Imatinib Mesylate Induces High Complete Cytogenetic and Molecular Response Rates in Children and Adolescents with Philadelphia Chromosome-Positive (Ph+) Chronic Myelogenous Leukemia (CML) in Chronic Phase (CP)

Abstract

Imatinib mesylate (IM), a BCR-ABL tyrosine kinase inhibitor, is an effective therapy for CML in adults and has shown efficacy in children with Ph+ leukemias. The aim of this study was to evaluate the efficacy of IM in Ph+ CML patients (pts) in CP aged <18 years at diagnosis, previously untreated or resistant to Interferon (IFN). In all pts, IM therapy, started at a dose of 340 mg/m2/day, was modulated according to the hematologic parameters. Cytogenetic studies were performed on bone marrow (BM) cells at baseline and, during IM therapy, every 3 months (mo). Complete cytogenetic response (CCyR) was also confirmed by FISH. BCR-ABL transcripts were measured in the peripheral blood (PB) cells every mo and in the BM cells every 3 mo by real-time quantitative PCR (RQ-PCR). Molecular response (MolR) was defined as major in the presence of a BCRABL: ABL ratio <0.05% and as complete with a ratio <0.001. Between February 2001 and October 2007, 13 Ph+ CML pts (9 M and 4 F; median age 128/12 years) in CP were recruited from 2 pediatric centers (Rome and Padua). Eight of the 13 pts (7 M and 1 F; median age 11 years) received IM at diagnosis and 5 (3 F and 1 M; median age 146/12 years) after IFN therapy given at a mean dose of 6.000.000 UI/day for a median of 18 mo. All but 1 pt tolerated well IM treatment. The mean dose of IM administered was 326 mg/m2/day for untreated pts and 227 mg/m2/day for those resistant to IFN. The characteristics and followup of the pts are summarized in the Table:Sex/Age at diagn/Age at treat (yrs)IFN duration/%Ph+IM mg/m2/dayCCyR/time (mo)Max Bcr-Abl:Abl (%)/time (mo) (BM)Max Bcr-Abl:Abl (%)/time (mo) (PB)CCyR duration (mo)Follow-up.F/11/146/1240 mo/100193.540/600/4+80Alive CCyR, Bcr-Abl:Abl (%)BM 0 PB 0.0023F/179/12/1810/129 mo/10018261.27/90.89/9+7Lost to follow-up in CCyR at + 13 moM/91/12/117/1226 mo/5020830/360/12+65Alive CCyR, Bcr-Abl:Abl (%)BM 0 PB 0F/89/12/910/1213 mo/5035030/440/66+66Alive CCyR, Bcr-Abl:Abl (%)BM 0.009 PB 0M/172/12/189/1218 mo/8020590.029/680.114/72+82Alive CCyR, Bcr-Abl:Abl (%)BM 0.05 PB 0.15M/126/12−/10031040/420/30+66Alive CCyR, Bcr-Abl:Abl (%): BM 0 PB 0M/161/12−/100327n.e.n.e.n.e.n.e.IM tox; alive CCyR after SCT (sibl) (+40 mo)M/144/12−/10029140/420/24+61Alive CCyR, Bcr-Abl:Abl (%) BM 0 PB 0M/811/12−/100357.560.044/90.057/9CyRel/33Alive CCyR after SCT (+ 8 mo)M/95/12−/10032630.013/120.028/9+12Alive CCyR,Bcr-Abl:Abl (%) BM 0.013 PB 0.15M/410/12−/100328.530.02/90/12BMT/+13SCT (sibl) in CCyR->Alive in CCyR +43 moM/137/12−/10034960.012/300.025/30+32Alive CCyR, Bcr-Abl:Abl (%) BM 0.012 PB 0.025F/94/12−/10032030.009/90.003/9+7Alive CCyR, Bcr-Abl:Abl (%) BM 0.02 PB 0.003Twelve of the 13 pts (92%) achieved a CCyR after a median of 4 mo (range 3–9). Eleven of the latter 12 pts were evaluated for MolR: 11/11 (100%) pts achieved a MolR, 6 major (54.5%) and 5 complete (45.5%), on BM cells after a median of 36 mo (range 9–68) and 9/11 pts (82%) on PB cells, 4 major (44.4%) and 5 complete (55.6%), after a median of 12 mo (range 4–66). To date, 12 evaluable pts are alive in CCyR: 3 after a stem cell transplantation (SCT) and 9 still receiving IM for a median time of 68 mo (range 10–89). MolR persists on BM cells in 9/9 pts (100%), 4 complete (44%), and on PB cells in 7/9 pts (78%), 4 complete. Our experience indicates that IM is highly effective in children and adolescents with Ph+ CML in CP, capable also of inducing high and persistent CCyR and MolR rates also in pts resistant to IFN.