Discussion
CDKN2A deletions have a high frequency in pediatric acute lymphoblastic
leukemia and FISH is an accurate and reliable method for this
deletion[2,4,8-10].Data from our study
demonstrated the incidence of CDKN2A deletion in pediatric ALL was
16.9%,which was lower than most previous
studies(22-45%)[4,6,11-15].The apparent
difference in incidence is might due to the fact that previous studies
had different detection methods such as MLPA or SNP and wide detection
range including CDKN2Bdetection.
Most researchers acknowledged that CDKN2A-deleted patients have high WBC
counts,prominent hepatosplenomegaly and expression of predominantly
T-cell surface markers[2,6,16].In our
cohort,CDKN2A deletion was presented in 14.6% of B-ALL and 40.0% of
T-ALL.To find out whether any discrepancy between the B-ALL subgroup and
the T-ALL subgroup with CDKN2A deletion,we compared clinical-biological
characteristics and early treatment responsesamongthe two
groups.Itrevealed that CDKN2A deletion was more prevalent among
older(>10 years) males
(P <0.05) and
those with a WBC counts of greater than
50x109/L(P <0.001).However,Sulong S
hasdemonstrated that CDKN2A deletion was more prevalent among older
children (10>years) and high WBC counts in BCP-ALL but not
among T-ALL patients[11].
According to the previous study,TEL-AML1 occurs in 20-25% of pediatric
B-ALL,MLLr occurs in 2-20%
pediatric ALL,BCL-ABL1 occurs in
2-5% of pediatric ALL and E2A-PBX1 occurs in 2-6% of pediatric
ALL[16-17]. Sulong S had revealed that the
incidence of CDKN2A deletions in pediatric ALL varying markedly by
different cytogenetic subgroups and CDKN2A-deleted patients had low
frequenciesof TEL-AML1,MLLr whereas had high frequenciesof
BCL-ABL1,E2A-PBX1[11].Data
from our research(Figure1A-B)showed a similarincidence of
TEL-AML1,MLLr,BCL-ABL1compared toSulong’s conclusion.
The prognostic value of theCDKN2A deletion in pediatric acute
lymphoblastic leukemia is still controversial.Most results found that
CDKN2A deletion was an independent prognostic indicator for poor
outcomesand relapse in childhood ALLor
B-ALL[4,6,9,11-15].
Because the majority of patients in this cohort are being treated on an
ongoing clinical trial,we are incapable of further survival
analysis.Therefore,We demonstrated the prognostic factor that might
affect the event-free survival of CDKN2A-deleted patients in our
cohort.It turned out that EFS ofCDKN2A-deleted patients was
significantly associated with CNS2, cytogenetic risk groups, PPR,PER,
and MRD≥0.01% at day 46 in the log-rank test.It suggested that
co-occurrence of BCR-ABL1,MLL rearrangements, chromosome <44,
or t[17;19]/E2A-HIF in CDKN2A-deleted patients had inferior
outcomes.Furthermore,both PPR and MRD≥0.01% at day 46werepoor
independent markersfor EFS.It was not surprising that PPR and MRD
positive can predict the clinical outcome even in patients with CDKN2A
deletion.Unexpectedly,our research showed T phenotype didn’t result in
apoor prognosis for event-free survival.Lack ofsignificant difference
for early treatment responses among B-ALL subgroup and T-ALL subgroup
was acting as a hint of theclinical outcome.
Although FISH was confirmed as a reliable technique for CDKN2A
deletion,chromosomal abnormalities of CDKN2A carriers had rarely been
described.In our research,we found that only afew patients(9.0%) were
observed thekaryotype with del(9)(p21).According to the
literature,del(9)(p13) can lead to monosomy of the tumor suppressor gene
CDKN2A in T-cell prolymphocytic leukemia[18],but
it didn’t been provedin childhood ALL.
One patient occurred second malignancy—Langerhans cell
histiocytosis(LCH) duringmaintenance therapy who only carried CDKN2A
deletion.Xerri L pointed outco-occurrence ofCDKN2A/B deletion and
mutations of the MAPK pathway underlay the aggressive behavior of
Langerhans cell tumors[19],it suggests that
pediatric ALL with CDKN2A deletion might have potential risk in
reemerging LCH.
In summary,CDKN2A deletions are significantly more prevalent in
older(>10 years old) males with leukocyte counts of greater
than 50x109/L among T-ALL.PPR and MRD≥0.01% at day 46
are independent prognostic factor for EFS in pediatric CDKN2A-deleted
ALL.In future research,the targeted therapy such as CDK4/6 inhibitor
might be an effective treatment strategy for those patients.