ALK Anaplastic Large Cell Lymphoma Research Articles

T-Cell Lymphomas in Mexico: Experience of a Third Level Reference Hospital

Introduction ——- Mature T-cell lymphomas have a global incidence ranging from 9.3% to 13.4% of the total amount of non-Hodgkin lymphomas worldwide. However, in Asian and South and Central America countries, incidence has been reported up to 20%. This suggests that there is a wide range of environmental and racial factors that modify the frequency of T-cell lymphomas and its subtypes. The common subtypes of these lymphomas also have been reported to vary greatly across the world. Studies have placed the NK/T cell lymphoma as the most prevalent T-cell lymphoma of Mexico, with 40% of all T cell lymphomas diagnosed, while the US reported frequency ranges in the 5 to 6%. Our objective is to report our experience in a third level reference Hospital in northeast Mexico.Materials and Methods —- A retrospective and observational study was conducted. Utilizing the database manager Pathox, we collected all the cases of patients diagnosed with lymphoma from January 2010 to January 2017. We included in the study all cases that were diagnosed with a variant of T-cell lymphoma that had available material for revision. They were assigned to groups by sex, subtype of lymphoma in accordance to the World Health Organization (WHO) classification of lymphoid neoplasms 2016, and the anatomical location of the primary tumor. Data analysis was performed in the statistical programming environment R version 3.3.2. Descriptive statistics were reported as percentages, central tendency and dispersion statistics.Results ——— We found a total of 771 lymphomas in our study. 88 of those had a diagnosis of T-cell lymphoma. The location of the primary tumor was a lymph node in 36.26% of the cases, and in the rest of the primary tumors, the skin was the most frequent location with 57.14%; the nasal and retronasal tissue followed, with 5.49%. For the subtypes, the most frequent was mycosis fungoides (MF) (29.67%) followed by Peripheric T-cell Lymphoma, Not Otherwise Specified, (PTCL, NOS) (23.08%). NK/T-Cell lymphoma nasal type, accounted for 10.99%. Anaplastic Large Cell Lymphoma (ALCL) ALK+ (4.4%), ALCL ALK - (7.69%), Angioinmunoblastic T-cell lymphoma (AITL) (2.20%) and subcutaneous Panniculitis- like T-cell lymphoma (1.1%) were also reported. The rest of the cases were reclassified into a non T-cell lymphoma or different diagnosis. Of the IHQ stains used to for diagnosis, the most commonly used were CD20, CD4, CD3, CD7 and CD8, with an average number of IHQ stains of 4.4 per case.Conclusions — Available literature places the frequency of T-cell lymphomas between 5 and 15% for developed countries, in concordance to our frequency (11.4%). For anatomic location of the primary tumor, the most frequent location was the skin (57.14%), followed by the lymph nodes (36.26%) and the nasal tissue (5.49%), while the rest distributed among the bone marrow, soft tissues, and tonsils. Frequency was not significant among males or females. Subtype frequency predominated for MF (29.67%) and PTCL, NOS (23.08%). NK/T-cell lymphomas account for only 10.99%. Our data suggests that the environmental, geographical and race factors create wide variations in the frequency of these lymphomas and their subtypes, giving way for additional studies to find and explain this variations. DisclosuresNo relevant conflicts of interest to declare.

Distribution of Lymphomas in Mexico: A Descriptive Study

IntroductionLymphomas are a heterogeneous group of hematological malignancies of which incidence, prevalence, and epidemiological factors are still not well described in the Mexican population. Most of the recent descriptive studies do not specify details of their analysis and were not based on the WHO classification of tumours. In our study we analyzed 5772 lymphomas diagnosed over a period of 10 years between 2005 and 2014, and classified them according to the 2008 WHO Classification of Tumours of Lymphoid Tissues. The aim of our study is to determine frequencies and subtypes of the main non-Hodgkin's and Hodgkin's lymphomas in a heterogeneous sample of biopsies in the Mexican population.MethodsFiles for tissue samples for lymphomas stored in 5 different hospitals in Mexico City were retrieved for re-analysis. All cases where tissue samples were available were stained with hematoxylin and eosin as well as immunostained. Analysis was performed to differentiate the main mature B-cell, T-cell, Hodgkin's, and precursor lymphoid neoplasms according to the 2008 WHO classification of tumours. Age and sex were obtained and registered from the original submitted request for pathology assessment. All stains were performed in the same laboratory and interpreted by 3 pathologists who provided a diagnosis.Results5772 neoplasms were included in this study. Of these, 4213 were mature B-cell neoplasms (73%; 95%CI 71.83 - 74.12), 888 Hodgkin's lymphomas (HL) (15%; 95%CI 14.48 - 16.34), 496 mature T-cell / NK neoplasms (9%; 95%CI 7.89 - 9.34), and 175 precursor lymphoid neoplasms (3%; 95%CI 2.62 - 3.5). Neoplasms had an even distribution between sexes, with 51% of the cases being male patients.All 4 different categories of neoplasms were further analysed and classified. Six main mature B-cell lymphomas accounted for almost 95% of our cohort. These included diffuse large B-cell lymphoma (DLBCL) (56%; 95%CI 54.39 - 57.39), follicular lymphoma (FL) (20%; 95%CI 18.92 - 21.34), mantle cell lymphoma (6.7%; 95%CI 6.02 - 7.53), marginal zone/MALT lymphoma (5.2%; 95%CI 4.59 - 5.93), chronic lymphocytic leukemia/small lymphocytic lymphoma (4.6%; 95%CI 4.01 - 5.28), and Burkitt's lymphoma (2.5%; 95%CI 2.04 - 2.98). Hodgkin's lymphomas were also classified in 6 main subtypes, with nodular sclerosis (47%; 95%CI 44.14 - 50.7) and mixed cellularity (38%; 95%CI 34.49 - 40.85) being the most common. Several mature T-cell / NK neoplasms were identified, with the majority of cases being peripheral T-cell lymphoma NOS / anaplastic large cell lymphoma ALK negative (44%; 95%CI 39.85 - 48.84) and extranodal NK/T-cell lymphoma, nasal type (30%; 95%CI 25.5 - 33.76). Please refer to Table 1, 2, and 3 for further information.Analysis of cases by group age was also performed for mature B-cell neoplasms and HL. As expected, the majority of cases of DLBCL were seen in the age groups of 41-60 as well as 61-80. The same applied to FL. In the case of HL, the majority of nodular sclerosis subtypes were seen in the group age of 21-40 and mixed cellularity subtype showed a more even distribution in the age groups between 21-80.ConclusionTo our knowledge, this is the first descriptive study with a large sample of confirmed lymphoid neoplasms, using a standardized method of staining, classified according to the 2008 WHO Classification of Tumors representative of the Mexican population. It is a complement to the current epidemiologic registry of neoplasms in Mexico, adding classification details according to global standards set by the WHO. The results obtained are in keeping with the numbers described in other population studies worldwide. [Display omitted] DisclosuresLazo-Langner:Bayer: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Research Funding; Alexion: Research Funding.

NPM-ALK: A Driver of Lymphoma Pathogenesis and a Therapeutic Target.

Simple SummaryAnaplastic lymphoma kinase (ALK) is a tyrosine kinase associated with Anaplastic Large Cell lymphoma (ALCL) through oncogenic translocations mainly NPM-ALK. Chemotherapy is effective in ALK(+) ALCL patients and induces remission rates of approximately 80%. The remaining patients do not respond to chemotherapy and some patients have drug-resistant relapses. Different classes of ALK tyrosine kinase inhibitors (TKI) are available but used exclusively for EML4-ALK (+) lung cancers. The significant toxicities of most ALK inhibitors explain the delay in their use in pediatric ALCL patients. Some ALCL patients do not respond to the first generation TKI or develop an acquired resistance. Combination therapy with ALK inhibitors in ALCL is the current challenge.Initially discovered in anaplastic large cell lymphoma (ALCL), the ALK anaplastic lymphoma kinase is a tyrosine kinase which is affected in lymphomas by oncogenic translocations, mainly NPM-ALK. To date, chemotherapy remains a viable option in ALCL patients with ALK translocations as it leads to remission rates of approximately 80%. However, the remaining patients do not respond to chemotherapy and some patients have drug-resistant relapses. It is therefore crucial to identify new and better treatment options. Nowadays, different classes of ALK tyrosine kinase inhibitors (TKI) are available and used exclusively for EML4-ALK (+) lung cancers. In fact, the significant toxicities of most ALK inhibitors explain the delay in their use in ALCL patients, who are predominantly children. Moreover, some ALCL patients do not respond to Crizotinib, the first generation TKI, or develop an acquired resistance months following an initial response. Combination therapy with ALK inhibitors in ALCL is the current challenge.

A Case Report of Fever in an Intravenous Drug User: A Reminder of Cognitive Bias

The practice of medicine requires a widespread knowledge base. Both experienced and newly trained physicians develop heuristics to help sort through the extensive list of diagnoses and the symptoms, signs, and sequelae associated with each one. This case highlights the importance of taking a diagnostic time out when a patient is not improving clinically despite aggressive treatment. Fever is a common symptom encountered in clinical practice, and our case highlights a rare etiology of fever in a young male. This report presents a young male with fever, back pain, and a history of intravenous drug use. It was initially labeled as a straight-forward case of an epidural abscess; however, after a long hospital course, it evolved into a diagnostic dilemma. The patient was ultimately diagnosed with ALK-anaplastic large cell lymphoma, an extremely rare and aggressive malignancy. Diagnosis may have been delayed due to cognitive bias and anchoring on an initial diagnosis suspected to be from an infectious process. It is essential for all practitioners to be mindful of their heuristics in clinical practice and susceptibility to cognitive biases. This can avoid delays in diagnosis and ensure timely treatment of potentially aggressive malignancies.

Treatment of Aggressive Non-Hodgkin’s Lymphomas in Pregnancy

Background. The management of aggressive lymphomas in pregnancy depends on the time of diagnosis and immu-nomorphological variant of tumor. The rarity of aggressive lymphomas in pregnant women, the absence of consistent approaches to the treatment of such patients, the lack of data on physical growth of children as well as the incidence of newborns’ congenital and acquired pathology make this subject of vital importance. Aim. To analyze the treatment results in patients with newly diagnosed aggressive lymphoma at different stages of pregnancy. Materials & Methods. From 1993 to 2020 at the National Research Center for Hematology 74 pregnant women with lymphomas were treated. Aggressive tumors were detected in 17 (23 %) of them: primary mediastinal (thymic) large B-cell lymphoma (п = 14), anaplastic large-cell lymphoma ALK+ (п = 1), high-grade B-cell lymphoma, unspecified (п = 1), and diffuse large B-cell lymphoma (п = 1). The median age of patients was 30 years (range 21-37 years). The median pregnancy stage on the diagnosis of aggressive lymphoma was 21 weeks (range 11-32 weeks). Results. In 1 case on the diagnosis of aggressive lymphoma at 11 weeks gestation dexamethasone 8 mg daily was administered up to the second trimester of pregnancy, afterwards the patient received polychemotherapy. On the diagnosis of aggressive lymphoma in the second (п = 13) and third (п = 2) trimesters of pregnancy the patients received polychemotherapy followed by delivery. In the third trimester of pregnancy delivery was performed with subsequent polychemotherapy in 1 patient. There were born 18 babies (1 pregnancy was multifetal): 8 girls and 10 boys. Conclusion. As a result of the chosen tactics and the work of interdisciplinary team of doctors all patients, who completed the treatment, are followed-up in complete remission. All born babies, despite chemotherapy and perinatal complications, are alive and develop without abnormalities.

Effect of Immunotherapy and Stem Cell Transplant on Survival in T Cell Lymphoma. NCDB Analysis

Introduction T cell lymphomas contribute to less than 15 percent of Non-Hodgkin lymphoma in adults. Peripheral T cell lymphoma, not otherwise specified (PTCL, NOS), Anaplastic large cell lymphoma (ALCL), Angioimmunoblastic T cell lymphoma (AITL) contribute to approximately 75 percent of these T cell lymphomas. We did a population based study to evaluate the role of stem cell transplant and immunotherapy on survival outcome in stage four T cell lymphoma. Methods Data was analyzed from 4395 men and women (≥ 18 years of age) registered in the National Cancer Database (NCDB) who were diagnosed with stage four T cell lymphoma – PTCL, ALCL and AITL between 2004 and 2013 and had follow-ups to end of 2014. The primary predictor variable was treatment received, and overall survival was the outcome variable. Additional variables addressed and adjusted included gender, age, race, Charleston Comorbidity Index and histology. Results The mean age of patients was 58 years with standard deviation of 16. In multivariate analysis, after adjusting for secondary predictor variables, treatment modality was a statistically significant predictor of overall survival. Chemotherapy, SCT and immunotherapy decreased the mortality risk by 52, 70 and 22 %, respectively. Among the group with immunotherapy, pts with PTCL NOS and AITCL ALK negative derived the greatest benefit. Conclusion SCT and immunotherapy leads to improved survival in pts with T cell lymphoma. Among pts with T cell lymphoma, PTCL and ALCL ALK -, derive the greatest benefit from immunotherapy. Further clinical; research needs to be done to evaluate the role of immunotherapy in T cell lymphoma

An algorithmic approach to diagnose haematolymphoid neoplasms in effusion by combining morphology, immunohistochemistry and molecular cytogenetics.

There are limited studies of cytology diagnosis of haematopoietic and lymphoid tumours in serosal effusion except for occasional case reports. We would like to demonstrate an algorithmic approach for accurate diagnosis, especially in patients without previous history. We reviewed 36 cases of lymphoma diagnosed in serosal effusion following an algorithmic approach. Suspected tumour cells were classified into small, intermediate and large sizes and two characteristic forms of plasmacytoid and Reed Sternberg-like on smears (step 1), followed by utilising panels of immunohistochemical markers and Epstein-Barr encoding region in situ hybridisation on cell blocks (step 2). A panel of CD3, CD20 and Ki-67 formed the basic workup, followed by pertinent batteries of immunostaining. Molecular tests were applied in 22 selected cases by fluorescence in situ hybridisation (step 3). There were 15 diffuse large B-cell lymphomas; 12 plasma cell myelomas; two mantle cell lymphomas; one anaplastic large cell lymphoma ALK +; one small lymphocytic lymphoma; one plasmablastic lymphoma; one peripheral T-cell lymphoma, not otherwise specified, one extranodal NK/T-cell lymphoma, nasal type and two T-cell lymphoblastic lymphomas. 14 cases with previous history had complete concordance in immunophenotype between cytology and histology. Another 14 cases were primarily diagnosed in patients with initial symptom of effusion based on immunophenotyping and cytogenetic test in selected cases. Eight cases were diagnosed based on morphology alone. An algorithmic approach based on morphology and immunohistochemistry is the key to making an accurate diagnosis of haematopoietic and lymphoid tumours in effusion. A molecular test is also important for confirmation and prognostic prediction. We reviewed 36 haematolymphoid neoplasms diagnosed in effusion including 14 cases primarily diagnosed in patients without previous history following an algorithmic approach by combining morphology, immunohistochemistry and molecular cytogenetics.

EMMPRIN (CD147) is induced by C/EBPβ and is differentially expressed in ALK+ and ALK− anaplastic large-cell lymphoma

Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is characterized by expression of oncogenic ALK fusion proteins due to the translocation t(2;5)(p23;q35) or variants. Although genotypically a T-cell lymphoma, ALK+ ALCL cells frequently show loss of T-cell-specific surface antigens and expression of monocytic markers. C/EBPβ, a transcription factor constitutively overexpressed in ALK+ ALCL cells, has been shown to play an important role in the activation and differentiation of macrophages and is furthermore capable of transdifferentiating B-cell and T-cell progenitors to macrophages in vitro. To analyze the role of C/EBPβ for the unusual phenotype of ALK+ ALCL cells, C/EBPβ was knocked down by RNA interference in two ALK+ ALCL cell lines, and surface antigen expression profiles of these cell lines were generated using a Human Cell Surface Marker Screening Panel (BD Biosciences). Interesting candidate antigens were further analyzed by immunohistochemistry in primary ALCL ALK+ and ALK− cases. Antigen expression profiling revealed marked changes in the expression of the activation markers CD25, CD30, CD98, CD147, and CD227 after C/EBPβ knockdown. Immunohistochemical analysis confirmed a strong, membranous CD147 (EMMPRIN) expression in ALK+ ALCL cases. In contrast, ALK− ALCL cases showed a weaker CD147 expression. CD274 or PD-L1, an immune inhibitory receptor ligand, was downregulated after C/EBPβ knockdown. PD-L1 also showed stronger expression in ALK+ ALCL compared with ALK− ALCL, suggesting an additional role of C/EBPβ in ALK+ ALCL in generating an immunosuppressive environment. Finally, no expression changes of T-cell or monocytic markers were detected. In conclusion, surface antigen expression profiling demonstrates that C/EBPβ plays a critical role in the activation state of ALK+ ALCL cells and reveals CD147 and PD-L1 as important downstream targets. The multiple roles of CD147 in migration, adhesion, and invasion, as well as T-cell activation and proliferation suggest its involvement in the pathogenesis of ALCL.

Long-term outcomes of adults with first-relapsed/refractory systemic anaplastic large-cell lymphoma in the pre-brentuximab vedotin era: A LYSA/SFGM-TC study

BackgroundLong-term outcomes of adults with first-relapsed/refractory (R/R) systemic anaplastic large-cell lymphoma (ALCL) are not definitively established and should be evaluated. Patients and methodsWe previously published the long-term outcomes of adults with ALCL initially treated with polychemotherapy in LYmphoma Study Association (LYSA) prospective clinical trials conducted during the pre-brentuximab vedotin era. Herein, we report the long-term outcomes of those patients after the first-relapsed/refractory (R/R) events. ResultsAmong the 138 (64 (anaplastic lymphoma kinase (ALK(+)) and 74 ALK(−) ALCL) adults initially treated in clinical trials, 40 (14 ALK(+) and 26 ALK(−)) first-R/R ALCL patients and their long-term outcomes were analysed. Median follow-up from the first-R/R events was 12.5 years. For ALK(+) and ALK(−) patients, respectively, median [range] findings were as follows: age at first-R/R event: 35 [19–76] and 61 [34–81] years; time between inclusion in first-line clinical trials and first-R/R events was 6 [1.5–34] and 11.1 [1–67] months (P = 0.36); with median (95% confidence interval) progression-free survival after the first-R/R events: 3.8 (0.7–14.8) and 5.3 (2.4–8.4) months (P = 0.39); and overall survival: 13.6 (0.7–89) and 8.1 (3.3–25) months (P = 0.96). ALCL was the main cause of death. ConclusionMost adults with first-R/R ALCL have poor outcomes, with no significant differences between patients with ALK(+) or ALK(−) disease. These results could be used as reference for the evaluation of new drugs to treat R/R ALCL.

Tenascin-C Is Highly Expressed in T-Cell Non-Hodgkin Lymphomas and Represents an Attractive Target for Radioimmunotherapy

Introduction: Tenascins are a family of large glycoproteins present in extracellular matrix, overexpressed in tumors compared to healthy tissues. Tenatumomab (ST2146) is an anti tenascin-C monoclonal antibody that is currently under development for radio immunotherapy (RIT) in tenascin-C expressing cancer. T-cell non-Hodgkin lymphomas (T-NHL) are a heterogeneous and rare group of poor prognosis malignancies lacking of standard treatments. Aim of the study was to evaluate the expression of tenascin-C in a cohort of T-NHL.Material and Methods: Under an IRB-approved protocol, 100 patients with a diagnosis of T-NHL in charge at the Hematology Unit of "Papa Giovanni XXII" Hospital were included in the study. Paraffin-embedded tumor samples were investigated using standard immunohistochemistry (IHC) for tenascin-C expression using tenatumomab antibody. Slides were assessed by two independent investigators. Staining was scored using the four different levels "no staining", "weak", "moderate" and "strong" (0-3). A grading system was used to express the proportion of involved areas in each case, as follows: 0 (0% to 25%), 1 (26% to 50%), 2 (51% to 75%), 3 (76% to 100%). Pattern of expression (stromal, vascular and/or cytoplasmic) was as well recorded. Tenascin C gene expression data were extracted from publicly available datasets. Association among variables was assessed with Chi square or Fisher exact test.Results:Of the 100 patients evaluated, 75 cases were peripheral T-NHL (PTCL) and 25 cutaneous T-NHL (CTCL). Specific diagnosis was, anaplastic large cell lymphoma (ALCL) ALK negative (n=21) or positive (n=19), PTCL-not otherwise specified (NOS, n=20), mycosis fungoides (n=13), angioimmunoblastic T-cell lymphoma (AITL, n=9), CD30+ primary cutaneous T-NHL (n=6) and other subtypes (n=12). Tenatumomab revealed the expression of tenascin-C in all the patients, with a staining that was weak, moderate and strong in 21, 51 and 28 of the cases. There was no significant different distribution among histologies (P=0.334). A high (>50%, grade 2-3) proportion of involved areas in pathologic samples were shown in half of the patients and this proportion was higher in ALCL ALK- (81%), AITL (78%) and ALCL ALK+ (58%) while was lower for PTCL NOS (30%) and CTCL (24%) (P=0.0019). A stromal pattern of expression was present in all the cases, vasculature was stained in 47 patients while in 21 tenascin-C was as well cytoplasmic. Vascular pattern was revealed in 56% of PTCL and 20% of CTCL (P=0.0018). To further evaluate the presence of tenascin C in T-NHL, gene expression datasets from published reports were retrieved and expression values of tenascin-C gene were extracted. Significant overexpression was present in T-NHL compared to normal tissues in both of the two considered datasets (Piccaluga et al., 2007 and Iqbal et al., 2010).Conclusions: Tenatumomab revealedthat tenascin-C is uniformly present in T-NHL with a high proportion of cases showing a strong and diffuse expression. Thus, tenascin-C represent an attractive target for RIT in this category of poor prognosis rare diseases. DisclosuresPetronzelli:Sigma Tau S.p.A: Employment.

Population-Based Analysis of Elderly Patients (>70 YEARS) with Peripheral T-CELL Lymphoma: A Results from Czech Lymphoma Study Group (CLSG) Registry

INTRODUCTIONPeripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas with usually poor prognosis. Age was identified as the independent risk factors in many studies. Elderly patients suffer from comorbidities, impaired organ functions, and poor performance status resulting in worse tolerance of therapy and its efficacy. Data on outcome, prognosis and treatment efficacy for elderly patients with PTCLs are sparse. METHODSWe used data of 941 newly diagnosed PTCLs registered into CLSG database between January 1999 and March 2015 with last follow-up in February 2016. CLSG database covers approximately 85% of all newly diagnosed NonHodgkin´s lymphomas (NHLs) in Czech Republic. For the analysis, 208 patients with age >70 years at diagnosis were selected. RESULTSTotally, PTCLs accounted for about 8.7% (454/5210) patients of all NHLs in population younger 60 years, but only about 5.8% (208/3561) NHL patients older 70 years. Median age was 76ys (71-91ys), 94 (45%) were women, lactate dehydrogenase (LDH) was elevated in 130/208 (62.5%) pts., ECOG ≥2 had 80 (38%) pts., and advanced clinical stage III-IV presented 132/208 (63.5%) pts. We identified following PTCL subtypes: PTCL-NOS (Peripheral T-cell lymphoma not otherwise specified) 89/208 (43%), Anaplastic large cell lymphoma (ALCL) 34/208 (16.3%), Cutaneous Anaplastic large cell lymphoma (C-ALCL) 10/208 (4.8%), Mycosis fungoides/ Sézary syndrome (MF/SS) together 29/208 (14%), NK/T nasal lymphoma (NK/T) 2/208 (1%), Angioimmunoblastic lymphoma (AITL) 17/208 (8.1%), Cutaneous CD30+ T lymphoproliferative disease 1/208 (0.5%), T-lymphoblastic lymphoma/leukemia (T-LBL) 3/208 (1.4%), T-cell lymphoma without specification (T-NHL) 17/208 (8.1%). Distribution of PTCL subtypes changed significantly with age. There was higher proportion of PTCL-NOS (43% vs. 34%; p.001) and MF/SS (14% vs. 4.8%; p<.001) in elderly patients (>70ys) compared to younger cohort (≤70ys; n=725). Contrary, percentage of ALCL (16.3% vs. 27%; p<.001) with main difference in ALK+ cases (2% vs. 11%; p<.001), and NK/T (1% vs. 5%; p.003) was lower in elderly PTCLs, whereas the incidence of AITL (8.1% vs. 6.6%) or EATL (3.4% vs. 3%) was similar in both age subgroups.For the whole cohort of PTCLs (>70ys), the 5-year overall survival (OS) was 30% and 5-year progression free survival (PFS) was 21% regardless of subtype or stage. Progression is fatal event in elderly patients with median survival about 8 months only. There were significant survival differences between patients (>70ys vs. ≤70ys) according to PTCL subtype; PTCL-NOS 5 yr-OS 23% vs. 43% (p.00001), ALCL ALK+ 5-yr OS not reached vs. 79% (p.01), ALCL ALK- 5 yr-OS 24% vs. 50% (p.001). Patients with AITL or EATL showed no age-related survival differences.First-line chemotherapy was administered in majority of cases (67%); CHOP-like regimen was given in 78 (37%) pts., COP-like in 44 (21%) pts., and other chemotherapy in 18 (9%) cases. Local therapy (surgery, radiotherapy) was administered in first line in 17 (8%) pts., no or palliative therapy (corticoids) was given in 34 (17%) pts., initial therapy was unknown in 17 (8%) cases.We compared two subgroups of patients according to first line chemotherapy CHOP (n=75) vs. COP (n=41). Median age was 74ys (71-84) vs. 79ys (71-89), high IPI was presented in 29% vs. 50% of patients (p.001). Complete response (CR) was achieved in 35/75 (47%) CHOP treated patients, and in 7/41 (17%) patients managed with COP (p.001). Contrary, there were 12/75 (16%) progression in CHOP arm compared to 10/41 (24%) COP treated pts. Five-year OS was 28% vs. 15% better in CHOP group (p.029) and 5-yr PFS 25% vs. 10%, respectively. CONCLUSIONSIn population-based analysis of adult Caucasian PTCL patients, we identified mild decreasing incidence with age. There were significant age-related distribution differences of PTCL subtypes with shift to preponderance of PTCL-NOS, Mycosis fungoides, and NK/T nasal lymphoma in elderly. Worse survival in elderly PTCLs in comparison to younger patients was evident especially for PTCL-NOS and ALCL subtypes. Despite the baseline differences (COP managed pts. had higher IPI), there is tendency that anthracycline-based chemotherapy (CHOP) brings better results with higher proportion of CR and lower progression/relapse rate projected in longer survival. DisclosuresBelada:Seattle Genetics: Research Funding. Mayer:AOP Orphan Pharmaceuticals: Research Funding; Novartis: Research Funding.

Therapeutic efficacy of the bromodomain inhibitor OTX015/MK-8628 in ALK-positive anaplastic large cell lymphoma: an alternative modality to overcome resistant phenotypes.

Anaplastic large cell lymphomas (ALCL) represent a peripheral T-cell lymphoma subgroup, stratified based on the presence or absence of anaplastic lymphoma kinase (ALK) chimeras. Although ALK-positive ALCLs have a more favorable outcome than ALK-negative ALCL, refractory and/or relapsed forms are common and novel treatments are needed. Here we investigated the therapeutic potential of a novel bromodomain inhibitor, OTX015/MK-8628 in ALK-positive ALCLs.The effects of OTX015 on a panel of ALK+ ALCL cell lines was evaluated in terms of proliferation, cell cycle and downstream signaling, including gene expression profiling analyses. Synergy was tested with combination targeted therapies.Bromodomain inhibition with OTX015 led primarily to ALCL cell cycle arrest in a dose-dependent manner, along with downregulation of MYC and its downstream regulated genes. MYC overexpression did not compensate this OTX015-mediated phenotype. Transcriptomic analysis of OTX015-treated ALCL cells identified a gene signature common to various hematologic malignancies treated with bromodomain inhibitors, notably large cell lymphoma. OTX015-modulated genes included transcription factors (E2F2, NFKBIZ, FOS, JUNB, ID1, HOXA5 and HOXC6), members of multiple signaling pathways (ITK, PRKCH, and MKNK2), and histones (clusters 1-3). Combination of OTX015 with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib led to cell cycle arrest then cell death, and combination with suboptimal doses of the ALK inhibitor CEP28122 caused cell cycle arrest. When OTX015 was associated with GANT61, a selective GLI1/2 inhibitor, C1156Y-resistant ALK ALCL growth was impaired.These findings support OTX015 clinical trials in refractory ALCL in combination with inhibitors of interleukin-2-inducible kinase or SHH/GLI1.

ALK-anaplastic Large Cell Lymphoma of the Small Bowel: A Case Report

ALK-anaplastic Large Cell Lymphoma of the Small Bowel: A Case Report

Anaplastic Large Cell Lymphoma in Adults: Results and New Approach of Treatment

Anaplastic Large Cell Lymphoma (ALCL) represents subgroupe of peripheral T-cell lymphoma and constitutes 10-12% of this group. According to WHO 2008 classification two types depending on presence of ALK gene rearrangement subdivide ALCL: ALK-positive (ALCL ALK+) and ALK-negative (ALCL ALK-). ALCL ALK+ has a favorable prognosis with CHOP in patients without adverse prognostic factors and event free survival (EFS) reaches 70-75%. ALCL ALK- has worse treatment results: when using CHOP overall survival (OS) and EFS does not reach more than 50%. Autologous stem cell transplantation (auto-SCT) in first complete remission takes an advantage.

Improved Survival in Peripheral T-Cell Lymphoma (PTCL) Following Complete Response to First-Line Chemotherapy: 10 Year Experience at the Royal Marsden and the Christie Hospitals 2002-2012

Introduction: PTCL is a rare and heterogeneous group of non-Hodgkin lymphoma (NHL) comprising ~10% of cases. CHOP is frequently used first-line, but with the exception of ALK+ anaplastic large-cell lymphoma (ALCL), long term outcomes are historically poor with reported 5-yr overall survival (OS) rates of 36%. We retrospectively evaluated the outcomes following first-line chemotherapy for patients with PTCL treated at the Royal Marsden (RM) and Christie (CH) hospitals over a 10-year period.Methods: All eligible patients with PTCL aged ≥18 years and treated at the RM and CH between 1st January 2002 and 31st January 2012 were included. The study was approved by our institutional review boards. Patients were identified from hospital databases and included if they had received at least 1 cycle of first-line chemotherapy. Precursor T-cell malignancies, mycosis fungoides and adult T-cell leukaemia/lymphoma were excluded, as was cutaneous T-cell lymphoma not requiring combination chemotherapy. Clinical data were collated from electronic patient records and the diagnosis of PTCL was confirmed in all cases by an expert haematopathologist. Response was assessed using the IWG 1999 criteria. OS and progression free survival (PFS) were calculated from date of start of 1st line treatment and analysed using Kaplan Meier methods and Cox regression model. The impact of clinical factors on survival was assessed using Cox regression analysis.Results: A total of 143 (RM n=69, CH n=74)patients were evaluable and the median follow-up was 63.4 months. The median age at diagnosis was 59 yrs (range 18-89 yrs). PTCL subtypes were: PTCL not otherwise specified (NOS) (n=48), angioimmunoblastic T-cell lymphoma (AITL) (n=37), ALCL ALK- (n=24), ALCL ALK+ (n=14) and other (n=20). First-line chemotherapy included CHOP (n=97), GEM-P (gemcitabine, cisplatin and methylprednisolone) (n=16), other gemcitabine containing regimen (n=7), asparaginase (n=2) or other (n=21). OS by PTCL subtype is shown in Figure 1.Response was evaluable for 125/143 patients. Overall response (ORR) to first-line chemotherapy was 81.4% with complete response (CR) seen in 42.4%. For the entire cohort (n=143) 5-yr PFS was 20.6% and 5-yr OS was 39.6%. For CHOP treated patients ORR was 80.5% with CR in 43.7%, 5-yr PFS was 25.5% and 5-yr OS was 41.2%. ORR with GEM-P was 78.6% with CR in 50%, 5-yr PFS was 13.6% and 5-yr OS was 39.1%. No statistically significant difference between CHOP and GEM-P was seen in terms of response, OS or PFS.Autologous stem cell transplantation (autoSCT) was performed post first-line induction in 15% (n=22). For patients in CR post induction (CR1) (n=41), we compared survival for those treated with (n=12) and without (n=29) subsequent autoSCT. AutoSCT in CR1 was associated with a trend towards better PFS (HR 0.36, 95%CI 0.13-1.02; p=0.056) but not OS (HR 0.72, 95% CI 0.21-2.47; p=0.599).Uni- (UVA) and multivariate analyses (MVA) were performed to determine the impact of the following on OS and PFS: age (≤60 vs > 60yrs), gender, stage (I-III vs IV), performance status (PS, 0-1 vs 2), B symptoms (present vs absent), ethnicity (white vs other), LDH (normal vs elevated), IPI (low vs intermediate vs high), PTCL subtype, number of extranodal sites (0-1 vs >1), chemotherapy (CHOP vs gemcitabine based vs other), CR post induction (present vs absent) and autoSCT (performed vs not). Factors with a p-value of <0.1 in UVA were entered into MVA and independently significant risk factors (p<0.05) are shown in Table 1.Conclusion: With the exception of ALK+ ALCL, outcomes for PTCL following first-line chemotherapy remain disappointing and a more effective induction regimen is urgently required. Our data indicates that achieving a CR with first-line induction is a key factor for optimising OS and PFS. To this end, the currently accruing UK NCRI randomised phase II CHEMO-T study is comparing CHOP with GEM-P as first-line regimens in PTCL. AutoSCT in CR1 may offer a PFS benefit and should be considered in eligible patients.Table 1MVA for OS and PFS (n=104)Risk FactorHR95% CIp-valueOSIntermediate risk IPI4.561.79-11.60.001High risk IPI12.04.32-33.1<0.001CR post induction0.360.21-0.64<0.001PFSFemale sex0.330.19-0.58<0.001Intermediate risk IPI3.171.61-6.240.001High risk IPI7.763.35-17.6<0.001CR post induction0.360.22-0.60<0.001AutoSCT post induction0.300.13-0.660.003 [Display omitted] DisclosuresChau:Roche: Research Funding. Cunningham:Merrimack: Research Funding; Bayer HealthCare Pharmaceuticals: Research Funding; Medimmune: Research Funding; Astra Zeneca: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Merck Serono: Research Funding; Sanofi: Research Funding.

Recurrent Systemic Anaplastic Lymphoma Kinase–Negative Anaplastic Large Cell Lymphoma Presenting as a Breast Implant–Associated Lesion

A woman aged 48 years presented with fevers, chills, weight loss, and night sweats. She had significant lymphadenopathy of the left neck as well as the left axilla. Her history was significant for bilateral breast augmentation with textured silicone implants more than 25 years ago. Excisional biopsy of a cervical lymph node revealed large, atypical cells positive for CD4 and CD30 and negative for Epstein-Barr virus-encoded ribonucleic acid, CD2, CD3, CD5, CD7, CD8, CD15, CD20, pan-keratin, S100, anaplastic lymphoma kinase (ALK), and paired box 5. These findings were consistent with Ann Arbor stage IIIB ALK-anaplastic large cell lymphoma (ALCL). The patient was started on 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone. She initially had no signs or symptoms of breast involvement; however, after developing seroma during the clinical course, the patient underwent capsulectomy and removal of the intact, textured silicone implants. Pathological evaluation demonstrated ALK-ALCL in the left breast capsule with cells displaying a significant degree of pleomorphism with binucleated forms and numerous mitoses. Fluorescence in situ hybridization confirmed the tumor was negative for t(2;5). She presented 8 weeks later showing evidence of recurrent systemic disease.

Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation.

Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM–ALK) fusion protein (ALCL ALK+). However, little is known about the molecular features and tumour drivers in ALK-negative ALCL (ALCL ALK−), which is characterized by a worse prognosis. We found that ALCL ALK−, in contrast to ALCL ALK+, lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPβ and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK+ cell lines and demonstrated reduced levels of C/EBPβ and SOCS1. In murine engraftment models of ALCL ALK−, we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPβ target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK− and blocking miR-155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1). © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

MicroRNA and ALK-positive anaplastic large cell lymphoma

In this review we describe the current literature covering the role of microRNA in anaplastic large cell lymphoma (ALCL). MicroRNA is one of the best characterized subgroups of non-coding RNAs and it is now becoming clear that its importance in oncogenesis has been greatly underestimated. In ALCL the deregulation of a diverse range of microRNA has been demonstrated however much less is known about the physiological consequences of this deregulation. Here we focus on the subgroup of ALCL bearing the anaplastic lymphoma kinase (ALK) translocation (ALK+). The pathways linking oncogenic ALK signaling and the regulation of microRNA are now becoming established with the transcription factor STAT3 appearing to play an important role in the epigenetic regulation. This review will discuss our current understanding of the role of microRNAs in ALK-mediated oncogenesis and will explain why we believe these new findings suggest that the use of methyltransferase inhibitors together with microRNA-specific drugs could be a useful addition to our current armamentarium in the fight against ALK(+) ALCL.

MicroRNA and ALK-positive anaplastic large cell lymphoma

Tau proteins are major microtubule-associated proteins (MAPs), which promote polymerization of tubulin and determine spacings between microtubules in axons of both the central and peripheral nervous systems (CNS and PNS). Here, we cloned and identified a tau-like protein BmTau from silkworm, Bombyx mori (GenBank accession number FJ904935). The coding sequence of BmTau is 723 bases long and encodes an approximate 30 kDa protein. In the C-terminus of BmTau are contained four predicted microtubule-binding domains, which share strong sequence homology to its ortholog in Drosophila melanoganster. Relative real-time PCR analysis showed ubiquitous expression of BmTau in both neurons and non-neural cells, with its mRNA abundantly expressing in brain but significantly less detected in trachea, fat body, and silkgland. Furthermore, immunocytochemical studies in BmN cells transfected with EGFP-BmTau indicated that BmTau functioned as microtubule bundling protein as its orthologues.

Nodal Peripheral T-Cell Lymphoma – a Clinical and Epidemiological Analysis at Medicine School of Sao Paulo University

Background: Peripheral T-cell lymphoma (PTCL) are a biologically and clinically heterogeneous group of rare diseases arising from mature or activated post-thymic T lymphocytes. Correspond to 10% to 15% of lymphoid malignancies with marked geographical variation in incidence. According to the WHO classification they are divided into nodal, extranodal, primary cutaneous and leukemic or disseminated and encompass 18 distinct entities. The nodal group involves the peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), angioimmunoblastic lymphoma (AITL), anaplastic large cell lymphoma ALK positive (ALCL-ALK+) and anaplastic large cell lymphoma ALK negative (ALCL-ALK-). The literature of PTCL is scarce, especially in our country where data of epidemiology, clinical features and outcomes are usually rarely available. So, to better understand PTCL we performed a retrospective study with patients treated in a reference service for cancer treatment in Brazil.Methods: Eight-seven nodal PTCL patients treated with anthracyclne-based regimen (CHOP or, CHOEP) from January 2000 to June 2014 were evaluated retrospectively at the Medicine School of Sao Paulo University, Brazil. All patients lower than 60 years were consolidated with autologous hematopoietic stem cell transplantation (ASCT) in first CR or PR except that with ALCL-ALK+ diagnosis. Refractory and relapsed patients were salvaged with 3-4 cycles of IVAC (Ifosphamide 1.5 g/m2 i.v D1-D5, etoposide 100mg/m2 i.v D1-D5, aracytin 2g/m2 i.v twice a day D1-D2) regimen and submitted to ASCT. It was performed a central histopathological review and clinical and epidemiological data were obtained from medical records. Patients were evaluated for overall response (OR) including complete response (CR) and partial response (PR), overall survival (OS) and progression free survival (PFS). Statistical analysis was performed using the STATA-3 program using and a p-value ≤ 0.05 was considered statistically significant.Results: Of the 87 patients, 34 (39.08%) cases were classified as ALCL-ALK-, 27 (31.03%) as PTCL-NOS, 16 (18.39%) as ALCL-ALK+, 6 (6.89%) as AITL and in 4 (4.1%) cases the diagnosis could not be performed and an expansion of the immunohistochemical is ongoing. Thirty-six (45.38%) cases were female and 51(54.62%) were male, 59(67.81%) patients were lower than 60 years. Seventy-six (87.35%) patients presented in advanced stage (III or IV) at diagnosis but 73(83.90%) patients presented an ECOG < 2 and 14(16.10%) ≥ 2. Eighteen (20.70%) patients were of low-risk, 26 (29.88%) of low-intermediate risk and 43(49.42%) of high-intermediate and high-risk of international prognostic index (IPI). The CR and PR was obtained for 44(50.57%) and 8(9.19%), respectively with 59.76% OR. Thirty (34.48%) patients were primary refractory and five remain under treatment. In a median of follow of 30 months, ALCL-ALK+ show higher OS (median 140.98 months) than ALCL-ALK- (44.20 months), PTCL-NOS (median 20.62 months) and AITL (median 7.24 months) (p=0.41) (Figure 1A). The median of PFS was 3.84 months for AITL, 23.44 months for ALCL-ALK+, 40.03 months for PTCL-NOS and was not yet reached for ALCL-ALK- (p=0.0006) (Figure 1B). [Display omitted] [Display omitted] Conclusion: In this study we showed that ALCL-ALK+ as well as found in the literature presented a better OS in comparison to others nodal T-cell lymphoma as AITL, PTCL-NOS and ALCL-ALK-. Surprisingly the PFS of ALCL-ALK+ was statistically significant lower than of ALCL-ALK-. We thought that this result may be explained because in our service until to perform this analysis we did not indicate ASCT in first CR for ALCL-ALK+, but for all ALCL-ALK-. This hypothesis may be reinforced as the most of our cases presented high-intermediate and high-risk of IPI and that could equalize the favorable effect of ALK expression. In addition, we changed our approach and we are also indicating ASCT in first line for patients with ALCL-ALK+ with intermediate-high and high-risk of IPI. DisclosuresNo relevant conflicts of interest to declare.