Pediatric Hematology and Oncology, 31:509–517, 2014 C Informa Healthcare USA, Inc. Copyright ISSN: 0888-0018 print / 1521-0669 online DOI: 10.3109/08880018.2014.940434
ORIGINAL ARTICLE Lymphoma
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Cornell University on 09/27/14 For personal use only.
Clinical Features and Treatment Results of Children with Diffuse Large B-Cell Lymphoma ¨ 1 Gulsev ¨ Erman Atas¸,1 M. Tezer Kutluk,1 Canan Akyuz, Kale,2 Ali Varan,1 1 1 ¨ ¨ ukpamukc ¨ Bilgehan Yalc¸ın, Burc¸a Aydın, and Munevver Buy ¸ u1 1 Department of Pediatric Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey; 2 Department of Pediatric Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey
The demographic, clinical characteristics, and treatment groups of 33 children with diffuse large Bcell lymphoma (DLBCL) were recorded and analyzed among 1486 non-Hodgkin lymphoma (NHL) cases since 1972. The median age was 9.7 years (range 1.4–16.9) and male/female ratio was 24/9 = 2.6. Kaplan–Meier methods and logrank tests were used in treatment analysis. The frequency of DLBCL among 1486 NHL cases was 2.2%, however, the percentage was 9.3% in cases diagnosed after 2000. The event-free survival (EFS) and overall survival (OS) rates for 33 children were 61% and 65.1% at 5 years, respectively. The EFS and OS rates of low stage (stages I and II) disease decreased to lower level in advanced stage (stages III and IV) disease. Associated conditions and ages older than 14 years were found as poor prognostic factors in multivariate analysis. The survival rates in children with DLBCL need further improvement. This is mainly related with late referral of those children with advanced disease. The proper diagnosis and early referral is essential in these children for a better survival rate. The children with associated conditions and older children must be handled with care since these are found as poor prognostic factors. Keywords children, diffuse large B-cell lymphoma, treatment
INTRODUCTION Lymphomas are the second most common tumors (17.2%) among children in Turkey [1]. Non-Hodgkin lymphomas (NHL) account for about 6 to 8% of pediatric malignancies [2, 3] and diffuse large B-cell lymphoma (DLBCL) comprises about 10% of pediatric and adolescent NHL [4–6]. The survival rates for NHLs have increased to 88% for children and 77% for adolescents in recent years [7]. Dramatic improvements in survival have also been achieved for children and adolescents with DLBCL. Diffuse large B-cell lymphoma is known to have a favorable prognosis compared to adults [2, 8]. Clinical features of DLBCL were reported as favorable prognosis and the high survival rates in large series by Oschlies et al. [2] and Burkhardt et al. [4]. The real incidence of DLBCL is unknown and there are limited data on treatment outcomes in our country. The aim of this study was to analyze the clinical features and treatment results of pediatric patients with DLBCL. Received 27 March 2014; accepted 27 June 2014. Address correspondence to M. Tezer Kutluk, Department of Pediatric Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey. E-mail: [email protected]
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Cornell University on 09/27/14 For personal use only.
E. Atas et al.
Patients and Methods This was a single institutional study. The demographic and clinical characteristics of 33 consecutively diagnosed DLBCL patients younger than 18 years of age were recorded and analyzed among 1486 NHL cases from the files of Department of Pediatric Oncology between 1972 and 2012. Approval for the study was obtained from Institution Ethics Committee. The Murphy [9] and LMB systems were used for staging or grouping and all cases were classified according to the histopathological classification of tumors of hematopoietic and lymphoid tissues by the World Health Organisation (WHO) [10]. For unknown pathological subgroup of large cell lymphoma, histological slides were reviewed in four cases. Others diagnosed DLBCL were not re-reviewed for classification. Before LMB protocols we used different protocols as LSA2L2, mBACOP, and only prednisolone. Because of using different protocols, we preferred Murphy system for staging before LMB protocol. After LMB protocols (89 and 96) were the main treatments, we performed for grouping and staging both Murphy and LMB group. Lymphomas presenting in extranodal organs with or only minor lymph node involvement were considered primary extranodal DLBCL. B-cell lineage was also confirmed by immunophenotyping studies (CD19, CD20, CD23, CD30, CD79a, CD3, CD15, Tdt, bcl-2, LCA, Ki-67, EBV). Lymphomas with clinically dominant lymph node involvement category, as well as those presenting at the spleen, thymus, and Waldeyer’s ring involvement categories, were considered as primary nodal DLBCL. Lymphomas with extensive disease involving both nodal and extranodal sites were considered nodal DLBCL. Patients were stratified in three groups according to Patte et al. [11, 12] before deciding on the treatment in cases treated with LMB regimens. From 1994 to 2011, patients with DLBCL were treated with the LMB89 [11] protocol. In 2011, it has been changed with LMB96 [12] protocol. The children were treated by LMB89 in 24 cases and LMB96 in 4 cases. LSA2L2 in three cases and other protocols in two cases diagnosed earlier than 1994. Overall survival was calculated from the first day of chemotherapy to death or to the date of the last follow-up for the patients who were alive. Event-free survival was defined as the interval from the start of treatment to one of the following events: death from any cause, disease progression during treatment, relapse, or to the date of last follow-up if patient did not experience any event. Statistical analyses were performed by using the SPSS software version 15. The Kaplan–Meier survival estimates were calculated. The logrank test was used for the statistical comparisons [13]. Univariate and multivariate analysis were also done to investigate the effects of prognostic factors on survival rates [14]. RESULTS The frequency of DLBCL among 1486 NHL cases was 2.2%, the percentage was 9.3% in 235 cases diagnosed after 2000. The median age was 9.7 years (range 1.4–16.9) and M/F ratio was 24/9 = 2.6. The average follow-up was 56 months (0.6–253 months). The primary tumor localizations were abdominal in 6 (18.2%), primary intestinal in 5 (15.2%), Waldeyer in 5 (15.2%), cervical in 5 (15.2%), disseminated in 5 (15.2%), bone in 3 (9%), mediastinal in 2 (6%), parenchymal central nervous system (CNS) in 1 (3%), and lung in 1 (3%). Forty percent had extranodal disease and the rest had nodal disease. Bone marrow infiltration was present in 6.1% of cases and none had cerebrospinal fluid involvement. The associated conditions were combined with immunodeficiency, DOCK8 deficiency (dedicator of cytokinesis 8), ataxia-telangiectasia, post-kidney transplant immunosupression, anticonvulsant use, atrophic kidney, and ventricular septal defect. Immunochemical staining for EBV was performed by pathology in 6 of 33 cases. One of them was positive and others were negative for EBV. The stage distributions were stage I in 3 (9%) cases, stage II in 6 (18.2%) cases, stage III in Pediatric Hematology and Oncology
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Cornell University on 09/27/14 For personal use only.
Results of Children with DLBCL
FIGURE 1
Overall survival and event-free survival in 33 subjects.
20 (60.6%) cases, and stage IV in 4 (12.2%) cases. The group distributions for LMB89 were group A in 2 (8.3%) cases, group B in 19 (79.2%) cases, group C in 3 (12.5%) cases and for LMB96 were 2 (50%) cases in group B and 2 (50%) cases in group C. The children were treated by LMB89 in 24 cases, LMB96 in 4 cases, LSA2L2 in 2 cases, other protocols (mBACOP and prednisolone only) in 2 cases, only surgery without chemotherapy in 1 case. The event-free survival (EFS) and overall survival (OS) rates for 33 children were 61% and 65.1% at 5 years, respectively (Figure 1). The OS and EFS were significantly high in low stage (stages I and II, n = 9) and low in advanced stage (stages III and IV, n = 24) disease (OS; 100% vs. 50%, P = .015, EFS; 100% vs. 46%, P = .009). The OS and EFS were found 79% and 41% in nodal group (n = 21) and 71% and 41% in extranodal group (n = 12), respectively. Event was detected in 13 cases (relapse in 7 cases, progression in 2 cases, resistant disease in 3 cases, exitus in 1 case who died shortly at the beginning of treatment) within 8 months. Eleven of these cases died within 16 months (Figures 2 and 3). The OS and EFS in LMB89 (n = 24) protocol for group B (n = 19) were 68.4% and 68.4% at 5 years. Eleven (33.33%) patients died with disease (treatment regiments; mBACOP in one case, prednisolone only in one case, LMB89 group B in six cases, LMB89 group C in two cases, LMB96 group C in one case). Seven patients with progressive disease were reinduced with second line treatment (NHL-BFM90 in two cases, NHL-BFM90 plus inguinal radiotherapy in one case, RICE (rituximab, ifosfamide, carboplatin, etoposide) with autologous stem cell transplantation (ASCT) in one case, LMB89 group C which was changed from LMB89 group B in two cases, rituximab plus methylprednisolone in one case). Remission was documented in only one patient treated with RICE plus ASCT. The other protocols were unsuccessful and these patients died from progressive disease). The OS and EFS rates were 63.6% and 63.6% before 2000s (n = 11) and 65.9% and 63.6% after 2000s (n = 22) at 5 years, respectively (OS, P = .898 and EFS, P = .616). After excluding other protocols, the OS and EFS of LMB protocols were 65.7% and 64.3%, respectively. C Informa Healthcare USA, Inc. Copyright
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Cornell University on 09/27/14 For personal use only.
E. Atas et al.
FIGURE 2
Event-free survival in patients with early and advanced stage disease.
The number of patients need radiotherapy were 6 of 33 and the survival rates of patients received radiotherapy were 25% for OS and 17% for EFS. These rates were lower than patients those do not need radiotherapy (EFS; 70% and OS; 70%). Variables with P < .2 values were shown in univariate analysis, however, variables with P < .05 were included in multivariate analysis for model. The presence of associated conditions and the age older than 14 years was found as poor prognostic factors in a multivariate analysis (associated conditions; P = .024, HR = 78.39, age older than 14 years; P = .009, HR = 45.8) (Table 1).
FIGURE 3
Overall survival in patients with early and advanced stage disease. Pediatric Hematology and Oncology
∗
2.45 2.78 1.60 3.76 3.6 2.9 36.7 2.32 3.4 0.5 2.2 2.9
ORIGINAL ARTICLE Lymphoma
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Cornell University on 09/27/14 For personal use only.
Clinical Features and Treatment Results of Children with Diffuse Large B-Cell Lymphoma ¨ 1 Gulsev ¨ Erman Atas¸,1 M. Tezer Kutluk,1 Canan Akyuz, Kale,2 Ali Varan,1 1 1 ¨ ¨ ukpamukc ¨ Bilgehan Yalc¸ın, Burc¸a Aydın, and Munevver Buy ¸ u1 1 Department of Pediatric Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey; 2 Department of Pediatric Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey
The demographic, clinical characteristics, and treatment groups of 33 children with diffuse large Bcell lymphoma (DLBCL) were recorded and analyzed among 1486 non-Hodgkin lymphoma (NHL) cases since 1972. The median age was 9.7 years (range 1.4–16.9) and male/female ratio was 24/9 = 2.6. Kaplan–Meier methods and logrank tests were used in treatment analysis. The frequency of DLBCL among 1486 NHL cases was 2.2%, however, the percentage was 9.3% in cases diagnosed after 2000. The event-free survival (EFS) and overall survival (OS) rates for 33 children were 61% and 65.1% at 5 years, respectively. The EFS and OS rates of low stage (stages I and II) disease decreased to lower level in advanced stage (stages III and IV) disease. Associated conditions and ages older than 14 years were found as poor prognostic factors in multivariate analysis. The survival rates in children with DLBCL need further improvement. This is mainly related with late referral of those children with advanced disease. The proper diagnosis and early referral is essential in these children for a better survival rate. The children with associated conditions and older children must be handled with care since these are found as poor prognostic factors. Keywords children, diffuse large B-cell lymphoma, treatment
INTRODUCTION Lymphomas are the second most common tumors (17.2%) among children in Turkey [1]. Non-Hodgkin lymphomas (NHL) account for about 6 to 8% of pediatric malignancies [2, 3] and diffuse large B-cell lymphoma (DLBCL) comprises about 10% of pediatric and adolescent NHL [4–6]. The survival rates for NHLs have increased to 88% for children and 77% for adolescents in recent years [7]. Dramatic improvements in survival have also been achieved for children and adolescents with DLBCL. Diffuse large B-cell lymphoma is known to have a favorable prognosis compared to adults [2, 8]. Clinical features of DLBCL were reported as favorable prognosis and the high survival rates in large series by Oschlies et al. [2] and Burkhardt et al. [4]. The real incidence of DLBCL is unknown and there are limited data on treatment outcomes in our country. The aim of this study was to analyze the clinical features and treatment results of pediatric patients with DLBCL. Received 27 March 2014; accepted 27 June 2014. Address correspondence to M. Tezer Kutluk, Department of Pediatric Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey. E-mail: [email protected]
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Cornell University on 09/27/14 For personal use only.
E. Atas et al.
Patients and Methods This was a single institutional study. The demographic and clinical characteristics of 33 consecutively diagnosed DLBCL patients younger than 18 years of age were recorded and analyzed among 1486 NHL cases from the files of Department of Pediatric Oncology between 1972 and 2012. Approval for the study was obtained from Institution Ethics Committee. The Murphy [9] and LMB systems were used for staging or grouping and all cases were classified according to the histopathological classification of tumors of hematopoietic and lymphoid tissues by the World Health Organisation (WHO) [10]. For unknown pathological subgroup of large cell lymphoma, histological slides were reviewed in four cases. Others diagnosed DLBCL were not re-reviewed for classification. Before LMB protocols we used different protocols as LSA2L2, mBACOP, and only prednisolone. Because of using different protocols, we preferred Murphy system for staging before LMB protocol. After LMB protocols (89 and 96) were the main treatments, we performed for grouping and staging both Murphy and LMB group. Lymphomas presenting in extranodal organs with or only minor lymph node involvement were considered primary extranodal DLBCL. B-cell lineage was also confirmed by immunophenotyping studies (CD19, CD20, CD23, CD30, CD79a, CD3, CD15, Tdt, bcl-2, LCA, Ki-67, EBV). Lymphomas with clinically dominant lymph node involvement category, as well as those presenting at the spleen, thymus, and Waldeyer’s ring involvement categories, were considered as primary nodal DLBCL. Lymphomas with extensive disease involving both nodal and extranodal sites were considered nodal DLBCL. Patients were stratified in three groups according to Patte et al. [11, 12] before deciding on the treatment in cases treated with LMB regimens. From 1994 to 2011, patients with DLBCL were treated with the LMB89 [11] protocol. In 2011, it has been changed with LMB96 [12] protocol. The children were treated by LMB89 in 24 cases and LMB96 in 4 cases. LSA2L2 in three cases and other protocols in two cases diagnosed earlier than 1994. Overall survival was calculated from the first day of chemotherapy to death or to the date of the last follow-up for the patients who were alive. Event-free survival was defined as the interval from the start of treatment to one of the following events: death from any cause, disease progression during treatment, relapse, or to the date of last follow-up if patient did not experience any event. Statistical analyses were performed by using the SPSS software version 15. The Kaplan–Meier survival estimates were calculated. The logrank test was used for the statistical comparisons [13]. Univariate and multivariate analysis were also done to investigate the effects of prognostic factors on survival rates [14]. RESULTS The frequency of DLBCL among 1486 NHL cases was 2.2%, the percentage was 9.3% in 235 cases diagnosed after 2000. The median age was 9.7 years (range 1.4–16.9) and M/F ratio was 24/9 = 2.6. The average follow-up was 56 months (0.6–253 months). The primary tumor localizations were abdominal in 6 (18.2%), primary intestinal in 5 (15.2%), Waldeyer in 5 (15.2%), cervical in 5 (15.2%), disseminated in 5 (15.2%), bone in 3 (9%), mediastinal in 2 (6%), parenchymal central nervous system (CNS) in 1 (3%), and lung in 1 (3%). Forty percent had extranodal disease and the rest had nodal disease. Bone marrow infiltration was present in 6.1% of cases and none had cerebrospinal fluid involvement. The associated conditions were combined with immunodeficiency, DOCK8 deficiency (dedicator of cytokinesis 8), ataxia-telangiectasia, post-kidney transplant immunosupression, anticonvulsant use, atrophic kidney, and ventricular septal defect. Immunochemical staining for EBV was performed by pathology in 6 of 33 cases. One of them was positive and others were negative for EBV. The stage distributions were stage I in 3 (9%) cases, stage II in 6 (18.2%) cases, stage III in Pediatric Hematology and Oncology
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Cornell University on 09/27/14 For personal use only.
Results of Children with DLBCL
FIGURE 1
Overall survival and event-free survival in 33 subjects.
20 (60.6%) cases, and stage IV in 4 (12.2%) cases. The group distributions for LMB89 were group A in 2 (8.3%) cases, group B in 19 (79.2%) cases, group C in 3 (12.5%) cases and for LMB96 were 2 (50%) cases in group B and 2 (50%) cases in group C. The children were treated by LMB89 in 24 cases, LMB96 in 4 cases, LSA2L2 in 2 cases, other protocols (mBACOP and prednisolone only) in 2 cases, only surgery without chemotherapy in 1 case. The event-free survival (EFS) and overall survival (OS) rates for 33 children were 61% and 65.1% at 5 years, respectively (Figure 1). The OS and EFS were significantly high in low stage (stages I and II, n = 9) and low in advanced stage (stages III and IV, n = 24) disease (OS; 100% vs. 50%, P = .015, EFS; 100% vs. 46%, P = .009). The OS and EFS were found 79% and 41% in nodal group (n = 21) and 71% and 41% in extranodal group (n = 12), respectively. Event was detected in 13 cases (relapse in 7 cases, progression in 2 cases, resistant disease in 3 cases, exitus in 1 case who died shortly at the beginning of treatment) within 8 months. Eleven of these cases died within 16 months (Figures 2 and 3). The OS and EFS in LMB89 (n = 24) protocol for group B (n = 19) were 68.4% and 68.4% at 5 years. Eleven (33.33%) patients died with disease (treatment regiments; mBACOP in one case, prednisolone only in one case, LMB89 group B in six cases, LMB89 group C in two cases, LMB96 group C in one case). Seven patients with progressive disease were reinduced with second line treatment (NHL-BFM90 in two cases, NHL-BFM90 plus inguinal radiotherapy in one case, RICE (rituximab, ifosfamide, carboplatin, etoposide) with autologous stem cell transplantation (ASCT) in one case, LMB89 group C which was changed from LMB89 group B in two cases, rituximab plus methylprednisolone in one case). Remission was documented in only one patient treated with RICE plus ASCT. The other protocols were unsuccessful and these patients died from progressive disease). The OS and EFS rates were 63.6% and 63.6% before 2000s (n = 11) and 65.9% and 63.6% after 2000s (n = 22) at 5 years, respectively (OS, P = .898 and EFS, P = .616). After excluding other protocols, the OS and EFS of LMB protocols were 65.7% and 64.3%, respectively. C Informa Healthcare USA, Inc. Copyright
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Cornell University on 09/27/14 For personal use only.
E. Atas et al.
FIGURE 2
Event-free survival in patients with early and advanced stage disease.
The number of patients need radiotherapy were 6 of 33 and the survival rates of patients received radiotherapy were 25% for OS and 17% for EFS. These rates were lower than patients those do not need radiotherapy (EFS; 70% and OS; 70%). Variables with P < .2 values were shown in univariate analysis, however, variables with P < .05 were included in multivariate analysis for model. The presence of associated conditions and the age older than 14 years was found as poor prognostic factors in a multivariate analysis (associated conditions; P = .024, HR = 78.39, age older than 14 years; P = .009, HR = 45.8) (Table 1).
FIGURE 3
Overall survival in patients with early and advanced stage disease. Pediatric Hematology and Oncology
∗
2.45 2.78 1.60 3.76 3.6 2.9 36.7 2.32 3.4 0.5 2.2 2.9
