Mantel Cell Lymphoma Research Articles

Open-Label Study of Bendamustine Hydrochloride in Chinese Patients with Indolent Non-Hodgkin Lymphoma (NHL) Refractory to Rituximab Treatment

Introduction: The addition of rituximab to chemotherapy has been associated with substantial responses in patients with indolent NHL, but patients usually relapse. Bendamustine hydrochloride (bendamustine; Treanda®) is an alkylating agent approved globally for multiple indications including chronic lymphocytic leukemia, indolent B-cell NHL, mantel cell lymphoma, and multiple myeloma. This open-label, single-arm, multicenter study in China aims to determine the overall response rate (ORR) to bendamustine treatment in patients with indolent B-cell NHL refractory to a rituximab-containing regimen.Methods: Patients with documented relapse from indolent B-cell NHL after rituximab treatment and 1-3 previous chemotherapy regimens were included. Patients received bendamustine intravenous 120 mg/m2 infusion (over 60 minutes) on day 1 and 2 of each 21-day cycle for at least 6 cycles and were allowed to continue treatment for up to 8 cycles. Primary endpoint was response rate based on the modified International Workshop Response Criteria; secondary endpoints were duration of response (DOR), progression-free survival (PFS), and safety.Results: A total of 102 patients from 20 centers were enrolled. All enrolled patients were analyzed for safety and efficacy. The ORR was 73% (95% CI: 62.82-80.92) per independent review committee (IRC) including 19% complete response (CR) and 54% partial response (PR). The ORR per investigator assessment was 78% (30% CR and 48% PR). Among 31 patients with disease refractory to last alkylator therapy, the ORR was 68% (95% CI: 48.63-83.32). The median DOR was 16.5 months (95% CI: 10.9-NA) per IRC and 12.5 months per investigator. Durable responses were observed across all baseline patient and disease characteristics. Median DOR was not reached in patients refractory to last alkylator or chemotherapy treatment. The median PFS was 18.6 months and was similar across baseline characteristics. Disease characteristics did not significantly impact PFS.The overall safety profile was consistent with known adverse events (AEs). The most common AEs (≥40%) were white blood cell count decreased (54%), neutrophil count decreased (47%), neutropenia (46%), leukopenia (45%), nausea (44%), and platelet count decreased (40%). Most patients completed planned treatment; the mean relative dose intensity was 82%. Neutropenia was the most common reason for dose reductions. Four patients died during the study, three of which were attributed to bendamustine. At least one serious AE was experienced by 29 patients, and AEs that resulted in discontinued treatment occurred in 25 patients.Conclusions: Single-agent bendamustine is effective in the treatment of Chinese patients with rituximab-refractory, relapsed indolent B-cell NHL including those with previous alkylator exposure, with a safety profile consistent with known AEs.Sponsor: Teva Branded Pharmaceutical Products R&D DisclosuresMueller:Teva Pharmaceuticals, Inc.: Employment, Equity Ownership.

Single-Agent Ibrutinib in Recurrent/Refractory Central Nervous System Lymphoma

BACKGROUNDPrimary Central Nervous System Lymphoma (PCNSL) is an aggressive primary brain tumor with median progression free survival (PFS) after upfront methotrexate-based chemotherapy of 2-3 years. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. Response rates (ORR) range between 30-60% with a PFS of 2-5 months. Ibrutinib has shown promising clinical response in Mantel cell lymphoma, CLL, and Waldenström. This trial investigates Ibrutinib in patients with r/r PCNSL and SCNSL. METHODSEligible patients had r/r PCNSL or Secondary CNS Lymphoma (SCNSL), age≥18, ECOG≤2, normal end-organ function, and unrestricted number of CNS directed prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. RESULTSTwenty patients were enrolled (3 at 560 mg; 17 at 840 mg). Median age was 69 (range 21-85); 12 were women. Median ECOG was 1 (0: 2, 1: 12, 2: 6). 65% had PCNSL and 35% SCNSL; 70% had recurrent disease. Eleven had parenchymal disease, 3 isolated cerebrospinal fluid (CSF) involvement and 6 both. Five grade 4 adverse events were observed in 4 patients (lymphopenia (2), sepsis (1), neutropenia (2)). Ten patients developed grade 3 toxicities, including lymphopenia in 3 patients, thrombocytopenia in 2, hyperglycemia in 2, lung infection in 2, neutropenia in 1, urinary tract infection in 1, colitis in 1, and fungal encephalitis in 1. The most common toxicities were hyperglycemia, anemia, and thrombocytopenia. After a median follow-up of 193 days, 19/20 patients were evaluated for response: 8 CR, 7 PR, 1 SD and 3 PD; 75% (15/20) ORR. The median PFS is 7.29 months (95% CI: 3.80-15.43 months (longest: 15.3 months)). The mean Ibrutinib concentration in the CSF 2h post administration at day 1 and 29 is 1.75 ng/mL (3.97 nM) and 2.51 ng/mL (5.6 nM) which is above the IC50 (1nM) required in vitro to reduce growth of lymphoma cells.An additional treatment arm has been added to the trial which will evaluate adverse events of the combination of ibrutinib and high-dose methotrexate chemotherapy. Enrollment into the combination arm is ongoing and updates will be presented at the meeting. CONCLUSIONPatients with CNS lymphoma tolerate Ibrutinib with manageable adverse events. Drug concentrations in CSF are higher at steady state (day 29) and meaningful CSF concentrations are reached. Clinical response was seen in 75% of CNS lymphoma patients. A combination arm will assess the adverse events of ibrutinib in combination with high-dose methotrexate chemotherapy. DisclosuresNo relevant conflicts of interest to declare.

Pharmacokinetics of Bendamustine Hydrochloride in Chinese Patients with Indolent Non-Hodgkin Lymphoma (iNHL) Refractory to Rituximab Treatment

Introduction: Bendamustine hydrochloride (bendamustine; Treanda®) is an alkylating agent approved globally for multiple indications including chronic lymphocytic leukemia, indolent B-cell NHL, mantel cell lymphoma, and multiple myeloma. The plasma concentration-time profile of a single intravenous (IV) dose of bendamustine follows a triphasic pattern, with a very rapid distribution and intermediate phases followed by a slow terminal decline. The initial phases represent most of the observed area under the plasma drug concentration-by-time curve (AUC), and the effective half-life (t1/2) of 40 minutes is based on the elimination rate of the intermediate phase. Two active circulating metabolites (gamma-OH-bendamustine [M3] and N-desmethyl-bendamustine [M4]) are produced via the CYP1A2 pathway, but both metabolites are generally found at low levels relative to parent bendamustine. However, relatively little is known regarding the effect of race/ethnicity on the pharmacokinetics (PK) of bendamustine. The present investigation had the goal of defining the PK of bendamustine in a subset of ethnic Chinese patients with relapsed/refractory iNHL from an open-label, single-arm, multicenter study in China.Methods: Patients with documented relapsed indolent B-cell NHL after rituximab treatment and 1-3 previous chemotherapy regimens were included. Patients received bendamustine IV 120 mg/m2 infusion (over 60 minutes and not more than 120 minutes) on day 1 and 2 of each 21-day cycle for at least 6 cycles and were allowed to continue treatment for up to 8 cycles. Blood samples for PK were collected at the following time points on day 1 of cycle 1: before, during, and immediately after the infusion, and 15, 30, and 45 min, and 1, 2, 4, 6, 8, 10, 12, and 24 h after the end of infusion. PK parameters were estimated using noncompartmental methods. The PK evaluable population included those patients for whom at least one PK parameter was calculable.Results: PK parameters were characterized in 15 Chinese patients with relapsed/refractory iNHL. Results of the analyses are summarized and presented in the table. Highest plasma concentrations were observed at either the midpoint or end of infusion in all patients. The subsequent decrease in plasma concentration occurred in a multiphasic manner as shown in the figure. The data suggested that bendamustine has a high plasma clearance and does not readily distribute beyond the extracellular space. The metabolites M3 and M4 were observed at lower concentrations than parent bendamustine. Total systemic exposure (AUC0-∞) to M3 was approximately 1/10 of that to bendamustine and approximately 10-fold higher than that to M4.Conclusion: The PK characteristics of bendamustine and its known active circulating metabolites, M3 and M4, in Chinese patients with cancer are generally consistent with those reported in other ethnic populations.Sponsor: Teva Branded Pharmaceutical Products R&D [Display omitted] [Display omitted] DisclosuresHellriegel:Teva Pharmaceuticals, Inc.: Employment, Equity Ownership. Robertson:Teva Pharmaceuticals, Inc.: Employment, Equity Ownership.

177lu-Satetraxetan-Lilotomab in the Treatment of Patients with Indolent Non-Hodgkin B-Cell Lymphoma (NHL), Phase 1/2 Safety and Efficacy Data from Four Different Pre-Dosing Regimens

177Lu-Satetraxetan-lilotomab (Betalutin®) is a novel CD37-binding IgG1 antibody labelled with the beta-emitter lutetium-177, in a ready-to-use formulation currently in Phase 1/2 clinical development for the treatment of Non-Hodgkins lymphoma. CD37 is an internalizing transmembrane antigen highly expressed on most B-cell malignancies, and is a promising therapeutic target. The optimisation of the pre-dosing regimen prior to administration of 177Lu-Satetraxetan-lilotomab may result in an improved safety and efficacy profile. The phase 1 stage of this study is designed with 4 arms to test different pre-dosing regimens (no pre-dosing, rituximab and two doses of lilotomab) on the effect of 177Lu-Satetraxetan-lilotomab.Methods:Patients with relapsed incurable NHL of follicular grade I-IIIA, marginal zone, mantle cell, lymphoplasmacytic and small lymphocytic subtypes and with platelet counts ≥ 150 x109/l were eligible for inclusion in the study.All patients received pre-treatment with rituximab (375 mg/m2) to deplete peripheral B cells and improve biodistribution of the labelled antibody. Pre-dosing with lilotomab (cold anti-CD37 antibody) was given in arms 1 and 4 or rituximab in arm 3, within 4 hours of 177Lu-Satetraxetan-lilotomab to block binding in the non-tumour tissue. The pre-treatment and pre-dosing regimen used in each arm is summarised below:Arm 1: rituximab day1 and 8, lilotomab (40 mg) plus Betalutin day 29Arm 2: rituximab day 1 and 8, Betalutin day 29Arm 3: rituximab day 1, rituximab plus Betalutin day 15Arm 4: rituximab day 1, lilotomab (100 mg/m2) plus Betalutin day 15The starting dose for Arm 1 was10 MBq/kg and was 15 MBq/kg for arm 2, 3 and 4 and in phase 2. Response was assessed by FDG PET/CT scans at 3 and 6 months post-treatment and then by CT scan up to 5 years after treatment. The results of the protocol specified interim analysis will be presented.Results:A total of36 patients have been enrolled into study, of which 24 are currently evaluable. Patients enrolled into the study had either follicular (n=20), mantel cell (n=2) or marginal zone (n=2) lymphoma. The number of prior therapies ranged from 1 to 8. The efficacy and safety results from patients enrolled into Arms 3 and 4 and treated with two different pre-dosing regimens will be presented for the first time.The most common toxicities observed were hematologic with all dose limiting toxicities (DLTs) being reversible and manageable and related to thrombocytopenia and neutropenia. At a dose of 15 MBq/kg, pre-dosing with 40 mg of lilotomab (Arm 1 and phase 2) reduced the incidence of hematological DLTs to 14% (2/14 patients) compared with 100% (2/2 patients) with no pre-dosing in Arm 2.No DLTs have been reported at 10 MBq/kg in either Arm 1 or 2. Fourteen serious adverse events (SAEs) were reported by 8 patients: Atrial fibrillation (n=2) and platelet count decreased (n=2) were the only SAEs reported by more than one patient. There have been no deaths and no secondary malignancies or other long-term safety events.The overall tumor response rate observed in 23 patients evaluable for efficacy was 57%, comprising 7/23 complete responses, 6/23 partial responses, 5/23 stable disease and 5/23 with progressive disease. In addition, one patient had a confirmed transformed lymphoma at 3 months. One patient is still in remission more than 3 years after treatment and two further patients are still in remission more than 2 years after treatment.Conclusions: Betalutin has the potential to be a novel, safe and effective therapy for B-cell malignancies with durable responses. Betalutin, a single dose, ready-to-use formulation, has a predictable and manageable safety profile which is improved by pre-dosing. Most AEs were haematological, all transient and reversible. DisclosuresKolstad:Nordic Nanovector: Other: Membership of Scientific Advisory Board. Illidge:Nordic Nanovector: Consultancy. Dahle:Nordic Nanovector ASA: Employment, Equity Ownership. Baylor Curtis:Nordic Nanovector: Employment. Østengen:Nordic Nanovector: Employment. Turner:Nordic Nanovector: Employment. Hartvig Larsen:Nordic nanovector: Equity Ownership. Holte:Mundipharma: Research Funding; Amgen: Research Funding.

Lymphoma of Ocular and Periocular Tissues - Clinicopathological Correlations

Lymphomas of the ocular adnexa and intraocular tissue include a wide range of lymphoproliferative neoplastic disorders. They are predominantly extranodal non-Hodgkin lymphomas (NHL). The World Health Organization (WHO) classification of lymphoid neoplasm and individual morphological, immunophenotypical, and molecular genetic features, indicate that they may be divided into B-cell (approximately 80 % of all NHL) and T-cell lymphomas (approximately 10-20 % of all NHL). The most common forms of ocular NHL are extranodal marginal zone lymphoma (EMZL) of the mucosa-associated lymphoid tissue (MALT-type), follicular lymphoma (FL), diffuse large B-cell lymphoma, and mantel cell lymphoma. The clinical signs and symptoms are usually very unspecific and depend on the location, size, and extent of the underlying lymphoma subtype. Typical low grade lymphomas have an indolent clinical course and often remain unrecognized for many years. On the other hand, high grade NHLs, such as DLBCL or MCL, are frequently aggressive, with rapid tumour growth and poor prognosis, despite early detection. Histopathology is still the gold standard in the diagnosis of ocular lymphomas. Basic understanding of the principal pathophysiological and clinical aspects of the development and progression of orbital and ocular lymphomas seems to be mandatory for optimal diagnosis and treatment and for improving survival and prognosis. Both residents in training and board certified ophthalmologists should be aware of these problems.

Cyclin-dependent kinase pathways as targets for women's cancer treatment.

In this article, we not only review the preclinical and clinical studies of cyclin-dependent kinase (CDK) 4/6 inhibitors in breast cancer, liposarcoma, mantel cell lymphoma, melanoma and germ cell tumors, but also examine promising preclinical data in glioblastoma, renal and ovarian cancer models that may provide directions for future development. Targeting CDKs has been the focus of considerable basic science and clinical research. The CDK 4/6 inhibitors are a novel class of therapeutics that target the CDK 4/6 kinases that promote transition through the cell cycle. Currently, palbociclib (PD0332991, Pfizer), abemaciclib (LY2835219, Lilly) and ribociclib (LEE011, Novartis) are being investigated in clinical trials. These oral agents offer the hope of clinical efficacy in many tumor types, and have been associated with minimal toxicity. Amplification/overexpression of cyclin D, loss of CDKN2A (p16) and amplification/overexpression of CDK4 are proposed biomarkers of improved response to CDK4/6 inhibition. Palbociclib, abemaciclib and ribociclib have demonstrated very promising clinical activity in breast cancer, liposarcoma, mantel cell lymphoma and melanoma. Moreover, CDK4/6 inhibitors have shown promising preclinical activity in glioblastoma, renal and ovarian cancer models that may provide directions for their future clinical development. Further preclinical and clinical research is needed to better understand mechanisms of resistance and develop rational combination therapies with other targeted agents.

Lenalidome in combination with rituximab for relapsed or refractory mantel cell lymphoma: Updated analysis of a phase 2 trial.

8542 Background: We previously reported favorable safety and efficacy of lenalidomide plus rituximab in relapsed or refractory (R/R) mantle cell lymphoma (MCL) in a phase 1/2 trial (Wang et al, Lan...

Bortezomib prevents the expression of MMP-13 and the degradation of collagen type 2 in human chondrocytes

The structural backbone of extracellular matrix in cartilage is the collagen fibril, which is mainly composed of type II collagen. A measurable increase in type II collagen denaturation and degradation has been found in early Osteoarthritis (OA). Pro-inflammatory cytokine such as TNF-α produced in OA cartilage induced the expression of matrix metalloproteinase-13 (MMP-13), which targets and degrades type II collagen. Bortezomib is a proteasome inhibitor approved by the FDA for treatment of multiple myeloma and mantel cell lymphoma. The effects of bortezomib in OA have not been reported before. In this study, we found that bortezomib is able to suppress the degradation of type II collagen induced by TNF-α in human chondrocytes. Mechanistically, bortezomib treatment inhibits the expression of IRF-1 through blunting JAK2/STAT1 pathway, thereby prevents the induction of MMP-13 as well as the degradation of type II collagen. Our findings suggest the therapeutic potentials of bortezomib in patients with OA.

Ibrutinib.

Abnormal B-cell receptor (BCR) signaling is a key mechanism of disease progression in B-cell malignancy. Bruton's tyrosine kinase (BTK) has a pivotal role in BCR signaling. Ibrutinib (PCI-32765) is a novel agent which serves as a covalent irreversible inhibitor of BTK. It is characterized by high selectivity for BTK and high potency. Preliminary data from phase I and ongoing phase II trials have proven very promising so far. It suggests the substance has high efficacy in B-cell malignancies such as chronic lymphocytic leukemia (CLL); diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantel cell lymphoma (MCL), and multiple myeloma (MM) and is very well tolerable. Most notably, the substance does not cause myelosuppression. This chapter discusses structure, mechanism of action, and toxicities of ibrutinib and also presents important preclinical and clinical data. Phase III trials will have to determine the definite role of ibrutinib in clinical practice but the data available so far suggests it may be a powerful new weapon in the battle against B-cell malignancies.

Immunophenotyping of B chronic lymphoproliferative syndromes (CLL excluded): confrontation with the histology

Immunophenotyping is a major tool for the diagnosis of the chronic lymphoïd leukaemia (CLL). Its interest remains limited in the classification of the other B chronic lymphoproliférative syndromes (B-CLPS). We evaluate the place of the flow cytometry (CMF) in the diagnosis and classification of the non CLL B-CLPS. The cases with Matutes score of 4 or more are excluded. A confrontation of the results to the histology is made. 28 cases of non CLL B-CLPS are diagnosed. CMF shows a κ monoclonal population in 15 cases and λ in 13 cases. A co-expression CD19+CD5 + is found in 11 cases concording with an atypic CLL or a mantel cell lymphoma in 6 cases with Matutes score of 3. In 5 cases, we concluded to non CLL B-CLPS (Matutes<3). The histology retained the diagnosis of a mantel cell lymphoma (4 cases), a SLVL (1 case) and an atypical LLC (1 case). CD5 is negative in 17 cases. In 5 cases, the diagnosis of hairy cell leukemia (HCL) is retained (CD 11c+ CD103+) and confirmed by the histology. The diagnosis of a marginal zone lymphoma is retained in 2 cases, a SLVL in 2 cases, a follicular lymphoma in 3 cases and prolymphocytes leukaemia in 1 case. Nine cases of non CLL B-CLPS were difficult to classify by histology. CMF is insufficient for the classification of most of the non CLL B-CLPS. Only the phenotype of the HCL is characteristic. The confrontation of the histology results remains essential.

The Use of Salivary Protein Secretions as an In Vivo Model to Study Mantel Cell Lymphoma Progression and Treatment

Purpose: The objective of this study was to compare the salivary protein profiles from an individual diagnosed with MCL before, during, and after chemotherapy. Methods: Saliva specimens acquire prior, during, and after chemotherapy. Specimens were analyzed using a LC-MS/MS mass spectrometer. Results: The results of the study suggest salivary protein alterations secondary to MCL and that a number of the proteins were changed as a result of chemotherapeutic intervention suggesting that the treatment, from a proteomic perspective, was efficacious. The study suggests that salivary secretions may be used as in vivo model for studying MCL progression and treatment efficacy.

Characterization of Peripheral B Cells Expressing CLL-Associated Receptor Tyrosine Kinase ROR1 in Healthy Donors

AbstractAbstract 1787Recent studies have described an extensive expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1) on the surface of malignant B cells in patients suffering from chronic lymphoid leukemia (CLL). ROR1 expression has also been detected in ovarian cancer, renal cancer, melanoma, and lung adenocarcinoma, suggesting a general role of ROR1 in cancer genesis and/or maintenance. However, low levels of ROR1 mRNA or protein expression have also been found on undifferentiated embryonic stem cells, adipose tissue and on early stage of B-cells in bone marrow, but not in major adult tissues and peripheral B cells.In contrast, our results describe for the fist time expression of ROR1 on rare B cells in peripheral blood of healthy donors. Using magnetic cell sorting techniques we were able to enrich ROR1 positive B cells from PBMCs of healthy donors. The average frequency of ROR-1+ B cells in PBMCs ranged from 1×10−3 to 1×10−4. Interestingly, ROR1+ B cells revealed a heterogeneous phenotype and could further be classified into a CD19+/CD27+/CD38− and a CD19+/CD27−/CD38+ subpopulation as assessed by flow cytometry. Remarkably, in contrast to the CD27+ subpopulation the CD38+ subpopulation showed higher levels of CD5 and CD23 expression, which are both markers known to be upregulated on B cells of CLL patients. Both populations do not show elevated expression of transcription factor ZAP70 and Bcl-2 but expressed higher level of Bcl-6 compared to CD19 B cells. Bcl-6 is known to be required for pre-B cell self-renewal but has also been described to play an essential role in resistance of leukemic cells to therapeutic tyrosine kinase inhibitors. Moreover ROR1+ B cells revealed an immature and non-activated sate as evidenced by the expression of IgD and IgM, and the lack of IgG and CD69. Further functional examination and immunophenotyping of these rare cells are under investigation.We have identified rare B cells expressing the tumor-associated receptor tyrosine kinase ROR1, which are heterogenic in CD27 and CD38 expression and show an immature phenotype. We are currently assessing a potential relationsphip ROR1+ peripheral B cells and ROR1 expressing B cells in malignancies like CLL, mantel cell (MCL) and marginal zone lymphoma (MZL). Disclosures:Milleck:Miltenyi Biotec GmbH: Employment. Assenmacher:Miltenyi Biotec GmbH: Employment. Schmitz:Miltenyi Biotec GmbH: Employment. Jähn:Miltenyi Biotec GmbH: Employment.

Blastoid mantle cell lymphoma involving skin and orbit with hypercalcemia: A case report and literature review

Abstract Mantel cell lymphoma is one of the small B-cell non-Hodgkin's lymphomas and usually involves lymph nodes, bone marrow, spleen, liver, gastrointestinal tract, and Waldeyer's ring, but rarely skin and orbit. A 53-year-old man presented skin nodules and plaques on the head, trunk, and lower extremities for half a month, and the left periorbital region swelled 4 days ago. Serum calcium and lactate dehydrogenase were increased to 3.12mmol/L (normal 2.03–2.65mmol/L) and 853U/L (normal 71–231U/L), respectively. Histopathologic examination of the skin nodule revealed tumor cells infiltrated nodular distribution in the dermis and subcutaneous tissue. Immunophenotyping of the abnormal lymphocytes indicated positive reactions for L26, CD79a, Bcl-2, Cyclin D1, and Ki-67 (>80%), but negative for CD5, CD21, CD23, CD38, CD3, CD10, UCHL-1, TdT, MPO, CD30, ALK, CD117, and CD34. Fluorescence in situ hybridization analysis with the CCND1/IGH probe revealed a fusion signal on the abnormal lymphocytes. The final diagnosis was a rare case of blastoid mantle cell lymphoma involving skin and orbit with hypercalcemia. Following the R-Hyper-CVAD treatment plan, the patient achieved a quick and excellent recovery on the 6th day. Unfortunately, the patient eventually died of pneumonia one month later.

Benign Breast Cyst without Associated Gynecomastia in a Male Patient: A Case Report

Benign simple breast cysts are commonly seen in female breasts and can present as palpable masses. They are distinctly uncommon, however, in the male breast. We report a case of simple benign cyst of the breast in a 58-year-old man newly diagnosed with mantel cell lymphoma. The cyst was first identified incidentally on a staging contrast-enhanced chest computed tomography. Further evaluation with mammography and ultrasound revealed a mass that would be typically characterized as a benign simple cyst, but was biopsied since cysts are not known to occur in male breasts. Pathology results from ultrasound-guided core needle biopsy revealed benign cyst and focal fibrosis which was concordant with the imaging findings. In this case report, we will briefly discuss breast cysts in men and their imaging features including mammography and ultrasound.

Focal Adhesion Kinase as a Therapeutic Target of Bortezomib

Bortezomib, a modified dipeptidyl boronic acid, is a selective potent proteasome inhibitor that has been approved for clinical treatment of multiple myeloma and mantel cell lymphoma. Results from a growing number of basic studies and clinical trials reveal that bortezomib could be used to treat diverse types of solid tumors alone or in combination with other chemotherapeutic drugs. It has been shown that bortezomib transcriptionally suppresses focal adhesion kinase (FAK) expression by interrupting the nuclear factor kappa B (NFκB) pathway, which suggests that FAK could be a potential molecular target for bortezomib. Analysis of FAK promoter sequences revealed that FAK promoter harbors the NFκB and p53 binding domains. Further studies of FAK promoter activity, real-time PCR, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay revealed that bortezomib inhibits NFκB binding on the FAK promoter, thereby reducing FAK expression. Thus, bortezomib could inhibit cancer cell growth and migration or invasion by repressing FAK expression. Since activation and overexpression of FAK has been implicated in the progression and invasion of malignant tumors, it is likely that targeting FAK with bortezomib is a potential strategy for preventing cancer metastasis. This review focuses on the molecular regulation of FAK and the potential clinical application of bortezomib.

Targeting Translation Bypasses Pim Kinase Activity, a Common and Adverse Prognostic Marker In Lymphoma

AbstractAbstract 119The PI3K/AKT/mTOR pathway is frequently activated in lymphoma, but rapamycin-analog (rapalog) mTOR inhibitors have shown only modest benefits in clinical trials on lymphoma patients. To better understand the resistance of lymphomas to rapalogs, we have undertaken a study of the Pim family kinases, which signal in parallel to PI3K/AKT/mTOR and whose expression has been detected in multiple subtypes of non-Hodgkin lymphoma (NHL). The two pathways converge on activation of cap-dependent translation, suggesting new treatment possibilities by targeting this common downstream output. To assess the clinical relevance of Pim activity, we have quantified Pim1 and Pim2 expression in multiple NHL subtypes using tissue microarray (TMA) technology. We find common expression of Pim1, Pim2, or both proteins in diffuse large B-cell lymphoma (DLBCL, 65.5%), follicular lymphoma (58%), small lymphocytic lymphoma (76.5%) and mantel cell lymphoma (89.7%). Importantly, Kaplan-Meier survival analysis of clinical data linked to our DLBCL TMAs show a strong trend toward a worse overall survival when Pim expression is present in diagnostic tumor samples compared to Pim-negative tumors (p=0.0965). Studies in vivo demonstrate Pim's ability to accelerate oncogenesis in a manner similar to AKT in model systems specific to Burkitt's lymphoma (Eμ -Myc) and follicular lymphoma (VavP-Bcl2). Treatment studies in secondary recipient animals show that Pim promotes resistance to anthracycline chemotherapy like AKT. However, Pim tumors completely resist rapamycin in stark contrast to AKT tumors. To elaborate on these findings, we have employed a genetically defined system of rapamycin sensitivity lacking mTOR's upstream repressor TSC2. These studies show that Pim's ability to mediate rapamycin resistance is dependent on its ability to maintain inhibitory phosphorylation of the translation repressor 4EBP1. Specifically, a phosphorylation-site deficient mutant of 4EBP1 completely abrogates Pim's ability to maintain the viability of the TSC2 −/− cells. We have expanded on this finding using the drug silvestrol, which inhibits cap-dependent translation by targeting eIF4A. Silvestrol shows high potency against Pim-expressing TSC2 −/− cells (IC50 < 1 nM) and also against a panel of Pim-expressing lymphoma cell lines (IC50 1–10 nM). Indeed, targeting cap-dependent translation appeared more effective than the Pim kinase inhibitor SGI-1776 (IC50 1–10 μ M against lymphoma cell lines), which has significantly higher potency against Pim1 than Pim2. In conclusion, we have more clearly defined Pim kinase activity as a major mediator of oncogenesis in multiple NHL subtypes and as a likely negative prognostic marker in DLBCL. Our mechanistic and treatment studies provide a strong rational basis for targeting cap-dependent translation as a treatment strategy to bypass Pim activity and improve lymphoma patients' responses to both cytotoxic and rapalog therapies. Disclosures:No relevant conflicts of interest to declare.

Staphylococcus warneri meningitis in a patient with Strongyloides stercoralis hyperinfection and lymphoma: first report of a case

A case of meningitis due to Staphylococcus warneri in a patient with a hyperinfection with Strongyloides stercoralis possibly associated with rituximab treatment for mantel cell lymphoma is reported for the first time in the literature. The patient was a 59-year-old woman, with a 3-year history of an apparently well controlled lymphoma after treatment with chemotherapy-immunotherapy and then immunotherapy alone, and diagnosis of strongyloidiasis. Meningitis was diagnosed by cerebrospinal fluid culture and tested with an automated plate system. The patient was successfully treated with vancomycin; although fever and productive cough persisted. Severe gastrointestinal symptoms and pneumonia developed three weeks later. Hyperinfection syndrome by S. stercoralis was diagnosed, with abundant larvae in feces and expectoration.

Response of Patients with Aggressive Non Hodgkin's Gastro Intestinal Tract Lymphoma to Upfront Rituximab Based Chemotherapy: A Single Institution Experience.

Abstract 4791 BackgroundResponse and factors affecting response in patients with aggressive Non Hodgkin's Gastro Intestinal (GI) tract lymphoma to upfront Rituximab based chemotherapy is not well characterized. Methods41 consecutive pts diagnosed and treated with GI tract lymphoma in 2002 to 2009 were studied as a retrospective cohort for clinical presentation, prognostic characteristics and long term survival. Prognostic characteristics and survival was analyzed using logistic regression and Cox Proportional Hazards model. Multiple imputation methods were used for missing data. Results41 pts, median age at presentation was 58 yr (28-80). 10 (24.4%) were African Americans, 22 (51.2%) were Hispanics and 10 (24.4%) were Caucasians. 35 (85.4%) had gastric lymphoma and 6 (14.6%) had intestinal lymphoma. 33 pts had aggressive NHL. 31 had Diffuse large B cell lymphoma, 2 Mantel cell lymphoma and 1 Burkitt's lymphoma. 6 (17.6%) presented with stage IE, 4 (11.8) stage II1, 6(17.6%) Stage II2, 7(20.6%) Stage IIE, and 10 (29.4%) Stage IV. 28(82.3%) pts were diagnosed by endoscope. 5 (14.7%) pts underwent surgery as they presented with obstruction or bleeding, none underwent curative resection. All pts received Rituximab based chemotherapy upfront. 29 received CHOPR, 2 CVPR and 2 Hyper CVAD R. Mean follow up was 23.7 months.22 (64.8%) pts had a complete response, 6 (17.6%) partial response and 6 (17.6%) had progressive disease. 11 pts relapsed. The median disease free survival (DFS) was 13 months (1-105). Age was the sole significant prognostic factor that influenced DFS OR 1.047 CI 1.003-1.094). Age (OR 1.164 CI 1.045-1.296), stage (OR 1.743 CI 1.053-2.888) and performance status (OR 2.703 CI 1.030-7.097) were factors which significantly affect survival.Survival function was 100%, 55.6% and 58.3% for low, intermediate and high risk group of stage modified IPI for gastric lymphoma. 100%, 70% 58.3% for low intermediate and high risk group as per the revised IPI but survival functions are not significant.12 (35.3%) of pts tolerated chemotherapy with no grade 3 or 4 adverse events. 13 (38%) had g 3or 4 hematological toxicity. 5 (15%) had surgery post chemotherapy. 2 (6%) has GI perforation and 3 (9%) developed GI bleeding post chemotherapy. Surgical complications occurred after the 1st cycle of chemotherapy. ConclusionAggressive Non Hodgkins GI lymphoma can be effectively treated with Rituximab based chemotherapy as upfront therapy with a response rate of 83%. Age, stage and performance status significantly effect survival. R IPI may need to be revised to predict survival in gastric lymphoma. 15% treated with chemotherapy upfront may need surgery for complications. Perforation rate was about 3% and most surgical complications occur after 1st cycle of chemotherapy. Disclosures:No relevant conflicts of interest to declare.

256. CD20-Targeted Virus Eliminates Primary Mantel Cell Lymphoma Xenografts by Amplifying Locally the Therapeutic Effects of Fludarabine and Cyclophosphamide

256. CD20-Targeted Virus Eliminates Primary Mantel Cell Lymphoma Xenografts by Amplifying Locally the Therapeutic Effects of Fludarabine and Cyclophosphamide

Initial Experience with Rituximab and 90Y-Ibritumomab Tiuxetan for the Treatment of Mature B-Cell Lymphoma.

Introduction: Rituximab and 90Y-ibritumomab tiuxetan constitute a relatively new radioimmunotherapeutic regimen for patients with CD20 low-grade non-Hodgkin's lymphoma (NHL).Methods and Results: We have so far treated 9 patients, with mature CD 20 positive B-cell lymphoma, according to a standard protocol of Zevalin. All patients received 250 mg m2 of cold rituxemab infusion over 2 hours followed 7 days later by the same infusion of rituxemab plus within 4 hours by IV Y90 -ibritumomab tiuxetan (3– 4 microCuri/kg depending upon platelet counts). Labeling of cold antibody with Y90 was carried out and tested for quality prior to administration on the day of therapy. There were 4 male & 5 females with a mean age of 59.13 + 5.7 years. All patients except one had been previously treated with cold tiuxetan as part of standard chemotherapy (R-CHOP, R-DHAP, R-CVP, R-Cholorambucil). Five patients had follicular lymphoma grade I, II or III. Three out 5 of these patients were treated with Zevalin after a mean period of 4.26 years from diagnosis after failing 2nd line therapy (2 patients) or with significant residual disease thereafter (one patient). 1 patient with Follicular lymphoma grade III was treated with Zevalin 22 years 3 months after initial diagnosis who was progressing after 2nd line chemotherapy, and one patient with Follicular lymphoma grade I who had significant residual disease 7 months post first line therapy. two patients had diffuse large B-cell Lymphoma. One treated with Zevalin 9 months after initial diagnosis and failing first line therapy and significant residual disease following 2nd line therapy, the other receiving Zevalin 6 months of initial diagnosis, as consolidation therapy following minimal residual disease after first line chemotherapy. 1 patient with Nodal Marginal Zone B-cell Lymphoma was treated 2 years 7 months after initial diagnosis who had significant residual disease after 2nd line chemotherapy. The last patient with mantel cell lymphoma was treated 2 years 7 months after initial diagnosis with Zevalin who had significant residual disease following first line chemotherapy. All patients were followed weekly for 2 months after initial therapy with Zevalin to monitor hematological toxicity and at 3 months interval with follow up CT scans to monitor response to therapy.Patients are under follow up after Zevalin therapy now for a mean period of 0.77 + 0.44 years (range1 year 4 months to 1 month). 3 patients suffered from sever thrombocytopenia and severe neutropenia requiring supportive treatment, rest of the patient had moderate to sever hematological toxicity requiring no treatment. Response to therapy was judged according to well known international criteria based on serial CT scans, although gallium 67 and MRI scans were also done in selective cases. Three patients were in complete remission, 3 patients had good response to therapy with more than 75 % reduction in tumor volume, and 2 patients have not yet been evaluated for response to therapy. The only remaining patient with mantel cell lymphoma had good response at 2 months with progression after 8 months.Conclusion: Radioimmunotherapy is an effective and a feasible treatment option for the management of lymphoid malignancies.