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Background: Alterations in the ALK (anaplastic lymphoma kinase) gene play a critical role in pathogenesis of anaplastic large cell lymphoma (ALCL). Crizotinib is a small molecule competitive inhibitor of ALK, ROS1, and MET kinases and was approved for pediatric patients with ALK-positive relapsed or refractory, systemic ALCL, and ALK-positive unresectable, recurrent, or refractory inflammatory myofibroblastic tumors (IMT)., Procedure: Crizotinib data from pediatric patients with relapsed or refractory solid tumors, IMT, or ALCL were included in the analyses. All patients received crizotinib orally at doses ranging from 100 to 365 mg/m 2 twice daily (BID). PopPK analyses were conducted to characterize crizotinib disposition in pediatric patients. Exposure-response (ER) safety and antitumor analyses were conducted to characterize relationships between crizotinib dose or exposure with safety and antitumor activity endpoints of interest., Results: The population pharmacokinetic (popPK), ER safety, and ER antitumor analysis included 98, 110, and 36 pediatric patients, respectively. A one-compartment pharmacokinetic model with allometric scaling, first-order elimination, and first-order absorption with lag time adequately described the data. Natural log-transformed model-predicted crizotinib AUC ss (steady-state area under the concentration-time curve) demonstrated a significant, positive relationship with Grade ≥3 NEUTROPENIA and Any Grade VISION DISORDER. Crizotinib dose demonstrated a positive relationship with objective response rate., Conclusions: No significant differences in PK were identified across a wide range of ages or across tumor types, suggesting body surface area (BSA)-based dosing adequately adjusted for differences in patient size to achieve similar systemic crizotinib exposures across young children and adolescent pediatric patients. None of the myelosuppressive events except Grade ≥3 NEUTROPENIA had significant relationships identified with crizotinib dose or exposure, suggesting crizotinib is a tolerable treatment with less hematological toxicity than traditional chemotherapy regimens for pediatric patients with ALK-mutated cancers. Results from the presented analyses support the pediatric dosing recommendations in the product label., (© 2024 Wiley Periodicals LLC.)

Anaplastic large-cell lymphoma is a rare disease and account for approximately 10% to 15% of pediatric non-Hodgkin lymphomas. They are characterized by extended stages, a high frequency of B signs and extra nodal involvement. Multiagent chemotherapy cures ∽60% to 75% of patients and relapse occurs in 35% of cases. For relapsed patients, various treatments ranging from vinblastine monotherapy to therapeutic intensification with hematopoietic stem cell transplantation have been evaluated, but there is currently no consensus on the optimal therapeutic strategy. New therapeutic perspectives are being evaluated for relapses and refractory forms as well as high-risk forms including monoclonal antibodies (Anti CD30), ALK inhibitors, and CART cells., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Primary cutaneous anaplastic large-cell lymphoma (PC-ALCL) is a rare T-cell lymphoma belonging to the CD30 + T-cell lymphoproliferative disorders. The case of PC-ALCL in the temporal region is exceedingly rare. Herein, we report a case of PC-ALCL involving the temporal region mimicking infratemporal space infection., Case Presentation: A 78-year-old woman presented to maxillofacial surgery service with a 6-month history of swelling and pain in the left side of her face. Laboratory investigations found an elevated C-reactive protein (CRP). Imaging findings showed enlarged lymph nodes and extensive thickening of subcutaneous tissue of the left temples. Based on these findings, the infratemporal space infection was suspected initially. The patient underwent incision and drainage, and we unexpectedly found no pus in the lesion area. Incisional biopsy showed necrosis and extensive involvement of the left temples by a diffuse infiltrate containing large, atypical cells. The tumor cells were positive for CD30, CD3, Ki67. They were negative for ALK (SP8), CD5, CD8, CD20 and PAX5. After considering these findings, a diagnosis of PC-ALCL was rendered. The patient was admitted to the lymphoma department for systemic chemotherapy and no relapse occurred during a follow-up period of six months., Conclusions: This report suggests that if there are suspicious intraoperative manifestations, carrying out a biopsy simultaneously, using Hematoxylin and eosin (HE) staining, and a comprehensive Immunohistochemistry (IHC) panel are essential to diagnosing PC-ALCL to prevent misdiagnosis., (© 2024. The Author(s).)

Background: Anaplastic Large Cell Lymphoma (ALCL) is one of the most common subtypes of T-cell lymphoma. Among these, refractory and relapsed (r/r) ALK positive ALCL lacks effective therapies. The chimeric antigen receptor-modified T (CAR-T) cell therapy holds great promise as a therapeutic strategy for this disease. However, it is not known yet whether anti-CD5 CAR-T cells are sufficient for the definitive treatment of relapsed ALK + ALCL, nor the role of accurate laboratory-based diagnoses during CAR-T treatment., Case Presentation: The adolescent patient received autologous T cells containing sequences encoding V H domains specific to CD5. Following the infusion, there was an increase in both the copy number and proportion of CAR-T cells in peripheral blood. IL-6 and ferritin levels in the patient exhibited significant fluctuations, with increases of 13 and 70 folds respectively, compared to baseline after the treatment. Additionally, adverse effects were observed, including grade 4 rash, grade 1 headache, nausea, and neck-pain. Surprisingly, a relapsed disease phenotype was identified based on the results of PET/CT and histopathological analysis of the inguinal lymph node biopsy. After conducting a thorough diagnostic assessment, which included flow cytometry, next-generation sequencing (NGS), examination of immune-related gene rearrangements, and analysis of the immune repertoire of T-cell receptors (TCR), we conclusively determined that the hyperplastic T cells identified in the lymph node were the result of an expansion of CAR-T cells. Ultimately, the patient has attained complete remission (CR) and has sustained a disease-free survival state for 815 days as of the cutoff date on August 30, 2023., Conclusion: Taken together, the results demonstrate that anti-CD5 CAR-T cells can induce a clinical response in r/r ALK + ALCL patient. Furthermore, this case underscores the importance of utilizing advanced technologies with high sensitivity and accuracy for biological detection in clinical laboratory diagnosis and prognosis in CAR-T cell treatment., Trial Registration Number: NCT04767308., Competing Interests: GH was employed by the company Nanjing IASO Therapeutics Ltd. and held interest in the company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mu, Zhang, Hu, Han, Mao, Chen, Shen, Dai, Zhu, Zhou, Huang, Ao and Xiao.)

Anaplastic large cell lymphoma (ALCL), a subgroup of mature T-cell neoplasms with an aggressive clinical course, is characterized by elevated expression of CD30 and anaplastic cytology. To achieve a comprehensive understanding of the molecular characteristics of ALCL pathology and to identify therapeutic vulnerabilities, we applied genome-wide CRISPR library screenings to both anaplastic lymphoma kinase positive (ALK+) and primary cutaneous (pC) ALK- ALCLs and identified an unexpected role of the interleukin-1R (IL-1R) inflammatory pathway in supporting the viability of pC ALK- ALCL. Importantly, this pathway is activated by IL-1α in an autocrine manner, which is essential for the induction and maintenance of protumorigenic inflammatory responses in pC-ALCL cell lines and primary cases. Hyperactivation of the IL-1R pathway is promoted by the A20 loss-of-function mutation in the pC-ALCL lines we analyze and is regulated by the nonproteolytic protein ubiquitination network. Furthermore, the IL-1R pathway promotes JAK-STAT3 signaling activation in ALCLs lacking STAT3 gain-of-function mutation or ALK translocation and enhances the sensitivity of JAK inhibitors in these tumors in vitro and in vivo. Finally, the JAK2/IRAK1 dual inhibitor, pacritinib, exhibited strong activities against pC ALK- ALCL, where the IL-1R pathway is hyperactivated in the cell line and xenograft mouse model. Thus, our studies revealed critical insights into the essential roles of the IL-1R pathway in pC-ALCL and provided opportunities for developing novel therapeutic strategies.

Background: The French phase II AcSé-crizotinib trial aimed to evaluate the safety and efficacy of crizotinib in patients with ALK, ROS1, and MET-driven malignancies, including ALK-positive anaplastic large-cell lymphoma (ALK + ALCL)., Methods: ALK + ALCL patients 12 months or older with measurable disease and no standard care options available received crizotinib twice daily at 165 mg/m 2 in children and adolescents and 250 mg in adults. The primary end-point was the response rate at 8 weeks., Results: Twenty-eight patients were enroled between February 2014 and March 2018. Three patients who were not treated were excluded from the analysis. The median age was 19 years. The median previous line of chemotherapy was two. In the 24 patients with an evaluable response, the response rate at 8 weeks was 67% (95% CI: 47-82%). All patients discontinued crizotinib after a median treatment duration of 3.7 months: eight for progression, two for adverse events (AEs) related to prior treatments, and 15 by choice, including six for allogeneic stem-cell transplantation. The median follow-up was 45 months. Nine patients experienced an event: eight relapses (seven after crizotinib discontinuation and one after dose reduction), and one died in complete remission. The median duration of response was 43.3 months (95% CI: 8.3-not reached). The 3-year progression-free and overall survival rates were 40% (95% CI: 23-59%) and 63% (95% CI: 43-79%). Grade 3 or 4 treatment-related AEs occurred in 32% of patients., Conclusion: Crizotinib shows efficacy and an acceptable safety profile in ALK + ALCL relapsed/refractory patients. However, a large proportion of patients experience a relapse after crizotinib discontinuation. Future studies will assess if prolonged ALK inhibitor exposure has curative potential without consolidation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) relapse are particularly difficult to treat with a 3-year overall survival of 49% and a median survival of 23.5 months. The second-generation ALK inhibitor brigatinib shows superior penetration of the blood-brain barrier unlike the first-generation drug crizotinib and has shown promising results in ALK+ non-small-cell lung cancer. However, the benefits of brigatinib in treating aggressive paediatric ALK+ ALCL are largely unknown. We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Golgi membrane protein 1 (GOLM1) is aberrantly expressed in many types of solid tumors and contributes to cancer development; however, its role in hematopoietic and lymphoid neoplasms remains unknown. Here, we report that GOLM1 was significantly upregulated in anaplastic large cell lymphoma (ALCL), particularly in anaplastic lymphoma kinase-positive (ALK+) ALCL. Mechanistically, the expression of GOLM1 was induced by nucleophosmin-ALK in both ALK-transformed T cells and ALCL cell lines through AKT/mTOR pathway. Knockdown of GOLM1 expression led to a reduction in the growth and viability of ALCL cells with increased spontaneous apoptosis, whereas ectopic expression of GOLM1 protected ALCL cells from apoptosis induced by staurosporine treatment. Moreover, GOLM1 directly interacted with B-cell lymphoma-extra large protein (a crucial anti-apoptosis regulator) and significantly prolonged its stability. Introduction of GOLM1 promoted ALK+ ALCL cells colony formation in vitro and tumor growth in a murine xenograft model. Taken together, our findings demonstrate, to our knowledge, for the first time that GOLM1 plays a critical role in suppressing apoptosis and promoting the progression of ALK+ ALCL and provide evidence that GOLM1 is a potential biomarker and therapeutic target in ALK-induced hematological malignancies., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

CD30, also known as TNFRSF8 (tumor necrosis factor receptor superfamily member 8), is a protein receptor that is heavily glycosylated inside the Golgi apparatus, as well as a tumor marker that is found on the surface of specific cells in the body, including certain immune cells and cancer ones. This review aims to shed light on the critical importance of CD30, from its emergence in the cell to its position in diagnosing various diseases, including Hodgkin lymphoma, where it is expressed on Hodgkin and Reed-Sternberg cells, as well as embryonal carcinoma, anaplastic large cell lymphoma (ALCL), and cutaneous T-cell lymphoma (CTCL). In addition to its role in positive diagnosis, targeting CD30 has been a promising approach treating CD30-positive lymphomas, and there is ongoing research into the potential use of CD30-targeted therapies for autoimmune disorders. We aim to elaborate on CD30's roles as a tumor marker, supporting thus the hypothesis that this receptor might be the aim of cytostatic treatment.

Purposeof Review: The main aim of this review is to summarize first-line therapy of nodal T-cell non-Hodgkin lymphoma., Recent Findings: Current treatment with CHOP chemotherapy results in poor outcomes in the majority of patients. However, there are advances within the field. First breakthrough is the ECHELON-2 trial which showed that the addition of brentuximab vedotin improves outcomes in anaplastic large cell lymphoma. However, other types of peripheral T-cell non-Hodgkin lymphoma were underrepresented with optimal treatment not known. Second breakthrough is an increase of autologous stem cell transplantation usage in the first complete metabolic remission, except in ALK + anaplastic large cell lymphoma, offering better disease control. Despite advances in the field, CHOP remains the standard treatment for the majority of these lymphomas, but multiple trials are underway with the aim to improve this unmet need in hematology and, hopefully, leading us to a new era in the treatment of peripheral T-cell lymphomas., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show potent efficacy in several ALK-driven tumors, but the development of resistance limits their long-term clinical impact. Although resistance mechanisms have been studied extensively in ALK-driven non-small cell lung cancer, they are poorly understood in ALK-driven anaplastic large cell lymphoma (ALCL). Here, we identify a survival pathway supported by the tumor microenvironment that activates phosphatidylinositol 3-kinase γ (PI3K-γ) signaling through the C-C motif chemokine receptor 7 (CCR7). We found increased PI3K signaling in patients and ALCL cell lines resistant to ALK TKIs. PI3Kγ expression was predictive of a lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3Kγ, and PI3Kδ were up-regulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3Kγ isoform cooperated with oncogenic ALK to accelerate lymphomagenesis in mice. In a three-dimensional microfluidic chip, endothelial cells that produce the CCR7 ligands CCL19/CCL21 protected ALCL cells from apoptosis induced by crizotinib. The PI3Kγ/δ inhibitor duvelisib potentiated crizotinib activity against ALCL lines and patient-derived xenografts. Furthermore, genetic deletion of CCR7 blocked the central nervous system dissemination and perivascular growth of ALCL in mice treated with crizotinib. Thus, blockade of PI3Kγ or CCR7 signaling together with ALK TKI treatment reduces primary resistance and the survival of persister lymphoma cells in ALCL.

ALK-negative anaplastic large cell lymphoma (ALCL) comprises subgroups harboring rearrangements of DUSP22 (DUSP22- R) or TP63 (TP63-R). Two studies reported 90% and 40% 5-year overall survival (OS) rates in 21 and 12 DUSP22-R/TP63- not rearranged (NR) patients, respectively, making the prognostic impact of DUSP22-R unclear. Here, 104 newly diagnosed ALK-negative ALCL patients (including 37 from first-line clinical trials) from the LYSA TENOMIC database were analyzed by break-apart fluorescence in situ hybridization assays for DUSP22-R and TP63-R. There were 47/104 (45%) DUSP22-R and 2/93 (2%) TP63-R cases, including one DUSP22-R/TP63-R case. DUSP22-R tumors more frequently showed CD3 expression (62% vs. 35%, P=0.01), and less commonly a cytotoxic phenotype (27% vs. 82%; P<0.001). At diagnosis, DUSP22- R ALCL patients more frequently had bone involvement (32% vs. 13%, P=0.03). The patient with DUSP22-R/TP63-R ALCL had a rapidly fatal outcome. After a median follow-up of 4.9 years, 5-year progression-free survival (PFS) and OS rates of 84 patients without TP63-R treated with curative-intent anthracycline-based chemotherapy were 41% and 53%, respectively. According to DUSP22 status, 5-year PFS was 57% for 39 DUSP22-R versus 26% for 45 triple-negative (DUSP22-NR/TP63-NR/ALK-negative) patients (P=0.001). The corresponding 5-year OS rates were 65% and 41%, respectively (P=0.07). In multivariate analysis, performance status and DUSP22 status significantly affected PFS, and distinguished four risk groups, with 4-year PFS and OS ranging from 17% to 73% and 21% to 77%, respectively. Performance status but not DUSP22 status influenced OS. The use of brentuximab vedotin in relapsed/refractory patients improved OS independently of DUSP22 status. Our findings support the biological and clinical distinctiveness of DUSP22- R ALK-negative ALCL. Its relevance to outcome in patients receiving frontline brentuximab vedotin remains to be determined.

Anaplastic large cell lymphoma (ALCL) is the most common type of mature T-cell non-Hodgkin lymphoma in children/adolescents. ALCL is characterized by expression of CD30 in the neoplastic lymphoid cells with frequent expression of anaplastic lymphoma kinase (ALK), especially within the pediatric population. Despite multiple efforts to optimize the use of conventional chemotherapy, outcomes in children, adolescents, and adults with ALCL remain suboptimal. Thus, there is a need to improve survival for those with high-risk disease and decrease therapy exposures and toxicities for those with low-risk disease. Targeted therapies, such as the anti-CD30 antibody-drug conjugate, brentuximab vedotin, are new important therapeutic options. Phase I and II studies in adults with relapsed/refractory CD30 + lymphomas, including ALCL, demonstrated the safety and efficacy of brentuximab vedotin, leading to FDA approval for relapsed/refractory ALCL in adults and successful incorporation into frontline therapies. Clinical trials in the pediatric population demonstrated similar results in those with relapsed/refractory ALCL. Incorporation of brentuximab vedotin into upfront therapy for children and adolescents with ALCL showed that this novel combination therapy has clinical advantages in comparison to conventional agents alone. Brentuximab vedotin is well-tolerated in both the pediatric and adult populations, even when used in combination with conventional agents. Brentuximab vedotin is an ideal agent to treat ALCL with excellent targeted activity and limited toxicity. Future studies are needed to identify how brentuximab vedotin should be utilized when combined with immunotherapy or other targeted agents (e.g., ALK inhibitors) in both the upfront and relapsed/refractory setting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Agrusa, Egress and Lowe.)

Approximately one-third children with anaplastic large cell lymphoma (ALCL) relapse after completion of chemotherapy, particularly for those high-risk patients. The introduction of novel therapeutic modalities is much needed for these sub-group patients. Two groups (n = 3, n = 4) of ALCL patients were treated with crizotinib- and alectinib-included ALCL-99 therapy, respectively, achieving complete remission rates of 66.7% and 100%. Two patients of crizotinib group relapsed, while none relapsed among the alectinib-treated patients. Adding alectinib instead of crizotinib sufficiently suppressed and maintained the deep NPM-ALK molecular response. ALK inhibitors were well tolerated with only grade 1 adverse events in both groups. Though a relatively small case number, this study raised the possibility that alectinib-included therapeutic regimens may benefit the early response, in-depth molecular remission, and persistent remission to some extent. Further studies are warranted to validate our preliminary findings., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is a CD30-positive T cell lymphoma characterized by signalling from constitutively activated ALK fusion proteins. Most children and adolescents present in advanced stages, often with extranodal disease and B symptoms. The current front-line therapy standard of six cycles polychemotherapy reaches an event-free survival of 70%. The strongest independent prognostic factors are minimal disseminated disease and early minimal residual disease. At relapse, ALK-inhibitors, Brentuximab Vedotin, Vinblastine, or second line chemotherapy are effective re-inductions. Survival at relapse exceeds 60-70% with consolidation according to the time of relapse (Vinblastine monotherapy or allogeneic hematopoietic stem cell transplantation) so that the overall survival reaches 95%. It needs to be shown whether check-point inhibitors or long-term ALK-inhibition may substitute for transplantation. The future necessitates international cooperative trials testing whether a shift of paradigm to a chemotherapy-free regimen can cure ALK-positive ALCL., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Anaplastic large cell lymphoma (ALCL) and classical Hodgkin lymphoma (HL) share a similar cytological and high surface expression of CD30, and novel therapeutic strategies are needed. The EP300 and CREBBP acetyltransferases play essential roles in the pathogenesis of non-Hodgkin B cell lymphoma, but their functions in ALCL and HL are unknown. In the current study, we investigated the physiological roles of EP300 and CREBBP in both ALCL and HL, and exploited the therapeutic potential of EP300/CREBBP small molecule inhibitors that target either the HAT or bromodomain activities. Our studies demonstrated distinct roles for EP300 and CREBBP in supporting the viability of ALCL and HL, which was bolstered by the transcriptome analyses. Specifically, EP300 but not CREBBP directly modulated the expression of oncogenic MYC/IRF4 network, surface receptor CD30, immunoregulatory cytokines IL10 and LTA, and immune checkpoint protein PD-L1. Importantly, EP300/CREBBP HAT inhibitor A-485 and bromodomain inhibitor CPI-637 exhibited strong activities against ALCL and HL in vitro and in xenograft mouse models, and inhibited PD-L1 mediated tumor immune escape. Thus, our studies revealed critical insights into the physiological roles of EP300/CREBBP in these lymphomas, and provided opportunities for developing novel strategies for both targeted and immune therapies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Anaplastic large-cell lymphoma (ALCL) constitutes 10-15% of non-Hodgkin lymphoma in children. With short-course chemotherapy, outcome has improved up-to 90% in developed-countries. There is limited-data on outcome of pediatric ALCL treated with ALCL99 protocol from low-middle income countries. Children ≤14 years, diagnosed with ALCL between 1 st January 2007 and 31 st December 2016 were analyzed. Details regarding clinical-presentation and treatment were recorded and outcome was analyzed. Fourteen-children were diagnosed. Median-age was 114 months (range 24 - 162 months). Male:female ratio was 3.6:1. Stage-I, II and III disease was seen in three (21.4%), three (21.4%), and eight (57.1%) children, respectively. Low, standard and high-risk disease was seen in two (14.2%), six (42.9%) and six (42.9%), respectively. All children were treated using ALCL99 protocol. Three (21.4%) children had disease-progression/relapse and five (35.7%) died (three from treatment-related mortality, and two from disease). At median follow-up of 54-months, four-year EFS and OS were 64.3% and 64.3%, respectively. Log-rank test demonstrated female gender ( p  = 0.005), stage-III disease ( p  < 0.001), visceral-organ involvement ( p  = 0.035), high-risk disease ( p  = 0.016) and, serum albumin ≤3.5 g/dL ( p  = 0.031) associated with significantly worse 4-year EFS. Cox-regression analysis demonstrated female gender associated with poor EFS ( p  = 0.02) and female gender and visceral-organ involvement associated with poor OS ( p  = 0.02, p  = 0.011, respectively). Good survival could be achieved for children with ALCL using uniform treatment protocol in a resource-limited setting, especially among low and standard-risk children. Female-sex, high-risk disease, stage-III disease, visceral organ involvement and low albumin levels were associated with poor outcome, however these findings need to be corroborated in larger studies.

The T-cell Lymphoma Project is an international registry prospective study that enrolled patients with newly diagnosed peripheral T-cell and NK-cell lymphomas (PTCL). The main objective was to define the clinical features and outcomes, establishing a robust benchmark for future clinical trials. Seventy-four institutions from 14 countries in North America, South America, Europe, and Asia collected data on patients diagnosed and treated at their respective centers between September 2006 and February 2018. Among 1553 PTCL patients, 131 (8.4% of the total cohort) were confirmed to have anaplastic large cell lymphoma - kinase positive (ALCL, ALK+). The median age of the patients was 39 years (18-84). Sixty-five patients (66%) had advanced-stage disease, although majority (45 patients, 54%) had a low-risk International Prognostic Index (IPI) score (0-1). Of 97 patients treated with chemotherapy, 97% received anthracycline-containing regimens. The overall response rate was 81%, with 69 patients (70%) achieving complete remission. Estimated OS and PFS at 3 years were 77% (95% CI: 54%-99%) and 68% (95% CI: 46%-90%), respectively, and at 5 years were very similar, 77% of OS (95% CI: 62%-92%) and 64% of PFS (95% CI: 34%-94%). Multivariate analysis for PFS showed advanced stage (hazard ratios [HR]: 4.72, 95% CI: 1.43-23.9, p = 0.015), elevated lactate dehidrogenade (LDH) (HR 4.85; 95% CI: 1.73-13.60, p = 0.001), and Eastern Cooperative Oncology Group Performance Status scale (ECOG-PS) ≥2 (HR: 5.25; 95% CI: 1.68-16.4, p = 0.024). For OS, elevated LDH (HR: 3.77; 95% CI: 1.98-14.17, p = 0.014) and ECOG-PS ≥2 (HR: 4.59; 95% CI: 1.46-14.39, p = 0.004) were identified. In summary, although the outcome of ALK+ ALCL is superior to that of other PTCLs, it remains sufficiently favorable, given the young median age of the patients. Our results confirm the usefulness of both IPI and Prognostic Index for T-cell Lymphoma (PIT) in identifying groups of patients with different outcomes. Clinical Trials ID: NCT01142674., (© 2022 John Wiley & Sons Ltd.)

Ribosomally synthesized and post-translationally modified peptides, such as plant cyclotides, are a diverse group of natural products well known as templates in drug discovery and therapeutic lead development. The cyclotide kalata B1 (kB1) has previously been discovered as immunosuppressive agent on T-lymphocytes, and a synthetic version of this peptide, [T20K]kB1 (T20K), has been effective in reducing clinical symptoms, such as inflammation and demyelination, in a mouse model of multiple sclerosis. Based on its T-cell modulatory impact we studied the effects of T20K and several analogs on the proliferation of anaplastic large cell lymphoma (ALCL), a heterogeneous group of clinically aggressive diseases associated with poor prognosis. T20K, as a prototype drug candidate, induces apoptosis and a proliferation arrest in human lymphoma T-cell lines (SR786, Mac-2a and the Jurkat E6.1) in a concentration dependent fashion, at least partially via increased STAT5 and p53 signaling. In contrary to its effect on IL-2 signaling in lymphocytes, the cytokine levels are not altered in lymphoma cells. In vivo mouse experiments revealed a promising activity of T20K on these cancer cells including decreased tumor weight and increased apoptosis. This study opens novel avenues for developing cyclotide-based drug candidates for therapy of patients with ALCL., Competing Interests: Conflict of interest statement C.W.G. is scientific advisor of Cyxone AB. The other authors declare no competing financial interests., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Histone deacetylases (HDACs) target acetylated lysine residues in histone and non-histone proteins. HDACs are implicated in the regulation of genomic stability, cell cycle, cell death and differentiation and thus critically involved in tumorigenesis. Further, HDACs regulate T-cell development and HDAC inhibitors (HDACis) have been approved for clinical use in some T-cell malignancies. Still, the exact targets and mechanisms of HDAC inhibition in cancer are understudied. We isolated tumor cell lines from a transgenic mouse model of anaplastic large cell lymphoma (ALCL), a rare T-cell lymphoma, and abrogated HDAC activity by treatment with the HDACis Vorinostat and Entinostat or Cre-mediated deletion of Hdac1 . Changes in overall protein expression as well as histone and protein acetylation were measured following Hdac1 deletion or pharmacological inhibition using label-free liquid chromatography mass spectrometry (LC-MS/MS). We found changes in overall protein abundance and increased acetylation of histones and non-histone proteins, many of which were newly discovered and associated with major metabolic and DNA damage pathways. For non-histone acetylation, we mapped a total of 1204 acetylated peptides corresponding to 603 proteins, including chromatin modifying proteins and transcription factors. Hyperacetylated proteins were involved in processes such as transcription, RNA metabolism and DNA damage repair (DDR). The DDR pathway was majorly affected by hyperacetylation following HDAC inhibition. This included acetylation of H2AX, PARP1 and previously unrecognized acetylation sites in TP53BP1. Our data provide a comprehensive view of the targets of HDAC inhibition in malignant T cells with general applicability and could have translational impact for the treatment of ALCL with HDACis alone or in combination therapies., Competing Interests: The authors declare no conflict of interest.

In January 2021, the U.S. Food and Drug Administration (FDA) approved crizotinib for pediatric patients 1 year and older and young adults with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). This is the first approval for pediatric sALCL. Approval was based on a single-arm trial of crizotinib monotherapy that included 26 patients, aged 1-20 years, with previously treated sALCL. Efficacy was based on centrally assessed objective response rate (88%) and duration of response. Herein, we highlight unique aspects of the regulatory review, including extension of the indication to young adults, postmarketing safety, and dose optimization strategies., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA.)

Anaplastic large cell lymphoma (ALCL) is a CD30-positive non-Hodgkin's T‑cell lymphoma. Despite the implementation of CD30 antibody-drug conjugate-targeted therapy into front-line treatment regimens, the prognosis of some subtypes of the disease remains unsatisfactory. In the relapsed/refractory setting, effective second-line treatment options are still lacking. However, it has been reported that blockade of direct downstream targets of activator protein‑1 (AP-1) transcription factors, which are highly dysregulated in ALCL, results in complete and sustained remission in late-stage relapsed/refractory anaplastic lymphoma kinase (ALK)-positive ALCL patients. Moreover, it has been identified that involvement of the BATF3/AP‑1 module promotes lymphomagenesis via oncogenic BATF3/IL-2/IL-2R signaling through hyperphosphorylation of ERK1/2, STAT1, and STAT5 in ALCL cells regardless of their ALK status. Therefore, targeting BATF3/IL-2/IL-2R signaling may represent a novel therapeutic alternative for ALCL patients., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Competing Interests: Giannoula Lakka KlementEmployment: CSTS Health Care Inc, Hessian LabsLeadership: CSTS Health Care IncStock and Other Ownership Interests: CSTS Health Care Inc, Hessian LabsConsulting or Advisory Role: Ipsen Lenka Zdrazilova DubskaHonoraria: Roche Ondrej SlabyHonoraria: Roche, Bristol Myers SquibbConsulting or Advisory Role: Roche, Bristol Myers Squibb Jaroslav SterbaResearch Funding: Roche/Genentech (Inst)Travel, Accommodations, Expenses: BMSNo other potential conflicts of interest were reported.

Context.—: In the early 1980s, a monoclonal antibody termed Ki-1 was developed against a cell line derived from a patient with Hodgkin lymphoma. This antibody detected a limited number of benign activated lymphocytes in lymphoid tissue, whereas in Hodgkin lymphoma it appeared to be nearly specific for Reed-Sternberg cells and their mononuclear variants. Subsequent studies showed that Ki-1 expression defined a new type of lymphoma that was later designated anaplastic large cell lymphoma with or without anaplastic large cell kinase expression/translocation. In the past 30 years, numerous new lymphoma entities have been defined, many of which are variably positive for CD30. Many virally transformed lymphoproliferative disorders are also frequently positive for CD30., Objective.—: To illustrate the broad spectrum of CD30+ hematologic malignancies and to provide an update of CD30-targeted therapies., Data Sources.—: Personal experiences and published works in PubMed., Conclusions.—: Because of its low expression in normal tissue, CD30 was studied as a therapeutic target for many years. However, the first functional humanized antibody against CD30 was developed only about 10 years ago. Brentuximab vedotin is a humanized anti-CD30 antibody linked to a cytotoxin, and was approved by the US Food and Drug Administration in 2012 for treating refractory Hodgkin lymphoma and anaplastic large cell lymphoma. Since then, the list of Food and Drug Administration-approved CD30-targeted hematologic malignancies has grown. Recently, the therapies using tumor antigen-specific chimeric antigen receptor T cells targeting CD30 have incited a great deal of enthusiasm and are studied in clinical trials.

Primary central nervous system anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is an extremely rare type of primary central nervous system lymphoma (PCNSL). There are only nine cases reported in the literature to date, most of which have an overall survival time of no more than 8 months. Herein, we report such a rare case who has a good outcome with the longest survival time and perform a review of the literature. A 19-year-old male patient was admitted to the hospital complaining of dizziness. CT and MRI imaging showed a heterogeneous enhanced lesion in the left parieto-occipital lobe and the leptomeninges of the occipital lobe and the cerebellum. The lesion was resected and confirmed to be ALK-negative ALCL by pathological examination. Then, the patient received 10 cycles of chemotherapy with high-dose methotrexate (HD-MTX) and whole-brain radiotherapy. The patient recovered well and was regularly followed up. He was free of symptoms without recurrence on imaging examination 3 years later. ALCL is a rare type of PCNSL. HD-MTX combined with radiation is an effective therapeutic approach. However, further prospective studies with a large number of patients are needed to identify the biological characteristics of this rare type of PCNSL.

Anaplastic large cell lymphomas (ALCLs) frequently carry oncogenic fusions involving the anaplastic lymphoma kinase (ALK) gene. Targeting ALK using tyrosine kinase inhibitors (TKIs) is a therapeutic option in cases relapsed after chemotherapy, but TKI resistance may develop. By applying genomic loss-of-function screens, we identified PTPN1 and PTPN2 phosphatases as consistent top hits driving resistance to ALK TKIs in ALK+ ALCL. Loss of either PTPN1 or PTPN2 induced resistance to ALK TKIs in vitro and in vivo. Mechanistically, we demonstrated that PTPN1 and PTPN2 are phosphatases that bind to and regulate ALK phosphorylation and activity. In turn, oncogenic ALK and STAT3 repress PTPN1 transcription. We found that PTPN1 is also a phosphatase for SHP2, a key mediator of oncogenic ALK signaling. Downstream signaling analysis showed that deletion of PTPN1 or PTPN2 induces resistance to crizotinib by hyperactivating SHP2, the MAPK, and JAK/STAT pathways. RNA sequencing of patient samples that developed resistance to ALK TKIs showed downregulation of PTPN1 and PTPN2 associated with upregulation of SHP2 expression. Combination of crizotinib with a SHP2 inhibitor synergistically inhibited the growth of wild-type or PTPN1/PTPN2 knock-out ALCL, where it reverted TKI resistance. Thus, we identified PTPN1 and PTPN2 as ALK phosphatases that control sensitivity to ALK TKIs in ALCL and demonstrated that a combined blockade of SHP2 potentiates the efficacy of ALK inhibition in TKI-sensitive and -resistant ALK+ ALCL., (© 2022 by The American Society of Hematology.)

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.)

Overexpression of antiapoptotic BCL2 family proteins occurs in various hematologic malignancies and contributes to tumorigenesis by inhibiting the apoptotic machinery of the cells. Antagonizing BH3 mimetics provide an option for medication, with venetoclax as the first drug applied for chronic lymphocytic leukemia and for acute myeloid leukemia. To find additional hematologic entities with ectopic expression of BCL2 family members, we performed expression screening of cell lines applying the LL-100 panel. Anaplastic large cell lymphoma (ALCL) and primary effusion lymphoma (PEL), 2/22 entities covered by this panel, stood out by high expression of MCL1 and low expression of BCL2. The MCL1 inhibitor AZD-5991 induced apoptosis in cell lines from both malignancies, suggesting that this BH3 mimetic might be efficient as drug for these diseases. The ALCL cell lines also expressed BCLXL and BCL2A1, both contributing to survival of the cells. The combination of specific BH3 mimetics yielded synergistic effects, pointing to a novel strategy for the treatment of ALCL. The PI3K/mTOR inhibitor BEZ-235 could also efficiently be applied in combination with AZD-5991, offering an alternative to avoid thrombocytopenia which is associated with the use of BCLXL inhibitors., (© 2022. The Author(s).)

Objectives: Systemic anaplastic large-cell lymphoma (sALCL) is a rare hematological malignancy with poor prognosis, which is associated with a significant economic burden. This study aimed to evaluate the cost-effectiveness of brentuximab vedotin (BV) in comparison to conventional chemotherapy in patients with relapsed/refractory sALCL, from a Chinese healthcare perspective., Methods: A partitioned survival model with three health states (progression-free survival, post-progression survival, and death) was adapted to compare BV against chemotherapy. Comparator represented a basket of commonly used chemotherapies in China. Two cohorts in each arm were estimated, representing patients receiving no transplant and autologous stem cell transplant (ASCT) after BV or chemotherapy. Clinical data was obtained from the pivotal phase-II trial (NCT00866047) for BV and also from the literature for a comparator. Resource use items covered drug acquisition and administration; concomitant medications; ASCT; treatment of adverse events; and long-term follow-up. Cost parameters were based on Chinese sources. Outcomes were measured in quality-adjusted life-years (QALYs). Both costs and effects were discounted at 5% according to Chinese guidelines. The impact of uncertainty was evaluated using deterministic and probabilistic sensitivity analyses., Results: The incremental cost-effectiveness ratio (ICER) for BV vs. chemotherapy was $9,610 (¥62,084) per QALY in the base case. The main model driver was superior progression-free and overall survival benefits of BV. The ICERs were relatively robust in the majority of sensitivity analyses, ranging around ±10% of the base case. Under the conventional decision thresholds (1-3 times of Chinese per capita GDP), the probability of BV being cost-effective ranged from 56 to 100%. Limitations of the study included the lack of comparative data from the trial and the small and heterogeneous sample due to its disease nature., Conclusions: BV may be a cost-effective treatment vs. chemotherapy in treating relapsed or refractory systemic anaplastic large-cell lymphoma in China.

Relapsed and refractory ALK-positive anaplastic large cell lymphoma (ALCL) has a poor prognosis. In this report, we present 3 relapsed/refractory pediatric ALCL patients, 1 of these with central nervous system involvement. All 3 patients were treated with ALK inhibitor and achieved complete response. Both crizotinib and alectinib have shown significant activity in pediatric patients with refractory ALK-positive ALCL., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

A 28-year-old male patient presented with multiple lymphadenopathies and extranodal masses. He was diagnosed with stage IVB ALK-positive anaplastic large cell lymphoma after the right axillary lymph node biopsy. A partial metabolic response with fluorodeoxyglucose accumulation was observed in the residual disease of the upper left hilar lymph node after eight courses of brentuximab vedotin, cyclophosphamide, adriamycin, and prednisolone. We started alectinib at 600 mg daily, which achieved a complete metabolic response (CMR) after three months. The CMR was maintained and alectinib was continuously administered without adverse events at the last follow up. Alectinib showed high efficacy and tolerability, though the optimal period and long-term adverse effects of administration remain unclear. Therefore, further studies are necessary.

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.)

Primary endobronchial presentation of anaplastic large cell lymphoma is rare in the paediatric age group. We present a 12-year-old boy with breathlessness, fever, cough and weight loss, who was misdiagnosed as a case of tuberculosis and started on antitubercular therapy, which showed no improvement. Chest X-ray showed a completely opacified left hemithorax and chest computed tomography revealed a mass encircling the left main bronchus with collapse- consolidation of the left lung. Fibreoptic bronchoscopy revealed a growth in the left main bronchus. Subsequently, fine-needle aspiration cytology and biopsy from the mass confirmed it to be a malignancy consistent with anaplastic large cell lymphoma. Metastatic work-up revealed no other sites of involvement. Chemotherapy resulted in rapid and complete regression of the tumour. No evidence of local or distant recurrence was reported after 18 months of follow-up. Clinicians and pathologists should be aware of this presentation as prompt diagnosis and treatment can give promising results. This case highlights the importance of timely tissue diagnosis in patients with non-resolving pyrexia and organ lesions on imaging.