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Summary: In a prospective phase II trial, pentostatin combined with cyclophosphamide and rituximab (PCR) induced strong responses and was well‐tolerated in previously untreated patients with advanced‐stage, indolent non‐Hodgkin lymphoma (iNHL). After a median patient follow‐up of more than 108 months, we performed an intent‐to‐treat analysis of our 83 participants. Progression‐free survival (PFS) rates at 108 months for follicular lymphoma (FL), marginal zone lymphoma (MZL) and small lymphocytic lymphoma (SLL) were 71%, 67% and 15%, respectively, and were affected by clinicopathological characteristics. Ten‐year PFS rates for those with beta‐2‐microglobulin levels <2·2 and ≥2·2 mg/l prior to treatment were 71% and 21%, respectively. Patients without bone marrow involvement had 10‐year PFS rates of 72% vs. 29% for those with involvement. At time of analysis, the median overall survival (OS) had not been reached. The OS rate was 64% at 10 years and differed significantly based on histology: 94% for FL, 66% for MZL and 39% for SLL. Long‐term toxicities included 18 (21·7%) patients with second malignancies and 2 (2·4%) who developed myelodysplastic syndrome after receiving additional lines of chemotherapy. Our 10‐year follow‐up analysis confirms that PCR is an effective, robust and tolerable treatment regimen for patients with iNHL. [ABSTRACT FROM AUTHOR]

We conducted a phase II study of the AKT inhibitor, MK2206 in patients with relapsed or refractory lymphoma of any histology excluding Burkitt lymphoma or lymphoblastic lymphoma. MK-2206 was administered orally at 200 mg once weekly in 28-d cycles up to 12 cycles in the absence of progression or significant toxicity. The dose was adjusted based on tolerance. A total of 59 patients were enrolled. The final doses patients received were 300 mg ( n = 33), 250 mg ( n = 2), 200 mg ( n = 16) and 135 mg ( n = 8). Based on intent-to-treat analysis, objective response was observed in 8 (14%) patients (2 complete response and 6 partial response), with median response duration of 5·8 months. The overall response rate was 20% in 25 patients with classical Hodgkin lymphoma. Rash was the most common toxicity (any grade 53%, Grade 3 in 15%) and was observed in a dose-dependent manner. The correlative cytokine analysis showed paradoxical increase in several cytokines, which may be explained by negative feedback mechanism induced by the on-target effect of AKT inhibitor. Our data demonstrate that MK2206 has a favourable safety profile with a modest activity in patients with relapsed Hodgkin lymphoma. The future studies should explore mechanism-based combinations (clinicaltrials.gov NCT01258998). [ABSTRACT FROM AUTHOR]

A phase II study was performed to evaluate the efficacy of hyper-fractionated cyclophosphamide, vincristine, pegylated liposomal doxorubicin and dexamethasone alternating with methotrexate/cytarabine ( HCVIDD/ MA) in patients with newly diagnosed peripheral T-cell lymphoma ( PTCL), excluding ALK-positive anaplastic large cell lymphoma. Fifty-three patients were enrolled. Treatment was planned for up to 8 cycles but only 9% of patients received more than 6 cycles due primarily to disease progression ( n = 13) or prolonged thrombocytopenia ( n = 12). The overall response rate was 66% with a complete response rate of 57%. Median progression-free survival ( PFS) was 7·5 months. With a median follow-up of 7·6 years, 5-year PFS and overall survival ( OS) were 21% and 48%, respectively. The patients with extranodal Natural Killer-cell lymphoma had a shorter PFS (median, 2·4 months) than other subtypes. Grade 3/4 anaemia, neutropenia and thrombocytopenia were observed in 66%, 74% and 79% of patients, respectively. Of note, 23% of patients discontinued therapy due to prolonged thrombocytopenia. In conclusion, HCVIDD/ MA for the first-line treatment of PTCL patients is associated with significant myelosuppression leading to poor treatment adherence, and the response and survival outcomes with this regimen are similar to standard CHOP. This study was registered at as # NCT00290433. [ABSTRACT FROM AUTHOR]

The role of B cells in T-cell priming is unclear, and the effects of B-cell depletion on immune responses to cancer vaccines are unknown. Although results from some mouse models suggest that B cells may inhibit induction of T cell–dependent immunity by competing with antigen-presenting cells for antigens, skewing T helper response toward a T helper 2 profile and/or inducing T-cell tolerance, results from others suggest that B cells are necessary for priming as well as generation of T-cell memory. We assessed immune responses to a well-characterized idiotype vaccine in individuals with severe B-cell depletion but normal T cells after CD20-specific antibody–based chemotherapy of mantle cell lymphoma in first remission. Humoral antigen- and tumor-specific responses were detectable but delayed, and they correlated with peripheral blood B-cell recovery. In contrast, vigorous CD4+ and CD8+ antitumor type I T-cell cytokine responses were induced in most individuals in the absence of circulating B cells. Analysis of relapsing tumors showed no mutations or change in expression of target antigen to explain escape from therapy. These results show that severe B-cell depletion does not impair T-cell priming in humans. Based on these results, it is justifiable to administer vaccines in the setting of B-cell depletion; however, vaccine boosts after B-cell recovery may be necessary for optimal humoral responses. [ABSTRACT FROM AUTHOR]

Lymphomas express a tumor-specific antigen which can be targeted by cancer vaccination. We evaluated the ability of a new idiotype protein vaccine formulation to eradicate residual t(14;18)+ lymphoma cells in 20 patients in a homogeneous, chemotherapy-induced first clinical complete remission. All 11 patients with detectable translocations in their primary tumors had cells from the malignant clone detectable in their blood by PCR both at diagnosis and after chemotherapy, despite being in complete remission. However, 8 of 11 patients converted to lacking cells in their blood from the malignant clone detectable by PCR after vaccination and sustained their molecular remissions. Tumor-specific cytotoxic CD8[sup +] and CD4[sup +] T cells were uniformly found (19 of 20 patients), whereas antibodies were detected, but apparently were not required for molecular remission. Vaccination was thus associated with clearance of residual tumor cells from blood and long-term disease-free survival. The demonstration of molecular remissions, analysis of cytotoxic T lymphocytes against autologous tumor targets, and addition of granulocyte-monocyte colony-stimulating factor to the vaccine formulation provide principles relevant to the design of future clinical trials of other cancer vaccines administered in a minimal residual disease setting. [ABSTRACT FROM AUTHOR]

The article offers information on Classical Hodgkin lymphoma (HL). It discusses the causes for the development of relapsed or refractory disease in the patients. The treatment for Hodgkin lymphoma through bortezomib plus ifosfamide, carboplatin, etoposide (BICE) has also been discussed in the article.

The clonotypic surface Ig receptor expressed by malignant B cells,idiotype,is a tumor-specific antigen and an attractive target for active immunotherapy.While Ab's specific for tumor idiotype have been well described in patients with B cell malignancies,the precise antigenic epitopes in human idiotype recognized by autologous T cells remain largely unknown.We report here that T cell lines generated from lymphoma patients actively immunized with idiotype protein specifically recognized multiple,unique immunodominant epitopes in autologous tumor idiotype.Synthetic peptides corresponding to hypervariable,but not frame- work,regions of Ig heavy chain specifically stimulated CD4 +and CD8 +T cells to proliferate and secrete proinf lammatory cytokines in an MHC-associated manner.Detailed analysis revealed a minimal determi- nant of an immunodominant epitope,comprising critical residues at the amino terminus that may be a prod- uct of somatic hypermutation.Association of idiotype-specific T cell responses with previously documented molecular remissions in idiotype-vaccinated patients suggests that the newly identified T cell epitopes may be clinically relevant.Such antigenic epitopes may serve as candidates for novel peptide-vaccine strategies,and as tools to selectively expand tumor antigen --specific T cells for adoptive immunotherapy and for monitoring T cell immunity in vaccinated patients. [ABSTRACT FROM AUTHOR]

Summary Background Standard treatments for indolent non-Hodgkin lymphomas are often toxic, and most patients ultimately relapse. Lenalidomide, an immunomodulatory agent, is effective as monotherapy for relapsed indolent non-Hodgkin lymphoma. We assessed the efficacy and safety of lenalidomide plus rituximab in patients with untreated, advanced stage indolent non-Hodgkin lymphoma. Methods In this phase 2 trial, undertaken at one instution, patients with follicular lymphoma and marginal zone lymphoma were given lenalidomide, orally, at 20 mg/day on days 1–21 of each 28-day cycle. For patients with small lymphocytic lymphoma, dosing began at 10 mg/day to avoid tumour flare, with an escalation of 5 mg/month to 20 mg/day. Rituximab was given at 375 mg/m 2 as an intravenous infusion on day 1 of each cycle. Patients responding after six cycles could continue therapy for up to 12 cycles. The primary endpoint was overall response, defined as the proportion of patients who achieved a partial or complete response; patients were assessed for response if they had any post-baseline tumour assessment. This trial is registered with ClinicalTrials.gov , number NCT00695786 . Findings 110 patients with follicular lymphoma (n=50), marginal zone lymphoma (n=30), and small lymphocytic lymphoma (n=30) were enrolled from June 30, 2008, until Aug 12, 2011. 93 of 103 evaluable patients had an overall response (90%, 95% CI 83–95). Complete responses occurred in 65 (63%, 95% CI 53–72) and partial responses in 28 patients (27%, 19–37). Of 46 evaluable patients with follicular lymphoma, 40 (87%) patients had a complete response and five (11%) had a partial response. Of 27 evaluable patients with marginal zone lymphoma, 18 (67%) had a complete response and six (22%) had a partial response. Of 30 evaluable patients with small lymphocytic lymphoma, seven (23%) had a complete response and 17 (57%) had a partial response. The most common grade 3 or 4 adverse events were neutropenia (38 [35%] of 110 patients), muscle pain (ten [9%]), rash (eight [7%]), cough, dyspnoea, or other pulmonary symptoms (five [5%]), fatigue (five [5%]), thrombosis (five [5%]), and thrombocytopenia (four [4%]). Interpretation Lenalidomide plus rituximab is well tolerated and highly active as initial treatment for indolent non-Hodgkin lymphoma. An international phase 3 study ( NCT01476787 ) to compare this regimen with chemotherapy in patients with untreated follicular lymphoma is in progress. Funding Celgene Corporation and Richard Spencer Lewis Memorial Foundation and Cancer Center Support Grant. [ABSTRACT FROM AUTHOR]

Ag activation of the BCR may play a role in the pathogenesis of human follicular lymphoma (FL) and other B cell malignancies. However, the nature of the Ag(s) recognized by tumor BCRs has not been well studied. In this study, we used unbiased approaches to demonstrate that 42 (19.35%) of 217 tested FL Igs recognized vimentin as a shared autoantigen. The epitope was localized to the N-terminal region of vimentin for all vimentin-reactive tumor Igs. We confirmed specific binding to vimentin by using recombinant vimentin and by performing competitive inhibition studies. Furthermore, using indirect immunofluorescence staining, we showed that the vimentin-reactive tumor Igs colocalized with an anti-vimentin mAb in HEp-2 cells. The reactivity to N-terminal vimentin of IgG FL Igs was significantly higher than that of IgM FL Igs (30.4 versus 10%; p = 0.0022). However, vimentin-reactive FL Igs did not share CDR3 motifs and were not homologous. Vimentin was expressed in the T cell–rich regions of FL, suggesting that vimentin is available for binding with tumor BCRs within the tumor microenvironment. Vimentin was also frequently recognized by mantle cell lymphoma and multiple myeloma Igs. Our results demonstrate that vimentin is a shared autoantigen recognized by nonstereotyped FL BCRs and by the Igs of mantle cell lymphoma and multiple myeloma and suggest that vimentin may play a role in the pathogenesis of multiple B cell malignancies. These findings may lead to a better understanding of the biology and natural history of FL and other B cell malignancies. [ABSTRACT FROM AUTHOR]

Abstract: Idiotypic sequences, specific to the hypervariable regions of immunoglobulins expressed by malignant B cells offer a therapeutic target in B cell lymphoma. Efficient approaches have been described to clone a single chain fragment of the tumor immunoglobulin (Ig) comprising of heavy and light Ig chains (sFv) fused with proinflammatory chemokines. Tumor associated, poorly immunogenic self antigens encoded by plasmid DNA (pDNA) have been rendered immunogenic by chemokine fusion, thereby targeting to antigen presenting cells (APCs) which differentially express chemokine receptors. Here we present an injectable (parenteral) approach using synthetic polymer based cationic microparticle formulations for enhancing the potency of such chemokine/self antigen expressing plasmid construct. Branched and linear polyethyleneimine (PEI) were conjugated on poly (d, l lactide-co-glycolide) (PLGA) microparticles using carbodiimide chemistry followed by efficient loading of plasmid DNA. In addition to imparting significant buffering ability to these cationic microparticles, flow cytometry studies indicate that these DNA loaded microparticles significantly up regulate CD80 and MHC class II markers in phagocytic RAW264.7 cells, indicating intrinsic adjuvant effects. Intradermal injections in Balb/c mice with these formulations induced significant protection upon tumor challenge with 2.5 times the minimal lethal dose. Long term survival rates were significant (p <0.05) in comparison with saline injected controls or blank microparticles. Further studies indicated that intramuscular delivery might provide better protection compared to intradermal injections and perform similar to gene gun mediated administration. We conclude, based on these promising in vivo results, that such surface-functionalized microparticles offer an attractive strategy to improve the potency of self antigen-based cancer DNA vaccines. [Copyright &y& Elsevier]

Mantle cell lymphoma (MCL) is a subtype of B-cell Non-Hodgkin’s Lymphoma (NHL) and accounts for approximately 6% of all lymphomas. Unlike small lymphocytic lymphoma and chronic lymphocytic lymphoma, which are relatively sensitive to chemotherapy, MCL is highly refractory to most chemotherapy, and has the worst survival rate among NHL patients. Stem-like cells in MCL, which we have termed mantle cell lymphoma-initiating cells (MCL-ICs), enriched in the population that are lack of prototypic B-cell marker CD19. These cells were able to self-renew upon serial transplantation and are highly tumorigenic. Importantly, these stem-like cells confer chemotherapeutic resistance to MCL. In this report, we show that stem-like MCL-ICs are resistant to bortezomib, as well as chemotherapeutic regimens containing bortezomib, despite constitutive nuclear factor-κB (NF-κB) expression. Interestingly, bortezomib treatment induced MCL-IC differentiation in plasma-like cells with upregulated expression of CD38 and CD138. This process was accompanied by expression of plasma cell differentiation transcriptional factors, BLIMP-1 and IRF4. This article is the first to show that stem-like MCL cells utilize constitutive NF-κB expression for survival. Given that the NF-κB expression in MCL-ICs is resistant to bortezomib, it will be important to find alternative therapeutic strategies to inhibit NF-κB expression. [ABSTRACT FROM AUTHOR]