Cytogenetics and Outcome Of Infants With Acute Lymphoblastic Leukemia and Absence Of MLL Rearrangements

Acute lymphoblastic leukemia (ALL) in infants less than one year of age is characterized by a high frequency of rearrangements of the MLL gene (MLL-R) and poor prognosis. Infants with no MLL rearrangements (MLL-G) have a better outcome than those with MLL-R. To better understand the association of chromosomal abnormalities and outcome among MLL-G infants, we carried out a detailed cytogenetic investigation of patients from two infant ALL trials: Interfant-99 and Children’s Oncology Group (COG)-P9407. Among 162 MLL-G patients, an abnormal karyotype was detected in 90/128 (70%) patients with a successful result. They were categorised according to cytogenetic risk group (good, intermediate and poor) as previously defined for childhood ALL. Compared with childhood ALL (1-18 years) using data from the UKALL97/99 treatment trial, the frequency of good risk cytogenetic abnormalities among MLL-G infants was significantly lower (12% v 60%, p<0.01), while the frequency of poor risk abnormalities (excluding MLL translocations) was similar (8% v 10%). While ETV6-RUNX1 fusion is present in 25% of childhood ALL, no ETV6-RUNX1 cases were found among 75 patients tested by FISH or RT-PCR. High hyperdiploidy was the most prevalent abnormality, although the frequency was also much lower than childhood ALL (12% v 38%, p<0.01). Other established translocations were observed in a small number of cases: t(9;22)(q34;q11)/BCR-ABL1 (n=2), t(1;19)(q23;p13)/TCF3-PBX1 (n=3) and the infant specific, t(7;12)(q36;p13)/ETV6-HLXB9 fusion (n=1). Interestingly the incidence of t(9;22) and t(1;19) among MLL-G infants was not markedly different from childhood ALL: 1.6% v 2.6% and 2.3% v 3.5%, respectively. Abnormalities of the short arm of chromosome 9 (9p) were observed in 14 (11%) cases at a similar incidence to childhood ALL. Chromosome 15 abnormalities were found in 12 patients. This more frequent occurrence of 15q abnormalities in infant ALL has been previously noted.

It is well established that MLL-R infants are younger than their MLL-G counterparts. Classification of MLL-G patients by cytogenetic risk group showed further correlation with age. The majority of cytogenetic good risk and all poor risk patients were >9 months old, whereas half of the cytogenetic intermediate risk patients were <9 months. In addition, there was evidence of outcome heterogeneity according to cytogenetic risk group. Event free survival at 4 years was 93% (SE 6.9), 66% (SE 4.7) and 50% (SE 15.8) for good, intermediate and poor risk groups, respectively, similar to that observed in childhood ALL when the same cytogenetic classification was applied.

Low FLT3 expression has been associated with an excellent outcome in infants with ALL treated on COG-P9407, and the majority (10/11) of cases with low expression were MLL-G. However, low FLT3 expression was not simply a reflection of MLL-G status, as 7 MLL-G patients had high FLT3 expression. We have shown that low expression in MLL-G patients is not associated with a particular cytogenetic risk group. Interestingly, none of the MLL-G patients with low expression had an event, whereas all 5 of the events occurred in the high expressers.

We have confirmed a unique cytogenetic profile among infants with MLL-G ALL. We demonstrate that the MLL-G infants share the same cytogenetic abnormalities as older children with ALL, but the distribution of abnormalities differs. Generally infants with MLL-G ALL are older, have low FLT3 expression and have an improved outcome compared to their MLL-R counterparts. Despite small numbers of MLL-G infants, when classified into the same good, intermediate and poor risk cytogenetic subgroups as childhood ALL, their pattern of outcome was very similar to that observed in older children. However, their overall worse outcome likely reflects the differences in distribution of good and poor risk abnormalities: lower incidence of the good risk abnormality: high hyperdiploidy, absence of ETV6-RUNX1, and higher incidence of poor risk abnormalities. Nevertheless, these data suggest that some MLL-G infants, especially those with good risk cytogenetics, may benefit from treatment on childhood protocols, which are generally less intensive and less toxic than infant ALL regimens.