[Show abstract][Hide abstract] ABSTRACT: Bendamustine has achieved widespread international regulatory approval and is a standard agent for the treatment for chronic lymphocytic leukemia (CLL), indolent non-Hodgkin lymphoma and multiple myeloma. Since approval, the number of indications for bendamustine has expanded to include aggressive non-Hodgkin lymphoma and Hodgkin lymphoma and novel targeted therapies, based on new bendamustine regimens/combinations, are being developed against CLL and lymphomas. In 2010, an international panel of bendamustine experts met and published a set of recommendations on the safe and effective use of bendamustine in patients suffering from hematologic disorders. In 2014, this panel met again to update these recommendations since the clarification of issues including optimal dosing and management of bendamustine-related toxicities. The aim of this report is to communicate the latest consensus on the use of bendamustine, permitting the expansion of its safe and effective administration, particularly in new combination therapies.
Preview · Article · Nov 2015 · Leukemia and Lymphoma
[Show abstract][Hide abstract] ABSTRACT: Chronic lymphocytic leukemia/small lymphocytic lymphoma is the most prevalent form of adult leukemia in western countries. Chemotherapy has been the mainstay of treatment for the last several decades. The introduction of biological, targeted agents (e.g., monoclonal antibodies) has dramatically improved treatment options. The addition of rituximab to fludarabine and cyclophosphamide has improved patient outcomes, as compared to fludarabine and cyclophosphamide. Nevertheless, chronic lymphocytic leukemia remains incurable, leaving considerable room for improvement. One approach would be to enhance the activity of the CD20 antibody. The next-generation monoclonal antibody ofatumumab has not demonstrated superiority over rituximab, whereas obinutuzumab-chlorambucil is superior to rituximab-chlorambucil. Recent efforts to combine anti-CD20 antibodies with new targeted therapies offer the potential to move toward alternative non-chemotherapy-based treatment approaches.
No preview · Article · Sep 2015 · Expert Review of Hematology
[Show abstract][Hide abstract] ABSTRACT: 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 < 0·0001)]. IPS-3 outperformed the IPS-7 on risk prediction for both FFP and OS by model fit and discrimination criteria. Using reclassification calibration, 18% of IPS-7 low risk patients were re-classified as intermediate risk and 13% of IPS-7 intermediate risk patients as low risk. For patients with advanced HL, the IPS-3 may provide a simpler and more accurate framework for risk assessment in the modern era. Validation of these findings in other large data sets is planned.
No preview · Article · Sep 2015 · British Journal of Haematology
[Show abstract][Hide abstract] ABSTRACT: Standardized response criteria for lymphoma are critical for the evaluation of new therapies. Widely adopted recommendations, most recently the Lugano classification, have been developed primarily for assessment of conventional chemotherapeutic regimens. More recently, several classes of drugs, including immunomodulatory agents, B cell receptor pathway targeting kinases, and checkpoint (PD-1, PDL-1) inhibitors have demonstrated impressive activity in a broad range of histologies. However, they may be associated with features during treatment suggestive of progressive disease despite clinical benefit. Immune response criteria have been proposed for solid tumors, and a modification is needed to be more applicable to lymphomas. Following treatment, conservative use of imaging is recommended based on clinical indications. As newer targeted agents with unique mechanisms of action are developed, current response and follow-up criteria must be made sufficiently flexible for optimal evaluation.
No preview · Article · Jun 2015 · Current Oncology Reports
[Show abstract][Hide abstract] ABSTRACT: Staging and response criteria were initially developed for Hodgkin lymphoma (HL) over 60 years ago, but not until 1999 were response criteria published for non-HL (NHL). Revisions to these criteria for both NHL and HL were published in 2007 by an international working group, incorporating PET for response assessment, and were widely adopted. After years of experience with these criteria, a workshop including representatives of most major international lymphoma cooperative groups and cancer centers was held at the 11th International Conference on Malignant Lymphoma (ICML) in June, 2011 to determine what changes were needed. An Imaging Task Force was created to update the relevance of existing imaging for staging, reassess the role of interim PET-CT, standardize PET-CT reporting, and to evaluate the potential prognostic value of quantitative analyses using PET and CT. A clinical task force was charged with assessing the potential of PET-CT to modify initial staging. A subsequent workshop was help at ICML-12, June 2013. Conclusions included: PET-CT should now be used to stage FDG-avid lymphomas; for others, CT will define stage. Whereas Ann Arbor classification will still be used for disease localization, patients should be treated as limited disease [I (E), II (E)], or extensive disease [III-IV (E)], directed by prognostic and risk factors. Since symptom designation A and B are frequently neither recorded nor accurate, and are not prognostic in most widely used prognostic indices for HL or the various types of NHL, these designations need only be applied to the limited clinical situations where they impact treatment decisions (e.g., stage II HL). PET-CT can replace the bone marrow biopsy (BMBx) for HL. A positive PET of bone or bone marrow is adequate to designate advanced stage in DLBCL. However, BMBx can be considered in DLBCL with no PET evidence of BM involvement, if identification of discordant histology is relevant for patient management, or if the results would alter treatment. BMBx remains recommended for staging of other histologies, primarily if it will impact therapy. PET-CT will be used to assess response in FDG-avid histologies using the 5-point scale, and included in new PET-based response criteria, but CT should be used in non-avid histologies. The definition of PD can be based on a single node, but must consider the potential for flare reactions seen early in treatment with newer targeted agents which can mimic disease progression. Routine surveillance scans are strongly discouraged, and the number of scans should be minimized in practice and in clinical trials, when not a direct study question. Hopefully, these recommendations will improve the conduct of clinical trials and patient management.
[Show abstract][Hide abstract] ABSTRACT: Antibody drug conjugates (ADCs), in which cytotoxic drugs are linked to antibodies targeting antigens on tumor cells, represent promising novel agents for the treatment of malignant lymphomas. Pinatuzumab vedotin is an anti-CD22 ADC and polatuzumab vedotin an anti-CD79B ADC that are both linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE). In the present study, we analyzed the activity of these agents in different molecular subtypes of diffuse large B-cell lymphoma (DLBCL) both in vitro and in early clinical trials. Both anti-CD22-MMAE and anti-CD79B-MMAE were highly active and induced cell death in the vast majority of activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL cell lines. Similarly, both agents induced cytotoxicity in models with and without mutations in the signaling molecule CD79B. In line with these observations, relapsed and refractory DLBCL patients of both subtypes responded to these agents. Importantly, a strong correlation between CD22 and CD79B expression in vitro and in vivo was not detectable, indicating that patients should not be excluded from anti-CD22-MMAE or anti-CD79B-MMAE treatment due to low target expression. In summary, these studies suggest that pinatuzumab vedotin and polatuzumab vedotin are active agents for the treatment of patients with different subtypes of DLBCL.Leukemia accepted article preview online, 24 February 2015. doi:10.1038/leu.2015.48.
[Show abstract][Hide abstract] ABSTRACT: Introduction: Follicular lymphoma, the most common of the indolent non-Hodgkin lymphomas, exhibits a highly variable clinical course. The disease is characterized by a high response rate to therapy, but due to repeated relapses additional treatment options are necessary. Areas covered: The rediscovered chemotherapeutic agent, bendamustine, has demonstrated remarkable efficacy and tolerability when paired with rituximab and has been established as a front-line regimen. More recently, a number of new targeted therapies have been developed, directed against intrinsic drivers of malignant B-cell proliferation and survival, and extrinsic factors such as the tumor microenvironment and escape from the immune response. For the first time, a targeted oral agent, idelalisib, is now FDA approved for the treatment of this disease. Expert opinion: The promise of these new therapies has enabled us to move forward with multi-targeted biologic regimens and toward a future of individualized treatment without traditional chemotherapy.
No preview · Article · Feb 2015 · Expert Opinion on Orphan Drugs