Abstract
BackgroundInfants with KMT2A-rearranged B-cell precursor acute lymphoblastic leukemia (ALL) have poor outcomes. There is an urgent need to identify novel agents to improve survival. Proteasome inhibition has emerged as a promising therapeutic strategy for several hematological malignancies. The aim of this study was to determine the preclinical efficacy of the selective proteasome inhibitor carfilzomib, for infants with KMT2A-rearranged ALL.MethodsEight infant ALL cell lines were extensively characterized for immunophenotypic and cytogenetic features. In vitro cytotoxicity to carfilzomib was assessed using a modified Alamar Blue assay with cells in logarithmic growth. The Bliss Independence model was applied to determine synergy between carfilzomib and the nine conventional chemotherapeutic agents used to treat infants with ALL. Established xenograft models were used to identify the maximal tolerated dose of carfilzomib and determine in vivo efficacy.ResultsCarfilzomib demonstrated low IC50 concentrations within the nanomolar range (6.0–15.8 nm) across the panel of cell lines. Combination drug testing indicated in vitro synergy between carfilzomib and several conventional chemotherapeutic agents including vincristine, daunorubicin, dexamethasone, L-asparaginase, and 4-hydroperoxycyclophosphamide. In vivo assessment did not lead to a survival advantage for either carfilzomib monotherapy, when used to treat both low or high disease burden, or for carfilzomib in combination with multi-agent induction chemotherapy comprising of vincristine, dexamethasone, and L-asparaginase.ConclusionsOur study highlights that in vitro efficacy does not necessarily translate to benefit in vivo and emphasizes the importance of in vivo validation prior to suggesting an agent for clinical use. Whilst proteasome inhibitors have an important role to play in several hematological malignancies, our findings guard against prioritization of carfilzomib for treatment of KMT2A-rearranged infant ALL in the clinical setting.
Highlights
The last 70 years have seen significant progress in the treatment of children with acute lymphoblastic leukemia (ALL)
Eight cell lines were established from six infants with KMT2Arearranged ALL (Table 1)
Four of the infants were less than 90 days old at diagnosis, with one infant diagnosed with congenital leukemia on day 9 of life
Summary
The last 70 years have seen significant progress in the treatment of children with acute lymphoblastic leukemia (ALL). Considered an incurable disease, 5-year overall survival rates are over 90% This has largely been achieved through successive randomized clinical trials facilitated by international cooperative study groups, with risk stratification of patients and treatment adaptation based on presenting features, blast genetics, and early response to therapy (1). There is an urgent need to identify novel agents to improve outcome of infants with KMT2A-rearranged ALL without further increasing toxicity. We aimed to investigate the potential of the selective proteasome inhibitor carfilzomib, for the treatment of infants with KMT2A-rearranged ALL. Infants with KMT2A-rearranged B-cell precursor acute lymphoblastic leukemia (ALL) have poor outcomes. The aim of this study was to determine the preclinical efficacy of the selective proteasome inhibitor carfilzomib, for infants with KMT2A-rearranged ALL
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