The presence of CNS disease at was 11% on recent CCG AML studies, within the 6–29% range reported previously1–6
. Previous studies conflict regarding the effect of CNS disease on outcome1,3,4,7,8,10,11
, and we found no difference in overall survival among the 3 CNS groups.
Previous studies have not consistantly shown the prognostic value of CNS disease at diagnosis. Some have found that the presence of CNS disease at diagnosis is not an adverse prognostic factor1,3,4,10,11
. Conversely, others have found a decrease in survival7,8
and an increased risk of marrow and CNS relapse2
. A Pediatric Oncology Group study found that patients with CNS disease at diagnosis were more likely to experience a CNS relapse15
. We found that the presence of CNS disease at diagnosis did not affect remission rates, overall survival, event free survival or risk of isolated BM relapse. However, CNS disease at diagnosis affected the disease free survival, relapse risk, risk of a concurrent BM and CNS relapse, and the risk of isolated CNS relapse. A previous study of isolated CNS relapse showed that the presence of CNS disease at diagnosis was predictive of isolated CNS relapse and these patients had an 8 year OS of 26%16
compared to 54% for all patients treated on CCG-289112
. Our current finding of increased risk of isolated relapse in patients with CNS disease at diagnosis is not surprising. The fact that overall survival and event free survival were not affected by the presence of CNS disease is surprising given our previous results. However, it may reflect small differences in the patient populations with CNS disease in these studies.
An interesting finding of this study was an apparent absence of CNS disease continuous variable effect of CNS disease on outcome. Patients with CNS2 disease had an increased (although not significant − 59% vs 50%) overall survival and event free survival than CNS1 patients. Patients with CNS2 disease did not receive the extra intrathecal therapy that CNS3 patients received, but were treated identically to CNS1 patients. The practice of treating CNS2 patients in the same fashion as CNS1 patients is done in some studies1,2,5,6
, while others treat all patients with blasts in the CNS (CNS2 and CNS3) as CNS positive3,4,15
. The current Children’s Oncology Group AML protocol treats all patients with blasts in the CNS as CNS positive. This current study confirms though that extra therapy is unlikely to be needed for CNS2 patients, but in contrast is needed in CNS3 patients.
Patients with CNS3 status in this study received extra intrathecal therapy, as is the case in most studies1–6
. A study from St. Jude Children’s Research Hospital found patients with CNS3 status had a superior outcome, but they utilized radiation therapy in over half of these patients4
. Radiation therapy is known to have significant side effects17
, and its use no longer standard in pediatric patients because of the excellent CNS penetration of high dose cytarbine containing regimens. Given that the patients in this current study with CNS3 status had an increased incidence of CNS relapse, perhaps an increase in the number of intrathecal therapies given may be warranted. This question cannot be easily addressed in future randomized pediatric AML studies, since numbers of patients exceeds those available in COG and other cooperative group trials.
Studies conflict about factors associated with the presence of CNS disease3,4,8
. This large study confirmed that the presence of CNS disease was significantly associated with young age, hepatosplenomegaly, high WBC, M4 morphology, abnormal chromosome 16, and hyperdiploid cytogenetics. Young age has previously been demonstrated to be a risk factor for the presence of CNS disease1,3,4,5,8,18
, and we also found this to be the case. This risk may be due to a greater proportion of vasculature in the leptomeninges in infants and preschool children19
. Certain FAB subtypes or cytogenetic abnormalities, which are more common in young children, may lead to more extramedullary leukemia. There is a higher incidence of M5 disease in infants under the age of 2 years9
, but we did not find a higher incidence of CNS disease in patients with M5 leukemia, contrary to previous studies1,4,8
. Also, infants under the age of 1 year with 11q23 abnormality have been reported to have an increased incidence of CNS disease20
, but in this study, chromosome 11 abnormalities were not associated with CNS disease, thus again not explaining the increased incidence of CNS disease in these young patients.
Patients with FAB M2 and M7 were significantly less likely to have CNS disease at diagnosis. Previous studies have shown that patients with constitutional trisomy 21 (Down syndrome) more commonly display M7 AML morphology, but M7 in the absence of trisomy 21 has a worse overall prognosis in pediatric AML11,21–23
. Patients with Down syndrome were excluded from this analysis but are known to have a lower incidence of CNS disease2,24,25
, and this may partially explain the lower incidence of CNS disease in patients with clonal trisomy 21 cytogenetics.
Cytogenetics affect survival in AML. There is a favourable prognosis in patients with chromosome 16 inversion and chromosome (8;21) translocation26–29
. We found that patients with AML with abnormalities of chromosome 16 had an increased incidence of CNS2 and CNS3 disease, as did those with AML with hyperdiploid cytogenetics. Our previous study found that these patients did not have an increased incidence of CNS relapse; only 1 of 26 patients with chromosome 16 abnormality had a CNS relapse, while none of those with t(8;21) or hyperdiploidy had a CNS relapse16
. The finding of increased incidence of chromosome 16 abnormalities has previously been found to be associated with CNS disease at diagnosis and this is likely secondary to an increase in M4 morphology in these patients4,8,30
. Hyperdiploidy has not previously been reported as a risk factor for CNS disease, but was a significant finding in this large study. On the other hand, patients with t(8;21) had a significantly higher incidence of CNS1 and CNS2 status. The decreased incidence of t(8;21) in patients with CNS3 disease contradicts previous studies which found this abnormality to be associated with extramedullary leukemia4,31
. The POG 8821 study showed that extramedullary leukemia, including in the CNS, significantly decreased the EFS in patients with the favourable cytogenetic findings of t(8;21) and inv(16)32
. Previous studies also have shown an increased incidence of 11q23 abnormalities8
and chromosome 11 abnormalities in patients with extramedullary leukemia30
, as well as a significant risk for isolated CNS relapse in patients with chromosome 11 abnormalities16
. In our analysis, abnormalities of chromosome 11, including 11q23, were not found to be predictive of CNS disease.
Patients with an elevated WBC at diagnosis have been shown to have a higher incidence of extramedullary involvement of leukemia3,7,8
and we also found this. Previous studies have found that a low WBC at diagnosis confers a better prognosis15,18
, but other reports have found that high WBC was a significant predictor of survival10
. Results of CCG 2861 and 2891 found that an elevated WBC at diagnosis was associated with a lower rate of remission following induction therapy and lower overall survival rate compared to low WBC at diagnosis9
. We found that the WBC was significantly higher at diagnosis in patients with CNS disease but this did not affect the overall survival rates.
In summary, this study represents a large cohort of pediatric patients with AML examined for the presence of CNS disease at diagnosis. It confirms that the presence of CNS disease in pediatric AML is associated with young age, high WBC, hepatomegaly or splenomegaly at diagnosis, M4 morphology, chromosome 16 abnormalities and hyperdiploid cytogenetics. A lack of CNS disease at diagnosis was significantly associated with M2 and M7 morphology, as well as (8;21) chromosome translocation. Patients with CNS disease at diagnosis had no difference in overall survival compared to those without CNS disease, but they were at an increased risk of isolated CNS relapse, indicating a need to investigate more aggressive CNS directed therapy for these patients.