peripheral blood lymphocyte recovery and overall survival in pediatric acute lymphoblastic leukemia

Pediatr Blood Cancer

LETTER TO THE EDITORPeripheral Blood Lymphocyte Recovery and Overall Survival in

Pediatric Acute Lymphoblastic Leukemia

To the Editor: We read with great interest two previously

published studies by Rabin et al. [1] and Alkayed et al. [2]

concerning the prognostic significance of absolute lymphocyte

count (ALC) recovery in children with ALL. Previous studies in

adults have demonstrated the predictive role of ALC after induction

chemotherapy for a range of hematological malignancies,

associating ALC with patients’ survival [3–5]. Data regarding the

prognostic impact of ALC repopulation following induction

chemotherapy or hematopoetic transplantation in the pediatric

setting is limited [1,2,6–9]. Most importantly, a systematic review

of the literature highlighted a lack of consensus on critical ALC cut

off values and revaluation time points (Table I). The aim of the

present study was to analyze the impact of ALC on the 5-year OS

at three different cut off levels (ALC1,500< or �1,500 cells/ml,ALC1,000< or �1,000 cells/ml and ALC350< or �350 cells/ml,respectively) in children with ALL at Day þ29 after induction

chemotherapy [1,7,8]. We retrospectively evaluated 117 children

with de novo diagnosis of ALL treated with the BFM/ALLIC 2009

chemotherapy protocol at the Pediatric Hematology Oncology Unit

of our Department. According to our results, B-ALL was recorded

in 81.2% (95 cases), T-ALL in 17.1% (20 cases), and bi-phenotypic

ALL in two cases (1.7%), respectively. The median age at diagnosis

was 5.8 years (range: 0.6–17 years). MedianWBC at diagnosis was

12.650 cells/ml (range: 400–560.000 cells/ml). Furthermore, the

median WBC at Day þ29 was 2.100 cells/ml for the children with

favorable outcome and 3.800 cells/ml for the children with

unfavorable outcome, respectively (P¼ 0.04). Relapse was

recorded in 11.1% (13 cases) and the mortality rate in 9.4% (11

cases), respectively. Median ALC at Day þ29 was 1,003 cells/ml(range: 100–7.130 cells/ml). In particular, the median ALC at Day

þ29 was 1,039 cells/ml in children that survived and 520 cells/mlfor the children that died (P¼ 0.012). The cut off value of ALC

�350 cells/ml was associated with a favorable prognosis, with a 5-

year OS of 92.3% versus 69.2% for ALC <350 cells/ml (HR 2.2,

P¼ 0.05). For the cut-off values of ALC1,000 and ALC1,500, a

statistical significant difference with OS was not observed.

According to previous literature, ALC seems to be a simple and

powerful prognostic factor for evaluating OS in pediatric patients

with ALL after completion of induction therapy or following HSCT

(Table I). Partially contradictory results might have been attributed

to the variable ALC cut off values used or due to ethnic differences,

as mentioned also by Alkayed et al. [2]. In our case series, very low

ALC (ALC350) at Dayþ29 remained a significant prognostic factor

for OS that is in concordancewith the results of DeAugulo et al. [8].

The future establishment of ALC as prognostic factor might

represent a supplementary or even an alternative to MRD risk

stratification in ALL, especially in low income countries. This

emphasizes the urgent need for further multicentered prospective

studies to evaluate firstly the independent prognostic value of ALC

and secondly to standardize the appropriate ALC cut off values in

pediatric ALL.

Emmanuil Hatzipantelis, MD, PHD

Pediatric Hematology–Oncology Unit,

2nd Pediatric Department of Aristotle

University of Thessaloniki

AHEPA General Hospital

Thessaloniki, Greece

Zoe Dorothea Pana, MD, MSC, PHD*






Maria Vlachou, MD






Theodotis Papageorgiou, MD, PHD






Athanassios Tragiannidis, MD, PHD






Fani Athanassiadou, MD, PHD






�Correspondence to: Zoe Dorothea Pana, Pediatric Hematology–

Oncology Unit, 2nd Pediatric Department of Aristotle University of

Thessaloniki, AHEPA General Hospital, Thessaloniki, Greece.

E-mail: [email protected]

Received 13 June 2013; Accepted 18 July 2013

�C 2013 Wiley Periodicals, Inc.DOI 10.1002/pbc.24736Published online in Wiley Online Library(wileyonlinelibrary.com).

TABLEI.

Review

oftheLiterature

RegardingthePrognostic

Role

ofALC

inPediatric

CasesWithALLorAfter

HSCT

Refs.

No.of

children

Underlying

condition

Cut-off

valueofALC

Day

ofALC

measurement

Overallsurvival

Eventfree

orrelapse-freesurvival

Comments

Han

etal.[6]

69

Transplantation

<500/mlor

�500/ml

Dþ2

1andD

þ30after

transplantation

HighD

þ30groupbetter5years

OS(71%

vs.53%)P¼0.043

HighD

þ30groupbetterEFS

(72%

vs.53%)P¼0.065

Low

Dþ3

0groupincreasedrisk

fortransplant-relatedmortality

(P¼0.019)

ALL(n¼34)

Nodifference

inrelapse

rate

Nodifference

inII-IVacute

and

chronic

(GVHD)

AML(n¼26)

CL(n

¼7)

JML(n

¼2)

Rabin etal.[1]

171

ALL

<1,500/mlor

�1,500/ml

Dþ2

9afterinitiationof

inductiontherapy

HighD

þ29groupbetterOS

(96�2%

vs.74�8%)P¼0.001

HighD

þ29groupbetter6-year

relapse-freesurvival

(80�4%

vs.

62�8%)P¼0.018

ALC

provides

refinem

entofcur-

rentMRD-based

risk

stratifica-

tion

Anoceto

Martınez

etal.[7]

105

ALL

<1,000/mlor

�1,000/ml

Dþ1

5andD

þ28after

initiationofinductiontherapy

HighD


OS(86%

vs.66%)P¼0.01

HighD


relapse-freesurvival

(83%

vs.51%)

P¼0.02

ALC

remained

apredictorin

multivariate

analysis

DeAngulo

etal.[8]

171

�21years

AML

<350/mlor

�350/ml

Dþ1

5andD

þ28after

initiationofinductiontherapy

ForAML:HighD

þ15group

better5-yearOS(85%)HR

0.2,

P¼0.012

ForAML:Low

Dþ2

8groupPoor

5-yearrelapse

free

survival

(10%)HR

3.7,P¼0.03

ALC

remained

apredictorin

multivariate

analysis

ALL

ForALL:HighD

þ15group

better6-yearOS(87%)HR

0.2,

P¼0.018

ForALL:Low

Dþ1

5groupPoor

6-yearrelapse

free

survival

(43%)HR

4.5,P¼0.002

Ishaqi

etal.[9]

136

Transplantation

<300/mlor

�300/ml

Dþ2

1andD

þ30after

transplantation

Low

Dþ2

1group

Low

Dþ2

1groupPoorrelapse

free

survival

HR5.3,P¼0.002

HighALC

atD

þ21andD

þ30

was

notassociated

withincreased

incidence

ofacute

orchronic

GVHD

ortransplant-related

mortality(TRM)

ALL

Pooreventfree

survival

0.42vs.

0.66,P¼0.02

Low

Dþ3

0groupweremore

than

twiceas

likelyto

relapse

compared

to

those

withhighD

þ30groupHR2.2,

P¼0.01

Low

Dþ3

0grouphad

aninferior

3-yearEFS,0.30versus0.57,P

¼0.0001

Alkayed

etal.[2]

136

ALL

Continuousvalue

(ANCcon)and

<1,500/mlor�1

,500/ml

(ALC1,500)

Dþ2

9afterinitiationof

inductiontherapy

ANCconD

þ29noprognostic

valueforOSHR0.82,P¼

0.65

ANCconD

þ29noprognostic

value

forEFSHR0.61,P¼0.19

Lackofsignificance

dueto

patientpopulation(ethnicity)

ALC1,500D

þ29noprognostic

valueforOSHR

1.2,P¼0.80

ALC1,500D

þ29noprognostic

value

forEFSHR2.2,P¼0.27

Presentstudy

117

ALL

<1,500/mlor�1

,500/ml

(ALC1,500)

Dþ2

9afterinitiationof

inductiontherapy

HighD

þ29(A

LC350)group

betterOS(69.2

%vs.92.3%)

P¼0.05

NR

AppropriateALC

cut-offvalues

remainsto

beestablished

<1,000/mlor�1

,000/ml

(ALC1,000)

Lackofsignificance

For

(ALC500)and(A

LC350)

<350/mlor�3

50/ml

(ALC350)

CL,chronic

leukem

ia;JM

L,juvenilemyelomonocyticleukem

ia;GVHD,graftversushostdisease.

Pediatr Blood Cancer DOI 10.1002/pbc

2 Hatzipantelis et al.

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2. Alkayed K, Halalsheh H, Khattab E, et al. Lack of prognostic significance of absolute lymphocyte count

after intensive induction therapy in childhood acute lymphoblastic leukemia. Pediatr Blood Cancer

2012;59:351.

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and overall survival in adults with newly diagnosed acute lymphoblastic leukemia. Am J Hematol 2012;

87:957–960.

4. Porrata LF, Rsitow K, Inwards DJ, et al. Lymphopenia assessed during routine follow-up

after immunochemotherapy (R-CHOP) is a risk factor for predicting relapse in patients with diffuse

large B-cell lymphoma. Leukemia 2010;24:1343–1349.

5. Tiwari D, Gao F, Hidalgo J, et al. Prognostic significance of early lymphocyte recovery after post-

autografting administration of GM-CSF in non-Hodgkin’s lymphoma. Bone Marrow Transplant

2007;40:671–675.

6. Han DK, Baek HJ, Kim SY, et al. Implication of early lymphocyte recovery after allogeneic

hematopoietic stem cell transplantation in children with leukemia. Yonsei Med J 2013;54:62–70.

7. Anoceto Martınez A, Gonzalez Otero A, Guerchicoff de Svarch E, et al. Absolute lymphocyte count

as a prognostic factor in children with acute lymphoblastic leukemia. An Pediatr (Barc) 2012;76:

10.e1–10.e6.

8. De Angulo G, Yuen C, Palla SL, et al. Absolute lymphocyte count is a novel prognostic indicator in ALL

and AML: Implications for risk stratification and future studies. Cancer. 2008;112:407–415.

9. Ishaqi MK, Afzal S, Dupuis A, et al. Early lymphocyte recovery post-allogeneic hematopoietic stem

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Pediatr Blood Cancer DOI 10.1002/pbc

Letter to the Editor 3

peripheral blood lymphocyte recovery and overall survival in pediatric acute lymphoblastic leukemia

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