MMS (hazard ratio [HR] = 3.08 and 2.92, respectively), age ≥60 years (HR = 1.52 and 2.45, respectively), and in patients who failed to attain a complete remission following initial therapy (HR = 3.27 and 2.13, respectively). Elevated lactate dehydrogenase was associated with shorter PFS (HR = 1.92), while anemia (HR = 2.46) was associated with shortened OS. MALT-IPI ≥2 (HR = 2.47 and 4.75), FLIPI >2 (HR = 1.65 and 2.09), and IPI >2 (HR = 2.09 and 1.73) were associated with shorter PFS and OS, respectively. Higher grade transformation (HGT) occurred in 11 (25.6%) MMS patients with a 5-year cumulative incidence of 13.2% (95% CI 4.7-26.1%). EMZL patients with MMS presentation represent a novel clinical subset associated with shorter PFS, OS, and higher incidence of HGT that needs novel therapeutic approaches.

Presented here are the 5-year end-of-study results from the pivotal phase 2 trial of brentuximab vedotin in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) after failed hematopoietic autologous stem cell transplantation. At 5 years, the overall patient population (N = 102) had an estimated overall survival (OS) rate of 41% (95% confidence interval [CI]: 31-51) and progression-free survival (PFS) rate of 22% (95% CI: 13-31). Patients who achieved a complete response (CR) to brentuximab vedotin (N = 34) had estimated OS and PFS rates of 64% (95% CI: 48-80%) and 52% (95% CI: 34-69%), respectively. The median OS and PFS were not reached in CR patients, with 13 patients (38% of all CR patients) remaining in follow-up and in remission at study closure. Of the 13 patients, 4 received consolidative hematopoietic allogeneic stem cell transplant, and 9 (9% of all enrolled patients) remain in sustained CR without receiving any further anticancer therapy after treatment with brentuximab vedotin. Of the patients who experienced treatment-emergent peripheral neuropathy, 88% experienced either resolution (73%) or improvement (14%) in symptoms. These 5-year follow-up data demonstrate that a subset of patients with R/R HL who obtained CR with single-agent brentuximab vedotin achieved long-term disease control and may potentially be cured. The trial was registered at www.clinicaltrials.gov as #NCT00848926.

B lymphocytes play a role in inhibiting the immune response against certain tumors, but the underlying mechanisms are poorly understood. EMT-6 mammary tumors grow well in wild-type (WT) mice but show reduced growth in B-cell-deficient μ−/− BALB/c mice (BCDM). WT mice demonstrate extensive B-cell infiltration into the tumor bed, reduced CD8+ T cell and CD49+ NK cell infiltration, and markedly reduced cytolytic T-cell response relative to BCDM. Expression of LAP/TGF-β1, CD80, CD86 and PD-L1 is significantly increased in tumor-infiltrating B cells (TIL-B) relative to splenic B cells. LAP/TGF-β1 expression on TIL-B progressively increased from 5.4±1.7% on day 8 to 43.1±6.1% by day 21 post tumor implantation. Co-culture of EMT-6 tumor cells with Naive-B cells ex vivo generated B cells (EMT6-B) with a similar immunophenotype to TIL-B. Purified TIL-B, or in-vitro-generated EMT6-B suppressed CD4+, CD8+ and CD4+CD25− T-cell proliferation, and Th1 cytokine secretion, and also suppressed purified NK-cell proliferation in response to IL-15, compared to naive splenic B cells. Acquired B regulatory function required direct tumor cell: B-cell contact, and was partially reversed by antibody to TGF-β or PD-L1, leading to tumor rejection in vivo. B-cell acquisition of a suppressive phenotype following tumor infiltration may result in profound inhibition of T-cell anti-tumor responses.

Antibody-directed therapies allow greater selectivity in targeting of tumor associated antigens and spare normal cells. Brentuximab vedotin is an anti-CD30 antibody–drug conjugate. It has demonstrated impressive activity in the treatment of refractory and or relapsed Hodgkin's lymphoma, anaplastic large cell lymphoma and other CD30+ lymphoid malignancies. Several ongoing trials are testing the potential use of brentuximab vedotin for treatment of various CD30+ and CD30- malignancies in the setting of high-risk untreated disease. It is being tested in combination with chemotherapy, and testing in combination with immune therapy is also planned. CD30 plays a pivotal role in immune regulation and is also an attractive new target for intervention in the setting of select auto-immune diseases, as well as graft versus host disease.

Purpose: Breg (B regulatory) cells have been implicated in suppression of anti-tumor response in murine and human solid tumors. Prior studies in our laboratory demonstrated that murine EMT-6 breast carcinoma is rejected in B cell deficient mice (BCDM), but not in wild type (WT) mice, due to an enhanced immune response. Tumor infiltrating B cells (TIL-B), and normal splenic B cells co-cultured with EMT-6 (EMT6-B), express LAP/TGF-β, PD-L1, and suppress CD8+ and NK cell proliferation in vitro. Increased CD8+ and NK cell infiltration into the tumor bed is seen in BCDM. BCDM tumor rejection is abrogated by NK depletion. We studied EMT6-B effects on NK cell phenotype, proliferation and cytokine expression in vitro and in vivo. Experimental design: Normal splenic B cells were co-cultured with mitomycin C treated EMT-6, and Breg phenotype, and effects on NK cell phenotype and proliferation and cytokine function were studied in vitro and in vivo. Results: EMT6-B but not WT splenic B cells inhibited CFSE labeled CD49b+ NK cell proliferation in response to IL-15 in dose dependent fashion. EMT-6-B suppressed expression of CD226 and NKG2D activating receptors on NK cells, and increased expression of PD-1 and PD-L1 respectively. EMT6-B suppressed the induction of IFNγ+/CD49b+ NK cells following PMA/ION stimulation as assayed by intracellular flow cytometry (10%±1.2 to 2%±0.5) and also suppressed IL-2 induced induction of IFNγ+/CD49b+ NK cells (70%±5 to 20%±7.8). EMT-6 and CT26 colon carcinoma conditioned B cells, but not C166 endothelial cell conditioned B cells suppressed NK degranulation (IFNγ+/CD107a+ NK cells). EMT6-B inhibited YAC-1 cell induced NK cell degranulation, and killing of YAC-1 targets, more effectively than naïve B cells (40%±6.2 to 18%±5.1) (P=0.05). NK suppression was inhibited by anti-PD-L1, and anti-TGF-β antibody. EMT6-B expressed increased FasL compared to splenic B cells, and induced NK apoptosis as measured by 7AAD/Annexin-V staining. Blocking antibody to FasL decreased NK apoptosis, and restored NK cell proliferation. Infiltrating NK cells in the EMT6 tumor bed demonstrated increased PD-1 compared to splenic and TDLN NK cells, and higher levels of IFN-γ, CD107a, and Granzyme B in BCDM vs. WT mice. EMT6 expressed high levels of CD155 NK inhibitory ligand compared to C166 endothelial cells. The EMT-6 tumor bed contained higher levels of CD19+CD155+ B cells (22% / tumor bed vs 6% / TDLN, vs 9%/ spleen). BCDM expressed higher levels of CD226+/Ki67+ NK cells in spleen compared to WT splenic NK cells. Antibodies to Fas-L, TGF-beta, and PD-L1 partially restored anti-tumor response in WT mice and decreased tumor growth. Conclusions: EMT-6 TIL-B or normal B cells conditioned by EMT-6 coculture acquire an NK suppressive phenotype which inhibits NK cell activation, proliferation, degranulation and cytotoxic function. Targeting of Breg-NK interactions may improve anti-tumor immune response. Citation Format: Yu Zhang, Muhammad Husnain, Zhifen Luo, Mahmood Al Bayati, Joseph D. Rosenblatt. EMT-6 tumor conditioned Breg cells inhibit NK cell proliferation and cytotoxic activity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3333.

Prolymphocytic transformation is a concept usually applied in the context of chronic lymphocytic leukemia/small lymphocytic lymphoma to describe the presence of a high percentage of prolymphocytes in peripheral blood (usually more than 55%). Prolymphocytic transformation has also been reported in mantle cell lymphoma (MCL) but only rarely in splenic marginal zone lymphoma (SMZL). We present two splenic B-cell lymphomas presenting in the leukemic phase and with increased prolymphocytes, both classified as SMZL with prolymphocytic transformation. One case clinically simulated B-prolymphocytic leukemia (B-PLL). Both lymphomas were very unusual because the tumor cells diffusely and strongly expressed cyclin D1 despite lacking the t(11; 14)(q13; q32) as detected by several approaches including next-generation sequencing, fluorescence in situ hybridization using CCND1 break apart probe and fusion probes for t(11; 14)(q13; q32), and conventional karyotyping. These cases therefore simulated prolymphocytic variants of MCL. The incidence of this phenomenon is unknown, and awareness of this potential alternate protein expression pattern is important in order to avoid diagnostic errors.

BACKGROUND: Mantle cell lymphoma is characterized by short remissions and a median overall survival (OS) of less than 6 years with standard chemotherapy. We previously reported results of a single-arm phase II clinical trial of intensive chemotherapy induction with R-MACLO-IVAM followed by thalidomide maintenance with promising progression-free survival (PFS) and OS (Lossos et al. Leuk Lymph 2010). A subsequent single-arm phase II clinical trial assessing rituximab (R) rather than thalidomide maintenance was conducted and preliminary data communicated (Hosein et al. Am J Hematol 2015). We now present the final results of these studies. METHODS: Two prospective single-arm phase II clinical trials conducted at the University of Miami were IRB approved. Eligible patients were chemotherapy-naïve with confirmed diagnosis of MCL using WHO criteria, age 18-75 years, ECOG PS: 0-2, adequate organ function and no history of HIV or prior cancer. Pretreatment staging included CT and PET scans, colonoscopy and bone marrow biopsy. The chemotherapy regimen has been previously described (Lossos et al. Leuk Lymph 2010). Patients who achieved complete responses (both radiologically and pathologically) were eligible for the maintenance phase. Between June 2004 and 2019, 44 patients were enrolled; the first 22 patients received maintenance therapy with thalidomide (200 mg daily until relapse/intolerable toxicity) and a subsequent cohort of 22 patients received R (375mg/m2 IV weekly x 4 weeks, repeated every 6 months for 3 years). OS was calculated from date of diagnosis to date of death or last follow up, and PFS from date of diagnosis to the date of pathological evidence of recurrence or death. Analysis was performed using the Kaplan-Meier method, and the log-rank or Wilcoxon test for group comparison. RESULTS: Median PFS in thalidomide and R cohorts were 7.8 and 8.1 years, and 10-year OS 63.6% and 57.8%, respectively. There was no statistically significant PFS or OS difference between patients treated with thalidomide or R maintenance (Wilcoxon p= 0.988 and p= 0.564, respectively). Therefore, all 44 patients were evaluable together for toxicity and 43 for response. Median age was 58 (range 39-73 years), most patients were males (35, 79.5%) and ECOG PS ≤ 1 (42, 95.5%). All patients had at least stage III disease, with bone marrow involvement in 38 (86.4%), gastrointestinal involvement in 23 out of 39 (59%), and elevated LDH in 14 (68.2%) patients. Ki67 was >30% in 20 (54.1%) and blastic variant in 6 (13.6%) patients. Most patients presented with IPI ≥ 3 (23, 52.3%) and intermediate-high MIPI (30, 68.1%) scores. 36 completed all 4 cycles of therapy, treatment was stopped in 6 after 3 cycles, and in 1 after 2 cycles. 1 patient died during the first cycle. Of the 43 patients completing 2 cycles of chemotherapy 41 (95.3%) achieved complete response (CR) and 2 (4.7%) partial response (PR). There were 23 (52.3%) events for PFS (19 relapses, 4 deaths without documented progression/relapse), and 14 (31.8%) total deaths over a median follow up of 6.7 years (range 1-15). The 5 and 10-year PFS were 54.9% (95%CI: 37.6-69.2%) and 39.2% (95%CI: 22.3-55.8%), respectively; median PFS 8 years (95%CI: 3.9-12.5 years). 5 and 10-year OS were 84.4% (95%CI: 68.4-92.7%) and 60.4% (95%CI: 41.2-75.1%), respectively; and median OS was not reached. PFS and OS were statistically significant shorter in the high-risk MIPI group than intermediate and low groups (5-year PFS rates: 23.1% vs. 53.8% vs. 92.9%, respectively, p CONCLUSIONS: These phase II clinical trials implementing frontline R-MACLO-IVAM in MCL demonstrate high overall response rates (95.3% CR and 4.7% PR) with encouraging PFS and OS. Notably, high risk patients such as those with blastic variant and high-risk MIPI score also demonstrated favorable outcomes compared to historical controls. Results demonstrate that R-MACLO-IVAM is an effective regimen to induce long-term remission and survival in MCL, without need for consolidation with stem-cell transplant. Disclosures Alderuccio: OncLive: Consultancy; Puma Biotechnology: Other: Immediate family member; Agios: Other: Immediate family member; Foundation Medicine: Other: Immediate family member; Inovio Pharmaceuticals: Other: Immediate family member; Targeted Oncology: Honoraria. Alencar:Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Rosenblatt:Mologen AG: Employment; Kite Pharma: Employment; Synergys Technologies: Employment; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Merck: Employment. Lossos:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Janssen Scientific: Membership on an entity's Board of Directors or advisory committees; NIH: Research Funding.

A phase II trial of R-MACLO-IVAM followed by thalidomide maintenance for mantle cell lymphoma (MCL) demonstrated promising progression-free survival (PFS) and overall survival (OS) rates. Thalidomide maintenance was associated with significant toxicity and was subsequently modified to rituximab maintenance. Herein, we present updated results and follow-up. Two sequential phase II trials included chemotherapy-naive patients with MCL up to 75 years old. Four cycles of R-MACLO-IVAM chemotherapy were delivered as previously described. Patients who achieved complete responses (CR) were eligible for thalidomide or rituximab maintenance therapy. Among 36 patients enrolled, the MCL International Prognostic Index (MIPI) was low in 53%, intermediate in 36% and high in 11%. Thirty-five patients completed at least 2 cycles of chemotherapy; 34 (94%) achieved a CR. After a median follow-up of 74.4 months, the 5-year PFS was 51% (95% CI 33–68%) and the 5-year OS was 85% (95% CI 73–97%). Two deaths occurred during the chemotherapy phase due to disease progression and neutropenic sepsis, respectively. One patient developed secondary acute myeloid leukemia after 7 years. R-MACLO-IVAM chemotherapy is effective for patients with newly diagnosed MCL. Am. J. Hematol. 90:E111–E116, 2015. © 2015 Wiley Periodicals, Inc.

Lymphoma is a common malignancy observed in companion animals. This type of naturally occurring neoplasia has been uncommonly reported in great apes. Diffuse large B-cell lymphoma was diagnosed in an 8-yr-old captive orangutan (Pongo pygmaeus) with gastrointestinal disease by histologic and immunohistochemical methodologies. The orangutan was treated with three cycles of combination chemotherapy (intravenous Rituxan, cyclophosphamide, doxorubicin, and vincristine). The primate has been in good health and exhibiting normal behaviors for more than 15 mo following treatment.

This pivotal phase 2 study evaluated the safety and efficacy of brentuximab vedotin in patients with relapsed or refractory (R/R) systemic anaplastic large cell lymphoma (ALCL). After a median observation period of approximately 6 years from first treatment, we examined the durability of remission, progression-free survival (PFS), overall survival (OS), and safety outcomes of patients treated on this trial. Among all enrolled patients (n = 58), no progressions were observed beyond 40 months, and median OS was not reached. Patients with a complete response (CR), as assessed by the investigator (38 of 58, 66%), continued to demonstrate improved outcomes with neither median OS nor PFS reached. Of the 38 CR patients, 16 received a consolidative stem cell transplant (SCT) with median PFS not reached. Among patients who were on-study and in remission at study closure, 16 patients had not received any new treatment after single-agent brentuximab vedotin other than consolidative SCT. Among this subset of 16 patients, 8 received SCT, and the remaining 8 patients (14% of all enrolled patients) remained in sustained remission without consolidative SCT or any new anticancer therapy. Thirty-three patients experienced peripheral neuropathy, among whom, the majority (30 of 33, 91%) had experienced resolution or improvement at their last assessment. These final results, which demonstrated a high rate of peripheral neuropathy resolution, and durable remissions in a subset of patients with relapsed or refractory systemic ALCL, provide evidence that single-agent brentuximab vedotin may be a potentially curative treatment option. This trial was registered at www.clinicaltrials.gov as #NCT00866047.

SUMMARY Brentuximab vedotin is a novel agent indicated for the treatment of relapsed and refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Brentuximab vedotin is an antibody–drug conjugate consisting of chimeric anti-CD30 antibody cAC10, linked to four molecules of monomethylauristatin E, a tubulin destabilizer. It was granted US FDA approval in 2011 following two pivotal Phase II studies showing objective responses of 75 and 86% in heavily pretreated relapsed and refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, respectively. Brentuximab vedotin can be used as a bridge to more definitive stem cell transplant. There are currently over 30 open clinical studies involving the use of brentuximab vedotin used as single agent or combined with chemotherapy in both front-line and salvage settings. These studies include use in other CD30-positive B- and T-cell lymphomas, as well as in CD30-positive germ cell tumors. In clinical practice brentuximab vedotin has been associated with significant sensory and motor neuropathies and clinicians should be alert to the potential for significant neuropathy and the need for dose reduction. However, the potential for significant neuropathy must be balanced against the remarkable clinical benefit of brentuximab vedotin in patients with heavily pretreated relapsed and refractory lymphomas.

Our laboratory has been investigating the role of B cells on tumor immunity. We have studied the immune response in mice that are genetically lacking in B cells (BCDM) using a variety of syngeneic mouse tumors and compared immune responses in BCDM with those seen in wild type (WT) immunocompetent mice (ICM). A variety of murine tumors are rejected or inhibited in their growth in BCDM, compared with ICM, including the EL4 thymoma, and the MC38 colon carcinoma in C57BL/6 mice, as well as the EMT-6 breast carcinoma in BALB/c mice. In all three murine models, tumors show reduced growth in BCDM which is accompanied by increased T cell and NK cell infiltration, and a more vigorous Th1 cytokine response, and increased cytolytic T cell response in the absence of B cells. Reconstitution of the mice with B cells results in augmented tumor growth due to a diminished anti-tumor immune response and in reduction in CD8+ T cell and NK cell infiltration. Studies involving BCR transgenic mice indicated that B cells inhibit anti-tumor T cell responses through antigen non-specific mechanisms. More recent studies using the EMT-6 model demonstrated that both the number and function of Treg cells in ICM was increased relative to that seen in BCDM. Increased expansion of Treg cells was evident following EMT-6 implantation in ICM relative to that seen in non-tumor-bearing mice or BCDM. The percentage and number of Tregs in spleen, tumor draining lymph nodes, and the tumor bed are increased in ICM compared with BCDM. Treg functional capacity as measured by suppression assays appears to be reduced in BCDM compared with ICM. In contrast to other described types of B regulatory activity, adoptive transfer of B cells can rescue tumor growth independently of the ability of B cells to secrete IL-10, and also independently of MHC-II expression. In experiments using the MC38 adenocarcinoma model, BCDM reconstituted with WT B cells support tumor growth while tumor growth continues to be inhibited in BCDM reconstituted with OX40L(-/-) B cells. This suggests that interaction between OX40 on T cells and OX40-ligand on B cells may be important in modulating anti-tumor immune response. Ongoing experiments in the laboratory indicate that B cells migrate to the site of tumor and acquire expression of immunosuppressive ligands and/or cytokines that contribute to the inhibition of anti-tumor immune response. Significant infiltration of human tumors by Treg cells as well as B cells suggests that observations made in murine systems may be applicable to human tumors as well.

This phase I trial was initiated to evaluate the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of the glycolytic inhibitor, 2-deoxy-D-glucose (2DG) in combination with docetaxel, in patients with advanced solid tumors.A modified accelerated titration design was used. 2DG was administered orally once daily for 7 days every other week starting at a dose of 2 mg/kg and docetaxel was administered intravenously at 30 mg/m(2) for 3 of every 4 weeks beginning on day 1 of week 2. Following the completion of dose escalation, cohorts of patients were then treated with 2DG for 21 days or every day of each 4-week cycle for up to 12 cycles.Thirty-four patients were enrolled: 21 on every other week, 6 on a 21 of 28-day cycle and 7 on the continuous 2DG dosing schedule. There were no dose-limiting toxicities which met the MTD criteria. The most common adverse events were fatigue, sweating, dizziness and nausea mimicking the hypoglycemic symptoms expected from 2DG administration. Therefore, 63 mg/kg was selected as the clinically tolerable dose. The most significant adverse effects noted at 63-88 mg/kg doses were reversible hyperglycemia (100 %), gastrointestinal bleeding (6 %) and reversible grade 3 QTc prolongation (22 %). Eleven patients (32 %) had stable disease, 1 patient (3 %) partial response and 22 patients (66 %) progressive disease as their best response. There was no PK interaction between 2DG and docetaxel.The recommended dose of 2DG in combination with weekly docetaxel is 63 mg/kg/day with tolerable adverse effects.

The balance between immune effector cells such as T cells and natural killer cells, and immunosuppressive Treg cells, dendritic, myeloid and monocytic sub-populations in the tumor microenvironment acts to calibrate the immune response to malignant cells. Accumulating evidence is pointing to a role for B cells in modulating the immune response to both solid tumors and hematologic cancer. Evidence from murine autoimmune models has defined B regulatory cell (Breg) subsets that express cytokines such as IL-10, TGF-β, and/or express immune regulatory ligands such as PD-L1, which can suppress T cell and/or natural killer cell responses. Multiple murine tumor models exhibit decreased tumor growth in B cell deficient or B cell depleted mice. In several of these models, B cells inhibit T cell mediated tumor immunity and/or facilitate conversion of T cells to CD4(+)CD25(+)FoxP3(+) T regs, which act to attenuate the innate and/or adaptive antitumor immune response. Mechanisms of suppression include the acquisition of inhibitory ligand expression, and phosphorylation of Stat3, and induction of IL-10 and TGF-β, resulting in a Breg phenotype. Breg suppressive activity may affect diverse cell subtypes, including T effector cells, NK cells, myeloid derived suppressor cells (MDSC) and/or tumor associated macrophages. B cells may also directly promote tumorigenesis through recruitment of inflammatory cells, and upregulation of pro-angiogenic genes and pro-metastatic collagenases. Breg infiltration has now been identified in a variety of solid tumor malignancies including but not limited to ovarian, gastric, non-small cell lung cancer, pancreatic, esophageal, head and neck, and hepatocellular carcinomas. Increasing evidence suggests that recruitment of B cells and acquisition of suppressive activity within the tumor bed may be an important mechanism through which B cells may modulate innate and/or adaptive anti-tumor immunity. B cell depletion in the clinic using anti-CD20 antibodies and/or inhibitors of BTK and/or other signaling pathways, may be a useful strategy for augmenting the anti-tumor immune response.

Clofazimine-induced crystal-storing histiocytosis is a rare complication of treatment previously reported in dermatology literature as a complication of leprosy therapy. We report a case of disseminated Mycobacterium abscessus requiring treatment with high-dose oral clofazimine resulting in enteropathy in a patient who presented with abdominal pain, malnutrition, and melena.

The mechanisms by which B lymphocytes inhibit anti-tumor immunity remain poorly understood. Murine EMT-6 mammary tumors grow readily in immune competent mice (BALB/c), but poorly in B-cell-deficient μ(-/-) BALB/c mice (BCDM). T regulatory cell (Treg) expansion and function were impaired in BCDM compared with BALB/c. In this study, we compared tumor growth, Treg cell proliferation, tumor lymphocyte infiltration and cytolytic T cell activity in BALB/c, BCDM and BCDM partially reconstituted with B cells by adoptive transfer (BCDM+B). Partial reconstitution of BCDM with adoptively transferred B cells restored EMT-6 tumor growth, which was independent of IL-10 secretion by B cells. Instead, high frequencies of intratumoral B cells were associated with increased recruitment and proliferation of Treg cells within the tumor microenvironment. The B-cell-dependent accumulation of Treg within the tumor microenvironment was associated with reduced tumor infiltration by CD49+ NK and CD8+ T cells and reduced cytotoxic T cell activity against EMT-6 targets. Our studies indicate that tumor-dependent immunosuppression of T-cell-mediated anti-tumor immunity is coordinated within the tumor microenvironment by B-cell-dependent cross talk with Treg cells, which does not require production of IL-10 by B cells.

To determine how patient race, ethnicity, and degree of poverty affect treatment and survival for acute myeloid leukemia (AML).A linked database of the Florida cancer registry and State inpatient and outpatient hospital data for 1998-2002 was queried. Effects of demographic and treatment characteristics on survival were explored using univariate and multivariate analyses methods.A total of 4659 patients with AML were identified. Over 50% of patients with AML were 70 years of age or older. African American (AA) patients were diagnosed at significantly younger ages than were whites (P0.001). In multivariate analysis, independent predictors of worse survival in AML were aged over 50 (hazard ratios [HRs]: 1.60, 2.15, 3.04, and 3.62 over the decade-cohorts, all P0.001), AA race (HR: 1.27, P0.001), being a former or current user of tobacco (HR: 1.13, P = 0.004 and HR: 1.28, P0.001, respectively), residing in an area with the highest poverty level (HR: 1.15, P = 0.007), and being covered only by Medicaid (HR: 1.23, P = 0.014). No differences in outcomes were observed related to gender or ethnicity. Receipt of chemotherapy was strongly associated with improved survival (HR: 0.59, P0.001). When only those patients who received and appeared to respond to treatment are included, AAs continued to demonstrate a worse outcome than Whites.AML disproportionately affects the elderly. AA patients and patients from poorer communities with AML have significantly worse survival. Interventions to provide earlier diagnosis in these patients as well as to improve overall outcomes are needed to address these disparities.

CD30 is abundantly and selectively expressed on the surface of Hodgkin Reed-Sternberg cells, anaplastic large cell lymphomas (ALCLs), and other lymphoid malignancies as well as on several non-lymphoid malignancies including selected germ cell tumors. Expression of CD30 on normal cells is highly restricted, thereby allowing differential targeting of malignant cells. CD30, a member of the tumor necrosis factor (TNF)-receptor family has pleiotropic biologic functions, and antibodies targeting CD30 and other TNF family receptors can exhibit both agonistic and antagonistic signaling functions. Recently, antibody-drug conjugates targeting CD30, such as brentuximab vedotin, have shown striking activity in phase I and II trials, with manageable toxicity. This has defined an important emerging role for targeting of CD30 in the setting of Hodgkin lymphoma, ALCL, and possibly other CD30+ malignancies.

Novel therapeutic approaches are needed in mantle cell lymphoma (MCL). We conducted a phase II study in MCL testing an intensive regimen, R-MACLO-IVAM-T, a modification of the NCI 89-C-41 protocol. Newly diagnosed patients were treated with rituximab, methotrexate, doxorubicin, cyclophosphamide, and vincristine (cycle 1) followed by rituximab, ifosfamide (and mesna), etoposide, and cytarabine (cycle 2). These two cycles were repeated once, and patients achieving complete response (CR) received maintenance thalidomide. Among the 22 patients enrolled, 21 completed two or more cycles and achieved a CR. Three patients relapsed, while 17 are alive and relapse-free after a median follow-up of 37 months (range 19-65 months). Two patients died: one from sepsis during cycle 1 and another at 38 months while in remission from MCL. The progression-free survival at 3 years was 78% (95% CI: 51-91%). These results compare favorably with previously reported outcomes suggesting that durable remissions can be achieved without myeloablative therapy.

Diffuse large B-cell lymphomas (DLBCLs) can be classified into two subtypes: germinal-centre B-cell (GCB)-like and Activated B-cell (ABC)-like tumours, which are associated with longer or shorter patient overall survival, respectively. In our previous studies, we have shown that, although DLBCL tumours of GCB-like and ABC-like subtypes express similar levels of IL4 mRNA, they exhibit distinct patterns of IL-4-induced intracellular signalling and different expression of IL-4 target genes. We hypothesized that these differences may contribute to the different clinical behaviour and outcome of DLBCL subtypes. Herein, we demonstrated that IL-4 increased the sensitivity of GCB-like DLBCL to doxorubicin-induced apoptosis and complement-dependent rituximab cell killing. In contrast, IL-4 protected ABC-like DLBCL from the cytotoxic effects of doxorubicin and rituximab. The distinct effects of IL-4 on doxorubicin sensitivity in GCB-like and ABC-like DLBCL cells may be partially attributed to the contrasting effects of the cytokine on Bcl-2 and Bad protein levels in the DLBCL subtypes. These findings suggest that the different effects of IL-4 on chemotherapy and immunotherapy-induced cytotoxicity of GCB- and ABC-like DLBCL could contribute to the different clinical outcomes exhibited by patients with these two subtypes of DLBCL.

Purpose To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics, and antitumor activity of dacetuzumab in patients with refractory or recurrent B-cell non-Hodgkin's lymphoma (NHL). Patients and Methods In this open-label, dose-escalation phase I study, dacetuzumab was administered to six cohorts of adult patients. In the first cohort, patients received 2 mg/kg weekly for 4 weeks; in all other cohorts, an intrapatient dose-escalation schedule was used with increasing doses up to a maximum of 8 mg/kg. Patients with clinical benefit after one cycle of dacetuzumab were eligible for a second cycle. Results In the 50 patients who received dacetuzumab, no dose dependence of adverse events (AEs) was observed. The most common AEs in ≥ 20% of patients were fatigue, pyrexia, and headache; most were grade 1 or 2. Noninfectious inflammatory eye disorders occurred in 12% of patients. AEs grade ≥ 3 occurred in 30% of patients and included disease progression, anemia, pleural effusion, and thrombocytopenia. Most laboratory abnormalities were grade 1 or 2; transient elevated hepatic aminotransferases occurred in 52% of patients. Two patients experienced dose-limiting toxicity: grade 3 conjunctivitis and transient vision loss in cohort (1), and grade 3 ALT elevation in cohort IV. The MTD of dacetuzumab was not established at the dose levels tested. Six objective responses were reported (one complete response, five partial responses). Tumor size decreased in approximately one third of patients. Conclusion Dacetuzumab monotherapy was well tolerated in patients with NHL in doses up to 8 mg/kg/wk. Preliminary response data are encouraging and support additional studies of dacetuzumab in this patient population.

P>SGN-30, a chimeric anti-CD30 monoclonal antibody, has demonstrated potent preclinical antitumour activity in both Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL). We conducted an open-label, Phase II study to determine the safety and objective response rate of SGN-30 in 79 patients with refractory/recurrent HL (n = 38) or systemic ALCL (n = 41). Each course of SGN-30 comprised 6 weekly intravenous infusions, followed by a 2-week treatment-free period. Patients had received a median of 3 (range 1-5) prior regimens of chemotherapy or systemic therapy. The initial 40 patients received 6 mg/kg weekly; the latter 39 patients received 12 mg/kg weekly. In the ALCL group, two patients achieved a complete response and five additional patients achieved a partial response, with response durations ranging from 27 to 1460+ d. No objective responses were observed in the HL group; however, 11 patients (29%) had stable disease (duration 62-242 days). Although adverse events were common, most were mild or moderate, and no specific pattern of adverse events was observed in either disease group. These results demonstrate that weekly administration of SGN-30 is safe, with modest clinical activity in patients with ALCL.

Phase 1 testing of SGN-30, a chimeric monoclonal antibody for the treatment of CD30+ malignancies, was conducted in a multicenter study. To explore the safety profile and establish the maximum tolerated dose (MTD), 24 patients with refractory or relapsed Hodgkin lymphoma or CD30+ non-Hodgkin lymphoma received 6 weekly doses of intravenous SGN-30 at 4 dose levels (2, 4, 8, or 12 mg/kg). Serum concentrations of SGN-30 rose rapidly and were dose dependent. Adverse events were mild, with nausea, fatigue, and fever attributed to study treatment. One episode of hypersensitivity rash was reported. The MTD was not reached. Serious adverse events included herpes zoster (n = 2), influenza, and pneumonia. One patient with cutaneous anaplastic large cell lymphoma (8 mg/kg) achieved a complete response. Six patients, of whom 4 had Hodgkin lymphoma, achieved stable disease with durations ranging from 6 to 16 months. The pharmacokinetic profile of SGN-30 showed a biphasic disposition, and estimated half-lives ranging between 1 to 3 weeks. The 6 weekly infusions of SGN-30 resulted in approximately 2- to 3-fold accumulation in serum exposures consistently across the dose range. These results demonstrate that weekly administration of SGN-30 is safe and has modest clinical activity in patients with CD30+ tumors. This trial is registered at as no. [NCT00051597][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00051597&atom=%2Fbloodjournal%2F111%2F4%2F1848.atom

Treatment of cancer with cytotoxic agents may induce lymphopenia. Adoptively transferred T cells have been reported to display enhanced anti-tumor efficacy in the lymphopenic setting. We reasoned that the anti-tumor effects of adoptively transferred cells in the lymphopenic host could be further augmented through local provision of an innate stimulus in the tumor bed. Utilizing a model in which mice were irradiated to induce lymphopenia, with limited shielding to allow tumor growth, we demonstrate that "triple" therapy consisting of radiation-induced lymphopenia, adoptive transfer of naïve CD8+ T cells, and intra-tumoral HSV amplicon injection resulted in reduced tumor growth compared to the combination of any two of the aforementioned interventions. To gain insight into the mechanism underlying this effect we studied the effects of HSV amplicon transduction into tumors on cytokine expression and on anti-tumor specific T cells. HSV amplicon transduction specifically induced several cytokine mRNAs including IFN-gamma, and IP-10. Adoptively transferred transgenic OT-1 T cells directed against Ovalbumin were more effective against Ovalbumin-expressing tumors when combined with intra-tumoral HSV amplicon injections in the lymphopenic host. Following intra-tumoral HSV-amplicon injections, anti-tumor T cells secreted higher levels of interferon-gamma in response to in-vitro re-stimulation with tumor cells, implying that HSV amplicon injection provided a strong signal for T cell activation. Combining adoptive transfer of naïve T cells in the lymphopenic setting with local T cell stimulation may facilitate expansion and activation of anti-tumor T cell populations in vivo, resulting in enhanced anti-tumor responses without the need to resort to prolonged in vitro T cell culture and/or manipulation.

Advances in understanding of the immune microenvironment have highlighted the role of immunosuppressive T cell, myeloid, dendritic and monocytic sub-populations in inhibition of the anti-tumor immune response. The role of B cells in modulating the immune response to solid tumors as well as lymphoid malignancies is less well understood. Murine models of autoimmune disease have defined B regulatory cell (Breg) subsets with immune suppressive activity, including B cell subsets that express IL-10, and transforming growth factor-β, which can facilitate T regulatory cell recruitment and expansion. Multiple murine tumor models point to the existence of similar immune suppressive B cell sub-populations that can migrate into tumor deposits and acquire an immune suppressive phenotype, which then leads to attenuation of the local anti-tumor immune response. Other murine models of viral or chemically induced skin carcinogenesis have identified a pivotal role for B cells in promoting inflammation and carcinogenesis. While many human solid tumors demonstrate significant B cell infiltration and/or tertiary lymphoid structure formation, the functional properties of tumor-infiltrating B cells and their effects on immunity are poorly understood. Recent successes in early Phase I/II trials using anti-checkpoint inhibitor antibodies such as nivolumab or pidilizumab directed against PD-1 in the setting of Hodgkin’s and non-Hodgkin’s lymphomas validate the therapeutic utility of reversing B cell-mediated immune suppression. Further studies to define Breg subsets, and mechanisms of suppression, may provide new avenues for modulation of the immune response and meaningful therapeutic intervention in both lymphoid and solid tumors.

We present response and survival outcomes of a pivotal phase 2 trial of the antibody-drug conjugate brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma following autologous stem cell transplant (N = 102) after a median observation period of approximately 3 years. Median overall survival and progression-free survival were estimated at 40.5 months and 9.3 months, respectively. Improved outcomes were observed in patients who achieved a complete remission (CR) on brentuximab vedotin, with estimated 3-year overall survival and progression-free survival rates of 73% (95% confidence interval [CI]: 57%, 88%) and 58% (95% CI: 41%, 76%), respectively, in this group (medians not reached). Of the 34 patients who obtained CR, 16 (47%) remain progression-free after a median of 53.3 months (range, 29.0 to 56.2 months) of observation; 12 patients remain progression-free without a consolidative allogeneic stem cell transplant. Younger age, good performance status, and lower disease burden at baseline were characteristic of patients who achieved a CR and were favorable prognostic factors for overall survival. These results suggest that a significant proportion of patients who respond to brentuximab vedotin can achieve prolonged disease control. The trial was registered at www.clinicaltrials.gov as #NCT00848926.

New approaches are needed to improve the current treatment of lung cancer. Inducing an immune response against lung tumour cells with vaccines represents an attractive therapy. However, lung tumours had not been considered good targets for vaccine therapy and, therefore, immune approaches have not been studied extensively in this setting. Current experimental strategies for antitumour vaccines include the generation of active immune responses against specific tumour antigens. Understanding the mechanisms of antitumour immunity and identifying relevant tumour-specific antigens will probably improve therapeutic strategies and provide avenues for the future of lung cancer therapy. There have been a number of preclinical immunotherapy trials suggesting activity, and a smaller number of human clinical trials using various vaccines in lung cancer. Initial data from these trials have shown preliminary evidence of induction of immune responses and suggest clinical activity. This paper reviews some of the most important developments in vaccines for lung cancer.

It is well established that the “switch” from an avascular to the vasculogenic phenotype is required for growth as well as metastasis of the tumor. Multiple regulators of angiogenesis, positive and negative, have been described. Due to the tumor growth dependence on angiogenesis, anti-angiogenic therapy is rapidly evolving as anticancer strategy. Antibodies and inhibitors directed against pro-angiogenic signaling proteins and growth factors pathways have been shown to mediate anti-tumor activity in preclinical models as well as in clinical trials. The development of anti-angiogenic antibody therapy had great impact in the treatment of human cancers. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody has been approved for the treatment of metastatic colorectal cancer. Other antibodies and Fc fusion proteins targeting VEGFR, nerve and blood vessel guidance pathways (Robo4), plasma membrane adhesion receptors (known as integrins) or selectively neutralizing the interaction between the angiopoietins and their receptors are being tested in preclinical models and clinical trials. Direct angiogenesis inhibitors have also been tested in an attempt to suppress pathologic angiogenesis. The prototypic anti-angiogenic peptides endostatin and angiostatin had generated enormous enthusiasm initially, but so far they have not fulfilled their promise in the human setting in part due to the instability of these proteins and their short serum half-lives. We have proposed increasing the effect of the anti-angiogenic agents by targeting them to the tumor microenvironment through the creation and optimization of anti-tumor anti-angiogenic peptide fusion proteins. We have tested this hypothesis using an antibody-endostatin fusion protein with specificity for the HER2/neu target antigen in breast and other solid tumors. Linkage of the endostatin to anti-HER2 antibody could expand the spectrum of anti-tumor activities of Herceptin by focusing the anti-angiogenic properties of endostatin on HER2 expressing targets and creating a multifunctional angiogenic inhibitor with powerful anti-tumor activity. Our data indicate that Traztuzumab targeting sequences fused with endostatin may possess significantly enhanced anti-angiogenic and anti-tumor activity. We anticipate therefore that such fusion proteins, could be combined with conventional chemotherapy, radiation, and surgical procedures and will prove superior to antibody (e.g. Traztuzumab) or endostatin administered alone. The combination of fusion protein with other angiogenic strategies such as PDGF blockade, VEGF blockade, thrombospondin-1 as well as with chemotherapy remains to be tested. Targeting anti-angiogenics using this and/or similar targeting strategies may in theory enhance the efficacy of this versatile approach and improve patient outcomes.

While the role of CD4+ T cells, cytolytic T cells, natural killer cells, and Th1 response in antitumor immunity has been appreciated for decades, a variety of human and murine tumors are heavily infiltrated with cells of B cell lineage. In contrast to the well-characterized role of T cells and adaptive immunity and of NK cells and the innate response in tumor rejection, as well as the suppressive role played by T-regulatory cells (Tregs), the role of B cells in the regulation of antitumor immunity is poorly understood. Increasing evidence points to a potential role of B cells in the suppression of immune responses in the context of malignancy. This includes a variety of murine models in which B cell infiltration has been associated with increased tumor growth, and even carcinogenesis, and the identification of subsets of B cells with unique regulatory properties. Several mechanisms have been implicated in B cell-mediated regulation of immune response. This includes preferential polarization of B cells along Th1 or Th2 pathways, the elaboration of immunosuppressive cytokines such as TGF-β and interleukin-10, B cell display of immunosuppressive co-stimulatory ligands such as CD86 and PD-L1, and/or B cell support for the development of Tregs within the tumor microenvironment. Evidence is also accumulating that malignant lymphoma and leukemia B cells may distort the balance between Tregs and so-called Th17 cells leading to a tumor microenvironment that is more conducive to lymphoma growth.

Purpose Generalized lymphadenopathy is a rare presentation of prostate cancer. We report a case and review reported cases in the literature. Because of the association of chemokine receptor expression with specific metastatic patterns, we tested for expression of chemokine receptors known to mediate migration to lymph nodes. Methods We performed a MEDLINE (National Library of Medicine, Bethesda, MD) database search for case reports during the last 32 years using “prostate cancer,” “lymphadenopathy,” “metastatic to lymph nodes,” and “mimicking lymphoma” as keywords. Expression of the CXCR4 and CCR7 chemokine receptors was assessed by immunohistochemistry. Laser capture microdissection and reverse transcription polymerase chain reaction for CXCR4 were used to exclude nonspecific binding. Results Of 153 patients with prostate cancer presenting with lymphadenopathy (LAD) described in the literature, 67 (44%) presented with supraclavicular adenopathy, 29 (19%) retroperitoneal, 22 (14%) mediastinal, 15 (10%) cervical, 9 (6%) inguinal, and 2 (1%) axillary LAD. Only 9 patients presenting with generalized LAD have been previously reported. Monoclonal antibodies to CCR7 showed intense staining in the patient’s tumor epithelium. Little or no staining was observed for CXCR4. Reverse transcription polymerase chain reaction for chemokine receptors on ribonucleic acid (RNA) recovered from the patient’s sample failed to express messenger RNA for CXCR4 but did express messenger RNA for CCR1, CCR4, and CCR5. Conclusions Prostate cancer may present on rare occasions with generalized adenopathy. Variable expression of chemokine receptors may be associated with organ specific patterns of metastasis. In this case, expression of CCR7 may have accounted for the unusual predilection of this patient’s prostate cancer for lymph nodes.

We present a patient with double hit Burkitt's like lymphoma who developed a catheter-related bloodstream infection due to Mycobacterium phocaicum that was identified by rpoB gene sequencing. His infection resolved with 7 weeks of antibiotics and port-a-cath removal.

Interferon-gamma (IFN-gamma) has been shown to upregulate MHC class I and II expression, and to promote generation of specific antitumor immune responses. We hypothesized that intratumoral administration of an IFN-gamma gene transfer vector facilitates its enhanced local production and may activate effector cells locally. We conducted a phase I dose-escalation study of a replication-deficient adenovirus-interferon-gamma construct (TG1041) to determine safety and tolerability of intratumoral administration, in advanced or locally recurrent melanoma.Patients were enrolled at four successive dose levels: 10(7) infectious units (iu) (n=3), 10(8) iu (n=3), 10(9) iu (n=3), and 10(10) iu (n=2) per injection per week for 3 weeks. TG1041 was injected in the same tumor nodule weekly in each patient. Safety, toxicity, local and distant tumor responses and biologic correlates were evaluated.A total of 11 patients were enrolled and received the planned three injections per cycle. One patient with stable disease received a second cycle of treatment. A maximum tolerated dose was not reached in this study. No grade 4 toxicities were observed. Two grade 3 toxicities, fever and deep venous thrombosis were observed in one patient. The most frequently reported toxicities were grade 1 pain and redness at the injected site (n=8), and grade 1 fatigue (n=5) patients. Clinical changes observed at the local injected tumor site included erythema (n=5), a minor decrease in size of the injected lesion (n=5) and significant central necrosis by histopathology (n=1). Systemic effects included stable disease in one patient. Correlative studies did not reveal evidence of immunologic activity.Weekly intratumoral administration of TG1041 appears to be safe and well tolerated in patients with advanced melanoma.

Objective Despite wide use of the anti-CD20 monoclonal antibody rituximab in the treatment of B cell lymphomas, the mechanism by which it causes B cell depletion remains a subject of controversy. As part of an ongoing phase I/II trial of rituximab in the treatment of systemic lupus erythematosus (SLE), we sought to determine whether the effectiveness of B cell depletion was influenced by polymorphisms of Fc receptors (FcR) on effector cells. Methods During rituximab treatment of 12 SLE patients, B cell depletion was monitored as a function of the serum rituximab level and FcγRIIa and FcγRIIIa genotypes at baseline and at 1 month and 2 months after treatment. FcR genotypes were determined by polymerase chain reaction. Serum levels of rituximab were measured by enzyme-linked immunosorbent assay (ELISA). B lymphocyte percentages were assessed by flow cytometry. Results B cell depletion was highly variable in this patient cohort, with B cell percentages at the 1–2-month posttreatment nadir ranging from undetectable (

Acute leukemia carries a poor prognosis, especially in older patients, emphasizing the need for novel therapies. Reasons for treatment failure include high rates of relapse and treatment-related toxicities. Farnesyltransferase inhibitors (FTIs), a new class of agents that can interfere with intracellular signaling, are good therapeutic candidates for study in these diseases, given the relatively high levels of the target enzyme, farnesyltransferase, expressed in bone marrow and by peripheral circulating lymphocytes. ZARNESTRA™ (formerly R115777, Ortho Biotech Oncology, Raritan, NJ) is an FTI that has clinical activity in solid tumors and antileukemic activity in vitro. In a phase I trial of Zarnestra in patients with high-risk leukemia (resistant or relapsed acute myeloid leukemia [AML] or acute lymphocytic leukemia [ALL], chronic myeloid leukemia [CML] in blast crisis, or AML in poor prognosis subgroups), patients experienced an overall response rate of 29%. Zarnestra was well tolerated with no dose-limiting toxicities through doses up to 900 mg twice daily. Assays measuring inhibition of farnesyltransferase activity showed a reliable inhibition at doses greater than 300 mg twice daily, and pharmacokinetic studies indicated that Zarnestra accumulated preferentially in the bone marrow in a dose-dependent fashion. These results suggest that Zarnestra should be studied further in patients with myeloid leukemia. Semin Hematol 39(suppl 2):31-35. Copyright 2002, Elsevier Science (USA). All rights reserved.

Aminobisphosphonates have shown significant antitumor activity in vitro and in vivo with selective pharmacodistribution to bone, and an established role in the treatment of malignant bone disease. Given that the mode of action of aminobisphosphonates involves decreasing the prenylation of the Rho family of proteins, through decreasing the availability of prenyl groups (farnesyl and geranylgeranyl isoprenoids), the authors sought the inhibition of Rho protein prenylation at two points, by using an aminobiphosphonate (alendronate) in conjunction with a prenyl transferase inhibitor (R115777, a specific farnesyl transferase inhibitor with limited effects in geranylgeranyl transferase). The authors show synergistic inhibition of the prenylation dependent membrane association and migratory function of Rho proteins, translating into a suppressive effect on in vitro tumor cell invasiveness and in vivo metastasis. The findings support the use of aminobisphosphonates in conjunction with farnesyl transferase inhibitors in the prevention of metastatic progression and suggest that metastatic progression is a valid end point in assessing the antitumor activity of farnesyl transferase inhibitors.

The best upfront therapy for patients with non-gastric extranodal marginal zone lymphomas (MZLs) is not defined. We assessed the safety and efficacy of radioimmunotherapy with 90yttrium (90Y) ibritumomab tiuxetan as upfront therapy in MZL (NCT00453102). A total of 16 patients were enrolled, 81% with advanced-stage disease and 44% with bulky disease. The overall response rate (ORR) at 12 weeks post-therapy was 87.5% (90% confidence interval [CI]: 65.6–97.7%), including a complete response in eight (50%), complete response unconfirmed in one (6%) and partial response in five (31%) patients. With a median follow-up of 65.6 months (range 4.0–96.5), the median progression-free survival (PFS) was 47.6 months (range 4.0–93.3) and median overall survival (OS) was not reached. The 5-year PFS was 40% (90% CI: 19.9–59.5%) and 5-year OS was 71.8% (90% CI: 46.8–86.5%). Overall, 90Y ibritumomab tiuxetan was well tolerated and led to long-term responses and PFS rates.

This chapter reviews the epidemiology, disease associations, molecular biology, and pathogenic mechanisms of human T-cell lymphotropic virus (HTLV) types I and II. Association of HTLV-I with two distinct disease processes, a malignancy and a chronic neurologic disorder, spurred worldwide surveys for prevalence of HTLV-I and associated diseases. Transmission of HTLV-I seems to require prolonged, close contact between individuals. Transfer of infected T cells is likely required. The three major reported routes of HTLV-I transmission include sexual intercourse, blood product transmission, and mother-to-child transfer. The most commonly used screening test for HTLV-I/HTLV-II is an enzyme-linked immunosorbent assay (ELISA) which uses a viral lysate-based antigen derived from HTLV-I infection of human T cells. Unlike human immunodeficiency virus (HIV), which has significant genetic differences between isolates, the various HTLV-I strains show a high degree of genetic conservation. There are two major hypotheses for pathogenesis in HTLV-I associated myelopathy (HAM)/tropical spastic paresis (TSP). The first hypothesis is that HTLV-I infects glial cells in the CNS and subsequently induces a cytotoxic immune response against these cells, leading to demyelination. The second hypothesis is that HTLV-I infection activates autoreactive T cells which then cause autoimmune destruction within the CNS (and perhaps in other areas). The molecular biology of HTLV-II is strikingly similar to that of HTLV-I. HTLV-I infection, however, has been linked to several disorders, especially adult T-cell leukemia/lymphoma (ATL) and HAM/TSP. HTLV-I and HTLVII have a similar genetic organization and regulation and share several unique transregulatory proteins.

Stage II colorectal carcinoma is characterized by negative lymph node pathology as determined by conventional microscopic examination. These patients generally do not receive adjuvant therapy although 20%-30% will die from metastatic disease. To determine whether K-ras mutations at codon 12 could be used as a sensitive indicator of occult lymph node metastasis in stage II colon carcinoma, a retrospective study was performed using restriction endonuclease-mediated selective polymerase chain reaction (REMS-PCR) amplification. Of 106 colonic tumors analyzed, 46 were identified as positive for a K12-ras mutation in the primary tumor. Multiple lymph node samples from 38 of these 46 patients were examined by a sensitive nested PCR protocol for the presence of a K12-ras mutation. Of these 38 patients, 14 had 1 or more positive lymph nodes by PCR (37%) and 24 were negative for the mutation (63%). Of the 14 patients with a K12-ras mutation detected in lymph nodes, 8 died of the disease within 5 years (57%) compared to only 4 of the 24 patients with ras-negative lymph nodes (17%). The difference in time to death from disease, stratified using K12-ras status of lymph nodes, was statistically significant (P = 0.036; log-rank test). These results suggest K-ras mutation status of lymph nodes in patients with stage II colon cancer might identify a subgroup of patients who are more likely to develop recurrent and/or metastatic disease and benefit from adjuvant therapy. Larger studies are indicated to determine whether detection of K-ras mutation positivity in histologically negative lymph nodes portends a poor prognosis and to determine whether more aggressive use of adjuvant therapy is warranted.

Herpes simplex virus (HSV)–based vectors have favorable biologic features for gene therapy of leukemia and lymphoma. These include high transduction efficiency, ability to infect postmitotic cells, and large packaging capacity. The usefulness of HSV amplicon vectors for the transduction of primary human B-cell chronic lymphocytic leukemia (CLL) was explored. Vectors were constructed encoding β-galactosidase (LacZ), CD80 (B7.1), or CD154 (CD40L) and were packaged using either a standard helper virus (HSVlac, HSVB7.1, and HSVCD40L) or a helper virus–free method (hf-HSVlac, hf-HSVB7.1, and hf-HSVCD40L). Both helper-containing and helper-free vector stocks were studied for their ability to transduce CLL cells, up-regulate costimulatory molecules, stimulate allogeneic T-cell proliferation in a mixed lymphocyte tumor reaction, and generate autologous cytotoxic T lymphocytes (CTLs). Although helper-containing and helper-free amplicon stocks were equivalent in their ability to transduce CLL cells, a vigorous T-cell proliferative response was obtained using cells transduced with hf-HSVB7.1 but not with HSVB7.1. CLL cells transduced with either HSVCD40L or hf-HSVCD40L were compared for their ability to up-regulate resident B7.1 and to function as T-cell stimulators. Significantly enhanced B7.1 expression in response to CD40L was observed using hf-HSVCD40L but not with HSVCD40L. CLL cells transduced with hf-HSVCD40L were also more effective at stimulating T-cell proliferation than those transduced with HSVCD40L stocks and were successful in stimulating autologous CTL activity. It is concluded that HSV amplicons are efficient vectors for gene therapy of hematologic malignancies and that helper virus–free HSV amplicon preparations are better suited for immunotherapy.

Background Systemic anaplastic large cell lymphoma (ALCL) is a CD30-expressing subtype of peripheral T-cell lymphoma (PTCL). Approximately 40 to 65% of ALCL patients (pts) will develop recurrent disease after frontline treatment, with median overall survival (OS) and progression-free survival (PFS) after relapse of 5.5 and 3.1 months (mos) (Savage 2008, Mak 2013). We have previously reported results of a pivotal phase 2 study of brentuximab vedotin in pts with relapsed or refractory (R/R) systemic ALCL (NCT00866047). Efficacy was demonstrated with an objective response rate (ORR) per investigator of 86% and a complete response (CR) rate of 66%. Peripheral sensory neuropathy was the most common adverse event (AE), experienced in 41% of pts. Herein, we present the end-of-study results with updated data on response durability and peripheral neuropathy (PN) resolution. Methods Fifty-eight pts with R/R systemic ALCL, ALK-positive or ALK-negative, 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 ORR per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Long-term follow-up to evaluate disease status was assessed per the investigator every 3 mos for 2 years, every 6 mos through Year 5, and annually thereafter. CT scans were required if progression was suspected clinically. Pts who experienced PN were followed for symptom improvement/resolution until approximately 3 years into long-term follow-up. Results The estimated 5-year OS and PFS for all enrolled patients was 60% (95% CI: 47%, 73%) and 39% (95% CI: 25%, 52%), respectively. At study closure, which occurred 5 years after the last patient's end-of-treatment (EOT) visit, the median OS was not reached (95% CI: 21.3, -), and the median PFS was 20 mos (95% CI: 9.4, -). Pts were observed for a median of 71.4 mos (range, 0.8 to 82.4) from first dose. Of the pts who achieved a CR per investigator (38 of 58, 66%), the median OS (endpoints of 95% CI not estimable) and PFS (95% CI: 21.3, -) were not reached. Median OS for pts who achieved partial response per investigator (PR, 12 of 58, 21%) was 11.6 mos (95% CI: 3.1, -). Median duration of objective response was 25.6 mos (95% CI: 11.8, - [range, 0.9 to 79.7+]) and was not reached for CR pts (95% CI: 20.0, - [range, 0.9 to 79.7+]). Of the 58 enrolled pts, 42 (72%) had ALK-negative disease. Median PFS for ALK-negative and ALK-positive ALCL was 20 mos (95% CI: 6.7, -) and 25.5 mos (95% CI: 8.0, -) respectively, with the median OS not reached for each. The estimated 5-year OS was 61% (95% CI: 47%, 76%) for ALK-negative and 56% (95% CI: 32%, 81%) for ALK-positive pts. Of the 38 CR pts, 16 received a consolidative stem cell transplant (SCT, 8 allogeneic, 8 autologous). Median PFS was not reached in these pts who underwent transplant. Median PFS for the CR pts that did not undergo transplant was 39.4 mos (95% CI: 14.3, -). Sixteen pts, with a median observation time of 75.4 mos (range 69 to 82.4), remained in remission at the end of the study without the start of new therapy other than consolidative SCT. Among these pts, 8 received a consolidative SCT, and the remaining 8 pts (14% of all enrolled pts) remained on study and in remission without any additional therapy after single-agent brentuximab vedotin. Thirty-three pts (57% of enrolled pts) experienced PN. Thirty pts (30 of 33, 91%) experienced resolution or improvement, of whom, 22 (67%) reported complete resolution, and 8 (24%) reported some resolution or improvement at last assessment. Of the 11 pts with ongoing neuropathy at last follow-up, 8 pts had Grade 1 severity and 3 pts had Grade 2. Conclusions These end-of-study results demonstrate that among pts with R/R systemic ALCL, the majority of pts have achieved clinically significant durable remissions, and a subset may have been cured with single-agent brentuximab vedotin. Furthermore, associated toxicities are manageable, with high rates of resolution for PN, the most common toxicity associated with brentuximab vedotin. A randomized phase 3 trial is ongoing to evaluate the combination of brentuximab vedotin with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-expressing peripheral T-cell lymphomas, including systemic ALCL (NCT01777152). Overall Survival and Progression-Free Survival Figure. Figure. Disclosures Pro: Takeda: Honoraria; Seattle Genetics: Honoraria; Celegene: Honoraria. Brice:Gilead: Honoraria; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Seattle Genetics: Research Funding; Bristol Myers-Squibb: Honoraria; Roche: Honoraria. Bartlett:Gilead: Consultancy. Rosenblatt:University of Miami: Employment; Seattle Genetics: Research Funding. Illidge:Takeda Pharmaceuticals International Co.: Consultancy, Honoraria; Seattle Genetics: Consultancy, Research Funding. Matous:Seattle Genetics: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau. Connors:Bristol Myers Squib: Research Funding; F Hoffmann-La Roche: Research Funding; Millennium Takeda: Research Funding; Seattle Genetics: Research Funding; NanoString Technologies: Research Funding. Fenton:Seattle Genetics: Employment, Equity Ownership. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Pinelli:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics: Research Funding; Celgene: Consultancy, Honoraria; Novartis: Research Funding; SPECTRUM: Consultancy, Research Funding; BMS: Consultancy, Honoraria.