Children with acute lymphoblastic leukemia (ALL) and high minimal residual disease (MRD) levels after initial chemotherapy have a poor clinical outcome. In this prospective, single arm, Phase 2 trial, 111 Dutch and Australian children aged 1-18 years with newly diagnosed, t(9;22)-negative ALL, were identified among 1041 consecutively enrolled patients as high risk (HR) based on clinical features or high MRD. The HR cohort received the AIEOP-BFM (Associazione Italiana di Ematologia ed Oncologia Pediatrica (Italy)-Berlin-Frankfurt-Münster ALL Study Group) 2000 ALL Protocol I, then three novel HR chemotherapy blocks, followed by allogeneic transplant or chemotherapy. Of the 111 HR patients, 91 began HR treatment blocks, while 79 completed the protocol. There were 3 remission failures, 12 relapses, 7 toxic deaths in remission and 10 patients who changed protocol due to toxicity or clinician/parent preference. For the 111 HR patients, 5-year event-free survival (EFS) was 66.8% (±5.5) and overall survival (OS) was 75.6% (±4.3). The 30 patients treated as HR solely on the basis of high MRD levels had a 5-year EFS of 63% (±9.4%). All patients experienced grade 3 or 4 toxicities during HR block therapy. Although cure rates were improved compared with previous studies, high treatment toxicity suggested that novel agents are needed to achieve further improvement.
Patients with a tumor thickness >4 mm experienced an increased risk of recurrence, especially nodal. Compared with patients having any radiotherapy, those undergoing surgery experienced a higher rate of locoregional recurrence. The addition of adjuvant radiotherapy in patients with inadequate excision significantly decreased the risk of recurrence.
The stratification of patients with acute lymphoblastic leukemia (ALL) into treatment risk groups based on quantification of minimal residual disease (MRD) after induction therapy is now well accepted but the relapse rate of about 20% in intermediate risk patients remains a challenge. The purpose of this study was to further improve stratification by MRD measurement at an earlier stage. MRD was measured in stored day 15 bone marrow samples for pediatric patients enrolled on ANZCHOG ALL8 using Real-time Quantitative PCR to detect immunoglobulin and T-cell receptor gene rearrangements with the same assays used at day 33 and day 79 in the original MRD stratification. MRD levels in bone marrow at day 15 and 33 were highly predictive of outcome in 223 precursor B-ALL patients (log rank Mantel-Cox tests both P<0.001) and identified patients with poor, intermediate and very good outcomes. The combined use of MRD at day 15 (≥1×10−2) and day 33 (≥5×1−5) identified a subgroup of medium risk precursor B-ALL patients as poor MRD responders with 5 year relapse-free survival of 55% compared to 84% for other medium risk patients (log rank Mantel-Cox test, P = 0.0005). Risk stratification of precursor B-ALL but not T-ALL could be improved by using MRD measurement at day 15 and day 33 instead of day 33 and day 79 in similar BFM-based protocols for children with this disease.
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