Background We conducted a clinical trial to test whether prophylactic cranial irradiation could be omitted in all children with newly diagnosed acute lymphoblastic leukemia. Methods A total of 498 evaluable patients were enrolled. Treatment intensity was based on presenting features and the level of minimal residual disease after remission induction treatment. Continuous complete remission was compared between the 71 patients who previously would have received prophylactic cranial irradiation and the 56 historical controls who received it. Results The 5-year event-free and overall survival probabilities (95% confidence interval) for all 498 patients were 85.6% (79.9% to 91.3%) and 93.5% (89.8% to 97.2%), respectively. The 5-year cumulative risk of isolated central-nervous-system (CNS) relapse was 2.7% (1.1% to 4.2%), and that of any CNS relapse (isolated plus combined) was 3.9% (1.9% to 5.9%). The 71 patients had significantly better continuous complete remission than the 56 historical controls (P=0.04). All 11 patients with isolated CNS relapse remain in second remission for 0.4 to 5.5 years. CNS leukemia (CNS-3 status) or a traumatic lumbar puncture with blasts at diagnosis and a high level of minimal residual disease (≥ 1%) after 6 weeks of remission induction were significantly associated with poorer event-free survival. Risk factors for CNS relapse included the presence of the t(1;19)[TCF3-PBX1], any CNS involvement at diagnosis, and T-cell immunophenotype. Common adverse effects included allergic reactions to L-asparaginase, osteonecrosis, thrombosis, and disseminated fungal infection. Conclusions With effective risk-adjusted chemotherapy, prophylactic cranial irradiation can be safely omitted in the treatment of childhood acute lymphoblastic leukemia.

Summary Background We sought to improve outcome of childhood acute myeloid leukemia (AML) by applying risk-directed therapy based on the genetic abnormalities of the leukemic cells and measurements of minimal residual disease (MRD) as determined by flow cytometry during treatment. Methods From October 13, 2002 to June 19, 2008, 232 patients with de novo AML (n=206), therapy- or myelodysplasia-related AML (n=12), or mixed-lineage leukemia (n=14) were enrolled at eight centers. Block, nonblinded randomization, stratified by cytogenetic or morphologic subtype, assigned patients to high-dose (18 g/m2, n=113) or low-dose (2 g/m2, n=117) cytarabine (A), given together with daunorubicin (D) and etoposide (E) (Induction I); achievement of MRD negative status was the primary endpoint. Induction II consisted of ADE with or without gemtuzumab ozogamicin (GO); consolidation therapy included three additional courses of chemotherapy or hematopoietic stem cell transplantation (HSCT). Levels of MRD were used to allocate GO and determine the timing of Induction II; both MRD and genetic abnormalities at diagnosis were used to determine final risk classification. Low-risk patients (n=68) received 5 courses of chemotherapy, whereas high-risk patients (n=79), as well as standard-risk patients (n=69) with matched sibling donors, were eligible for HSCT (performed in 48 high and 8 standard-risk patients). All randomized patients (n=230) were analyzed for the primary endpoint. The other analyses were limited to the 216 patients with AML, excluding mixed-lineage leukemia. This trial, closed to accrual, is registered with ClinicalTrial.gov, number NCT00136084. Findings The complete remission rates were 80% (173 of the 216) after Induction I and 94% (203 of 216) after Induction II. Induction failures included two toxic deaths and 10 cases of resistant leukemia. The introduction of high-dose cytarabine did not significantly lower the rate of MRD positivity after Induction I therapy (34% vs. 42%, P=0.17). The cumulative incidences of grade 3 or greater infection were 79.3% ± 4.0% and 75.5% ± 4.2% for patients treated on the high-dose or low-dose arms. The 3-year estimates (± SE) of event-free and overall survival were 63.0% ± 4.1% and 71.1% ± 3.8%, respectively. Achievement of MRD < 0.1% after Induction II identified a large group of patients (80%) with a cumulative incidence of relapse of only 17% ± 3%. Post-Induction I MRD ≥ 1% was the only independent adverse prognostic factor that was statistically significant (P < 0.05) for both event-free (HR, 2.41; CI 1.36–4.26; P=0.003) and overall survival (HR, 2.11; CI 1.09–4.11; P=0.028). Interpretation Our findings suggest that the use of targeted chemotherapy and HSCT, in the context of a comprehensive risk-stratification strategy based on genetic features and MRD findings, can improve the outcome of childhood AML.

A B S T R A C T PurposeTo conduct a pilot study to determine the safety, feasibility, and engraftment of haploidentical natural killer (NK) cell infusions after an immunosuppressive regimen in children with acute myeloid leukemia (AML). Patients and MethodsTen patients (0.7 to 21 years old) who had completed chemotherapy and were in first complete remission of AML were enrolled on the Pilot Study of Haploidentical Natural Killer Cell Transplantation for Acute Myeloid Leukemia (NKAML) study. They received cyclophosphamide (60 mg/kg on day Ϫ7) and fludarabine (25 mg/m 2 /d on days Ϫ6 through Ϫ2), followed by killer immunoglobulin-like receptor-human leukocyte antigen (KIR-HLA) mismatched NK cells (median, 29 ϫ 10 6 /kg NK cells) and six doses of interleukin-2 (1 million U/m 2 ). NK cell chimerism, phenotyping, and functional assays were performed on days 2, 7, 14, 21, and 28 after transplantation. ResultsAll patients had transient engraftment for a median of 10 days (range, 2 to 189 days) and a significant expansion of KIR-mismatched NK cells (median, 5,800/mL of blood on day 14). Nonhematologic toxicity was limited, with no graft-versus-host disease. Median length of hospitalization was 2 days. With a median follow-up time of 964 days (range, 569 to 1,162 days), all patients remain in remission. The 2-year event-free survival estimate was 100% (95% CI, 63.1% to 100%). ConclusionLow-dose immunosuppression followed by donor-recipient inhibitory KIR-HLA mismatched NK cells is well tolerated by patients and results in successful engraftment. We propose to further investigate the efficacy of KIR-mismatched NK cells in a phase II trial as consolidation therapy to decrease relapse without increasing mortality in children with AML. J Clin