Anaplastic Large T-cell Lymphoma Research Articles

Breast implant-associated anaplastic large t-cell lymphoma: Institutional experience and review of the literature

Introduction and aims: Breast Implant-Associated Anaplastic Large T-Cell Lymphoma (ALCL) is a rare disease reported in limited case reports. The purpose of this study is to report on the clinical presentation, treatment, and outcomes of ALCL within a single institution experience as well as to analyze the current research on the clinical manifestations of the disease.

The ALK inhibitor ASP3026 eradicates NPM-ALK⁺ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model.

NPM-ALK⁺ T-cell anaplastic large-cell lymphoma (ALCL) is an aggressive type of cancer. Standard treatment of NPM-ALK⁺ ALCL is CHOP polychemotherapy. Although patients initially respond favorably to CHOP, resistance, relapse, and death frequently occur. Recently, selective targeting of ALK has emerged as an alternative therapeutic strategy. ASP3026 is a second-generation ALK inhibitor that can overcome crizotinib resistance in non-small cell lung cancer, and is currently being evaluated in clinical trials of patients with ALK⁺ solid tumors. However, NPM-ALK⁺ ALCL patients are not included in these trials. We studied the effects of ASP3026 on NPM-ALK⁺ ALCL cell lines in vitro and on systemic lymphoma growth in vivo. ASP3026 decreased the viability, proliferation, and colony formation, as well as induced apoptotic cell death of NPM-ALK⁺ ALCL cells. In addition, ASP3026 significantly reduced the proliferation of 293T cells transfected with NPM-ALK mutants that are resistant to crizotinib and downregulated tyrosine phosphorylation of these mutants. Moreover, ASP3026 abrogated systemic NPM-ALK⁺ ALCL growth in mice. Importantly, the survival of ASP3026-treated mice was superior to that of control and CHOP-treated mice. Our data suggest that ASP3026 is an effective treatment for NPM-ALK⁺ ALCL, and support the enrollment of patients with this lymphoma in the ongoing clinical trials.

Phenotypic Variability in Primary Cutaneous Anaplastic Large T-cell Lymphoma

Primary cutaneous anaplastic large T-cell lymphoma (pcALCL) is a well-defined entity characterized by neoplastic cells expressing CD30, CD2, CD3, CD4, and CD5. Cases with different phenotype have been reported, including variable loss of CD2, CD3, and CD5, and expression of cytotoxic phenotype (CD8⁺) and/or of cytotoxic proteins. Aberrant phenotypes represent a diagnostic pitfall and may be the cause of misdiagnoses. We reviewed 35 cases of pcALCL (M:F = 19:16; mean age, 50.8 years; range, 14-92 years), to better characterize the immunophenotypic spectrum of the disease. Twelve cases (34%) had a T-helper phenotype (CD4⁺/CD8⁻), and TIA-1 was positive in 5 of 8 stained cases. Six cases (18%) had a T-cytotoxic phenotype (CD4⁻/CD8⁺) and were also positive for TIA-1. Positivity for both CD4 and CD8 was observed in 7 cases (20%), 4 of which were stained for TIA-1 and found to be positive, whereas both CD4 and CD8 were negative in 9 cases (26%, only 1/8 tested cases being TIA-1 positive). CD2 was positive in 21 of 27 tested cases (78%), CD3 in 21 of 34 cases (62%), and CD5 in 15 of 31 cases (48%). Interestingly, 11 cases (31%) showed a profoundly aberrant phenotype lacking simultaneously several T-cell markers. Our data allow a better characterization of pcALCL with aberrant phenotypes, showing the remarkable variability in expression of different markers.

Cutaneous Lymphoproliferative Disease

Cutaneous Lymphoproliferative Disease

Primary Diffuse Large B Cell Lymphoma Developing at the Ileocolonic Anastomosis Site after Right Hemicolectomy for Adenocarcinoma: A Case Report

Lymphoma is rarely associated with pouch surgery. To date, only five reports in the literature described lymphoma in an ileal pouch for ulcerative colitis (1-5) and only two papers reported about lymphoma in the anastomosis site for colonic adenocarcinoma which were anaplastic large cell lymphoma and T-cell lymphoma (6, 7). We report a very rare case of primary diffuse large B-cell lymphoma (DLBL) arising in an ileocolonic anastomosis site which was found five years after a right hemicolectomy for adenocarcinoma in the ascending colon.

Primary lymphoma of bone: A review

Lymphomas commonly occur in lymph nodes, while their origin in extranodal sites is less common. When nodal lymphomas spread systemically, they commonly involve the skeletal system, with bone involvement seen in 16–20% of patients. Lymphoma originating in the bone is rare and designated as primary bone lymphoma (PBL). Oberling was the first person to describe PBL in 1928. Subsequently, in 1932, Parker and Jackson described a series of PBLs under the designation of reticulum cell sarcoma of the bone. The lymphoid origin was later confirmed by the availability of immunohistochemistry. According to the World Health Organization, diagnosing a PBL entails having skeletal tumor(s) without visceral or regional lymph node involvement. PBL accounts for less than 1% of all malignant lymphomas, 7% of malignant bone tumors, and 4–5% of extranodal lymphomas. The majority of the PBLs are primary bone diffuse large B-cell lymphomas (PBDLBCL). Rarely, follicular, marginal zone, anaplastic large cell, Hodgkin, and T-cell lymphomas can originate in bone. In this review, we describe the clinical features, gross and microscopic findings, ancillary studies, differential diagnoses, prognostic markers, and treatment of PBDLBCL. Rare variants of PBL are also described briefly.

Lymphomatoid Papulosis Type D or an Aggressive Epidermotropic CD8+ Cytotoxic T-cell Lymphoma?

Lymphomatoid papulosis (LyP) is defined as a chronic, recurrent, self-healing eruption of papules and small nodules, characterised by a waxing and waning course, and by histological features of a CD30+ cutaneous T-cell lymphoma CTCL. Classically, 3 histologic subtypes of LyP are recognised: Type A (histiocytic), type B (MFlike) and type C (anaplastic like CTCL) (1). Together with primary cutaneous anaplastic large Tcell lymphoma, LyP is classified as a part of the primary cutaneous CD30+ lymphoproliferative disorders in the WHO-EORTC classification of cutaneous lymphomas (2). Recently, a new histologic LyP variant termed type D, simulating an aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, but with the typical clinical presentation and indolent course of LyP, has been described (3–5). We describe a new case of this variant, of which diagnosis is particularly challenging and emphasises the importance of cross-disciplinary collaboration.

Genetic Factors Predicting The Response To BET Bromodomain Inhibitors In Lymphoma Lead To New Synergistic Combinations

Epigenome deregulation in cancer cells affects transcription of oncogenes and tumor suppressor genes. BET Bromodomain proteins recognize chromatin modifications and act as epigenetic readers contributing to gene transcription. BET Bromodomain inhibitors showed promising pre-clinical activity in hematological and solid tumors and are currently in phase I studies. The mechanism of action and relevant affected genes are not fully characterized and there are no established response predictors. We have shown activity of BET Bromodomain OTX015 in lymphoma cell lines (ASH 2012; ICML 2013). This study aimed at elucidating pathways and genes affecting response/resistance to BET Bromodomain inhibitors in lymphomas. MethodsBaseline gene expression profiles (GEP) were obtained in 38 cell lines [22 diffuse large B-cell lymphoma (DLBCL), 8 anaplastic large T-cell lymphoma, 4 mantle cell lymphoma, 3 splenic marginal zone lymphoma, 1 chronic lymphocytic leukemia] with Illumina HumanHT-12 v4 Expression BeadChip. Genetic and biologic information were collected from literature. GEP/IC50 correlation (ASH 2012; ICML 2013) was assessed by Pearson correlation. Associations in two-way tables were tested for statistical significance using either chi-square or Fisher exact test, as appropriate. Differential expression analysis was performed using LIMMA, followed by multiple test correction using the BH method. Enrichment of functionally-related genes was evaluated by GSEA. For combination studies, 3 germinal center B-cell (GCB) and 2 activated B-cell (ABC) DLBCL were exposed to increasing doses of OTX015 alone or in combination with increasing doses of targeted agents for 72 hours, followed by MTT assay. Synergy was assessed by Chou-Talalay combination index (CI) with Synergy R package. ResultsTranscripts associated with resistance to OTX015 were significantly enriched of genes involved in cell cycle regulation, DNA repair, chromatin structure, early B-cell development, E2F/E2F2 target genes, IL6-dependent genes, and mRNA processing. Conversely, transcripts associated with OTX015 sensitivity were enriched of hypoxia-regulated genes, interferon target genes, STAT3 targets, and involved in glucose metabolism. Genes associated with OTX015 sensitivity included LDHA, PGK1 (glucose metabolism) and VEGFA (hypoxia), while BCL2L1/BCLXL, BIRC5/survivin (anti-apoptosis), ERCC1 (DNA repair), TAF1A and BRD7 (transcription regulation) were correlated with reduced sensitivity.GEP identified 50 transcripts differentially expressed, including IL6, HCK, SGK1, MARCH1 and TRAFD1, between cells undergoing or not apoptosis after OTX015 exposure. GSEA showed significant enrichment of genes involved in IL-10 signaling pathway. While there was no association between response to OTX015<500nM and presence of translocated MYC, analysis of genetic and biologic features identified the ABC phenotype (P=.008) and presence of concomitant somatic mutations in MYD88 and CD79B or CARD11 genes and wild type TP53 (P=.027) as associated with apoptosis. Based on these observations and since mutated MYD88 interacts with BTK and MYD88/CD79B mutations have been associated with clinical responses with the BTK inhibitor ibrutinib, we evaluated OTX015 combination with this compound. Synergy was observed in particular in ABC-DLBCL with a median CI of .04 (range .02-.1). The demonstrated down-regulation of the MYD88/JAK/STAT pathway after OTX015 treatment, as shown by additional GEP, highlighted the importance of this pathway for OTX015 activity. Other targeted agents (everolimus, lenalidomide, rituximab, decitabine, vorinostat) appeared to synergize with OTX015 (Fig 1). The mTOR inhibitor everolimus presented a very strong synergism with a median CI of .11 (.1-.2), in accordance with the association between OTX015 sensitivity to high glucose metabolism and high levels of SGK1 in cells undergoing apoptosis. [Display omitted] ConclusionsOur study identified genetic mechanisms contributing to the response to BET Bromodomain inhibitors and promising combination schemes, such as OTX015/everolimus, to be further investigated. Disclosures:Stathis:Oncoethix: NCT01713582 PI Other. Herait:Oncoethix: Membership on an entity's Board of Directors or advisory committees. Noel:Oncoethix: Membership on an entity's Board of Directors or advisory committees. Inghirami:Oncoethix: Research Funding. Bertoni:Oncoethix: Research Funding.

Phase II Trial Of Brentuximab Vedotin For CD30+ Cutaneous T-Cell Lymphomas and Lymphoproliferative Disorders

▪ IntroductionBrentuximab vedotin, an antibody drug conjugate comprising of an anti-CD30 monoclonal antibody (cAC10) attached by a protease-cleavable linker to a microtubule-disrupting agent monomethyl auristatin E (MMAE), was approved for relapsed Hodgkin lymphoma (ORR 75%) and systemic anaplastic large T-cell lymphoma (ALCL; ORR 86%) and the naked cAC10 antibody was shown active in CD30+ skin lymphomas (ORR 70%). Study designTo determine safety and activity of Brentuximab vedotin we completed a Phase II open-label trial of 48 patients with primary cutaneous CD30+ lymphoproliferative disorders including lymphomatoid papulosis (LyP) and primary cutaneous pc-ALCL (pc-ALCL) or CD30+ mycosis fungoides (MF). Eligibility required skin lesion expression of CD30, > 10 Lyp lesions, one or more tumors, and need for systemic therapy. Patients with CD30+ MF were stage IB or higher and had received one or more prior topical or systemic therapies. The antibody conjugate was infused at 1.8 mg/kg every 21 days. Patients achieving a complete response (CR) received two additional doses and those achieving partial responses (PR) after 8 cycles could receive up to 16 doses. Response criteria for LyP were a 50% decrease in lesions, for pc-ALCL were 50 % tumor reduction, and for MF were 50% decrease in modified skin weighted assessment tool mSWAT. CD30 pretreatment skin biopsies and serum sCD30 were correlated with response. ResultsThe 48 evaluable patients who received >2 doses of brentuximab vedotin included 22 females and 26 males with median age of 59.5 years (range 31-86). Their clinical diagnoses are in Table 1: 28 with MF, 2 with pc-ALCL, 9 with only LyP, 7 LyP with MF, and 2 with pc-ALCL/LyP/MF. Overall response rate (ORR) was 71% (34/48) with CR of 35% (17/48). The intent to treat response rate for all 56 patients receiving at least one dose was 61% (34/56). ORR was 50% in 28 MF patients regardless of whether their lesions had low, medium, or high CD30 at baseline. LyP and pc-ALCL patients had a 100% ORR and two pc-ALCL patients had CRs. For LyP, time to response (TTR) was 3 wks (range 3-6) and median duration of response (DOR) of 23 wks (range 6-44). For MF, TTR was 10.5 wks (range 3-39) and DOR was 13.5 wks (range 3-56 wks). Relapse rates in Lyp and pc-ALCL was 40% (8/20) with TTR of 25 wks (range 6-41). In MF responders, 5/14 (36%) relapsed and MTR was 3 wks (range 3-40). Median ORR and disease specific response (DSS) were not reached from date of diagnosis or from first dose. Median progression free survival (PFS) was 9.7 years from diagnosis and 1.68 years from first dose. Soluble CD30 levels from baseline to end of study differed significantly among those patients achieving a CR compared to those with PR or SD (p=.036).The most common related adverse event (AE) of any grade was peripheral neuropathy (PN) in 29/48 (60%): resolved in 14/29 (48%) and ongoing in 15/29 (52%) with 5 grade 2 and 10 grade one. Other AE > 10% were drug rashes (27%), diarrhea (24%), fatigue (30%), alopecia (16%), myalgias (16%), and nausea (14%). Grade 3-4 events included neutropenia (n=5), nausea (n=2), chest pain (n=2), deep vein thrombosis (n=1), transaminitis (n=1) and dehydration (n=1). Dose reductions to 1.2 mg/kg were for grade 2 neuropathy (n=2), transaminitis (n=1) and arthralgia/ fatigue (n=2). There were two deaths from untreated sepsis after one dose. ConclusionThis phase II clinical trial demonstrates that brentuximab vedotin is active for mycosis fungoides (ORR 50%) irrespective of level of CD30+ expression. The ORR was 100% for CD30+ pc-ALCL, and LyP patients and was 71% with a CR of 36% for all evaluable patients.Table 1Response to Brentuximab Vedotin by Clinical DiagnosisPrimary DiagnosisTotal ptsResponse 71% (34/48)Secondary ResponseTime to Response wksDOR (wks)MF2812PR, 2 CR50%10.5 (R 3-39)13.5(R3-56)LyP95 CR, 4 PR100%3 (R 3-6)23 (R 6-44)pc-ALCL22 CR100%3 (R 3)18LyP/MF76 CR, 1 PR100%MF 6 PR 1 SD3 (R 3-9)18 (18- 44)ALCL/LyP22 CR100%LyP PR,PD Disclosures:Duvic:Seattle Genetics: Research Funding. Off Label Use: This is an open label study for Cutaneous T-cell lymphoma and lymphoproliferative disorder. Brentuximab is approved for relapsed and refractory Hodgkins lymphoma. Tetzlaff:Seattle Genetic: Consultancy.

PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma

AbstractAnaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that can present as a systemic or primary cutaneous disease. Systemic ALCL represents 2% to 5% of adult lymphoma but up to 30% of all pediatric cases. Two subtypes of systemic ALCL are currently recognized on the basis of the presence of a translocation involving the anaplastic lymphoma kinase ALK gene. Despite considerable progress, several questions remain open regarding the pathogenesis of both ALCL subtypes. To investigate the molecular pathogenesis and to assess the relationship between the ALK+ and ALK− ALCL subtypes, we performed a genome-wide DNA profiling using high-density, single nucleotide polymorphism arrays on a series of 64 cases and 7 cell lines. The commonest lesions were losses at 17p13 and at 6q21, encompassing the TP53 and PRDM1 genes, respectively. The latter gene, coding for BLIMP1, was inactivated by multiple mechanisms, more frequently, but not exclusively, in ALK−ALCL. In vitro and in vivo experiments showed that that PRDM1 is a tumor suppressor gene in ALCL models, likely acting as an antiapoptotic agent. Losses of TP53 and/or PRDM1 were present in 52% of ALK−ALCL, and in 29% of all ALCL cases with a clinical implication.

Corrigendum to “Atypical presentation of anaplastic large T-cell lymphoma mimicking an articular relapse of rheumatoid arthritis in a patient treated with etanercept. A case report and literature review” [Leuk. Res. 36 (2012) e199–e201

orrigendum to “Atypical presentation of anaplastic large T-cell ymphoma mimicking an articular relapse of rheumatoid arthritis in a atient treated with etanercept. A case report and literature review” Leuk. Res. 36 (2012) e199–e201] ederico De Angelisa,∗, Alice Di Roccoa, Clara Minotti a, Guido Valesinib, Claudio Cartonia, ara Riminucci c, Fabrizio Contib, Erica Finolezzia, Daniele Armientoa, S. Grammaticoa, . Massarob, A. Famaa, G. Colafigli a, C. Viccaronea, R. Foaa, M. Martelli a

Relapsing lymphomatoid papulosis after allogenic bone-marrow transplant

Lymphomatoid papulosis (LyP) is a rare cutaneous lymphoproliferative disorder in children, which can rarely be associated with a cutaneous or systemic lymphoma. We report a 13-year-old girl who presented with typical LyP and pathological features of subtype A. Six months later, the patient presented with rapidly progressive peripheral and systemic lymphadenopathy. On examination of a lymph-node biopsy, a lymphoid infiltrate negative for anaplastic lymphoma kinase (ALK) and positive for CD30 was found, suggestive of systemic anaplastic large T-cell lymphoma (S-ALCL). The patient was treated with chemotherapy, followed by allogeneic bone-marrow transplant (BMT). Over the following 6 years, she presented with biopsy-confirmed LyP relapses with complete cutaneous, peripheral-blood and bone-marrow chimerism. This is only the third reported paediatric association of S-ALCL with LyP to our knowledge, and seems to be the first paediatric case of recurrent relapses of LyP after bone-marrow allograft for S-ALCL with total (100%) cutaneous and bone-marrow chimerism. LyP occurring after allogenic BMT does not appear to be donor-derived.

Recurrent ALK-Negative Anaplastic Large T-Cell Lymphoma Presenting as Necrotizing Vasculitis

Anaplastic large cell lymphoma (ALCL) is a T-cell lymphoma histologically characterized by expression of CD30, a cell surface receptor present on activated T cells and B cells. ALCL may occur in a primary cutaneous form or as systemic ALCL with lymph node involvement. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that induces neoplastic transformation as a result of translocational fusion with an activating promoter. The presence of ALK can be used to distinguish between primary cutaneous ALCL and systemic nodal ALCL in certain cases. Primary cutaneous and systemic ALCL metastatic to the skin are histologically indistinguishable. "Leukemic vasculitis"--an uncommon finding in cases of cutaneous leukemia and even more exceptional in cutaneous lymphoma--refers to a pattern of vasculitis occurring as a direct result of infiltrating neoplastic cells. We report a fatal case of recurrent ALK-negative ALCL presenting as ulcerating skin lesions in a patient previously treated with the new anti-CD30 agent brentuximab vedotin. Biopsy revealed a necrotizing vasculitis resulting from the infiltration of neoplastic cells reminiscent of the patient's primary malignancy. We review the clinical and pathological findings of ALCL and present this case to highlight a subtle diagnostic clue in assessing recurrence of cutaneous lymphoma.

Expression of CD8 is associated with non-common type morphology and outcome in pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma

Anaplastic lymphoma kinase-positive anaplastic large T-cell lymphoma is characterized by morphological variability. Morphological variants (non-common subtype) are associated with a poor outcome. They display abundant reactive bystander cells admixed with the lymphoma cells. So far, the difficulty in distinguishing lymphoma cells from bystander cells by visual inspection has prevented detailed and reliable immunophenotypic analysis using conventional immunohistochemistry. To overcome these limitations, we analyzed 124 cases of pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma treated within clinical trials using immunofluorescence multi-staining and digital image analysis combining antibodies against anaplastic lymphoma kinase to specifically identify lymphoma cells with antibodies against CD30, CD3, CD5, CD8, Ki67 and phosphorylated STAT3. Non-common type anaplastic lymphoma kinase-positive anaplastic large cell lymphomas express CD8 more frequently than common type anaplastic lymphoma kinase-positive anaplastic large cell lymphomas (35.4% and 5.6%, respectively; P=0.0002). CD8 expression was associated with a poorer outcome. Importantly, in a multivariate analysis including clinical risk factors, histological subtype and CD8 expression, CD8-positivity proved to be an independent prognostic predictor of worse outcome (hazard ratio for survival 3.38, P=0.042).

Anaplastic Large T-Cell Lymphoma of the External Ear in Childhood

Anaplastic large T-cell lymphoma is a very rare disease in childhood. The most common locations are lymph nodes and skin, while the external ear location is uncommon. We present the case of a 6-year-old child with an earlobe tumour. Surgical treatment was performed and the anatomopathological results showed anaplastic large cell lymphoma. Radiological tests were negative and there was no systemic involvement. El linfoma anaplásico de células grandes es una patología rara en la infancia. La localización más frecuente es en la piel y nódulos linfáticos, siendo infrecuente la afectación del pabellón auricular. Presentamos el caso de un niño de 6 años con tumoración en el lóbulo de la oreja. Se realizó tratamiento quirúrgico y el resultado de la anatomía patológica mostró linfoma anaplásico de células grandes. Los estudios radiológicos fueron negativos y no hubo afectación sistémica.

Abstract 1017: The BRD-inhibitor OTX015 affects proliferation and gene expression of cells derived from mature lymphoid neoplasms.

Abstract Inhibitors of the BET family members BRD2/3/4 are a promising new class of anti-cancer drugs. Here, we assessed the antitumor activity and the mechanism of action of OTX015, a selective orally bioavailable BRD2/3/4 inhibitor, in cells derived from human mature lymphoid neoplasms. OTX015 was evaluated in 31 B-cell malignancies cell lines: 13 diffuse large B-cell lymphomas (DLBCL), 8 anaplastic large T-cell lymphomas (ALCL), 4 mantle cell lymphomas (MCL), 3 splenic marginal zone lymphomas (SMZL), and 3 multiple myelomas (MM). Anti-proliferative effect was seen in the majority of the cell lines. The median IC50s, calculated at 72h, were: DLBCL, 0.19μM (range 0.07-12.68); ALCL, 0.48μM (0.04-9.1); SMZL, 0.16μM (0.1-0.24); MM, 0.45μM (0.06-0.7); MCL, 2μM (1.22- &amp;gt;15). There were apparently no IC50 differences based on the cell of origin (DLBCL) or ALK-positivity status (ALCL). Apoptosis did not appear as the main effect of the drug, being not observed in 11 cell lines treated with the IC50 defined by MTT test after 72-hour exposure. However, OTX105 determined a dose-dependent G1 cell cycle arrest in 12/12 cell lines (DLBCL, MM and ALCL), and an increased percentage of senescent cells in 3/3 sensitive cell lines (DLBCL and ALCL). MYC mRNA was suppressed in a dose-dependent manner in 4/5 DLBCL, 4/4 ALCL and 2/2 MM cell lines. Down-regulation was usually seen within 1h. Real-time PCR showed that MYC and also NFKB target genes were affected. Gene expression profiling (GEP), using the Illumina HumanHT-12 v4 Expression BeadChip array, was done in 3 sensitive DLBCL cell lines, exposed to DMSO or OTX015 (0.5μM) for 4h and 8h. MYC was the most down-regulated gene. Functional annotation of the down-regulated genes identified an over-representation of genes involved in RNA and DNA metabolism and cell cycle, putative MYC target genes and transcripts reported as down-regulated after treatment with aminopeptidase inhibitors and HDAC-inhibitors. Up-regulated transcripts were enriched of genes coding for proteins involved in chromatin structure, as well as putative MYC target genes and transcripts reported as up-regulated after treatment with HDAC-inhibitors, demethylating agents or aplidine. Also, GEP signature was similar to what reported for the BRD-inhibitor JQ1. In conclusion, OTX015 showed in vitro anti-tumoral activity in a large series of mature lymphoid neoplasms. The activity was largely cytostatic, with cell cycle G1 arrest and induction of senescence. Down-regulation of MYC and its putative targets appeared as the main effect, but it might not be the only mechanism of action, since a few cell lines did not appear to down-regulate MYC after exposure to OTX015, which also induced down-regulation of NFKB target genes and modulation of transcripts similar to what observed with HDAC-inhibitors. The compound appears worth of further investigation as a new promising therapeutic agent in lymphomas. Citation Format: Paola Bonetti, Michela Boi, Elena Bernasconi, Andrea Rinaldi, Ivo Kwee, Eugenio Gaudio, Maurilio Ponzoni, Maria Grazia Tibiletti, Anastasios Stathis, Eugenia Riveiro, Giorgio Inghirami, Emanuele Zucca, Francesco Bertoni. The BRD-inhibitor OTX015 affects proliferation and gene expression of cells derived from mature lymphoid neoplasms. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1017. doi:10.1158/1538-7445.AM2013-1017

Abstract 3538: Genetic biomarkers for risk stratification of patients with peripheral T-cell lymphoma.

Abstract Background: Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of generally aggressive malignancies, with 5-year overall survival (OS) rates of ∼35%. Only ALK translocations, which define ALK-positive anaplastic large T-cell lymphoma (ALCL), have emerged as a genetic biomarker predicting favorable outcome following conventional chemotherapy (e.g. CHOP). Using next-generation sequencing, we discovered additional recurrent chromosomal translocations in PTCLs involving either the DUSP22 locus on 6p25.3 or TP63 on 3q28. The purpose of this study was to evaluate the prognostic utility of combined testing for both these events in PTCL patients. Methods: We examined the clinicopathologic features of 134 systemic PTCLs using WHO criteria, including 49 ALCLs, 23 angioimmunoblastic PTCLs, 50 PTCLs of “not otherwise specified” type, and 12 PTCLs of other subtypes. Immunohistochemistry was used to determine ALK expression, an established surrogate for ALK translocations in ALCL. Fluorescent in situ hybridization (FISH) was performed to detect translocations of DUSP22 or TP63 in all cases. OS was plotted using the Kaplan-Meier method. Comparisons were made using the log-rank test. Results: There were 83 males and 51 females, with a mean age of 58 years (range, 6 to 90 years). Median OS for all patients was 22 months (5-year OS, 36%) with a median follow-up of 24 months (range, 0.1 to 354 months). Translocations of DUSP22, TP63, and ALK were mutually exclusive. Patients with ALK-positive ALCL (n=17) had a median OS of 176 months (median follow-up, 68 months; 5-year OS, 69%). Despite being ALK-negative, cases with translocations of DUSP22 or TP63 shared pathologic features with ALCL. Median OS was not reached in patients with DUSP22 translocations (n=7; median follow-up, 88 months; 5-year OS, 100%). Patients with tumors harboring TP63 translocations (n=9) had a median OS of 13 months (all dead at 76 months; 5-year OS, 11%). Patients with none of these abnormalities (n=101) had a median OS of 17 months (median follow-up, 13 months; 5-year OS, 29%). Differences in OS among these groups were highly significant (p=0.0002). Conclusions: PTCLs with DUSP22 translocations had a favorable prognosis similar to ALK-positive ALCLs. In contrast, TP63 were associated with very poor prognosis. FISH for these biomarkers is a promising tool for risk stratification, particularly since both translocations occurred in cases with overlapping pathologic features. PTCLs with DUSP22 translocations may represent a genetically defined subset of ALK-negative ALCLs. Like patients with ALK-positive ALCLs, these patients may not derive additional benefit from intensified up-front strategies such as early transplantation. Patients with none of these abnormalities comprised 75% of patients studied and had an intermediate prognosis, indicating the need for additional biomarkers in this group to improve risk stratification. Citation Format: Edgardo R. Parrilla Castellar, George Vasmatzis, Ryan A. Knudson, Rhett P. Ketterling, Karen L. Grogg, William R. Macon, Mark E. Law, Stephen M. Ansell, Ahmet Dogan, Andrew L. Feldman. Genetic biomarkers for risk stratification of patients with peripheral T-cell lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3538. doi:10.1158/1538-7445.AM2013-3538

Primary anaplastic large T cell lymphoma of central nervous system

Background Primary anaplastic large T cell lymphoma (ALCL) of central nervous system (CNS) can occur in people of all ages, and is usually unrelated with immunodeficiency. It is often misdiagnosed as meningitis, especially tuberculous meningitis, on clinical practice and imaging examination. In pathological diagnosis, the morphological changes of primary ALCL of CNS are similar to the systemic ALCL and the anaplastic lymphoma kinase⁃1 (ALK⁃1) can be positive or negative. Being misdiagnosed as meningitis, hormone therapy with glucocorticoid before biopsy is always used, and massive necrosis and a lot of histocyte proliferation and phagocytosis can be found under histological findings. Therefore, when the material is not enough, primary ALCL of CNS is often misdiagnosed as cerebral infarction or malignant histocytosis and so on. This paper reports a case of primary ALCL of CNS and makes a review of relevant literature, so as to summarize the clinical manifestations and elevate the recognition of clinicians and pathologists on this disease. Methods and Results A 12⁃year⁃old boy was admitted because of fever, worsening headache, numbness and weakness of right limbs. MRI showed local gyri swelling and abnormal enhancement of pia mater in the right parietal lobe, expanding to the right temporal lobe, and pia mater enhancement in the left parietal lobe. The right temporo⁃parietal lobe lesion biopsy revealed irregularly shaped tumor cells of large size, rich and eosinophilic cytoplasm and horseshoe⁃shaped or kidney⁃shaped nuclei. Immunohistochemical examination showed tumor cells positive for CD3, CD45RO, CD30, ALK⁃1 and epithelial membrane antigen (EMA), and negative for CD20 and CD79a. Conclusion Primary ALCL of CNS is an extremely rare tumor which is usually misdiagnosed as meningitis according to clinical and imaging examinations. Therefore, for those patients who are considered as meningitis but with poor treatment effect and replase of illness, brain tissue biopsy, which is an important means for diagnosis, or cerebrospinal fluid cytologic examination, should be carried out as soon as possible.

Primary Anaplastic Large Cell Lymphoma of the Nasal Cavity: A Case Report

Introduction: Anaplastic large-cell lymphoma occurring in the nasal cavity is a rare disease. The latest World Health Organization (WHO) Classification recognizes three distinct subtypes: primary systemic anaplastic lymphoma kinase positive been our case, primary systemic anaplastic lymphoma kinase negative and primary cutaneous types. Through this case study, we focus on the clinical presentation, treatment and prognostic characteristics of this pathology.Case Presentation: We report the case of a patient aged 32 years, who presented for seven months a runny nose associated with swelling of the face on the left side, without peripheral lymphadenopathy or general signs. A Blondeau scanner objectified a total filling of the frontal and left maxillary sinus, and a filling of the left nasal cavity. Complete resection of the tumor was performed. Histological examination was in favor of anaplastic large T-cell lymphoma anaplastic lymphoma kinase positive. The patient was stage IE according to Ann Arbor classification, with an International Prognostic Index estimated at one. Thus, the patient received six cycles of CHOP chemotherapy. Currently, he is in good loco-regional control with a decline of three months.Conclusion: The rarity of this case lies partly in the lymphomatous localization in the nasal cavity, and secondly in the anaplastic histology. It poses a diagnostic problem. So, we conclude that in case of any symptom of nasal cavities, it is necessary to explore and possibly biopsy if tumor, before surgery, because lymphomas are chemosensitive disease.

Immunohistochemical detection of CD3 in T-cell lymphomas: superior sensitivity of rabbit monoclonal 2GV6 antibody compared to mouse monoclonal F7·2·38 antibody

Immunohistochemical detection of cluster of differentiation 3 (CD3) expression is important for the diagnosis of peripheral T-cell and NK-cell lymphomas. We compared CD3 staining intensity and percentage of CD3-positive cells in 28 T-cell lymphomas was compared using mouse anti-human CD3 antibody (clone F7·2·38) and rabbit anti-human CD3 antibody (clone 2GV6). Analysis was performed on tissue microarray sections containing 12 peripheral T-cell lymphomas unspecified, 4 angioimmunoblastic T-cell lymphomas, 6 adult T-cell leukemia/lymphomas, and 6 anaplastic large T-cell lymphomas. Compared to mouse antibody, CD3 staining intensity and the fraction of CD3-positive cells increased significantly with rabbit antibody in the vast majority of the T-cell lymphomas analyzed. The mean staining intensity of positive cells (weak: +1; moderate: +2; strong: +3) of all 28 lymphomas rose from 2·1 with mouse antibody to 2·5 with rabbit antibody. Notably, the mean fraction of strongly positive cells (+3) was 17·7% with mouse antibody and increased considerably to 49·1% with rabbit antibody. In addition, there was an overall 8% increase in CD3-positive cells if rabbit antibody was used. The results show that detection of CD3 expression in T-cell lymphomas with rabbit antibody represents an improved standard by increasing sensitivity and staining intensity.