Acute lymphoblastic leukemia (ALL) in infants under 1 year is strongly associated with translocations involving 11q23 (MLL gene), CD10-negative B-lineage (proB) immunophenotype, and poor outcome. The present study analyses the relationship between age, MLL rearrangements, proB-lineage, and in vitro drug resistance determined using the MTT assay. Compared to 425 children aged over 1 year with common/preB (c/preB) ALL, the 44 infants were highly resistant to steroids (for prednisolone (PRED) more than 580-fold, P = 0.001) and L-asparaginase (L-ASP) (12-fold, P = 0.001), but more sensitive to cytarabine (AraC) (1.9-fold, P = 0.001) and 2-chlorodeoxyadenosine (2-CdA) (1.7-fold, P < 0.001). No differences were found for vincristine, anthracyclines, thiopurines, epipodophyllotoxines, or 4-hydroperoxy (HOO)-ifosfamide. ProB ALL of all ages had a profile similar to infant ALL when compared with the group of c/preB ALL: relatively more resistant to L-ASP and PRED (and in addition thiopurines), and more sensitive to AraC and 2-CdA. Age was not related to cellular drug resistance within the proB ALL group (< 1 year, n = 32, vs ≥ 1 year, n = 19), nor within the MLL-rearranged ALL (< 1 year, n = 34, vs ≥ 1 year, n = 8). The translocation t(4;11)(q21;q23)-positive ALL cases were more resistant to PRED (> 7.4-fold, P = 0.033) and 4-HOO-ifosfamide (4.4-fold, P = 0.006) than those with other 11q23 abnormalities. The expression of P-glycoprotein, multidrug-resistance protein, and lung-resistance protein (LRP) was not higher in infants compared to older c/preB ALL patients, but LRP was higher in proB ALL and MLL-rearranged ALL of all ages. In conclusion, infants with ALL appear to have a distinct in vitro resistance profile with the proB immunophenotype being of importance. The role of MLL cannot be excluded, with the t(4;11) being of special significance, while age appears to play a smaller role.

Acute lymphoblastic leukemia, Chemotherapy, In vitro drug resistance, Infant, MLL rearrangement,
Department of Pediatrics

Ramakers-van Woerden, N.I, Beverloo, H.B, Veerman, A.J.P, Camitta, B, Loonen, A.H, van Wering, E.R, … Pieters, R. (2004). In vitro durg-resistance profile in infant acute lymphoblastic leukemia in relation to age, MLL rearrangements and immunophenotype. Leukemia, 18(3), 521–529. doi:10.1038/sj.leu.2403253