A venetoclax and azacitidine <scp>bridge‐to‐transplant</scp> strategy for NPM1‐<scp>mutated</scp> acute myeloid leukaemia in molecular failure

Sartor, C.; Brunetti, L.; Audisio, E.; Cignetti, A.; Zannoni, L.; Cristiano, G.; Nanni, J.; Ciruolo, R.; Zingarelli, F.; Ottaviani, E.; Patuelli, A.; Bandini, L.; Forte, D.; Sciabolacci, S.; Cardinali, V.; Papayannidis, C.; Cavo, M.; Martelli, M. P.; Curti, A.

doi:10.1111/bjh.18887

Cited by 12 publications

(8 citation statements)

References 40 publications

(135 reference statements)

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“…Here, we report molecular complete remission rates of 56% to 79% (depending on the type of failure), and this is consistent with previous smaller studies in the molecular failure setting reporting MRD negativity in 82% to 92% of patients. 13 , 14 MRD negativity rates were similar to those reported with SC, despite the much higher toxicity and health care resource use associated with the latter. 9 , 20 We found a rapid response to venetoclax, with best response achieved in more than half of the patients before the third cycle, consistent with previous literature.…”

Section: Discussionsupporting

confidence: 72%

“…In the RELAZA2 trial, 17 of 32 patients (55%) with NPM1 mut AML treated with azacitidine at MRD relapse achieved MRD negativity. 12 More recently, 2 retrospective studies using venetoclax and azacitidine or low-dose cytarabine (LDAC) in this situation reported MRD negativity in 11 of 12 (92%) and 9 of 11 patients (82%), 13 , 14 and a number of patients in both studies subsequently received an allogeneic transplant. Because of the convenience and low toxicity of these regimens compared with salvage chemotherapy (SC) and the lack of alternatives, off-label use of venetoclax combinations in this situation has become common in several European countries.…”

Section: Introductionmentioning

confidence: 99%

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Venetoclax–based low intensity therapy in molecular failure of NPM1-mutated AML

Jimenez-Chillon,

Othman,

Taussig

et al. 2024

Blood Advances

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Molecular failure in NPM1 mutated AML inevitably progresses to frank relapse if untreated. Recently published small case series show that venetoclax combined with low dose cytarabine or azacitidine can reduce or eliminate measurable residual disease (MRD). Here we report an international multicentre cohort of 79 patients treated for molecular failure with venetoclax combinations and report an overall molecular response (≥1-log reduction in MRD) in 66/79 (84%) and MRD negativity in 56/79 (71%). 18/79 (23%) patients required hospitalisation and no deaths were reported during treatment. 41 patients were bridged to allogeneic transplant with no further therapy and 25/41 were MRD negative assessed by RT-qPCR before transplant. Overall survival (OS) for the whole cohort at 2 years was 67%, event-free survival (EFS) was 45% and in responding patients there was no difference in survival in those who received a transplant using time-dependent analysis. Presence of FLT3-ITD mutation was associated with a lower response rate (64 vs. 91%, p<0.01), worse OS (HR 2.50, 95% CI 1.06-5.86, p=0.036) and EFS (HR 1.87, 95% CI 1.06-3.28, p=0.03). 18/35 non-transplanted patients became MRD negative and stopped treatment after a median of 10 months, with 2-year molecular relapse free survival of 62% from the end of treatment. Venetoclax based low intensive chemotherapy is a potentially effective treatment for molecular relapse in NPM1 mutated AML, either as a bridge to transplant or as definitive therapy.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Venetoclax–based low intensity therapy in molecular failure of NPM1-mutated AML

Jimenez-Chillon,

Othman,

Taussig

et al. 2024

Blood Advances

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“…The combination of venetoclax and low-dose chemotherapy has demonstrated remarkable efficacy in NPM1-mutated AML, with CR/CRi rates of 93% in firstline treatments and MRD negativity reached in 4/4 patients monitored [36]. In patients treated at MRD relapse, MRD negativity rates are between 78 and 92% [37][38][39]. These good results in favourable-risk patients (particularly NPM1-mutated FLT3 wild type) [31,40,41] have motivated an ongoing clinical trial in this subgroup comparing intensive chemotherapy (DA + GO, DA and 2 HDAC consolidations) with 12 cycles of LDAC+VEN (EudraCT: 2020-000,273-24) [42].…”

Section: Low-dose Chemotherapymentioning

confidence: 99%

“…Multiple studies have concluded that pre-transplant positive MRD (assessed by multiparameter flow cytometry or RT-qPCR) is independently associated with a higher relapse incidence and lower survival [80][81][82][83][84]. There is a growing evidence that intervening MRD prior to haematological relapse may lead to better outcomes [37,39,[85][86][87][88]. Some studies have evaluated the treatment of molecular failure (monitored by RT-qPCR for fusion genes or NPM1) including some patients prior to allo-HSCT [85].…”

Section: Eradication Of Mrd Prior To Allogeneic Transplantationmentioning

confidence: 99%

“…Recent evidence proves that detectable MRD in NPM1 mut AML can be successfully cleared with venetoclax combined with low-intensity chemotherapy (AZA, decitabine, or LDAC) [37,87,88]. In recent Optimal Post-Remission Therapy in AML Acta Haematol 2024;147:148-159 DOI: 10.1159/000535457 reports, patients treated for MRD failure achieved MRD negativity rates of 71-92% [37,85,87], with venetoclax combinations being an interesting option as a bridge to allo-HSCT in molecular failure of NPM1 mut AML [85,87,88].…”

Section: Eradication Of Mrd Prior To Allogeneic Transplantationmentioning

confidence: 99%

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Optimal Post-Remission Consolidation Therapy in Patients with AML

Jimenez-Chillon,

Dillon,

Russell

2023

Acta Haematol

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Background: Despite recent advances, 40–85% of patients with acute myeloid leukaemia (AML) achieve complete remission after intensive chemotherapy. However, without optimal treatment after remission, the risk of relapse remains high. Summary: A variable number of consolidation cycles consisting of intermediate doses of cytarabine are the most commonly used regimens in low-intermediate-risk AML, while patients at higher risk of relapse should consolidate response by proceeding to HSCT. Different post-consolidation (maintenance therapies) have demonstrated their benefit in prolonging relapse-free survival, and others are still under investigation. Careful consideration should be given to which patients benefit most from each of these interventions, considering that the risk of relapse is dynamic. Key Messages: Patients consolidated with chemotherapy should receive either 2 courses of HDAC or no more than 3–4 cycles of IDAC with dose reduction in patients over 60 years. Patients with mutated FLT3 AML benefit from post-consolidation maintenance with FLT3 inhibitors, and selected patients not fit for adequate consolidation may benefit from CC-468 maintenance. Patients at higher risk of relapse should proceed to allogeneic SCT as soon as possible, opting for a more intensive conditioning in patients younger than 55 years. However, autologous HSCT may still have role in favourable-risk MRD-negative AML. Multiple treatment options targeting MRD are emerging, either as definitive treatment or as a bridge to allogeneic transplantation, and are likely to become increasingly relevant.

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NPM1‐mutated acute myeloid leukemia: New pathogenetic and therapeutic insights and open questions

Falini

2023

American J Hematol

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The nucleophosmin (NPM1) gene encodes for a multifunctional chaperone protein that is localized in the nucleolus but continuously shuttles between the nucleus and cytoplasm. NPM1 mutations occur in about one‐third of AML, are AML‐specific, usually involve exon 12 and are frequently associated with FLT3‐ITD, DNMT3A, TET2, and IDH1/2 mutations. Because of its unique molecular and clinico‐pathological features, NPM1‐mutated AML is regarded as a distinct leukemia entity in both the International Consensus Classification (ICC) and the 5th edition of the World Health Organization (WHO) classification of myeloid neoplasms. All NPM1 mutations generate leukemic mutants that are aberrantly exported in the cytoplasm of the leukemic cells and are relevant to the pathogenesis of the disease. Here, we focus on recently identified functions of the NPM1 mutant at chromatin level and its relevance in driving HOX/MEIS gene expression. We also discuss yet controversial issues of the ICC/WHO classifications, including the biological and clinical significance of therapy‐related NPM1‐mutated AML and the relevance of blasts percentage in defining NPM1‐mutated AML. Finally, we address the impact of new targeted therapies in NPM1‐mutated AML with focus on CAR T cells directed against NPM1/HLA neoepitopes, as well as XPO1 and menin inhibitors.

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A venetoclax and azacitidine bridge‐to‐transplant strategy for NPM1‐mutated acute myeloid leukaemia in molecular failure

Cited by 12 publications

References 40 publications

Venetoclax–based low intensity therapy in molecular failure of NPM1-mutated AML

Venetoclax–based low intensity therapy in molecular failure of NPM1-mutated AML

Optimal Post-Remission Consolidation Therapy in Patients with AML

NPM1‐mutated acute myeloid leukemia: New pathogenetic and therapeutic insights and open questions

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