Blood, 1 May 2003, Vol. 101, No. 9, pp. 3341-3341
MRD in AML: it's time to face the FACS
Improvements in the treatment outcome for childhood AML
have lagged behind those achieved for childhood ALL, in part because of
a dearth of well-defined prognostic factors. Whereas the prognostic impact of minimal residual disease (MRD) measurements in ALL is well
established, relatively little is known about the impact of residual
disease detection in childhood AML. In this issue, Sievers and
colleagues (page 3398) have narrowed this gap in knowledge. Extending
their previous work, the investigators used multidimensional flow
cytometry to evaluate bone marrow specimens of 252 pediatric patients
with AML for the presence of leukemic cells. Overall, 41 (16%)
patients had immunophenotypic evidence of leukemia at one or more time
points before relapse. Multivariate analysis demonstrated that residual
disease was the most significant prognostic factor. Compared with
patients who had no detectable leukemia by flow cytometry, those who
were positive for residual disease had significantly increased risks of
relapse and death. It should be noted, however, that the authors
analyzed "responsive" patients, defined as those with fewer than
30% morphologically detectable blasts after one course of therapy.
Because some of the patients may have had microscopically detectable
blasts at the time of analysis (eg, 5% to 30% blasts), it might be
more relevant to limit the analysis to patients with fewer than 5%
marrow blasts, thereby identifying and analyzing only patients with
"minimal" or occult residual disease.
The investigators used a standard panel of antibodies to identify
phenotypic abnormalities in bone marrow specimens. Although this
approach is practical and allowed the investigators to study 100% of
samples at a stated sensitivity of 0.5%, its sensitivity may actually
be quite variable. In fact, because the immunophenotypes of leukemic
cells obtained from each patient at the time of diagnosis were not
determined, it is not possible to know the sensitivity of their assay
in each case. This might explain the observations that only 16% of
patients were positive for residual leukemia and only one-third of
subsequent relapses were predicted. Nevertheless, the authors clearly
demonstrated the prognostic impact of residual disease in childhood
AML: patients with detectable disease had a 3-year overall survival
estimate of 41%, compared with 69% for those without measurable leukemia.
I share the authors' hope that early intensification of therapy for
patients with detectable residual disease before overt relapse occurs
will improve their outcome. But for this strategy to have a clinical
impact, it will be important to study all patients early in therapy.
Although the investigators successfully analyzed all bone marrow
samples received by their laboratory, specimens were submitted from
only 48% of patients before intensification therapy (ie, at a time
when increased intensification could potentially improve outcome). In
addition, optimal use of residual disease studies may require more
sensitive assays. The use of patient-specific antibody panels, which
considerably increase the sensitivity of residual disease studies, may
permit the identification of more patients who are at high risk of
relapse. The application of such methods to all patients early in
therapy should provide a more accurate estimate of the leukemic burden
at the time of morphologic remission and a rational means of
selecting postremission therapy. Moreover, as suggested by the results
of the present study, sequential monitoring of residual disease, which
has proven to be useful in ALL, may also add prognostic information in
AML by identifying patients who have slow regression of disease or
increasing levels of disease and are thus at a particularly high risk
of treatment failure.
Jeffrey E. Rubnitz
St Jude Children's Research
Hospital
