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Clinical Trial
. 2025 Apr 22;9(8):1827-1835.
doi: 10.1182/bloodadvances.2024014900.

Final analysis of the phase 1b Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT)

Chong Chyn Chua  1   2   3   4 , Sun Loo  2   3   5 , Chun Yew Fong  6   7 , Stephen B Ting  8 , Ing Soo Tiong  5   9 , Shaun Fleming  4 , Natasha S Anstee  2   10 , Adam Ivey  4 , Michael Ashby  4 , Tse-Chieh Teh  4   8 , John Reynolds  4 , Andrew W Roberts  2   5   11 , Andrew H Wei  2   5   10
Affiliations
Clinical Trial

Final analysis of the phase 1b Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT)

Chong Chyn Chua et al. Blood Adv. .

Abstract

Venetoclax plus azacitidine represents a key advance for older, unfit patients with acute myeloid leukemia (AML). The Chemotherapy and Venetoclax in Elderly AML Trial (CAVEAT) was first to combine venetoclax with intensive chemotherapy in newly diagnosed patients aged ≥65 years. In this final analysis, 85 patients (median age, 71 years) were followed up for a median of 41.8 months. The CAVEAT induction combined cytarabine and idarubicin with 5 dose levels of venetoclax (50-600 mg) for up to 14 days. Two additional cohorts explored adjusted-dose venetoclax (50 mg and 100 mg) with posaconazole. CAVEAT induction was well tolerated, with low mortality (4%) and limited high-grade gastrointestinal toxicity (4%). Delayed hematologic recovery after consolidation was ameliorated by omitting idarubicin from postremission therapy. The overall response rate (ORR; complete response [CR] + CR with partial hematologic recovery + CR with incomplete count recovery) was 75%, with a median overall survival (OS) of 19.3 months (95% confidence interval [CI], 11.1-31.3). Among de novo AML, ORR was 88% and median OS was 33.1 months (95% CI, 19.3-54.3). Almost one-third have not relapsed, many benefiting from prolonged treatment-free remission (median, 17.9 months). CAVEAT induction was well tolerated and associated with high ORR that was durable, particularly for de novo AML. CAVEAT represents an effective time-limited treatment option for fit, older patients with AML. This trial was registered at https://www.anzctr.org.au as #ACTRN12616000445471.

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Conflict of interest statement

Conflict-of-interest disclosure: C.C.C. has participated in advisory board meetings for AbbVie, Pfizer, and Sumitomo Pharma Oncology, and received honoraria from Otsuka, Bristol Myers Squibb (BMS), AstraZeneca, AbbVie, and Pfizer. S.L. has received honoraria for speaker's bureau from AbbVie. I.S.T. has received honoraria from Jazz Pharmaceuticals, Novartis, and Pfizer. C.Y.F. has consulted for, served on advisory boards of, or received honoraria for speakers bureau from Astellas, AbbVie, BeiGene, BMS, Jazz Pharmaceuticals, Limbic, Novartis, Novotech, Otsuka, and Pfizer, and received research funding from Jazz Pharmaceuticals and Astellas. S.F. has consulted for, served on advisory boards of, and received honoraria for speakers' bureaus from Astellas, AbbVie, Amgen, BMS, Gilead/Kite, Jazz Pharmaceuticals, Limbic, Novartis, and Pfizer, and has received research funding from Amgen. J.R. holds stock in Novartis AG, Sandoz AG, and Alcon AG, and his employer, Alfred Health, receives funds from AbbVie for his involvement in 1 research project. A.H.W. has served on advisory boards for Novartis, AstraZeneca, Astellas, GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Amgen, Roche, Pfizer, AbbVie, Servier, Gilead, BMS, and BeiGene; has consulted for AbbVie, Servier, Novartis, Shoreline, and Aculeus; receives research funding to the institution from Novartis, AbbVie, Servier, BMS, Janssen, Syndax, Astex, AstraZeneca, and Amgen; and serves on speakers' bureaus for AbbVie, Novartis, BMS, Servier, and Astellas. A.H.W., A.W.R., and N.S.A. are employees of the Walter and Eliza Hall Institute (WEHI). WEHI receives milestone and royalty payments related to the development of venetoclax. Current and past employees of WEHI may be eligible for financial benefits related to these payments. A.H.W., A.W.R., and N.S.A. receive such a financial benefit. A.W.R. is an inventor on a patent related to venetoclax. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Time to hematologic recovery. (A-B) Hematologic recovery for POSA-augmented cohorts F (VEN 50 mg) and H (VEN 100 mg) during induction and consolidation cycle 1: (A) days to neutrophil recovery, ≥0.5 × 109/L; and (B) days to platelet recovery, ≥50 × 109/L. (C-D) Hematologic recovery for non–POSA-augmented cohorts A to E and H during consolidation cycle 1: (C) days to neutrophil recovery, ≥0.5 × 109/L; and (D) days to platelet recovery, ≥50 × 109/L. Individual patient data are shown. Orange points indicate patients who received VEN monotherapy as consolidation. POSA, posaconazole; VEN, venetoclax.
Figure 2.
Figure 2.
Clinical outcomes after CAVEAT therapy. (A) Clinical response (best response at any time on study) for all patients and by key molecular subgroups (most frequently occurring gene mutations). (B) OS of all patients. (C) OS stratified by de novo vs secondary AML. (D) OS stratified by ELN 2022 risk classification: pairwise comparisons between the 3 risk groups show significant differences only between favorable and adverse risk (P = .02; ∗, corrected for multiple testing), with nonsignificant P values for favorable vs intermediate (P = .218) and intermediate vs adverse (P = 1.00). (E-H) OS stratified by mutation status: (E) IDH1/2 mut vs wt, (F) NPM1 mut vs wt, (G) TP53 mut vs wt, and (H) SRSF2 mut vs wt. CI, confidence interval; CRh, CR with partial hematologic recovery; CRi, CR with incomplete count recovery; mut, mutant; MLFS, morphologic leukemia free state; NA, not assessable; wt, wild-type.
Figure 2.
Figure 2.
Clinical outcomes after CAVEAT therapy. (A) Clinical response (best response at any time on study) for all patients and by key molecular subgroups (most frequently occurring gene mutations). (B) OS of all patients. (C) OS stratified by de novo vs secondary AML. (D) OS stratified by ELN 2022 risk classification: pairwise comparisons between the 3 risk groups show significant differences only between favorable and adverse risk (P = .02; ∗, corrected for multiple testing), with nonsignificant P values for favorable vs intermediate (P = .218) and intermediate vs adverse (P = 1.00). (E-H) OS stratified by mutation status: (E) IDH1/2 mut vs wt, (F) NPM1 mut vs wt, (G) TP53 mut vs wt, and (H) SRSF2 mut vs wt. CI, confidence interval; CRh, CR with partial hematologic recovery; CRi, CR with incomplete count recovery; mut, mutant; MLFS, morphologic leukemia free state; NA, not assessable; wt, wild-type.
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References

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