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BackgroundThere is evidence indicating that pesticide exposure is a risk factor for non-Hodgkin lymphoma (NHL) development. However, the association between pesticide exposure and NHL survival is not well-established.MethodsUsing the California Cancer Registry, we identified patients with a first primary diagnosis of NHL from 2010 to 2016 and linked these patients with CalEnviroScreen 3.0 to obtain production agriculture pesticide exposure to 70 chemicals from the state-mandated Pesticide Use Reporting (PUR) by census tract from 2012 to 2014. In addition, data from PUR was integrated into a geographic information system that employs land-use data to estimate cumulative exposure to specific pesticides previously associated with NHL (glyphosate, organophosphorus, carbamate, phenoxyherbicide, and 2,4-dimethylamine salt) between 10 years prior up to 1 year after NHL diagnosis. Multivariable Cox proportional hazards regression models were used to evaluate the association between total pesticide exposure from CalEnviroScreen 3.0 and individual pesticide exposure from geographic land use data and lymphoma-specific and overall survival.ResultsAmong 35,808 NHL patients identified, 44.2% were exposed to pesticide in their census tract of residence. Glyphosate, organophosphorus, carbamate, phenoxyherbicide, and 2,4-dimethylamine salt exposure was observed in 34.1%, 26.0%, 10.6%, 14.0%, and 12.8% of NHL patients, respectively. Total pesticide exposure at the time of diagnosis was not associated with lymphoma-specific or overall survival. In addition, no association was consistently found between glyphosate, organophosphorus, carbamate, phenoxyherbicide, and 2,4 dimethylamine salt exposure and lymphoma-specific or overall survival.ConclusionsAlthough we found no consistent associations between agricultural pesticide exposure at the neighborhood level and worse survival, these results provide a platform for designing future studies to determine the association between pesticide and NHL.

Relapse after allogeneic stem cell transplant in unfavorable-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) portends a poor prognosis. We conducted a single-center phase I dose-escalation study with lenalidomide maintenance in high-risk MDS and AML patients after allogeneic transplantation. Sixteen patients enrolled in a "3 + 3" study design starting at lenalidomide 5 mg daily, increasing in increments of 5 mg up to 15 mg. Lenalidomide was given for 21 days of a 28-day cycle for a total of six cycles. Most common dose-limiting toxicities were lymphopenia, diarrhea, nausea, and neutropenia. Two patients had acute graft-versus-host disease (GVHD), and five patients developed chronic GVHD. The maximum tolerated dose was 10 mg, after dose-limiting toxicities were seen in the 15 mg group. Two dose-limiting toxicities were seen from development of acute GVHD and grade III diarrhea. Limitations of the study include time to initiation at 6 months post transplant, as many high-risk patients will have relapsed within this time frame before starting maintenance lenalidomide. Overall, lenalidomide was well tolerated with minimal GVHD and low rates of relapse rates, warranting further study.

Abstract: Introduction: While previous studies propose pesticide exposure to be a risk factor for non-Hodgkin lymphoma (NHL) development, results are inconclusive. In addition, the impact of pesticide exposure on NHL survival is not well-established. Therefore, we identified NHL patients from the California Cancer Registry and linked these patients with the statewide pesticide use reporting database to determine the impact of pesticide exposure on NHL-related incidence and outcomes. Methods: Using the California Cancer Registry, we identified patients with a first primary diagnosis of NHL from 2010-2016 and linked these patients with CalEnviroScreen 3.0 to obtain production agriculture pesticide exposure to 70 chemicals from the state mandated Pesticide Use Reporting (PUR) by census tract from 2012-2014. In addition, data from PUR was integrated into a geographic information system that employs land use data to estimate cumulative exposure to specific pesticides previously associated with NHL (glyphosate, organophosphorus, carbamate, phenoxyherbicide and 2,4-dimethylamine salt) between 10 years prior up to 1 year after NHL diagnosis. SEER*Stat software was used to calculate NHL subtype incidence rates by census tract pesticide use level. Multivariable cox proportional hazards regression models were used to evaluate the impact of total pesticide exposure from CalEnviroScreen 3.0 and individual pesticide exposure from geographic land use data on lymphoma-specific and overall survival. Results: Among 35,808 NHL patients identified, 44.2% were exposed to pesticide in their census tract of residence. Pesticide exposure was higher in Hispanic/Latino (46.5%) and non-Hispanic white (45.6%) then Asian/Pacific Islander (37.2%) and African American (34.9%) patients with NHL. Glyphosate, organophosphorus, carbamate, phenoxyherbicide and 2,4-dimethylamine salt exposure was reported in 34.1%, 26.0%, 10.6%, 14.0% and 12.8% of NHL patients, respectively. Pesticide exposure was not associated with increased NHL incidence by NHL subtype or subgroups defined by sociodemographic factors. Total pesticide exposure at time of diagnosis was not associated with lymphoma-specific or overall survival. In addition, no association was consistently found between glyphosate, organophosphorus, carbamate, phenoxyherbicide and 2,4 dimethylamine salt exposure and lymphoma-specific or overall survival. Conclusion: In this large population-based study of neighborhood agricultural pesticide exposure, pesticide exposure was noted to be prevalent among patients diagnosed with NHL, with high pesticide exposure particularly observed in Hispanics/Latinos and non-Hispanic whites. However, pesticide exposure was not consistently associated with increased NHL incidence or worse NHL lymphoma-specific or overall survival. Disclosures: Poh: Acrotech: Honoraria; Incyte: Research Funding; Morphosys: Consultancy. Tuscano: BMS: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Acrotech: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding.

PurposeRituximab and lenalidomide are effective for previously untreated and relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). However, long-term survival and predictive biomarkers are not well described.Patients and methodsWe conducted two phase II open-label trials involving 60 patients with previously untreated and R/R advanced-stage iNHL. Patients received lenalidomide and rituximab induction followed by continuous lenalidomide until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Correlative studies included plasma cytokine monitoring, flow cytometry of peripheral blood mononuclear cells (PBMC; days 0, 15, 30, and 60), and RNA sequencing (RNA-seq) of pretreatment tumor biopsies.ResultsAt a median follow-up of 63 months for previously untreated and 100 months for R/R, ORR was 82% for both. The 11 R/R patients who achieved complete remission remained in continuous remission for 16 to 141 months, thereafter. Median overall survival (OS) was not reached in the previously untreated and was 140 months (95% confidence interval, 53.4-140) in the R/R group. A mixed-effects linear regression model identified significant associations between Granzyme B+ (GranB+) CD8+ T cells and long-term complete response (LTCR; P = 5.3e-4). Furthermore, prior to start of therapy, treatment response could be predicted by B-cell and GranB+ CD8+ T-cell levels (% total lymphocytes).ConclusionsRituximab plus lenalidomide followed by continuous lenalidomide is effective with manageable toxicity in patients with previously untreated and R/R iNHL. This regimen produces durable remissions, even in heavily pretreated patients, with some lasting greater than 10 years. GranB+ CD8+ T cells, B cells, and plasma IFNγ allowed prediction of LTCR but need validation in larger trials.

Relapsed/refractory acute myeloid leukemia (AML) is a devastating disease with a poor prognosis and represents a major unmet medical need. We report on a real-world academic center experience of treating 25 patients with relapsed/refractory AML using venetoclax in combination with decitabine or azacitidine, which is not otherwise widely evaluated in the current literature. Our patients come from a large, socioeconomically and geographically diverse area including the majority of Northern California. Most had ELN Adverse Risk (52%) or Intermediate Risk (44%) AML, and most had an ECOG Performance Status of 1 (64%). Over half (52%) had prior hypomethylating agent exposure, and 40% had Secondary AML. We observed an overall response rate of 52%, with eight patients (32%) achieving composite complete remission. Median overall survival was 5.5 months, and for patients achieving composite complete remission this was 21.6 months. One-year estimated overall survival was 38%. Three patients were able to proceed directly to stem cell transplant for consolidation, and all three were alive at last follow-up, ranging 13.8-24.0 months. We found venetoclax in combination with hypomethylating agents to be well tolerated and potentially efficacious in securing long-term remissions for patients with relapsed/refractory AML.

In herpesvirus replicating cells, host cell gene transcription is frequently down-regulated because important transcriptional apparatuses are appropriated by viral transcription factors. Here, we show a small peptide derived from the Kaposi's sarcoma-associated herpesvirus transactivator (K-Rta) sequence, which attenuates cellular MYC expression, reduces cell proliferation, and selectively kills cancer cell lines in both tissue culture and a xenograft tumor mouse model. Mechanistically, the peptide functions as a decoy to block the recruitment of coactivator complexes consisting of Nuclear receptor coactivator 2 (NCOA2), p300, and SWI/SNF proteins to the MYC promoter in primary effusion lymphoma cells. Thiol(SH)-linked alkylation for the metabolic sequencing of RNA (SLAM seq) with target-transcriptional analyses further confirm that the viral peptide directly attenuates MYC and MYC-target gene expression. This study thus provides a unique tool to control MYC activation, which may be used as a therapeutic payload to treat MYC-dependent diseases such as cancers and autoimmune diseases.

IntroductionEverolimus and bendamustine both have single-agent activity against lymphoid hematologic malignancies. We examined this combination in a group of heavily pretreated patients with non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and multiple myeloma (MM).Patients and methodsIn this phase I trial, 18 patients (8 with NHL, 6 with MM, and 4 with HL) were treated with bendamustine 90 mg/m2 on days 1 and 2 and everolimus from 5 to 10 mg daily on a 28-day cycle, for up to 4 cycles.ResultsAdverse events were generally mild and mostly hematologic in nature. The most frequent grade 3/4 adverse events were lymphopenia (61%), thrombocytopenia (22%), leukopenia (22%), neutropenia (17%), and fatigue (17%). Overall response rate varied by malignancy: diffuse large B-cell lymphoma, 20% (1 of 5 patients); HL (2 of 4 patients), 50%; MM, 80% (4 of 5 patients); and indolent lymphomas, 100% (3 of 3 patients). The maximum tolerated dose of everolimus was determined to be 7.5 mg daily.ConclusionThe combination of everolimus and bendamustine appeared to be well-tolerated and relatively efficacious.

• Hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (Hyper-CVAD) results in high complete remission (CR) rates, long-term survival in 30-40%1 , and measurable/minimal residual disease (MRD) negativity in 50% adults with acute lymphoblastic leukemia (ALL).• Proteasome inhibitors have synergistic activity with chemotherapy in relapsed ALL.• Carfilzomib, a next-generation irreversible and selective inhibitor of the chymotrypsin-like activity of the proteasome, shows increased specificity, potency, and cellular apoptotic sensitivity compared to bortezomib in ALL.• Carfilzomib shows preclinical activity in ALL ex vivo studies, and has promising synergism with dexamethasone.• We hypothesized that adding carfilzomib to Hyper-CVAD would be safe and could better outcomes in adults with ALL.

PurposeBased on the potential for ipilimumab (I) to augment T-cell activation, we hypothesize that ipilimumab would augment the efficacy of rituximab (R) in patients with relapsed/refractory (R/R) CD20+non-Hodgkin's lymphoma (NHL). This phase I study aimed to identify a recommended phase 2 dose, document toxicities, and preliminarily assess efficacy and potential predictive biomarkers.Patients and methodsThirty-three patients with R/R CD20+B-cell lymphoma received R at 375 mg/m2weekly for 4 weeks and I at 3 mg/kg on day 1 and every 3 weeks for four doses. Responding patients went on to maintenance with each agent given every 12 weeks. To facilitate correlative analysis, the expansion phase randomized patients to simultaneous R+I versus R with I delayed 2 weeks.ResultsToxicity was manageable; no dose-limiting toxicity was observed at the doses studied. When considering the entire cohort, efficacy was modest, with an objective response rate (ORR) of 24% and median progression-free survival (PFS) of 2.6 months. However, in follicular lymphoma patients, the ORR was 58% with a median PFS of 5.6 months. The randomized comparison of R with R+I demonstrated that R+I resulted in more effective B-cell depletion (BCD). Both B-cell depletion and the ratio of CD45RA-regulatory T cell (Treg) to Treg were associated with response at all time points.ConclusionsThe combination of R+I has manageable toxicity and encouraging efficacy in R/R follicular lymphoma. The ratio of CD45RA-Tregs to total Tregs, and peripheral BCD should be studied further as potential predictors of response.

The aryl hydrocarbon receptor (AhR) is known for mediating the toxicity of environmental pollutants such as dioxins and numerous dioxin-like compounds, and is associated with the promotion of various malignancies, including lymphoma. The aryl hydrocarbon receptor repressor (AhRR), a ligand-independent, transcriptionally inactive AhR-like protein is known to repress AhR signaling through its ability to compete with the AhR for dimerization with the AhR nuclear translocator (ARNT). While AhRR effectively blocks AhR signaling, several aspects of the mechanism of AhRR's functions are poorly understood, including suppression of inflammatory responses and its putative role as a tumor suppressor. In a transgenic mouse that overexpresses AhRR (AhRR Tg) we discovered that these mice suppress 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)- and inflammation-induced tumor growth after subcutaneous challenge of EL4 lymphoma cells. Using mouse embryonic fibroblasts (MEF) we found that AhRR overexpression suppresses the AhR-mediated anti-apoptotic response. The AhRR-mediated inhibition of apoptotic resistance was associated with a suppressed expression of interleukin (IL)-1β and cyclooxygenase (COX)-2, which was dependent on activation of protein kinase A (PKA) and the CAAT-enhancer-binding protein beta (C/EBPβ). These results provide mechanistic insights into the role of the AhRR to suppress inflammation and highlight the AhRR as a potential therapeutic target to suppress tumor growth.

Relapsed/Refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is an aggressive disease with poor prognosis and limited therapeutic options. High-dose chemotherapy with autologous hematopoietic stem cell transplantation (autoHCT) was historically the curative-intent treatment for patients who demonstrated chemosensitivity to salvage therapy. However, a significant portion of patients do not make it autoHCT due to disease progression or overall fitness and eligibility. This is of particular concern in the older adult population. In recent years, significant advances in cellular therapies including chimeric antigen receptor (CAR) T-cells and bispecific antibodies, in addition to improvement in autoHCT tolerability, have allowed for additional treatment options for patients with R/R DLBCL. These novel therapies offer the potential for durable remissions and cure, and should be considered in older patients. We present a review focused on the safety and efficacy of cellular therapies in the older adult population with R/R DLBCL. [ABSTRACT FROM AUTHOR]

Current treatments for lymphoma are plagued by substantial toxicity and the inability to overcome drug resistance, leading to eventual relapse and rationalizing the development of novel, less toxic therapeutics and drug combinations. Histone deacetylase inhibitors (HDACis) are a broad class of epigenetic modulators that have been studied in multiple tumor types, including lymphoma. Currently, HDACis are FDA-approved for treating relapsed T-cell lymphomas and multiple myeloma, with ongoing trials in other lymphomas and solid tumors. As single agents, HDACis frequently elicit toxic side effects and have limited efficacy; therefore, many current treatment strategies focus on combinations to boost efficacy while attempting to minimize toxicity. Fermented wheat germ extract (FWGE) is a complementary agent that has shown efficacy in several malignancies, including lymphoma. Here, we utilize a more potent FWGE derivative, known as fermented wheat germ protein (FWGP), in combination with the HDACi AR42, to assess for enhanced activity. We report increased in vitro killing, cell cycle arrest, and in vivo efficacy for this combination compared to each agent alone with minimal toxicity, suggesting a potentially new, minimally toxic treatment modality for lymphoma. [ABSTRACT FROM AUTHOR]

We performed a phase I study of GTI-2040, an antisense oligonucleotide against ribonucleotide reductase mRNA, on a novel dosing schedule of days 1-4 and 15-18 by continuous infusion to examine efficacy and tolerability in patients with leukemia. A dose of 11 mg/kg/d was safely reached. Dose-limiting toxicities (DLTs) at the higher levels included elevated troponin I and liver function enzymes. There were no objective responses to GTI-2040 in this study; 7/24 patients were able to complete the predetermined three infusion cycles. Pharmacokinetic and pharmacodynamic studies were performed, indicating a trend towards increasing intracellular drug levels and decreasing RRM2 gene expression with increasing doses. This dose schedule may be considered if appropriate combinations are identified in preclinical studies.

In this study, HB22.7, an anti-CD22 monoclonal antibody, was used for specific, targeted delivery of monomethyl auristatin E (MMAE) to non-Hodgkin lymphoma (NHL). MMAE was covalently coupled to HB22.7 through a valine-citrulline peptide linker (vc). Maleimide-functionalized vcMMAE (mal-vcMMAE) was reacted with thiols of the partially reduced mAb. Approximately 4 molecules of MMAE were conjugated to HB22.7 as determined by residual thiol measurement and hydrophobic interaction chromatography-HPLC (HIC-HPLC). HB22.7-vcMMAE antibody-drug conjugate (ADC) retained its binding to Ramos NHL cells and also exhibited potent and specific in vitro cytotoxicity on a panel of B cell NHL cell lines with IC50s of 20-284 ng/ml. HB22.7-vcMMAE also showed potent efficacy in vivo against established NHL xenografts using the DoHH2 and Granta 519 cell lines. One dose of the ADC induced complete and persistent response in all DoHH2 xenografts and 90 % of Granta xenografts. Minimal toxicity was observed. In summary, HB22.7-vcMMAE is an effective ADC that should be evaluated for clinical translation.

The exponential rise in molecular and genomic data has generated a vast array of therapeutic targets. Oligonucleotide-based technologies to down regulate these molecular targets have promising therapeutic efficacy. However, there is relatively limited success in translating this into effective in vivo cancer therapeutics. The primary challenge is the lack of effective cancer cell-targeted delivery methods, particularly for a systemic disease such as leukemia. We developed a novel leukemia-targeting compound composed of a monoclonal antibody directly conjugated to an antisense oligonucleotide (ASO). Our compound uses an ASO that specifically targets the transcription factor MAX dimerization protein 3 (MXD3), which was previously identified to be critical for precursor B cell (preB) acute lymphoblastic leukemia (ALL) cell survival. The MXD3 ASO was conjugated to an anti-CD22 antibody (αCD22 Ab) that specifically targets most preB ALL. We demonstrated that the αCD22 Ab-ASO conjugate treatment showed MXD3 protein knockdown and leukemia cell apoptosis in vitro. We also demonstrated that the conjugate treatment showed cytotoxicity in normal B cells, but not in other hematopoietic cells, including hematopoietic stem cells. Furthermore, the conjugate treatment at the lowest dose tested (0.2mg/kg Ab for 6 doses - twice a week for 3 weeks) more than doubled the mouse survival time in both Reh (median survival time 20.5 vs. 42.5 days, p

The International Prognostic Score (IPS-7) is the most commonly used risk stratification tool for advanced Hodgkin lymphoma (HL), however recent studies suggest the IPS-7 is less discriminating due to improved outcomes with contemporary therapy. We evaluated the seven variables for IPS-7 recorded at study entry for 854 patients enrolled on Eastern Cooperative Oncology Group 2496 trial. Univariate and multivariate Cox models were used to assess their prognostic ability for freedom from progression (FFP) and overall survival (OS). The IPS-7 remained prognostic however its prognostic range has narrowed. On multivariate analysis, two factors (age, stage) remained significant for FFP and three factors (age, stage, haemoglobin level) for OS. An alternative prognostic index, the IPS-3, was constructed using age, stage and haemoglobin level, which provided four distinct risk groups [FFP (P = 0·0001) and OS (P

PurposeThe phase III North American Intergroup E2496 Trial (Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Hodgkin's Lymphoma) compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with mechlorethamine, doxorubicin, vincristine, bleomycin, vinblastine, etoposide, and prednisone (Stanford V). We report results of a planned subgroup analysis in patients with stage I or II bulky mediastinal Hodgkin lymphoma (HL).Patients and methodsPatients were randomly assigned to six to eight cycles of ABVD every 28 days or Stanford V once per week for 12 weeks. Two to 3 weeks after completion of chemotherapy, all patients received 36 Gy of modified involved field radiotherapy (IFRT) to the mediastinum, hila, and supraclavicular regions. Patients on the Stanford V arm received IFRT to additional sites ≥ 5 cm at diagnosis. Primary end points were failure-free survival (FFS) and overall survival (OS).ResultsOf 794 eligible patients, 264 had stage I or II bulky disease, 135 received ABVD, and 129 received Stanford V. Patient characteristics were matched. The overall response rate was 83% with ABVD and 88% with Stanford V. At a median follow-up of 6.5 years, the study excluded a difference of more than 21% in 5-year FFS and more than 16% in 5-year OS between ABVD and Stanford V (5-year FFS: 85% v 79%; HR, 0.68; 95% CI, 0.37 to 1.25; P = .22; 5-year OS: 96% v 92%; HR, 0.49; 95% CI, 0.16 to 1.47; P = .19). In-field relapses occurred in < 10% of the patients in each arm.ConclusionFor patients with stage I or II bulky mediastinal HL, no substantial statistically significant differences were detected between the two regimens, although power was limited. To the best of our knowledge, this is the first prospective trial reporting outcomes specific to this subgroup, and it sets a benchmark for comparison of ongoing and future studies.

Checkpoint kinase inhibition has been studied as a way of enhancing the effectiveness of DNA-damaging agents. More recently, histone deacetylase inhibitors have shown efficacy in several cancers, including non-Hodgkin lymphoma. To evaluate the effectiveness of this combination for the treatment of lymphoma, we examined the combination of AR42, a histone deacetylase inhibitor, and checkpoint kinase 2 (CHEK2) inhibitor II in vitro and in vivo. The combination resulted in up to 10-fold increase in potency in five Burkitt lymphoma cell lines when compared with either drug alone. Both drugs inhibited tumor progression in xenograft models, but the combination was more effective than either agent alone, resulting in regression of established tumors. No toxicity was observed. These results suggest that the combination of histone deacetylase inhibition and checkpoint kinase inhibition represent an effective and nontoxic treatment option that should be further explored in preclinical and clinical studies.

Conventional chemotherapy for precursor B-cell (preB) acute lymphoblastic leukaemia (ALL) has limitations that could be overcome by targeted therapy. Previously, we discovered a potential therapeutic molecular target, MDX3 (MAX dimerization protein 3), in preB ALL. In this study, we hypothesize that an effective siRNA therapy for preB ALL can be developed using antiCD22 antibody (αCD22 Ab) and nanoparticles. We composed nanocomplexes with super paramagnetic iron oxide nanoparticles (SPIO NPs), αCD22 Abs and MXD3 siRNA molecules based on physical interactions between the molecules. We demonstrated that the MXD3 siRNA-αCD22 Ab-SPIO NP complexes entered leukaemia cells and knocked down MXD3, leading the cells to undergo apoptosis and resulting in decreased live cell counts in the cell line Reh and in primary preB ALL samples in vitro. Furthermore, the cytotoxic effects of the MXD3 siRNA-αCD22 Ab-SPIO NP complexes were significantly enhanced by addition of the chemotherapy drugs vincristine or doxorubicin. We also ruled out potential cytotoxic effects of the MXD3 siRNA-αCD22 Ab-SPIO NP complexes on normal primary haematopoietic cells. Normal B cells were affected while CD34-positive haematopoietic stem cells and non-B cells were not. These data suggest that MXD3 siRNA-αCD22 Ab-SPIO NP complexes have the potential to be a new targeted therapy for preB ALL.

We performed a phase II study of belinostat in patients with acute myeloid leukemia (AML). In this open label phase II study (NCT00357032), patients with relapsed/refractory AML, or newly diagnosed patients with AML over the age of 60, were eligible. Belinostat was administered intravenously (IV) at a dose of 1000 mg/m(2) daily on days 1-5 of a 21-day cycle until progression or unacceptable toxicity. The primary endpoint was complete response (CR) rate, with secondary endpoints of overall response rate (CR + partial response [PR]), time to treatment failure (TTF), overall survival and safety. Twelve eligible patients with AML were enrolled, of whom six had received at least one prior line of therapy. No CR or PR was seen. Four patients had stable disease for at least five cycles. Grade 3 non-hematological toxicities occurred in four patients. Belinostat as monotherapy has minimal single-agent effect in AML on this dosing schedule.

Purpose The clinical efficacy of anti-CD20 radioimmunotherapy (RIT) is due to a combination of extracellular mechanisms involving immune-mediated cytotoxicity, and intracellular mechanisms related to inhibition of CD20 signaling and DNA damage from ionizing radiation. In 2002, the first RIT was approved by the U.S. Food and Drug Administration for the treatment of patients with indolent B-cell follicular non-Hodgkin lymphoma (NHL). The 2 approved agents, 90 Y-ibritumomab tiuxetan (90Y-IT, Zevalin, Acrotech Biopharma) and 131 I-tositumomab (131-IT, Bexxar, GlaxoSmithKline) both target CD20. The aim of this study was to review the clinical applications and supporting clinical trial data of anti-CD20 RIT for lymphoma. Methods A review of published articles and abstracts on the clinical efficacy and safety of 90Y-IT and iodine I 131 tositumomab was performed. Results The clinical efficacy and safety of anti-CD20 RIT have been demonstrated in numerous clinical trials and case series. Agents have produced significant responses in patients with follicular NHLs and in off-label applications. Importantly, RIT has demonstrated promising findings in high-risk lymphomas and heavily pretreated and refractory patient populations. Associated toxicity profiles are noted as tolerable, acceptable, and most often reversible. Conclusions In the 2 decades since its approval, anti-CD20 RIT continues to demonstrate efficacy, particularly with a proportion of patients maintaining long-term remissions. The combination of prolonged efficacy, tolerability, and treatment convenience makes RIT a reasonable alternative to other systemic therapies. It is recommended that further research on RIT should focus on biomarkers of long-term response, pretargeting, and sequencing of RIT in the treatment course. [ABSTRACT FROM AUTHOR]

Antibody drug conjugates (ADCs) can deliver potent drugs to cancer cells by employing the specificity of monoclonal antibodies (mAbs). ADCs have demonstrated significant anticancer activity and, in 2011, brentuximab vedotin has been approved by the FDA for the treatment of Hodgkin's and anaplastic large cell lymphomas. CD22 is an ideal target for ADC against B-cell malignancies because of its lineage-specific expression and rapid internalization upon antibody binding. In this study, we evaluated the anti-CD22 mAb HB22.7 as a vehicle for the targeted delivery of the potent toxin saporin (SAP). In vitro, HB22.7-SAP was cytotoxic against a panel of non-Hodgkin's lymphoma (NHL) cell lines representing the most common types of the disease. Moreover, in a xenograft model of NHL, HB22.7-SAP significantly inhibited the growth of established lesions and completely prevented tumor development when treatment was initiated within 24 h from tumor-cell inoculation. HB22.7-SAP had no significant in vivo toxicity. In conclusion, HB22.7 constitutes a potential platform for CD22-targeted ADCs.

Abstract Most non-Hodgkin's lymphomas (NHL) initially respond to chemotherapy, but relapse is common and treatment is often limited by chemotherapy-related toxicity. Bortezomib, is a highly selective proteasome inhibitor with anti-NHL activity; it is currently FDA approved for second-line treatment of mantle cell lymphoma (MCL). Bortezomib exerts its activity in part through the generation of reactive oxygen species (ROS) and also by the induction of apoptosis. We previously validated CD22 as a potential target in treating NHL and have shown that the anti-CD22 ligand blocking antibody, HB22.7, has significant independent lymphomacidal properties in NHL xenograft models. We sought to determine whether or not these agents would work synergistically to enhance cytotoxicity. Our results indicate that treatment of NHL cell lines with HB22.7 six hours prior to bortezomib significantly diminished cell viability. These effects were not seen when the agents were administered alone or when bortezomib was administered prior to HB22.7. Additionally, HB22.7 treatment prior to bortezomib increased apoptosis in part through enhanced ROS generation. Finally, in a mouse xenograft model, administration of HB22.7 followed 24 hours later by bortezomib resulted in 23% smaller tumor volumes and 20% enhanced survival compared to treatment with the reverse sequence. Despite the increased efficacy of HB22.7 treatment followed by bortezomib, there was no corresponding decrease in peripheral blood cell counts, indicating no increase in toxicity. Our results suggest that pre-treatment with HB22.7 increases bortezomib cytotoxicity, in part through increased reactive oxygen species and apoptosis, and that this sequential treatment combination has robust efficacy in vivo.

Previous studies have shown that bispecific antibodies that target both CD20 and CD22 have in vivo lymphomacidal properties. We developed a CD20-CD22 bispecific antibody (Bs20x22) from anti-CD20 and the anti-CD22 monoclonal antibodies (mAb), rituximab and HB22.7, respectively. Bs20x22 was constructed using standard methods and was shown to specifically bind CD20 and CD22. In vitro cytotoxicity assays showed that Bs20x22 was three times more effective than either parent mAb alone and twice as effective as a combination of both parent mAb used at equimolar concentrations. Bs20x22 was also nearly four times more effective at inducing apoptosis than either mAb alone. Examination of the MAPK and SAPK signaling cascades revealed that Bs20x22 induced significantly more p38 phosphorylation than either mAb alone. In an in vivo human NHL xenograft model, treatment with Bs20x22 resulted in significantly greater tumor shrinkage and improved overall survival when compared to either mAb alone or treatment with a combination of HB22.7 and rituximab. The effect of the initial tumor volume was assessed by comparing the efficacy of Bs20x22 administered before xenografts grew versus treatment of established tumors; significantly, greater efficacy was found when treatment was initiated before tumors could become established.

Non-Hodgkin’s lymphoma (NHL) is the sixth most common cause of cancer deaths in the U.S. Most NHLs initially respond well to chemotherapy, but relapse is common and treatment is often limited due to the toxicity of chemotherapeutic agents. Pegylated-liposomal doxorubicin (PLD, Ben Venue Laboratories, Inc), a produces less myelotoxicity than non-liposomal (NL) doxorubicin. To further enhance efficacy and NHL targeting and to decrease toxicity, we conjugated an anti-CD22 monoclonal antibody (HB22.7) to the surface of PLD, thereby creating CD22-targeted immunoliposomal PLD (IL-PLD). HB22.7 was successfully conjugated to PLD and the resulting IL-PLD exhibits specific binding to CD22-expressing cells as assessed by immunofluorescence staining. IL-PLD exhibits more cytotoxicity than PLD in CD22 positive cell lines but does not increase killing of CD22 negative cells. The IC50 of IL-PLD is 3.1 to 5.4 times lower than that of PLD in CD22+ cell lines while the IC50 of IL-PLD is equal to that of PLD in CD22- cells. Furthermore, IL-PLD remained bound to the CD22+ cells after washing and continued to exert cytotoxic effects, while PLD and NL- doxorubicin could easily be washed from these cells.

CD22 is a cell-surface adhesion molecule on most B-cell NHL, so it is a promising target for immunotherapy. HB22.7 is an anti-CD22 mAb that binds the two NH2-terminal immunoglobulin domains and specifically blocks the interaction of CD22 with its ligand. CD22-blocking mAbs induce apoptosis in neoplastic B-cells and are functionally distinguishable from other anti-CD22 mAbs. This study assessed the optimal dose, route, schedule, and the targeted CD22 epitope. Raji NHL-bearing nude mice were studied. A non-blocking anti-CD22 mAb (HB22.27) was used as a control. HB22.27 had minimal effect, whereas HB22.7 improved survival and shrank tumors substantially. HB22.7 doses greater than 1.4 mg/week did not further increase efficacy (or toxicity). Tumors less than 200 mm3 had a higher response rate than did larger tumors. Various schedules of HB22.7 administration were tested; one dose every other week was more effective than more or less frequent dosing. Pharmacokinetic studies revealed that the half-life of HB22.7 was 28 days; this correlated with the time needed to re-populate cell-surface CD22 after treatment with HB22.7. Immuno-PET showed that NHL was rapidly and specifically targeted by copper-64-labeled-HB22.7. This study provided data as to an optimal dose, route, schedule and interval between doses of HB22.7.