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Systemic anaplastic large-cell lymphoma (sALCL) is a rare T-cell lymphoma associated with poor prognosis after relapse. The immunoconjugate brentuximab vedotin (BV) first became available for relapsed sALCL in England in 2013, following the results of a pivotal phase II study. We present a population-based study describing outcomes of relapsed sALCL in England after BV, using Public Health England data. We obtained information on all relapsed/refractory (r/r) sALCL patients ≥18 years treated with BV monotherapy in England between 1 January 2014 and 31 December 2019. The final cohort comprised 127 patients with a median age of 60 years (range 19-89). Eighteen (14·2%) had received stem cell transplant in first remission. Median two-year overall survival (OS) was 46·6%. The vast majority of deaths (59) occurred within 18 months, with very few events after this. Receipt of BV as second line compared to third or fourth line was associated with significantly improved survival (two-year OS 50·3% vs 29·7%, P = 0·03). There was no difference in OS for different subgroups, including anaplastic lymphoma kinase status, age, gender, or receipt of stem cell transplantation in first response. We report excellent survival following treatment with BV in a real-world setting, comparable with previous clinical trial data., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: c-MYC plays an important role in regulating cellular growth and apoptosis, and it is aberrantly expressed in many human malignancies. Although c-MYC has been extensively investigated in Burkitt lymphoma and diffuse large B cell lymphoma, little has been reported in anaplastic large cell lymphoma (ALCL). The aim of this study was to investigate the expression and genetic alterations of c-MYC in primary systemic ALCL, characterize its clinicopathologic features and immunophenotypes, and discuss their implications in prognosis., Methods: Tissue microarrays using samples from 85 ALCL patients were used to evaluate expression of c-MYC and anaplastic lymphoma kinase (ALK). c-MYC and ALK genetic alterations were detected using fluorescence in situ hybridization. The Kaplan-Meier and multivariate Cox regression methods were used for survival analysis., Results: c-MYC was expressed in 24 of 85 samples (28.2%), and ALK was expressed in 54 (63.5%). c-MYC and ALK were co-expressed in 16 samples (18.8%). c-MYC expression and c-MYC and ALK co-expression increased with ALCL clinical stages and the International Prognostic Index (IPI) score (p < 0.05). Fifty of the samples (58.8%) had ALK rearrangement, and 18 (22.1%) had aneuploidy. c-MYC rearrangement was not detected, but aneuploidy was observed in 19 cases (22.4%). c-MYC aneuploidy was significantly different based on c-MYC expression and the IPI score (p < 0.05). c-MYC was a significant independent prognostic factor for progression-free survival and overall survival in patients with ALCL., Conclusion: c-MYC protein expression and c-MYC aneuploidy could predict worse survival in patients with ALCL., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Primary cutaneous anaplastic large-cell lymphoma (PC-ALCL) is a rare T-cell lymphoma. A prior analysis of the Surveillance, Epidemiology, and End Results (SEER) database reported only 157 cases of localized primary cutaneous CD30+ T-cell lymphoproliferative disorders (PC-ALCL and lymphomatoid papulosis) from 1973 to 2004. Our analysis of the SEER database since 2004 is the largest to date and our results improve our understanding of this disease and their potential prognostic factors., Methods: We used the SEER database to retrospectively identify patients. Survival was analysed using the Kaplan-Meier method, and log-rank tests were used to compare survival distributions., Results: There were 501 cases of PC-ALCL recorded from 2005 to 2016. Overall survival rates at 5 and 10 years were found to be 80.6% (95% CI 76.3%-84.3%) and 61.5% (95% CI 54.1%-68.1%) respectively. Age ≥ 60 years [hazard ratio (HR) = 1.09, P = 0.001 and use of chemotherapy (HR = 1.86, P = 0.01)] were associated with lower overall survival. In contrast to the 1973-2004 cohort, the head and neck site was not significantly associated with prognosis on multivariate analysis., Conclusion: PC-ALCL has been increasingly recognized over the past decade. Age > 60 years and use of chemotherapy are associated with a worse outcome. Contrary to prior studies, location was not associated with poor survival., (© 2021 British Association of Dermatologists.)

Breast implant-associated anaplastic large cell lymphoma (ALCL) is a distinctive type of T-cell lymphoma that arises around textured-surface breast implants. In a subset of patients, this disease can involve surrounding tissues, spread to regional lymph nodes, and rarely metastasize to distant sites. The aim of this study was to assess sequential pathologic specimens from patients with breast implant-associated ALCL to better understand the natural history of early-stage disease. To achieve this goal, we searched our files for patients who had breast implant-associated ALCL and who had undergone earlier surgical intervention with assessment of biopsy or cytologic specimens. We then focused on the patient subset in whom a definitive diagnosis was not established, and patients did not receive current standard-of-care therapy at that time. We identified a study group of ten patients with breast implant-associated ALCL in whom pathologic specimens were collected 0.5 to 4 years before a definitive diagnosis was established. A comparison of these serial biopsy specimens showed persistent disease without change in pathologic stage in three patients, progression in five patients, and persistence versus progression in two patients. Eventually, six patients underwent implant removal with complete capsulectomy and four underwent partial capsulectomy. Seven patients also received chemotherapy because of invasive disease, three of whom also received radiation therapy, two brentuximab vedotin after chemotherapy failure, and one allogeneic stem cell transplant. Eight patients achieved complete remission and two had partial remission after definitive therapy. At time of last follow-up, six patients were alive without disease, one had evidence of disease, one died of disease, and two patients died of unrelated cancers. In summary, this analysis of sequential specimens from patients with breast implant-associated ALCL suggests these neoplasms persist or progress over time if not treated with standard-of-care therapy., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

The anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a clinically distinct but heterogeneous entity and lacks the specific immunophenotypic or genetic features compared with the ALK-positive ALCL. Recent molecular studies have provided genetic landscapes of ALK-negative ALCL that have prognostic significance. In this study, we subtyped ALK-negative ALCL based on DUSP22 rearrangements and TP63 expression and also looked for mutations in JAK-STAT pathway. The subtyping of the ALK-negative ALCL in relation to DUSP22 rearrangement and TP63 expression was done using fluorescence in situ hybridization and immunohistochemistry, respectively. The hotspot JAK-STAT mutations were analyzed using Sanger sequencing and amplification refractory mutation system polymerase chain reaction (PCR) and Signal transducer and activator of transcription 3 (STAT3) expression by immunohistochemistry. Forty-eight cases of ALCL were included with median age of 30 years and sex ratio of 1.8:1. The p63 expression was detected in 26.7% of ALK-negative ALCL cases. DUSP22 rearrangement was noted in 12.5% cases of p63-negative ALK-negative ALCLs. DUSP22 rearranged cases had better overall survival in contrast to p63 expressing and triple negative ALCLs. Triple negative ALCLs showed inferior overall survival rate. STAT3 expression was evident in 61.1% and 60% of ALK-positive and ALK-negative ALCLs, respectively. None of the cases subjected to Sanger sequencing as well as amplification refractory mutation system PCR for hotspot mutation analysis of JAK1 (exon 24) and STAT3 (exon 21) revealed any mutation. ALK-negative ALCL is a genetically heterogeneous disease with widely disparate clinical outcomes. Subtyping of ALK-negative ALCL based on DUSP22 rearrangement and p63 expression provides prognostic information., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Approximately 30% of pediatric patients with anaplastic large cell lymphoma (ALCL) relapse. Although brentuximab vedotin has demonstrated excellent activity in ALCL, it has not been used for newly diagnosed patients. Children's Oncology Group (COG) trial ANHL12P1 determined the toxicity and efficacy of brentuximab vedotin with chemotherapy in children with newly diagnosed nonlocalized anaplastic large cell lymphoma kinase (ALK)+/CD30+ ALCL. From 2013 to 2017, 68 children with ALK+ ALCL were enrolled and received brentuximab vedotin. All patients received 5-day prophase, followed by 6 cycles of chemotherapy. Brentuximab vedotin was given on day 1 of each of the 6 cycles. Of the 67 patients eligible for toxicity evaluation, 66 completed all 6 cycles of chemotherapy, resulting in 399 evaluable cycles. There were no toxic deaths, no case of progressive multifocal leukoencephalopathy syndrome, and no case of grade 3 or 4 neuropathy. The 2-year event-free survival (EFS) was 79.1% (95% confidence interval [CI], 67.2-87.1). The 2-year overall survival (OS) was 97.0% (95% CI, 88.1-99.2). Fourteen patients relapsed. Eleven of 14 (79%) relapses occurred within 10 months of diagnosis; only 1 patient (1.5%) relapsed during therapy. Quantitative reverse transcription polymerase chain reaction for NPM-ALK at baseline (minimal disseminated disease) demonstrated prognostic value for EFS (P = .0004). Overall, the addition of brentuximab vedotin to standard chemotherapy does not add significant toxicity or alter the desired interval between cycles. The addition of brentuximab vedotin prevented relapses during therapy, and the OS and EFS estimates compare favorably with results obtained using conventional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01979536., (© 2021 by The American Society of Hematology.)

Relapses involving the central nervous system (CNS) are rare in children and adolescents with ALK+ anaplastic large cell lymphoma (ALCL) treated with regimens including CNS prophylaxis. Early identification of patients at high-risk for CNS relapse would enable stratification and better adaptation of initial treatment especially in the light of the upcoming targeted therapies with limited CNS penetration. We analyzed clinical and histological data of all ALK+ALCL patients with CNS relapse registered in ALCL99-database with the aim to describe risk factors and outcome. Characteristics of patients with no relapse, relapse without CNS involvement and CNS relapse were compared. At a median follow-up of 8 years (0.05-18 years), a CNS involvement was reported at first or subsequent relapse in 26/618 patients. Median interval between initial diagnosis and first CNS relapse was 8 months (IQR 5.55-10.61/range 1.31-130.69). The 5-year cumulative risk of CNS relapse was 4% (95% CI 2.9-5.5). Bone marrow involvement, peripheral blasts and CNS involvement at diagnosis were more frequent in patients with CNS relapse than in patients with no relapse or with relapse with no CNS involvement. The treatment of CNS relapse was heterogeneous. The median survival after CNS relapse was 23.7 months. Eleven patients were alive at last follow-up. Three-year overall survival after CNS relapse was 48.70% (95% CI 30.52-67.23)., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Anaplastic large cell lymphoma (ALCL) with uniform CD56 expression is a rare condition, that has been described in limited literature, and its clinicopathological features have not yet been well illustrated. The aim of our study was to fully investigate the clinical, histological, immunohistochemical and molecular features of CD56+ ALCL., Methods: The clinical and histological characteristics of CD56+ ALCL cases were retrospectively evaluated. The immunohistochemical phenotype, status of Epstein-Barr virus (EBV) and T-cell receptor (TCR) gene rearrangement were examined. Overall survival was also analyzed., Results: Eighteen (5.8%) cases with diffuse CD56 expression were identified out of 313 archived ALCL cases with CD56 test. CD56 expression was significantly higher in ALK+ systemic ALCLs (sALCLs) (13/64, 20.3%) than in ALK- sALCLs (3/101, 3.0%) (p < 0.001) as well as primary cutaneous ALCLs (2/148, 1.4%) (p < 0.001). Regarding the CD56+ ALK+ sALCLs, the median age was 20 years (range, 8-60 years) with a male-to-female ratio of 2.3:1, and these cases more frequently affected extranodal sites (11/38, 28.9%) rather than lymph nodes (2/26, 7.7%) (p = 0.038). Eleven (84.6%) cases presented with stage I-II diseases, which was significantly more than their CD56- ALK+ counterparts (45.5%) (p = 0.015). Histologically, 2 ALK+ cases were of small cell variant and all the others displayed characteristic morphology of classic ALCL. Regarding the immunophenotype, both CD30 and CD56 were diffusely positive in all cases. CD3, CD43, anaplastic lymphoma kinase-1 (ALK1), TIA-1, EMA expression was observed in 30.8% (4/13), 90.9% (10/11), 100% (13/13), 100% (9/9), and 80.0% (8/10) cases, respectively. EBV infection was consistently absent. Monoclonal TCR gene rearrangement was found in 100% (5/5) of investigated ALK+ cases. Chemotherapy with a CHOP regimen was most frequently employed. The 3-year overall survival (OS) rate for CD56+ ALK+ patients was 92.0%, compared with 73.0% for their CD56- counterparts, but there was no significant difference in OS between the two groups (p = 0.264)., Conclusions: Uniform CD56 expression is an unexpected condition in ALCL. Of ALK+ ALCLs, CD56 expression correlated with a high frequency of early stage and an extranodal predominance. It is of great importance to raise awareness of this condition and familiarity with its characteristic features to avoid diagnostic and therapeutic pitfalls. Further investigations are warranted for a better understanding of this unusual phenotype and the significance of CD56 expression in ALCL.

Anaplastic lymphoma kinase (ALK) inhibition is expected to be a promising therapeutic strategy for ALK-positive malignancies. We aimed to examine the efficacy and safety of alectinib, a second-generation ALK inhibitor, in patients with relapsed or refractory ALK-positive anaplastic large cell lymphoma (ALCL). This open-label, phase II trial included patients (aged 6 years or older) with relapsed or refractory ALK-positive ALCL. Alectinib 300 mg was given orally twice a day (600 mg/d) for 16 cycles, and the duration of each cycle was 21 days. Patients who weighed less than 35 kg were given a reduced dose of alectinib of 150 mg twice a day (300 mg/d). Ten patients were enrolled, and the median age was 19.5 years (range, 6-70 years). Objective responses were documented in eight of 10 patients (80%; 90% confidence interval, 56.2-95.9), with six complete responses. The 1-year progression-free survival, event-free survival, and overall survival rates were 58.3%, 70.0%, and 70.0%, respectively. The median duration of therapy was 340 days. No unexpected adverse events occurred. The most common grade 3 and higher adverse event was a decrease in neutrophil count in two patients. Alectinib showed favorable clinical activity and was well tolerated in patients with ALK-positive ALCL who had progressed on standard chemotherapy. Based on the results of the current study, the Ministry of Health, Labour and Welfare of Japan approved alectinib for the treatment of recurrent or refractory ALK-positive ALCL in February 2020., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Introduction: To report the clinical characteristics of primary central nervous system T-cell lymphoma with anaplastic lymphoma kinase-1 (ALK-1) positive in an 8-year-old male., Patient Concerns: The patient presented cognitive impairment, dizziness, vomiting, fever, and convulsions during the disease, followed by progressive and persistent severe headache, progressive increase of intracranial pressure, indifference, disorder of consciousness, mild increase in white blood cells in cerebrospinal fluid, progressive decrease of sugar, progressive increase of protein, abnormal signal of left parietal-occipital, local meningeal enhancement, and cerebrospinal fluid cytology., Diagnosis: He was diagnosed with ALK-1-positive central nervous system T-cell lymphoma., Interventions: Meropenem and vancomycin were administered to counter the infection, while dexamethasone alleviated the inflammation., Outcomes: The patient died of cerebral hernia due to intracranial hypertension in the eighth week of the disease., Conclusions: PCNS ALK-1-positive anaplastic large cell lymphoma is extremely rare. Also, it is difficult to distinguish from central meningeal lymphoma and central nervous system infection, which might lead to delayed diagnosis. However, early diagnosis depends on the pathological diagnosis of brain tissue biopsy.

Background: The treatment outcomes and prognosis of lymphoma are affected by various factors such as hospital types. This study was to describe the temporal trend in the survival of lymphoma in an academic center in China., Methods: A total of 3840 consecutive patients with lymphoma diagnosed between 1996 and 2015 were reviewed. Eighty patients were excluded, and finally, 3760 patients were analyzed in this study. The cohort was divided into four groups according to calendar periods at diagnosis: 1996-2000, 2001-2005, 2006-2010, and 2010-2015. The overall survival (OS) rates among the four groups were compared., Results: The 5- and 10-year OS for the whole cohort were 62% and 52%, respectively. The 5-year OS of patient with classic Hodgkin lymphoma (cHL), mature B-cell lymphoma (BCL), and peripheral T-cell lymphoma (PTCL) were 79%, 63%, and 50%, respectively. Among mature BCL, the 5-year OS was highest in follicular lymphoma (77.8%), followed by Burkitt lymphoma (76.5%), marginal zone lymphoma (74.1%), diffuse large B-cell lymphoma (61.5%), small lymphocytic lymphoma/chronic lymphocytic leukemia (55.1%), and mantle cell lymphoma (44.3%). Among PTCL, the 5-year OS was highest in ALK+anaplastic large cell lymphoma (79.0%), followed by ALK-anaplastic large cell lymphoma (63.1%), natural killer/T-cell lymphoma (57.7%), angioimmunoblastic T-cell lymphoma (34.9%, and peripheral T-cell lymphoma not otherwise specified (27.6%). Significant improvement in the survival of lymphoma was observed, with the 5-year OS increasing from 48% in 1996-2000 to 65% in 2011-2015 (P < .001). The 5-year OS of patients with cHL, mature BCL, and PTCL changed from 55%, 49%, and 41% in 1996-2000 to 79%, 65%, and 51% in 2011-2015, respectively (P values were .014, .002, and .592, respectively)., Conclusion: The survival of most types of lymphoma such as cHL and mature BCL, rather than PTCL, was improved significantly during the past two decades., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Peripheral T cell lymphomas form a heterogeneous group with a usually dismal prognostic. The place of allogeneic stem cell transplantation to treat PTCL is debated., Methods: We retrospectively analyzed the overall survival (OS), event-free survival (EFS), relapse, and transplant-related mortality (TRM) and associated variables in 285 adults with non-primary cutaneous PTCL (PCTL-NOS (39%), angioimmunoblastic T cell lymphomas (29%), anaplastic T cell lymphomas (15%), and other subtypes (17%)), who received alloSCT in 34 centers between 2006 and 2014., Results: AlloSCT was given as part of front-line therapy (n = 138) to 93 patients in first complete response (CR) and 45 in first partial response (PR), and of salvage therapy (n = 147) to 116 patients for second or more CR/PR and 31 for progressive disease. Reduced-intensity conditioning (RIC) was given to 172 patients (62%), while 107 (38%) received myeloablative conditioning (MAC). The median follow-up was 72.4 months. The 2- and 4-year OS were 65% and 59%, respectively, and the cumulative incidence of relapse was 18% after 1 year and 19% after 2 years. TRM was 21% at 1 year, 24% after 2 years, and 28% after 4 years. In multivariate analysis, grade III-IV acute GvHD (HR = 2.57, 95% CI 1.53-4.31; p = 0.00036), low Karnofsky score < 80% (HR = 5.14, 95% CI 2.02-13.06; p = 0.00058), and progressive disease status before transplant (HR = 2.21, 95% CI 1.25-3.89; p = 0.0062) were significantly associated with a reduced OS., Conclusions: The data demonstrate in the largest retrospective cohort of non-cutaneous PTCL so far reported that alloSCT after RIC or MAC is an effective strategy, even in chemoresistant patients.

The programmed cell death 1 (PD-1) pathway is a recently recognized mechanism of tumor immune evasion. In this study, programmed cell death ligand 1 (PD-L1) expression was evaluated in 95 patients with systemic anaplastic large cell lymphoma: 45 ALK+ and 50 ALK-. ALK+ anaplastic large cell lymphoma was more often positive for PD-L1 than ALK- anaplastic large cell lymphoma (76% vs 42%, p = 0.002). ALK- anaplastic large cell lymphoma showed a strong correlation between PD-L1 expression and STAT3 activation (measured by pSTAT3 Tyr705 ) (r = 0.8, p < 0.0001). In contrast, the PD-L1/pSTAT3 correlation was weaker in ALK+ anaplastic large cell lymphoma (r = 0.4, p = 0.08). In ALK- anaplastic large cell lymphoma, the PD-L1+ subgroup was more often EMA positive (69% vs 20%, p = 0.02) and tended to be less often CD2+ (50% vs 83%, p = 0.059). In ALK+ anaplastic large cell lymphoma, PD-L1 was not associated with pathologic features (all p > 0.05). Negative ALK status and high IPI score (≥3) were associated with shorter overall survival (p = 0.009 and p = 0.0005, respectively). Overall survival was not different between patients with PD-L1+ vs PD-L1- anaplastic large cell lymphoma (p = 0.44), regardless of ALK status and International Prognostic Index (IPI) score. We conclude that PD-L1 expression is more common in ALK+ anaplastic large cell lymphoma than ALK- anaplastic large cell lymphoma. In ALK- anaplastic large cell lymphoma, PD-L1 is strongly correlated with STAT3 activation and is associated with more frequent EMA and less frequent CD2 expression. PD-L1 has no prognostic significance in predicting the outcome of patients with systemic anaplastic large cell lymphoma, regardless of ALK status. PD-L1 expression on the anaplastic large cell lymphoma cells suggests these patients as potential candidates for PD-1 blockade immunotherapy.

Galectin-1 (Gal-1) has been associated with adverse prognosis in several cancers including lymphoma entities with CD30 expression. However, Gal-1 expression has not been systematically assessed in peripheral T-cell lymphomas (PTCL). Specimens from 169 nodal PTCL were assessed for intratumoural Gal-1 expression by immunohistochemistry. Overall survival (OS) in groups exhibiting high and low Gal-1 expression was compared in the cohort and in a subset analysis of CD30-positive PTCL only. Gal-1 expression was also correlated with biomarkers of the tumour microenvironment. No significant difference in OS based on Gal-1 expression was observed in the entire PTCL cohort. However, in the CD30-positive cohort, patients with high Gal-1 levels had significantly poorer outcome (5 years OS 10%, 95% confidence interval CI, 1-36) than their low Gal-1 counterparts (5 years OS 48%, 95% CI, 30-64, P = .021). In univariate analyses age 60 or younger, non-elevated lactate dehydrogenase (LDH), and performance score less than 2 correlated with superior survival but high Gal-1 expression significantly predicted adverse outcome at both univariate (HR 2.5, 95% CI, 1.1-5.7, P = .026) and multivariate levels (HR 3.2, 95% CI, 1.2-8.5, P = .017). Tumours with high Gal-1 had few cytotoxic T cells in the tumour microenvironment. High intratumoural Gal-1 expression before therapeutic intervention correlates with adverse outcome in nodal CD30 + , ALK - PTCL patients., (© 2019 John Wiley & Sons Ltd.)

We report a retrospective analysis of 38 patients (age ≤ 30 years) who underwent allogeneic hematopoietic stem cell transplantation (allo-SCT) for relapsed or refractory anaplastic large-cell lymphoma (ALCL). Median follow-up for survivors after undergoing allo-SCT was 72 months (range, 35-96 months). Eight patients received reduced-intensity conditioning (RIC) regimens, including three patients with fludarabine plus melphalan-based regimens and five patients with fludarabine plus busulfan-based regimens. The remaining 30 patients received myeloablative conditioning (MAC) regimens. Median ages in the RIC and MAC groups were 24 and 15 years, respectively. The 5-year overall survival rates in the RIC and MAC groups were 100% and 49%, respectively (P = 0.018). The 5-year event-free survival rates in the RIC and MAC groups were 88% and 43%, respectively (P = 0.039). In the RIC group, four of the eight patients showed residual disease at allo-SCT, but all eight patients survived with complete remission (CR), including one patient with relapse. This result suggests that allo-SCT using the RIC regimen may be effective for relapsed or refractory ALCL in children, adolescents, and young adults, even in non-CR cases.

We present an analysis of 98 consecutive patients with peripheral T-cell lymphoma (PTCL) treated over a 10-year period within Western Australia. The most common frontline therapies were CHO(E)P (47%), HyperCVAD (21%), and reduced intensity therapy or supportive care alone (19%). Median and 4-year overall survival (OS) for the whole cohort were 1.59 years and 34%. Amongst CHO(E)P and HyperCVAD-treated patients, elevated LDH, advanced stage, IPI >1, and non-ALK + ALCL histology predicted inferior progression-free survival (PFS). Inferior OS was predicted by elevated LDH, age >60, IPI >1, and non-ALK + ALCL histology. Response rates and PFS were not significantly different between patients treated with CHO(E)P or HyperCVAD. OS was longer in the HyperCVAD group, however this was not significant on multivariable analysis and appears to relate to the younger age and more aggressive therapy at relapse in this group. Our data confirmed the prognostic utility of the IPI in patients with PTCL and do not demonstrate a clear benefit of HyperCVAD.

Anaplastic large T-cell lymphoma (ALTCL) is a rare subtype of non-Hodgkin T-cell lymphoma that occasionally occurs in the gastrointestinal tract of humans. Enteropathy-associated T-cell lymphoma (EATL) type 1 is the most common type of intestinal lymphoma in dogs, and ALTCL has not previously been reported in the intestinal tract of dogs. Thirteen dogs with intestinal masses diagnosed as intestinal lymphoma with anaplastic morphology were reviewed. Clinical data, including treatment protocols, were available for 11 cases. Immunohistochemistry for CD3, CD20, and CD30 was performed for all cases in addition to PCR for Antigen Receptor Rearrangements (PARR) for assessment of clonality. Eight (62%) of the cases presented with intestinal perforation, and all cases had 1 or more masses arising from the small intestine. Histologically, all cases were characterized by transmural infiltrates of large, CD3-positive and frequently CD30-positive cells. Neoplastic T cells had marked anisocytosis and anisokaryosis, prominent nucleoli, and occasionally indented to reniform nuclei. There was abundant necrosis and inflammation with occasional vascular invasion within neoplastic masses. All cases had a monoclonal T-cell receptor γ gene rearrangement. The median survival time was 5 days, with 1 dog surviving 2 years after the initial diagnosis. ALTCL can occur as an aggressive transmural lymphoma in the gastrointestinal tract of dogs and commonly causes intestinal perforation. ALTCL can be differentiated from EATL type 1 and might have implications for accurate prognostication and selection of therapeutic options in the future.

Introduction: The aim of the current study is to report the epidemiologic data, response rate, treatment outcome, and overall survival of anaplastic large cell lymphoma (ALCL) patients during the 8-year period., Patients and Methods: A retrospective study included all patients with newly diagnosed ALCL from July 2007 till December 2015., Results: A total of 48 patients were enrolled. The majority (66.7%) were male individuals. Twenty-one patients (43.7%) were low stage I or II, whereas 27 (56.2%) had advanced stage III or IV. Two patients (4.2%) died during induction chemotherapy. Disease status at last follow-up showed 35 patients (72.9%) in complete remission, 5 (10.5%) relapse, and 5 disease progression. The median time to relapse was 17.2 months. Four patients (8.4%) were salvaged by high-dose chemotherapy ifosphamide, carboplatine, etoposide followed by autologous hematopoietic stem cell transplantation, whereas 5 (10.5%) died out of disease progression. The 5-year overall survival and event-free survival were 81.2% and 68.6%, respectively. Median FU period was 58.7 month. Multivariate analysis included age, sex, stage, and response to chemotherapy and showed no statistical significance., Conclusion: Treatment of ALCL according to the Children's Oncology Group ANHL 0131 protocol is well tolerated. The relapsing patient could be salvaged by high-dose chemotherapy and autologous hematopoietic stem cell transplantation.

Studies of childhood anaplastic large cell lymphoma (ALCL) are less reported from East Asian countries. Clinical features and outcome of 90 children with ALCL in Taiwan were analyzed. The median age at diagnosis was 11.7 years. The most common presentation was lymph node involvement (86.7%). Advanced diseases accounted for 70% of patients at diagnosis. Most patients (93.1%) had positive staining for anaplastic lymphoma kinase. The five-year overall survival and event-free survival (EFS) rates were 79.7% and 73.3%, respectively. Bone marrow involvement, advanced stage, and thoracopulmonary ALCL were adverse prognostic factors for EFS ( p =.05, .04, and .03, respectively). In multivariate analysis, only thoracopulmonary ALCL had a marginal significance on worse EFS ( p = .054). We suggested that children with thoracopulmonary ALCL may need to intensify the treatment, and introduction of new targeted therapies for relapsed/refractory disease will be required.

Background: The Wnt/β-catenin signaling pathway is a major target of p53. β-Catenin/p53 coexpression predicts poorer survival in carcinoma patients. Conversely, CD99 inhibits tumor metastasis through the Wnt/β-catenin pathway. We therefore assessed p53, β-catenin, and CD99 by immunohistochemistry., Patients and Methods: We studied 45 patients with systemic anaplastic large-cell lymphoma (ALCL), including 20 anaplastic lymphoma kinase (ALK)-positive and 25 ALK-negative ALCL. β-Catenin expression was analyzed using phospho-β-catenin-S552 antibody because its nuclear localization indicates Wnt signaling., Results: In this cohort, p53 expression was associated with ALK-negative ALCL. Furthermore, p53 or β-catenin expression alone or β-catenin/p53 double expression showed poorer overall survival and disease-free survival in patients with ALCL overall and in patients with ALK-negative ALCL. CD99 expression was more frequent in ALK-positive ALCL but had no prognostic significance., Conclusion: This is the first study to evaluate phospho-β-catenin-S552 expression in ALCL. The results of this study, although limited by small patient size, suggest that β-catenin and p53 may play a role in pathogenesis and may be helpful in risk stratification of ALCL patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Different approaches have been adopted in the treatment of anaplastic large cell lymphoma (ALCL); there is a lack of consensus with regard to standard treatment. Because of paucity of data from low and middle-income countries, we reviewed the clinical features and treatment outcomes of children with ALCL., Methods: All ALCL patients under 16 years of age diagnosed from 2005 to 2015 at Aga Khan University Hospital and The Indus Hospital were identified. Clinical features and treatment outcomes were analyzed., Results: Thirty-two (n=32) patients met the inclusion criteria. Cervical Lymphadenopathy was the most common presentation (34.3%, n=11). Advanced disease was seen in 68.7% (n=22) (stages III and IV). Fourteen (42.4%) were treated on ALCL-99, 30.3% (n=10) on multicenter protocol-842 regimen, 9% (n=3) on adriamycin-prednisolone-oncovin (doxorubicin, prednisone, vincristine) regimen, and 16% (n=5) were treatment abandonments. Five-year overall survival was 70.6% (95% confidence interval: 47.8%-84.9%), and 5-year event-free survival (EFS) considering treatment abandonment and death as an event was 52.3 % (95% confidence interval: 23.5%-74.8%)., Conclusions: Significant therapy-related mortality (27.7%) was observed. Treatment abandonment and therapy-related toxicity were the major barriers for better outcomes. However, less intensive outpatient regimens, such as adriamycin-prednisolone-oncovin regimen, may decrease the number of hospitalizations, hence reducing treatment abandonment in the low and middle-income country.

Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate that is highly effective in patients with relapsed/refractory anaplastic large cell lymphoma (ALCL). However, survival outcomes following suboptimal response or subsequent relapse are not well known. We conducted a multicenter study analyzing outcomes of patients with relapsed/refractory ALCL who have received BV with a secondary focus on survival after progression following BV. A total of 56 patients were treated with BV for relapsed or refractory ALCL. The overall response rate to BV was 73% with complete response (CR) rate of 46%. The median failure-free survival and overall survival (OS) after BV were 15.5 month and not reached, respectively. The median duration of response was 27.6 months in patients who achieved CR by BV, while the median OS of those who did not achieve CR by BV was 9.5 months. There was no significant difference in OS between those who underwent stem cell transplant (SCT) and those who did not in patients who achieved CR after BV. However, if patients were in PR after BV, SCT was associated with significantly longer OS. Thirty patients experienced progressive disease on BV or required a subsequent treatment. The median OS after BV failure was 2.9 months with 2-year OS of 27.1%. There were seven long-term survivors (≥12 months) following failure. After an adequate response to subsequent salvage therapy, five patients underwent subsequent SCT (three allogeneic and two autologous), four of which were long-term survivors (17+, 25+, 32+, and 50+ months). In conclusion, BV failure is associated with a poor outcome in patients with ALCL, which defines a small but important group with unmet need. SCT may have benefit in patients with relapsed/refractory ALCL who failed BV., (© 2018 John Wiley & Sons, Ltd.)

Objective: To determine clinical and pathologic profiles for anaplastic large cell lymphoma (ALCL).
 Methods: The clinical data of 22 patients with ALCL were analyzed retrospectively. Therapentie effect of different treatment strategies on ALCL was evaluated.
 Results: The median age for these patients was 32(9-70) years old and the patients with positive ALK accounted for 68.2% (15/22). All patients underwent chemotherapy, including regiments of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CHOPE (CHOP plus etoposide) or BEACOP (CHOP plus etoposide and bleomycin). Fourteen (63.6%) patients achieved initial complete remission (CR) and the CR rate for patients with ALK+ was significantly higher than that of patients with ALK- (P<0.05), while the age, gender, stage, beta 2-microglobulin (2-MG) level, lactate dehydrogenase (LDH) level, B symptoms had no significant effect on the rate of CR (P>0.05). After a median follow-up of 41 (2-150) months, 12 patients were overall survival, the median progression free time was 22.5 (2-150) months, and the age, gender, stage, IPI index, ALK expression level, beta 2-MG level, LDH level, and B symptoms had no significant effect on the rate of overall survival (P>0.05).
 Conclusion: ALK-positive occurs mainly in ALCL patients. The chemotherapy is still the main treatment, and CHOPE regimen is a better initial treatment scheme because the most patients show good prognosis.

Systemic anaplastic lymphoma kinase positive (ALK+) anaplastic large cell lymphoma with extranodal involvement (ALCL-E) is a rare form of non-Hodgkin lymphoma. No large study in the literature has compared the survival outcomes among different primary extranodal sites of involvement in ALK+ ALCL-E. We identified 1306 patients with ALK+ ALCL-E diagnosed between 2004 and 2014 in the US National Cancer Database, among whom 387 had primary extranodal site in the chest/abdomen/pelvis, 103 in the bone, 62 in the central nervous system, 134 in the head and neck and 620 in the cutaneous/soft tissue. Younger age, lower Charlson-Deyo score, lower clinical stage, receipt of chemotherapy and receipt of radiotherapy were predictors of longer overall survival. Patients with extranodal involvement of central nervous system and chest/abdomen/pelvis had shorter overall survival than those with involvement of head and neck, bone, and cutaneous/subcutaneous tissue after adjusting for confounding variables. We recommend treating these patients upfront with more aggressive therapy., (© 2018 John Wiley & Sons Ltd.)

Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is a rare T-cell lymphoma that arises around breast implants. Most patients manifest with periprosthetic effusion, whereas a subset of patients develops a tumor mass or lymph node involvement (LNI). The aim of this study is to describe the pathologic features of lymph nodes from patients with BI-ALCL and assess the prognostic impact of LNI. Clinical findings and histopathologic features of lymph nodes were assessed in 70 patients with BI-ALCL. LNI was defined by the histologic demonstration of ALCL in lymph nodes. Fourteen (20%) patients with BI-ALCL had LNI, all lymph nodes involved were regional, the most frequent were axillary (93%). The pattern of involvement was sinusoidal in 13 (92.9%) cases, often associated with perifollicular, interfollicular, and diffuse patterns. Two cases had Hodgkin-like patterns. The 5-year overall survival was 75% for patients with LNI and 97.9% for patients without LNI at presentation (P=0.003). Six of 49 (12.2%) of patients with tumor confined by the capsule had LNI, compared with LNI in 8/21 (38%) patients with tumor beyond the capsule. Most patients with LNI achieved complete remission after various therapeutic approaches. Two of 14 (14.3%) patients with LNI died of disease compared with 0/56 (0%) patients without LNI. Twenty percent of patients with BI-ALCL had LNI by lymphoma, most often in a sinusoidal pattern. We conclude that BI-ALCL beyond capsule is associated with a higher risk of LNI. Involvement of lymph nodes was associated with decreased overall survival. Misdiagnosis as Hodgkin lymphoma is a pitfall.

Background: Brentuximab vedotin is currently approved for patients with relapsed or refractory Hodgkin's lymphoma who previously received an autologous stem cell transplant or two previous multiagent chemotherapy regimens, and for patients with relapsed or refractory systemic anaplastic large-T-cell lymphoma who previously received at least one chemotherapy regimen. A high proportion of patients with CD30-expressing relapsed or refractory lymphomas have durable responses to single-agent brentuximab vedotin and show longer progression-free survival than do patients treated with chemotherapy. In patients with Hodgkin's lymphoma and peripheral T-cell lymphoma, treatment with bendamustine alone only achieves modest improvements in progression-free survival compared with that for chemotherapy. The objective of this study was to explore the safety and clinical activity of the combination of brentuximab vedotin plus bendamustine in heavily pretreated patients with relapsed or refractory Hodgkin's lymphoma and anaplastic large-T-cell lymphoma., Methods: In this international, multicentre, single-arm, phase 1-2 trial, eligible patients were aged 18 years or older, had histologically confirmed relapsed or refractory Hodgkin's lymphoma or anaplastic large-T-cell lymphoma, had biopsy-proven CD30-positive tumours, had an Eastern Cooperative Oncology Group performance status of 2 or less, and received at least one previous multiagent chemotherapy regimen. In phase 1, patients were assigned following a 3+3 dose-escalation design to one of four cohorts to receive one dose of either 1·2 mg/kg or 1·8 mg/kg of brentuximab vedotin intravenously on day 1 of a 21 day cycle, plus one dose of bendamustine (70 mg/m 2 , 80 mg/m 2 , or 90 mg/m 2 ) on days 1 and 2 of the treatment cycle. In phase 2, all patients were assigned to receive brentuximab vedotin plus bendamustine at the recommended phase 2 dose from phase 1. The primary endpoints were maximum tolerated dose and dose-limiting toxicity for phase 1, and the proportion of patients achieving an overall response in phase 2. For both phases 1 and 2, all patients receiving at least one dose of study drug were evaluable for toxicity and all patients completing at least one cycle of therapy were evaluable for response. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01657331., Findings: Between July 26, 2012, and May 31, 2017, we enrolled and assigned 65 patients to treatment (64 [98%] with Hodgkin's lymphoma and one [2%] with anaplastic large-T-cell lymphoma; 28 [43%] during phase 1 and 37 [57%] during phase 2). In the phase 1 part, the maximum tolerated dose of the combination was not reached. Dose-limiting toxicities were observed in three (11%) of 28 patients, including grade 4 neutropenia at 1·8 mg/kg brentuximab vedotin plus 80 mg/m 2 of bendamustine in two (7%) patients and diffuse rash at 1·2 mg/kg brentuximab vedotin plus 70 mg/m 2 of bendamustine in one (4%) patient. The recommended phase 2 dose was deemed to be 1·8 mg/kg of brentuximab vedotin and 90 mg/m 2 of bendamustine, which are the standard doses of the drugs when given as single agents. In the phase 2 part, an overall response was achieved in 29 (78% [95% CI 62-91]) of 37 patients. Serious adverse events included grade 3 lung infection in five (14%) of 37 patients in the phase 2, and grade 3-4 neutropenia in 16 (25%) of 65 patients across phases 1 and 2. There were no treatment-related deaths., Interpretation: This study shows that brentuximab vedotin plus bendamustine, with a favourable safety profile, is an active salvage regimen for heavily pretreated patients with relapsed or refractory Hodgkin's lymphoma. This salvage regimen can potentially serve as an efficacious and safe alternative to platinum-based chemotherapy before autologous stem cell transplant., Funding: Seattle Genetics, Lymphoma Research Fund of Columbia University and National Center for Advancing Translational Sciences, and National Institutes of Health., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The prognostic impact of minimal disseminated disease (MDD) and anti-anaplastic lymphoma kinase (ALK) antibody titer in children with ALK-positive anaplastic large cell lymphoma (ALCL) was reported by an Italian/German group. Here, we examine their prognostic value in Japanese children with ALK-positive ALCL. We evaluated nucleophosmin (NPM)-ALK transcripts in 60 patients at diagnosis by RT-PCR and real-time PCR (qPCR). The antibody titer was assessed in 35 patients. Fifty-two percent were MDD positive by RT-PCR and 37% had more than 10 copies of NPM-ALK per 10 4 copies of ABL (10NCNs) by qPCR. Fifty-one percent of 35 patients had high antibody titer (> 1/750). Progression-free survival (PFS) of the patients with > 10 NCNs or low antibody titers was significantly poorer than that of patients with ≤ 10 NCNs or high antibody titers (> 1/750) (P = 0.016, 0.029), respectively, although we observed no difference in PFS associated with positive MDD on RT-PCR. On stratification using a combination of MDD and antibody titer, PFS for patients with > 10 NCNs and low antibody titer was extremely low (30.0%). Combined evaluation of MDD and anti-ALK antibody titer at diagnosis may thus be valuable for stratification of treatment for childhood ALCL.

Chemotherapy is the mainstream treatment of anaplastic large cell lymphoma (ALCL). However, chemotherapy can cause severe adverse effects in patients because it is not ALCL-specific. In this study, a multifunctional aptamer-nanomedicine (Apt-NMed) achieving targeted chemotherapy and gene therapy of ALCL is developed. Apt-NMed is formulated by self-assembly of synthetic oligonucleotides containing CD30-specific aptamer and anaplastic lymphoma kinase (ALK)-specific siRNA followed by self-loading of the chemotherapeutic drug doxorubicin (DOX). Apt-NMed exhibits a well-defined nanostructure (diameter 59 mm) and stability in human serum. Under aptamer guidance, Apt-NMed specifically binds and internalizes targeted ALCL cells. Intracellular delivery of Apt-NMed triggers rapid DOX release for targeted ALCL chemotherapy and intracellular delivery of the ALK-specific siRNA induced ALK oncogene silencing, resulting in combined therapeutic effects. Animal model studies reveal that upon systemic administration, Apt-NMed specifically targets and selectively accumulates in ALCL tumor site, but does not react with off-target tumors in the same xenograft mouse. Importantly, Apt-NMed not only induces significantly higher inhibition in ALCL tumor growth, but also causes fewer or no side effects in treated mice compared to free DOX. Moreover, Apt-NMed treatment markedly improves the survival rate of treated mice, opening a new avenue for precision treatment of ALCL., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The prognostic value of anaplastic lymphoma kinase (ALK) expression in patients with anaplastic large-cell lymphoma (ALCL) remains controversial. Data on the clinical features of ALCL in a Chinese population are limited. We retrospectively reviewed 1293 patients with pathologically diagnosed lymphoma at Guangdong General Hospital from June 2007 through August 2016. We evaluated the incidence of ALCL, clinical characteristics, survival status, and outcome of crizotinib use in four relapsed/refractory ALK-positive patients. Among the 1293 patients, 1193 (92.3%) were non-Hodgkin's lymphoma, and 53 (4.4%) of whom were ALCL. Of the 50 ALCL patients, with a median age of 34 years, were evaluated. Among them, 33 (66.0%) were ALK-positive and 17 (34.0%) were ALK-negative. Significantly, more patients younger than 40 years old were ALK-positive than ALK-negative (66.7 vs. 23.5%; P = 0.003). The 5-year progression-free survival (PFS) for ALK-positive and ALK-negative patients were 61 and 11%, and the 5-year overall survival (OS) were 70 and 22%, respectively. Median PFS and OS were significantly better for patients with ALK-positive than ALK-negative (60.1 vs. 9.4 months, P = 0. 017; not reached vs. 32.7 months, P = 0.021). Multivariate analyses identified ALK expression, stage, and bone marrow involvement as independent prognostic factors for PFS and OS. Four relapsed ALK-positive patients were treated with crizotinib and two died. Our results suggest that ALK expression has different prognostic significance in patients with ALCL. Mechanisms underlying early relapse after chemotherapy and resistance to crizotinib need further investigation.

Between November 2012 and July 2014, in accordance with national law 648/96, brentuximab vedotin was available in Italy for patients with relapsed systemic anaplastic large cell lymphoma outside a clinical trial context. A large Italian observational retrospective study was conducted on the use of brentuximab vedotin in everyday clinical practice to check whether clinical trial results are confirmed in a real-life context. The primary endpoint of this study was best response; secondary endpoints were the overall response rate at the end of the treatment, duration of response, survival and safety profile. A total of 40 heavily pretreated patients were enrolled. Best response was observed after a median of four cycles in 77.5%: globally, 47.5% patients obtained a complete response, 64.2% in the elderly subset. The overall response rate was 62.5%. At the latest follow up, 15/18 patients are still in complete remission (3 with consolidation). The progression-free survival rate at 24 months was 39.1% and the disease-free survival rate at the same time was 54% (median not reached). All the long-term responders were aged <30 years at first infusion. The treatment was well tolerated even in this real-life context and no deaths were linked to drug toxicity. Brentuximab vedotin induces clinical responses quite rapidly, i.e. within the first four cycles of treatment in most responders, thus enabling timely use of transplantation. For patients ineligible for transplant or for those in whom a transplant procedure failed, brentuximab vedotin may represent a feasible effective therapeutic option in everyday clinical practice., (Copyright© Ferrata Storti Foundation.)

Introduction: Systemic anaplastic large cell lymphoma (ALCL) accounts for 5%-10% of adult non Hodgkin's lymphoma (NHL) and 10%-30% of childhood NHL. Owing to significant differences in survival and gene expression profile, current WHO classifies ALCL into two distinct entities as anaplastic lymphoma receptor tyrosine kinase (ALK) positive and ALK negative ALCL with ALK expression by tumour as a good prognostic indicator. However, in our institute which is a cancer referral institute, our preliminary experience was that even ALK positive tumours did not fare well as compared to ALK- negative ALCL. So, the current study aims at exploring more clinical and pathological factors impacting survival in ALCL patients., Objective: To study clinical and pathological prognostic factors in cases of ALCL., Methods: 102 cases of ALCL were retrieved from pathology database. Pathological features and clinical features of these cases were recorded and factors found to impact overall survival (OAS) and disease-free survival (DFS) curves were identified based on univariate and multivariate analysis., Results: ALK 1 expression was seen in 71/102 (69.6%) cases and was not found to impact OAS or DFS. The 2 year OAS rate for ALK positive patients was 63.5% and DFS rate was 54.4%, while for ALK negative patients, the OAS was 60.5% and DFS was 43.5%. The Ann Arbor stage, performance status, international prognostic index, histological subtype, and the degree of the background inflammatory infiltrate were found to impact the OAS significantly. Increased reactive inflammatory component also negatively impacted DFS. In the multivariate analysis, only the histologic type emerged as significant for OAS., Conclusion: Though ALK plays a role in prognostication of systemic ALCL, advanced stage disease and an inflammatory milieu may modulate the final outcome. We report a study of clinical and pathologic prognostic features in 102 cases of anaplastic large cell lymphoma (ALCL) from a cancer referral institute in India. Anaplastic lymphoma receptor tyrosine kinase (ALK-1) expression was seen in 71/102 (69.6%) cases and was not found to impact overall survival (OAS) or disease-free survival (DFS). The 2-year OAS rate for ALK-positive patients was 63.5% and DFS rate was 54.4%, while for ALK-negative patients, the OAS was 60.5% and DFS was 43.5%. The Ann Arbor stage, performance status, international prognostic index, histological subtype, and the degree of the background inflammatory infiltrate were found to impact the OAS significantly. Increased reactive inflammatory component also negatively impacted DFS. In the multivariate analysis, only the histologic type emerged as significant for OAS. Thus, though ALK plays a role in prognostication of systemic ALCL, advanced stage disease and an inflammatory milieu may modulate the final outcome.

Anaplastic large cell lymphomas (ALCLs) are rare CD30+ peripheral T-cell lymphomas (PTCLs) classified according to the expression of the anaplastic lymphoma kinase (ALK+) protein or not (ALK-). We have analysed the outcome and risk factors for survival in a population-based bi-national cohort of patients with systemic ALK+ ALCL. A total of 122 adult (≥18 years) patients diagnosed with ALK+ ALCL between 2000 and 2010 were identified from the Danish and Swedish lymphoma registries, representing 0·4% of all lymphomas. The median age of the cohort was 40 years (range 18-85). The 5-year overall survival and progression-free survival (PFS) was 78% and 64%, respectively. Age was strongly associated with outcome, and only bone marrow (BM) involvement was independently associated with poorer PFS in multivariate analysis (Hazard Ratio [HR] = 8·57, P < 0·001). Age stratification of the patients demonstrated an association between treatment with CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisolone) and improved overall survival for patients aged 41-65 years, even when adjusted for risk factors (HR = 0·38, P = 0·047). Our results suggest that the addition of etoposide to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) in the treatment for ALK+ ALCL seems reasonable in this age group., (© 2017 John Wiley & Sons Ltd.)

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) continues to be a rare and elusive malignancy. Because BIA-ALCL does not behave like traditional lymphomas, additional research needs to be conducted to further delineate the lymphoproliferative nature of BIA-ALCL. An estimated 35 million women worldwide have breast implants and the total reported deaths from BIA-ALCL is 12 to date. The term micromort was introduced in 1979 by Ronald Howard as a person's risk of dying as 1 in a million. Drinking 0.5 L of wine or walking 17 miles all increase your risk of death by 1 micromort. Risk of death from BIA-ALCL is 0.4 micromorts for a woman having bilateral breast implants. This information is important for counseling new patients and those presenting with delayed onset seromas., (© 2017 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com.)

Background: Primary breast lymphoma (PBL) has gained attention with the description of breast implant-associated anaplastic large cell lymphoma (ALCL). Less is known about PBL incidence, treatment, and survival by lymphoma subtype., Methods: The Surveillance, Epidemiology, and End Results (SEER) registry database was queried for patients with PBL as first malignancy, with attention to non-Hodgkin Lymphoma PBL subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma (MZL), and ALCL. Incidence was estimated by age and subtype with joinpoint analyses, along with initial local therapy. Five-year relative and overall survival estimates were compared using z and two-sided log-rank tests., Results: PBL incidence (per 1 000 000 women) increased from 0.66 (1975-1977) to 2.96 (2011-2013) with an annual percentage change (APC) of 5.3% (95% confidence interval [CI] = 3.8% to 6.9%, P <  .001) from 1975 to 1999 and no statistically significant change thereafter. Incidence continues to increase for women younger than age 50 years (APC = 2.8%, 95% CI = 1.0% to 4.6%, P = .003) and for ALCL-PBL (APC = 11.8%, 95% CI = 0.2% to 24.9%, P =  .047) and MZL-PBL (APC = 2.3%, 95% CI = -0.2% to 4.9%, P =  .07), with the latter increasing significantly from 1995 to 2013 (APC = 7.5%, 95% CI = 3.4% to 11.8%, P =  .001). Surgery and surgery with radiation declined from 2000 to 2013 as initial local therapy for PBL. Five-year relative survival for PBL improved markedly over four decades and was superior for stage I DLBCL-PBL and stage I follicular PBL than for corresponding systemic presentations., Conclusions: PBL has increased in incidence over the last four decades and continues to increase for younger women and for some subtypes. The rise in imaging and procedures to the breast might enhance diagnostic sensitivity for PBL. Further study of the etiologies of PBL is needed., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Systemic ALK-positive anaplastic large cell lymphoma (ALK-positive ALCL) is a T-cell lymphoma. Owing to its rarity, variations in incidence and survival at the population level are not clearly known., Materials and Methods: Using the Surveillance Epidemiology and End Results database (SEER 18), we selected patients aged ≥ 20 years with ALK-positive ALCL, diagnosed between 2001 and 2013. Incidence rate, overall survival (OS), and its determinants were analyzed with a significance level of P < .05., Results: We identified 1604 patients with a median age of 54 years. The disease incidence increased significantly with advancing age, with higher incidence in Blacks and lower incidence in American Indians and Asian/Pacific Islanders as compared with Whites. The 5-year OS significantly declined as the age advanced (age 20-40 years, 68.7%; age 41-60 years, 53.8%; age 61-80 years, 28.9%; age > 80 years, 15.2%; P < .01) and varied with race (Whites, 49.7% vs. Blacks, 37.7% vs. Asian/Pacific Islander, 42.8% vs. American Indian, 35.8%; P = .03). On multivariate analysis, treatment with radiation (hazard ratio [HR], 0.72; 95% confidence interval [95% CI], 0.59-0.87; P < .01) and year of diagnosis from 2009 through 2013 (HR, 0.77; 95% CI, 0.65-0.93; P < .01) were associated with lower mortality. Advanced age, Black race (HR, 1.37; 95% CI, 1.14-1.65; P < .01), and advanced disease stage (HR, 1.74; 95% CI, 1.51-2.02; P < .01) were associated with higher mortality., Conclusion: Incidence and survival of ALK-positive ALCL varies significantly with patients' demographic characteristics as identified in our study. Treatment strategies need to be tailored accordingly to address these variations and ensure uniform access to care., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Anaplastic large cell lymphoma (ALCL) is one of the most common peripheral T-cell lymphomas, and the incidence is higher in blacks than non-Hispanic whites. ALK-positive and ALK-negative ALCL are distinct subtypes that have different characteristics and clinical outcomes. Breast implant-associated ALCL is a rare lymphoma that has a good survival outcome, and a recent study showed that total capsulectomy is essential for treatment. Brentuximab vedotin (BV) is a standard treatment for relapsed/refractory ALCL. The response rate is high at 80-90%; however, once the disease progresses in patients on BV, survival outcome is very poor, with a median overall survival of less than two months., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Primary cutaneous CD30 + lymphoproliferative disorders encompass lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (pcALCL), and indeterminate cases. LyP is a benign disorder characterized by recurrent crops of red or violaceous papulonodules. Patients with LyP are at an increased risk of a secondary malignancy. pcALCL is characterized by a solitary red to violaceous nodule or tumor larger than 20 mm. LyP is benign, is limited to the skin, and self-resolves, with a 5-year survival rate of 100%; pcALCL is limited to the skin and responsive to directed therapies, with a 5-year survival rate of over 95%. Aggressive chemotherapeutic regimens should be avoided., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Anaplastic large cell lymphoma (ALCL) is the second most common T cell lymphoma and 2% of all non-hodgkin lymphoma (NHL). It is an aggressive lymphoma with three subtypes, primary cutaneous ALCL, primary systemic ALK +ve ALCL and primary systemic ALK-ve ALCL depending upon rearrangement of Anaplastic Lymphoma Kinase (ALK) gene into ALK +ve and ALK -ve ALCL. Purpose of study is to determine the outcome of patients with ALCL treated at our institute., Methods: In this retrospective analysis, 49 patients with ALCL from 2000 to 2012 were included. Their base line IPI score, stage at presentation, bone marrow involvement, type of chemotherapy, ALK status, extra nodal sites and outcome were recorded., Results: Median age was 34 years (range 20-72 years), with males' predominance, i.e., 75.5%. At presentation, 7 (14.3%), 12 (24.5%), 14 (28.6%) and 16 (32.7%) were in stage I-IV, respectively. According to IPI risk categorization, there were 27 (55.1%) in low risk, 12 (24.5%) in low intermediate risk, 8 (16.3%) in high intermediate risk and 2 (4%) in high risk. Seventeen patients (34.7%) were ALK +ve while 21 patients (43%) were ALK +ve and 11 patients (22.4%) had unknown status. Kaplan Meir overall survival (OS) at 5 years was 49.9%. Five-year OS in ALK +ve tumour was 67.4% compared to 39.7% in ALK -ve, p=0.05., Conclusions: Based on our study results, ALCL is common in males with a trend towards better outcome in Alk+ disease. The majority of patients are in advanced stage of disease at the time of presentation.

Background: Brentuximab vedotin (BV) has shown high overall response rate in refractory/relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL) with reported long-term response duration in clinical trials, but few data are available regarding its role in long-term outcomes in real life., Patients and Methods: A single-center observational study was conducted on patients treated with BV in daily clinical practice to evaluate the long-term effectiveness of BV in HL and sALCL patients and to check whether clinical trial results are confirmed in a real-life context., Results: The best response rate in the treated 53 patients (43 HL and 10 sALCL) was 69.8% (with 46.5% complete response [CR]) in HL and 100% (80% CR) for sALCL, respectively. With a median patient follow-up of 36.8 months, the estimated median duration of response was 31.5 months for HL and 17.8 for sALCL, respectively. At the latest available follow-up, 75% of patients were still in response, with 43% without any consolidation. Toxicity was primarily neurological and it was rarely so serious to require dose reduction or interruption. In addition, it always reversed completely after the end of treatment., Conclusion: Our data showed that 51% of patients treated with BV can be regarded as "long-term responders." Among these cases, for all patients who underwent stem cell transplantation immediately after BV, the procedure was consolidative. For patients who have remained in continuous CR without any consolidation after therapy, BV can induce prolonged disease control., Implications for Practice: Brentuximab vedotin (BV) has shown a high overall response rate in refractory/relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma, with reported long-term response duration in clinical trials, whereas few data are available regarding its role in long-term outcomes in real life. The data reported in this study suggest that BV can induce the same results in daily clinical practice. The data showed that 51% of patients treated with BV can be regarded as "long-term responders." Among these cases, BV can induce prolonged disease control in patients who have remained in continuous complete response without any consolidation after the drug., Competing Interests: of potential conflicts of interest may be found at the end of this article., (©AlphaMed Press.)

Anaplastic large cell lymphoma (ALCL) is a heterogeneous disease of debateable origin that, in children, is largely anaplastic lymphoma kinase (ALK) positive with aberrant ALK activity induced following the formation of chromosomal translocations. Whilst the survival rates for this disease are relatively high, a significant proportion (20-40%) of patients suffer disease relapse, in some cases on multiple occasions and therefore suffer the toxic side-effects of combination chemotherapy. Traditionally, patients are treated with a combination of agents although recent data from relapse patients have suggested that low risk patients might benefit from single agent vinblastine and, going forward, the addition of ALK inhibitors to the therapeutic regimen may have beneficial consequences. There are also a plethora of other drugs that might be advantageous to patients with ALCL and many of these have been identified through laboratory research although the decision as to which drugs to implement in trials will not be trivial., (© 2016 John Wiley & Sons Ltd.)

Background: ALK-negative anaplastic large cell lymphoma associated with breast implant (i-ALCL) has been recently recognized as a distinct entity. Among 43 830 lymphomas registered in the French Lymphopath network since 2010, 300 breast lymphomas comprising 25 peripheral T-cell lymphomas (PTCL) were reviewed. Among PTCL, ALK-negative ALCL was the most frequent and all of them were associated with breast implants., Patients and Methods: Since 2010, all i-ALCL cases were collected from different institutions through Lymphopath. Immuno-morphologic features, molecular data and clinical outcome of 19 i-ALCLs have been retrospectively analyzed., Results: The median age of the patients was 61 years and the median length between breast implant and i-ALCL was 9 years. Most implants were silicone-filled and textured. Implant removal was performed in 17 out of 19 patients with additional treatment based on mostly CHOP or CHOP-like chemotherapy regimens (n = 10/19) or irradiation (n = 1/19). CHOP alone or ABVD following radiation without implant removal have been given in two patients. The two clinical presentations, i.e. effusion and less frequently tumor mass correlated with distinct histopathologic features: in situ i-ALCL (anaplastic cell proliferation confined to the fibrous capsule) and infiltrative i-ALCL (pleomorphic cells massively infiltrating adjacent tissue with eosinophils and sometimes Reed-Sternberg-like cells mimicking Hodgkin lymphoma). Malignant cells were CD30-positive, showed a variable staining for EMA and were ALK negative. Most cases had a cytotoxic T-cell immunophenotype with variable T-cell antigen loss and pSTAT3 nuclear expression. T-cell receptor genes were clonally rearranged in 13 out of 13 tested cases. After 18 months of median follow-up, the 2-year overall survival for in situ and infiltrative i-ALCL was 100% and 52.5%, respectively., Conclusions: In situ i-ALCLs have an indolent clinical course and generally remain free of disease after implant removal. However, infiltrative i-ALCLs could have a more aggressive clinical course that might require additional therapy to implant removal., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Lymphomatoid papulosis (LyP) is a CD30(+) lymphoproliferative disorder, with a self-regressing clinical course and malignant histopathology., Objective: The aim of this study was to evaluate characteristics, risk factors, associated malignancies, long-term outcome, and treatment of LyP in a large cohort representing the experience of the MD Anderson Cancer Center., Methods: Patient charts and clinical and histopathologic data of 180 patients with LyP were retrospectively assessed., Results: A total of 56.7% of patients was men. Histologic subtype A was found in 47.2%, type B in 17.2%, type C in 22.8%, type D in 7.8%, type E in 0.6%, and mixed subtype in 4.4% of the patients. One hundred fourteen lymphomas were observed in 93 patients, with mycosis fungoides (61.4%) and anaplastic large cell lymphoma (26.3%) being the most common forms. Risk factors for development of lymphoma included sex and histologic subtype. Number of lesions and symptom severity were not associated with lymphoma development. Patients with type D were less likely to have lymphomas. Treatment provided symptomatic relief but did not prevent progression to lymphoma., Limitations: The limitation of this study is the retrospective study design., Conclusion: Patients with LyP are at increased risk of associated lymphomas. Thorough patient counseling is needed and long follow-up periods are required to detect and treat secondary lymphomas., (Copyright © 2015 American Academy of Dermatology, Inc. All rights reserved.)

Background: Although anaplastic large cell lymphoma (ALCL) is curable in high-income countries (HIC), data from low- and middle-income countries (LMIC) are lacking. We therefore conducted a retrospective study of the Central American Association of Pediatric Hematology Oncology (AHOPCA) experience in treating ALCL., Procedure: We included all patients age <18 years newly diagnosed with ALCL treated between 2000 and 2013 in seven AHOPCA institutions. Retrospective data were extracted from the Pediatric Oncology Network Database., Results: Thirty-one patients met inclusion criteria. Twenty-five (81%) had advanced disease (stages III and IV), six (19%) were treated on the APO (doxorubicin, prednisone, vincristine) regimen, 15 (49%) on multi-agent chemotherapy designed for T-cell lineage malignancies (GuatALCL protocol), and 10 (32%) on BFM-based treatment regimens. Five-year overall event-free survival and overall survival were, respectively, 67.1 ± 8.6% and 66.7 ± 8.7%. All 10 events occurred in patients treated on BFM-based treatment regimens or the GuatALCL protocol, none on APO treatment: two patients experienced relapse, six treatment related mortality (TRM), and two abandonment., Conclusions: Treatment of ALCL in countries with limited resources is feasible with similar outcomes as in HIC, though the causes of treatment failure differ. Less intensive regimens may be preferable in order to decrease TRM and improve outcomes. Prospective clinical trials determining the ideal treatment for LMIC children with ALCL are necessary., (© 2015 Wiley Periodicals, Inc.)

According to the updated guidelines for imaging in lymphoma, 18F-FDG positron emission tomography/computed tomography (PET/CT) is recommended for staging and evaluation of treatment response in FDG-avid lymphomas. The purpose of the study was to evaluate the utility of PET/CT in nodal peripheral T-cell lymphomas (PTCL). Patients with newly diagnosed nodal PTCL (peripheral T-cell lymphoma NOS, anaplastic large-cell lymphoma, or angioimmunoblastic T-cell lymphoma) seen at five Danish hematology centers during the period 2006 to 2012 were included, if they had been pretherapeutically staged with PET/CT. Medical records were reviewed for baseline clinical and follow-up information. Staging, interim (I-PET), and end-of-treatment PET/CT (E-PET) studies were centrally reviewed, and reported using the Deauville 5-point score (DS). A total of 124 patients fulfilled the inclusion criteria. The median age was 58 years, and 88% received CHOP/CHOP-like therapy. Five years PFS and OS of the study population was 36.8% (95% CI 27.3-46.4) and 49.7% (95% CI 38.9-59.6), respectively. The presence of PET/CT-ascertained lung and/or liver involvement was associated with a worse outcome. The sensitivity of PET/CT for detecting biopsy-defined bone marrow involvement was only 18% (95% CI 4-43). An interim DS >3 was not prognostic for worse OS and PFS among CHOP/CHOP-like treated patients in uni- or multivariate analyses. A DS >3 after treatment predicted a worse prognosis. In conclusion, I-PET was not predictive of outcome in CHOP/CHOP-like treated PTCL patients when using the DS. Prospective studies are needed to determine the optimal use of PET/CT in PTCL including the role of quantitative PET/CT analysis., (© 2015 Wiley Periodicals, Inc.)