Systemic Anaplastic Large Cell Lymphoma Research Articles

Clinicopathological features of primary mucosal CD30-positive T-cell lymphoproliferative disorders

Objective: To investigate the clinicopathological features and differential diagnosis of primary mucosal CD30-positive T-cell lymphoproliferative disorders (pmCD30+TLPD). Methods: Eight cases of pmCD30+TLPD diagnosed from 2013 to 2023 at the Department of Pathology, Beijing Friendship Hospital Affiliated to Capital Medical University and Beijing Ludaopei Hospital were retrospectively collected. The immunophenotype, EBV infection status and T-cell receptor (TCR) clonability of tumor cells were examined. The clinicopathological features were analyzed and related literatures were reviewed. Results: There were 5 females and 3 males, aged 28 to 73 years, without B symptoms, lack of trauma and autoimmune diseases. Seven cases occurred in oral mucosa and one in anal canal mucosa. Submucosal nodules with ulcerations were presented in all cases except one, which only submucosal nodule. Morphologically, there was different distribution of allotypic lymphocytes in inflammatory background. Four cases showed "kidney-shaped", "embryonic" and "horseshoe-shaped" cells, and one case resembled Hodgkin and Reed/Sternberg (HRS) cells. Allotypic lymphocytes expressed CD3 (7/8), CD4+/CD8-(7/8) and CD4-/CD8-(1/8). CD30 was uniformly strongly positive while ALK and CD56 were negative. In situ hybridization of EBER was negative in five cases (5/5). Clonal TCR gene rearrangement was positive in two cases. Four patients did not receive radiotherapy or chemotherapy. All the seven patients survived without disease except one died due to concurrent leukopenia. Conclusions: pmCD30+TLPD had a broad morphological spectrum and could be easily confused with primary cutaneous CD30+TLPD and systemic ALK-negative anaplastic large cell lymphoma involving mucosa, which may lead to misdiagnosis. Although the majority of the cases had a favorable prognosis, a few cases relapsed or progressed to lymphoma.

DUSP22-rearranged primary cutaneous CD30-positive T-cell lymphoproliferative disorders and adult T-cell leukemia/lymphoma frequently share the LEF1+/TIA1− immunophenotype

DUSP22 rearrangements are genetic alterations observed in a subset of systemic anaplastic large cell lymphoma (S-ALCL), primary cutaneous anaplastic large cell lymphoma (C-ALCL), and lymphomatoid papulosis (LyP). Previous investigations have shown that the LEF1+/TIA1− immunoprofile and MSC E116K mutations are highly associated with DUSP22 rearrangement in ALCL. However, the existing literature primarily focuses on S-ALCL. Our understanding of the LEF1/TIA1 immunoprofile and MSC mutation status in C-ALCL/LyP is still limited. In this study, we aimed to assess LEF1/TIA1 expression and MSC mutations in a cohort of 23 C-ALCL/LyP cases, along with a control group of histological mimickers. DUSP22 rearrangements were detected by fluorescence in situ hybridization in eight cases (6/10 C-ALCL, 2/13 LyP). We found LEF1 expression in five out of eight (63%) DUSP22-rearranged cases (3/6 C-ALCL, 2/2 LyP), and none of the 15 cases lacking DUSP22 rearrangements. Furthermore, we also found frequent LEF1 expression in adult T-cell leukemia/lymphoma (ATLL; 10 of 11, 91%) within the control group. TIA1 expression was consistently negative in all DUSP22-rearranged C-ALCL/LyP and ATLL cases tested. MCS E116K mutation was identified in one of five DUSP22-rearranged C-ALCL cases. RNA sequencing of a DUSP22-rearranged C-ALCL revealed a novel DUSP22::SNHG fusion coexisting with a CD58::WNT2B fusion. In conclusion, our findings demonstrated a lower rate of LEF1 expression in DUSP22-rearranged C-ALCL/LyP compared to previous reports that predominantly focused on S-ALCL. Moreover, we observed that the majority of ATLL cases also expressed LEF1, suggesting that the LEF1+/TIA1− immunoprofile does not differentiate DUSP22-rearranged C-ALCL/LyP from ATLL.

Brentuximab Vedotin Retreatment in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma or Peripheral T-Cell Lymphoma: A Retrospective United States Claims Analysis.

Brentuximab vedotin (BV) monotherapy (BV-M) and combination (BV-C) therapies are safe and effective for classical Hodgkin lymphoma (cHL) and CD30-expressing peripheral T-cell lymphomas (PTCLs). Although the sample sizes have been small (12-29 patients), in clinical studies, response rates of 53-88% have been reported for BV retreatment in patients with an initial BV response. We evaluated the real-world characteristics and treatment patterns of cHL/PTCL patients who received BV and were retreated in the United States. Symphony Health Patient Claims (11/2013-1/2022) were retrospectively analyzed to identify cHL/PTCL patients treated with BV and retreated with BV-M, BV-C, or non-BV therapy. Patient characteristics were described by retreatment, and predictors of BV-M retreatment were identified. Among the cHL and PTCL patients treated with BV (n = 6442 and 2472, respectively), 13% and 12%, respectively, were retreated with BV; the median times from initial BV to BV-M retreatment were 5 and 7 months, respectively; and the numbers of BV-M retreatment doses were 4 and 5, respectively. Among cHL patients, the predictors of BV-M retreatment were age (18-39 vs. ≥60 years), sex (women vs. men), and previous stem cell transplantation (yes vs. no). Among PTCL patients, the only predictor of BV-M retreatment was systemic anaplastic large-cell lymphoma subtype (yes vs. no). Real-world data support clinical study results suggesting earlier BV treatment be considered, as BV retreatment may be an option.

Paediatric onset lymphomatoid papulosis: results of a multicentre retrospective cohort study, on behalf of the EORTC Cutaneous Lymphoma Tumours Group (CLTG).

Lymphomatoid Papulosis (LyP) is a rare cutaneous T-cell lymphoproliferative disorder. Comprehensive data on LyP in the paediatric population is scarce. To characterize epidemiological, clinical, histopathological, and prognostic features of paediatric LyP. This was a retrospective, multicentre international cohort study including 87 cases of children and adolescents with LyP diagnosed between 1998 and 2022. Patients aged ≤ 18 years old at disease onset were included. Diagnosis was made in each centre based on clinical-pathological correlation. Eighty-seven patients from 12 centres were included. The mean age at onset was 7.0 years (range 3 months-18 years) with a male to female ratio of 2:1. The mean time between onset of first cutaneous lesions and diagnosis was 1.3 years (range 0-14 years). Initial misdiagnosis concerned 26.4% of patients. Initially, LyP was most often misdiagnosed as Pityriasis lichenoides et varioliformis acuta (PLEVA), insect bites, or mollusca contagiosa. Erythematous papules or papulonodules were the most frequent clinical presentation. Pruritus was specifically mentioned for 20.7% of patients. The main histological subtype was type A in 55.1% of the cases. If analysed, monoclonal TCR rearrangement was found in 76.5% of the skin biopsies. The overall survival rate was 100% with follow up at 5 years available for 33 patients and at 15 years for 8 patients. A development of associated haematological malignancy (HM) occurred in 9.6% of the cases (7/73), including four mycosis fungoides (MF) cases, one primary cutaneous anaplastic large cell lymphoma (pc-ALCL), one systemic ALCL and one case of acute myeloid leukaemia. If we compare incidence rates of cancer with the world 0-19 years old population from 2001-2010, we estimate a significantly higher risk of associated malignancy in general, occurring before the age of 19 years old with incidence rate ratio of 87.49 (CI 86.01-88.99). We report epidemiological data from a large international cohort of children and adolescents with LyP. Overall the prognosis of the disease is good, with excellent survival rates for all patients. Due to increased risk of associated HM, a long-term follow-up should be recommended for LyP patients.

Challenges in utilizing ALK expression to distinguish primary cutaneous from systemic anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is a CD30+ peripheral T-cell lymphoma with a clinical spectrum including cutaneous and systemic presentations. While primary cutaneous ALCL (pcALCL) has a favorable prognosis, systemic ALCL (sALCL) has poorer survival outcomes. Expression of anaplastic lymphoma kinase (ALK) by malignant cells has been suggested to distinguish sALCL from pcALCL. However, there have been documented cases of ALK-positive ALCL confined to the skin. The present study reviewed characteristics of published cutaneous ALK-positive ALCL cases to distinguish between these two entities. In 23 identified adults with ALK-positive pcALCL, 26% developed systemic involvement and 74% had skin-limited disease. In 14 pediatric patients, 36% had both cutaneous and systemic involvement and 64% had cutaneous disease only. This analysis revealed that pcALCL and sALCL could not reliably be distinguished by ALK expression or nuclear vs. cytoplasmic localization. Localized treatment with frequent monitoring may be sufficient in ALK-positive pcALCL until there is evidence of progression. Physicians should be aware of the overall spectrum of ALCL, including cutaneous limited disease, systemic disease, disease with NPM-ALK translocation, disease with ALK positivity and disease with skin recurrence.

Cardiac toxicity of brentuximab vedotin: a real-word disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database.

Brentuximab vedotin (BV) has obtained approval for the therapeutic management of classical Hodgkin lymphoma as well as systemic anaplastic large cell lymphoma. Given the inherent constraints of conventional clinical trials, the correlation between BV and cardiac adverse events (AEs) remains enigmatic. The objective of this investigation is to comprehensively assess cardiac AEs attributed to BV by employing advanced data mining techniques, utilizing the FDA Adverse Event Reporting System (FAERS). The indices for the assessment of disproportionality encompass the reporting odds ratio (ROR), the proportional reporting ratio, the information component, and the empirical Bayesian geometric mean. Employing these sophisticated metrics, we gauged the extent of disproportionate occurrences. The dataset was sourced from the FAERS from the first quarter of 2012 to first quarter of 2023, facilitating a comprehensive analysis of the potential correlation between BV and cardiac AEs. This scrutiny encompassed a comparative analysis of both cardiac and non-cardiac AEs. A total of 495 cases of BV's cardiac AEs were discerned, with the identification of 31 preferred terms (PTs). Among these, 8 PTs emerged as conspicuous signals of cardiac AEs, notably encompassing ventricular hypokinesia (ROR 7.59), tachyarrhythmia (ROR 7.06), sinus tachycardia (ROR 6.18), cardiopulmonary failure (ROR 4.44), pericardial effusion (ROR 4.32), acute coronary syndrome (ROR 4.02), cardiomyopathy (ROR 3.30), and tachycardia (ROR 2.76). The manifestation of severe outcomes demonstrates a discernible correlation with the cardiac AEs (P < 0.001). Our investigation furnishes invaluable insights for healthcare practitioners to proactively mitigate the incidence of BV-associated cardiac AEs.

Up to Date of Cyanobacterial Natural Products

More than 2000 compounds have been reported from cyanobacteria. The most successful example is dolastatin 10, of which a related compound monomethylauristatin E is used as antibody-drug conjugate (ADC) for Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Recently genome-based analyses by Piel led to the discovery of novel compounds from cyanobacteria. W. H. Gerwick found a potential as anti-SARS-CoV-2 agent in gallinamide A, which was reported as a cathepsin L inhibitor. In our group columbamides were isolated from the marine cyanobacterium Moorena bouillonii. The geometry of the double bond was determined by the coupling constant obtained using non-decoupled heteronuclear single quantum coherence (HSQC). The configuration of chloromethine in a long-chain acyl moiety was determined by the Ohrui method at room temperature using a chiral HPLC column. Columbamide D showed biosurfactant activity. One strain many compounds (OSMAC) is a method to discover new compounds by changing culture conditions. Prior to our experiments, attempts to apply OSMAC in cyanobacteria resulted in the induction or up-regulation of only known compounds. The heat shock culture of the freshwater cyanobacterium Microcystis aeruginosa up-regulated a ribosomal peptide argicyclamide C. At the same time, we discovered bis-prenylated and monoprenylated argicyclamides A and B. More recently iron-limited culture produced hydroxylated argicyclamide A. OSMAC and genome-based screening could lead the discovery of unique biologically active compounds from cyanobacteria.

The Unusual Sequence of Lymphomatoid Papulosis Following Hodgkin's Disease: A Case Report

Lymphomatoid papulosis (LyP) is a rare skin disease which is characterised by chronic, recurrent self-healing papulo-nodular skin lesions. It is classified under the group of primary cutaneousCD30+ve lymphoproliferative disorders. It is important to diagnose LyP as it is usually associated with other malignant lymhoproliferative disorders like mycosis fungoides, cutaneous or systemic anaplastic large cell lymphoma and Hodgkin's lymphoma. LyP associated malignancies may occur before, concurrent with or after the onset of LyP. In most of the cases previously described, Hodgkin's disease has developed after, or concurrently with, the onset of LyP. Here we report a case of LyP that developed 5 years after the onset and therapy for Hodgkin's lymphoma.

Distinct Subtypes of Chemotherapy-Resistant Systemic ALK-Positive Anaplastic Large Cell Lymphoma Demonstrate Long-Term Complete Remissions to Imatinib

Background Platelet-derived growth factor receptor (PDGFR) is expressed in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) positive anaplastic large cell lymphomas (ALCL ALK+). Our previous preclinical research suggested that PDGFR blockade by the Abl/c-Kit/PDGFR kinase inhibitor imatinib could be an effective treatment strategy for ALCL ALK+. An indicator patient whose ALCL cells expressed PDGFR and who failed three treatment lines (including autologous stem cell transplantation) achieved complete remission (CR) with imatinib. Methods We treated 6 relapsed/refractory (r/r) ALK+ ALCL patients with imatinib, 4 of which within the prospective clinical trial, EudraCT No.: 2013-003505-26. Median follow-up was 40 months (160 weeks, range 4 - 428). Patients were characterized by whole exome sequencing, bisulfite sequencing, RNA-sequencing and immunological profiling. Whole exome sequencing data were integrated and compared to 32 additional ALK+ ALCL patients (Larose et. al., Haematologica, 2021; Creszenzo et al., Cancer Cell 2015; Mologni et al. (unpublished). Results 5-year progression-free survival (PFS) was 67%. 4 out of 6 patients achieved a CR that was maintained throughout the follow-up of 3.3 - 8.9 years. Lymphoma cells of the non-responding patients did not express PDGFRA/B as confirmed by immunohistochemistry and RNA-scope (panel figure A). Cytoplasmic co-expression of both, ALK and PDGFRA/B, in ALCL tumor cells was associated with complete response to imatinib in ALK+ ALCL patients. Methylation profiling confirmed a differentially activated PDGFR axis between responders and non-responders and identified a specific protein kinase profile that included a significant inflammatory upregulation of HGFAC, VEGFa, and TNFa in serum cytokine profiling. The transcriptional differential gene expression includes an upregulation of genes of GO:0045859 (regulation of protein kinase activity) in non-resonders. Ident pathologic variants resulting in amino-acid changes were detected in non-responders in mutated genes linked to kinase activity ( TBC1D28 E56A), protein processing ( EMC1 S323T: cosmicV64345386 and EMC1S325N: cosmicV100916421; and GOLGA8S) and cytokine signaling ( IFNL2, ZFYVE19). The imatinib-resitance profile involving mutations in EMC1 and GOLGA8S could be detected at a frequency of 6/32 (19%) in an independent reference cohort of r/r ALK+ALCL (panel figure B). Exclusive mutations in PPP1R13B linked to p53-pathway were found in all responders. PDGFRA mutations with low allele frequencies (2-5%) were identified soley in imatinib-responders. Additionally, non-responders were characterized by an exclusive mutational signature linked to vesicular endocytosis and cytokine signaling as a resistance mechanism to pan-kinase inhibitor imatinib. Conclusion PDGFRA/B expression in tumour cells of therapy-resistant ALK-positive ALCL patients can discriminate genetically and functionally distinct lymphoma subgroups that are directly related to long-term treatment response to kinase inhibitor imatinib. Our data suggests that significant imatinib responses may be achieved in more than 80% of chemotherapy-resistant ALK+ ALCL cases.

Gene Expression Profiling Reveals Two Overarching Types of Anaplastic Large Cell Lymphoma with Distinct Targetable Biology: An L.L.M.P.P. Study

Background: Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell lymphomas that share pathologic features but differ in clinical presentation, outcome, and molecular features. The World Health Organization (WHO) and International Consensus Classification (ICC) classify ALCLs by presence or absence of ALK rearrangements (R) and clinical presentation (systemic, cutaneous [c], or breast implant-associated [BIA]). ICC, but not WHO, recognizes DUSP22-R as defining a new genetic subtype of ALK- ALCL. The classifications otherwise do not reflect additional molecular heterogeneity in genetics (e.g., TP63-R) or therapeutic vulnerabilities (e.g., JAK-STAT3 pathway activation). Methods: ALCLs (N=689) underwent expert consensus review (WHO/ICC) through the Lymphoma/Leukemia Molecular Profiling Project (LLMPP). All cases also underwent genetic subtyping (ALK, DUSP22, TP63, and triple-negative [TN]) using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), as well as IHC for phospho-STAT3 Tyr705 (pSTAT3). RNAseq was performed and evaluable in 393 cases; the remaining cases had insufficient tissue, tumor content, RNA yield or quality, and/or sequencing data quality. Sequenced and non-sequenced sub-cohorts had similar demographics and subtype distribution. Results: Unsupervised gene expression profiling (GEP) identified 2 main molecular types of ALCL. Type I ALCLs predominantly included ALK+ ALCLs, BIA-ALCLs, and a subset of TN ALCLs (designated TN-I), whereas Type II ALCLs predominantly included ALCLs with DUSP22-R, TP63-R, or both (double-hit; DH), and the remaining TN ALCLs (TN-II). Type I ALCLs were strongly associated with pSTAT3 expression (74.2±26.4% positive malignant cells vs 9.9±22.7% for Type II; P&amp;lt;0.0001). An independently derived pSTAT3 staining threshold of 30% assigned Type I vs II with 91% accuracy. A third cluster of ALCLs, mostly cALCL, showed an epithelial GEP signature rather than a lymphoma signature; these cases were assigned to Types I or II based on pSTAT3 IHC. Distinct sub-signatures were identified for ALK+, DUSP22-R, TP63-R, and BIA ALCL (Fig. 1), but not ALK- ALCL or cALCL. Gene set enrichment analysis showed Type I ALCLs to be enriched for JAK-STAT3 signaling genes (normalized enrichment score [NES], 2.22; FDR&amp;lt;0.0001) and related pathways, such as TNFα-NFκB signaling (NES, 2.21; FDR&amp;lt;0.0001). In contrast, Type II ALCLs were enriched for cell cycle, DNA repair, epigenetic, and metabolic pathway genes, but not for major tyrosine kinase-mediated signaling pathway genes. Enriched epigenetic pathways included chromatin modifying enzymes (NES, -1.86; FDR=0.002) and histone methylation (NES, -1.71; FDR=0.002). EZH2 was the most overexpressed gene in Type II ALCLs (fold-change, 7.74; FDR=8.84×10 -306). At the protein level, EZH2 IHC H-scores were 275±45 in Type II and 168±70 in Type I ALCLs (P&amp;lt;0.0001); H3K27me3 H-scores were 170±81 and 76±63, respectively (P&amp;lt;0.001). The top metabolic gene set involved cholesterol biosynthesis (NES, -1.88; FDR=0.002). Overall survival (OS) data were available in 257 systemic ALCL patients (145 sequenced and 112 non-sequenced; cALCL and BIA-ALCL were excluded). Non-sequenced TN ALCLs were assigned to TN-I or TN-II using pSTAT3 IHC. The results supported earlier data indicating favorable prognosis of DUSP22-R ALCL (5 y OS, 95%) and ALK+ ALCL (87%), intermediate prognosis of TN ALCL (TN-I, 52% and TN-II, 38%; P=NS), and poor prognosis of TP63-R/DH ALCL (0%)(P&amp;lt;0.0001; Fig. 2). Conclusions: Two overarching molecular types of ALCL exist, predominantly associated with the presence (Type I) or absence (Type II) of the JAK-STAT3 signaling program. Distinct GEP signatures exist for ALK+ ALCL and BIA-ALCL (predominantly Type I), and DUSP22-R ALCL and TP63-R ALCL (predominantly Type II). TN ALCLs lacking ALK-R, DUSP22-R, and TP63-R can be stratified into TN-I and TN-II subtypes. pSTAT3 IHC has &amp;gt;90% accuracy as a surrogate for GEP-based subtyping. ALK- ALCL and cALCL cluster by molecular subtype rather than by defining GEP signatures. Type II ALCLs are enriched for targetable epigenetic and metabolic pathways, including EZH2/histone methylation and cholesterol biosynthesis. This molecular classification is diagnostically, prognostically, and potentially therapeutically relevant, and can be applied using FISH and IHC in routine practice and in the clinical trial setting.

Primary cutaneous CD30+ lymphoproliferative disorders with DUSP22 translocation.

Primary cutaneous CD30+ lymphoproliferative disorders (LPD) encompass abroad category of clonal Tcell proliferations with varied clinical presentations. Classically, lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (ALCL) have been recognized as distinct clinicopathological entities according to their differing clinical features. Recently, asubset of LyP and both cutaneous and systemic ALCL have been shown to carry aDUSP22 translocation [1-3], adefining molecular feature for the novel entity "LyP with DUSP22t" [1]. In cutaneous biopsies, both primary cutaneous DUSP22-translocated ALCL and LyP with DUSP22 rearrangements are characterized by abiphasic pattern with significant small cell epidermotropism. Adistinct protein expression profile with preserved T Cell Receptor (TCR) expression, positivity for CD30, LEF1, HLA, and CD58, and negativity for cytotoxic marker expression as well as phospho-STAT3 protein is consistently found in these cases.

Updates in pathobiological aspects of anaplastic large cell lymphoma.

Anaplastic large cell lymphomas (ALCL) encompass several distinct subtypes of mature T-cell neoplasms that are unified by the expression of CD30 and anaplastic cytomorphology. Identification of the cytogenetic abnormality t(2;5)(p23;q35) led to the subclassification of ALCLs into ALK+ ALCL and ALK- ALCL. According to the most recent World Health Organization (WHO) Classification of Haematolymphoid Tumours as well as the International Consensus Classification (ICC) of Mature Lymphoid Neoplasms, ALCLs encompass ALK+ ALCL, ALK- ALCL, and breast implant-associated ALCL (BI-ALCL). Approximately 80% of systemic ALCLs harbor rearrangement of ALK, with NPM1 being the most common partner gene, although many other fusion partner genes have been identified to date. ALK- ALCLs represent a heterogeneous group of lymphomas with distinct clinical, immunophenotypic, and genetic features. A subset harbor recurrent rearrangement of genes, including TYK2, DUSP22, and TP63, with a proportion for which genetic aberrations have yet to be characterized. Although primary cutaneous ALCL (pc-ALCL) is currently classified as a subtype of primary cutaneous T-cell lymphoma, due to the large anaplastic and pleomorphic morphology together with CD30 expression in the malignant cells, this review also discusses the pathobiological features of this disease entity. Genomic and proteomic studies have contributed significant knowledge elucidating novel signaling pathways that are implicated in ALCL pathogenesis and represent candidate targets of therapeutic interventions. This review aims to offer perspectives on recent insights regarding the pathobiological and genetic features of ALCL.

A Case of Systemic Anaplastic Large Cell Lymphoma with Secondary Cutaneous Involvement

A Case of Systemic Anaplastic Large Cell Lymphoma with Secondary Cutaneous Involvement

Efficacy and safety of crizotinib in ALK-positive systemic anaplastic large-cell lymphoma in children, adolescents, and adult patients: results of the French AcSé-crizotinib trial

BackgroundThe 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). MethodsALK+ ALCL patients 12 months or older with measurable disease and no standard care options available received crizotinib twice daily at 165 mg/m2 in children and adolescents and 250 mg in adults. The primary end-point was the response rate at 8 weeks. ResultsTwenty-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. ConclusionCrizotinib 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.

BRENTUXIMAB VEDOTIN IN COMBINATION WITH CHEMOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED CD30‐POSITIVE PERIPHERAL T‐CELL LYMPHOMAS: REAL‐WORLD DATA

Background: Based on the results of ECHELON-2 trial, Brentuximab vedotin (BV) in combination with cyclophosphamide, doxorubicin and prednisone (CHP) has been approved by EMA for the treatment of newly diagnosed systemic anaplastic large cell lymphoma (ALCL) and become the standard of care for this patient population. In Czech Republic, BV plus CHP is approved as 1st line treatment for CD30-positive peripheral T-cell lymphomas (PTCL), including non-ALCL PTCL since 8/2020. The aim of this analysis is to provide real world data with this combination. Methods: Using the prospective observational NiHiL project (NCT03199066), we identified patients (pts) ≥ 18 years of age with histologically confirmed CD30+ PTCL (diagnosed between August 2020 to October 2022), who received BV in combination with chemotherapy as 1st line treatment. Results: A total of 63 pts were recruited; 31 (49%) had ALCL (12 ALK+, 19 ALK-) and 32 (51%) had non-ALCL PTCL (16 with PTCL NOS, 14 with AITL, and 2 with EATL). Median age was 60 years (range; 19-82). Most pts showed adverse clinical features at lymphoma diagnosis, including Ann Arbor stage III-IV (n = 46; 73%) or elevated LDH (n = 34; 54%). Of note, 18 (29%) pts had ECOG performance status ≥ 2 (incl. 6 pts ECOG 3 and 1 pt ECOG 4). By IPI, 16 (25%), 18 (29%), 12 (19%), and 17 (27%) pts belonged to low, low-intermediate, high-intermediate, and high-risk groups, respectively. The most common chemotherapy backbone was CHP administered in 45 (71%) pts, followed by CHP + etoposide administered in 13 (21%) pts. Five (8%) pts received attenuated regimen. Nine (14%) pts underwent pre-planned consolidative autologous stem cell transplant. Sixty (95%) pts received G-CSF prophylaxis. The most common grade ≥3 adverse events were neutropenia (49%), anaemia (30%), febrile neutropenia (19%), thrombocytopenia (19%), and infections (18%). Neuropathy (all grades) occurred in 21 pts (33%); grade 3 neuropathy in 3 pts (5%). Grade 5 AE occurred in 2 (3%) pts, sepsis in both cases. Out of 63 there were 56 (89%) pts evaluable for response (PET/CT) at the time of database lock. The overall objective response rate (ORR) was 80% with 63% complete response (CR). The ORR/CR rates in ALCL (n = 26) versus non-ALCL (n = 30) pts were 89%/73% versus 73%/53%, respectively. The median follow-up of surviving pts is 16.6 months (range; 4.3- 31.3). The overall 18-months PFS and OS probability were 61.8% and 73.7%, respectively (Figure 1). By lymphoma subtype, the 18-months PFS and OS probability were 77.6% and 83.5% in ALCL and 50.3% and 65.9% in non-ALCL, respectively (Figure 1). Evaluation of the relationship between % of CD30+ neoplastic cells and clinical outcome is ongoing. The research was funded by: The study is supported by the Cooperation Program, research area “Oncology and Haematology” and NU20-03-00253 and NU22-03-00370. Keywords: Aggressive T-cell non-Hodgkin lymphoma, Combination Therapies Conflicts of interests pertinent to the abstract A. Sykorova Other remuneration: ROCHE, GILEAD, TAKEDA H. Mocikova Consultant or advisory role Takeda, Roche, Astra Zeneca, Janssen, Abbvie D. Belada Other remuneration: Roche, Gilead Sciences M. Trneny Consultant or advisory role Takeda Honoraria: Takeda

Retrospective Analysis With Propensity Score Matching of Peripheral T-Cell Lymphoma Treated Frontline With Brentuximab Vedotin and Chemotherapy.

Since Food and Drug Administration approval of brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (A + CHP) as initial therapy for previously untreated CD30-expressing peripheral T-cell lymphoma (PTCL), there has been limited research on real-world patient characteristics, treatment patterns, and clinical outcomes. We retrospectively analyzed claims of patients with PTCL treated with frontline A + CHP or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) using the Symphony Health Solutions database. Adults with International Classification of Diseases-9/10 PTCL diagnosis codes who initiated A + CHP or CHOP between November 2018 and July 2021 were included. A 1:1 propensity score matching analysis was performed that adjusted for potential confounders between groups. A total of 1344 patients were included (A + CHP, n = 749; CHOP, n = 595). Before matching, 61% were men; median age at index was 62 (A + CHP) and 69 (CHOP) years. The most common A + CHP-treated PTCL subtypes were systemic anaplastic large cell lymphoma (sALCL; 51%), PTCL-not otherwise specified (NOS; 30%), and angioimmunoblastic T-cell lymphoma (AITL; 12%); the most common CHOP-treated subtypes were PTCL-NOS (51%) and AITL (19%). After matching, similar proportions of patients treated with A + CHP and CHOP received granulocyte colony-stimulating factor (89% vs. 86%, P = .3). Fewer patients treated with A + CHP received subsequent therapy than CHOP overall (20% vs. 30%, P < .001) and specifically with the sALCL subtype (15% vs. 28%, P = .025). Characteristics and management of this real-world PTCL population who were older and had a higher comorbidity burden than that in the ECHELON-2 trial demonstrate the importance of retrospective studies when assessing the impact of new regimens on clinical practice.

How to Diagnose Anaplastic Large Cell Lymphoma on Cytological Samples? A Series with Emphasis on Diagnostic Clue and Pitfalls

Introduction: Anaplastic large cell lymphoma (ALCL) is a rare mature T-cell non-Hodgkin’s lymphoma characterized by large and pleomorphic neoplastic CD30-positive T cells. ALCL includes different subtypes with different clinical and biological features: systemic ALCL, primary cutaneous ALCL, breast implant-associated ALCL (BIA-ALCL). Anaplastic lymphoma kinase (ALK) is overexpressed and rearranged in some systemic cases. Diagnosis of ALCL may be challenging on cytological samples, but the correct diagnosis is mandatory for the management of the patient. Methods: A retrospective series of 12 ALCLs diagnosed by cytology is reported. Cytological samples included lymph nodes and skin lesions fine needle aspiration cytology, peritoneal effusion, and periprosthetic fluid. Microscopic evaluation was performed on direct smears, cell-block sections, and cytocentrifugated slides. Immunocytochemistry was performed on cell-block sections, direct smears, and cytocentrifugated slides. Molecular evaluation by fluorescent in-situ hybridization (FISH) was performed on cell-block sections. Results: The series included 4 ALK+ ALCLs, 5 ALK− ALCLs, and 3 BIA-ALCLs. FNAC was performed on lymph nodes in 8 cases and on skin lesion in 1 case. In this last case, a peritoneal effusion was also evaluated. Breast periprosthetic fluids were evaluated in 3 cases. A large immunocytochemical panel was performed in each case, and FISH in 3 cases, demonstrating ALK rearrangement in a case of ALK+ ALCL. A final diagnosis was rendered in all cases. In the case of skin lesion, the differential diagnosis between systemic ALCL and primary cutaneous ALCL was possible. Conclusion: The cytological diagnosis of ALCL may be challenging, and the proper management of the collected sample is mandatory. The rapid on-site evaluation and the realization of a cell block are strongly recommended. Immunocytochemistry is mandatory for the diagnosis and a large antibodies panel is needed as differential diagnosis includes many different neoplasms. FISH may be useful to evaluate ALK rearrangements. When properly managed, cytology can lead to a reliable final diagnosis of ALCL.

Clinicopathological findings, prognosis, and Epstein–Barr virus infection in rheumatoid arthritis patients with other iatrogenic immunodeficiency-associated T- and NK-cell lymphoproliferative disorders

BackgroundOther iatrogenic immunodeficiency-associated (OIIA) T- and natural killer (NK)-cell lymphoproliferative disorders (TNK-LPDs) are rare in patients with rheumatoid arthritis (RA).MethodsWe investigated the clinicopathological characteristics, Epstein–Barr virus (EBV) infection, genetic findings, therapeutic response, and prognostic factors in 21 RA patients with OIIA TNK-LPDs and compared these with those of 39 with OIIA B-cell LPDs (B-LPDs) and 22 with non-OIIA B-LPDs.ResultsImmunohistologically, 11 patients (52%) showed CD4+ T-LPDs, and 7 had a T follicular helper (TFH) phenotype. The other nine patients (43%) showed CD8+ T-LPDs, and the remaining one (5%) had features of CD3+ CD4− CD8− nasal type TNK-cell lymphoma. CD30+, p53+, and CMYC+ atypical lymphocytes were identified in seven (33%), eight (38%), and five (24%) patients, respectively. In situ hybridisation detected EBV-encoded RNA (EBER) + large atypical lymphocytes in five patients (24%). Nine of 17 patients (53%) showed clonal peaks of TCRγ by polymerase chain reaction. Withdrawal of MTX and biologic drugs was effective in 12 patients (57%), and 8 (38%) received chemotherapies. Two patients with TFH+ or EBV+ CD4+ CD30+ large cell peripheral T-cell lymphoma, one with CD8+ systemic anaplastic large cell lymphoma, and two with systemic EBV+ CD8+ T-cell lymphoma of childhood showed a lethal progressive clinical course within 13 months. Moreover, > 500 U/L LDH, large atypical lymphocytes, expression of CD30, p53, and CMYC, and EBER+ atypical lymphocytes were significantly poor prognostic factors for overall survival (p < 0.05). Median interval from RA onset to OIIA TNK-LPDs was 72 months, which was shorter than 166 months in OIIA B-LPDs (p = 0.003). EBV+ atypical and reactive lymphocytes were frequently found in 15 patients with OIIA TNK-LPDs (71%), in 27 with OIIA B-LPDs (69%), and only in 3 with non-OIIA B-LPDs (14%).ConclusionsOIIA TNK-LPDs occurred in early phase of RA, compared with OIIA B-LPDs, and occasionally showed a lethal progressive clinical course. Detection of OIIA TNK-LPD patients with poor prognostic factors is necessary. EBV infection in immunosuppressed patients due to persistent RA, MTX, and biologic drugs may play a role in forming the tumour microenvironment and lymphomagenesis of TNK-LPDs.

DUSP22 rearrangement is associated with a distinctive immunophenotype but not outcome in patients with systemic ALK-negative anaplastic large cell lymphoma.

DUSP22 rearrangement (R) has been associated with a favorable outcome in systemic ALK-negative anaplastic large cell lymphoma (ALCL). However, a recent study found that patients with DUSP22-R ALK-negative ALCL have a poorer prognosis than was reported initially. In this study, we compared the clinicopathological features and outcomes of patients with ALKnegative ALCL with DUSP22-R (n=22) versus those without DUSP22-R (DUSP22-NR; n=59). Patients with DUSP22-R ALCL were younger than those with DUSP22-NR neoplasms (P=0.049). DUSP22-R ALK-negative ALCL cases were more often positive for CD15, CD8, and less frequently expressed pSTAT3Tyr705, PD-L1, granzyme B and EMA (all P<0.05). TP63 rearrangement (TP63-R) was detected in three of the 66 (5%) ALK-negative ALCL cases tested and none of these cases carried the DUSP22-R. Overall survival of patients with DUSP22-R ALCL was similar to that of the patients with DUSP22-NR neoplasms regardless of International Prognostic Index score, stage, age, or stem cell transplantation status (all P>0.05), but was significantly shorter than that of the patients with ALK-positive ALCL (median overall survival 53 months vs. undefined, P=0.005). Five-year overall survival rates were 40% for patients with DUSP22-R ALCL versus 82% for patients with ALK-positive ALCL. We conclude that DUSP22-R neoplasms represent a distinctive subset of ALK-negative ALCL. However, in this cohort DUSP22-R was not associated with a better clinical outcome. Therefore, we suggest that current treatment guidelines for this subset of ALK-negative ALCL patients should not be modified at present.

Efficacy and Safety of Retreatment with Brentuximab Vedotin in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma or CD30-Expressing Peripheral T Cell Lymphoma

Introduction Brentuximab vedotin (BV) is approved for the treatment of adult patients (pts) with classical Hodgkin lymphoma (cHL), systemic anaplastic large cell lymphomas (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL). BV has been evaluated in combination with doxorubicin, vinblastine, and dacarbazine (A+AVD) in adult pts with advanced stage cHL in ECHELON-1 (Ansell S, 2022) and in combination with cyclophosphamide, doxorubicin, and prednisone (A+CHP) in pts with sALCL, PTCL-not otherwise specified (NOS), and angioimmunoblastic T-cell lymphoma (AITL) in ECHELON-2 (Horwitz S, 2022), demonstrating BV is well tolerated with a favorable efficacy profile in the first-line setting. Moreover, BV is approved as monotherapy for treatment of adults with cHL at high risk of relapse as consolidation therapy post autologous stem cell transplant, as well as in relapsed or refractory (r/r) sALCL. BV has also been studied in r/r cHL after auto-stem cell transplant (Younes A, 2012) and retreatment setting (Trümper L, 2020), with favorable efficacy. CD30 expression persists after BV treatment and SGN35-006 demonstrated that BV monotherapy is an effective retreatment option in pts with r/r cHL or sALCL who previously achieved an objective response with BV monotherapy (Bartlett N, 2014). Herein, we present efficacy and safety results from a phase 2 study, where BV was evaluated in pts with r/r cHL or CD30-expressing PTCL who previously received BV either alone or in combination. Methods SGN35-028 (NCT03947255) is a multicentered, single arm, phase 2 clinical trial that enrolled adult pts with r/r cHL and sALCL or other CD30-expressing PTCL who were previously treated with a BV-containing regimen at least 6 months prior that had evidence of an objective response, and subsequently experienced disease progression or relapse after discontinuing treatment. Pts were treated with BV 1.2 or 1.8 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity. The primary endpoints were objective response rate (ORR) and the safety and tolerability of BV retreatment. Results Of the 12 pts enrolled, 11 received at least 1 dose of study treatment including 5 pts with cHL and 6 pts with PTCL (4 pts with sALCL, 1 pt with PTCL-NOS, 1 pt with AITL). Both pts with non-ALCL PTCL had CD30 expression on 1% of tumor cells. Of the 11 pts that received at least 1 dose of study treatment, most were Black or African American (55%), not of Hispanic, Latino, or Spanish origin (91%), and <65 years old (73%). Pts received a median of 8 doses of BV (range: 1, 16) over a median of 25 weeks (range: 3, 55), 3 pts (27%) had dose reductions. Three pts were still on treatment as of data cutoff date. For pts with cHL, median time from initial diagnosis to first dose was 76.2 months (range: 34, 162), 2 pts achieved complete response (CR) and 3 pts partial response (PR) on prior BV therapy, median time from completion of last BV therapy to first dose was 28.2 months, and median age was 31 years (range: 28, 55). The ORR per investigator assessment was 60% (95% CI: 14.7, 94.7) with 1 pt achieving CR. For pts with PTCL, median time from initial diagnosis to first dose was 31.2 months (range: 23, 138), 5 pts achieved CR and 1 pt PR on prior BV therapy, median time from completion of last BV therapy to first dose was 20.1 months, and median age was 63 years (range: 35, 77). The ORR per investigator assessment was 83% (95% CI: 35.9, 99.6) with 4 pts achieving CR. The 4 pts with sALCL had an ORR of 100% with a CR rate of 75%. Eight pts discontinued study treatment, 4 pts discontinued treatment due to disease progression, 2 pts due to investigator decision, and 2 pts due to treatment emergent adverse events (TEAEs), both with peripheral sensory neuropathy. Thirty-six percent of pts experienced ≥ Grade 3 treatment-related TEAEs, 2 (18%) each for neutropenia and peripheral sensory neuropathy and 1 (9%) each for amylase increased, fatigue, malaise, and nausea. One pt experienced a Grade 5 adverse event of decreased appetite related to progressive PTCL disease that was not treatment related. Conclusions Preliminary results from this study show BV is a viable retreatment option for adults with r/r cHL, sALCL, and PTCL. Moreover, safety results were consistent with the known safety profile and no new safety signals were observed. This study is ongoing, updated efficacy and safety results will be presented at the meeting.