Anaplastic large cell lymphoma (ALCL) has been recognized as a
unique subset of peripheral T cell lymphoma by the World Health
Organisation (WHO) and is the most common subtype [1]. In
children, it comprises 10% of pediatric non-Hodgkin lymphoma
[2]. The clinical presentation is varied with extranodal site
involvement commonly posing challenges in diagnosis. Event-free
survival (EFS) of 60-75% with intensive protocols has been
reported worldwide [3-5]. A characteristic anaplastic lymphoma
kinase (ALK) mutation is present in the majority of pediatric
ALCL [6,7]. Literature from South Asia is limited in this subset
due to the rarity of the disease. Here we report EFS, overall
survival (OS) and predictors of the outcome of pediatric ALCL
treated uniformly at our center Berlin-Frankfurt-Munster (BFM).
METHODS
We retrieved data from medical records of our institute of
pediatric ALCL managed from January, 2003 to May, 2016. The
institute and ethics committee approved the study. The diagnosis
of ALCL was based on clinical presentation, morphology,
histopathology, and immuno-histochemistry. Data of all patients
of age 1 to 18 years were analyzed, except partially treated,
relapsed patients and patients who did not receive treatment.
The B symptoms were defined as non-infectious fever (no obvious
focus of infection) more than 100.4ºF without evidence of
infections, significant weight loss of more than 10%, and
history of night sweats. For completion of staging workup, all
patients underwent contrast-enhanced computed tomography (CECT)
of neck, chest, and abdomen along with cerebrospinal fluid
cytopathology, and bone marrow aspiration and biopsy
examination. Symptom duration before presentation at our centre
was categorized into early (£30
days) and delayed (>30 days) presentation. The staging was done
as per St Jude staging [8].
We categorized patients’ performance status into 1 and 2 vs
3 and 4 [9], nodal and extra nodal sites, presence or absence of
pleural effusion, B symptoms, and expression of a Anaplastic
lymphoma kinase (ALK) and cluster of differentiation (CD) 3.
All patients of early stage were
treated with chemotherapy protocol as per Link, et al.
[10] and those with advanced disease were treated with
Berlin-Frankfurt-Munster (BFM) BFM 90 NHL protocol [11]. After
the end of two blocks of treatment, patients underwent CECT of
neck, chest, and abdomen for response evaluation. After
completion of treatment post six cycles of therapy, the response
was documented with re-imaging. After completion of treatment,
patients were followed up every three months for the initial two
years and then every six-months till five years, and yearly
thereafter. Patients who did not attend the scheduled visit were
contacted telephonically. Relapse was defined as disease
recurrence after the achievement of complete remission post
completion of therapy and progressive disease was defined as
progression during treatment.
Statistical
analyses:
Baseline patient characteristics were assessed for survival. An
event was defined as relapse, the progression of the disease,
lost to follow up or death due to any cause. The EFS was
calculated from the day of diagnosis until the date of the
event. OS was calculated from the date of diagnosis until the
date of death due to any cause. The data were censored on 31
March, 2019 or the date of the last follow-up for survival
analysis.
STATA ver.13 (StataCorp, USA) was
used for statistical analyses. Kaplan-Meiler method was used for
survival analysis and the Log-rank test was used for comparison.
The chi-square method was used to see the association between
variables affecting outcomes. Cox proportional model was used
for hazard calculation for univariate analysis, and for
multivariate analysis Cox regression model was used. The
significant univariate variables of value up to P=0.10,
were considered for multivariate analysis.
RESULTS
A total of 27
patients (3 females) of pediatric ALCL were studied. The
baseline clinicopathological characteristics and demographics
are shown in Table I. Stage IV disease was
observed in 7 (26%) patients. Extranodal involvement was seen in
20 (74%) patients; the most common site was bone in 9 (33%)
patients and skin involvement in 5 (18%); other uncommon sites
were adrenal glands, breast and lung parenchyma in one patient
each. No patient had bone marrow involvement. Two patients had
involvement of parenchymal central nervous system involvement;
one patient had temporal lobe mass and the other had suprasellar
mass. We also evaluated baseline absolute neutrophil count
divided by total leukocyte count (ANC/TLC) ratio; categorized
into two groups based on the median value of 0.65.
Table I Baseline Characteristics of Children With Anaplastic Large Cell Lymphoma (N=27)
|
Age, y* |
12 (1-17) |
|
Male gender |
24 (89) |
|
Symptom duration, mo* |
3 (0.5-12) |
|
>30 days |
23 (85) |
|
Stage | |
|
I |
1 (4) |
|
II |
2 (7) |
|
III |
17 (63) |
|
IV |
7 (26) |
|
Performance status (ECOG) | |
|
1 and 2 |
14 (52) |
|
3 and 4 |
13 (48) |
|
Extranodal site |
20 (81) |
|
B symptom |
21 (78) |
|
Pleural effusion |
6 (22) |
|
ALK positive |
18 (95) |
|
CD 3 negative |
13 (62) |
|
Hemoglobin, (g/dL)* |
10.1 (4.3-15.1) |
|
WBC*, per cu.mm |
9100 (2300-26200) |
|
>12000 per cu.mm |
11 (41) |
|
ANC/TLC ratio* |
0.65 (0.29-0.86) |
|
Serum albumin, (g/dL)* |
3.7 (2.3-5.3) |
|
£3.5 g/dL |
10 (37) |
|
Normal serum LDH# |
15 (68) |
|
LDH: Lactate dehydrogenase; ANC: Absolute neutrophil count; TLC: Total leucocyte count; ECOG: Eastern co-operative group; Values in no. (%) except *median (range). ALK: anaplastic large kinase#, ALK evaluated in 19 children, CD3 in 21 children, and LDH in 22 children. |
EFS at 3 years of the whole cohort was 70.4 (8.8)% (CI:
0.49-0.84) and OS was 77.2 (8.2)% (CI: 0.56-0.89), respectively.
Median EFS and OS were not reached. Ten events occurred from the
date of diagnosis. Three patients progressed while on therapy.
There were four deaths unrelated to disease, progression or
relapse; two patients died of chemotoxicity (one with
gastrointestinal bleed and other with septic shock); one died of
complication of complex congenital heart disease (patient was in
CR at three years of follow up); cause of death in the fourth
patient was viral hepatitis. There were three nodal relapses,
out of which one died while two patients were treated with
salvage therapy and autologous stem cell transplant. Of these,
one died 3 years post-transplant due to central nervous system
infection and refractory seizures, and the other patient is
alive without disease.
The univariate analysis of prognostic factors for EFS and OS are
depicted in Table II. On univariate analysis,
stage III and IV, hemoglobin less than 10 g/dL and presence of
pleural effusion had a trend towards predicting inferior EFS and
OS with P<0.1. On multivariate analysis, only pleural
effusion emerged as a significant predictor for EFS (P=0.011)
and OS (P=0.02).
Table II Factor Predicting Event Free Survival in Children with Anaplastic Large Cell Lymphoma (N=27)
|
Variable |
No |
Event free survival HR (CI) |
P |
Overall survival HR (CI) |
P |
|
Age <12 y |
13 |
0.52 (0.15-1.86) |
0.32 |
0.53 (0.15-1.90) |
0.33 |
|
Female sex |
3 |
1.35 (0.17-10.69) |
0.77 |
1.41 (0.18-11.17) |
0.75 |
|
Rural residence |
14 |
1.25 (0.36-4.36) |
0.73 |
1.43 (0.41-5.05) |
0.57 |
|
Symptom duration >30 d |
23 |
1.78 (0.38-8.45) |
0.47 |
1.13 (0.24-5.34) |
0.88 |
|
Performance status ECOG 1 and 2 |
14 |
0.42 (0.11-1.62) |
0.21 |
0.35 (0.09-1.37) |
0.13 |
|
No B symptom |
6 |
1.07 (0.23-5.04) |
1.07 |
1.13 (0.24-5.34) |
0.88 |
|
No Pleural effusion |
21 |
8.51 (2.34-30.90) |
0.00 |
1 7.77 (2.14-28.19) |
0.002 |
|
#CD 3 positive (n=21) |
8 |
4.04 (0.73-22.18) |
0.11 |
2.58 (0.46-14.34) |
0.28 |
|
Hb £10.0 g/dL |
13 |
0.32 (0.08-1.24) |
0.10 |
0.29 (0.07-1.12) |
0.07 |
|
WBC £11 × 109 |
16 |
0.71 (0.20-2.51) |
0.59 |
0.64 (0.18-2.27) |
0.49 |
|
ANC/TLC ratio £0.65 |
13 |
1.78 (0.50-6.33) |
0.37 |
2.41 (0.66-8.76) |
0.18 |
|
Serum albumin (g/dL) £3.5 |
10 |
0.36 (0.10-1.29) |
0.12 |
0.39 (0.11-1.40) |
0.15 |
|
#Raised Serum LDH (n= 22) |
7 |
1.62 (0.33-7.80) |
0.55 |
1.57 (0.33-7.61) |
0.57 |
|
ALK: Anaplastic large kinae; ANC/TLC: Absolute neutrophil count /Total leukocyte count; CD: Cluster differentiation; CI: Confidence interval; ECOG: Eastern co-operative group, Hb: hemoglobin; HR: Hazard ratio, LDH: Lactate dehydrogenase; ULN: Upper limit of normal; WBC: White blood count; #Data was not available for all patients; $As all patient in stage I and II survived, hazard ratio and confidence interval was not evaluable; Since only one patient was ALK negative, data was not evaluable and it was excluded from multivariate analysis. |
Notably, there was no significant difference in pleural effusion
patients with hypoalbuminemia (40%) and in those without
hypoalbuminemia (12%), P=0.09. We also did not find any
significant difference in pleural effusion in patients with poor
performance status (36%) and good performance status (8%), P=0.08.
Out of six patients who had pleural effusion, one patient
received anti-tubercular therapy. In our study, pleural effusion
was not drained and on the initiation of therapy, it resolved.
DISCUSSION
In this cohort of pediatric non-Hodgkin lymphoma, we only
analyzed clinical factors as predictors of EFS and OS. Minimal
disseminated disease in peripheral blood and bone marrow at
diagnosis, minimal residual disease, and Anaplastic large kinase
titer which are novel biological predictors of outcome were not
evaluated [12]. The strength of this study is that it includes a
cohort of a relatively rare subtype of NHL treated with a
uniform protocol. However, the fact that it is a retrospective
study with a limited number of subjects is a limitation of the
study.
In this study, the EFS of patients with ALCL is 10-15% lower as
compared to other contemporary series from developed countries
[3-5,13,14]. When the results are compared with developing
countries, the outcomes are similar [9,15,16]. Our study
highlights some of the challenges as almost 90% of our patients
presented in an advanced stage of the disease and more than 50%
of subjects had a poor performance status. Further, the median
duration of symptoms was three months, and one-fifth of the
patients received anti-tubercular therapy before being diagnosed
as a malignancy. This is similar to the observation in pediatric
Hodgkin lymphoma [17].
Prognostic factors for ALCL are not
consistent across studies due to mostly retrospective series, a
small number of patients and varying protocols [18]. We found
pleural effusion as a predictor of poor EFS and OS. In a study
of 225 patients [19], the involvement of the lymph nodes,
mediastinum, skin and liver was associated with the risk of
relapse; however, it is to be noted that three different
protocols were used in treating these groups of patients. In
NHL-BFM 90 trial, only B symptoms were associated with poor EFS
[4].
Our study implies that the presence
of pleural effusion is a potential clinical marker of poor
outcomes in pediatric patients with ALCL. Pleural effusion
resolves with treatment and that no additional intervention is
usually required. There is a need to spread awareness about this
subtype of NHL amongst pediatricians and primary care physicians
so that they are referred early for treatment and thereby
presentation of the disease in advanced stages is minimized.
Ethical clearance:
Institutional Ethics Committee of AIIMS, Delhi; No. IESC/T-331,
June 23, 2015.
Contributors:
AP: designed the research study, analysed the data, drafted the
paper; DP: analyzed the data and drafted the paper; MCS,ST:
acquisition and interpretation of the data for the paper,
drafted the paper; SB: conception and designed the research
study, analyzed the data, drafted the paper. All authors
contributed to the drafting of the work, finally approved the
work and agreed to be accountable for integrity of the data.
Funding:
None; Competing interest: None stated.
|
What This Study Adds? |
Pleural effusion is a potential
clinical predictor of poor outcome in pediatric
anaplastic large cell lymphoma.
|
REFERENCES
1. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert
R, et al. The 2016 revision of the World Health
Organization (WHO) classification of lymphoid neo-plasms. Blood.
2016;127:2375-90.
2. Burkhardt B, Zimmermann M, Oschlies I, Niggli F, Mann G,
Parwaresch R, et al. The impact of age and gender on
biology, clinical features and treatment outcome of non-Hodgkin
lymphoma in childhood and adolescence. Br J Haematol.
2005;131:39-49.
3. Lowe EJ, Sposto R, Perkins SL, Gross TG, Finlay J, Zwick D,
et al. Intensive chemotherapy for systemic anaplastic
large cell lymphoma in children and adolescents: Final results
of Children’s Cancer Group Study 5941. Pediatr Blood Cancer.
2009;52:335-9.
4. Seidemann K, Tiemann M, Schrappe M, Yakisan E, Simonitsch I,
Janka-Schaub G, et al. Short-pulse B-non-Hodgkin
lymphoma-type chemotherapy is efficacious treatment for
pediatric anaplastic large cell lymphoma: A report of the
Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood.
2001;97:3699-706.
5. Rosolen A, Pillon
M, Garaventa A, Burnelli R, d’Amore ES, Giuliano M, et al.
Anaplastic large cell lymphoma treated with a leukemia-like
therapy: report of the
Italian Association of Pediatric Hematology and
Oncology (AIEOP) LNH-92 protocol. Cancer.
2005;104:2133-40.
6. Gambacorti-Passerini C, Messa C, Pogliani EM. Crizotinib in
anaplastic large-cell lymphoma. N Engl J Med. 2011; 364:775-6.
7. Mossé YP, Lim MS, Voss SD, Wilner K, Ruffner K, Laliberte J,
et al. Safety and activity of crizotinib for paediatric
patients with refractory solid tumours or anaplastic large-cell
lymphoma: A Children’s Oncology Group phase 1 consortium study.
Lancet Oncol. 2013;14: 472-80.
8. Murphy SB, Fairclough DL, Hutchison RE, Berard CW.
Non-Hodgkin’s lymphomas of childhood: An analysis of the
histology, staging, and response to treatment of 338 cases at a
single institution. J Clin Oncol. 1989;7:186-93.
9. Lakshmaiah KC, Guruprasad B, Shah A, Kavitha S, Abraham LJ,
et al. Anaplastic large cell lymphoma: A single
institution experience from India. J Cancer Res Ther.
2013;9:649-52.
10. Link MP, Shuster JJ, Donaldson SS, Berard CW, Murphy SB.
Treatment of children and young adults with early-stage
non-hodgkin’s lymphoma. N Engl J Med. 1997;337: 1259-66.
11. Reiter A, Schrappe M, Tiemann M, Ludwig WD, Yakisan E,
Zimmermann M, et al. Improved treatment results in
childhood B-cell neoplasms with tailored intensification of
therapy: A report of the Berlin-Frankfurt-Münster Group Trial
NHL-BFM 90. Blood. 1999;94:3294-306.
12. Damm-Welk C, Pillon M, Woessmann W, Mussolin L. Prognostic
factors in paediatric anaplastic large cell lymphoma: Role of
ALK. Front Biosci Sch Ed. 2015;7:
205-16.
13. Pillon M, Gregucci F, Lombardi A, Santoro N, Piglione M,
Sala A, et al. Results of AIEOP LNH-97 protocol for the
treatment of anaplastic large cell lymphoma of childhood.
Pediatr Blood Cancer. 2012;59:828-33.
14. Alexander S, Kraveka JM, Weitzman S, Lowe E, Smith L, Lynch
JC, et al. Advanced stage anaplastic large cell lymphoma
in children and adolescents: results of ANHL0131, a randomized
phase III trial of APO versus a modified regimen with
vinblastine: A report from the Children’s Oncology Group.
Pediatr Blood Cancer. 2014; 61:2236-42.
15. Ceppi F, Ortiz R, Antillón F, Vasquez R, Gomez W, Gamboa J,
et al. Anaplastic large cell lymphoma in Central America:
A report from the Central American Association of Pediatric
Hematology Oncology (AHOPCA): Treatment of ALCL: A Report From a
LMIC. Pediatr Blood Cancer. 2016;63:78-82.
16. Resham S, Khan R, Ashraf S, Rizvi A, Altaf S. Clinical
features and treatment outcomes of children with anaplastic
large cell lymphoma in Pakistan: A multicenter study. J Pediatr
Hematol Oncol. 2019;41:5.
17. Arya LS, Dinand V, Thavaraj V, Bakhshi S, Dawar R, Rath GK,
et al. Hodgkin’s disease in Indian children: outcome with
chemotherapy alone. Pediatr Blood Cancer. 2006;46: 26-34.
18. Lowe EJ, Gross TG. Anaplastic large cell lymphoma in
children and adolescents. Pediatr Hematol Oncol. 2013;30:
509-19.
19. Le Deley M-C, Reiter A,
Williams D, Delsol G, Oschlies I, McCarthy K, et al.
Prognostic factors in childhood anaplastic large cell lymphoma:
Results of a large European intergroup study. Blood.
2008;111:1560-6.
