Clinical analysis of primary systemic anaplastic large cell lymphoma

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1 [Chinese Journal of Cancer 28:1, 49-53; January 2009]; Clinical 2009 analysis Sun Yat-Sen of primary University systemic Cancer anaplastic Centerlarge cell lymphoma: A report of 57 cases Clinical Research Paper Clinical analysis of primary systemic anaplastic large cell lymphoma A report of 57 cases Feng-Hua Wang, 1,2 Yu-Hong Li, 1,2, * Jing Zeng, 1,3 Hui-Lan Rao, 1,3 Zhong-Jun Xia, 1,2 Xiao-Fei Sun, 1,2 Hui-Qiang Huang, 1,2 Tong-Yu Lin, 1,2 Wen-Qi Jiang 1,2 and Zhong-Zhen Guan 1,2 1 State Key Laboratory of Oncology in South China; Guangzhou, Guangdong P.R. China; 2 Department of Medical Oncology; 3 Department of Pathology; Cancer Center; Sun Yat-sen University; Guangzhou, Guangdong P.R. China Key words: non-hodgkin s lymphoma, anaplastic lymphoma kinase, immunohistochemistry, chemotherapy, efficacy, prognosis Background and Objective: the clinical characteristics and prognosis of primary systemic anaplastic large cell lymphoma (ALCL) are various according to different reports. Anaplastic lymphoma kinase (ALK), a specific marker of primary systemic ALCL, is related with its clinical characteristics and prognosis. This study was to investigate the clinical characteristics and prognosis of primary systemic ALCL, and to explore the expression and clinical significance of ALK. Methods: Clinical data of 57 primary systemic ALCL patients, treated in Cancer Center of Sun Yat-sen University from January 1997 to January 2006, were reviewed. The expression of ALK in 46 tumor specimens was detected by SP immunohisochemistry. Results: The median age of the 57 patients was 30. The male/female ratio was 1.9:1. Of the 57 patients, 33 (57.9%) had B symptoms, 23 (40.4%) had Ann Arbor stage III IV tumors, and 23 (40.4%) had extranodal disease at diagnosis. All patients received chemotherapy. Of the 56 evaluable patients, 40 (71.4%) achieved complete remission. The overall response rate was 96.4%. With a median follow-up of 49.1 months, the median time to progression was 35.2 months and the expected 5-year survival rate was 65.2%. The expected 5-year survival rate was significantly higher in low/low-intermediate International Prognostic Index (IPI) risk group than in high-intermediate/high IPI risk group (68.9% vs. 33.3%, p = 0.010). The positive rate of ALK was 63.0% in the 46 cases detected. Compared with ALK-negative patients, ALK-positive patients were younger (p = 0.001) and had higher expected 5-year survival rate (p < 0.01). Multivariate analysis confirmed the independent prognostic values of ALK expression, primary disease site and lactate dehydrogenase (LDH) *Correspondence to: Yu-Hong Li; State Key Laboratory of Oncology in South China; and Department of Medical Oncology; Cancer Center; Sun Yat-sen University; Guangzhou, Guangdong P.R. China; Tel.: ; Fax: ; liyuhong@mail.sysu.edu.cn Submitted: 06/14/08; Revised: 07/22/08; Accepted: 10/15/05 This paper was translated into English from its original publication in Chinese. Translated by: Wei Liu on 15/15/08. The original Chinese version of this paper is published in: Ai Zheng (Chinese Journal of Cancer), 28(1); Previously published online as a Chinese Journal of Cancer E-publication: level. Conclusions: Primary systemic ALCL usually occurs in young patients, with good response to chemotherapy and good prognosis. No ALK expression, high-intermediate/high IPI, extranodal disease and elevated LDH level are correlated to unfavorable prognosis. Anaplastic large cell lymphoma (ALCL) is a rare subtype of mature T-cell non-hodgkin's lymphoma (NHL). Its clinical manifestations, histomorphologic features, immunophenotype and cytogenetics are various. Clinically, ALCL may be primary or secondary to progressive lymphoproliferative disorders. The primary type is further classified into systemic and cutaneous types. According to cell immunophenotype, ALCL is classified into T-cell and null-cell types. Regarding cytogenetic features, a chromosomal abnormality, t (2, 5), exists in some ALCLs and leads to the expression of anaplastic lymphoma kinase (ALK). Thus, ALCL can be classified into ALK-positive and ALK-negative types. 1 In 2000, we had reported the clinical characteristics, treatment and prognosis of 20 ALCL patients treated at the Sun Yat-sen University Cancer Center. However, in that study, the sample size was too small, some B-cell ALCLs were included, and the impact of ALK expression on patients' survival was not investigated. 2 In the present study, we further investigated the clinical characteristics, treatment and prognosis of 57 primary systemic ALCL patients treated at the Sun Yat-sen University Cancer Center, determined the expression of ALK in tumor samples derived from 46 patients by immunohistochemistry, and explored its clinical significance. Materials and Methods Clinical data. The clinical and follow-up data of 57 primary systemic ALCL patients, treated from January 1997 to June 2006 at the Sun Yat-sen University Cancer Center, were analyzed. Of the 57 patients, 37 (64.9%) were men and 20 (35.1%) were women with a ratio of 1.9:1. The median age of these patients was 30 years (range, 8 75 years); 15 patients were aged of 18 years. Of the 57 patients, 45 (78.9%) had T-cell ALCL and 12 (22.1%) had null-cell ALCL; 43 (75.4%) had performance status (PS) scores of 0 1 point and 14 (24.6%) had scores > 1 point; 33 (57.9%) had B symptoms; 28 (49.1%) showed an elevated level of lactate dehydrogenase (LDH); 23 (40.4%) had large masses ( 5 cm); 23 (40.4%) had Ann Arbor stage III IV tumors; 34 (59.6%) had only intranodal invasion and Chinese Journal of Cancer 49

2 Table 1 First-line and second-line regimens for 57 primary systemic anaplastic large cell lymphoma (ALCL) patients Table 2 Correlation of anaplastic lymphoma kinase (ALK) expression to clinical characteristics of primary systemic ALCL patients CR, complete remission; PR, partial remission. CHOP: cyclophosphamide (CTX), vincristine (VCR), adriamycin (ADM), and prednisone (Pred). EPOCH: CTX, VCR, ADM, Pred and etoposide (VP-16). IMVP-16: ifosfamide (IFO), ethotrexate (MTX) and VP-16. DHAP: dexamethasone (DXM), cytarabine (Ara-C), and cisplatin (DDP). DICE: DXM, DDP and VP-16. MINE: IFO, mitoxantrone (MIT) and VP-16. GEM, gemcitabine; ASCT: autologous stem cell transplantation. 23 (40.4%) had extranodal disease at diagnosis (five had soft tissue invasion, four had gastrointestinal tract invasion, four had bone invasion, three had skin invasion, two had bone marrow invasion, two had nasopharyngeal invasion, one had lung invasion, liver invasion, one had tonsil invasion, and one had pleural effusion and ascites); according to the International Prognostic Index (IPI) scores, 35 (61.3%) had low risk (0 1 point), 16 (28.1%) had intermediate-low risk (2 points), and six (10.6%) had high-intermediate or high risk ( 3 points). All 57 patients initially underwent systemic chemotherapy (Table 1), of which 44 (77.2%) underwent chemotherapy alone, ten underwent chemotherapy and radiotherapy, two underwent surgery and chemotherapy, and one underwent surgery, chemotherapy and radiotherapy. Pathologic diagnosis and immunohistochemistry. According to WHO classification and diagnostic criteria of NHL (2001 version), 3 all cases were definitely diagnosed as CD30 +, T-cell or null-cell systemic ALCL after morphologic review and immunohistochemical examination by pathologists. The expression of ALK in 46 specimens of ALCL was detected protein by SP immunohistochemistry. Immunohistochemical results were evaluated according to the scores of staining intensity (no staining was scored as 0 point, pale yellow staining as 1 point, yellowish brown staining as 2 points, and dark brown staining as 3 points) and the percentage of positive cells (the specimens with no positive cells was scored as 0 point, those with a positive rate of 10% was scored as 1 point, 11 50% as 2 points, 51 75% as 3 points, and > 75% as 4 points). Immunohistochemical staining result was considered positive when multiplying the two scores and got a value of > 3 points. Staging and evaluation of therapeutic response. The staging was conducted according to the Ann Arbor staging system. Therapeutic response was evaluated according to the International Standard Response Criteria for NHL. 4 Statistical analysis. Statistical analysis was conducted using the SPSS12.0 software. Measurement data were analyzed using the t-test while count data were analyzed using the Chi-square test. Patients survival was analyzed using the Kaplan-Meier method. The log-rank test was used for univariate analysis; the Cox proportional-hazards regression model was used for multivariate prognostic analysis. Results Correlation of ALK expression to clinical characteristics of primary systemic ALCL. Of the 46 patients from whom tumor specimens were taken for ALK detection, 29 (63%) were ALK-positive and had a median age of 27 years (range, 8 72 years), and 17 (37%) were ALK-negative and had a median age of 54 years (range, 8 75 years). The age of ALK-positive patients was significantly lower than that of ALK-negative patients (p = 0.001); ALK expression had no significant correlation with sex, PS score, LDH level, large mass, B symptoms, cell phenotypes, primary site, clinical stage and IPI score (p > 0.05) (Table 2). 50 Chinese Journal of Cancer 2009; Vol. 28 Issue 1

3 Figure 1. Overall survival curve of 57 primary systemic anaplastic large cell lymphoma (ALCL) patients. Therapeutic outcomes. Among the 57 patients, one had no evaluable lesion after operation and 56 were evaluable for chemotherapeutic response. Of the 56 patients, 40 (71.4%) achieved complete remission (CR) and 14 (25.0%) achieved partial remission (PR), resulting in an objective response rate (CR + PR) of 96.4%; one patient had stable disease (SD) and one had progressive disease (PD). Of 42 evaluable patients who received CHOP regimen, 30 (71.4%) achieved CR, resulting in an objective response rate of 95.2%. Of the 15 pediatric patients, eight received B-NHL-BFM-90 protocol, of which seven (87.5%) achieved CR and one achieved PR; seven received CHOP regimen, of which four (57.1%) achieved CR, two achieved PR, and one had PD. The CR rate was higher in B-NHL-BFM-90 regimen group than in CHOP group though there was no significant difference (p = 0.231). The CR rate of ALK-positive patients (79.3%; 23/29) was higher than that of ALK-negative patients (58.8%; 10/17) with no statistically significant difference (p = 0.136). Eighteen CR patients had disease progressed later with a median CR duration of 4.9 months (range, months). Of the 18 patients, two abandoned further treatment, one received radiotherapy alone, and 15 received second-line chemotherapy (Table 1). Of the 15 patients who received second-line chemotherapy, eight achieved CR and two achieved PR, resulting in an objective response rate of 66.7%; one had SD, and four had PD. Of the 14 PR patients, three abandoned further treatment, one received radiotherapy alone, and ten received second-line chemotherapy (Table 1). Of the ten patients who received second-line chemotherapy, six achieved CR, two achieved PR, one had SD, and two had PD. By January 2008, with a median follow-up duration of 49.1 months (range, months), the median progression-free survival (PFS) for all patients was 35.2 months [95% confidence interval (CI), months]. The median overall survival (OS) duration was not obtained, and the estimated 5-year survival rate was 65.2% (Fig. 1). For the 17 ALK-negative patients, the median PFS was 7.3 months (95% CI, months), the median OS was 17.8 months (95% CI, months), and the estimated 5-year survival rate was 35.2%. For the 29 ALK-positive patients, the median PFS and median OS were not obtained, and the estimated 5-year survival rate was 85.9%. The median PFS and OS were significantly longer in ALK-positive patients than in ALK-negative patients (p < 0.01) (Fig. 2). Univariate analysis showed that the Figure 2. Progression-free survival curves (A) and overall survival curves (B) of the patients with or without anaplastic lymphoma kinase (ALK) expression. estimated 5-year survival rate was higher in the patients with normal level of LDH than in those with high levels of LDH (p = 0.049), higher in the patients with intranodal invasion than in those with extranodal invasion (p = 0.041), and higher in the patients with low/ intermediate-low IPI score than in those with high-intermediate/high IPI score (p = 0.010), while the prognosis had no correlation with sex, age, B symptoms, clinical stage, large mass, and PS score (p > 0.05) (Table 3). Cox multivariate prognostic analysis further proved that ALK expression, primary site (intranodal or extranodal) and LDH level had significant impacts on survival (p < 0.05) (Table 4). Discussion Since ALCL was first reported by Stein et al. 5 in 1985, significant achievements have been made in the study on the pathology of this disease over the years. However, the knowledge on the clinical characteristics and outcomes of ALCL was based on small case series. Moreover, the results of different studies are inconsistent, which may relate to the inconsistence in the age distribution of patients, ALK expression, therapeutic protocols and subtype distribution (such as Chinese Journal of Cancer 51

4 Table 3 Univariate prognostic analysis of primary systemic ALCL patients Table 4 Multivariate prognostic analysis of primary systemic ALCL patients HD-like ALCL, B-cell ALCL and primary cutaneous ALCL). In this study, we retrospectively analyzed and summarized the clinical characteristics, treatment and prognosis of primary systemic ALCL (the most common ALCL subtype) patients. Our results showed that primary systemic ALCL mainly occurs in young patients (a median age of 30 years), T-cell ALCL is the predominant type (78.9%), B symptoms (57.9%) and extranodal invasion (40.4%) are commonly seen. Our findings are similar to those in previous reports. 6-8 The incidence of primary systemic ALCL was higher in men than in women, with a ratio of 1.9:1, laying in the range ( ) reported previously. 6-9 The percentage of patients with advanced disease (stages III-IV) was 40.4%, lower than the range (52 60%) reported in literature Extranodal invasion was most frequently seen in soft tissue, bone and gastrointestinal tract, which is inconsistent with other reports that extranodal invasion was most frequently seen in the skin. 8, 9, 11 Primary systemic ALCL is considered as a progressive disease. Current main therapeutic strategy is combination chemotherapy. However, large randomized controlled studies have not been performed and standard treatment is unavailable. In most studies, adult patients were treated with anthracycline-based regimens, such as CHOP and MACOP regimens, while pediatric patients were treated with lymphoblastic leukemia protocols such as LNH-92 regimen 12 or Burkitti lymphoma protocols such as B-NHL-BFM-90 regimen. 13 Previous studies indicated that the overall response rates, CR rates and 5-year OS rates of primary systemic ALCL patients undergoing initial chemotherapy were 60 95%, 60 85% and 40 80%, respectively, and most recurrent patients were still sensitive to chemotherapy and achieved remission again. 8, 14 In our study, the overall response rate, CR rate and estimated 5-year OS rate of the patients undergoing first-line chemotherapy were 96.4%, 71.4% and 65.2%, respectively, which are similar to those reported in literature. The CR rate of pediatric ALCL patients was higher in B-NHL-BFM-90 regimen group (87.5%) than in CHOP regimen group (57.1%), suggesting that more intensive chemotherapy regimens may achieve better efficacy on pediatric ALCL. ALK protein is a relatively specific marker for primary systemic ALCL, with detection rates of 60 85%. 1 Some studies showed that ALK-positive and ALK-negative ALCL patients had different gene expression profiles, clinical characteristics and prognosis. 15 ALK-positive ALCL patients are characterized by younger age and better prognosis. Most ALK-positive ALCL patients are below 30 years old, and their 5-year OS rates were 70 95%, while the 5-year OS rates of ALK-negative ALCL patients were 28 46% Ten Berge et al. 20 reported that the prognosis of ALK-negative ALCL patients was similar to that of unspecific peripheral T-cell lymphoma patients. In this study, the detection rate of ALK in 46 ALCL tissue samples was 63%; the median age of ALK-positive ALCL patients (27 years) was significantly lower than that of ALK-negative ALCL patients; however, ALK expression had no significant correlation with sex, B-symptoms, cell phenotype, primary site, clinical stage and response rate (p > 0.05). Our results are similar to those reported in literature. 8,9,21 The 5-year OS rate was significantly higher in ALK-positive patients than in ALK-negative patients (85.9% vs. 35.2%, p < 0.01). ALK expression was further confirmed to be an independent prognostic factor of ALCL. Many studies proved that IPI score is an important prognostic factor of ALCL, the 5-year OS rate is higher in low/intermediate-low risk patients than in high-intermediate/high risk patients. 8,10,17,18 In this study, the 5-year OS rates were 68.9% in low/intermediate-low risk patients and 33.3% in high-intermediate/high risk patients (p = 0.010). Besides IPI score, multivariate analysis showed that primary site (intranodal or extranodal) and LDH level were also independent prognostic factors of primary systemic ALCL, which is inconsistent 52 Chinese Journal of Cancer 2009; Vol. 28 Issue 1

5 with that reported in literature. Li et al. 9 analyzed the prognosis of 81 ALCL patients, and found that their prognosis was correlated with B symptoms but not with age, clinical stage, immunophenotype, primary site and histological type. A study in South Korea showed that age, PS score, LDH level and the extent of extranodal invasion were independent prognostic factors of ALCL. 8 Le Deley et al. 22 analyzed the prognosis of 225 European pediatric ALCL patients treated from 1987 to 1997, and found that B symptoms, clinical stage and LDH level had no significant correlation with the prognosis while the presence of mediastinal invasion, visceral invasion and skin involvement were independent prognostic factors. In summary, combination chemotherapy had achieved remarkable efficacy on primary systemic ALCL when compared with other types of invasive lymphomas, especially in ALK-positive patients and patients with low/intermediate-low IPI scores. 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