Successful treatment of a chemotherapy‐resistant t(17;19) paediatric <scp>ALL</scp> with a combination of inotuzumab, venetoclax and navitoclax

Gottardi, Francesca; Baccelli, Francesco; Leardini, Davide; Battista, Antonia Di; Castellucci, Paolo; D’Amico, Domenico; Serravalle, Salvatore; Bertuccio, Salvatore Nicola; Messelodi, Daria; Prete, Arcangelo; Masetti, Riccardo

doi:10.1111/bjh.18936

Cited by 4 publications

(1 citation statement)

References 20 publications

(31 reference statements)

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“…The maximum tolerated dose of idasanutlin is still under investigation in pediatric patients (NCT04029688). The TCF3::HLF -rearranged PDX#4 xenograft — an almost universally-fatal, rare ALL subtype typically associated with relapse and death within two years from diagnosis [ 46 , 56 , 57 ] — exhibited substantially decreased extramedullary leukemic growth in response to combination therapy but not total leukemia burden at these subclinical plasma concentrations. We further identified activation of the RAS/MAPK signaling axis as a potential mediator of acquired in vivo resistance to the drug combination in this model; a mechanism described previously in studies of venetoclax in AML [ 53 ] but not yet reported in ALL.…”

Section: Discussionmentioning

confidence: 99%

Combination p53 activation and BCL-xL/BCL-2 inhibition as a therapeutic strategy in high-risk and relapsed acute lymphoblastic leukemia

Bell,

Blair,

Jepson Gosling

et al. 2024

Leukemia

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Due to the rarity of TP53 mutations in acute lymphoblastic leukemia (ALL), p53 re-activation by antagonism of the p53-MDM2 interaction represents a potential therapeutic strategy for the majority of ALL. Here, we demonstrate the potent antileukemic activity of the MDM2 antagonist idasanutlin in high-risk and relapsed ex vivo coculture models of TP53 wildtype ALL (n = 40). Insufficient clinical responses to monotherapy MDM2 inhibitors in other cancers prompted us to explore optimal drugs for combination therapy. Utilizing high-throughput combination screening of 1971 FDA-approved and clinically advanced compounds, we identified BCL-xL/BCL-2 inhibitor navitoclax as the most promising idasanutlin combination partner. The idasanutlin-navitoclax combination was synergistically lethal to prognostically-poor, primary-derived and primary patient blasts in ex vivo coculture, and reduced leukemia burden in two very high-risk ALL xenograft models at drug concentrations safely attained in patients; in fact, the navitoclax plasma concentrations were equivalent to those attained in contemporary “low-dose” navitoclax clinical trials. We demonstrate a preferential engagement of cell death over G1 cell cycle arrest, mechanistically implicating MCL-1-binding pro-apoptotic sensitizer NOXA. The proposed combination of two clinical-stage compounds independently under clinical evaluation for ALL is of high clinical relevance and warrants consideration for the treatment of patients with high-risk and relapsed ALL.

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Section: Discussionmentioning

confidence: 99%

Combination p53 activation and BCL-xL/BCL-2 inhibition as a therapeutic strategy in high-risk and relapsed acute lymphoblastic leukemia

Bell,

Blair,

Jepson Gosling

et al. 2024

Leukemia

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Multiple drugs

2023

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Venetoclax: a new player in the treatment of children with high-risk myeloid malignancies?

Masetti,

Baccelli,

Leardini

et al. 2024

Blood Advances

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Venetoclax selectively inhibits BCL-2 and restores apoptotic signaling of hematological malignant cells. Venetoclax in combination with hypomethylating and low-dose cytotoxic agents has revolutionized the management of elderly patients affected by acute myeloid leukemia (AML), as well as that of patients unfit to receive intensive chemotherapy. In a single phase 1 pediatric trial conducted on relapsed/refractory AML, the combination of venetoclax with intensive chemotherapy was shown to be safe and yielded promising response rates. In addition, several retrospective studies in children with AML reported that venetoclax combined with hypomethylating agents and cytotoxic drugs appears a safe and efficacious bridge to transplant. Promising results on the use of venetoclax combinations in advanced myelodysplastic syndromes (MDS) and therapy-related MDS/AML have also been reported in small case series. This review summarizes the available current knowledge about venetoclax use in childhood high-risk myeloid neoplasms, discussing a possible integration of BCL-2 inhibition in the current treatment algorithm of these children. It also focuses on specific genetic subgroups potentially associated with response in preclinical and clinical studies.

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Successful treatment of a chemotherapy‐resistant t(17;19) paediatric ALL with a combination of inotuzumab, venetoclax and navitoclax

Cited by 4 publications

References 20 publications

Combination p53 activation and BCL-xL/BCL-2 inhibition as a therapeutic strategy in high-risk and relapsed acute lymphoblastic leukemia

Combination p53 activation and BCL-xL/BCL-2 inhibition as a therapeutic strategy in high-risk and relapsed acute lymphoblastic leukemia

Multiple drugs

Venetoclax: a new player in the treatment of children with high-risk myeloid malignancies?

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