Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia

Abstract

Key Points• Venetoclax demonstrates potent in vitro and in vivo single-agent activity in MLLrearranged ALL xenografts.• Clinically efficacious BH3-mimetic therapy for other high-risk ALL subtypes is likely to require concurrent BCL-2 and BCL-X L inhibition.The clinical success of the BCL-2-selective BH3-mimetic venetoclax in patients with poor prognosis chronic lymphocytic leukemia (CLL) highlights the potential of targeting the BCL-2-regulated apoptotic pathway in previously untreatable lymphoid malignancies. By selectively inhibiting BCL-2, venetoclax circumvents the dose-limiting, BCL-X L -mediated thrombocytopenia of its less selective predecessor navitoclax, while enhancing efficacy in CLL. We have previously reported the potent sensitivity of many high-risk childhood acute lymphoblastic leukemia (ALL) xenografts to navitoclax. Given the superior tolerability of venetoclax, here we have investigated its efficacy in childhood ALL. We demonstrate that in contrast to the clear dependence of CLL on BCL-2 alone, effective antileukemic activity in the majority of ALL xenografts requires concurrent inhibition of both BCL-2 and BCL-X L . We identify BCL-X L expression as a key predictor of poor response to venetoclax and demonstrate that concurrent inhibition of both BCL-2 and BCL-X L results in synergistic killing in the majority of ALL xenografts. A notable exception is mixed lineage leukemia-rearranged infant ALL, where venetoclax largely recapitulates the activity of navitoclax, identifying this subgroup of patients as potential candidates for clinical trials of venetoclax in childhood ALL. Conversely, our findings provide a clear basis for progressing navitoclax into trials ahead of venetoclax in other subgroups. (Blood. 2016;128(10):1382-1395

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

“…18 By selecting 8 BCP-ALL and 19 T-ALL samples, we confirmed improved survival of most of these samples on MSCs compared with cell suspension cultures (supplemental Figure 5A-B). 50 values from coculture and monoculture were significantly correlated for 22 drugs tested under both conditions (Spearman r 5 0.64; P , .001), there were several discrepancies in drugs of interest. We observed a significant correlation of drug activity in cocultures with in vivo drug responses (supplemental Figure 5D-F), most evident for venetoclax (supplemental Figure 5D), docetaxel and dasatinib, and to a lesser extent for cytarabine (supplemental Figure 5E).…”

“…Our findings are confirmed independently by others who showed strong venetoclax activity in MLL-rearranged ALL. 50 Supportive information using other biomarkers would be desirable for monitoring response in clinical trials. The BCL2:BCL-XL expression ratio was proposed as a predictive biomarker for venetoclax response, 44 but our results and other data 50 suggest that this approach may not detect all cases.…”

“…We detected unexpected responses to the ABL1/SRC inhibitor dasatinib (IC 50 ,100 nM) in 12 T-ALL patients (30%) without the typical ABL1 kinase translocation ( Figure 6A). Importantly, these For personal use only.…”

“…As expected, the response to oral administration of venetoclax in vivo correlated with in vitro activity for 3 T-ALL patients with strong, intermediate, and low venetoclax sensitivity. Single-agent venetoclax treatment delayed leukemia progression significantly in the patient with strong in vitro sensitivity (hazard ratio, 20; IC 50 ,1 nM; low E max ; treated vs untreated P , .005) compared with patients with low IC 50 (,100 nM) but higher E max (HR, 0.07; treated vs untreated P , .005) or high IC 50 (.1 mM). In addition, complete response was detected when treating the T-VHR-03 case in mice with high leukemia burden (75% engraftment; supplemental Figure 8).…”

“…We profiled PDX samples from 12 patients with relapsed ALL refractory to salvage therapy (RR) who did not achieve the second or third remission required for inclusion in early clinical trials ( Figure 4A) and primary leukemia cells from 5 patients with refractory disease in real time prospectively ( Figure 4B; Table 1). Figure 4 shows IC 50 values for a selection of therapeutic agents in samples of interest against those obtained for all other samples on our platform (gray). RR ALL samples were generally more resistant to agents used for induction in ALL such as dexamethasone (10 of 12 patients), cytarabine (9 of 12 patients), and doxorubicin (9 of 12 patients) compared with other diagnostic and relapse ALL patients ( Figure 4A).…”