AbstractAnaplastic Large Cell Lymphoma Research Articles

Leukemic Presentation of Anaplastic Large Cell Lymphoma: A Diagnostic Challenge Mimicking T-Cell Prolymphocytic Leukemia

Abstract Anaplastic large cell lymphoma (ALCL) is a rare systemic T-cell neoplasm that typically involves nodal and extranodal sites and is further classified into 2 subgroups: anaplastic lymphoma kinase (ALK-) positive (ALK+) and ALK-negative. Leukemic presentation of ALCL is extremely rare. Most cases with leukemic presentation are the small-cell variant of ALK+ ALCL, are positive for the t(2;5)(p23;q35) translocation, and are associated with a poor prognosis. We report a case of ALK+ ALCL that presented with a high white blood cell count and morphologic and phenotypic features resembling T-cell prolymphocytic leukemia.

BRG1 and NPM-ALK Are Co-Regulated in Anaplastic Large-Cell Lymphoma; BRG1 Is a Potential Therapeutic Target in ALCL.

Simple SummaryT-cell lymphoma is a cancer of the immune system. One specific sub-type of T-cell lymphoma is a malignancy called anaplastic large cell lymphoma (ALCL), which is distinct from the other forms, as in general, it has a better prognosis. Research conducted to understand why ALCL develops has shown that a specific genetic event occurs, whereby a new protein is created that drives tumour growth. This protein is called nucleophosmin–anaplastic lymphoma kinase (NPM-ALK). Our research, described here, shows that NPM-ALK regulates another protein, called BRG1, to drive proliferation of tumour cells. In turn, when the gene that leads to expression of BRG1 is inactivated, the tumour cells die. These data suggest that therapeutic targeting of BRG1 might be a novel therapy for this form of cancer.Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy driven in many cases by the product of a chromosomal translocation, nucleophosmin–anaplastic lymphoma kinase (NPM-ALK). NPM-ALK activates a plethora of pathways that drive the hallmarks of cancer, largely signalling pathways normally associated with cytokine and/or T-cell receptor-induced signalling. However, NPM-ALK is also located in the nucleus and its functions in this cellular compartment for the most part remain to be determined. We show that ALCL cell lines and primary patient tumours express the transcriptional activator BRG1 in a NPM-ALK-dependent manner. NPM-ALK regulates expression of BRG1 by post-translational mechanisms dependent on its kinase activity, protecting it from proteasomal degradation. Furthermore, we show that BRG1 drives a transcriptional programme associated with cell cycle progression. In turn, inhibition of BRG1 expression with specific shRNA decreases cell viability, suggesting that it may represent a key therapeutic target for the treatment of ALCL.

Pediatric Anaplastic Large Cell Lymphoma with Concomitant Involvement of Spine and Central Nervous System: A Case Report and Review of Literature

Anaplastic large cell lymphoma (ALCL) is a histological subtype of non-Hodgkin lymphoma, largely characterized by anaplastic lymphoma kinase (ALK) positivity, resulting from the chromosomal translocation t(2;5). We report a pediatric case of ALK-positive ALCL with primary concomitant involvement of bone and central nervous system (CNS); thereafter, a literature review about pediatric primary bone and primary CNS ALCL was conducted. According to the analyzed data, our case is unique because it is characterized by the contemporary involvement of the spine and CNS. During and after chemotherapy, our patient was monitored by detecting minimal residual disease (MRD) through the analysis of fusion transcript nucleophosmin-ALK. MRD assessment, not only in bone marrow but also in peripheral blood, seems to be a very powerful tool for predicting the prognosis of pediatric ALCL patients, as already described in the literature. Moreover, as shown in our case, it could be used during the follow-up for early recognition of relapse.

Diagnosing a Rare Cutaneous Presentation of Anaplastic Large Cell Lymphoma

Anaplastic Large Cell Lymphoma (ALCL) is a rare aggressive neoplasm. Rapid and progressive lymphadenopathy is common. Due to its aggressive nature, two-thirds of initial presentations are in stage III or IV. Multifocal disease that is primarily cutaneous is rare and extracutaneous spread of the cancer occurs in up to 13 percent of cases. In this case, a patient with systemic ALCL went undiagnosed for two months across three hospitalizations. A 33-year old male presented with multiple cutaneous lesions that had erupted bilaterally on his lower extremities and a fever which was unresponsive to over the counter medication. The patient required three hospitalizations and extensive work up before a diagnosis of Anaplastic Lymphoma Kinase (ALK) -negative CD30+ T-cell lymphoma was made by skin and lymph node biopsy. Diagnosis was delayed due to this patient’s uncommon presentation, the broad list of differential diagnoses, inaccuracies in biopsy, and communication delays from multiple hospital visits. This patient had aggressive ALCL and passed away during the first week of chemotherapy treatment. When there is a concern for malignancy, properly performed biopsies are important to collect from appropriate sites with non-necrotic tissue. Additionally, this case demonstrates the consequences of inadequate communication during handoff between transfer centers. It is important to have a broad differential diagnosis as well as prompt investigation and constant communication between all providers involved when a patient presents with abnormal and aggressively progressing symptoms.

Preclinical Evaluation of Gilteritinib on NPM1-ALK-Driven Anaplastic Large Cell Lymphoma Cells.

Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin lymphoma. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL cases express the nucleophosmin 1 (NPM1)-ALK fusion gene as a result of t(2;5) chromosomal translocation. The homodimerization of NPM1-ALK fusion protein mediates constitutive activation of the chimeric tyrosine kinase activity and downstream signaling pathways responsible for lymphoma cell proliferation and survival. Gilteritinib is a tyrosine kinase inhibitor recently approved by the FDA for the treatment of FMS-like tyrosine kinase mutation-positive acute myeloid leukemia. In this study, we demonstrate for the first time gilteritinib-mediated growth inhibitory effects on NPM1-ALK-driven ALCL cells. We utilized a total of five ALCL model cell lines, including both human and murine. Gilteritinib treatment inhibits NPM1-ALK fusion kinase phosphorylation and downstream signaling, resulting in induced apoptosis. Gilteritinib-mediated apoptosis was associated with caspase 3/9, PARP cleavage, the increased expression of proapoptotic protein BAD, and decreased expression of antiapoptotic proteins, survivin and MCL-1. We also found downregulation of fusion kinase activity resulted in decreased c-Myc protein levels. Furthermore, cell-cycle analysis indicated gilteritinib induced G0-G1-phase cell-cycle arrest and reduced CD30 expression. In summary, our preclinical studies explored the novel therapeutic potential of gilteritinib in the treatment of ALCL cells expressing NPM1-ALK and potentially in other ALK or ALK fusion-driven hematologic or solid malignancies. IMPLICATIONS: Our preclinical results explore the use of gilteritinib for the treatment of NPM1-ALK-driven ALCL cells and pave a path for developing future clinical trials. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/5/913/F1.large.jpg.

Abstract PO-17: Microphysiologic model of ALK+ anaplastic large cell lymphoma and vascular interactions predicts drug efficacy in a 3D microfluidic chip

Abstract Anaplastic large-cell lymphoma (ALCL) initially responds well to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) therapies (e.g., crizotinib); however, resistance appears once the treatment is concluded and persistent cells are not eradicated. ALCL preferentially grows around blood and lymphatic vessel in the lymph node, and our preliminary data have shown that CCL19/21-CCR7 chemokine-receptor signaling axis might be involved in TKI resistance of ALCL cells. To investigate this mechanism, we developed a microphysiologic model of ALCL interacting with a 3D vasculature using a microfluidic chip. Microfluidic technology has the potential to impact cancer diagnosis and therapy by overcoming the limitations of 2D culture. These ex vivo models are able to uncover the continuous interactions and chemokine signaling that exist between cells of the tumor microenvironment (TME) and evaluate the preclinical efficacy of novel and personalized cancer therapeutics. Two ALK+ ALCL cell lines (COST and Karpas299) were knocked out by CRISPR/Cas9 of the CCR7 receptor, transduced with GFP for microscopic visualization. A commercial microfluidic chip with a central gel channel, flanked by two fluidic media channels, was used to develop the model. A collagen hydrogel (2.5 mg/mL) was injected into the central region of the 3D chip, incubated in sterile humidity chambers, and channels were hydrated with RPMI. 50 µL of 3x106 cells/mL human umbilical vein endothelial cells (HUVECs) suspension was injected twice on the fluidic channel, and the chip was rotated twice to create a confluent hollow-lumen 3D macrovessel. Then, 2x105 cells/mL ALCL cells were added inside the 3D macrovessel. Medium was refreshed daily, supplemented +/- 300 nM crizotinib (ALK TKI). Image analysis was performed using a confocal microscope. The model consisted of a well-formed perfusable macrovessel with ALCL cells flowing inside and interacting with HUVECs. ALCL viability was evaluated with a luminescent readout assay after 3 days of interactions with HUVECs. Strikingly, ALCL cells cultivated within the vasculature showed marked resistance to treatment with ALK TKI compared to cells cultivated in the absence of vessels. CCR7 KO cells showed decreased viability and decreased perivascular localization compared to wild-type control cells. The results suggest that the 3D ALCL-vascular microphysiologic model is a feasible platform with great potential to unveil the molecular mechanisms of drug resistance in a complex TME. The presence of macrovessels was sufficient to induce resistance to ALK TKI, which was decreased in CCR7 KO cells. These data indicate that CCL19/21 and possibly other cytokines produced by vessels generate survival signals in ALCL cells treated with ALK TKI. This physiologically relevant ALCL-vascular model offers a tool to genetically dissect the TME contribution to drug resistance, predict more reliably therapeutic vulnerabilities, and recapitulate patient-specific cell-cell interactions. Citation Format: Marco Campisi, Claudia Voena, Ines Mota, Enrico Patrucco, Roger Dale Kamm, Roberto Chiarle. Microphysiologic model of ALK+ anaplastic large cell lymphoma and vascular interactions predicts drug efficacy in a 3D microfluidic chip [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-17.

Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma presenting as diffuse pulmonary infiltrates.

Anaplastic large cell lymphoma has a characteristic sinusoidal growth pattern that presents as pulmonary lymphangitic involvement causing respiratory distress. Recognition and prompt treatment of this entity can result in dramatic response to therapy.

Chronic fatigue syndrome in patient with ALK-positive anaplastic large cell lymphoma

Anaplastic large cell lymphoma (ALCL) is a rare type of NHL, and more common subtypes of T-cell lymphoma, we report a case of ALK-positive anaplastic large cell lymphoma preceded by long history of chronic fatigue syndrome. A 75-year-old patient recently developed cervical lymphadenopathy, pyrexia, weight loss, night sweats. Chest computed tomography scan showed widening of the superior mediastinum. Magnetic resonance imaging of the spine demonstrated spinal effacement at T7 raising the risk of cord compression. A lymph node biopsy showed positive anaplastic large cell lymphoma. Patient was treated with standard first-line chemotherapy proceed to the autologous stem cell transplantation.

Favorable outcomes and reduced toxicity with a novel vinblastine-based non-high dose methotrexate (HDMTX) regimen (modified MCP-842) in pediatric anaplastic large cell lymphoma (ALCL): experience from India

Anaplastic large cell lymphoma (ALCL) is a rare form of non-Hodgkin lymphoma (NHL) in children. Most treatment regimens include high-dose methotrexate (HDMTX), which is logistically difficult to administer in resource-limited settings. We evaluated the outcomes of pediatric ALCL patients treated on a uniform protocol (Modified Multicentric Protocol, MCP-842 regimen) at our hospital between January 2005 and December 2016. Of the 68 patients who received treatment on the Modified MCP842 protocol, 46 patients are alive in remission, 11(16%) had disease progression, 9(13%) relapsed after achieving remission, and 5(7%) had treatment-related mortality (TRM). Seventeen of 20 relapsed/progressed patients subsequently expired. With a median follow-up of 55 months (range 2–165 months), the 4-year event-free survival (EFS) and overall survival (OS) are 63% (95% CI of 50–73%) and 70%(95% CI of 57–79%), respectively. An indigenous protocol using vinblastine (without HDMTX and steroids) is feasible in a resource-limited setting and achieves outcomes comparable to regimens incorporating HDMTX, with lower toxicity.

The DNA Helicase Hells Is a New Unconventional Player in ALK- Anaplastic Large Cell Lymphoma Biology

Anaplastic Large Cell Lymphoma (ALCL) is an aggressive subtype of T-cell lymphoma. ALCLs are stratified based on the presence of anaplastic lymphoma kinase (ALK) translocations. ALK negative (ALK-ALCLs) are heterogeneous subtypes characterized by higher aggressiveness and poorer outcome than ALK+ALCL. The molecular and genetic asset of ALK-ALCLs has recently begun to emerge (i.e. JAK/STAT3 activating mutations, DUSP22, TP63, TP53 and IRF4 rearrangements), but an exhaustive picture of the molecular drivers leading to ALK-ALCLs transformation, progression, and immune evasion is still lacking. Long non coding RNAs (LncRNAs) are transcripts longer than 200 nucleotides with different regulatory functions ranging from transcriptional regulation to structural functions, which are emerging as relevant players in many cellular processes including cancer. Using deep RNA-sequencing profiling combined with de novo transcriptome assembly, we explored and validated the potential contribution of non-coding RNAs in a large series of ALCLs. 24 lncRNAs were found specifically enriched in ALCL samples. Among these, a 70Kb chromatin associated lncRNA (BlackMamba) was identified as preferentially associated with the ALK-ALCLs subtypes and was shown to be a target of the JAK/STAT3 signaling. BlackMamba was overexpressed in ALK-ALCL patient samples as well as in patient-derived tumor xenograft (PDTX) models. Its shRNA mediated knockdown (KD) in ALK-ALCL cells reduces cell proliferation and clonogenicity. BlackMamba KD cells also showed a remarkable increase in the number of multinucleated cells (without ploidy alteration) providing evidence that this lncRNA may be required for correct cytokinesis. To better characterize the role of BlackMamba we performed RNA-sequencing profiling in BlackMamba KD ALK-ALCL cells showing that this lncRNA affects primarily the expression of genes involved in cytoskeleton organization and remodeling. Noticeably, the DNA-helicase HELLS emerged among the most relevant BlackMamba target gene in ALK-ALCL cells and patients. Loss of BlackMamba causes profound reduction of HELLS concomitant with a reorganization of chromatin markers (reduction of K4me3 and increase of K27me3) in the HELLS locus. To test whether HELLS enforces BlackMamba-mediated transcription, we silenced HELLS by shRNA approach in ALK-ALCLs. Noticeably, loss of HELLS led to a reduction in cell growth, a delay in the duplication rate and a dramatic drop of clonogenicity potential of ALK-ALCL cells. This phenotype was also associated with an increased number of multinucleated cells, phenocopying the BlackMamba KD cells. We also showed that, HELLS KD causes expression changes in a subset of cytoskeleton-related genes previously identified as BlackMamba targets confirming that HELLS is a crucial mediator of BlackMamba function. Indeed, ectopic over-expression of HELLS in BlackMamba KD cells rescued the cell growth defects induced by the loss of lncRNA mitigated the polynucleation phenotype and restored the baseline expression of BlackMamba target genes. Being established that lncRNAs affect gene expression by recruiting chromatin remodeling complexes to target promoters or enhancers we also investigated whether BlackMamba may associates with HELLS and dictates its chromatin positioning in ALK-ALCL cells. By RNA-immunoprecipitation (RIP) we showed that HELLS binds to BlackMamba at in two distinct regions the 3'-end of the lncRNA. Next, by Chromatin Immunoprecipitation (ChIP) we demonstrated that HELLS is associated to BlackMamba target gene promoters exclusively in ALK-ALCLs in which BlackMamba is expressed. Collectively, these data demonstrate the existence of a new lncRNA-dependent mechanism controlling the recruitment of HELLS on chromatin sites and its expression in lymphomas. The axis BlackMamba-HELLS sustains the neoplastic phenotype of ALK-ALCL representing a potential vulnerability of ALCL cells. Disclosures Merli: Mundipharma: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Janssen: Honoraria; Takeda: Honoraria, Other: Travel Expenses; Gilead: Honoraria.

Zastosowanie brentuksymabu vedotin w trzeciej linii leczenia ch orego na pierwotnie opornego układowego chłoniaka anaplastycznego z dużych komórek ALK(–)

Anaplastic large cell lymphoma (ALCL) is rare hematological malignancy and subtype of mature T-cell lymphoma. Most patients with diagnosed systemic ALCL (sALCL) respond to common first-line chemotherapy based on antracycline (CHOP [doxorubicin, vincristine, prednisone], or CHOEP [doxorubicin, vincristine, etoposide, prednisone]). Long-term treatment results depends on a subtype and other prognostic factors. About 40–65% patients with ALCL ALK(–) develop reccurent disease. High-dose chemotherapy and autologous hematopoietic stem cell trasplantation improve outcome in this group of patients. Brentuximab vedotin has shown efficacy with relapsed sALCL and enable gaining objective respones in 86% of cases.

PD-L1/PD-1 Check Point in Anaplastic Large Cell Lymphoma, ALK+: A Case Report with Immunohistochemical and Molecular Study

Anaplastic large cell lymphoma, ALK+ (ALK+ ALCL) is a T-cell lymphoma consisting of large and pleomorphic lymphoid cells, often with horseshoe-shaped nuclei, with a chromosomal translocation involving the ALK gene and expression of ALK protein and CD30. ALK+ ALCL must be distinguished from primary cutaneous ALCL and from other subtype of T-cell or B-cell lymphoma with anaplastic features and/or CD30 expression. PD-L1/PD-1 check point physiologically plays a key role in induction and maintenance of immune tolerance to self-antigens and limits normal immune response against microorganisms. PD-L1 has been demonstrated in the whole spectrum of normal hematopoietic and non-hematopoietic cells, as well as in a large variety of epithelial cells. Moreover, it is also very commonly expressed by a large number of malignant cell types of epithelial and hematopoietic cell origin, and its activation is one of the major mechanisms exerted by neoplastic cells to evade elimination by the host immune system. Here we report a case of an ALK+ ALCL, with confirmed FISH rearrangement of ALK gene, PD-L1-positive and discuss the molecular mechanism involved in its immunohistochemical profile.

Breast Implant-Associated Anaplastic Large Cell Lymphoma

Anaplastic large cell lymphoma is a rare disease associated with breast implants. We present the case of a woman who had had breast augmentation and multiple revisions over a period of 13 years and presented with recurrent fluid collections. The cause was determined to be anaplastic large cell lymphoma, which required removal of the implants, capsulectomy, and evaluation by a medical oncologist. The patient was not found to have metastatic disease on imaging studies. Breast implant–associated anaplastic large cell lymphoma is a poorly understood disease entity, and optimal treatment is unclear.

Infant ALK-Positive Anaplastic Large Cell Lymphoma with Unfavourable Prognostic Features and Neutrophilia at Presentation

Anaplastic large cell lymphoma (ALCL) is an uncommon form of non-Hodgkin lymphoma in younger patients, accounting for less than 15% of cases. It is exceedingly rare in infants, with a median age at diagnosis of 12 years. Various treatment strategies have been studied in pediatric ALCL, however the long-term event free survival is approximately 70% regardless of treatment approach. We present the case of six month old infant with anaplastic lymphoma kinase (ALK) positive ALCL with unfavourable prognostic features. We elected to treat with upfront brentuximab in addition to combination chemotherapy. This achieved a clinical and molelcular remission of the disease. The treament was well tolerated.

Abstract 3144: Development of immunotherapy for anaplastic large cell lymphoma (ALCL) using CSF1R retargeted human T lymphocytes

Abstract Anaplastic large cell lymphoma (ALCL), a type of T/null-cell lymphoma, represents about 20-30% of paediatric lymphomas and has an aggressive clinical course with frequent relapse. Recently, high-level expression of CSF1R on malignant cells in ALCL has been linked to shorter progression free survival, providing a rationale to test adoptive C28ζ-mediated T-cell therapy. This approach encompasses the genetic modification of T-cells to express a chimeric antigen receptor (CAR) named C28ζ, a fusion receptor coupling the recognition of CSF1R on the tumour cell surface to the delivery of tailored T-cell activation signal provided by a fused CD28+CD3ζ endodomain. To optimize this approach for human translation, the C28ζ CAR was co-expressed with the chimeric cytokine receptor 4αβ (combination termed “C4”), which allows for selective expansion and enrichment of CAR-transduced T-cells using IL-4. PBMCs of healthy donors were isolated and activated using anti-CD3/CD28 beads. Following retroviral T-cell transduction and 14 days expansion of C4+ T-cells in the presence of IL-4, co-cultures with a panel of ALCL cell lines (2 ALK positive and 2 ALK negative ALCL cell lines) were set up to test C4 efficacy in vitro. Successful re-targeting of C4+ T-cells was confirmed by monitoring target cell destruction. Conditioned media was collected and analysed for IFN-γ and IL-2 production. Cytotoxicity, cytokine release and T-cell proliferation data demonstrated Ag-specific activation of the C4+ cells, which contrasted with T-cells expressing a control CAR with truncated endodomain. This data provides for the first time the basis for successful application of CAR-based immunotherapy against CSF1R-expressing malignancies. Citation Format: Daniela Achkova, James Spicer, John Maher. Development of immunotherapy for anaplastic large cell lymphoma (ALCL) using CSF1R retargeted human T lymphocytes. [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 3144. doi:10.1158/1538-7445.AM2015-3144

Abstract 776: Pre-clinical evaluation of ceritinib in anaplastic large cell lymphoma

Abstract Anaplastic large cell lymphoma (ALCL) is an aggressive CD30+ T-Cell lymphoma that accounts for 2-8% and 10-15% non-Hodgkin lymphomas in adults and children, respectively. The currently used standard therapy for anaplastic lymphoma kinase (ALK, a member of insulin receptor superfamily) positive ALCL has limited effectiveness, resulting in a substantial percentage of cases with poor outcome, either failing to enter remission or relapsing within a few months after starting the treatment. Thus, there is a clear unmet clinical need for developing novel, effective and safer therapeutic strategies for ALCL. Nucleophosmin 1 (NPM1) is a nucleolar phosphoprotein, which functions as a molecular chaperone for proteins and nucleic acids. Approximately 50% of ALCL cases are positive for the NPM-ALK fusion chimera generated by the t(2;5) chromosomal translocation. The oligomerization domain of NPM1 in the fusion protein NPM-ALK, mediates the ligand-independent dimerization of chimeric protein, which results in constitutive activation of the chimeric tyrosine kinase activity leading to downstream signaling pathways responsible for the oncogenicity. Ceritinib is a second generation FDA approved ALK inhibitor for the treatment of ALK-positive metastatic non-small cell lung cancer. Here we report the first preclinical evaluation of ceritinib growth inhibitory effects on ALK-positive ALCL cells. The NPM-ALK expressing ALCL model cell line SUDHL-1 used in our studies. Treatment with ceritinib significantly induced apoptosis dose dependently (10-50nM) in ALCL cells associated with poly (ADP-ribose) polymerase cleavage. Mechanistically, ceritinib blocked phosphorylation of ALK and its downstream signaling effectors STAT3, AKT and ERK1/2. Cell cycle analysis by flow cytometry showed that ceritinib induced G0/G1 arrest with concomitant decrease in the percentage of cells in S and G2/M phases which was associated with decreased cyclin D1 and increased p21 expression. ALCL is also characterized by strong expression of the cytokine receptor CD30 (a member of the TNF receptor family). CD30 stimulation leads to NF-kB activation and the induction of anti-apoptotic mechanisms. In response to ceritinib treatment, flow cytometry data showed that reduced CD30 expression in a dose dependent manner. Altogether, these pre-clinical results demonstrate that ceritinib induces apoptosis in ALCL cells by inhibiting ALK downstream signaling cascade and support the rational for in vivo testing of ceritinib for the treatment of ALK positive lymphomas. Citation Format: Siddhartha Ganguly, Sudhakiranmayi Kuravi, Satyanarayana Alleboina, Brandon Weckbaugh, Deepti Satelli, Jensen Roy, Scott Weir, Joseph McGuirk, Ramesh Balusu. Pre-clinical evaluation of ceritinib in anaplastic large cell lymphoma. [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 776. doi:10.1158/1538-7445.AM2015-776

Abstract 2219: STAT3 network dissection in ALK positive Anaplastic Large Cell Lymphomas

Abstract Anaplastic large cell lymphoma (ALCL) represents a category of T-cell Non-Hodgkin Lymphomas characterized by marked cellular pleomorphism, and expression of CD30. Two systemic forms of ALCL are defined by the presence or absence of chromosomal translocations involving the Anaplastic Lymphoma Kinase (ALK) gene at 2p23 locus. Among several pathways triggered by ALK signaling, it has been widely shown that the constitutive activation of STAT3 is strictly required for ALK-mediated transformation and survival. To discover essential mediators of STAT3 oncogenic activity that may represent feasible targets for ALCL therapies, we performed gene and miRNA expression profiling experiments in association with functional validation approaches. The transcriptome of STAT3 was analysed in ALK positive ALCL cell lines using a tightly controlled time course experimental condition, in which the STAT3 signalling was abrogated by an inducible short hairpin RNA (shRNA). Gene expression profiling analysis identified a selected number of genes (1730) specifically modulated by STAT3 silencing. A significant overrepresentation of putative STAT3 binding sites was found in regulatory regions of early down-regulated genes. Functional studies using a shRNA lentiviral library established that Interferon Regulatory Factor-4 (IRF4) targeting specifically affect cell viability of ALK+ ALCL cells. In contrast, forced expression of IRF4 partially rescued STAT3 knock-down sustaining the survival of ALK+ cells. In a parallel experiment, genome-wide miRNA expression profiling identified 48 miRNAs concordantly modulated by the inducible knock down of ALK and STAT3. Among these, we demonstrated that expression of miR-17∼92 cluster significantly reverted STAT3 deprivation, sustaining both proliferation and survival of ALCL cells. In conclusion, genes and miRNA expression profiling associated to functional screenings allowed the identification of new biologically relevant targets for ALK+ALCL. We speculate that IRF4 and miR-17∼92 cluster are involved in the lymphomagenesis of STAT3+ ALCL, and that their inhibition might represent an alternative avenue to interfere with ALK signaling in Anaplastic Large Cell Lymphomas. Citation Format: Elisa Spaccarotella, Aldi Pupuleku, Elisa Pellegrino, Cecilia Bandini, Manuela Ferracin, Daniela Cantarella, Andrea Rinaldi, Paolo Provero, Ferdinando Di Cunto, Enzo Medico, Francesco Bertoni, Giorgio Inghirami, Roberto Piva. STAT3 network dissection in ALK positive Anaplastic Large Cell Lymphomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2219. doi:10.1158/1538-7445.AM2014-2219

Cutaneous anaplastic large cell lymphoma in HIV exceptional case in Algeria

Anaplastic large cell lymphoma is a rare and account for 10 % of cases of cutaneous lymphoma T is characterized by the presence of anaplastic tumor cells, pleomorphic or immunoblastic for the majority of them (over 75 %) antigen CD30 . It is in the form of single or multiple nodules or as patches in adult patients.

Anaplastic large cell lymphoma presenting with a leukemoid reaction in infants

Anaplastic large cell lymphoma, ALK-(+), is an aggressive type of T-cell lymphoma characterized by large cells with bizarre morphologic features, prominent sinusoidal invasion and expression of CD30 and ALK antigens. The majority of patients present with advanced clinical stage have nodal and extranodal involvements and complain of B-symptoms. The disease is most frequent in the first three decades of life with a median age of 35 years. The development of ALCL-ALK(+) in infants is very rare, with only very few case reports in the literature. We report two cases of male infants who presented with fever and a progressive leukemoid reaction. The leukocytosis was mainly neutrophilic and monocytic without lymphoma cells, and in one case the neutrophils were severely toxic. Extensive workup for infections and acute leukemia did not reveal any cause. The diagnosis of ALCL-ALK(+) was established after demonstration of enlarged neck and abdominal lymph nodes in the first and second patients, respectively, when they underwent histologic evaluation. Although rare, our cases show that ALCL-ALK(+) is still a likely cause of a leukemoid reaction in infants in a manner similar to infectious diseases, and a survey of lymph nodes enlargement would prevent delay in diagnosis.

Primary Anaplastic Large Cell Lymphoma of the Lung in a Child

Anaplastic large cell lymphoma [ALCL] is a rare disease in children accounting for 10-15% of all childhood non-Hodgkin lymphomas. Primary ALCL characteristically involves the lymph node/skin and is a rare malignancy in the lung accounting for only 0.3% of primary lung neoplasms. A case of primary ALCL of the lung in a 5-year old boy is discussed detailing …