ALBERT

Description: Prognosis of refractory and relapsed ALL is poor and its improvement requires the introduction of novel agents with a new mechanism of action. Bortezomib (BTZ) as proteasome inhibitor is such an agent, and has been shown to be safe as single agent in phase I studies in children with either solid tumors (Blaney 2004) or leukemias (Horton 2007). Recently, Messinger (2012) reported in a single-arm study that BTZ can be combined safely with vincristine (VCR), dexamethasone (DXM), pegylated asparaginase (PEG-ASP) and doxorubicin and that the combination was remarkably effective in B-cell precursor ALL. BTZ has been reported to sensitise malignant cells to other agents, both in vitro for leukemias as well as for multiple myeloma patients in vivo. In patients with ALL, the sensitizing effect of BTZ regarding the efficacy of glucocorticoids (GC) has not been addressed yet. Considering the lack of any clinical experience with BTZ in children, we developed a European multicenter feasibility and phase II study in refractory or relapsed ALL, in which all patients receive BTZ, with day 8 peripheral blast count as primary endpoint. The study is performed in compliance with the Declaration of Helsinki. Patients are randomised for BTZ to be administered “early”, or “late”. Bortezomib is then given as iv push for 4 doses at 1.3 mg/m2/dose, thus in group “early” on days 1, 4, 8 and 11 and in group “late” on days 8, 11, 15 and 18. In addition, all patients receive DXM (10 mg/m2/day in 3 doses for 2 weeks, orally or iv) and VCR (1.5 mg/m2/dose with a maximum of 2 mg as 1-hour infusion on days 8 and 15), as well as one intrathecal administration of methotrexate (MTX, dose age-adjusted) on day 1. No ASP and no anthracycline is given. Cycles can be repeated in case of a good response. Eligible patients have 2nd or greater relapsed ALL, 1strelapsed ALL after allogeneic stem cell transplantation (allo-SCT) in CR1, or refractory first relapsed ALL, and bone marrow (BM) involvement and at least 100 leukemic cells per µl blood. Exclusion criteria include symptomatic CNS leukemia. It is planned to evaluate 24 fully evaluable randomised patients. This analysis, not being an official interim-analysis and not evaluating the primary endpoint of the study, focusses on haematological responses with this modestly intensive regimen. BM M1 indicates 15% blasts. Between October 2010 and March 2014, a total of 21 eligible patients with information on response and/or toxicity after cycle 1 has been enrolled, 11 boys and 10 girls, median 9.8 years of age (range, 1.2 – 17.5). Most had second relapsed ALL (n=11), others first relapsed ALL following allo-SCT in CR1 (n=8) or refractory first relapsed ALL (n=2). Regarding efficacy, 17 patients were evaluable (1 patient no material received, 2 patients discontinued treatment due to toxicity, and 1 patient had early progression which led to treatment discontinuation). Day 22 BM showed M1 in 5, M2 in 6, and M3 in 6 patients. There was no relation between day 22 BM status and the administration of BTZ being early or late. There was no association between response and disease status, being either refractory or relapsed, although numbers are small. Two patients with a relapse after allo-SCT achieved BM M1, as well as 3 patients with a second or subsequent relapse. Four patients (23.5%) achieved hematological remission after cycle 1, while 11 out of 17 patients (65%) had a good initial response (day 22 BM M1 or M2). A total of 10 patients received a 2ndcycle and 5 out of them achieved a complete remission, 4 of whom already had a day 22 BM M1. Eight out of 21 (38%) patients suffered from grade 3 and/or 4 toxicity during cycle 1, and most frequently reported were pain (n=4), peripheral neuropathy and fatigue (n=2 each). After 2 cycles, grade 3/4 toxicity was reported in 3 out of 10 patients: one with peripheral neuropathy, one with peripheral neuropathy, haemorrhage and hematuria, and one with raised ALAT. Future analyses will focus on sensitisation to GC by BTZ and on the efficacy of BTZ in relation to PK and PD. Meanwhile, BTZ in combination with VCR, DXM and intrathecal MTX is effective in a significant subset of pediatric relapsed and refractory ALL, and repetitive cycles could be given in several children without undue toxicity. This research is financially supported by the Dutch Foundation Children Cancer-free (clinical research support) and by Janssen Pharmaceuticals (clinical research support and free drug). Disclosures Baruchel: Janssen-Cilag: Consultancy.

Description: Background Cranial radiotherapy (CRT) is associated with early and late side effects. Intrathecal (IT) and systemic chemotherapy could successfully replace CRT in most protocols for standard risk ALL. However, in medium and high risk ALL patients (pts) its omission is still debatable. Aim We investigated the long-term outcome, the occurrence of second malignant neoplasms (SMN) and the incidence of late toxicities in pts randomized for receiving or not CRT in the EORTC 58832 study. Methods From 1983 to 1989, ALL children under 18 years (yrs) were included in EORTC Children Leukemia Group BFM-oriented studies, either 58831, for standard risk pts (Riehm-Langerman Risk Factor (RF) 〈 1.2), or 58832, for medium risk (RF 1.2-1.69) and high risk pts (RF ≥1.7). Pts with central nervous system (CNS) involvement at diagnosis were ineligible. The present report focusses on pts included in the 58832 trial (randomized for receiving or not prophylactic CRT). Prophylactic CNS therapy consisted of 4 high-dose methotrexate (HD-MTX) injections (2500 mg/m2) during consolidation and 7 IT MTX injections scheduled during the treatment period. Pts still in complete remission (CR) after the end of late intensification were randomized for receiving prophylactic CRT (standard arm) or not (experimental arm) before the start of continuation therapy. Dose of CRT was age dependent: 24 Gy (〉 2 yrs), 20 Gy (1-2 yrs) and 16 Gy (〈 1 yr). Endpoints were: disease-free survival (DFS) (event: relapse, death in CR), incidence of SMN, event-free survival (EFS) (event: relapse, death in CR, SMN), incidence of late toxicities, and overall survival (OS) from randomization. Results 788 pts were included in the 58831/58832 study. Among them, 189 were randomized in the 58832 study to receive CRT (n=93) or No CRT (n=96). A total of 6 pts did not meet eligibility criteria, 2 had an early relapse, 3 had an early protocol violation and 2 refused allocated treatment. Finally, 176 randomized pts were included in the analyses: 84 in the CRT group and 92 in the No CRT group. The median follow-up was 20 yrs (range 4-32 yrs). Omission of CRT did not increase the 25-yr incidence of isolated CNS relapse, any CNS relapse or non-CNS relapse (4.8 vs 6.5; 11.9 vs 8.7 and 16.7 vs 21.8 in the CRT vs No CRT arms, respectively). No relapses occurred after 10 yrs. The 25-yr DFS rates were similar in both arms: 70.2% with CRT and 67.4% without CRT; No CRT vs CRT hazard ratio (HR)=1.08, 95% CI (0.63, 1.83). CRT was associated with an increase of the 25-yr SMN incidence: 13.2% with CRT and 3.9% without CRT. In the CRT arm, 9 pts (10.7%) developed SMN: 2 acute myeloid leukemias (AML), 1 non-Hodgkin lymphoma, 1 thyroid carcinoma, 4 meningiomas and 1 malignant histiocytosis. One SMN (meningioma) occurred after a CNS combined relapse. Three pts developed second SMN (meningiomas): 1 after an AML and 2 after a first meningioma. In the No CRT arm, 3 pts (3.3%) had SMN: 1 pleomorphic xanthoastrocytoma, 1 melanoma and 1 adenocarcinoma of the ileum. One SMN occurred after a bone marrow (BM) relapse. The 25-yr EFS rates were similar in both arms: 60.3% with CRT and 63.2% without CRT, HR=0.90, 95% CI (0.55, 1.46). CRT was also associated with an increase of late CNS and endocrine toxicities. Five pts (19.2% of the pts with available data) developed leukoencephalopathy in the CRT arm, versus 2 pts (8.7%) in the No CRT arm. Noteworthy, 1 of those 2 pts received CRT for a BM relapse, while the other received total body irradiation for a CNS relapse. Stroke was observed in 2 pts (7.7%) who received CRT. In contrast, there was no clear increase of the incidence of cognitive disturbance after CRT: 33.3% in the CRT arm vs 25.0% in the No CRT arm. Regarding endocrine toxicities, GH deficiency, hypothyroidism and precocious puberty were more frequent in the CRT arm: 53.1% vs 29.6%, 27.8% vs 0% and 29.4% vs 0%, respectively. Finally, the 25-yr OS rates were similar in both arms: 78.5% with CRT and 78.1% without CRT, HR=1.00, 95% CI (0.53, 1.88). Conclusion In medium and high risk pts without CNS involvement at diagnosis and treated with HD-MTX in the EORTC trial 58832 (1983-1989), omission of CRT did not increase the risk of CNS or non-CNS relapse. On long-term evaluation, CRT was associated with a higher incidence of SMN, late CNS and endocrine toxicities. These long-term results indicate that prophylactic CRT can be safely omitted in childhood medium and high risk ALL pts receiving IT and systemic chemotherapy (including HD-MTX) as CNS prophylaxis. Table Table. Disclosures No relevant conflicts of interest to declare.

Description: BTZ is a proteasome inhibitor and could improve the poor prognosis of rALL (Messinger 2012). We developed a European phase II study in pediatric rALL, in which patients were randomised for 'early' or 'late' BTZ, in compliance with the Declaration of Helsinki. BTZ was given as iv push for 4 doses at 1.3 mg/m2/dose, in group 'early' on days 1, 4, 8 and 11 and in group 'late' on days 8, 11, 15 and 18. All patients also received DXM (10 mg/m2/day in 3 doses for 2 weeks) and VCR (1.5 mg/m2/dose (maximum 2 mg) as 1-hour infusion on days 8 and 15), plus intrathecal methotrexate (i.t. MTX, dose age-adjusted) on day 1. Cycles could be repeated in case of a good response. The number of 12 patients in each group provides a power of 80% to detect a statistically significantly lower absolute number of circulating leukemic blasts on day 8 of treatment in patients exposed to 'BTZ early' as compared to patients not yet exposed to BTZ ('BTZ late') of at least 30% (2-sided test, alpha