https://orcid.org/0000-0001-5404-6483
In this issue of Blood, Montefiori et al1 describe the preclinical evaluation of a novel targeted treatment for acute leukemia characterized by aberrantly high BCL11B expression and FLT3-ITD positivity. In addition to T-cell acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), this combination is also found in a rare group of acute leukemias of ambiguous lineage (ALALs) including acute undifferentiated leukemia and mixed phenotype leukemia (MPAL).2 Although ALL protocols have been reported to achieve overall survival rates of 80% and higher for CD19-positive ALALs, there are currently no agreed protocols established for the treatment of CD19-negative ALALs.3
In their investigation of acute leukemias with aberrant BCL11B (BCL11B-a) expression, the authors observed high expression levels of the tyrosine receptor kinase gene FLT3 and elevated transcript levels of and dependency on the antiapoptotic protein BCL2. In fact, these leukemias frequently carry the FLT3-ITD mutation leading to a constitutively-activated kinase. Based on these findings, the authors chose 3 patient-derived xenograft (PDX) models of BCL11B comprising a T-ALL, MPAL and AML and examined their respective sensitivity toward the FLT3 inhibitor gilteritinib and the BCL2 inhibitor venetoclax, 2 agents regularly used in the treatment of AML and ALL. Although responses to venetoclax or gilteritinib monotherapy varied, all 3 PDXs responded strongly to combined treatment with venetoclax and gilteritinib (VenGilt). These findings are in line with prior studies in FLT3-mutated AML showing that gilteritinib reduces MCL1 protein levels via inhibition of ERK activity. The combination with BCL2 inhibition by venetoclax increases the release of the proapoptotic protein BIM (encoded by the gene BCL2L11), thereby promoting apoptosis.4,5
However, despite strong initial reductions in leukemic burden, 2 of the 3 PDXs relapsed after treatment, suggesting the persistence of a small therapy-resistant leukemic subpopulation. These relapsing cells retained FLT3-ITD positivity but displayed increased dependence on the antiapoptotic protein MCL1, while remaining sensitive to VenGilt in vitro. Inspection of global transcriptomic changes during and after treatment revealed an initial repression of DNA damage and MYC-regulated pathways consistent with the observed cell cycle arrest. However, these transcriptomic alterations were transient and only minor long-term changes in global gene expression were found after the end of treatment. These combined data support a model where VenGilt eliminates the leukemic bulk but spares a self-renewing leukemic subpopulation. This population might be quiescent or at least not actively proliferating. Furthermore, the virtual lack of transcriptional changes strongly suggests that this population resides in a niche protecting it against VenGilt actions.6
The persistence of a resistant or protected leukemic-cell population raises critical questions about how to achieve their complete eradication and how to combine VenGilt with other treatments for a curative therapy. One interesting observation was that the VenGilt combination did not synergize with more conventional chemotherapy agents but also did not show substantial antagonism, leaving the possibility of integrating of VenGilt into existing chemotherapy regimens for ALALs. Whether VenGilt should be combined with ALL- or AML-based chemotherapy protocols and whether it is best used concurrently or sequentially, remains to be determined.3 Alternatively, VenGilt might also have a role in sufficiently debulking disease in relapsing or refractory cases to enable curative stem cell transplantation, as is currently clinically explored with a range of targeted treatments including the VenGilt combination.7,8 Another question that can be preclinically addressed is whether VenGilt exerts comparable efficacy across other ALALs beyond FLT3-ITD–positive BCL11B-a leukemias.
Despite these open questions, this study represents a significant step toward a targeted therapy for acute leukemias with aberrant BCL11B expression. Further preclinical and clinical studies will clarify the therapeutic potential and optimal use of this combination in BCL11B-a and related ALALs.
Conflict-of-interest disclosure: O.H. declares research support from Kura, Roche, and Syndax.
