Improving outlook for older patients with AML – Commentary on CAVEAT Study

Dr Ng Chin Hin,
Senior Consultant Haematologist, CFCH
Former Head of Adult Leukaemia Service, National University Cancer Institute, Singapore
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#The prognosis of older patients with AML is generally poor. However, newer novel treatments mean that the outcomes for older AML are improving significantly over the past 2-3 years.
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The addition of the oral targeted agent Venetoclax to the previous standard of care in elderly unfit AML has led to significant improvement of response rate and survival in the phase 2 studies. Recently reported phase 3 studies – VIALE-C (Venetoclax plus Cytarabine) and VIALE-A (Venetoclax plus Azacitidine) have confirmed the superiority of outcomes in these combinations as compared to the standard of care (Azacitidine or Low dose cytarabine). The combination of Venetoclax with Azacitidne or low dose cytarabine have since become the new standard of care for older unfit AML above 60 years old. The overall response rate, ORR (complete remission and complete remission with incomplete count recovery) were 48% and 68% for Cytarabine and Azacitidine combination, respectively. The results were even appealing to those who are deemed fit for intensive chemotherapy in older AML patients.
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The CAVEAT Study is a phase 1b study using a relatively more intensive induction chemotherapy regimen (5 days of IV Cytarabine 100mg/m2 and 2 days of idarubicin 12mg/m2) with an addition of 14 days Venetoclax (dose ranging from 50mg to 600mg od) in fit older AML patients (age >60 years old). This is followed by 4 cycles of consolidation which consist of 2 days of IV Cytarabine 100mg/m2, 1 day of Idarubicin 12mg/m2 and 14 days of Venetoclax. Among the 51 evaluable patients, there was no significant added toxicity for the induction phase with a median neutrophil count (>0.5) and platelet count (>50) recovery of 25 days and 26 days, respectively. The 30-day all-cause mortality was 6%. The reported overall response rate was 72% (CR rate 41% and CRi rate 31%). The ORR in de novo AML was very impressive at 97% (CR 68%, CRi 29%). The ORR in secondary AML was 43% (CR 9%, CRi 34%). The response was particularly poor in TP53 mutated AML (no CR but CRi 33%). Venetoclax plus Azacitidine may produce a higher ORR (55%) as reported in VIALE-A study. With a median follow-up of 22.9 months, median Overall Survival (OS) of 31.3 months was seen in de novo AML while only 6.1 months in secondary AML.
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The results appeared to be more impressive than those in reported VIALE-A or VIALE-C study especially those with de novo AML. However, the study population in CAVEAT Study might be slightly fitter. We are eagerly awaiting the confirmation from phase 2 and 3 studies. Venetoclax added to 5+2 regimen may become the new standard of care in older and fit AML.
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Reference:

1. 1. Chua CC, Roberts AW, Reynolds J, et al. Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): A Phase Ib Dose-Escalation Study of Venetoclax Combined With Modified Intensive Chemotherapy [published online ahead of print, 2020 Jul 20]. J Clin Oncol. 2020;JCO2000572. doi:10.1200/JCO.20.00572
   2. Wei AH, Strickland SA Jr, Hou J-Z, et al: Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: Results from a phase Ib/II study. J Clin Oncol 37:1277-1284, 2019
   3. Wei AH, Montesinos P, Ivanov V. MD, et al: Venetoclax plus LDAC for patients with untreated AML ineligible for intensive chemotherapy: Phase 3 randomized placebo-controlled trial. Blood 135:2137-2145, 2020
   4. DiNardo CD, Pratz K, Pullarkat V, et al: Venetoclax combined with decitabine or azacitidine treatment-naive, elderly patients with acutemyeloid leukemia. Blood 133:7-17, 2019

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