A Prospective Phase 2 Study of Venetoclax and Low Dose Ara-C (VALDAC) to Target Rising Molecular Measurable Residual Disease and Early Relapse in Acute Myeloid Leukemia

Hiwase, Devendra; Abro, Emad Uddin; Bajel, Ashish; Palfreyman, Emma; Loo, Sun; Fleming, Shaun; Fong, Chun Yew; Teh, Tse‐Chieh; Ivey, Adam; Wei, Andrew H.

doi:10.1182/blood-2022-163041

Cited by 9 publications

(5 citation statements)

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“… 20 In the VALDAC study, patients received LDAC and venetoclax after MRD or oligoblastic relapse (defined as <15% bone marrow blasts); of those with NPM1 mut AML, 11 of 20 patients (55%) with MRD relapse, and 6 of 8 with oligoblastic relapse achieved MRD negativity. 21 …”

Section: Discussionmentioning

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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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: Discussionmentioning

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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“…Single agent azaciditine was able to achieve molecular responses in 58% of patients in a prospective study, but only 43% in the subset with FLT3 -ITD mutations [ 17 ]. Finally venetoclax combinations have shown promise, with molecular responses in 69% in the prospective Phase 2 VALDAC study [ 18 ] and over 80% in case series [ 28 , 29 ]. However, FLT3 mutations are a known resistance mechanism when venetoclax is used in the frontline setting [ 21 ], and indeed 43% of patients who relapsed in the VALDAC study had a detectable FLT3 -ITD.…”

Section: Discussionmentioning

confidence: 99%

“…Patients destined to relapse can be reliably identified by rising levels of MRD (here called molecular failure) and this provides a potential window for pre-emptive intervention [ 11 – 13 ]. There is a growing body of evidence that intervening prior to haematological relapse may be associated with improved outcomes [ 14 – 18 ], but the optimal treatment in this situation remains undefined. Proceeding directly to transplant with detectable MRD is associated with very poor outcomes in patients with FLT3 mutated disease [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML

Othman,

Potter,

Mokretar

et al. 2023

Leukemia

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Patients with FLT3-mutated AML have a high relapse rate and suboptimal outcomes. Many have co-mutations suitable for measurable residual disease (MRD) monitoring by RT-qPCR and those destined to relapse can be identified by high or rising levels of MRD, called molecular failure. This provides a window for pre-emptive intervention, but there is little evidence to guide treatment. The use of FLT3 inhibitors (FLT3i) appears attractive but their use has not yet been evaluated. We identified 56 patients treated with FLT3i at molecular failure. The FLT3 mutation was an ITD in 52, TKD in 7 and both in 3. Over half of patients had previously received midostaurin. Molecular failure occurred at a median 9.2 months from diagnosis and was treated with gilteritinib (n = 38), quizartinib (n = 7) or sorafenib (n = 11). 60% achieved a molecular response, with 45% reaching MRD negativity. Haematological toxicity was low, and 22 patients were bridged directly to allogeneic transplant with another 6 to donor lymphocyte infusion. 2-year overall survival was 80% (95%CI 69–93) and molecular event-free survival 56% (95%CI 44–72). High-sensitivity next-generation sequencing for FLT3-ITD at molecular failure identified patients more likely to benefit. FLT3i monotherapy for molecular failure is a promising strategy which merits evaluation in prospective studies.

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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%

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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A Prospective Phase 2 Study of Venetoclax and Low Dose Ara-C (VALDAC) to Target Rising Molecular Measurable Residual Disease and Early Relapse in Acute Myeloid Leukemia

Cited by 9 publications

References 0 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

FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML

Optimal Post-Remission Consolidation Therapy in Patients with AML

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