Post-induction residual leukemia in childhood acute lymphoblastic leukemiaquantified by PCR correlates with in vitro prednisolone resistance

Most prognostic factors in childhood acute lymphoblastic leukemia (ALL) are informative for groups of patients, whereas new approaches are needed to p redict the efficacy of chemotherapy for the individual patient. The residua l leukemia following 4 weeks of induction therapy with prednisolone, vincri stine, doxorubicin and i.t. methotrexate and the in vitro resistance to pre dnisolone, vincristine, and doxorubicin were measured in 30 boys and 12 gir ls with B (n = 34) or T lineage (n = 8) ALL. The residual leukemia was quan tified 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 m edian MRD-D15 and MRD-PI were 0.50% (75% range 0.008-8.1%) and 0.014% (75% range 0.001-2.0%), respectively, and these levels correlated significantly (n = 29, r(S) = 0.75, P < 0.001). Both the MRD-D15 and the MRD-PI were rela ted to the age of the patient (MRD-D15: r(S) = 0.48, P = 0.009; MRD-PI: r(S ) = 0.45, P = 0.003). Patients with T lineage ALL had higher MRD-PI than th ose 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 mug/m l (75% range 0.05-668). Both MRD-D15 and MRD-PI correlated significantly wi th the in vitro resistance to prednisolone (MRD-D15: r(S) = 0.41, P = 0.03; MRD-PI: r(S) = 0.39, P = 0.01); but not to in vitro vincristine or doxorub icin resistance. The correlations between MRD and in vitro prednisolone res istance were even more pronounced when B cell precursor and T cell leukemia were analyzed separately (B cell precursor ALL: MRD-PI vs prednisolone LC5 0: n = 33, r(S) = 0.47, P = 0.006; T cell ALL: MRD-PI vs prednisolone resis tance: n = 8, r(S) = 0.84, P = 0.009), After a median follow-up of 5.0 year s (75% range 3.2-6.9) eight patients have relapsed, All of the 21 patients with a MRD-PI less than or equal to0.5% and a prednisolone LC50 less than o r equal to 10 mug/ml have remained in remission whereas the 7 year event-fr ee survival for the remaining 20 patients was 0.45 +/- 0.16 (P = 0.002) Pro spective studies in childhood ALL are needed to clarify whether combined mo nitoring of in vitro drug resistance and residual leukemia early during che motherapy could offer new ways to classify patients and stratify the intens ity of therapy.