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.

Atypical Sweet syndrome: skin sinus tracts in an acutely febrile patient after lymphoma treatment: a case report.

Sweet syndrome (SS) is an uncommon inflammatory disease that involves painful skin, edematous, red papules, plaques, or nodules often accompanied by fever and leukocytosis. SS has three subtypes, including classical, malignant-tumor associated, and drug-induced SS (DISS). Patients with DISS have clear histories of recent drug exposure. The incidence of SS is high in hematological malignancy but rare in lymphomas. Glucocorticoid treatment is the recommended treatment for all subtypes of SS. This case study describes a male patient who had a history of sALCL(Systemic anaplastic large cell lymphoma) and was treated with multiple cycles of monoclonal-antibody (mAb) therapy. They also received the G-CSF injection at the site where skin lesions later developed. They met the diagnosis criteria for DISS, which was considered to be caused by the G-CSF injection. In addition, BV(Brentuximab vedotin) administration might predispose them to DISS. This case illustrates the first reported SS during the lymphoma treatment, with rare clinical presentations of local crater-like suppurative skin lesions. This case expands the available literature on SS and hematologic neoplasms and reminds clinicians to promptly recognize and diagnose SS to minimize patient morbidity and long-term sequelae.

Genomic Analysis of Cutaneous CD30-Positive Lymphoproliferative Disorders.

Primary cutaneous CD30+ T-cell lymphoproliferative disorders are the second most common cutaneous lymphomas. According to the World Health Organization, CD30+ T-cell lymphoproliferative disorders include primary cutaneous anaplastic large cell lymphoma (C-ALCL) and lymphomatoid papulosis (LyP) as well as borderline lesions. C-ALCL and LyP are thought to represent two ends of a spectrum of diseases that have different clinical presentations, clinical courses, and prognoses in their classic forms but share the same histology of medium to large CD30+ atypical lymphoid cell infiltrates. Because the behavior of these entities is different clinically and prognostically, we aim to search for oncogenic genomic variants using whole-exome sequencing that drive the development of LyP and C-ALCL. Clinical information, pathology, immunohistochemistry, and T-cell rearrangements on six cases of LyP and five cases of C-ALCL were reviewed to confirm the rendered diagnosis before whole-exome sequencing of all specimens. Both LyP and C-ALCL had recurrent alterations in epigenetic modifying genes affecting histone methylation and acetylation (SETD2, KMT2A, KMT2D, and CREBBP). However, they also harbor unique differences with mutations in signal transducer and activator of transcription gene STAT3 of the Jak/signal transducer and activator of transcription pathway and EOMES, a transcription factor involved in lymphocyte development, only noted in C-ALCL specimens. Genomic characterization of LyP and C-ALCL in this series confirms the role of multiple pathways involved in the biology and development of these lymphomatous processes. The identification of similar aberrations within the epigenetic modifying genes emphasizes common potential development mechanisms of lymphomagenesis within lymphoproliferative disorders being shared between LyP and C-ALCL; however, the presence of differences may account for the differences in clinical course.

Cost-effectiveness of brentuximab vedotin for relapsed or refractory systemic anaplastic large-cell lymphoma in China.

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.

Molecular profiling of Chinese systemic anaplastic large cell lymphoma patients: novel evidence of genetic heterogeneity.

BACKGROUND: Anaplastic large cell lymphoma (ALCL) is a rare non-Hodgkin lymphoma. A comprehensive understanding of the genetic and clinical heterogeneity of ALCL may help to improve the clinical management of patients with ALCL. However, due to the rarity of the disease, the genetic heterogeneity of ALCL has not been well elucidated. This study aimed to comprehensively elucidate the mutational landscape of tumor tissue samples from patients with systemic ALCL. METHODS: Thirty-six patients with systemic ALCL were enrolled in this retrospective study. Immunohistochemistry (IHC) was performed on tumor tissues at baseline to identify anaplastic lymphoma kinase (ALK) fusions. Capture-based targeted next-generation sequencing (NGS) with a panel spanning 112 lymphoma-related genes, including ALK rearrangements, was also performed on tumor tissue samples. RESULTS: A total of 102 mutations were identified in the entire cohort. Among the 36 patients included in this analysis, 14 (38.8%) were ALK positive, as determined by IHC, while NGS showed 12 patients (33.3%) to harbor ALK rearrangements. Younger patients were more likely to have ALK-positive ALCL (P=0.011). Patients with wild-type (WT) ALK were more likely to have single-nucleotide variants (SNVs) and insertions or deletions (INDELs) than patients with ALK rearrangements (P=0.027). Among the 22 patients with WT ALK, the most commonly mutated genes were TP53 (n=6, 27.3%), followed by NOTCH1 (n=5, 22.7%), KMT2D (n=3, 13.6%), KRAS (n=3, 13.6%), TET2 (n=3, 13.6%), and JAK1 (n=2, 9.1%). Mutations in PRDM1, a commonly mutated gene in ALK-negative patients, were not detected in our ALK-negative cohort. Start-loss of beta-2-microglobulin (B2M) was detected in another patient; this patient had a favorable prognosis, with an overall survival exceeding 19 months. CONCLUSIONS: Our study revealed the unique genomic profiles of Chinese ALCL patients and represents an incremental step in deepening the understanding of the genetic heterogeneity of ALCL patients.

Evaluation of Associated Lymphomas and Their Risk Factors in Patients with Lymphomatoid Papulosis: A Retrospective Single-Center Study from Turkey

Objective: Lymphomatoid papulosis (LyP) is an indolent skin disease with variable clinical features classified among the primary cutaneous CD30+ T-cell lymphoproliferative disorders. It may show association with cutaneous and systemic lymphomas. We aimed to identify the frequency and characteristics of associated lymphomas among Turkish patients with LyP and to determine the risk factors for secondary lymphomas. Materials and Methods: The files of patients diagnosed with LyP between 1998 and 2018 in a tertiary dermatology clinic were retrospectively analyzed. Univariate and multivariate models were used to assess the possible risk factors for secondary lymphomas, such as demographic and clinical characteristics of the patients. Results: Among 61 patients (47 adults, 14 children) with LyP, a total of 22 secondary lymphomas were observed in 20 patients. Nineteen of them were adults. Mycosis fungoides (MF) was the major associated lymphoma (n=19) followed by systemic anaplastic large cell lymphoma (ALCL) (n=2) and primary cutaneous ALCL (n=1). The most common stage in patients with accompanying MF was stage IB (n=11). While 18 patients showed the classical type of MF, one patient had folliculotropic MF. When the risk factors for association between LyP and other lymphomas were evaluated, only older age was found to be a significant risk factor and existence of ulcerated lesions was found to be a negative indicator. Conclusion: LyP is not rare in the pediatric population. MF is the most common associated lymphoma in patients with LyP. Adult LyP patients are more commonly associated with secondary lymphomas than pediatric patients. Older age at the time of diagnosis of LyP is a significant risk factor for associated lymphomas.

Safety profile of brentuximab vedotin in Japanese patients with relapsed/refractory Hodgkin lymphoma or systemic anaplastic large cell lymphoma: a post-marketing surveillance study.

Brentuximab vedotin (BV) was initially approved in Japan for the treatment of relapsed/refractory (R/R) CD30-positive Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). As requested by the Japanese Ministry of Health, Labour and Welfare, we conducted a post-marketing surveillance (PMS) study to assess the safety of BV in Japanese patients with R/R HL or sALCL. PMS forms were collected from 284 patients (182 with HL, 101 with sALCL and one with another lymphoma) treated between April and September 2014. The median age was 62 (range 14-93) years and the median number of treatment cycles was 5.5 for HL and 4 for sALCL. Adverse drug reactions (ADRs) were reported in 74.3% of patients. The most commonly observed ADRs included peripheral sensory neuropathy (39.1%; grade ≥ 3, 6.3%), neutropenia (34.5%; grade ≥ 3, 22.2%) and lymphopenia (7.0%; grade ≥ 3, 5.3%). Ten patients had fatal ADRs including interstitial lung disease (n = 3). This study showed that BV has an acceptable safety profile in Japanese patients with R/R HL and R/R sALCL in the clinical practice setting. However, close monitoring rare, but potentially fatal, ADRs such as pulmonary toxicity may be warranted, especially in patients with prior or ongoing pulmonary disorders.

The expressions of MUM-1 and Bcl-6 in ALK-negative systemic anaplastic large cell lymphoma with skin involvement and primary cutaneous anaplastic large cell lymphoma.

BACKGROUND: It is important to differentiate between primary cutaneous anaplastic large cell lymphoma (PC-ALCL) and ALK-negative systemic ALCL with skin involvement, as the prognoses and treatments for these two diseases are considerably different. OBJECTIVE: This study aimed to compare the expressions of multiple myeloma oncogene 1 (MUM-1) and B-cell lymphoma 6 (Bcl-6) in PC-ALCL and ALK-negative systemic ALCL. METHODS: This retrospective qualitative study investigated the clinical features of 7 patients with ALK-negative PC-ALCL, 5 patients with ALK-negative systemic ALCL with skin involvement, and 6 patients with ALK-positive systemic ALCL with skin involvement. The MUM-1 and Bcl-6 expressions were evaluated using immunohistochemistry. RESULTS: The MUM-1 expression rates were 85.7% in the PC-ALCL cases and 100% in the ALK-negative systemic ALCL with skin involvement cases. The Bcl-6 expression rates were 28.5% in the PC-ALCL cases and 20% in the ALK-negative systemic ALCL cases with skin involvement. CONCLUSION: Although the cutaneous manifestations of ALK-negative systemic ALCL and PC-ALCL are similar, the prognoses and treatment approaches are considerably different. Our results indicate that MUM-1 expression is commonly expressed in both types of ALCL, but Bcl-6 is less commonly expressed in PC-ALCL cases and systemic ALCL with skin involvement cases.

Adverse reactions related to brentuximab vedotin use: A real-life retrospective study.

Post-marketing data regarding brentuximab vedotin (BV) are sparse. The aim of this study was to assess the frequency and nature of significant adverse drug reactions (ADRs) in patients treated with BV in a real-world setting. We conducted a systematic retrospective study of patients treated with BV in a French university hospital. Significant ADRs were collected using the electronic patient records. Between January 2009 and December 2016, 39 patients received BV. Median age was 43.2 and 53.8% were males. Overall, 20 patients (51.3%) experienced at least one significant ADR and 24 reactions were reported in total. Twelve (50%) out of 24 ADRs were severe. The most frequently observed significant ADRs were peripheral sensory neuropathy and CMV reactivation. ADRs led to drug discontinuation for 4 patients and dose reduction for 6 patients. Only 29.2% of the events were spontaneously reported. Prospective monitoring is needed to better assess BV safety.

CD30, CD15, CD50, and PAX5 Expressions as Diagnostic Markers for Hodgkin Lymphoma (HL) and Systemic Anaplastic Large Cell Lymphoma (sALCL).

BACKGROUND: the expression of CD30, CD15, CD50, and PAX5 are used to help in confirming diagnosis of HL and sALCL; however data on the proportion of these markers have not been available. The study was aimed to identify the proportion of CD30, CD15, CD50 and PAX5 expressions and characteristics of patients with HL and sALCL at Dharmais National Cancer Center Hospital between 2005 and 2015. METHODS: a retrospective observational study was conducted using data from medical records and histopathological results of HL and sALCL adult patients who sought treatment at the hospital between 2005 and 2015. Immunohistochemistry (IHC) examinations were performed and data on the proportion of positive CD30, CD15, CD50, and PAX5 expressions were analyzed descriptively. RESULTS: a total of 45 patients were recruited in this study, with the majority (42 patients, 93.3%) were HL patients and only 6.7% were sALCL patients. The median age of HL patients was younger than sALCL patients; 35 (18-72 years old) versus 54 (49-61 years old). Moreover, the immunohistochemistry examination demonstrated that the positive CD15, CD30, CD50, and PAX5 expressions were found respectively in 37.5%, 88.9%, 31.2%, and 31.2% patients with HL; while in patients with sALCL, in spite of their small sample size, positive CD30, CD15, CD50 and PAX5 expressions were found in 100%; 66,7%; 50%; and 50%, respectively. Overall, CD15, CD50, and PAX5 positive expressions were found in 39.5%, 32.4%, and 32.4% patients who had HL and sALCL; while positive expression of CD30 was found in 89.5% of them. CONCLUSION: present study shows that almost 90% patients have positive CD30 expression;  while the positive expressions of CD15, CD50, and PAX5 are found in less than 40% patients. It indicates that CD30 is an important diagnostic marker for HL and sALCL and it may improve treatment strategy.

Extended use of brentuximab vedotin before autologous stem-cell transplantation would benefit refractory systemic anaplastic large-cell lymphoma.

The optimal number of brentuximab vedotin cycles in the treatment of systemic anaplastic large-cell lymphoma (sALCL) prior to autologous stem-cell transplantation (ASCT) is unknown. This case illustrates the possible benefit of prolonged brentuximab vedotin before ASCT in sALCL and may help clinical decision-making, especially in chemorefractory disease.

A Cost-effectiveness Analysis of Brentuximab Vedotin in Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma.

Objective: To evaluate the cost-effectiveness of brentuximab vedotin in patients with R/R sALCL from a UK NHS perspective. Methods: A partitioned survival model used clinical outcomes for brentuximab vedotin from the pivotal phase-2 single-arm trial of brentuximab vedotin in 58 patients with R/R sALCL (SG035-0004; NCT00866047), over a lifetime (30-year) time horizon. Comparison with conventional chemotherapy was based on data from the Canadian British Columbia Cancer Agency registry from 40 patients starting salvage chemotherapy after front-line treatment between 1980 and 2012. Survival was extrapolated using parametric distributions, with brentuximab vedotin risk after the trial period assumed equal to conventional chemotherapy. Other modelling assumptions were based on a systematic literature review and clinical expert opinion. Results: Based on statistical extrapolation, brentuximab vedotin was associated with 3.1 years longer duration in the progression-free survival health state and an overall survival improvement of 5.4 years, prior to discounting. In addition, brentuximab vedotin was associated with 2.5 quality-adjusted life years (QALYs) gained at a total incremental cost of £88 556, resulting in an incremental cost-effectiveness ratio (ICER) of approximately £35 400. Sensitivity analyses of alternative model assumptions provided ICERs ranging from approximately £28 100 to £61 900. Comparing only first-line salvage patients reduced the ICER to £26 800 per QALY gained. Conversely, considering only patients with Eastern Corporative Oncology Group performance status of 0 or 1 increased the ICER to approximately £38 200. At a willingness-to-pay threshold of £50 000, the estimated probability that brentuximab vedotin is cost-effective compared with conventional chemotherapy was 86.5%. Conclusion: Compared to conventional chemotherapy, and considering the full survival period, brentuximab vedotin may provide a valuable treatment choice for patients with R/R sALCL, a population with limited therapeutic options.

Long-Term Responders After Brentuximab Vedotin: Single-Center Experience on Relapsed and Refractory Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma Patients.

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

The European Medicines Agency Review of Brentuximab Vedotin (Adcetris) for the Treatment of Adult Patients With Relapsed or Refractory CD30+ Hodgkin Lymphoma or Systemic Anaplastic Large Cell Lymphoma: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use.

BACKGROUND: On October 25, 2012, a conditional marketing authorization valid throughout the European Union (EU) was issued for brentuximab vedotin for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL) and for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). For HL, the indication is restricted to treatment after autologous stem cell transplantation (ASCT) or after at least two previous therapies when ASCT or multiagent chemotherapy is not a treatment option. MATERIALS AND METHODS: Brentuximab vedotin is an antibody-drug conjugate (ADC) composed of a CD30-directed monoclonal antibody (recombinant chimeric IgG1) that is covalently linked to the antimicrotubule agent monomethyl auristatin E (MMAE). Binding of the ADC to CD30 on the cell surface initiates internalization of the MMAE-CD30 complex, followed by proteolytic cleavage that releases MMAE. The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. RESULTS: Brentuximab vedotin as a single agent was evaluated in two single-arm studies. Study SG035-003 included 102 patients with relapsed or refractory HL. An objective response was observed in 76 patients (75%), with complete remission in 34 (33%). Study SG035-004 included 58 patients with relapsed or refractory sALCL. An objective response was observed in 50 patients (86%), with complete remission in 34 (59%). The most frequently observed toxicities were peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, vomiting, pyrexia, and upper respiratory tract infection. CONCLUSION: The present report summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of the product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu). IMPLICATIONS FOR PRACTICE: Brentuximab vedotin was approved in the European Union for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma or systemic anaplastic large cell lymphoma. For Hodgkin lymphoma, brentuximab vedotin should only be used after autologous stem cell transplantation or following at least two prior therapies when transplantation or multiagent chemotherapy is not a treatment option. In two studies involving 160 patients, partial or complete responses were observed in the majority of patients. Although there was no information on the survival of patients treated in the studies at the time of approval, the responses were considered a clinically relevant benefit.

Brentuximab Vedotin in CD30-Positive Lymphomas: A SIE, SIES, and GITMO Position Paper.

Brentuximab vedotin (BV) is approved for the treatment of patients with relapsed or refractory CD30-positive Hodgkin lymphoma, and relapsed or refractory systemic anaplastic large-cell lymphoma. Several uncertainties remain regarding the optimal use of the drug in its approved indications as well as outside them. This article reports recommendations on the use of BV issued during a consensus project, sponsored by the Italian Society of Hematology (SIE) and its affiliate societies, Società Italiana di Ematologia Sperimentale (SIES) and Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Scientific evidence on BV was evaluated by a panel of experts, and consensus was developed by group discussion for key questions selected according to the clinical relevance. The following key issues were addressed: testing CD30 positivity to assess eligibility to BV; assessing practice indications of BV in Hodgkin lymphoma and systemic anaplastic large-cell lymphoma; providing pretreatment evaluation of patients candidates to BV; monitoring the response to BV; managing patients treated with BV; and assessing the role of BV in other CD30-positive lymphomas.

Primary Cutaneous Anaplastic Large Cell Lymphoma With Positive ALK Expression and a Rapidly Progressive Cutaneous Nodule.

Primary cutaneous anaplastic large cell lymphoma (pcALCL) is a distinct entity from systemic ALCL (sALCL). sALCL usually shows immunohistochemical positivity for anaplastic lymphoma kinase (ALK) and epithelial membrane antigen (EMA), whereas these tests are negative in pcALCL. In contrast to sALCL, pcALCL is rarely found in children and young adults. We present here a case of a rare clinical condition in a 21-year-old woman, who has pcALCL with positive ALK and patchy EMA expression. She experiences a large, rapidly growing nodule without any outside-nodule manifestation. In conclusion, both ALK and EMA expression alone cannot distinguish pcALCL from secondary skin involvement by a sALCL.