Recruitment started on Jan 1, 2004, and ended on Dec 31, 2009. 229 patients were screened, 213 met eligibility criteria, and 178 (age range 1·5–17·9 years) were enrolled and stratified as good risk (108; 61%) or poor risk (70; 39%; ). Up to 2008 (when evidence for adults became fully available), eight of 90 good-risk patients (9%) refused to be assigned, in 2009, ten of 18 eligible good-risk patients (56%) were not assigned, resulting in 90 good-risk patients being randomly assigned. More patients were older than 10 years in the poor-risk group than in the good-risk group and fewer patients had white blood cell counts of less than 50 cells per μL at diagnosis ().
All patients except two had progenitor-B Philadelphia-chromosome-positive acute lymphoblastic leukaemia. Of 85 patients for whom detection of p190 and p210 was possible, p210 was detected more often in poor-risk patients than in good-risk patients.
Four patients achieved early response but not complete response at the end of induction and were classified as poor risk. Minimal residual disease at the end of induction was higher in poor-risk patients than in good-risk patients.
Baseline characteristics were much the same in each good-risk group, except for post-induction minimal residual disease, with low levels (<5×10−4) more frequent in the good-risk, no imatinib than in the good-risk, imitinab (). Median follow-up of the 178 enrolled patients was 3·1 years (2·0–4·6). For these patients 4-year event-free survival was 61·9% (95% CI 52·2–69·8) and 4-year overall survival was 72·1% (95% CI 64·5–79·7). For the 160 patients who were randomly assigned or in the poor-risk group, 4-year event-free survival was 61·0% (95% CI 53·0–69·0) and overall survival was 72·2% (95% CI 64·4–80·0).
Allogeneic stem-cell transplantation was done in first complete remission in 137 of 178 (77%) patients (78 with good risk, 59 with poor risk) at a median of 155 days from first complete remission, and after the HR3 block for 112 (82%) patients (). The most common type of transplant was from HLA-matched unrelated donors in both risk groups (44 [56%] good risk, 27 [46%] poor risk).
At 4 years, disease-free survival was 72·9% (95% CI 56·1–84·1) in the good-risk, imatinib group and 61·7% (45·0–74·7) in the good-risk, no imatinib group (p=0·24), with an absolute difference of 11·2% (95% CI −9·2 to 31·6; ) when calculated by intention to treat. The HR for any event was 0·71 (95% CI 0·33–1·54; p=0·38) and was 0·63 (95% CI 0·28–1·41; p=0·26) when adjusted for minimal residual disease after induction. 4-year overall survival was 85·1% (95% CI 69·6–93·1) in the good-risk, imatinib group and 72·9% (53·9–85·0) in the good-risk, no imatinib group (p=0·37). The HR for death was 0·68 (95% CI 0·26–1·81; p=0·44) and 0·59 (0·21–1·65; p=0·31) when adjusted for minimal residual disease after induction.
Disease-free survival and cumulative incidence of relapse and of death in continuous complete remission in good risk patients, analysed by intention to treat
Relapse was the most frequent event in both good-risk groups, involving the bone marrow in all except four patients and half of relapses occurred after stem-cell transplantation, which was done in 37 (80%) of 46 patients in the good-risk, imatinib group versus 32 (73%) of 44 patients in the good-risk, no imatinib group at a median time of 5·3 months (IQR 4·8–6·4) versus 5·4 months (4·7–6·1). Cumulative incidence of relapse at 4 years was 24·8% (95% CI 11·1–38·5) in the good-risk, imatinib group and 29·2% (14·9–43·5) in the good-risk, no imatinib group (p=0·66) and all relapses occurred within 3 years of entry into the study (). After relapse, roughly half of patients died, mainly from disease progression. More deaths in continuous complete remission occurred in patients in the good-risk, no imatinib group than in the good-risk, imatinib group and none were related to imatinib ().
When censored at stem-cell transplantation during first complete remission, 2-year disease-free survival was 81·2% (95% CI 30·7–96·4) in the good-risk, imatinib group versus 65·4% (30·4–86·0) in the good-risk, no imatinib group (p=0·97). 2-year disease-free survival without censoring was 78·9% (95% CI 63·2–88·4) versus 67·6% (51·5–79·4; appendix
The as-treated analyses compared 58 good-risk patients who received imatinib (including 12 assigned to the good-risk, no imatinib group), with 31 patients who did not. 4-year disease-free survival was 75·2% (95% CI 61·0–84·9) versus 55·9% (36·1–71·7), with an absolute difference of 19·3% (–2·0 to 41·0; p=0·06). HR adjusted by post-induction minimal residual disease was 0·35 (0·14–0·90; p=0·03; ). The cumulative incidence of relapse at 4 years was 21·2% (95% CI 9·8–32·6) for patients receiving imatinib and 34·4% (16·4–52·4) for those not receiving imatinib (p=0·21; ).
Disease-free survival curves and cumulative incidence of relapse and of death in continuous complete remission for good-risk patients, analysed as treated
Of the 58 patients receiving imatinib, 11 did not have a transplant, of whom four relapsed. Of the 31 patients who did not receive imatinib, nine were not transplanted. Four of nine relapsed and one died in continuous complete remission. 13 of the 18 good-risk patients not included in the randomisation received imatinib, although not always according to protocol. None relapsed and three died in continuous complete remission (one after stem-cell transplantation in first complete remission).
Of the 70 poor-risk patients, 35 (50%) were not in complete remission at the end of induction. All patients eventually attained complete remission; 28 after protocol IB, five after HR1, and two after HR2. 59 (84%) received allogeneic stem-cell transplantation during first complete remission at a median time of 4·9 months (IQR 4·1–5·4). 4-year event-free survival was 53·5% (95% CI 40·4–65·0) and 4-year overall survival was 63·5% (95% CI 50·2–74·2; ). 35 patients who were in complete remission at the end of induction had a 4-year event-free survival of 58·5% (95% CI 40·9–76·1) versus 48·9% (95% CI 31·5–49·1) for the remaining 35 who achieved complete remission at a later time (p=0·45). Disease-free survival at 4 years from complete remission was the same as event-free survival, because no patient was resistant to protocol.
23 patients relapsed () within 24 months of study entry, mostly involving bone marrow (n=21). Roughly 70% of these patients died because of disease progression. Eight patients died in continuous complete remission and none were judged to be related to imatinib.
Proportions of patients with the most commonly reported serious adverse events did not differ substantially between groups (p=0·64 when comparing good-risk patients treated with imatinib to those without) and were mainly related to myelosuppression (). Infections were the most common serious adverse event. Minor delays (≤1 week) in administration of chemotherapy were more common in good-risk patients not receiving imatinib than those receiving imatinib (14/31 [45·2%] vs 13/58 [22·4%]) whereas major delays (>1 week) occurred in 25 of 58 (43·1%) patients in the good-risk, imatinib group versus six of 31 (19·4%) patients in the good-risk, no imatinib group. However, this difference was not significant (p=0·07). Poor-risk patients had similar results (20 had minor and 25 had major delays). 13 of 31 (41·9%) patients in the good-risk, no imatinib group, 26 of 58 (44·8%) patients in the good-risk, imatinib group, and 40 of 70 (57·1%) patients in the poor-risk group had a dose decrease of more than 10% for chemotherapy and imatinib cumulative doses between the beginning of protocol IB and the end of HR3.