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Venetoclax and Low-Dose Cytarabine for Measurable Residual Disease or Oligoblastic Relapse in Patients With AML
abstract
This abstract is available on the publisher's site.
Access this abstract nowPURPOSE
A prospective phase II study examined the safety and efficacy of venetoclax combined with low-dose cytarabine (LDAC) in AML at first measurable residual disease (MRD) or oligoblastic relapse.
METHODS
Patients with either MRD (≥1 log10 rise) or oligoblastic relapse (blasts 5%-15%) received venetoclax 600 mg once daily D1-28 plus LDAC once daily D1-10 in 28-day cycles. The primary objective was MRD response in the MRD relapse cohort or complete remission (CR/CRh/CRi) in the oligoblastic relapse cohort.
RESULTS
Forty-eight adults with either MRD (n = 26) or oligoblastic (n = 22) relapse were enrolled. Median age was 67 years (range, 18-80) and 94% had received previous intensive chemotherapy. Patients received a median of four cycles of therapy; 17% completed ≥12 cycles. Patients with oligoblastic relapse had more grade ≥3 anemia (32% v 4%; P = .02) and infections (36% v 8%; P = .03), whereas grade 4 neutropenia (32 v 23%) or thrombocytopenia (27 v 15%) were comparable with the MRD relapse cohort. Markers of molecular MRD relapse included mutant NPM1 (77%), CBFB::MYH11 (4%), RUNX1::RUNX1T1 (4%), or KMT2A::MLLT3 (4%). Three patients with a log10 rise in IDH1/2 (12%) were included. By cycle 2 in the MRD relapse cohort, a log10 reduction in MRD was observed in 69%; 46% achieved MRD negative remission. In the oligoblastic relapse cohort, 73% achieved CR/CRh/CRi. Overall, 21 (44%) underwent hematopoietic cell transplantation. Median overall survival (OS) was not reached in either cohort. Estimated 2-year OS rate was 67% (95% CI, 50 to 89) in the MRD and 53% (95% CI, 34 to 84) in the oligoblastic relapse cohorts.
CONCLUSION
For AML in first remission and either MRD or oligoblastic relapse, venetoclax plus LDAC is well tolerated and highly effective.
Additional Info
Disclosure statements are available on the authors' profiles:
Targeting Molecular Measurable Residual Disease and Low-Blast Relapse in AML With Venetoclax and Low-Dose Cytarabine: A Prospective Phase II Study (VALDAC)
J. Clin. Oncol 2024 Mar 01;[EPub Ahead of Print], IS Tiong, DK Hiwase, E Abro, A Bajel, E Palfreyman, A Beligaswatte, J Reynolds, N Anstee, T Nguyen, S Loo, CC Chua, M Ashby, KM Wiltshire, S Fleming, CY Fong, TC Teh, P Blombery, R Dillon, A Ivey, AH WeiFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Quenching the spark before it becomes a wildfire: Targeting molecular measurable residual disease in acute myeloid leukemia
Measurable residual disease (MRD) monitoring is increasingly used to guide therapeutic decision–making in acute myeloid leukemia (AML). The prognostic relevance of MRD is unequivocal1,2; however, the differential impact of the methods by which MRD is detected and the best markers of AML MRD remain debatable and continue to be a subject of investigation. The European Leukemia Net (ELN) MRD working party released their consensus guidelines on MRD monitoring in 2021, in which they put forth recommended methods, markers, and time points for molecular MRD monitoring and provided a definition of MRD relapse.1,3 The ELN adopted NPM1 mutations, PML–RARA, RUNX1–RUNX1T1, and CBFB–MYH11 as isolated molecular markers of MRD while suggesting that surveillance for FLT3 and other signaling pathway mutations may be a less sensitive approach due to the often subclonal nature of these mutations in AML; however, subsequent randomized trials have shown that the persistence or emergence of FLT3 mutations and FLT3 ITD mutation clearance are associated with patient outcomes.4,5 Furthermore, the persistence of gene mutations associated with clonal hematopoiesis (particularly DNMT3A, TET2, and ASXL1) and IDH1/2 in the absence of immunophenotypically detectable MRD seems to be inconsequential,6-8 whereas the significance of the persistence of other myelodysplasia-related gene mutations (SF3B1, SRSF2, EZH2, etc) is more controversial.9,10Nevertheless, MRD-directed therapy is a welcome shift in the treatment paradigm of AML as it offers the opportunity to intervene and halt an impending frank relapse while the patient is in a more stable condition and residual normal hematopoiesis is still preserved. Therefore, after establishing the significance of MRD on patient outcomes, the next logical step is to determine when and how to intervene. Increasing robust evidence demonstrates that NPM1 and FLT3 ITD MRD could guide decisions regarding hematopoietic stem cell transplantation in patients with NPM1- and/or FLT3 ITD–mutated AML in first remission.6,11 However, in patients who become or remain MRD-positive after induction therapy, the optimal approach to MRD clearance has yet to be fully established.
The VALDAC study12 aimed to address this question in a prospective phase II trial by assessing the safety and efficacy of subcutaneous low-dose cytarabine (LDAC) in combination with the BCL-2 inhibitor venetoclax (VEN) for patients with oligoblastic (10%–15% blasts; n = 22) or MRD (≥1 log10 rise; n = 26) relapse after intensive induction therapy for AML. The primary objective was an MRD response in the MRD relapse cohort or composite complete remission (cCR) in the oligoblastic relapse cohort. Eligible patients were VEN-naïve, and the MRD status was determined by polymerase chain reaction or targeted next-generation sequencing testing for NPM1, RUNX1–RUNX1T1, CBFB–MYH11, and KMT2A–MLLT3. In addition, 3 patients with ≥1 log10 rise increase in IDH1/2 were also included in the MRD relapse cohort. Among patients in the MRD relapse cohort, 69% achieved a log10 reduction in MRD and 46% achieved MRD negative remission. In the oligoblastic relapse cohort, 73% achieved cCR. Overall, 21 patients (44%) underwent hematopoietic cell transplantation. The median overall survival was not reached in either cohort. The 2-year overall survival rate was 67% in the MRD relapse cohort and 53% in the oligoblastic relapse cohort.
The investigators concluded that the use of LDAC/VEN is effective in treating MRD relapse in specific molecular subgroups. However, the choice of therapy at the time of MRD positivity must be personalized based on molecular subgroups and initial induction therapy. MRD-directed therapy should not be a “one size fits all” approach. For example, in the MRD relapse cohort, complete molecular clearance of the NPM1 mutation was achieved in 55%, whereas a molecular MRD response was observed in 2 of 3 patients with rising IDH1/2. Patients with KMT2A–MLLT3 or CBFB–MYH11 also demonstrated MRD responses, with MRD clearance in both cases. Notably, FLT3 ITD was detected in 9 of 38 patients (24%) at screening: 8 had a concurrent NPM1 mutation, and 1 had RUNX1–RUNX1T1. Among these, 6 patients presented with MRD relapse, and 3 had oligoblastic relapse. Despite the initial treatment response, all 3 patients with FLT3 ITD–associated oligoblastic relapse had early disease progression. Among patients with FLT3 ITD MRD <1% at the study baseline, survival outcomes appeared comparable to those of patients with FLT3 ITD–negative disease. NPM1-mutated MRD clearance was achieved in 5 of 7 patients, with a ≥3 log10 MRD reduction in another patient. Dynamic changes in FLT3 ITD MRD mirrored those in the NPM1 mutation in patients carrying both variants, suggesting that, in the NPM1/FLT3 double mutant disease setting, NPM1 MRD monitoring may serve as the primary marker of MRD.
These results further support that NPM1- and IDH1/2-positive MRD generally confer VEN sensitivity and will likely confer benefit from VEN-based therapies. However, FLT3 ITD clones may benefit from FLT3 inhibition in combination with VEN or menin inhibition for KMT2A-rearranged or NPM1-mutated AML. The number of IDH1/2 MRD relapses was small in the study (n = 3). Although all 3 patients responded to therapy, it is debatable whether these patients, if left untreated, would have experienced earlier frank relapse compared with those with stable IDH1/2 positivity.
This study highlights the role of robust methods of MRD detection in the therapeutic journey of patients with AML and the notion that MRD is a useful prognostic marker in identifying patients who are at the highest risk for relapse and may benefit from early detection and intervention, which can help optimize salvage therapies to improve outcomes. Several prospective studies are currently ongoing to establish the best approach for MRD-targeted therapies.13,14 As the treatment paradigm for AML changes with the earlier use of VEN-based therapies, it will be of interest to determine the utility of LDAC/VEN as a salvage therapy for MRD or oligoblastic relapse in previously VEN-exposed patients.
References