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J.P. Loftus et al.
Chemotherapy resistance and subsequent relapse remain a major cause of childhood cancer mortality, espe- cially for infants with KMT2A-R B-ALL who have extremely poor EFS. In one study, Pieters et al. reported 3- fold higher risk of relapse or death in infants with KMT2A-R ALL (irrespective of KMT2A rearrangement subtype) versus those without KMT2A rearrangements.10 Outcomes for infants with the KMT2A-AFF1 subtype from t(4;11) are particularly poor, although differences in associated HOX family gene expression and presence or absence of reciprocal AFF1-KMT2A fusions may con-
tribute to differential clinical outcomes, as shown recently by Agras-Doblas and Bueno et al. in a large analysis of infant ALL specimens from the European co-operative groups’ Interfant-99 and -06 trials47-49 and reviewed by Slany.20
Several groups have hypothesized that addition of tar- geted inhibitors to frontline chemotherapy could decrease relapse risk and improve survival for infants with ALL, as has been shown with tyrosine kinase inhibitors (TKI) for patients with BCR-ABL1-rearranged (Ph+) ALL. Unfortunately, addition of the FMS-like tyrosine kinase 3
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Figure 5. Entospletinib potently inhibits in vivo acute lymphoblastic leukemia (ALL) proliferation with enhanced efficacy in combination with chemotherapy. Animals engrafted with KMT2A-R (ALL3103, ALL135MR, ALL142MR, ALL150MD, ALL3113) or non-KMT2A-R (ALL132GD, ALL185GD, ALL83GD) ALL were treated with control chow, 0.05% ENTO chow, 0.1 mg/kg vincristine (VCR) IP weekly, or both ENTO and VCR. Human CD45+CD19+ ALL cells were quantified by flow cytometry in end-of-study murine spleens and peripheral blood. (A) Combined ENTO+VCR significantly inhibited leukemia proliferation with enhanced activity compared to ENTO and/or VCR monotherapies in KMT2A-R PDX models without RAS mutations. (B) Conversely, potent VCR effects were observed in KMT2A-R ALL PDX models with NRAS or KRAS mutations without additional activity of combination treatment. (C) A KMT2A-R RAS wild-type ALL PDX model was sensitive to ENTO and not to VCR. (D) No treatment effects of ENTO or VCR were observed in a non-KMT2A-R KRAS-mutant ALL PDX model, while single-agent activity of VCR and/or ENTO and enhanced effects of combination treatment were detected in (E) non-KMT2A-R RAS wild-type PDX control models with other ALL-associated translocations. Data were analyzed by one-way ANOVA with Tukey’s post-test for multiple comparisons. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.
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haematologica | 2021; 106(4)