Primary CD30 (Ki-1)-positive anaplastic large cell lymphoma of the duodenum

Summary Ki-1 anaplastic large cell lymphoma (ALCL) commonly affects the skin, lymph nodes, and bone. Primary ALCL of the alimentary tract is rare. The authors describe a case of primary ALCL of the duodenum in a 62-year-old man who presented with epigastric discomfort and weight loss. The patient was treated with modified CHOP and is in complete remission at 18 months. We reviewed all cases of primary ALCL of the alimentary tract in the literature and noted that this neoplasm often mimics gastrointestinal carcinoma.     

Anaplastic lymphoma kinase‐positive anaplastic large cell lymphoma: current and future perspectives in adult and paediatric disease

Anaplastic large cell lymphoma (ALCL) is a rare T‐cell lymphoma seen in both adults and children. ALCL is associated with a characteristic chromosomal translocation, t(2;5)(p23;35) which fuses the anaplastic lymphoma kinase (ALK) gene on chromosome 2 with the nucleophosmin (NPM) gene on chromosome 5, resulting in a NPM‐ALK fusion protein, ALK over‐expression and constitutive tyrosine kinase activity. This aggressive lymphoma is more prevalent in males and can present with extranodal involvement (lung, skin and marrow infiltration) and haemophagocytic lymphohistocytosis. The long‐term overall survival is approximately 70–90% in children and over 70% in adults. Staging systems and prognostic risk factors are different in both childhood and adult ALCL. Treatment in adults is typically anthracycline‐based, with autologous stem cell transplantation (ASCT) salvaging patients in relapsed disease. There is evidence for ALL‐like therapy or intensive, pulsed anthracycline‐based induction in children. ASCT, allogeneic SCT and vinblastine maintenance are all considered reasonable options in relapsed childhood disease. The anti‐CD30 immunoconjugate Brentuximab Vedotin and the specific ALK inhibitor Crizotinib are changing the treatment paradigm in ALCL (ALK‐positive or negative) and ALK‐positive ALCL respectively. Both agents have shown encouraging responses in relapsed ALCL. It remains to be seen how these novel agents are used, but it is very possible that they may improve overall responses and survival in both children and adults. This review highlights the presentation, histopathological features, prognostic factors, and evidence‐based treatment approaches in the first line and relapsed setting in ALK‐positive ALCL. The review concludes by discussing the novel approaches using Brentuximab and Crizotinib which are being tested in clinical trials.     

Pretargeted antibody-guided radioimmunotherapy in a child affected by resistant anaplastic large cell lymphoma

Anaplastic large cell lymphoma (ALCL) is characterized by preferential paracortical and intrasinusoidal lymph node involvement by large anaplastic tumor cells expressing the CD30 antigen. Up to 80% of pediatric patients with ALCL can be cured with multi-agent chemotherapeutic regimens. Patients resistant to chemotherapy or suffering from early relapse have a poor prognosis and a poor chance of survival. In these cases, the highly aggressive clinical course of ALCL, associated with systemic symptoms and extranodal involvement, has been treated with different approaches in various cooperative trials, including conventional chemotherapy and human stem cell transplantation (HSCT). However, the optimal treatment has not yet been defined, in particular in cases of relapse. More recently, radioimmunotherapy has been studied with encouraging results in cancer patients, including non-Hodgkin's lymphoma. Here we describe the case of a pediatric ALCL, relapsing after HSCT, treated with pretargeted antibody-guided radioimmunotherapy, obtaining a complete remission, with excellent quality of life over the past 10 months.     

Disease site as a determinant of survival outcome in patients with systemic anaplastic lymphoma kinase positive anaplastic large cell lymphoma with extranodal involvement: an analysis of 1306 cases from the US National Cancer Database

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

29例原发系统性间变大细胞淋巴瘤的病理特点及临床分析

目的:探讨原发系统性间变大细胞淋巴瘤(ALCL)的病理特点、临床特征与预后的关系.方法:对29例原发系统性ALCL患者的病理特点、临床特征、完全缓解率(CR)、长期生存率和预后因素进行了分析.结果:所有病例的瘤细胞均强表达CD30,58.62%间变性淋巴瘤激酶(ALK)阳性.接受了治疗的28例患者的CR率为50.0%,2年和5年生存率分别为51.3%与27.1%.ALK阳性患者CR为68.8%,2、5年无病生存率分别为60.2%、42.5%,明显高于ALK阴性组(P<0.05).国际预后指数(IPI)0～2分患者组CR率为57.1%,2年、5年无病生存率分别为80.2%、65.1%,明显高于IP13～5分患者组(P<0.05).Cox比例风险回归分析表明ALK的表达、IPI评分对预后的影响有统计学意义(P<0.05).结论:ALK表达、IPI评分有助于判断原发系统性ALCL的预后,并为个体化治疗提供了依据.     

Cardiac presentation of ALK positive anaplastic large cell lymphoma

Cardiac involvement as an initial presentation of malignant lymphoma is a rare occurrence. We report the case of an immunocompetent 29-year-old male who presented with syncope and arrythmias secondary to a ventricular cardiac mass. Transcutaneous cardiac biopsy was non-diagnostic, therefore an open cardiac biopsy was performed from which a provisional diagnosis of a cardiac inflammatory pseudotumour was made. Six months after presentation, he developed several subcutaneous lesions with systemic symptoms. Histological and immunophenotypic review of the initial cardiac biopsy revealed features consistent with a diagnosis of CD30, ALK1 positive anaplastic large cell lymphoma (ALCL). Despite intensive treatment with combination chemotherapy, there was significant progression of disease, and he died 11 months after diagnosis. The overall prognosis of cardiac lymphoma remains poor, which may be due to the often late presentation of the tumour. To our knowledge, this is the first reported case of a cardiac ALK positive ALCL. Although rare, cardiac presentation of ALCL should be added to the list of differential diagnoses of cardiac lymphomas.     

间变性大细胞淋巴瘤的临床细胞病理学分析

目的:探讨间变性大细胞淋巴瘤(anaplastic large cell lymphoma,ALCL)的临床细胞病理学特点、免疫表型及鉴别诊断,提高对ALCL的认识。方法:分析经组织病理学证实的13例ALCL的临床表现、细胞病理学形态及免疫表型,并结合相关文献进行讨论。结果:13例ALCL患者中,ALK阳性11例,ALK阴性2例;全部表达CD30,部分表达EMA、CD3、CD45RO、CD43,不表达CD3、CD56、CD20、CD79a、PCK、CD117;Ki67LI 60%~100%。结论:ALCL是一种少见的非霍奇金淋巴瘤,依据其细胞病理学形态特征,细胞病理学可以做出正确的诊断,但应注意与霍奇金淋巴瘤、弥漫大B细胞淋巴瘤、恶性黑色素瘤、未分化癌等进行鉴别;当鉴别诊断有困难时,应行活检及免疫组织化学染色以确诊。     

23例间变性大细胞淋巴瘤临床特征及预后分析

目的探讨间变性大细胞淋巴瘤（ALCL）的临床特征和免疫组化特点,并分析其预后因素。方法收集23例ALCL患者的临床资料。从临床特征和预后因素等几方面进行回顾性分析。结果本文完全缓解率68.75%,3 a生存率为60.82%;单因素分析显示,Ann Arbor分期、LDH及国际预后指数（IPI）与疾病预后相关。IPI≥3是ALCL的独立的预后不良因素。结论Ann Arbor分期、LDH与国际预后指数对预测患者长期生存和指导治疗有重要意义。     

Paediatric anaplastic large cell lymphoma with leukaemic presentation in children: a report of nine French cases

This study aimed to describe the clinical features and outcome of anaplastic large cell lymphoma (ALCL) with leukaemic presentation in children. Among 267 patients included in the French paediatric ALCL database between 1989 and 2012, nine (3%) were described as having cytologically detectable circulating tumour cells. Clinical features combined fever (8/9), nodal and extra‐nodal disease (9/9), including hepato‐splenic (9/9) and lung involvement (7/9). The level of hyperleucocytosis ranged from 30 to 120 × 10⁹/l, with 12–90% of tumour cells. Diagnosis relied on a lymph node biopsy, with a positive ALK+ antibody immunostain in all nine cases, a T‐cell immunophenotype in 7/9 cases and CD3 positivity in 5/9 cases. A small cell component was present in 6/9 cases. Only four patients achieved a complete remission with first‐line therapy and 3/4 relapsed. Four patients are alive with a median follow‐up of 31 months, two of them after allogeneic haematopoietic stem cell transplantation (HSCT), and five patients died, two of them of disease. In conclusion, ALCL with leukaemic presentation is very unusual and should be considered as high‐risk lymphoma requiring new therapeutic strategies. The respective role of new agents and allogeneic HSCT in first complete remission still has to be assessed.     

Detection of NPM-ALK DNA rearrangement in CD30 positive anaplastic large cell lymphoma

CD30 positive anaplastic large cell lymphoma (ALCL) is a type of non-Hodgkin's lymphoma associated with a specific chromosome translocation between chromosomes 2 and 5. Recent molecular characterization of the translocation breakpoint has identified a gene fusion between NPM (nucleophosmin) and ALK (anaplastic lymphoma kinase). Using a DNA hybridization technique, the NPM rearrangement was found among 5/5 ALCL samples. We have developed a PCT methodology which has enabled the detection of the NPM-ALK rearrangements amongst seven t(2; 5)(p23; q35) ALCL cases based on a long-range PCR of genomic DNA. The rapidity and robustness of this method may have diagnostic applications for ALCL.     

A Phase II study of SGN-30 (anti-CD30 mAb) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma

SGN-30, a chimeric anti-CD30 monoclonal antibody, has demonstrated potent preclinical antitumour activity in both Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL). We conducted an open-label, Phase II study to determine the safety and objective response rate of SGN-30 in 79 patients with refractory/recurrent HL ( n  = 38) or systemic ALCL ( n  = 41). Each course of SGN-30 comprised 6 weekly intravenous infusions, followed by a 2-week treatment-free period. Patients had received a median of 3 (range 1–5) prior regimens of chemotherapy or systemic therapy. The initial 40 patients received 6 mg/kg weekly; the latter 39 patients received 12 mg/kg weekly. In the ALCL group, two patients achieved a complete response and five additional patients achieved a partial response, with response durations ranging from 27 to 1460+ d. No objective responses were observed in the HL group; however, 11 patients (29%) had stable disease (duration 62–242 days). Although adverse events were common, most were mild or moderate, and no specific pattern of adverse events was observed in either disease group. These results demonstrate that weekly administration of SGN-30 is safe, with modest clinical activity in patients with ALCL.     

MACOP-B treatment in patients with Ki-1-positive large-cell anaplastic lymphoma

Summary Nine adult patients with Ki-1-positive largecell anaplastic lymphoma were treated with MACOP-B. Two suffered from relapsed disease and had previously received chemotherapy; a third patient had received a single dose of 100mg/m² cisplatin before initiation of MACOP-B. The stage of lymphoma was determined according to the Ann Arbor Conference criteria and was II in one, III in two and IV in six patients. All patients had constitutional symptoms. Five patients had achieved complete remission 4 weeks after termination of the protocol and there were two partial remissions. One patient died of massive pulmonary embolism during the 4th week of treatment; another patient, who had received MACOP-B as salvage therapy, died of progressive lymphoma 1 month after completion of the regimen. Maximal observed toxicities according to WHO were mucositis grade 3 (n=3) and there were three cases with thromboembolic complications, including a fatal pulmonary embolism in a young patient. However, MACOP-B appears an effective, fairly well-tolerated and feasible therapy for patients with Ki-1-positive large-cell anaplastic lymphoma.Abbreviations MACOP-B methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin, cotrimoxazole - LCAL large-cell anaplastic leukemia     

Anaplastic large cell lymphoma (CD30+/Ki-1+): results of a prospective clinico-pathological study of 69 cases

Summary. Sixty-nine anaplastic large cell lymphomas (ALCLs) were selected from an Italian comparative trial on MACOP-B and F-MACHOP. As no significant difference in effectiveness of the protocols emerged, they were considered homogenously treated. The ALCLs were divided into two groups according to previously defined criteria: 41 were common type (ALCLs-CT) and 28 Hodgkin-related (ALCLs-HR). T-cell phenotype was most common (58%), while B-cell, null and hybrid forms accounted for 27%, 13% and 2%. Clinically, ALCLs CT and HR differed as to mean age (27 v 34·3 years) and presentation; all ALCLs-HR showed mediastinal involvement, with bulky disease in 57%, and more frequent occurrence in stage II. In contrast, ALCLs-CT showed mediastinal masses in 58·5%, infrequently revealed bulky disease (24%), and were not specifically associated to stage. Among the ALCLs-CT, 68·4% achieved complete remission (CR), 24·4% partial remission (PR), one (2·4%) was resistant to therapy, and two (4·8%) had fatal drug toxicity. Of the ALCLs-HR, 67·8% reached CR, 14·3% PR, and 17·9% did not respond. In CR, ALCLs-CT showed a greater tendency to relapse (32·1% v 14·2%). At present, 65·8% of ALCLs-CT and 67·8% of ALCLs-HR are alive with overall survival/disease-free survival averages of 31/27 and 29/24 months respectively. Our data emphasize that, independently of subtype, ALCLs benefit from the application of third-generation protocols for high-grade non-Hodgkin's lymphomas.     

Allogeneic haematopoietic cell transplant in patients with relapsed/refractory anaplastic large cell lymphoma

The prognosis of relapsed/refractory (R/R) anaplastic large cell lymphoma (ALCL) is poor. Large studies evaluating outcomes of allogeneic haematopoietic cell transplantation (allo-HCT) in systemic R/R ALCL are not available. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we evaluated outcomes of 182 adults (aged ≥18 years) with R/R ALCL undergoing allo-HCT between 2008 and 2019. Non-relapse mortality (NRM), disease relapse/progression (REL), progression-free survival (PFS), and overall survival (OS) were modelled using Cox proportional hazards models. The median (range) follow-up of survivors was 62 (3–148) months. The 1-year NRM was 18%. The 5-year REL, PFS and OS were 32%, 41% and 56% respectively. On multivariable regression analysis African American race (hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.6–4.8; p < 0.001) and refractory disease at allo-HCT (HR 3.2, 95% CI 1.6–6.2; p < 0.001) were predictive of inferior OS. Similarly, African-American race (HR 2.1, 95% CI 1.3–3.4; p = 0.003), other minority race (HR 2.5, 95% CI 1.2–5.3; p = 0.02) and refractory disease (HR 2.2, 95% CI 1.2–4.3; p = 0.01) were predictive of inferior PFS. These data, demonstrate that allo-HCT can result in durable disease control in a sizable proportion of patients with R/R ALCL. Refractory disease and racial minority status predicted inferior allo-HCT outcomes. Whether the inferior outcomes of racial minorities with R/R ALCL after allo-HCT are driven by differences in disease biology or disparities in post allo-HCT care, or both, requires further investigation.     

Impact of treatment variability and clinicopathological characteristics on survival in patients with Epstein-Barr-Virus positive diffuse large B cell lymphoma

Patients with EBV-positive diffuse large B cell lymphoma not otherwise specified (EBV⁺ DLBCL (NOS)) recurrently present with advanced age and reduced performance status. They are therefore insufficiently represented in clinical trials and treatment is likely to differ. Here we assess clinicopathological characteristics, therapeutic variability and clinical outcome in the largest consecutively diagnosed EBV⁺ DLBCL (NOS) cohort published to date (n = 80; median age 70 years; range 19–90). Centralized and systematic haematopathological panel review was performed. By immunohistochemistry 60/80 patients were CD30-positive. Further, we identified nine EBV⁺ DLBCL (NOS) patients with associated or composite peripheral T cell lymphoma at diagnosis or relapse (preceded by clonal T cell populations within the initial DLBCL biopsy in 4/5 cases). Most patients (80%) were treated with R-CHOP-type therapy and 16 patients received none or less intensiveprotocols. Upon univariate analysis both R-CHOP-type therapy (OS: P < 0.0001; PFS: P = 0.0617) and negativity for CD30 (OS: P = 0.0002; PFS: P = 0.0002) showed a protective 66 effect, maintained upon multivariate analysis. In a propensity-score matched analysis with a cohort of non-EBV⁺ DLBCL (NOS) patients, balanced for all revised-international prognostic index factors, we found an EBV-association to hold no significant impact on progression-free and overall survival whilst exhibiting a trend favouring EBV-negativity (OS: P = 0.116; PFS: P = 0.269). Our findings provide insight into the clinical course of EBV⁺ DLBCL (NOS), highlight the ramifications of CD30-expression and underline the superior therapeutic efficacy of R-CHOP immunochemotherapy. Alternative therapies, incorporating tumour biology (e.g. CD30 directed therapies) need to be explored in EBV⁺ DLBCL (NOS) patients. Moreover our data advert to the close relationship between EBV⁺ DLBCL (NOS) and peripheral T cell lymphomas.     

Genomic profiling reveals different genetic aberrations in systemic ALK-positive and ALK-negative anaplastic large cell lymphomas

Anaplastic large cell lymphoma (ALCL) is a T/null-cell neoplasm characterized by chromosomal translocations involving the anaplastic lymphoma kinase (ALK) gene (ALK). Tumours with similar morphology and phenotype but negative for ALK have been also recognized. The secondary chromosomal imbalances of these lymphomas are not well known. We have examined 74 ALCL, 43 ALK-positive and 31 ALK-negative, cases by comparative genomic hybridization (CGH), and locus-specific alterations for TP53 and ATM were examined by fluorescence in situ hybridization and real-time quantitative polymerase chain reaction. Chromosomal imbalances were detected in 25 (58%) ALK-positive and 20 (65%) ALK-negative ALCL. ALK-positive ALCL with NPM-ALK or other ALK variant translocations showed a similar profile of secondary genetic alterations. Gains of 17p and 17q24-qter and losses of 4q13-q21, and 11q14 were associated with ALK-positive cases (P = 0.05), whereas gains of 1q and 6p21 were more frequent in ALK-negative tumours (P = 0.03). Gains of chromosome 7 and 6q and 13q losses were seen in both types of tumours. ALCL-negative tumours had a significantly worse prognosis than ALK-positive. However no specific chromosomal alterations were associated with survival. In conclusion, ALK-positive and negative ALCL have different secondary genomic aberrations, suggesting they correspond to different genetic entities.