Clinical Features and Treatment Results of Children With Diffuse Large B-Cell Lymphoma

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Pediatric Hematology and Oncology, 31:509517, 2014

Copyright C Informa Healthcare USA, Inc.


ISSN: 0888-0018 print / 1521-0669 online
DOI: 10.3109/08880018.2014.940434

ORIGINAL ARTICLE
Lymphoma

Clinical Features and Treatment Results of Children


with Diffuse Large B-Cell Lymphoma

Erman Atas,1 M. Tezer Kutluk,1 Canan Akyuz,


1 Gulsev
Kale,2 Ali Varan,1
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Cornell University on 09/27/14

1 1

Bilgehan Yalcn, Burca Aydn, and Munevver ukpamukc
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 diuse large B-
cell lymphoma (DLBCL) were recorded and analyzed among 1486 non-Hodgkin lymphoma (NHL)
cases since 1972. The median age was 9.7 years (range 1.416.9) and male/female ratio was 24/9 =
2.6. KaplanMeier methods and logrank tests were used in treatment analysis. The frequency of
For personal use only.

DLBCL among 1486 NHL cases was 2.2%, however, the percentage was 9.3% in cases diagnosed af-
ter 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 chil-
dren 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, diuse 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 malignan-
cies [2, 3] and diffuse large B-cell lymphoma (DLBCL) comprises about 10% of pedi-
atric and adolescent NHL [46]. The survival rates for NHLs have increased to 88% for
children and 77% for adolescents in recent years [7]. Dramatic improvements in sur-
vival 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 coun-
try. 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: tezerkutluk@gmail.com


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 On-
cology 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 classifica-
tion. 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 treat-
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Cornell University on 09/27/14

ments, we performed for grouping and staging both Murphy and LMB group. Lym-
phomas presenting in extranodal organs with or only minor lymph node involvement
were considered primary extranodal DLBCL. B-cell lineage was also confirmed by im-
munophenotyping studies (CD19, CD20, CD23, CD30, CD79a, CD3, CD15, Tdt, bcl-2,
LCA, Ki-67, EBV). Lymphomas with clinically dominant lymph node involvement cat-
egory, as well as those presenting at the spleen, thymus, and Waldeyers ring involve-
ment categories, were considered as primary nodal DLBCL. Lymphomas with exten-
sive 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 decid-
ing on the treatment in cases treated with LMB regimens. From 1994 to 2011, patients
For personal use only.

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
KaplanMeier 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 1.416.9) and
M/F ratio was 24/9 = 2.6. The average follow-up was 56 months (0.6253 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 im-
munodeficiency, 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 pathol-
ogy 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


Results of Children with DLBCL
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FIGURE 1 Overall survival and event-free survival in 33 subjects.


For personal use only.

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 with-
out 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 (re-
lapse 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 in-
guinal 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.

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E. Atas et al.
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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 pa-
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tients 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 associ-
ated 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.

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TABLE 1 Prognostic Factors of Diffuse Large B-Cell Lymphoma in Univariate and Multivariate Analysis
Univariate analysis Multivariate analysis

Prognostic factors Category HR 95% CI P HR 95% CI P
Age (year) <10/10 2.45 0.768.4 .153
Associated conditions No/yes 2.78 1.011.5 .038 78.39 1.73422 .024
Primary localization lymph node/abdominal/disseminated/other sites 1.60 1.12.3 .013 .430
Disease involvement Nodal/extranodal 3.76 1.012.9 .036 .572
14 years old, DLBCL No/yes 3.6 1.111 .034 45.8 2.6800 .009
Stage II/III/IV 2.9 1.07.8 .033 .942
LDH (IU/L) <500/500 36.7 0.113500 .230
LDH (IU/L) <1000/1000 2.32 0.68.6 .209
Radiotherapy No/yes 3.4 112 .049 .236
Surgery (diagnosis time) Yes/no 0.5 0.161.5 .244
BFM risk R2/R3/R4 2.2 15.1 .043
LMB 89 Group B/C 2.9 0.711 .124

Hazard ratio.

Confidence interval.

Diffuse large B-cell lymphoma.
Lactate dehydrogenase.
BerlinFrankfurtMunster.


Lymphoma Malign B.

E. Atas et al.

DISCUSSION
Diffuse large B-cell lymphoma in the pediatric population is a common type of large
cell NHL. While previous large-scale clinical studies indicate that it constitutes about
10 to 20% of pediatric NHL [4, 5, 15], as well as it is approximately two-thirds of large
cell lymphomas [16]. To our knowledge, this is the first report of DLBCL in Turkey.
The relative frequency of 2.2% during the 40 year period was increased to 9.3% in the
last decade and reached to a comparable level with international studies owing to im-
provement in pathology. The reason for the difference in the ratio of DLBCL before and
after 2000 included the following: (1) to apply only with pathology slides or without
adequate pathologic specimens from different medical center, (2) not to distinguish
DLBCL subtype in pathological result with lymphoma in old cases despite the review
of pathology. Today a case diagnosed large cell or B-cell lymphoma in the past can be
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diagnosed more precisely such as Burkitt lymphoma, DLBCL due to improvement in


pathology. However, there are still difficult cases that cannot be diagnosed today def-
initely. The reason for the lower ratio of DLBCL than international rates may not be
referred from different medical center to our center due to improvement on treatment
of lymphoma. We did not find any study for comparison this rate in our country.
Diffuse large B-cell lymphoma occurs more frequently during the second decade.
Male predominance has been observed with 65% of large cell lymphomas [17]. We
found the similar findings in this study, nearly 50% of patient were over 10 years of
age with a median age of 9.7 and a male predominance with a ratio of 2.6. To be more
common in male and to be seen at early age than industrialized countries are epidemi-
ological features of NHL in our country [18]. Pediatric DLBCL is more often localized
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and less often involves the bone marrow or cerebrospinal liquid [6]. The most com-
mon primary sites of DLBCL are the abdomen, the lymph nodes, and bone [19]. Our
analysis also confirmed that the abdominal location was the most common primary.
Patients with DLBCL have a favorable prognosis [11, 12]. Despite advances in di-
agnosis of DLBCL, the patients still present with advanced stage (stages III and IV)
of disease [16, 17]. For low stage mature B-cell NHL, EFS is about 94% [20]. Patients
with high-stage mature B-cell NHL have an 85% to 90% long-term survival [15]. In our
study, the stage distributions were low stage (stages I and II) in 27.2% of cases, and ad-
vanced stage (stages III and IV) in 72.8% of cases. These distributions were similar to
previous studies. Patients with low stage had a significantly longer OS and EFS com-
pared with advanced stage. In this study, the survival rates, OS and EFS, were lower in
advanced stage patients than the other published studies although our patients also
predominantly presented as advanced disease with low infiltration of the bone mar-
row in 6.1% and none had CNS involvement. That means, we have to invest on early
diagnosis of these children and also worked on increasing the survival rates in chil-
dren with advanced disease. Change the treatment modality is the other option in ad-
vanced stage disease. This is mainly related with late referral of those children with
advanced disease. The proper diagnosis and early referral is essential in these chil-
dren for a better survival rate. The event-free survival (EFS) and overall survival (OS)
rates for 33 children were 61% and 65.1%, respectively. Childhood cancer survival re-
mains dismal in low-income countries. Only about 2030% of new cases of cancer di-
agnosed annually are thought to be adequately diagnosed and treated. And most of
these cases are in high-income countries. The survival rates in childhood cancer are
also linked to annual government spending on health care per capita. Also, the num-
ber of pediatric cancer unit, dedicated pediatric oncology beds, pediatric oncology or
hematology specialist and patients seen by health-care providers annually, availabil-
ity of diagnostic services medication, palliative care unit, radiotherapy, blood prod-
ucts, and treatment guidelines are efficient factors on health quality. Per capita annual

Pediatric Hematology and Oncology


Results of Children with DLBCL

government health care expenditure, per capita annual total health care expenditure,
per capita gross domestic product, per capita gross national income, and number of
physicians and nurses per 1000 population are correlated with survival [21]. Incidence
of pediatric cancer will increase to higher level. The investments on health have in-
creased recently in our country. If the problems on number of cancer units, beds, pedi-
atric oncology and hematology specialist, doctor, nurse, diagnostic, therapeutics con-
tinue, the survival rates will be low. The factors affecting health care quality should
increase with investment. The quality of health will increase to more higher level than
todays condition as well as cancer treatment. But, cancer treatment is a team work.
Not only the pediatric oncologists but also all the partners must joined their forces to
increase the survival rates in low- and middle-income countries.
The treatment protocols showed the variation in our center and in the world. The
most appropriate treatment protocols for DLBCL are same strategy as Burkitt lym-
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phoma protocols [12]. Previous studies have shown satisfactory results with B type
protocol like Lymphoma malign B (LMB) and BerlinFrankfurt Mu nster (BFM) for
the treatment of DLBCL [11, 12, 20]. Following the international recommendations for
the NHL treatment in children, from 1994 to 2011, patients with DLBCL were treated
with the LMB89 [11] as a standard protocol in our center. In 2011, it has been changed
to LMB96 [12] protocol. The results with LMB89 protocol for DLBCL are reported 89%
of EFS rate [11]. Patte et al. [11] reported the EFS rates of 98%, 92%, and 84% in groups
A, B, and C, respectively [11]. Burkhardt et al. reported the EFS rate of 93% for DLBCL
[4]. Our results had a very low incidence as compared with others like Pattes studies.
We wanted to compare with a large patient series, and we used LMB protocols pre-
For personal use only.

dominantly. This is the first study from our country. We wanted to compare our results
with original protocol to see our situation in treatment for further modification. Event-
free survival rates were inferior than the results of Patte et al. studies (61% vs. 89%)
[11]. However, the EFS in group B patients treated with LMB89 regimen in our study
had better survival than whole groups EFS (68.4% vs. 61%). Two patients in group A
and one patient in group C have been followed in complete remission. We did not find
differences in treatment results before and after 2000s. Before 2000s we used different
protocols. Survival rates were slightly higher in LMB protocols than other protocols. In
the future, these rates may be increased to higher levels. It is an estimation. But, it de-
pends on working hard as cancer team with support and cooperation of palliative care,
radiology, surgery, algology, radiotherapy, and hematopoietic stem cell transplanta-
tion. The quality of health will increase to more higher level than todays condition
across the country. Also new protocols may be tried.
The survival rates in low-income and middle-income countries are lower than de-
veloped countries [21]. For example, the studies reported from Iraq and Pakistan
showed the rate of 6068% for OS and the rate of 5053% for EFS [22, 23]. We know
Turkey is another country with different ethnic source from these countries. These
rates may be associated with health conditions and low income. Significant progress
has been achieved recently in our country. However, there are some problems in diag-
nosis, lag time of disease, annual income, educational situation of patients, and health
conditions of center in our country. Some facilities as PET-CT are not found outside
the major cities. But After 2000s, our survival rates reached from 50% to 70%. We hope
to increase this rate to higher levels.
It would be useful to describe treatment-related mortality in our cohort of patients,
and this was the limitation of our study. Generally, we observed high treatment toxic-
ity in patients with DLBCL and associated disease. Three immunodeficiency patients
with lymphoma were dead with disease from treatment-related sepsis.
In conclusion, the prognosis of children with DLBCL have significantly improved
over the years in high-income countries but still needs investigation and investment

Copyright 
C Informa Healthcare USA, Inc.
E. Atas et al.

in rest of the world. Diffuse large B-cell lymphomas may reflect a spectrum between
Burkitt lymphomas and adult DLBLC. Pediatric DLBLC are not as homogenous as pre-
viously suggested [2]. Biological diversity in such rare tumors like DLBLC might ex-
plain the differences in clinical outcome. The research is a part of further improvement
in any countries, even in low- and middle-income countries. It is clear that the survival
rates in children with DLBCL need further improvement.

Declaration of Interest
The authors report no conflicts of interest. The authors alone are responsible for the
content and writing of the paper.
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