Most prognostic factors in childhood
acute lymphoblastic leukemia (ALL) are informative for groups of patients, whereas new approaches are needed to predict the efficacy of
chemotherapy for the individual patient. The residual
leukemia following 4 weeks of induction
therapy with
prednisolone,
vincristine,
doxorubicin and i.t.
methotrexate and the in vitro resistance to
prednisolone,
vincristine, and
doxorubicin were measured in 30 boys and 12 girls with B (n = 34) or T lineage (n = 8) ALL. The residual
leukemia was quantified after 2 (MRD-D15, n = 29) and 4 weeks (MRD-PI, n = 42) of induction
therapy with a precise and reproducible clone-specific PCR technique. The median MRD-D15 and MRD-PI were 0.50% (75% range 0.0088.1%) and 0.014% (75% range 0.001-2.0%), respectively, and these levels correlated significantly (n = 29, rs = 0.75, P < 0.001). Both the MRD-D15 and the MRD-PI were related to the age of the patient (MRD-D15: rs= 0.48, P= 0.009; MRD-PI: rs = 0.45, P = 0.003). Patients with T lineage ALL had higher MRD-PI than those with B lineage ALL (median MRD-PI: 0.5% vs 0.01%, P = 0.05). The median LC50 (concentration lethal to 50% of cells) for
prednisolone was 2.3 microg/ml (75% range 0.05-668). Both MRD-D15 and MRD-PI correlated significantly with the in vitro resistance to
prednisolone (MRD-D15: rs = 0.41, P = 0.03; MRD-PI: rs = 0.39, P = 0.01); but not to in vitro
vincristine or
doxorubicin resistance. The correlations between MRD and in vitro
prednisolone resistance were even more pronounced when B cell precursor and
T cell leukemia were analyzed separately (B cell precursor ALL: MRD-PI vs
prednisolone LC50: n = 33, rs = 0.47, P = 0.006; T cell ALL: MRD-PI vs
prednisolone resistance: n = 8, rs = 0.84, P = 0.009). After a median follow-up of 5.0 years (75% range 3.2-6.9) eight patients have relapsed. All of the 21 patients with a MRD-PI < or =0.5% and a
prednisolone LC50 < or =10 microg/ml have remained in remission whereas the 7 year event-free survival for the remaining 20 patients was 0.45 +/- 0.16 (P= 0.002) Prospective studies in
childhood ALL are needed to clarify whether combined monitoring of in vitro drug resistance and residual
leukemia early during
chemotherapy could offer new ways to classify patients and stratify the intensity of
therapy.