Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience

Rituximab is a human/murine, chimeric anti-CD20 monoclonal antibody with established efficacy, and a favorable and well-defined safety profile in patients with various CD20-expressing lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin lymphoma. Since its first approval 20 years ago, intravenously administered rituximab has revolutionized the treatment of B-cell malignancies and has become a standard component of care for follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma. For all of these diseases, clinical trials have demonstrated that rituximab not only prolongs the time to disease progression but also extends overall survival. Efficacy benefits have also been shown in patients with marginal zone lymphoma and in more aggressive diseases such as Burkitt lymphoma. Although the proven clinical efficacy and success of rituximab has led to the development of other anti-CD20 monoclonal antibodies in recent years (e.g., obinutuzumab, ofatumumab, veltuzumab, and ocrelizumab), rituximab is likely to maintain a position within the therapeutic armamentarium because it is well established with a long history of successful clinical use. Furthermore, a subcutaneous formulation of the drug has been approved both in the EU and in the USA for the treatment of B-cell malignancies. Using the wealth of data published on rituximab during the last two decades, we review the preclinical development of rituximab and the clinical experience gained in the treatment of hematologic B-cell malignancies, with a focus on the well-established intravenous route of administration. This article is a companion paper to A. Davies, et al., which is also published in this issue

Updated Safety And Efficacy Data In The Phase 1 Trial Of Patients With Mantle Cell Lymphoma (Mcl) Treated With Bruton Tyrosine Kinase (Btk) Inhibitor Zanubrutinib (Bgb‐3111)

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149513/1/hon55_2630.pd

Autologous Stem Cell Transplant is Feasible in Very Elderly Patients with Lymphoma and Limited Comorbidity

In patients with recurrent Hodgkin or non-Hodgkin\u27s lymphoma, autologous stem cell transplantation (ASCT) can offer potential for cure or long-term remission. Because of potential toxicity, elderly patients are usually not considered candidates, but data regarding tolerability and efficacy in this group are lacking. The transplant database at Weill Cornell Medical College was reviewed to identify patients with lymphoma undergoing ASCT at age 69 or greater. Clinical data and comorbidities were correlated with outcome. Twenty-one patients were identified. Sixteen of 19 evaluable patients (76%) achieved complete remission following ASCT, while 2 patients died before response assessment. Median progression-free survival following ASCT was 8 months and median overall survival was 18 months. Age was not predictive of overall survival, but patients 75 and older had inferior progression-free survival compared to younger patients. High-risk status by hematopoietic stem cell transplant comorbidity index (HCT-CI) was associated with short overall survival and high transplant-related mortality. ASCT is feasible and of potential benefit in selected elderly lymphoma patients. Consideration of comorbidities, rather than age alone, may allow selection of patients likely to tolerate and benefit from ASCT

Autologous Stem Cell Transplant is Feasible in Very Elderly Patients with Lymphoma and Limited Comorbidity

In patients with recurrent Hodgkin or non-Hodgkin\u27s lymphoma, autologous stem cell transplantation (ASCT) can offer potential for cure or long-term remission. Because of potential toxicity, elderly patients are usually not considered candidates, but data regarding tolerability and efficacy in this group are lacking. The transplant database at Weill Cornell Medical College was reviewed to identify patients with lymphoma undergoing ASCT at age 69 or greater. Clinical data and comorbidities were correlated with outcome. Twenty-one patients were identified. Sixteen of 19 evaluable patients (76%) achieved complete remission following ASCT, while 2 patients died before response assessment. Median progression-free survival following ASCT was 8 months and median overall survival was 18 months. Age was not predictive of overall survival, but patients 75 and older had inferior progression-free survival compared to younger patients. High-risk status by hematopoietic stem cell transplant comorbidity index (HCT-CI) was associated with short overall survival and high transplant-related mortality. ASCT is feasible and of potential benefit in selected elderly lymphoma patients. Consideration of comorbidities, rather than age alone, may allow selection of patients likely to tolerate and benefit from ASCT

Combinatorial epigenetic therapy in diffuse large B cell lymphoma pre-clinical models and patients

BACKGROUND: Refractory and/or relapsed diffuse large B cell lymphoma (RR-DLBCL) patients are incurable with conventional chemotherapy due to the aggressiveness and the chemorefractory state of these tumors. DNA hypermethylation and histone deacetylation are two major epigenetic modifications by which aggressive DLBCL maintain their oncogenic state. We have previously reported that DNA methyltransferase inhibitors (DNMTI) affect RR-DLBCL growth and improve chemosensitivity. Here, we hypothesized that the combination of DNMTI with histone deacetylase inhibitor (HDI) would be an active and feasible therapeutic strategy in RR-DLBCL. Thus, we evaluated the anti-lymphoma activity of the HDI vorinostat (VST) in combination with the DNMTI azacitidine (AZA) or decitabine (DAC) in pre-clinical models of RR-DLBCL, and we determined the feasibility of the combination by conducting a phase Ib trial in RR-DLBCL patients. RESULTS: Concurrent combination of DNMTI and HDI resulted in synergistic anti-lymphoma effect toward RR-DLBCL cells in vitro and in vivo, with no significant toxicity increase. In a phase Ib trial, a total of 18 patients with a median of three prior therapies were treated with four different dose levels of AZA and VST. The most common toxicities were hematological, followed by gastrointestinal and metabolic. The clinical benefit was low as only one subject had a partial response and three subjects had stable disease. Interestingly, two of the seven patients that received additional chemotherapy post-study achieved a complete response and three others had a significant clinical benefit. These observations suggested that the combination might have a delayed chemosensitization effect that we were able to confirm by using in vitro and in vivo models. These studies also demonstrated that the addition of VST does not improve the chemosensitizing effect of DAC alone. CONCLUSIONS: Our data supports the strategy of epigenetic priming by employing DNMTI in RR-DLBCL patients in order to overcome resistance and improve their outcomes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13148-016-0245-y) contains supplementary material, which is available to authorized users

Primary parotid gland lymphoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Mucosa associated lymphoid tissue lymphomas are the most common lymphomas of the salivary glands. The benign lymphoepithelial lesion is also a lymphoproliferative disease that develops in the parotid gland. In the present case report, we describe one case of benign lymphoepithelial lesion with a subsequent low transformation to grade mucosa associated lymphoid tissue lymphoma appearing as a cystic mass in the parotid gland.</p> <p>Case presentation</p> <p>A 78-year-old Caucasian female smoker was referred to our clinic with a non-tender left facial swelling that had been present for approximately three years. The patient underwent resection of the left parotid gland with preservation of the left facial nerve through a preauricular incision. The pathology report was consistent with a low-grade marginal-zone B-cell non-Hodgkin lymphoma (mucosa associated lymphoid tissue lymphoma) following benign lymphoepithelial lesion of the gland.</p> <p>Conclusions</p> <p>Salivary gland mucosa associated lymphoid tissue lymphoma should be considered in the differential diagnosis of cystic or bilateral salivary gland lesions. Parotidectomy is recommended in order to treat the tumor and to ensure histological diagnosis for further follow-up planning. Radiotherapy and chemotherapy should be considered in association with surgery in disseminated forms or after removal.</p

Activation of β-Catenin by Oncogenic PIK3CA and EGFR Promotes Resistance to Glucose Deprivation by Inducing a Strong Antioxidant Response

Glucose is an essential fuel for cell survival and its availability limits aberrant cellular proliferation. We have hypothesized that specific cancer mutations regulate metabolic response(s) to glucose deprivation (GD). By means of somatic knock-in cellular models, we have analyzed the response to glucose deprivation in cells carrying the frequent delE746-A750EGFR, G13DKRAS or E545KPIK3CA cancer alleles. We demonstrate that, in mammary epithelial cells, glucose has an essential antioxidant function and that these cells are very sensitive to GD. Conversely, isogenic cells carrying the delE746-A750EGFR or the E545KPIK3CA, but not the G13DKRAS allele, display high tolerance to GD by stimulating the expression of anti-oxidant genes (MnSOD and catalase). This adaptive transcriptional response is mediated by the activation of WNT/β-catenin and FOXO4 signalling. Our data highlights a new functional synergism between oncogenic EGFR and PIK3CA with WNT/β-catenin conferring high tolerance to oxidative stress generated by nutrient deprivation

Exploiting Mitochondrial Dysfunction for Effective Elimination of Imatinib-Resistant Leukemic Cells

Challenges today concern chronic myeloid leukemia (CML) patients resistant to imatinib. There is growing evidence that imatinib-resistant leukemic cells present abnormal glucose metabolism but the impact on mitochondria has been neglected. Our work aimed to better understand and exploit the metabolic alterations of imatinib-resistant leukemic cells. Imatinib-resistant cells presented high glycolysis as compared to sensitive cells. Consistently, expression of key glycolytic enzymes, at least partly mediated by HIF-1α, was modified in imatinib-resistant cells suggesting that imatinib-resistant cells uncouple glycolytic flux from pyruvate oxidation. Interestingly, mitochondria of imatinib-resistant cells exhibited accumulation of TCA cycle intermediates, increased NADH and low oxygen consumption. These mitochondrial alterations due to the partial failure of ETC were further confirmed in leukemic cells isolated from some imatinib-resistant CML patients. As a consequence, mitochondria generated more ROS than those of imatinib-sensitive cells. This, in turn, resulted in increased death of imatinib-resistant leukemic cells following in vitro or in vivo treatment with the pro-oxidants, PEITC and Trisenox, in a syngeneic mouse tumor model. Conversely, inhibition of glycolysis caused derepression of respiration leading to lower cellular ROS. In conclusion, these findings indicate that imatinib-resistant leukemic cells have an unexpected mitochondrial dysfunction that could be exploited for selective therapeutic intervention

Modulation of Glucose Transporter 1 (GLUT1) Expression Levels Alters Mouse Mammary Tumor Cell Growth In Vitro and In Vivo

Tumor cells exhibit an altered metabolism characterized by elevated aerobic glycolysis and lactate secretion which is supported by an increase in glucose transport and consumption. We hypothesized that reducing or eliminating the expression of the most prominently expressed glucose transporter(s) would decrease the amount of glucose available to breast cancer cells thereby decreasing their metabolic capacity and proliferative potential