Outcome of patients with relapsed or refractory anaplastic large cell lymphoma who have failed brentuximab vedotin

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

Cytomorphologic examination of anaplastic large cell lymphoma by fine‐needle aspiration cytology

BACKGROUND.

The cytomorphology of anaplastic large cell lymphoma (ALCL) is distinctive yet variable. To the authors' knowledge, to date only small case series have described the cytologic findings noted in patients with ALCL. The current series is the largest case series presented to date to retrospectively review the cytomorpholgic findings noted in patients with ALCL, with specific attention paid to those with anaplastic lymphoma kinase (ALK)‐negative ALCL.

METHODS.

Over a 13‐year period, the available Diff‐Quik cytology smears and surgical excision specimens taken from patients with ALCL were evaluated. Different clinical and morphologic parameters were evaluated, including ALK status.

RESULTS.

A total of 37 cases were retrieved and evaluated, 19 of which had both cytology and surgical pathology specimens available for review. ALK‐negative ALCL cytology smears were found to have a high number of anaplastic cells compared with ALK‐positive cases. The hallmark cells in the ALK‐negative cases were not classic.

CONCLUSIONS.

ALCL can be diagnosed accurately by fine‐needle aspiration cytology (FNAC) alone when aided by immunocytochemistry in ALK‐positive cases. Ancillary studies should be anticipated such that material for cell block preparation and molecular studies is taken at the time of FNAC. The results of the current study demonstrate the varied FNAC morphology of ALCL. The presence of severe pleomorphism and anaplasia was found to correlate with ALK‐negative status. Cancer (Cancer Cytopathol( 2007. © 2007 American Cancer Society.     

ALK阳性间变性大细胞淋巴瘤临床病理研究进展

约半数的间变性大细胞淋巴瘤（ALCL）病人中存在间变性淋巴瘤激酶（ALK）基因异常,ALK蛋白的异常激活使ALK阳性ALCL具有其典型的临床病理特征,并为ALK阳性ALCL的治疗提供新的靶点,提示ALK阳性ALCL的淋巴瘤可归类为一独立病种。     

Long-term remission of primary refractory ALK-positive anaplastic large cell lymphoma after allogeneic hematopoietic stem cell transplantation

ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) has a favorable prognosis in general; however, some cases are resistant to chemotherapy, which leads to a poor clinical outcome. We herein report the case of a 32-year-old male with aggressive ALK+ ALCL who presented with hemorrhage from a large tumor in the duodenum and multiple tumors in the lungs, mediastinum, and peritoneal cavity. Although induction chemotherapy resulted in a marked reduction of the tumor lesions, premature progression with massive pulmonary infiltration and central nervous system invasion occurred immediately after the completion of chemotherapy. The patient was then promptly treated with brentuximab vedotin (BV) and high-dose methotrexate, which resulted in complete remission. Subsequently, he successfully underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an unrelated donor and has been healthy and did not relapse for more than 3 years after transplantation without any additional therapy. Allo-HSCT may be a promising treatment option for ALK+ ALCL due to its graft-versus-lymphoma effect. In addition, molecular targeting agents, such as BV, may be promising as a bridging therapy before allo-HSCT to achieve disease remission.     

Diagnostic assays for identification of anaplastic lymphoma kinase‐positive non–small cell lung cancer

In series dominated by adenocarcinoma histology, approximately 5% of non–small cell lung cancers (NSCLCs) harbor an anaplastic lymphoma kinase (ALK) gene rearrangement. Crizotinib, a tyrosine kinase inhibitor with significant activity against ALK, has demonstrated high response rates and prolonged progression‐free survival in ALK‐positive patients enrolled in phase 1/2 clinical trials. In 2011, crizotinib received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of proven ALK‐positive NSCLC using an FDA‐approved diagnostic test. Currently, only break‐apart fluorescence in situ hybridization testing is FDA approved as a companion diagnostic for crizotinib; however, many other assays are available or in development. In the current review, the authors summarize the diagnostic tests available, or likely to become available, that could be used to identify patients with ALK‐positive NSCLC, highlighting the pros and cons of each. Cancer 2013. © 2012 American Cancer Society.     

Long‐term survival of a child with refractory anaplastic large cell lymphoma following therapy with an antisense oligonucleotide,topotecan, and vinblastine

Anaplastic large cell lymphoma includes a subset of highly aggressive tumours and has a relapse rate of 30% at 2 years. Relapsed patients often have poor clinical outcome. The use of antisense oligonucleotides to down‐regulate Bcl‐2 protein can reverse chemotherapy resistance. The authors describe an 11‐year‐old boy with recurrent anaplastic large cell lymphoma who had received double high‐dose chemotherapy followed by autologous haematopoietic stem‐cell transplantation, had refractory disease and then had achieved long‐term remission with the use of an antisense oligonucleotides in combination with vinblastine and topotecan. Copyright © 2011 John Wiley & Sons, Ltd.     

Research progresses in the pathogenesis of anaplastic large cell lymphoma

Anaplastic large cell lymphoma(ALCL) is a distinct subset of T-cell non-Hodgkin's lymphoma.As a consequence of its low incidence,general pathogenic consideration of ALCL is lacking.In this review,we summarize the pathogenesis,epidemiology,clinical manifestations,and treatment of ALCL,so as to better understand key stages of the development of this disease and provide valuable information for future treatment.     

Breast implant-associated anaplastic large cell lymphoma: A comprehensive review

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently recognized non-Hodgkin lymphoma of T-cell origin. Despite the low incidence of this new disease, the increasing use of breast implants for cosmetic or post-mastectomy reconstruction purposes places BIA-ALC as an emerging and compelling medical challenge. The real BIA-ALCL pathogenesis has not been fully uncovered so far, while different putative causal factors have been proposed. Breast implants with textured surfaces seem to be associated with nearly all cases of BIA-ALCL, while the real the risk of disease development has not been well estimated so far. Late onset, persistent seroma around breast implant represents the classical clinical presentation. Most of the BIA-ALCL patients presents with localized disease, which confers an excellent prognosis. Unlike other non-Hodgkin lymphomas, surgical excision of the mass has a key role in the treatment. For patients with advanced and disseminated diseases, the treatment did not differ from other types of T-cell lymphoma. For these reasons, BIA-ALCL represents an emerging disease which requires multidisciplinary team approach to well define diagnostic workup and treatment for each patient. This review article aims to summarize available data on BIA-ALCL. First, we will outline available data on BIA-ALCL epidemiology, pathogenesis, diagnostic work-up, and treatment. Second, we will point out the potential psychological implications as well as the risk of perception distortion for women with breast implants, especially for those with previous breast cancer. Lastly, we will summarize the current national recommendations regarding textured breast implants and discuss the diagnostic-therapeutic algorithm for BIA-ALCL management.     

Phase I / II study of brentuximab vedotin in Japanese patients with relapsed or refractory CD30‐positive Hodgkin's lymphoma or systemic anaplastic large‐cell lymphoma

Brentuximab vedotin is an antibody–drug conjugate that selectively delivers the antimicrotubule agent monomethyl auristatin E into CD30‐expressing cells. To assess its safety, pharmacokinetics, and efficacy in Japanese patients with refractory or relapsed CD30‐positive Hodgkin's lymphoma or systemic anaplastic large‐cell lymphoma, we carried out a phase I/II study. Brentuximab vedotin was given i.v. on day 1 of each 21‐day cycle up to 16 cycles. In the phase I part of a dose‐escalation design, three patients per cohort were treated at doses of 1.2 and 1.8 mg/kg. In the phase II part, a dose of 1.8 mg/kg was given to 14 patients (nine with Hodgkin's lymphoma and five with systemic anaplastic large‐cell lymphoma). The median number of treatment cycles was 16 (range, 4–16). In the phase I part, no dose‐limiting toxicity event was observed. In the total population, common adverse events included lymphopenia (80%), neutropenia (65%), leukopenia (65%), and peripheral sensory neuropathy (60%). Grade 3/4 adverse events in more than two patients were lymphopenia (50%) and neutropenia (15%). The pharmacokinetic profile was similar to that observed in the previous studies in the USA. In the phase II part, six patients (67%) with Hodgkin's lymphoma achieved an objective response with 56% of complete response rate, and five patients (100%) with systemic anaplastic large‐cell lymphoma achieved an objective response with 80% of complete response rate. These results show that brentuximab vedotin has an acceptable safety profile and promising antitumor activity in the Japanese population. This trial was registered in JAPIC Clinical Trials Information (JapicCTI‐111650).     

间变性大细胞淋巴瘤的临床病理与免疫组化研究(附3例报告及文献复习)

目的　研究间变性大细胞淋巴瘤 (ALCL)的临床病理和免疫组化特征。方法　应用免疫组化染色 (SP法 )对 3例ALCL进行免疫表型标记 ,采用了一种新的间变性大细胞淋巴瘤的特异性抗体ALKp80 (间变性淋巴瘤激酶 )。 结果　 3例ALCL的ALKp80均呈强阳性 ,2例CD30 阳性 ,2例LCA阳性 ,2例EMA阳性 ,1例CD685 0 %以上细胞阳性。 3例T、B细胞标记均不表达 ,CD15均呈阴性。结论　ALKp80不仅是ALCL的一个特异性标记物 ,而且对判断ALCL的预后有重要的意义。     

罕见部位原发性间变性大细胞淋巴瘤的临床病理学观察

目的:探讨2例原发于骨和鼻腔的间变性大细胞淋巴瘤(anaplastic large cell lymphoma,ALCL)的临床病理学特点、鉴别诊断和预后。方法:2例ALCL均经4%中性福尔马林固定、石蜡包埋、常规HE和免疫组化染色后观察其组织病理学特点和免疫学表型特征,并进行随访。结果:光镜下,2例病变区肿瘤细胞均呈弥漫性生长,异型性明显,体积大,界限清楚、胞浆丰富,核圆形或卵圆形,核仁明显,核分裂像易见。免疫组化结果示肿瘤细胞表达CD30、EMA、ALK和Clusterin。结论:原发于骨和鼻腔的ALCL罕见,明确诊断须依赖组织病理学观察和免疫学表型。     

Phase II study of ceritinib in alectinib‐pretreated patients with anaplastic lymphoma kinase‐rearranged metastatic non‐small‐cell lung cancer in Japan: ASCEND‐9

Clinical experience of ceritinib in patients who progressed on alectinib is limited. In this prospective phase II study, we evaluated the activity of ceritinib in alectinib‐pretreated patients with anaplastic lymphoma kinase (ALK)‐rearranged metastatic (stage IIIB/IV) non‐small‐cell lung cancer (NSCLC) in Japan. All patients were required to have ≥1 measurable lesion per RECIST, 1.1, and a World Health Organization Performance Status (WHO PS) of 0‐1. Prior crizotinib and/or up to 1 chemotherapy regimen was allowed. Primary endpoint was investigator‐assessed overall response rate (ORR) per RECIST 1.1. Ceritinib was given at a dose of 750 mg/day fasted. A total of 20 patients were enrolled from August 2015 to March 2017. All patients received prior alectinib (100%), 13 (65.0%) patients received prior platinum‐based chemotherapy, and 4 (20%) patients received prior crizotinib. Median duration of exposure and the follow‐up time with ceritinib were 3.7 months (range: 0.4‐15.1) and 11.6 months (range: 4.8‐23.0), respectively. Investigator‐assessed ORR was 25% (95% CI: 8.7‐49.1). Key secondary endpoints, all investigator assessed, included disease control rate (70.0%; 95% CI: 45.7‐88.1), time to response (median, 1.8 months; range: 1.8‐2.0), and duration of response (median, 6.3 months; 95% CI: 3.5‐9.2). Median progression‐free survival was 3.7 months (95% CI: 1.9‐5.3). The most common adverse events reported were diarrhea (85.0%), nausea (80.0%), and vomiting (65.0%). Based on our findings, ceritinib could be considered as one of the treatment options for patients with ALK‐positive NSCLC who progressed on alectinib. (Trial registration no. NCT02450903)     

Targeting autophagy enhances the anti-tumoral action of crizotinib in ALK-positive anaplastic large cell lymphoma

Anaplastic Lymphoma Kinase-positive Anaplastic Large Cell Lymphomas (ALK+ ALCL) occur predominantly in children and young adults. Their treatment, based on aggressive chemotherapy, is not optimal since ALCL patients can still expect a 30% 2-year relapse rate. Tumor relapses are very aggressive and their underlying mechanisms are unknown. Crizotinib is the most advanced ALK tyrosine kinase inhibitor and is already used in clinics to treat ALK-associated cancers. However, crizotinib escape mechanisms have emerged, thus preventing its use in frontline ALCL therapy. The process of autophagy has been proposed as the next target for elimination of the resistance to tyrosine kinase inhibitors. In this study, we investigated whether autophagy is activated in ALCL cells submitted to ALK inactivation (using crizotinib or ALK-targeting siRNA). Classical autophagy read-outs such as autophagosome visualization/quantification by electron microscopy and LC3-B marker turn-over assays were used to demonstrate autophagy induction and flux activation upon ALK inactivation. This was demonstrated to have a cytoprotective role on cell viability and clonogenic assays following combined ALK and autophagy inhibition. Altogether, our results suggest that co-treatment with crizotinib and chloroquine (two drugs already used in clinics) could be beneficial for ALK-positive ALCL patients.     

R-CHOP方案治疗复发、难治弥漫大B细胞淋巴瘤的临床研究

 【摘要】　目的　观察R-CHOP方案治疗复发、难治弥漫大B细胞淋巴瘤（DLBCL）的临床疗效及患者不良反应。方法　选择30例经病理证实为CD20阳性的DLBCL患者,前期常规方案化疗（不含利妥昔单抗）2～6个疗程后评估为复发或难治患者,其中复发患者16例,难治患者14例。应用R-CHOP方案治疗4～6个周期,每个周期21 d。所有淋巴瘤患者均为Ⅲ～Ⅳ期,搜集治疗前后相关临床资料,采用回顾性分析方法,将R-CHOP方案疗效与文献及自身对照比较,评价其疗效及不良反应。结果　全组30例患者均可评价疗效,完全缓解15例,部分缓解10例,稳定3例,进展2例,完全缓解率为50.0 %（15／30）,总有效率83.3 %（25／30）。出现Ⅱ度白细胞减少3例,Ⅰ度血小板降低1例,恶心等轻微的消化道反应2例。结论　R-CHOP方案对复发、难治DLBCL仍有良好的治疗效果,完全缓解率与总有效率明显优于常规二线化疗方案。接受R-CHOP方案治疗患者不良反应轻微,与常规化疗方案无显著区别,患者耐受良好。     

A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma.

BACKGROUND: Protein kinase C beta (PKCbeta), a pivotal enzyme in B-cell signaling and survival, is overexpressed in most cases of mantle cell lymphoma (MCL). Activation of PI3K/AKT pathway is involved in pathogenesis of MCL. Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCbeta/PI3K/AKT pathways, induces apoptosis, reduces proliferation, and suppresses tumor-induced angiogenesis. PATIENTS AND METHODS: Patients with relapsed/refractory MCL, and no more than four regimens of prior therapy, received 500 mg enzastaurin, orally, once daily. RESULTS: Sixty patients, median age 66 years (range 45-85), Eastern Cooperative Oncology Group performance status of zero to two (48% had baseline International Prognostic Index of 3-5), were enrolled. Most patients had prior CHOP-like chemotherapy and/or rituximab (median = 2 regimens). No drug-related deaths occurred. There was one case each of grade 3 anemia, diarrhea, dyspnea, vomiting, hypotension, and syncope. Fatigue was the most common toxicity. Although no objective tumor responses occurred, 22 patients (37%, 95% CI 25% to 49%) were free from progression (FFP) for > or =3 cycles (one cycle = 28 days); 6 of 22 were FFP for >6 months. Two patients remain on treatment and FFP at >23 months. CONCLUSION: Freedom from progression for >6 months in six patients and a favorable toxicity profile with minimal hematological toxicity indicate that enzastaurin warrants evaluation as maintenance therapy and combination chemotherapy in MCL.     

Germline mutations of the perforin gene are a frequent occurrence in childhood anaplastic large cell lymphoma

BACKGROUND: Monoallelic and biallelic mutations of the PRF1 gene have been reported in some cases of childhood lymphoma. Anaplastic large cell lymphoma (ALCL) accounts for 10% to 15% of all childhood lymphomas. To assess the possible role of PRF1 mutations in ALCL, the authors screened a series of patients collected by the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP). METHODS: The authors investigated 44 patients with ALCL by direct sequence of the PRF1 gene. To address the issue of the prevalence of the most frequently observed PRF1 mutations in the control population, the authors examined a series of 400 healthy white control subjects for the 272C>T mutation (A91V). RESULTS: A total of 6 different mutations were identified in 12 patients (27.3%). Eleven patients had 1 mutation whereas 1 patient was found to have 2 mutations. Of the 6 PRF1 mutations identified, 2 were novel mutations: 529C>T (resulting in R177C) and 1471G>A (resulting in D491N). The remaining 4 mutations were previously described; in particular, the 272C>T mutation (resulting in the A91V amino acid change) was found in 8 patients, whereas the 368G>A (R123H), 695G>A (R232H), and 1262T>G (F421C) mutations were all found in 1 case each. Overall, the incidence of PRF1 mutations was found to be significantly higher in patients with ALCL compared with 400 control subjects, among whom only heterozygous A91V was observed in 41 subjects (10.2%) (chi-square test, 10.9; P <.01). CONCLUSIONS: Patients with childhood ALCL have a higher probability of being a carrier of a PRF1 mutation compared with healthy controls, suggesting a possible predisposing role.     

Drug resistance mechanisms in Japanese anaplastic lymphoma kinase‐positive non–small cell lung cancer and the clinical responses based on the resistant mechanisms

The treatment for anaplastic lymphoma kinase (ALK)‐positive lung cancer has been rapidly evolving since the introduction of several ALK tyrosine kinase inhibitors (ALK‐TKI) in clinical practice. However, the acquired resistance to these drugs has become an important issue. In this study, we collected a total of 112 serial biopsy samples from 32 patients with ALK‐positive lung cancer during multiple ALK‐TKI treatments to reveal the resistance mechanisms to ALK‐TKI. Among 32 patients, 24 patients received more than two ALK‐TKI. Secondary mutations were observed in 8 of 12 specimens after crizotinib failure (G1202R, G1269A, I1171T, L1196M, C1156Y and F1245V). After alectinib failure, G1202R and I1171N mutations were detected in 7 of 15 specimens. G1202R, F1174V and G1202R, and P‐gp overexpression were observed in 3 of 7 samples after ceritinib treatment. L1196M + G1202R, a compound mutation, was detected in 1 specimen after lorlatinib treatment. ALK‐TKI treatment duration was longer in the on‐target treatment group than that in the off‐target group (13.0 vs 1.2 months). In conclusion, resistance to ALK‐TKI based on secondary mutation in this study was similar to that in previous reports, except for crizotinib resistance. Understanding the appropriate treatment matching resistance mechanisms contributes to the efficacy of multiple ALK‐TKI treatment strategies.     

具有明显浆细胞特征的骨原发ALK阳性的间变性大细胞淋巴瘤1例报道及文献复习

目的:探讨1例具有明显浆细胞特征的骨原发ALK阳性的间变性大细胞淋巴瘤(anaplastic large cell lymphoma,ALCL)的临床病理学特征及鉴别诊断要点.方法:收集1例原发于右股骨远端的具有明显浆细胞特征ALK阳性的间变性大细胞淋巴瘤临床及影像学资料、观察其病理学形态及免疫表型,并复习相关文献,探讨该肿瘤的病理诊断和鉴别诊断要点.结果:患者为16岁男性,因右膝关节疼痛6月,加重伴功能障碍3周入院.MRI显示:右股骨下段骨质及周围软组织可见团片状长T1长T2信号影,压脂呈高信号影,骨质呈明显破坏表现,增强扫描病灶呈明显不均匀强化.镜下观察可见:肿瘤由大小较一致的浆样细胞组成,细胞异型性明显,核分裂象多见,浸润周围骨组织.免疫组化示肿瘤细胞表达CD30、ALK-1、CD4、EMA及GramB(+).结论:骨原发性ALCL非常罕见,具有明显浆细胞特征的ALCL形态学特殊,明确诊断需结合组织病理学及免疫表型综合分析.     

A phase 2 study of methotrexate,etoposide, dexamethasone,and pegaspargase chemotherapy for newly diagnosed,relapsed, or refractory extranodal natural killer/T‐cell lymphoma,nasal type: a multicenter trial in Northwest China

The nasal type of extranodal natural killer/T‐cell lymphoma is a rare aggressive lymphoma with poor prognosis. To discover a successful treatment, we investigated the efficacy and safety of chemotherapy with methotrexate, etoposide, dexamethasone, and polyethylene glycol‐asparaginase (MESA). Three cycles of MESA were administered to 46 patients with new or relapsed/refractory natural killer/T‐cell lymphoma. Complete response after 3 treatment cycles was 43.5%, the overall response rate was 87%, and 2‐year overall survival was 83.4%. Complete response was significantly better for newly diagnosed patients than for patients with relapsed/refractory disease. Patients with newly diagnosed disease had a significantly better overall response rate after 1, but not after 2 or 3 treatment cycles. Overall survival and progression‐free survival did not differ over 2 years. Grade 1/2 toxicities were frequent, but MESA was associated with fewer grade 3/4 events or treatment‐related deaths. These results will require confirmation in larger prospective trials.