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.