Blood, 15 June 2002, Vol. 99, No. 12, pp. 4255-4256
Cure of childhood ALL: exacting a lower toll
The unpredictable oncogenic effects of contemporary treatment
for childhood acute lymphoblastic leukemia (ALL) warrant continuous long-term monitoring of patients for second neoplasms. Bhatia and
colleagues (page 4257) in the Children's Cancer Group (CCG) reported
cumulative rates of second neoplasms of 1.18% (95% CI, 0.8% to
1.5%) at 10 years and 2.08% (95% CI, 1.4% to 2.8%) at 15 years
among 8831 patients treated for childhood ALL between 1983 and 1995. Not surprisingly, irradiation and a history of relapse were associated
with an increased risk for the development of a second cancer. The
excess risk in females largely reflected an increased incidence of soft
tissue sarcomas, for reasons that remain obscure.
The findings agree with those reported by several other groups: 3.3%
at 15 years in clinical trials of the
Berlin-Frankfurt-Münster group, 2.7% at 18 years in those of the
Dana-Farber Cancer Institute, and 2.9% at 20 years in the studies
conducted in the Nordic countries. But the median follow-up times of
these studies ranged from 4.6 years to 7.6 years, and none had adequate
observations beyond 20 years. While the cumulative incidence of
therapy-related acute myeloid leukemia in the CCG study reached a
plateau within 11 years, there was a continuous rise in the rates of
brain tumors and other solid tumors (irradiation-related second
neoplasms; see Bhatia et al's Figure 1). Thus, one would predict
additional cases of second neoplasms with extended monitoring.
Indeed, my colleagues and I have observed a steady rise in the
cumulative incidence of second neoplasms, to above 20% at 30 years, in
a cohort of patients who received radiation (C.-H. P. et al,
unpublished data). Fortunately, most of the second neoplasms of
very late onset were benign or were low-grade malignancies (eg, basal
cell carcinoma and meningioma) with a median latency period of 27 and 22 years, respectively. These results underscore the importance of
greatly extended follow-up in fully appreciating the oncogenicity of
leukemia treatment programs.
Bhatia and colleagues found no difference in the incidence of second
malignancies within the first 5 years of follow-up between patients
treated in the early (1983 to 1989) and recent (1989 to 1995) eras. It
is reassuring that more intensive use of chemotherapy in contemporary
trials did not increase the risk of development of acute myeloid
leukemia, which has a relatively short incubation period. Given the
fact that irradiation was administered to 51% of patients in the
early era, compared with only 28% in the recent era, the final
cumulative incidence of second neoplasms in the latter cohort will
likely be lower than in the former. With the trend toward reduced use
of cranial irradiation at lower doses (eg, 12 Gy), we anticipate a
significant decrease in the incidence of second neoplasms in patients
entered in ongoing clinical trials.
Recent studies show that the genetic polymorphisms of many
drug-metabolizing enzymes are associated with the development of second
cancers. We and others have demonstrated that individuals with a
deficiency of thiopurine methyltransferase, an enzyme that catalyzes
the inactivation of thiopurines, are at increased risk of developing
therapy-related leukemia, especially when they received concomitant
epipodophyllotoxin therapy, and irradiation-related brain tumors when
intensive antimetabolite therapy is given before and during cranial
irradiation. Apparently, antimetabolites can potentiate the
carcinogenic effects of epipodophyllotoxins and irradiation.
Polymorphisms of glutathione S-transferase (GSTP1), NAD(P)H:quinone oxidoreductase, and cytochrome P450 3A4
have also been linked to an increased risk of therapy-related leukemia, because of the decreased inactivation of carcinogens or mutagens or
increased production of reactive metabolites. Remarkably, by using DNA microarray analysis, my colleagues and I recently found that
a certain gene expression profile at diagnosis of ALL
predicts the development of therapy-related leukemia (Yeoh et
al, Cancer Cell. 2002;1:133-143). These results suggest that
similar studies might identify individuals who are at greatest risk for
any therapy-related cancer, thus pointing the way to optimal therapy.
Ching-Hon Pui
St Jude Children's Research Hospital
