Cliona Grant

Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma.

BACKGROUND Primary mediastinal B-cell lymphoma is a distinct subtype of diffuse large-B-cell lymphoma that is closely related to nodular sclerosing Hodgkins lymphoma. Patients are usually young and present with large mediastinal masses. There is no standard treatment, but the inadequacy of immunochemotherapy alone has resulted in routine consolidation with mediastinal radiotherapy, which has potentially serious late effects. We aimed to develop a strategy that improves the rate of cure and obviates the need for radiotherapy. METHODS We conducted a single-group, phase 2, prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) and filgrastim without radiotherapy in 51 patients with untreated primary mediastinal B-cell lymphoma. We used results from a retrospective study of DA-EPOCH-R from another center to independently verify the outcomes. RESULTS The patients had a median age of 30 years (range, 19 to 52) and a median tumor diameter of 11 cm; 59% were women. During a median of 5 years of follow-up, the event-free survival rate was 93%, and the overall survival rate was 97%. Among the 16 patients who were involved in the retrospective analysis at another center, over a median of 3 years of follow-up, the event-free survival rate was 100%, and no patients received radiotherapy. No late morbidity or cardiac toxic effects were found in any patients. After follow-up ranging from 10 months to 14 years, all but 2 of the 51 patients (4%) who received DA-EPOCH-R alone were in complete remission. The 2 remaining patients received radiotherapy and were disease-free at follow-up. CONCLUSIONS Therapy with DA-EPOCH-R obviated the need for radiotherapy in patients with primary mediastinal B-cell lymphoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00001337.).

Low-Intensity Therapy in Adults with Burkitt’s Lymphoma

BACKGROUND Burkitts lymphoma is an aggressive B-cell lymphoma that occurs in children and adults and is largely curable with the use of intensive and toxic chemotherapy. Current treatments are less effective and have more severe side effects in adults and patients with immunodeficiency than in children. METHODS We studied low-intensity treatment consisting of infused etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (EPOCH-R) in patients with untreated Burkitts lymphoma. Two EPOCH-R regimens were tested: a standard dose-adjusted combination in human immunodeficiency virus (HIV)-negative patients (DA-EPOCH-R group) and a lower-dose short-course combination with a double dose of rituximab in HIV-positive patients (SC-EPOCH-RR group). RESULTS A total of 30 consecutive patients were treated; 19 patients were in the DA-EPOCH-R group, and 11 in the SC-EPOCH-RR group. The overall median age of the patients was 33 years, and 40% were 40 years of age or older; 73% of the patients had intermediate-risk disease, and 10% had high-risk disease. The principal toxic events, fever and neutropenia, were observed during 22% of the DA-EPOCH-R treatment cycles and 10% of the SC-EPOCH-RR treatment cycles. The tumor lysis syndrome developed in 1 patient; no treatment-related deaths occurred. The median cumulative doses of doxorubicin-etoposide and cyclophosphamide administered in the SC-EPOCH-RR group were 47% and 57% lower, respectively, than those administered in the DA-EPOCH-R group. With median follow-up times of 86 months in the DA-EPOCH-R group and 73 months in the SC-EPOCH-RR group, the rates of freedom from progression of disease and overall survival were, respectively, 95% and 100% with DA-EPOCH-R and 100% and 90% with SC-EPOCH-RR. None of the patients died from Burkitts lymphoma. CONCLUSIONS In this uncontrolled prospective study, low-intensity EPOCH-R-based treatment was highly effective in adults with sporadic or immunodeficiency-associated Burkitts lymphoma. (Funded by the National Cancer Institute; ClinicalTrials.gov numbers, NCT00001337 and NCT00006436.).

Pathogenic role of B-cell receptor signaling and canonical NF-κB activation in mantle cell lymphoma.

To interrogate signaling pathways activated in mantle cell lymphoma (MCL) in vivo, we contrasted gene expression profiles of 55 tumor samples isolated from blood and lymph nodes from 43 previously untreated patients with active disease. In addition to lymph nodes, MCL often involves blood, bone marrow, and spleen and is incurable for most patients. Recently, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib demonstrated important clinical activity in MCL. However, the role of specific signaling pathways in the lymphomagenesis of MCL and the biologic basis for ibrutinib sensitivity of these tumors are unknown. Here, we demonstrate activation of B-cell receptor (BCR) and canonical NF-κB signaling specifically in MCL cells in the lymph node. Quantification of BCR signaling strength, reflected in the expression of BCR regulated genes, identified a subset of patients with inferior survival after cytotoxic therapy. Tumor proliferation was highest in the lymph node and correlated with the degree of BCR activation. A subset of leukemic tumors showed active BCR and NF-κB signaling apparently independent of microenvironmental support. In one of these samples, we identified a novel somatic mutation in RELA (E39Q). This sample was resistant to ibrutinib-mediated inhibition of NF-κB and apoptosis. In addition, we identified germ line variants in genes encoding regulators of the BCR and NF-κB pathway previously implicated in lymphomagenesis. In conclusion, BCR signaling, activated in the lymph node microenvironment in vivo, appears to promote tumor proliferation and survival and may explain the sensitivity of this lymphoma to BTK inhibitors.

Therapy in primary mediastinal B-cell lymphoma.

To the Editor: Dunleavy et al. (April 11 issue)1 had exceptional survival rates when treating adults with primary mediastinal large-B-cell lymphoma with dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R), without radiotherapy. The biologic characteristics of the disease in children are similar to those of the disease in adults.2 Regimens (without rituximab) that have been effective in the treatment of children with other mature B-cell non-Hodgkin’s lymphomas have had limited efficacy in the treatment of children with primary mediastinal large-B-cell lymphoma.3,4 Consequently, the NonHodgkin’s Lymphoma Berlin–Frankfurt–Münster (NHL-BFM) study committee recommended DA-EPOCH-R5 for children and adolescents with primary mediastinal large-B-cell lymphoma as the best available clinical practice, and this treatment was adopted for patients in the B-Cell NHL-BFM04 study in 2010. Changes from the original study protocol included the addition of intrathecal prophylaxis and limitations in the cumulative doxorubicin dose to 360 mg per square meter of bodysurface area.2 Between the change in protocol in 2010 and May 2012, a total of 15 patients diagnosed with primary mediastinal large-B-cell lymphoma (in accordance with World Health Organization classification, reference pathology confirmed) were treated with DA-EPOCH-R. The median patient age was 16 years (range, 11.5 to 17.8), and the group included 7 female patients. One patient had an isolated central nervous system relapse. The mean (±SD) event-free and overall survival rates at 2 years were both 92±8%, and the median followup was 19.2 months (range, 9.6 to 28.8). Among 12 patients who had residual mediastinal masses at the end of therapy, 9 underwent positron-emission tomography and all had positive results for lymphoma. The masses were resected in 7 of these 9 patients, and none were vital tumors. Our observation confirms the efficacy of DA-EPOCH-R in the treatment of primary mediastinal large-B-cell lymphoma in children and adolescents. Long-term studies, including studies that address cardiac function, are needed. The evaluation of residual masses needs to become more efficient in terms of both timing and the methods used.

Gray zone lymphoma: better treated like hodgkin lymphoma or mediastinal large B-cell lymphoma?

Although primary mediastinal large B-cell lymphoma (PMBL) and classic Hodgkin lymphoma of the nodular sclerosis type (CHL-NS) are distinct diseases, they share several clinical characteristics and biologic features. Given that, it is not surprising that there exist mediastinal lymphomas that do not fit well into either category but have clinical and morphologic features overlapping and transitional between PMBL and CHL-NS. The term mediastinal gray zone lymphoma (MGZL) has been used for these tumors, which are included in the World Health Organization classification as “B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma.” Although several studies have evaluated different therapeutic strategies in PMBL and CHL-NS, there is a paucity of prospective experience treating MGZL, given its rarity and relatively recent recognition. Historically, diseases that today would be categorized as MGZL were probably called “anaplastic large-cell lymphoma Hodgkin-like,” and their outcome with standard approaches was poor, with short overall survivals. In this review—following a discussion of the biology and clinical features of MGZL, and how they compare to PMBL and CHL-NS—we outline how the treatment of PMBL and CHL-NS has evolved in recent years, and how we believe MGZL should be approached therapeutically.

Primary Mediastinal Large B-Cell Lymphoma, Classic Hodgkin Lymphoma Presenting in the Mediastinum, and Mediastinal Gray Zone Lymphoma: What is the Oncologist To Do?

In recent years, an overlap in biologic and clinical features has been identified between classic Hodgkin lymphoma (CHL) and primary mediastinal large B-cell lymphoma (PMBL). Further strengthening this relationship is the identification of lymphomas with clinical and morphologic features transitional between the two, known as gray zone lymphomas (GZL). However, this diagnostic gray zone is not just of theoretical interest: it presents a practical problem, as the treatment approaches for CHL traditionally differ from those for aggressive B-cell lymphomas. This article reviews the treatment approach for mediastinal lymphomas, including CHL of the nodular sclerosis subtype (CHL-NS), PMBL, and mediastinal GZL. Though several trials have evaluated different regimens with or without radiation in PMBL and CHL-NS, there is a lack of prospective experience in treating GZL because of the rarity of these tumors. Historical data indicate that they have done poorly with traditional approaches developed for the treatment of either CHL or diffuse large B-cell lymphoma.

Using biologic predictive factors to direct therapy of diffuse large B-cell lymphoma

While diffuse large B-cell lymphoma (DLBCL) was once considered to be a single disease entity, recent biological insights have demonstrated that it can be divided up into at least three molecular subtypes. Gene expression profiling has revealed that DLBCL consists of a germinal center B-cell like subtype (GCB), an activated B-cell like subtype (ABC) and a primary mediastinal B-cell lymphoma subtype (PMBL). These three entities arise from different stages of B-cell differentiation and are characterized by distinct mechanisms of oncogenic activation. In GCB DLBCL, the BCL6 transcription factor may play an important role in tumor survival and treatment resistance and strategies that target this are under investigation. ABC DLBCL is characterized by high expression of target genes of the nuclear factor kappa B (NF-κB)/Rel family of transcription factors and strategies that target NF-κB are in clinical trials. PMBL is a distinct clinicopathologic entity that shares many molecular features with nodular sclerosis Hodgkin lymphoma (HL) and may benefit from dose intensity approaches and inhibition of the Janus kinases. Other biologic predictive factors such as MYC and BCL2 may be overexpressed in both the GCB and ABC subtypes and strategies that target these complexes are also being tested.

Neutropenia associated with rituximab therapy.

Purpose of reviewSeveral recent studies have reported the occurrence of late-onset neutropenia (LON) following the use of rituximab or rituximab-based therapies. While this phenomenon is typically self-limiting and of no clinical significance, recognizing its existence is important given the expanding use of rituximab in both hematologic and nonhematologic disorders. This review discusses the incidence of LON and explores several hypotheses that have been proposed to explain its occurrence. Recent findingsWhile the etiology of LON is uncertain and poorly understood, mechanisms that have been suggested include the production of antineutrophil antibodies following rituximab, the expansion of large granular lymphocyte (LGL) populations that may induce neutrophil apoptosis through Fas and Fas-ligand interactions, and aberrant B-cell reconstitution following rituximab leading to immune dyscrasias and the development of neutropenia. We explored an alternative hypothesis that LON following rituximab is caused by perturbations of granulocyte homeostasis, mediated by a complex interaction between B-cell recovery and the chemokine stromal-derived factor-1 (SDF-1). SummaryWhile rituximab has been associated with both early and late neutropenia, LON occurring several weeks to several months after the administration of rituximab is a distinct biologic phenomenon that appears to be related to B-cell recovery. Though it occurs frequently, it is a self-limiting process and is rarely associated with significant clinical sequelae.

Interpreting MYC and BCL2 in diffuse large B-cell lymphoma

Translocations involving the MYC gene are the cytogenetic hallmark of Burkitt lymphoma (BL) and most commonly involve chromosomes 8 and 14 [1]. Th is leads to deregulated MYC expression and resultant up-regulation of cell proliferation genes that promote tumor survival [2]. While constitutive MYC overexpression is a classical feature of Burkitt lymphoma, recurrent MYC translocations in other aggressive B-cell lymphomas such as diff use large B-cell lymphoma (including plasmablastic lymphoma) have recently been described [3 – 5]. In fact, up to 10% of diff use large B-cell lymphomas (DLBCLs) harbor a MYC rearrangement. Th is has clinical relevance in that several studies have now demonstrated that this portends a worse prognosis with standard treatment [4,6]. In DLBCL, there are likely to be diff erent mechanisms of MYC activation and overexpression, other than the presence of a translocation. Th e prognostic role of high protein expression of MYC in the absence of a translocation has not been well established thus far, and is the subject of many recent clinical trials. In addition, when MYC is highly expressed, the role of high and low expression of other proteins such as BCL2 and BCL6 , with or without concomitant translocations, is an area of intense clinical interest. Herein, Kojima and colleagues retrospectively investigated the prognostic impact of a MYC rearrangement (as well as BCL2 and CD5 expression and postulated cell of origin) in a multicenter study of Japanese patients with DLBCL who received rituximab-containing chemotherapy [7]. Th eir fi ndings were consistent with other groups in that they showed, at 3 years ’ follow-up, a signifi cantly inferior progression-free (30% vs. 57.8%) and overall survival (50% vs. 67.8%) in the MYC -rearranged patients. CD5 and BCL2 expression did not predict outcome, and of three algorithms that were used to predict cell of origin, both the Hans and Muris methods demonstrated an inferior outcome for (predicted) non-germinal center tumors. While several groups have demonstrated a negative prognostic impact of a MYC rearrangement in patients with DLBCL treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) – with or without the addition of rituximab ® – the role of high MYC protein expression in the absence of a rearrangement is much less clear. Th ree recent studies have specifi cally investigated the association of high MYC expression by immunohistochemistry with clinical outcome [8 – 10]. In the fi rst two of these, the co-expression of BCL2 with MYC conferred a poor outcome following R-CHOP, and the third (RICOVER) study identifi ed a group of elderly patients with high MYC and BCL2 but low BCL6 who had an inferior outcome after R-CHOP. In these studies, interestingly, the prognostic predictability of immunohistochemistry held up even in the absence of translocations by fl uorescence in situ hybridization (FISH). So how do we interpret the fi ndings of these various studies with respect to the role of immunohistochemistry, and should they infl uence how we approach newly diagnosed patients with DLBCL? While FISH as a technique for detecting gene-activating breaks in MYC , BCL2 and BCL6 is well established and has high specifi city and reproducibility, this is not always the case with immunohistochemistry. Among diff erent centers, the reproducibility of immunohistochemical results may be challenging due to technical and interpretative variability. Techniques such as fi xation and processing methods as well as choice of antibody can diff er signifi cantly, as can scoring of staining and implementation of cut-off s for positive versus negative interpretation. Th is does not diminish the importance of these fi ndings, but suggests that these results should be validated in a prospective setting where large cohorts of patients receive identical therapy and standardized immunohistochemical analyses are implemented from the outset. It is also interesting to consider what underlying tumor biology and critical pathways and mutations are driving expression of these various markers. While many of these studies have interestingly demonstrated the persistence of a negative prognostic impact of high MYC and BCL2 after adjusting for cell of origin, this also warrants further investigation and prospective validation with techniques other than immunohistochemistry algorithms to predict cell of origin. At this point in time, it is unclear what the optimal management of patients who have tumors with MYC rearrangements (with or without rearranged BCL2 ) or high L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y 17 9. 18 0. 6. 21 1 on 0 5/ 20 /1 4

Composite Blastoid Variant of Mantle Cell Lymphoma and Classical Hodgkin Lymphoma

Composite lymphoma (CL) describes the rare occurrence of 2 or more distinct types of lymphoma in a single anatomical location. We present the case of a 78-year-old man presenting with a 3-month history of weakness, malaise, and increasing dyspnea. A lymph node excised from the posterior triangle of the neck revealed the coexistence of 2 morphologically and phenotypically distinct lymphoid neoplasms consistent with a blastoid variant of mantle cell lymphoma (MCL) occurring in composite with classical Hodgkin lymphoma (cHL), mixed cellularity subtype. A t(11;14)(q13;q32) translocation was demonstrated by fluorescence in situ hybridization in the MCL and Hodgkin Reed-Sternberg cells of the cHL. Multiplex polymerase chain reaction detected clonal Immunoglobulin heavy chain (VFR1-J, VFR2-J, and VFR3-J), clonal immunoglobulin light chain kappa (V-J and V/JC intron-kde) and clonal immunoglobulin light chain lambda (V-J) gene rearrangements in the MCL. This report represents the first case of a blastoid variant of MCL occurring in composite with cHL.