Inotuzumab ozogamicin as novel therapy in lymphomas

Importance of the field: More than 65,000 cases of non-Hodgkin's lymphoma are estimated to have been diagnosed in 2009; the majority are of B-cell lineage, and diffuse large cell lymphoma and follicular together account for nearly half of cases. Despite advances in treatment, most patients are not cured.

Areas covered in this review: The antigen CD22 is a transmembrane glycoprotein found on mature B-cells, and on up to 90% of B-cell malignancies. Inotuzumab ozogamicin (CMC-544) is a humanized anti-CD22 monoclonal antibody conjugated with calicheamicin. Preclinical data indicate activity against B-cell tumors, and early results from clinical trials indicate activity against B-cell lymphomas including follicular lymphoma and diffuse large cell lymphoma. This paper reviews the design, pharmacokinetic and pharmacodynamic characteristics, and preclinical and clinical experience of this promising novel targeted therapy, with data derived from abstracts and published reports from 2002 to the present.

What the reader will gain: This review will serve as an introduction to and overview of inotuzumab ozogamicin, and describe the rationale guiding advances in development.

Take home message: The data thus far confirm the tolerability and clinical activity of inotuzumab ozogamicin in B-cell malignancies, and further investigation as a single agent as well as in combination therapy is warranted.     

Ofatumumab,a human anti-CD20 monoclonal antibody

Importance of the field: Since relapse of chronic lymphocytic leukemia (CLL), and refractoriness to treatment following relapse, is inevitable after initial treatment, development of novel treatment strategies is necessary.

Areas covered in this review: CD20 as a therapeutic target for CLL, successes and limitations of current anti-CD20 monoclonal antibody (mAb) therapy, and implications of preclinical and clinical developments of novel alternatives, including ofatumumab, that may enhance anti-CD20 mAb therapy are reviewed. The literature reviewed encompasses papers and congress abstracts from the past 13 years.

What the reader will gain: While rituximab combined with chemotherapy has considerably improved outcomes for some but not all CLL patients, single-agent use is limited in relapsed/refractory CLL. Novel anti-CD20 mAbs in development, such as ofatumumab, may bypass some limitations by virtue of alternative epitope binding and modified effector functions. Ofatumumab induces significant complement-dependent cell lysis in vitro, particularly in cells with low CD20 expression. The FDA recently approved ofatumumab for treatment of CLL refractory to fludarabine and alemtuzumab.

Take home message: CD20-targetting chemoimmunotherapeutic options have advanced treatment of CLL. Results for single-agent ofatumumab and other new CD20 mAbs, in different lines of therapy and in combination with chemotherapy, will guide optimal use of these alternative therapies for B-cell malignancies.     

Rituximab biosimilars for lymphoma in Europe

ABSTRACT

Introduction: The approval of rituximab, a monoclonal antibody targeting CD20, revolutionized the treatment of B-cell non-Hodgkin lymphomas and became an undisputed standard of care. However, as with all biologic medicines, the complex development and manufacturing process for rituximab have meant that the medicine attracts high treatment costs. Approved rituximab biosimilars have been comprehensively demonstrated to match the reference medicine. With the potential to increase access to biologic therapy, they have a key role in helping to improve patient outcomes in lymphoma care.

Areas covered: In this review, we discuss the role of rituximab in the treatment of lymphoma. We explore development and regulatory requirements for biosimilar development and the potential impact of these medicines on access and sustainability. Focusing on biosimilars of rituximab, we examine in detail the evidence for biosimilarity for the two rituximab biosimilars that are approved in Europe and provide an overview of rituximab biosimilars currently in development.

Expert opinion: We foresee a wider uptake of biosimilar medicines for lymphoma treatment over the next 5 years. The associated cost savings should be invested in broadening patient access to biological therapies, enabling wider use of more expensive treatment strategies and driving innovation in cancer care.     

Anti-CD37 antibodies for chronic lymphocytic leukemia

Introduction: Immunotherapy using mAbs is a safe and effective method for the treatment of chronic lymphocytic leukemia (CLL) and other lymphoid malignancies. In recent years, mAbs based on selective B-cell depletion – rituximab, ofatumumab and obinutuzumab – have been approved for use in CLL therapy. More recently, CD37, a member of the tetraspanin superfamily of cell surface antigens, has been considered as a target for B-cell malignancies.

Areas covered: The results of preclinical and early clinical studies suggest that in patients with CLL, newer anti-CD37 agents, otlertuzumab (formerly known as TRU-016), BI 836826, IMGN529 and ¹⁷⁷Lu-tetulomab can be useful in the treatment of this disease.

Expert opinion: CD37 may offer advantages over CD20 as a target for CLL cells. It is selectively expressed on normal mature B cells and by most B-cell malignancies. Anti-CD37 antibodies may be useful for patients resistant or refractory to anti-CD20 mAb therapy or relapsing after such treatment. The development of these agents into a clinically useful therapy for CLL is probably many years away and will be followed with great interest by laboratory investigators and clinicians.     

Applications of monoclonal antibodies for the treatment of hematological malignancies

Background: The introduction of mAbs has changed the clinical approach to patients with lymphoma and leukemia. Objective: To summarize the most significant applications of mAb-based regimens in the treatment of hematological malignancies and explore their possible role in the future management of these patients. Results: Rituximab (anti-CD20) was the first mAb developed for the treatment of B-cell lymphomas. Several randomized studies have demonstrated its efficacy in lymphomas and low toxicity profile; rituximab also has significant activity in chronic lymphocytic leukemia (CLL). Alemtuzumab (anti-CD52) has shown efficacy in previously untreated or refractory CLL patients, while gemtuzumab ozogamicin (anti-CD33) appears to have significant activity in acute myeloid leukemias and myelodysplastic syndromes. Conclusions: In the next few years, investigations will be concentrated on the improvement of the older mAbs, and the development of new mAbs, targeting molecules important for malignant cell cycle and survival in an attempt to further improve patient survival.     

Inotuzumab ozogamicin in B-cell acute lymphoblastic leukemias and non-Hodgkin’s lymphomas

Introduction: The expression profile of the CD22 antigen and its role in B-cell function make it an important target in B-cell leukemias and lymphomas. Inotuzumab ozogamicin (IO), a humanized monoclonal antibody targeting CD22, is one of the most promising monoclonal antibodies for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL).

Areas covered: This article reviews the current literature of IO in adult leukemias and lymphomas.

Expert opinion: Single-agent IO has demonstrated activity in patients with relapsed B-cell ALL and non-Hodgkin lymphoma (NHL). It has also demonstrated favorable early results when combined with chemotherapy in older patients with ALL. There is potential for IO to be combined with other targeted therapies under development for these diseases; data are still early and further studies of IO are warranted. While the pivotal randomized study of IO for relapsed NHL versus physician’s choice did not show a statistically significant advantage in response rate, the results of the pivotal study in ALL are not yet available.     

Humoral immunotherapy of multiple myeloma: perspectives and perplexities

Importance of the field: Multiple myeloma (MM) is a hematological malignancy still remaining incurable despite the various therapies available, mainly because of the high fraction of refractory/relapsing cases. Therefore, the development of novel therapeutic approaches is urgently needed to overcome conventional treatment resistance.

Areas covered in this review: In the era of targeted therapies, treatments combining a high specificity for neoplastic cells and the capability to interfere with environmental signals should be regarded as the weapons of choice. Monoclonal antibody (mAb)-based humoral immunotherapy could satisfy both these requirements when applied to MM. Indeed, many of the molecules expressed on MM cells, such as CD38, CD40, CD49d, CD138 and CD162 are involved in the adhesive dynamics regulating the crosstalk between MM and the BM-microenvironment.

What the reader will gain: In this study we review those MM-associated molecules that have shown promising antitumor effects as targets of specific mAbs in preclinical settings, thus deserving to be considered for clinical investigation.

Take home message: mAbs directed against MM-associated adhesion markers should be taken into account in clinical practice, since they could possibly represent the best available combination of tumor cytotoxicity, environmental signal deprivation and immune system redirection.     

B-cell-targeted therapy in adult glomerulonephritis

Introduction: There are many mechanisms through which B lymphocytes have been implicated in the pathogenesis of glomerulonephritis. There are a number of trials and clinical studies in glomerulonephritis involving depletion of CD20⁺ B lymphocytes using rituximab. Newer anti-CD20 agents are currently under evaluation, as are drugs targeting alternative B-cell targets such as B lymphocyte stimulator. Such selective, targeted B-cell therapies, if shown to be effective, may be of value in minimising toxicity from more conventional agents.

Areas covered: This article reviews the role of B cells as a target for therapy in adult renal disease resulting from primary glomerulonephritis and that occurring secondary to systemic disease. It will not address intracellular signalling or co-stimulatory pathways as therapeutic targets.

Expert opinion: There are indications for B-cell targeted therapies in a number of adult glomerulonephritides, with varying degrees of evidence. Further understanding of the mechanisms of B-cell depletion and repletion, and interplay with B-cell survival factors, is necessary in order to identify patients who will respond favourably.     

I-131 tositumomab

Importance of the field: Follicular lymphoma (FL) is a subgroup of B-cell Non-Hodgkin's lymphomas (NHL) that account for 15 – 30% of all lymphomas. I-131 tositumomab is a radiommunoconjugate of ¹³¹I and the anti-CD20 monoclonal antibody tositumomab. It is one of two available radioimmunoconjugates for the treatment of recurrent, refractory, or transformed FL.

Areas covered in this review: This review describes the clinical pharmacology of I-131 tositumomab, dosing and administration guidelines, and the key clinical trials providing evidence of its efficacy and safety in patients with FL, transformed, or other aggressive B-NHL, in combination with chemotherapy, or its incorporation in transplant conditioning regimens. This review also covers safety and regulatory concerns regarding the use of I-131 tositumomab.

What the reader will gain: This review critically appraises the clinical trials behind approval of I-131 tositumomab as a second-line agent for FL and also outlines the data supporting its use in the upfront setting.

Take home message: I-131 tositumomab is a safe and effective option for patients with recurrent, refractory, or transformed FL and carries promise in the upfront treatment of FL, aggressive B-NHL, and as a transplant conditioning regimen.     

New antibody drug treatments for lymphoma

Introduction: The advent of anti-CD20 monoclonal antibody (mAb) rituximab heralded a new era in the treatment of non-Hodgkin's lymphoma leading to significant improvements in outcome for patients. This unprecedented success has changed the mindset of the clinical community and catalyzed the interest in the pharmaceutical industry to develop the next-generation of antibodies and antibody conjugates in cancer.

Areas covered: There are an ever increasing number of newer generation anti-CD20 and rituximab ‘bio-similars’ undergoing early phase clinical development. In addition emerging novel therapies including antibody drug conjugates (brentuximab vedotin, SGN-35) and mAb against T-cell lymphomas antigens (e.g., zanolimumab) offer hope of improved outcome for other lymphomas. Bispecific T-cell-engaging antibodies and combination immunotherapy, also provide the promise of further improvements. Radiolabelled antibodies or radioimmunotherapy (RIT) has also demonstrated high clinical activity and two drugs namely ¹³¹I-tositumomab (Bexxar) and ⁹⁰Y-ibritumomab (Zevalin) are licensed.

Expert opinion: Despite the large numbers of new anti-CD20 mAb currently undergoing clinical testing, improving on clinical efficacy of rituximab is a substantial challenge. Further improvements in outcome for patients will require rigorous testing in well designed clinical trials alongside the translation of new insights into mechanism of mAb action that lead to improvements in clinical efficacy.     

Rituximab in the management of acute lymphoblastic leukemia

Introduction: The anti-CD20 chimeric monoclonal antibody rituximab has revolutionized the treatment of B-cell malignancies, significantly improving patient clinical outcome. Recently, some single-group studies have suggested that adding rituximab to chemotherapy can improve the outcome of CD20-positive B-cell acute lymphoblastic leukemia (ALL) patients.

Areas covered: An overview of the current insights of rituximab in adult ALL patients is presented here. In particular, we focused on results of multicenter randomized phase III trial (GRAALL-2005 – Group for Research on Adult Acute Lymphoblastic Leukemia) that evaluated the benefit of associating rituximab to chemotherapy in Ph-negative, B-lineage ALL expressing the CD20 antigen.

Expert opinion: Data from clinical trials confirm that rituximab enhances the efficacy of chemotherapy without additive toxicity in ALL. However, results of GRAAL 2005 study represent only a modest incremental improvement in the treatment of ALL. Other promising compounds as single agent or in combination with chemotherapy are currently in different stages of clinical development. The GRAALL 2005 study sets the stage for other prospective studies which will further elucidate the role of monoclonal antibodies in the management of ALL.     

Anti-CD20 monoclonal antibodies in chronic lymphocytic leukemia

Introduction: The last decade has witnesd immense progress in the treatment of chronic lymphocytic leukemia (CLL). Chemoimmunotherapy (CIT) combining rituximab and fludarabine with cyclophosphamide (FCR) in the frontline setting has clearly been shown to improve outcomes in patients with CLL. Building on the success achieved with rituximab, other anti-CD20 monoclonal antibodies (mAbs) are being investigated. Novel bioengineering techniques have helped in the development of anti-CD20 mAbs. One antibody, ofatumumab, was recently approved for the treatment of refractory CLL. A type II anti-CD20 mAb, GA-101 (obinutuzumab), is currently in clinical trials. This short review focuses on ongoing clinical trials of anti-CD20 mAbs in CLL.

Areas covered: Literature search was performed using PubMed (www.clinicaltrials.gov (till August 2012)), and recent American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH), European Hematology association (EHA), International workshop on CLL (iwCLL) abstracts, using the primary search terms ‘anti-CD20 monoclonal antibody' with/without CLL. Articles were chosen on the basis of relevance of anti-CD20 mAbs to CLL therapy.

Expert opinion: Rituximab, the prototype anti-CD20 mAb, forms the core of CIT in CLL. The success of rituximab and ofatumumab has led investigators to evaluate other anti-CD20 mAbs in the treatment of CLL.     

Adenovirus vaccine immunotherapy targeting WT1-expressing tumors

Importance of the field: Tumor associated antigens (TAAs) offer specific targets for developing cancer immunotherapies. In particular, viral vectors encoding transgenic TAAs have been used in recent vaccination strategies. Wilm's Tumor gene (WT1) is a robust TAA which is overexpressed in many malignancies and has been recently used to develop a novel recombinant adenovirus (Ad-WT1) for antitumor immunotherapy.

Areas covered in this review: The lines of evidence over the past two decades leading to the development of Ad-WT1 immunotherapy are reviewed, including preclinical studies and clinical trials using WT1-based vaccines and TAA-expressing adenoviral vectors for antitumor therapy.

What the reader will gain: The fundamental immunogenic properties of WT1-based vaccines are detailed, as well as the recent progress in using adenoviral vectors for eliciting a TAA-specific immune response. The reader will also gain an understanding of the evidence supporting Ad-WT1 antitumor therapy in vivo.

Take home message: Ad-WT1 elicits a potent CD4⁺ and CD8⁺ T cell immune response and can effectively inhibit tumor growth in vivo, thus making it an important potential cancer therapy worthy of future investigation.     

Stem cell transplantation as a biological therapy for peripheral T-cell lymphomas

Importance of the field: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of non-Hodgkin's lymphomas in which conventional chemotherapy has been characterized by poor outcomes when compared with most aggressive B-cell lymphomas. Autologous, and to a lesser extent allogeneic, hematopoietic stem-cell transplant (HSCT) have been advocated as potential means to improve and consolidate remissions in PTCL.

Areas covered in this review: Given the absence of large-scale randomized clinical controlled trials of transplantation for PTCL, we review existing data addressing the role and timing of HSCT in PTCL.

What the reader will gain: A detailed overview of the available data of overall and progression-free survival associated with HSCT in PTCL with discussion of existing studies, data on determinants of HSCT outcome in PTCL, and future directions for research.

Take home message: The optimal roles and timing of HSCT in PTCL remain unclear. Accordingly, clinicians are encouraged to register their patients in PTCL registry studies and enroll them in clinical trials investigating the role of HSCT. Risk-adapted treatment strategies utilizing identified prognostic parameters may provide future means for identifying the optimal use of HSCT for patients with PTCL, but additional studies are needed before such approaches can be routinely applied.     

Monoclonal antibodies in neuroinflammatory diseases

Introduction: Monoclonal antibodies (mAbs) represent an emerging and rapidly growing field of therapy in neuroinflammatory diseases. Adhesion molecule blockade by natalizumab represents the first approved mAb therapy in neurology, approved for therapy of highly active multiple sclerosis (MS). Removal of immune cells by anti-CD52 mAb alemtuzumab or anti-CD20 mAb rituximab are other prime examples with existing positive Phase II and Phase III trials. MS clearly represents the neuroinflammatory disease entity with the largest body of evidence. However, some of these approaches are currently investigated or translated for use in other, rare neuroinflammatory diseases, such as neuromyelitis optica (NMO), inflammatory neuropathies and (neuro)-muscular disorders.

Areas covered: This review will highlight the most relevant therapeutic approaches involving mAbs in the field of neuroinflammatory diseases as published in peer-reviewed journals and presented on international meetings.

Expert opinion: There is continuously growing evidence on the therapeutic relevance of mAbs in neuroinflammatory disorders. In MS meanwhile several studies have provided evidence for efficacy: In addition to natalizumab, approved in 2006, several other candidates are under development, the most eminent examples with the most advanced study programs being anti-CD52 alemtuzumab, anti-CD20 principles and anti-CD25 daclizumab. Other intriguing candidates are anti-IL-17 strategies, and interference with the complement pathway, partly also developed for other neuroinflammatory disorders.     

Brentuximab vedotin for treatment of systemic T-cell lymphoma

Introduction: Brentuximab vedotin (BV) is an antibody-drug conjugate that consists of the anti-CD30 monoclonal antibody conjugated with monomethyl auristatin E. BV has been approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of relapsed or refractory Hodgkin lymphoma and anaplastic large cell lymphoma. These two diseases certainly show high levels of CD30 expression. Of interest, however, BV has shown activities in other lymphomas that express low or even undetectable levels of CD30.

Areas covered: We update and summarize a recent report of BV in T-cell lymphomas.

Expert opinion: Single-agent BV showed overall response rates of 54% in angioimmunoblastic T-cell lymphoma and 33% in peripheral T-cell lymphoma not otherwise specified in the recent trial. The efficacy of BV in T-cell lymphomas with low or undetectable CD30 expression was promising. The use of BV in combination with chemotherapy as frontline treatment is currently being investigated. Future studies should include correlative biomarker analysis and optimization of combination therapies.     

MicroRNAs in cancer therapeutics: “from the bench to the bedside”

Introduction: In vitro and in vivo experimental data have suggested new immunopathogenic mechanisms in primary Sjögren's syndrome (pSS). The availability of targeted treatment modalities has opened new ways to selectively target these mechanistic pathways in vivo. Amongst these new treatment modalities, monoclonal antibodies specific for the B-cell surface molecule CD20 have been shown to be the most promising treatment option to date.

Areas covered: A search of the Pubmed, MEDLINE, EMBASE, Cochrane and Ovid databases was performed to review literature on the efficacy and safety profile of anti-CD20 therapy in pSS patients.

Expert opinion: A single course of the chimeric humanized anti-CD20 antibody rituximab was effective in reducing disease activity in pSS patients for about six to nine months. Retreatment of responders resulted in a similar effect to initial treatment. When combined with corticosteroids during infusion, rituximab was shown to be a safe drug to administer. Thus, anti-CD20 therapy can be considered an effective treatment option in pSS patients. However, large randomized controlled trials with anti-CD20 therapy, for example rituximab, are warranted in order to: 1) assess long-term effects of such treatment, 2) determine which pSS patients will benefit most from anti-CD20 treatment and 3) assess which retreatment schedule should be followed.     

Diminished expression of CD19 in B-cell lymphomas

BACKGROUND: CD19 is expressed on most B-cell lymphomas; however, the frequency and types of B-cell lymphomas with low-level expression of CD19 are not well characterized. METHODS: We reviewed flow cytometric histograms specifically for decreased CD19 expression on 349 cases analyzed by the Flow Cytometry Laboratory at University Hospitals of Cleveland (Cleveland, Ohio). Results of flow cytometry were correlated with the morphologic diagnosis. RESULTS: Of the cases reviewed, 125 (36%) showed a visible decrease in CD19 expression compared with normal B lymphocytes. Decreased CD19 expression was noted in 79% of follicular lymphomas (27 of 34), 36% of small lymphocytic lymphomas/chronic lymphocytic leukemias (82 of 228), 31% of mantle cell lymphomas (4 of 13), 24% of diffuse large B-cell lymphomas (8 of 33), and 13% of marginal zone B-cell lymphomas/lymphoplasmacytoid lymphomas (4 of 30) and was not observed in any Burkitt lymphoma (0 of 5) or hairy cell leukemia (0 of 6). Decreased CD19 expression was significantly more frequent in follicular lymphomas than in other lymphoma subtypes (P < 0.001). No significant difference was observed in the frequency of decreased CD19 expression based on histologic grade of follicular lymphoma. CONCLUSIONS: Diminished expression of CD19 expression occurs frequently in B-cell lymphomas, in particular follicular lymphoma, and may be helpful in identifying B-cell lymphoma cells in complex cell mixtures such as bone marrow specimens.