Current status of antibody therapy in ALL

Despite the significant advances in modern chemotherapy, it remains challenging to treat adult patients with acute lymphoblastic leukaemia (ALL). The relapse rate remains high, and the outcome at the time of relapse is dismal. Antibody‐based therapies have demonstrated promising results in this patient group. Variable mechanisms have been applied to target surface antigens (CD20 [also termed MS4A1], CD22, CD52 and CD19) that are commonly expressed on malignant leukaemia cells. In this review, we will focus on the clinical application of such therapies in adult ALL, including the naked antibodies: Rituximab, Ofatumumab, Epratuzumab and Alemtuzumab; the immunotoxins: BL22 and Combotox; the immunoconjugates: inotuzumab and SAR 3419; as well as the Bi‐specific T cell engaging (BiTE)‐specific antibody, Blinatumomab.     

Current controversies in follicular lymphoma

Follicular lymphoma (FL) is characterized by its responsiveness to initial therapy, a pattern of repeated relapses, and a tendency for histologic progression to a process resembling diffuse, large B-cell lymphoma. Treatment decisions are complicated by the many effective options now available including combinations of conventional chemotherapy and monoclonal antibody, radioimmunotherapy, new targeted agents, and autologous and allogeneic stem cell transplantation. For selected patients, "watch and wait" or involved field irradiation may still be the most appropriate strategy. When therapy is required, a combination of rituximab and conventional chemotherapy results in improved outcomes compared to chemotherapy alone. Radioimmunotherapy alone or in combination with chemotherapy is an attractive strategy for patients with relapsed disease and may prove to be appropriate first line therapy. The role of stem cell transplant in FL requires further investigation. Novel agents with varied mechanisms of action continue to be developed. Enrollment of patients into clinical trials designed to address the many unanswered questions in FL is essential to improving clinical outcomes.     

Current and future management of follicular lymphoma

Follicular lymphoma is usually considered as incurable, but patient??s outcome has been steadily improving over the last decade. The introduction of anti-CD20 monoclonal antibodies represented a major step. Treatment of patients should take into account accurate staging results, symptoms related to lymphoma, tumor burden, age and comorbidities. Several options are still available for patients with localized or asymptomatic low risk disease, and randomized studies should be developed for those patients. When a systemic therapy is needed, the combination of rituximab with a few of the available cytotoxic regimens clearly provides the best results. Rituximab maintenance appears to further improve the progression-free interval. Since most patients will likely survive for many years, the quality and duration of response as well as the short- and long-term side effects of the treatments should be carefully weighted during this prolonged therapeutic management.     

Current prognostic and predictive factors in follicular lymphoma

Follicular lymphoma (FL) is generally considered an indolent disorder. With modern day treatments, long remissions are often achieved both in the front-line and relapsed setting. However, a subset of patients has a more aggressive course and a worse outcome. Their identification is the main purpose of modern day prognostic tools. In this review, we attempt to summarize the evidence concerning prognostic and predictive factors in FL, including (1) pre-treatment factors, from baseline clinical characteristics and imaging tests to histological grade, the microenvironment and genomic abnormalities; (2) post-treatment factors, i.e., depth of response, measured both by imaging tests and minimal residual disease; (3) factors at relapse and duration of response; and (4) prognostic factors in histological transformation. We conclude that, despite the existence of numerous tools, the availability of some of them is still limited; they generally suffer from notable downsides, and most have unproven predictive value, thus having scarce bearing on the choice of regimen at present. However, with the technological and scientific developments of the last few years, the potential for these prognostic factors is promising, particularly in combination, which will probably, in time, help guide therapeutic decisions.     

Early lesions of follicular lymphoma: a genetic perspective

The pathogenesis of follicular lymphoma is a multi-hit process progressing over many years through the accumulation of numerous genetic alterations. Besides the hallmark t(14;18), it is still unclear which other oncogenic hits contribute to the early steps of transformation and in which precursor stages these occur. To address this issue, we performed high-resolution comparative genomic hybridization microarrays on laser-capture micro-dissected cases of follicular lymphoma in situ (n=4), partial involvement by follicular lymphoma (n=4), and duodenal follicular lymphoma (n=4), assumed to represent, potentially, the earliest stages in the evolution of follicular lymphoma. Cases of reactive follicular hyperplasia (n=2), uninvolved areas from follicular lymphoma in situ lymph nodes, follicular lymphoma grade 1–2 (n=5) and follicular lymphoma grade 3A (n=5) were used as controls. Surprisingly, alterations involving several relevant (onco)genes were found in all entities, but at significantly lower proportions than in overt follicular lymphoma. While the number of alterations clearly assigns all these entities as precursors, the pattern of partial involvement by follicular lymphoma alterations was quantitatively and qualitatively closer to that of follicular lymphoma, indicating significant selective pressure in line with its faster rate of progression. Among the most notable alterations, we observed and validated deletions of 1p36 and gains of the 7p and 12q chromosomes and related oncogenes, which include some of the most recurrent oncogenic alterations in overt follicular lymphoma (TNFRSF14, EZH2, MLL2). By further delineating distinctive and hierarchical molecular and genetic features of early follicular lymphoma entities, our analysis underlines the importance of applying appropriate criteria for the differential diagnosis. It also provides a first set of candidates likely to be involved in the cascade of hits that pave the path of the various progression phases to follicular lymphoma development.     

High-dose therapy and stem cell transplantation in follicular lymphoma

 Indolent follicular lymphomas are diseases which are generally incurable with conventional therapy. Although patients can survive for prolonged periods, the median duration of first remissions is about 2.5 years, and subsequent remissions progressively shorten with time. High-dose therapy with hematopoietic stem cell support leads to prolonged disease-free and overall survival in a subset of patients with aggressive non-Hodgkin's lymphoma. Mounting evidence suggests similar findings for selected patients with indolent follicular non-Hodgkin's lymphoma. It is still unclear as to when this approach should be used; however, inferior results have been seen in heavily pretreated patients. In contrast, encouraging results are being reported in patients undergoing such treatment early in the course of their disease. Despite these data, many patients continue to relapse, and investigations are now focused on eradication of minimal residual disease, allogeneic transplantation, novel ablative regimens, and improvements in stem cell purging. Received: February 7, 1999 / Accepted: March 3, 1999     

Monoclonal antibody therapy for lymphoma

Monoclonal antibodies are an exciting advance in the treatment of lymphoma. They are safe and well-tolerated, and exhibit little cross-resistance with conventional chemotherapeutic agents. In indolent lymphomas, antibody therapy has shown useful response rates, both as first-line therapy and in relapsed disease. Follicular lymphomas appear to be particularly sensitive to rituximab, and chronic lymphocytic leukaemia to alemtuzumab. In aggressive lymphomas, the addition of rituximab to CHOP chemotherapy significantly lengthens disease-free and overall survival compared to CHOP alone as first-line therapy. Newer agents, including radiolabelled antibodies, immunotoxin-linked antibodies and antibodies against novel target antigens are showing promise in phase I and II trials in a variety of clinical settings.     

Monoclonal antibody therapy for B-cell lymphoma

Treatment strategies and outcomes for patients with non-Hodgkin's lymphoma (NHL) are undergoing rapid and important evolution. We have recently witnessed the advent of novel targeted therapies, such as gene therapies, active immunotherapies, antisense therapies, new small molecules and biologicals, and monoclonal antibodies (MoAbs). The first MoAb approved for the treatment of cancer, rituximab, was approved in 1997 and has been rapidly incorporated into treatment regimens for NHL. In a randomized trial in combination with CHOP chemotherapy (cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone), rituximab showed superiority to CHOP for patients with diffuse large cell NHL (DLCL).The rituximab + CHOP combination has become the gold standard for frontline therapy for DLCL and has shown significant activity in the management of follicular NHL. In February 2002, the first radioimmunotherapeutic agent for the treatment of cancer, ibritumomab tiuxetan (Zevalin), was approved. Ibritumomab tiuxetan, an yttrium-labeled antibody used in conjunction with rituximab, has significant activity in follicular and transformed NHL. Use of rituximab has proved that antibodies are safe and active even as single agents. The results have helped dispel the negativity and biases resulting from many years of disappointing results in this important area of research. Results with rituximab have opened the doors to continued research and have provided the impetus necessary for renewed enthusiasm and optimism in continuing the search for curative regimens for patients with NHL.     

Current status of prognostication in classical Hodgkin lymphoma

Classical Hodgkin lymphoma (cHL) is characterized by a paucity of neoplastic Hodgkin/Reed Sternberg (HRS) cells within a complex cellular milieu that is rendered immunologically incapable of reacting against CD30⁺HRS cells due to a plethora of immune escape mechanisms initiated by the neoplastic cells. Accounting for 25% of all lymphomas and nearly 95% of all Hodgkin lymphomas, patients with cHL are typically young adults. Besides traditional prognostic factors, such as the International Prognostic Index (IPI), newer imaging and ancillary biomarkers (CD68, Galectin‐1 and plasma microRNA) have shown promise. Furthermore, the evolution of gene expression profiling (GEP) in recent years has enabled the development of several practically feasible GEP‐based predictors with prognostic relevance. This review discusses the current status of clinical prognostication in cHL, the critical role of histological evaluation in light of several mimicking entities, and the relevance of tissue as well as serum biomarkers pertaining to immune escape mechanisms and recent GEP studies.     

Early event status informs subsequent outcome in newly diagnosed follicular lymphoma

Recent advances in follicular lymphoma (FL) have resulted in prolongation of overall survival (OS). Here we assessed if early events as defined by event‐free survival (EFS) at 12 and 24 months from diagnosis (EFS12/EFS24) can inform subsequent OS in FL. 920 newly diagnosed grade 1‐3A FL patients enrolled on the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002‐2012 were initially evaluated. EFS was defined as time from diagnosis to progression, relapse, re‐treatment, or death due to any cause. OS was compared to age‐and‐sex‐matched survival in the general US population using standardized mortality ratios (SMR) and 95% confidence intervals (CI). We used a cohort of 412 FL patients from two Lyon, France hospital registries for independent replication. Patients who failed to achieve EFS12 had poor subsequent OS (MER SMR = 3.72, 95%CI: 2.78‐4.88; Lyon SMR = 8.74, 95%CI: 5.41‐13.36). Conversely, patients achieving EFS12 had no added mortality beyond the background population (MER SMR = 0.73, 95%CI: 0.56‐0.94, Lyon SMR = 1.02, 95%CI: 0.58‐1.65). Patients with early events after immunochemotherapy had especially poor outcomes (EFS12 failure: MER SMR = 17.63, 95%CI:11.97‐25.02, Lyon SMR = 19.10, 95%CI:9.86‐33.36; EFS24 failure: MER SMR = 13.02, 95%CI:9.31‐17.74, Lyon SMR = 7.22, 95%CI:4.13‐11.74). In a combined dataset of all patients from both cohorts, baseline FLIPI was no longer informative in EFS12 achievers. Reassessment of patient status at 12 months from diagnosis in follicular lymphoma patients, or at 24 months in patients treated with immunochemotherapy, is a strong predictor of subsequent overall survival in FL. Early event status provides a simple, clinically relevant endpoint for studies assessing outcome in FL. Am. J. Hematol. 91:1096–1101, 2016. © 2016 Wiley Periodicals, Inc.     

Rituximab maintenance therapy: a step forward in follicular lymphoma

Whilst recent advances in the treatment of follicular lymphoma (FL) have improved the outlook for many patients, relapses still occur and the search continues for strategies to extend the duration of remission without significantly increasing toxicity. One such strategy is the use of rituximab maintenance therapy for patients responding to initial induction. There is now a large body of evidence demonstrating clear benefits of rituximab maintenance versus observation following induction with either rituximab plus chemotherapy (R chemo), chemotherapy alone, or rituximab monotherapy, in both first-line and relapsed/refractory settings. A very important finding is that rituximab maintenance can significantly improve overall survival in FL patients responding to induction with either R-chemo or chemotherapy alone. Also, compared with rituximab retreatment at disease progression, the maintenance approach produces much better complete remission rates and significantly longer continuous remissions and progression-free survival. Various maintenance schedules have been explored, all of which demonstrate clear benefits. However, the optimal dose, schedule, and duration of maintenance therapy still need to be established. Current data indicate that rituximab maintenance can be safely administered for up to 2 years, although assessment of long-term safety requires longer follow-up. From the patient's perspective, rituximab maintenance also prolongs the period in which patients are symptom-free and able to lead a relatively normal daily life. Also, rituximab maintenance may help patients feel they can control their disease, rather than passively waiting for relapse.