Venetoclax induces rapid elimination of <i>NPM1</i> mutant measurable residual disease in combination with low‐intensity chemotherapy in acute myeloid leukaemia

Tiong, Ing Soo; Dillon, Richard; Ivey, Adam; Teh, Tse‐Chieh; Nguyen, Phillip; Cummings, Nicholas James; Taussig, David; Latif, Annie‐Louise; Potter, Nicola; Runglall, Manohursingh; Russell, Nigel H.; Raj, Kavita; Schwarer, Anthony P.; Fong, Chun Yew; Grigg, Andrew; Wei, Andrew H.

doi:10.1111/bjh.16722

Cited by 66 publications

(76 citation statements)

References 15 publications

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“…Pt.38 had a clearance of IDH1 at relapse, supporting the possible enrichment of other venetoclax‐resistant clones during treatment. Though NPM1 mutated patients are sensitive to venetoclax treatment, 29 our NPM1 + Pt.14 and Pt.32 had progressive extramedullary AML during venetoclax salvage.…”

Section: Discussionmentioning

confidence: 66%

Outcomes of relapsed or refractory acute myeloid leukemia patients failing venetoclax‐based salvage therapies

Žučenka

Pileckyte

Trociukas

et al. 2020

European J of Haematology

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Objectives and methods We conducted a retrospective analysis to evaluate the outcomes of 28 heavily pretreated (median 3 (2‐6) treatment lines, sixteen (57%) allotransplanted) relapsed/refractory acute myeloid leukemia patients who had failed salvage venetoclax‐based therapies. Results The median age was 59 years (20‐80), 20 patients (71%) had ECOG 2‐4 status, and 18 patients (64%) were stratified to European Leukemia Network 2017 adverse risk group. The most common mutations were ASXL1 (21%), RUNX1 (18%), FLT3 ITD/TKD (18%), PTPN11 (15%), NRAS/KRAS (15%), and WT1 (15%). Twenty‐two patients (79%) received different post‐venetoclax salvage therapies with the overall response rate of 23% (complete remission + morphological leukemia‐free state). Three of six (50%) patients achieved complete remissions after therapy with venetoclax + actinomycin D ± low‐dose cytarabine. The remaining 6 patients did not receive any further salvage treatment mainly due to poor general condition. The median overall survival was 3.9 months for all patients (4.3 for those receiving post‐venetoclax salvage vs 1.3 months receiving palliative care alone, P < .001). Conclusions Though the remission rate and survival of patients failing venetoclax are poor, a small proportion of these R/R AML patients may still respond to cautious intensification of chemotherapy with venetoclax.

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Section: Discussionmentioning

confidence: 66%

Outcomes of relapsed or refractory acute myeloid leukemia patients failing venetoclax‐based salvage therapies

Žučenka

Pileckyte

Trociukas

et al. 2020

European J of Haematology

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“…These trials are mostly phase I/II studies that include CR based on MRD (CR MRD ) as the primary endpoint of their study ( 130 – 137 ). Recently, Tiong and colleagues published a retrospective study about venetoclax that could make patients with low-intensity chemotherapy achieve durable CR mrd status ( 138 ). The change in MRD levels ( 139 – 143 ) or the proportion of patients achieving MRD negativity ( 144 – 149 ) are also frequent primary endpoints of studies.…”

Section: Employment Of Measurable Residual Disease In the Clinicmentioning

confidence: 99%

MRD Tailored Therapy in AML: What We Have Learned So Far

et al. 2021

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Acute myeloid leukemia (AML) is a heterogeneous clonal disease associated with a dismal survival, partly due to the frequent occurrence of relapse. Many patient- and leukemia-specific characteristics, such as age, cytogenetics, mutations, and measurable residual disease (MRD) after intensive chemotherapy, have shown to be valuable prognostic factors. MRD has become a rich field of research where many advances have been made regarding technical, biological, and clinical aspects, which will be the topic of this review. Since many laboratories involved in AML diagnostics have experience in immunophenotyping, multiparameter flow cytometry (MFC) based MRD is currently the most commonly used method. Although molecular, quantitative PCR based techniques may be more sensitive, their disadvantage is that they can only be applied in a subset of patients harboring the genetic aberration. Next-generation sequencing can assess and quantify mutations in many genes but currently does not offer highly sensitive MRD measurements on a routine basis. In order to provide reliable MRD results, MRD assay optimization and standardization is essential. Different techniques for MRD assessment are being evaluated, and combinations of the methods have shown promising results for improving its prognostic value. In this regard, the load of leukemic stem cells (LSC) has also been shown to add to the prognostic value of MFC-MRD. At this moment, MRD after intensive chemotherapy is most often used as a prognostic factor to help stratify patients, but also to select the most appropriate consolidation therapy. For example, to guide post-remission treatment for intermediate-risk patients where MRD positive patients receive allogeneic stem cell transplantation and MRD negative receive autologous stem cell transplantation. Other upcoming uses of MRD that are being investigated include: selecting the type of allogeneic stem cell transplantation therapy (donor, conditioning), monitoring after stem cell transplantation (to allow intervention), and determining drug efficacy for the use of a surrogate endpoint in clinical trials.

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“…In a noteworthy small cohort study of patients with AML who carried the NPM1 mutation ( n = 12) and had either relapsed or remained with persistent molecular MRD, 92% achieved MRD negativity after one or two cycles of venetoclax with HMAs or LDAC. 20 …”

Section: Venetoclax-based Therapy For Relapsed/refractory Amlmentioning

confidence: 99%

Venetoclax-containing regimens in acute myeloid leukemia

Aldoss

Pullarkat

Stein

2021

Therapeutic Advances in Hematology

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Venetoclax in combination with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) has demonstrated exceptional activity in elderly and unfit patients with newly diagnosed acute myeloid leukemia (AML). Notably, the safety profile of venetoclax-based induction regimens was favorable, with a low rate of early treatment-related mortality, even in frail study participants. Thus, the introduction of venetoclax has transformed the landscape of AML therapy in elderly patients. Given these promising results, venetoclax in combination with other agents is now being studied as a frontline therapy in younger patients with AML, as well as in relapsed/refractory AML patients. Here, we review clinical data for venetoclax-based therapy in AML, both from prospective as well as retrospective studies, and highlight ongoing novel studies of venetoclax-containing regimens and discuss future research directions.

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Venetoclax induces rapid elimination of NPM1 mutant measurable residual disease in combination with low‐intensity chemotherapy in acute myeloid leukaemia

Cited by 66 publications

References 15 publications

Outcomes of relapsed or refractory acute myeloid leukemia patients failing venetoclax‐based salvage therapies

Outcomes of relapsed or refractory acute myeloid leukemia patients failing venetoclax‐based salvage therapies

MRD Tailored Therapy in AML: What We Have Learned So Far

Venetoclax-containing regimens in acute myeloid leukemia

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