Results of a Feasibility and Phase II Study on Bortezomib (BTZ) in Pediatric Multiply Relapsed or Refractory Acute Lymphoblastic Leukemia: Complete Hematological Responses with a Modestly Intensive Regimen Including BTZ

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 2^nd or greater relapsed ALL, 1^strelapsed 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 <5% blasts, M2 5-15% and M3>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 2^ndcycle 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).