Systemic Anaplastic Large Cell Lymphoma Research Articles

The European Medicines Agency Review of Brentuximab Vedotin (Adcetris) for the Treatment of Adult Patients With Relapsed or Refractory CD30+ Hodgkin Lymphoma or Systemic Anaplastic Large Cell Lymphoma: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

On October 25, 2012, a conditional marketing authorization valid throughout the European Union (EU) was issued for brentuximab vedotin for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL) and for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). For HL, the indication is restricted to treatment after autologous stem cell transplantation (ASCT) or after at least two previous therapies when ASCT or multiagent chemotherapy is not a treatment option. Brentuximab vedotin is an antibody-drug conjugate (ADC) composed of a CD30-directed monoclonal antibody (recombinant chimeric IgG1) that is covalently linked to the antimicrotubule agent monomethyl auristatin E (MMAE). Binding of the ADC to CD30 on the cell surface initiates internalization of the MMAE-CD30 complex, followed by proteolytic cleavage that releases MMAE. The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Brentuximab vedotin as a single agent was evaluated in two single-arm studies. Study SG035-003 included 102 patients with relapsed or refractory HL. An objective response was observed in 76 patients (75%), with complete remission in 34 (33%). Study SG035-004 included 58 patients with relapsed or refractory sALCL. An objective response was observed in 50 patients (86%), with complete remission in 34 (59%). The most frequently observed toxicities were peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, vomiting, pyrexia, and upper respiratory tract infection. The present report summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of the product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu). Brentuximab vedotin was approved in the European Union for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma or systemic anaplastic large cell lymphoma. For Hodgkin lymphoma, brentuximab vedotin should only be used after autologous stem cell transplantation or following at least two prior therapies when transplantation or multiagent chemotherapy is not a treatment option. In two studies involving 160 patients, partial or complete responses were observed in the majority of patients. Although there was no information on the survival of patients treated in the studies at the time of approval, the responses were considered a clinically relevant benefit.

Aberrant expression of napsin A in a subset of malignant lymphomas.

Napsin A is commonly expressed in pulmonary adenocarcinomas and some renal cell carcinomas. However, napsin A expression in lymphoid neoplasms has never been reported. Glycoproteomic analyses of lymphoma-derived cell lines revealed napsin A expression in anaplastic large cell lymphoma (ALCL) cells. We thus investigated napsin A expression in lymphoid neoplasms. A variety of lymphomas (n=672) and histiocytic tumors (n=55) was immunostained for napsin A using patient tissues. In reactive lymphoid tissues, only a few histiocytes were positive for napsin A. ALK-positive ALCLs most frequently expressed napsin A (34.4%, 11/32 cases) at a rate that was significantly higher compared with ALK-negative ALCL (8.6%, 3/35; P=0.015). Napsin A expression was also observed in 13.4% (20/149) of diffuse large B-cell lymphomas (DLBCL), 11.1% (15/134) of Hodgkin lymphomas, 4.9% (2/41) of follicular lymphomas, 6% (4/67) of peripheral T-cell lymphomas, and 3.8% (1/26) of plasma cell neoplasms. Otherwise, napsin A was not detected in any other types of lymphomas or histiocytic neoplasms. Napsin A expression in systemic ALCL was associated with a higher international prognostic index. ALCL and DLBCL patients with napsin A expression tended to have poor prognosis. These results demonstrated that napsin A is aberrantly expressed in a subset of lymphomas. The biological significance of napsin A in lymphomas warrants further study.

Expression of the chemokine receptor gene, CCR8, is associated With DUSP22 rearrangements in anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is one of the most common T-cell non-Hodgkin lymphomas and has 2 main subtypes: an anaplastic lymphoma kinase (ALK)-positive subtype characterized by ALK gene rearrangements and an ALK-negative subtype that is poorly understood. We recently identified recurrent rearrangements of the DUSP22 locus on 6p25.3 in both primary cutaneous and systemic ALK-negative ALCLs. This study aimed to determine the relationship between these rearrangements and expression of the chemokine receptor gene, CCR8. CCR8 has skin-homing properties and has been suggested to play a role in limiting extracutaneous spread of primary cutaneous ALCLs. However, overexpression of CCR8 has also been reported in systemic ALK-negative ALCLs. As available antibodies for CCR8 have shown lack of specificity, we examined CCR8 expression using quantitative real-time PCR in frozen tissue and RNA in situ hybridization (ISH) in paraffin tissue. Both approaches showed higher CCR8 expression in ALCLs with DUSP22 rearrangements than in nonrearranged cases (PCR: 19.5-fold increase, P=0.01; ISH: 3.3-fold increase, P=0.0008). CCR8 expression was not associated with cutaneous presentation, cutaneous biopsy site, or cutaneous involvement during the disease course. These findings suggest that CCR8 expression in ALCL is more closely related to the presence of DUSP22 rearrangements than to cutaneous involvement and that the function of CCR8 may extend beyond its skin-homing properties in this disease. This study also underscores the utility of RNA-ISH as a paraffin-based method for investigating gene expression when reliable antibodies for immunohistochemical analysis are not available.

Abstract 2469: Brentuximab vedotin-mediated immunogenic cell death

Abstract Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate (ADC) directed against CD30. It consists of an anti-CD30 monoclonal antibody conjugated to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. Brentuximab vedotin is approved for the treatment of relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL). Brentuximab vedotin antitumor activity is due to the binding of the ADC to CD30-expressing cells, followed by internalization, and release of MMAE after proteolytic cleavage resulting in apoptotic cell death. While Brentuximab vedotin induced cell death has been extensively studied, its potential immune modulatory activity has yet to be explored. Normal apoptosis is non-immunogenic, however multiple chemotherapeutic agents have been shown to induce a unique form of cell death termed Immunogenic Cell Death (ICD). ICD is characterized by exposure of danger-associated molecular patterns (DAMPs), many of which are Toll-like receptor ligands, which can reinitiate the immune responses suppressed by the tumor microenvironment. To test whether Brentuximab vedotin mediated tumor cell death induced ICD the phenotypic characteristics of Brentuximab vedotin-killed CD30+ HL tumor cell lines was examined. Brentuximab vedotin, dose-dependently induced surface exposure of the hallmark ICD markers calreticulin and HSP90 to similar levels induced by oxaliplatin, a chemotherapeutic agent known to mediate ICD. Since ICD is downstream of the ER stress response, Brentuximab vedotin was assessed for its ability to induce ER stress. Brentuximab vedotin treatment upregulated the apoptotic ER sensor C/EBP homologous protein (CHOP) and induced the cleavage and activation of ATF6, a transcription factor required for induction of the ER stress response. ER stress response occurred concurrently with induction of ICD markers and preceded the appearance of active caspase 3/7. These results indicate that Brentuximab vedotin mediated disruption of the microtubule network, in addition to perturbing the cell division cycle and mitosis, also induces ER stress contributing to ICD-dependent cellular toxicity. The functional consequence of ICD is activation of an immune reaction. Thus, exposure of dendritic cells to Brentuximab vedotin-killed tumor cells evoked an inflammatory phenotype including an increase in co-stimulatory markers CD86 and MHC Class II antigens, and activation of NFkB, an intermediate of inflammatory signaling pathways. Taken together, this report suggests that CD30-expressing tumor cells killed by Brentuximab vedotin may potentially activate the innate immune system to initiate antitumor immune response. It also provides a rationale for exploring therapeutic strategies that combine Brentuximab vedotin with other immune stimulatory regimens. Citation Format: Shyra J. Gardai, Angela Epp, Che-Leung Law. Brentuximab vedotin-mediated immunogenic cell death. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2469. doi:10.1158/1538-7445.AM2015-2469

Advances in the diagnosis and treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma

Abstract Current management of Hodgkin lymphoma (HL) allows high cure rates to be achieved with initial therapy in both early-stage and advanced-stage disease. However, adverse events and the emergence of late effects are important issues for patients who respond well to frontline treatment. A further challenge in HL is the treatment of patients who are either refractory to, or relapse following, initial therapy. High-dose chemotherapy with autologous stem cell transplantation (HDCT/ASCT) is a potentially curative second-line treatment option for many patients with relapsed/refractory (R/R) HL. However, not all patients are candidates for HDCT/ASCT, and the frequency and duration of responses vary. For patients who fail HDCT/ASCT, current treatment options include further salvage chemotherapy, allogeneic transplantation or novel targeted therapies. Similar issues surround the management of R/R systemic anaplastic large cell lymphoma (sALCL), which is a rare and aggressive tumour. CD30 is strongly expressed in both HL and sALCL tumour cells and is a promising therapeutic target, as demonstrated by the activity of the novel antibody–drug conjugate brentuximab vedotin. New approaches to individualising and optimising patient management, including improved application of imaging, better prognostication through use of biomarkers and the potential use of new treatment combinations and agents targeting signalling pathways in malignant cells, may help to improve outcomes. The case studies included herein were presented at a symposium during the European Hematology Association (EHA) meeting in 2014. This publication aims to share clinical experiences and solutions to the management of HL and sALCL patients in very challenging disease settings.

Brentuximab Vedotin in CD30-Positive Lymphomas: A SIE, SIES, and GITMO Position Paper.

Brentuximab vedotin (BV) is approved for the treatment of patients with relapsed or refractory CD30-positive Hodgkin lymphoma, and relapsed or refractory systemic anaplastic large-cell lymphoma. Several uncertainties remain regarding the optimal use of the drug in its approved indications as well as outside them. This article reports recommendations on the use of BV issued during a consensus project, sponsored by the Italian Society of Hematology (SIE) and its affiliate societies, Società Italiana di Ematologia Sperimentale (SIES) and Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Scientific evidence on BV was evaluated by a panel of experts, and consensus was developed by group discussion for key questions selected according to the clinical relevance. The following key issues were addressed: testing CD30 positivity to assess eligibility to BV; assessing practice indications of BV in Hodgkin lymphoma and systemic anaplastic large-cell lymphoma; providing pretreatment evaluation of patients candidates to BV; monitoring the response to BV; managing patients treated with BV; and assessing the role of BV in other CD30-positive lymphomas.

Impact of treatment on IL-4, IL-6, IL-10 and sCD25 levels in patients with Hodgkin’s Lymphoma

S222 in other PTCL with different CD30 expression levels. The aim of the study was to investigate the efficacy of BV in patients with relapsed or refractory PTCL. Methods: From March 2011 to January 2014, 74 patients were treated with BV in France in a compassionate patient program for recurrent PTCL. The diagnosis of PTCL was actually confirmed according to the 2008 WHO classification, after local histopathologic review, for 66 patients, including 56 patients with extensive immunohistochemical studies and centralized CD30 immunostaining. The primary end point was best response under BV. Progression free survival (PFS), OS, and safety, were analysed as secondary endpoints. Results: Patients were treated for: systemic ALCL (n1⁄425): ALCL ALK(n1⁄415) and ALCL ALK+ (n1⁄410); systemic PTCL (n1⁄422): PTCL NOS (n1⁄412), adult T-cell leukemia/lymphoma (n1⁄44), enteropathyassociated T-cell lymphoma (n1⁄44), and angioimmunoblastic T-cell lymphoma (n1⁄42); and cutaneous primary lymphoma (n1⁄419), Mycosis Fungoides/Sezary syndrome (n1⁄411) and Cutaneous CD30+ T-cell lymphoproliferative disorders (n1⁄48). CD30 was scored >75%, 10-70% and undetectable ( 75%) have a significant longer PFS (14.1 versus 5.7 months). Median OS was 25.9 months [95% CI 11.9; NR]. Conclusion: In this limited series of patients with different PTCL subtypes treated with BV, the level of expression of CD30 seems to impact outcome with a significantly poorer PFS for cases with a lower level of expression of CD30.

The outcome of ALK positive and ALK negative anaplastic large cell lymphoma (ALCL) following DA-EPOCH.

8564 Background: Systemic anaplastic large cell lymphoma (ALCL) is a clinically and molecularly heterogeneous type of peripheral T-cell lymphoma (PTCL). It may be sub-divided into cases with or wit...

PCN146 - Reimbursement Approval of Oncology Drugs In Canada Supported By a Data Package Lacking Phase III Trial Data

The Food and Drug Administration (FDA) have approved 28 oncologics across 37 indications on the basis of a clinical trial package lacking comparative Phase III data (Macaulay, ISPOR Toronto 2014). Approval was typically granted for indications with no therapeutic alternative where a response rate ≥10% was demonstrated. This research aims to define the circumstances under which oncologics can obtain both regulatory approval and public reimbursement in Canada on this basis. All pan-Canadian Oncology Drug (pCODR) final recommendations and Provincial Funding Summaries were analysed up to 26th November 2014 and the supportive trial package and key rationale were extracted. 36 submissions were extracted. 4 were pCODR-appraised on the basis of single-arm Phase II trial data. 3/4 were recommended (brentuximab vedotin [Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma]) and vismodegib) with pCODR deeming randomized controlled trials (RCTs) to be not feasible due to very small patient numbers and there being no standard of care. All 3 were also subject to additional restrictions to the approved label. Nevertheless, the incremental cost-effectiveness ratios (ICERs) generated on such data packages were regarded as highly uncertain; these recommendations were all conditional on cost-effectiveness being improved to an acceptable level. Nevertheless, within 12 months of all these recommendations, provincial approval was attained in ≥5 provinces including the largest 3 (Ontario, Alberta, and British Columbia). For the rejected submission (crizotinib), an RCT was deemed feasible and pCODR would not make a recommendation in the absence of comparative survival and quality of life benefits. A subsequent resubmission including Phase III data was recommended. pCODR will recommend oncologics based on single-arm Phase II data for indications where RCTs are not deemed feasible but discounting at a provincial level may be required to offset the inherent uncertainty in the resulting ICER estimation.

Expression of c-myc in anaplastic large cell lymphoma and its significance

Objective To investigate the protein expression and genetic alterations of c-myc in primary systemic anaplastic large cell lymphoma(ALCL)and discuss its relationship with clinicopathologic features and immunophenotypes. Methods 87 cases of ALCL were selected. Immunohistochemical method was used to detect the protein expression of c-myc, ALK, CD3, CD10, CD20, CD30 and EMA. c-myc and ALK genetic alterations were detected by using fluorescence in situ hybridization(FlSH). The interrelationships between protein expression, genetic alterations and clinicopathological parameters were analysed statistically. Results Immunohistochemical results: of 87 cases, ALK protein was expressed in 54 cases(62.1 %). c-myc protein was expressed in 27 cases(31.0 %). ALK and c-myc were co-expressed in 20 cases(23.0 %). c-myc protein expression, ALK and c-myc co-expression increased with the upgrade of ALCL clinical stages, and the expression was higher in International Prognostic Index(IPI)high-risk groups than in low-risk groups(P 0.05), while they were statistically significant in c-myc groups(P < 0.05)and in different IPI groups(P < 0.05). Conclusion c-myc protein expression and aneuploidy were related with ALCL clinical stages and IPI, which could be used as an indicator of estimating ALCL malignant degree and predicting prognosis. Key words: Anaplastic large cell lymphoma; c-myc; Immunohistochemistry; Fluorescence in situ hybridization

Breast implant-associated anaplastic large cell lymphoma: a systematic review.

There is substantial evidence that a type of anaplastic large cell lymphoma (ALCL) is associated with breast implants. However, the course in patients with breast implants seems to be unusually benign compared with other systemic ALCL. The purpose of this study was to identify and analyze recently published cases of breast implant-associated ALCL, with an emphasis on diagnosis, staging, treatment, and outcomes. The authors conducted a systematic literature review of reported cases of ALCL in patients with breast implants. Publications were identified with a search algorithm and forward searches. Case-based data were abstracted independently and reconciled by multiple investigators. Of 248 identified articles, only 102 were relevant to breast implant-associated ALCL, and 27 were included in this study. Fifty-four cases of ALCL in patients with breast implants were identified. Detailed clinical information was lacking in many cases. Most presented with a seroma (76 percent), and approximately half were associated with the capsule (48 percent). Most presented as stage IE (61 percent). All but one case were ALK-negative. Most received chemotherapy (57 percent) and radiation therapy (48 percent), and 11 percent received stem cell transplants. Approximately one-quarter recurred, and 9 percent died. Since the publication of guidance related to breast implant-associated ALCL in 2010, a number of cases have been reported. Despite the typically benign course, many of the cases have been treated with radiation therapy and/or chemotherapy. Increasing awareness of this disease entity among clinicians would be helpful, along with standardizing an approach to diagnosis, staging, and treatment. Risk, V.

Advances in understanding the pathogenesis of systemic anaplastic large cell lymphomas.

The currently used 2008 World Health Organization classification recognizes two types of systemic anaplastic large T cell lymphoma according to ALK protein expression in tumour cells. First, the 'anaplastic large cell lymphoma, ALK positive' (ALK(+) ALCL) that is characterized by the presence of ALK gene rearrangements and consequent ALK protein expression, and, second, the 'anaplastic large cell lymphoma, ALK negative' (ALK(-) ALCL) that is a provisional entity lacking ALK protein expression but cannot be distinguished morphologically from ALK(+) ALCL. In this review we summarize the current knowledge on the genetic lesions and biological features that underlie the pathogenesis of ALK(+) and the ALK(-) ALCL and that can lead to the use of targeted anti-cancer agents.

Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma arising in a patient with hypersensitivity to mosquito bites.

Hypersensitivity to mosquito bites is defined as the appearance of intense skin reactive lesions and systemic symptoms subsequent to mosquito bites. Most cases of hypersensitivity to mosquito bites reported thus far have been associated with chronic Epstein-Barr virus infection or natural killer cell leukemia/lymphoma. In this study, we describe the case of an 18-year-old Korean boy who had hypersensitivity to mosquito bites associated with primary systemic anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. After a mosquito bite, the patient developed a progressive cutaneous nodule on his left lower leg and regional lymphadenopathy in the left inguinal area. The histopathological and immunohistochemical findings suggested anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Positron emission tomography-computed tomography revealed increased fluorodeoxyglucose uptake in the left T4 vertebrae, left external iliac lymph nodes, left inguinal lymph nodes, and lateral subcutaneous region of the left lower leg. According to the clinical, histopathological, and immunohistochemical findings, as well as the imaging data, the patient was diagnosed with primary systemic anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Consequently, the patient received a total of 6 cycles of cyclophosphamide + doxorubicin + vincristine + prednisolone chemotherapy at 3-week intervals, after which the lesions regressed.

Antibody–Drug Conjugates in Relapsed/Refractory CD30-positive Lymphomas

Although chemotherapy and radiotherapy are associated with good outcomes in patients with advanced Hodgkin’s lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL), there is a need for alternative approaches to maximise control of the lymphoma in refractory and relapsed cases. Antibody–drug conjugates (ADCs) allow specific targeting of drugs to neoplastic cells. The ADC brentuximab vedotin (BV) has the ability to target cluster of differentiation (CD) 30+ tumour cells and initiate cytotoxic effects. In two phase II trials, BV resulted in objective responses in 75 % and 86 % of patients with refractory or relapsed HL and sALCL, respectively, with an acceptable toxicity profile. Based on these data, BV was granted accelerated approval by the US Food and Drug Administration for the treatment of refractory and relapsed HL and ALCL. A promising indication for BV is acting as a bridge to stem cell transplantation (SCT). Numerous studies are currently examining the role of BV as salvage therapy prior to autologous or allogeneic SCT, as well as in other clinical settings.

皮膚病変が急速に増大し，リンパ節，骨病変を生じたALK陰性未分化大細胞リンパ腫の1例

36歳，女性。左背部に1ヵ月前から急速に増大する腫瘤あり。緊急的に切除し，直後に判明した左腋窩リンパ節腫大部と切除部に放射線照射を実施。2ヵ月後に脊椎に浸潤し骨折，項部に新生結節があり切除。以後，CHOP療法を6クール施行し，その後，自家末梢血幹細胞移植を実施。病理組織所見ではCD30陽性，ALK陰性であり，当初は皮膚原発未分化大細胞リンパ腫（pcALCL）と診断。その後の経過および追加検査でのEMA陽性，DUSP22陰性により全身型ALCLと診断を修正した。ALCLが皮膚に単発腫瘤として出現する場合は予後良好のpcALCLであることが多いが，全身型ALCLの初期症状である可能性もある。EMA陽性所見は完全ではないが全身型であることを示す良い指標とされている。pcALCLで予後不良であった本邦報告13例の中にはEMA陽性例も含まれ，全身型ALCLが多く混在していた可能性がある。さらに本症例では全身型ALCLのあたらしい予後予測因子としてDUSP22を測定した。

The Use of Brentuximab Vedotin with or without Subsequent Allogeneic Stem Cell Transplantation in Selected Patient Groups

While combined chemotherapy regimens can be effective in classical Hodgkin’s lymphoma (cHL) and systemic anaplastic large cell lymphoma (sALCL), around a third of patients are unresponsive or relapse within a few years of treatment. Allogeneic stem cell transplantation (allo- SCT) may achieve long-term disease control in patients with chemoresistant disease, but many patients are unable to undergo allo-SCT. Brentuximab vedotin (BV) is a novel antibody-drug conjugate targeting CD30. Recent data have suggested that this treatment may be beneficial in patients who have had an unsatisfactory response to at least two prior treatments and are not eligible for allo-SCT. In addition, BV may be used to reduce tumour burden, allowing patients to subsequently progress to allo-SCT. This article discusses case studies of treatment-refractory patients with cHL and sALCL, for whom BV has provided durable complete responses (CRs).

Complete remission in CD30-positive refractory extranodal NK/T-cell lymphoma with brentuximab vedotin

TO THE EDITOR: [Abstract] The treatment outcome of relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma (ENKL) is poor. Brentuximab vedotin, an anti-CD30 antibody-drug conjugate, has recently been approved for the treatment of relapsed Hodgkin's lymphoma and anaplastic large-cell lymphoma (ALCL). We report on a case of a 63-year-old man who presented with multiple skin lesions, and was diagnosed with ENKL. Since the disease was refractory to most chemotherapy drugs, we performed an analysis of the skin biopsy to evaluate marker CD30. The patient's lymphoma cells demonstrated CD30-positivity, and treatment with single-agent brentuximab vedotin was commenced as of December 2013. Following 4 cycles of single-agent brentuximab vedotin treatment, all of the skin lesions had cleared, and a [18F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) scan demonstrated complete remission (CR) of the disease. This study suggests that single-agent brentuximab vedotin could be effective in the treatment of CD30-positive non-Hodgkin lymphomas other than ALCL. Extranodal natural killer (NK)/T-cell lymphoma (ENKL) is an aggressive, non-Hodgkin lymphoma for which a standard therapy has not yet been established. The treatment outcomes of advanced relapsed or refractory ENKL, with conventional chemotherapy, are extremely poor [1]. Brentuximab vedotin (Seattle Genetics Inc., Bothell, WA, USA) is an anti-CD30 antibody-drug conjugate that is covalently linked, via a protease-cleavable linker, to the microtubule-disrupting agent, monomethyl auristatin E. In a phase 1 clinical trial of 45 patients with relapsed or refractory CD30-positive lymphomas, treatment with single-agent brentuximab vedotin resulted in an overall response rate (ORR) of 67% [2]. In a phase 2 clinical trial for relapsed or refractory systemic anaplastic large-cell lymphoma (ALCL), single-agent brentuximab vedotin treatment resulted in an ORR of 86%, and a complete remission (CR) rate of 57% [3]. Based on these results, brentuximab vedotin was approved by the United States Food and Drug Administration, in August 2011, for the treatment of relapsed Hodgkin's lymphoma and ALCL. In a recent phase 2 clinical trial for relapsed T-cell lymphoma, treatment with single-agent brentuximab vedotin resulted in an ORR of 41% in relapsed T-cell lymphoma and 54% in angioimmunoblastic T-cell lymphoma patients, respectively [4]. Therefore, these studies demonstrate that single-agent brentuximab vedotin treatment in non-Hodgkin lymphoma patients with tumors expressing CD30 can induce objective responses. Here, we report on a case of a 63-year-old man with refractory CD30-positive ENKL in which CR was achieved with single-agent brentuximab vedotin treatment.

Four-Year Survival Data from an Ongoing Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma

Four-Year Survival Data from an Ongoing Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma

Systemic ALK Positive Anaplastic Large Cell Lymphoma – Analysis of Survival and Its Determinants in United States

Introduction:Systemic ALK positive Anaplastic large cell lymphoma (ALK+ALCL) is a rare T-cell lymphoma (TCL). It is generally considered to have a good prognosis as compared to other TCL cases. However, due to its rarity, the discrepancies in its survival at population level are unclear. In this study, we have described the trends and determinants of survival of systemic ALK+ALCL using the Surveillance Epidemiology and End Results (SEER) database.Methods:Patients were selected from the SEER 13registry (Nov 2013 submission data) using the ICD-0-3 code for ALK+ALCL (9714). Patients included had age 20 years and above, with microscopy confirmed ALK+ALCL as the first primary malignancy diagnosed between 1992-2011. We excluded patients diagnosed only at autopsy/death certificate and those with cutaneous or subcutaneous ALCL. Patients were evaluated by their demographic characteristics, radiotherapy status, disease stage and site of involvement. Five year overall survival (OS) was calculated by Kaplan-Meier method and compared by log rank test. Determinants of OS were analyzed with Cox-regression method. Statistical analyses were done with significance level of p < 0.05.Results:A total of1160 patients with systemic ALK+ALCL were identified. Median age of the cohort was 54 years (20-85 years) with majority of patients being > 60 years (20-40 years – 26.9%, 41-60 years-34.2% and > 60-38.9%). There were more males than females (59.9% vs 40.1%), more whites than blacks and other races (78.7% vs 21.3%). Patients commonly presented with nodal disease (81.3%) and advanced stage (stage III and IV-52.8%). The 5-year OS significantly declined as the age advanced (66.2% in age < 40, 46.6% in age 41-60 and 28.1% in age > 60, p<0.01). Females had a better OS than males (5 year OS 47.2% in females vs. 42.8% in males, p=0.02). 5 year OS did not significantly differ by patient’s race (Blacks 42.6% vs whites 44.4% vs others 42.5%, p=0.32).Although the 5-year OS was comparable for nodal and extranodal presentations overall (44.6% vs. 43.4% respectively, p=NS), certain extranodal presentations had a significantly poor outcome (5 year OS for disease in GI - 32.9%) while Head and neck involvement had a better outcome (5 year OS- 59.2%) (p=0.01). Treatment with radiotherapy improved the 5-year OS across the cohort (5 year OS for RT received- 57.8% vs RT not received -40.5%, p< 0.01). On Multivariate analysis, female sex (HR 0.83, CI 0.70-0.96, p=0.02), early disease stage (0.62, 0.52-0.73, p< 0.01), and treatment with radiation (HR 0.71, CI 0.57-0.87, p< 0.01) were associated with lower mortality and age > 60 was associated with higher mortality (HR 3.31, CI 2.64-4.14, P=0.001).Conclusion:Even though ALK+ALCL is considered to have a better prognosis, significant discrepancies in the survival have been identified in our large population based study. Treatment with radiotherapy significantly improves the outcome. Prospective studies with large patient population are needed to address these discrepancies and formulate better treatment strategies for these high risk groups. DisclosuresNo relevant conflicts of interest to declare.

Brentuximab Vedotin in Combination with RCHOP As Front-Line Therapy in Patients with DLBCL: Interim Results from a Phase 2 Study

Brentuximab Vedotin in Combination with RCHOP As Front-Line Therapy in Patients with DLBCL: Interim Results from a Phase 2 Study