Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia

Chyla, Brenda; Daver, Naval; Doyle, Kelly; McKeegan, Evelyn; Huang, Xin; Ruvolo, Vivian; Wang, Zixing; Chen, Ken; Souers, Andrew J.; Leverson, Joel D.; Potluri, Jalaja; Boghaert, Erwin R.; Bhathena, Anahita; Konopleva, Marina; Popovic, Relja

doi:10.1002/ajh.25146

Cited by 126 publications

(122 citation statements)

References 6 publications

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“…Moreover, drug synergy from combining BCL2 and MCL1 inhibitors can be achieved across all subtypes and mutational profiles of MDS in this model, even in the presence of RAS family mutations that are thought to confer resistance to VEN monotherapy (eg. CBL and PTPN11 in this cohort) [14][15][16][17][18] . 38 and in vivo 11 is limited at clinically meaningful doses.…”

Section: Discussionmentioning

confidence: 70%

“…As expected, we observed an increased number of SF3B1 mutations in the lower blast count MDS patient samples (MDS-RS) 13 . RAS-family mutants, particularly PTPN11-mutated AML have previously been shown to connote resistance to VEN [14][15][16][17][18] . In this small cohort, one of 2 PTPN11 mutant MDS samples, and 2/2 CBL mutant samples were completely resistant to BCL2 inhibition (MDS033, MDS005 and MDS031, respectively).…”

Section: Mds Subtypes Are Differentially Sensitive To Bcl2 Inhibitionmentioning

confidence: 99%

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MCL1 dependence across MDS subtypes and dual inhibition of MCL1 and BCL2 in MISTRG6 mice

Fischer

Song

Gbyli

et al. 2020

Preprint

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Treatment for myelodysplastic syndromes (MDS) remains insufficient due to clonal heterogeneity and clinical complexity. Dysregulation of apoptosis is observed across MDS subtypes regardless of mutations and represents an attractive therapeutic opportunity. Venetoclax (VEN), a selective inhibitor of anti-apoptotic protein B-cell lymphoma-2 (BCL2), has yielded impressive responses in older patients with acute myeloid leukemia (AML). BCL2 family antiapoptotic proteins BCL-X L and induced myeloid cell leukemia 1 (MCL1) are implicated in leukemia survival, and upregulation of MCL1 is seen in VEN-resistant AML and MDS. Here, we determined the in vitro sensitivity of MDS patient samples to selective inhibitors of BCL2, BCL-X L and MCL1. While VEN response positively correlated with increasing blast counts, all MDS subtypes responded to the MCL1 inhibitor, S63845. Treatment with combined VEN+S63845 was synergistic in all MDS subtypes and reduced MDS engraftment in MISTRG6 mice supporting the pursuit of clinical trials with combined BCL2+MCL1 inhibition in MDS.

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Section: Discussionmentioning

confidence: 70%

Section: Mds Subtypes Are Differentially Sensitive To Bcl2 Inhibitionmentioning

confidence: 99%

MCL1 dependence across MDS subtypes and dual inhibition of MCL1 and BCL2 in MISTRG6 mice

Fischer

Song

Gbyli

et al. 2020

Preprint

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“…Chyla et al have reported mutations in FLT3 and/or PTPN11 as possible mechanisms of intrinsic and acquired resistance to venetoclax, with 6 of 32 patients with relapsed or refractory AML carrying either of these mutations refractory to single-agent venetoclax in a phase 2 study and an additional 5 patients developing them at the time of relapse. 49 The same authors then investigated the efficacy of quizartinib, a FLT3 inhibitor, in combination with venetoclax in a FLT3-mutated xenograft mouse model and observed more durable responses with the use of both agents as compared with monotherapy. It is important to note that previous studies had shown that FLT3-ITD or PTPN11 mutations could enhance the expression of other members of the BCL-2 family, including BCL-XL and MCL-1, providing a potential explanation for the resistance to venetoclax.…”

Section: Novel Venetoclax-based Combinations and Future Directionsmentioning

confidence: 99%

“…Supporting this preclinical finding, 4 of 6 patients with relapsed refractory AML who responded to single-agent venetoclax in a phase 2 study carried an IDH1/2 mutation, and 12 of 16 patients with IDH1/2 mutation had a decrease in bone marrow blasts. 49,59 Furthermore, 18 of the 82 patients enrolled in the above-mentioned clinical trial investigating LDAC and venetoclax had IDH1/2 mutations. The CR/CRi for this group was 72% compared with a CR/CRi rate of 54% in the overall study population.…”

Section: Novel Venetoclax-based Combinations and Future Directionsmentioning

confidence: 99%

Venetoclax for AML: changing the treatment paradigm

Pollyea

Amaya

Strati³

et al. 2019

Blood Advances

137

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Venetoclax is a specific B-cell lymphoma-2 (BCL-2) inhibitor that can restore activation of apoptosis in malignancies, the survival of which depends on dysregulation of this pathway.Preclinical data, using various model systems including cell lines and patient samples, suggested targeting BCL-2 could be a successful therapeutic strategy in patients with acute myeloid leukemia (AML). As predicted by this work, the use of venetoclax in the clinical setting has resulted in promising outcomes for patients with this disease. Although venetoclax showed limited activity as a single agent in the relapsed disease setting, recent studies have shown that when combined with a backbone therapy of a hypomethylating agent or low-dose cytarabine, high response rates with encouraging remission durations for older patients with newly diagnosed AML who were not candidates for intensive induction chemotherapy were observed. Furthermore, venetoclax-based therapies allowed for rapid responses and were able to effectively target the leukemia stem cell population. Here we review the preclinical data that supported the development of venetoclax in AML, as well as the results of the promising clinical trials. Preclinical development The intrinsic apoptotic pathwayThe B-cell lymphoma-2 (BCL-2) family includes multiple proteins sharing BCL-2-like homology domains 1-4 (BH1-BH4), each playing a specific role in the intrinsic apoptotic pathway. The BCL-2 family proteins' roles can be divided into 4 main functions: suppressors (BCL-2, BCL-XL, BCL-W, BCL2-A1, and MCL-1), activators (BIM and PUMA), effectors (BAX and BAK), and sensitizers (NOXA). 8,9 Suppressors inhibit the activity of activators and effectors, preventing apoptosis, whereas sensitizers inhibit suppressors, releasing the brake on activators and effectors. The latter oligomerize, creating

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“…A retrospective study analyzed response rate after treatment with venetoclax plus HMA among 33 r/r AML (13 of them had prior allogeneic HSCT); 15 patients reached complete remission or complete remission with incomplete hematologic recovery, 8 of them were MRD negative by flow cytometry but no molecular data after therapy were reported. 5 Chyla et al 9 reported 10 AML cases with IDH1/2 mutations treated with venetoclax as monotherapy who remained positive for the mutation by next generation sequencing.…”

Section: Supporting Informationmentioning

confidence: 99%

Venetoclax plus decitabine induced complete remission with molecular response in acute myeloid leukemia relapsed after hematopoietic stem cell transplantation

et al. 2018

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Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia

Cited by 126 publications

References 6 publications

MCL1 dependence across MDS subtypes and dual inhibition of MCL1 and BCL2 in MISTRG6 mice

MCL1 dependence across MDS subtypes and dual inhibition of MCL1 and BCL2 in MISTRG6 mice

Venetoclax for AML: changing the treatment paradigm

Venetoclax plus decitabine induced complete remission with molecular response in acute myeloid leukemia relapsed after hematopoietic stem cell transplantation

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