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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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

The human T-cell lymphotropic viruses type I and type II are closely related human retroviruses that have similar biological properties, genetic organization and tropism for T lymphocytes. Along with the simian T-cell lymphoma virus type I, they define the group of retroviruses known as the primate T-cell leukemia/lymphoma viruses. Initially identified in 1980, the human T-cell lymphotropic virus type I has been implicated as the etiologic agent of adult T-cell leukemia/lymphoma and of a degenerative neurologic disorder known as tropical spastic paraparesis or human T-cell lymphotropic virus type I-associated myelopathy. The intriguing link between human T-cell lymphotropic virus type, T-cell malignancy, and a totally unrelated and non-overlapping neurological disorder suggests divergent and unique pathogenetic mechanisms. This review will address the epidemiology, molecular biology, and pathogenesis of human T-cell leukemia viruses.

Purpose Systemic anaplastic large-cell lymphoma (ALCL) is an aggressive subtype of T-cell lymphoma characterized by the uniform expression of CD30. The antibody-drug conjugate brentuximab vedotin delivers the potent antimicrotubule agent monomethylauristatin E to CD30-positive malignant cells. A phase II multicenter trial was conducted to evaluate the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory systemic ALCL. Patients and Methods Patients with systemic ALCL and recurrent disease after at least one prior therapy received brentuximab vedotin 1.8 mg/kg intravenously every 3 weeks over 30 minutes as an outpatient infusion. The primary end point of the study was overall objective response rate as assessed by independent central review. Results Of 58 patients treated in the study, 50 patients (86%) achieved an objective response, 33 patients (57%) achieved a complete remission (CR), and 17 patients (29%) achieved a partial remission. The median durations of overall response and CR were 12.6 and 13.2 months, respectively. Grade 3 or 4 adverse events in ≥ 10% of patients were neutropenia (21%), thrombocytopenia (14%), and peripheral sensory neuropathy (12%). Conclusion Brentuximab vedotin induced objective responses in the majority of patients and CRs in more than half of patients with recurrent systemic ALCL. Targeted therapy with this CD30-directed antibody-drug conjugate may be an effective treatment for relapsed or refractory systemic ALCL and warrants further studies in front-line therapy.

We report the case of an African American male with no significant past medical history presenting with recurrent, rapidly relapsing episodes of thrombotic thrombocytopenic purpura (TTP) despite aggressive treatment with several lines of treatment. Incidentally, these episodes were associated with severe abdominal pain which eventually developed into acute abdomen and prompted exploratory laparotomy, revealing diffuse carcinomatosis with a tumor located on the left pelvis that was encasing the distal sigmoid colon. Pathology made a final diagnosis of peritoneal mesothelioma. TTP-like syndrome (TTP-LS) has been described as a paraneoplastic phenomenon in several malignancies but never before in the setting of malignant mesothelioma. Paraneoplastic TTP-like syndrome has historically been associated with a dismal prognosis and particular clinical and laboratory abnormalities described in this paper. It is of utmost importance to make a prompt determination whether TTP is idiopathic or secondary to an underlying condition because of significant differences in their prognosis, treatment, and response. This paper also reviews the current literature regarding this challenging condition.

Background: Classical Hodgkin lymphoma (HL) is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells. The standard of care for patients (pts) with relapsed or refractory (R/R) HL is salvage chemotherapy followed by high dose chemotherapy and autologous stem cell transplant (auto-SCT). Approximately 50% of these pts will experience relapse or progression of HL after auto-SCT. For these individuals, outcomes have historically been poor, with median overall survival (OS) from time of relapse ranging from 10.5 to 27.6 mos (Crump, 2008; Fanale, 2013). A pivotal phase 2 study evaluated brentuximab vedotin, a CD30-directed antibody-drug conjugate, in pts with R/R HL after auto-SCT (ClinicalTrials.gov #NCT00848926). Primary results and 3-year follow-up data have been previously reported (Younes, 2012; Gopal, 2015). Here, we summarize final data from the 5-year follow-up period. Methods: Pts received 1.8 mg/kg brentuximab vedotin once every 3 wks as a 30-min outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Assessments of response and durability of response per an independent review facility (IRF) have been previously reported. Following a protocol amendment that removed the requirement for routine CT scanning during the follow-up period, disease status was only assessed per the investigator. Survival and disease status were assessed every 3 mos for 2 yrs and then every 6 mos through Year 5. CT scans were required if progression was suspected clinically. At the time of the amendment, 18 patients were still being assessed for progression; these patients had been in long-term follow-up for a median of over 30 months. Results: The enrolled population of 102 pts (53% female) was heavily pretreated and had a median age of 31 yrs (range, 15-77 yrs). Pts received a median of 9 cycles (range, 1-16) of brentuximab vedotin. Per investigator, the ORR to brentuximab vedotin was 72% and complete remission (CR) rate was 33%. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Adverse events of Grade 3 or higher that occurred in ≥5% of pts were neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. At study closure, which occurred approximately 5 yrs after the last patient's end-of-treatment visit, the median observation time for all enrolled patients from first dose was 35.1 mos (range, 1.8 to 72.9). The estimated 5-year overall survival rate was 41% (95% CI: 31 %, 51%) and the median OS was 40.5 mos (95% CI: 28.7, 61.9 [range, 1.8 to 72.9+]). Median OS by best clinical response was CR (n=34): median not reached; partial remission (PR, n=39): 39.4 mos; and stable disease (SD, n=28): 18.3 mos. The median PFS was 9.3 months overall, but was not reached in CR pts. Of the 102 enrolled patients, 15 remained in follow-up and in remission at study closure. Among these 15 pts, 6 received consolidative allo-SCT and 9 have received no further therapy since completing brentuximab vedotin. Conclusions: These end-of-study results demonstrate that single agent brentuximab vedotin can induce durable remissions and long-term survival in a subset of heavily pretreated patients with relapsed/refractory HL, particularly in pts that achieve CR. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with AVD (doxorubicin, vinblastine, and dacarbazine) versus ABVD (A, bleomycin, VD) for frontline treatment of advanced HL (ECHELON-1 trial, ClinicalTrials.gov #NCT01712490). Figure 1. Overall Survival Figure 1. Overall Survival Disclosures Chen: Seattle Genetics: Consultancy, Research Funding; Genentech: Consultancy; Gilead: Consultancy; Janssen: Consultancy. Gopal:BMS: Research Funding; Piramal: Research Funding; Emergent/Abbott: Research Funding; Millenium: Honoraria, Research Funding; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; BioMarin: Research Funding; Seattle Genetics: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sanofi-Aventis: Honoraria; Merck: Research Funding. Smith:Seattle Genetics: Research Funding; Celgene: Consultancy, Speakers Bureau. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Rosenblatt:Seattle Genetics: Research Funding. Savage:Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Engert:Takeda Millenium: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding. Larsen:Seattle Genetics Inc.: Employment, Equity Ownership. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Fong:Seattle Genetics, Inc.: Employment, Equity Ownership. Younes:Janssen: Honoraria; Novartis: Research Funding; Incyte: Honoraria; Takeda Millenium: Honoraria; Celgene: Honoraria; Bristol Meyer Squibb: Honoraria; Curis: Research Funding; Bayer: Honoraria; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria; Johnson and Johnson: Research Funding.

Purpose: The antibody–drug conjugate (ADC) brentuximab vedotin comprises a CD30-directed antibody covalently attached to the potent antimicrotubule agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. This study explored the safety, maximum-tolerated dose (MTD), and activity of weekly dosing of brentuximab vedotin in patients with relapsed or refractory CD30-positive hematologic malignancies. Experimental Design: In this phase I dose-escalation study, brentuximab vedotin was administered intravenously on Days 1, 8, and 15, of each 28-day cycle at doses ranging from 0.4 to 1.4 mg/kg. Forty-four patients were enrolled: 38 with Hodgkin lymphoma, five with systemic anaplastic large cell lymphoma, and one with peripheral T-cell lymphoma not otherwise specified. Doses were escalated in increments of 0.2 mg/kg until dose-limiting toxicity (DLT) was observed. Patients were monitored for antitherapeutic antibodies and pharmacokinetic parameters. Antitumor assessments were carried out every two cycles. Results: The MTD was 1.2 mg/kg. The most common adverse events were peripheral sensory neuropathy, fatigue, nausea, diarrhea, arthralgia, and pyrexia; and the majority of events were mild to moderate in severity. Tumor regression occurred in 85% of patients and the overall objective response rate was 59% (n = 24), with 34% (n = 14) complete remissions. The median duration of response was not reached at a median follow-up of 45 weeks on study. Conclusions: Weekly administration of brentuximab vedotin resulted in tumor regression and durable remissions in patients with CD30-positive malignancies. This ADC was associated with manageable toxicity, including peripheral neuropathy. Further study in CD30-positive malignancies is warranted. Clin Cancer Res; 18(1); 248–55. ©2011 AACR.

With countless biological details emerging from cancer experiments, there is a growing need for minimal mathematical models which simultaneously advance our understanding of single tumors and metastasis, provide patient-personalized predictions, whilst avoiding excessive hard-to-measure input parameters which complicate simulation, analysis and interpretation. Here we present a model built around a co-evolving resource network and cell population, yielding good agreement with primary tumors in a murine mammary cell line EMT6-HER2 model in BALB/c mice and with clinical metastasis data. Seeding data about the tumor and its vasculature from in vivo images, our model predicts corridors of future tumor growth behavior and intervention response. A scaling relation enables the estimation of a tumor's most likely evolution and pinpoints specific target sites to control growth. Our findings suggest that the clinically separate phenomena of individual tumor growth and metastasis can be viewed as mathematical copies of each other differentiated only by network structure.

Human T-cell leukemia virus type I (HTLV-I) is recognized as the etiologic agent of adult T-cell leukemia (ATL), a disease endemic in certain regions of southeastern Japan, Africa, and the Caribbean basin. Although HTLV-I can immortalize T lymphocytes in culture, factors leading to tumor progression after HTLV-I infection remain elusive. Previous attempts to propagate the ATL tumor cells in animals have been unsuccessful. Severe combined immunodeficient (SCID) mice have previously been used to support the survival of human lymphoid cell populations when inoculated with human peripheral blood lymphocytes (PBL). SCID mice were injected intraperitoneally with PBL from patients diagnosed with ATL, HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), or from asymptomatic HTLV-I-seropositive patients. Many of these mice become persistently infected with HTLV-I. Furthermore, after human reconstitution was established in these mice, HTLV-I-infected cells displayed a proliferative advantage over uninfected human cells. Lymphoblastic lymphomas of human origin developed in animals injected with PBL from two ATL patients. The tumor cells represented outgrowth of the original ATL leukemic clone in that they had monoclonal or oligoclonal integrations of the HTLV-I provirus identical to the leukemic clone and predominantly expressed the cell surface markers, CD4 and CD25. In contrast, cell lines derived by HTLV immortalization of T cells in vitro did not persist or form tumors when inoculated into SCID mice, indicating differences between in vitro immortalized cells and ATL leukemic cells. This system represents the first small animal model to study HTLV-I tumorigenesis in vivo.

The human T-cell leukemia virus type I (HTLV-I) and HTLV-II Tax proteins are potent transactivators of viral and cellular gene expression. Using deletion mutants, the downstream parathyroid hormone- related protein (PTHrP) promoter is shown to be responsive to both HTLV- I and HTLV-II Tax as well as the AP1/c-jun proto-oncogene. Transactivation of PTHrP by Tax was seen in T cells but not in B-cell lines or fibroblasts. A carboxy terminal Tax deletion mutant was deficient in transactivation of both the PTHrP and IL2R alpha promoters but not the HTLV-I long terminal repeat (LTR). Exogenous provision of NFkB rescued IL2R alpha expression but not the PTHrP promoter. Thus, HTLV-I Tax, HTLV-II Tax, and c-jun transactivate PTHrP and may contribute to the pathogenesis of hypercalcemia in adult T-cell leukemia.

OBJECTIVE Human T-cell leukemia virus types I (HTLV-I) and II (HTLV-II) are closely related human retroviruses. HTLV-I has been implicated in a chronic progressive myelopathy, known as tropical spastic paraparesis (TSP) or HTLV-I-associated myelopathy (HAM). We sought to determine whether autoantibodies to brain antigens were present in the cerebrospinal fluid (CSF) of a patient with chronic progressive spastic myelopathy with evidence of both HIV-1 infection and HTLV-I/II seropositivity. DESIGN A 54-year-old bisexual man with clinical features of HAM/TSP of over 20 years' duration was followed. METHODS We applied discriminatory DNA amplification (polymerase chain reaction) to distinguish HTLV-I from HTLV-II and to verify co-infection with HIV-1. The patient's CSF was used to screen a human brain cDNA expression library to identify antibodies directed against brain antigens. Autoreactive bacteriophage clones were isolated and sequenced. RESULTS The patient was found to be co-infected with both HIV-1 and HTLV-II, but not with HTLV-I. HTLV-II proviral levels in the peripheral blood remained relatively constant, despite therapy with zidovudine. Prominent oligoclonal banding of immunoglobulins was present in the patient's CSF. A single repeatedly reactive cDNA clone was identified, by screening with CSF antibody, sequenced, and found to be the human homologue of the rat insulinoma gene, rig. CONCLUSIONS HTLV-II infection may predispose to development of a HAM/TSP-like illness. Autoimmune mechanisms, such as autoantibody formation, may play a role in pathogenesis.

B-cell lymphoproliferative disorders are rare but serious complications of solid organ and bone marrow transplantation. We report that these tumors frequently express the CD-20 antigen, and immunotherapy directed at this antigen may be a well-tolerated and effective treatment.

Despite enormous effort, promising pre-clinical data in animal studies and over 900 clinical trials in the United States, no cancer vaccine has ever been approved for clinical use. Over the past decade a great deal of progress has been in both laboratory and clinical studies defining the interactions between developing tumors and the immune system. The results of these studies provide a rationale that may help explain the failure of recent therapeutic cancer vaccines in terms of vaccine principles, in selecting which tumors are the most appropriate to target and instruct the design and implementation of state-of-the-art cancer vaccines.

Infection with human T-cell leukemia virus type II (HTLV-II) has been associated with rare chronic T-cell malignancies and has recently been demonstrated in a significant proportion of American intravenous drug abusers (IVDA). Identification of an HTLV-II-infected cohort of IVDA has allowed analysis of the HTLV-II carrier state. We analyzed clinical, hematologic, and immunologic parameters in 21 HTLV-II- infected IVDA, two HTLV-I-infected IVDA, and 20 uninfected control IVDA identified by serologic screening and by analysis of peripheral blood mononuclear cell (PBMC) DNA by polymerase chain reaction (PCR). An elevated absolute lymphocyte count was observed in 4 of 21 HTLV-II- infected IVDA, 1 of 2 HTLV-I-infected IVDA, and 1 of 20 control IVDA. CD8+ T-cell elevation was observed in three of four HTLV-II IVDA with lymphocytosis and one of two HTLV-I-infected IVDA. Activation of CD8+ T cells in HTLV-II-infected IVDA was suggested by an overall increase in CD8+/HLA-DR+ lymphocytes. Cell fractionation and analysis by PCR of HTLV-II-infected carrier blood showed high levels of HTLV-II provirus in unfractionated PBMC and purified T cells and little or no detectable HTLV-II DNA in B cells or monocytes, indicating that T cells were the most likely target of infection in vivo. The frequency of HTLV-II- infected cells was estimated at approximately 1 in 500 cells or less using dilution analysis by PCR of PBMC DNA. Most HTLV-II-infected IVDA are asymptomatic and have no overt hematologic or immunologic abnormalities, although some manifest benign lymphocytosis.

Background: Marginal zone lymphomas (MZLs) account for 10% to 17% of all non-Hodgkin lymphomas (NHLs). Eradication of Helicobacter pylori (HP) is considered the initial therapy of choice for localized HP-positive gastric MALT and radiation is commonly used for other localized MALT or nodal MZL. While radiotherapy in localized MALT and nodal MZLs frequently results in long term local control and prolonged progression-free survival (PFS), it is not always feasible. Consensus guidelines on the best upfront therapy for patients with non-gastric MALT and disseminated extranodal MZLs are absent. Considering the excellent local control of MZLs with radiotherapy, targeted delivery of radiation by radioimmunotherapy may be the preferential approach for patients with untreated disseminated MZL. Based on this premise, we designed a single center Phase II clinical trial to examine 90Y Ibritumomab in the upfront treatment of patients with Marginal Zone Lymphoma. Methods: Eligible patients were 18 years and older with a diagnosis of untreated, histologically proven CD20-positive marginal zone lymphoma of all stages, including extranodal and nodal MZL variants. Patients with HP-negative and patients with HP-positive gastric MALT lymphoma who did not respond to antibiotic therapy were also eligible. Additional inclusion criteria were: measurable disease (at least one lymph node or tumor mass 2 cm in any axis), Eastern Cooperative Oncology (ECOG) performance status of 0, 1 or 2 and adequate bone marrow (neutrophils >1.5x109/L; platelets >100x109/L), hepatic and renal functions. Treatment consisted of intravenous rituximab 250 mg/m² on day 1 with appropriate premedications. On Day 8, patients received a second dose of rituximab 250 mg/m² prior to 0.4 mCi/kg (14.8 MBq/kg) of 90Y ibritumomab tiuxetan administered as a 10-minute intravenous push. Response assessment was made at week 12 post therapy by CT scan and physical examination. Patients underwent follow up with regular clinical reviews and CT scans of the neck, chest, abdomen, and pelvis every 3 months for the first 2 years and then every 6 months for an additional 3 years. Results: Between June 2006 and January 2014, 16 patients were enrolled. The median age was 62 years with a range of 37 to 84 years. The ORR at week 12 post treatment was 87.5% (14 of 16 patients) with a 90% confidence interval of 65.6% to 97.7%. The responses comprised of CR in 8 (50%), CRu in 1 (6%) and PR in 5 (31%) patients. A total of 2 patients (13%) were defined as having stable disease at week 12 restaging. With a median follow up of 65.6 months (range 4.0-96.5), the median PFS was 47.6 months (range 4.0-93.3) for all patients (Figure 1A), with median PFS of 47.6 months (range 4.0-74.2) for patients achieving CR. Of the 16 treated patients, 4 died (25%). None of the deaths was directly attributed to MZL and 2 patients died while being in continuous CR. Median OS by Kaplan-Meier method for all the patients was not attained (Figure 1B). 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%). The principal toxicity was hematological. Reversible grade 3 or 4 neutropenia occurred in 8 of 16 (50%) of patients, median duration 21 days (range 9-69 days). Reversible grade 3 or 4 thrombocytopenia was observed in 5 of 16 (31.3%) patients with a median duration of 28 days (range 13-42 days). Grade 4 anemia occurred in one (6.3%) patient and lasted for 15 days. Later adverse non-hematological events were typically mild and self-limiting. Conclusion: Our phase-II trial suggests that one single injection of 90Y ibritumomab tiuxetan may be a valid therapeutic option for front-line therapy of patients with MALT lymphoma, producing response rates similar to those achieved with immunochemotherapy treatment regimens. Further evaluation of this therapeutic approach in a prospective, preferentially randomized, multi-institutional clinical trial is needed. Figure 1A Figure 1A. Figure 1B Figure 1B. Disclosures No relevant conflicts of interest to declare.

The etiology of non-Hodgkin's lymphoma is unknown in the majority of the cases. Although Epstein-Barr virus, human T-cell leukemia-lymphoma virus and human herpes virus-8 have been established as casual agents in the pathogenesis of specific types of lymphoma, the role of hepatitis C virus (HCV) in lymphomagenesis remains controversial, with marked geographic variability. We conducted an epidemiologic study to evaluate the prevalence of hepatitis C virus infection in patients with lymphoma in South Florida. Ninety consecutive patients with lymphoma and 96 consecutive control patients with solid tumors were tested for HCV. HCV infection was detected in 2 patients with NHL (2.2%) and in 4 control patients (4.1%). Our study does not support the association between HCV and lymphoma in South Florida, US.