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S.R. McCurdy and S.M. Luger
apies, low-dose cytarabine (LDAC), prolongs survival when compared to either hydroxycarbamide or best sup- portive care. However, the CR rate is only 18% with a median OS of 18 weeks and there were no responders among patients with high-risk disease.62 In an effort to improve upon modest outcomes with LDAC alone, glas- degib, a hedgehog inhibitor that is also being studied in combination with 7+3,63 was combined with LDAC, where it was associated with a CR rate of 17% and an 8.8 month median survival compared with 2.3% and 4.9 months for LDAC alone in that study.64 Glasdegib is now FDA-approved for use in combination with LDAC and it could be considered in patients with renal failure or those deemed unfit for induction who have already failed HMA- based therapy. However, the widespread adoption of LDAC and glasdegib has been limited by the contempo- rary approval of LDAC and venetoclax discussed further below.
Azacitidine and decitabine, two HMAs in common use for myeloid diseases, were first approved for MDS in 2004 and 2006, respectively. Despite never receiving FDA approval as single agents for AML, HMAs have been com- monly employed to treat unfit older AML patients since that time. The data behind this approach include those from a study of 980 AML patients 70 years and older in whom the median OS was 14.4 months after HMA, 10.8 months after daunorubicin/cytarabine, 5.9 months after LDAC, and 2.1 months with best supportive care.65 Propensity score matching showed a significant benefit from HMA. At least two other studies retrospectively compared HMA and IC and suggested that survival was similar.66,67 However, when compared to lower-intensity AML chemotherapy such as single-agent GO, LDAC, or best supportive care, nothing outperforms HMA.32,68
Venetoclax lower-intensity combination therapies
In an effort to improve on the modest CR rate associat- ed with HMA as a single agent, HMA combination thera- pies, such as lenalidomide/HMA have been explored,69,70 but none garnered much attention until venetoclax. Based on encouraging early data, venetoclax/HMA received accelerated approval in 2018 for newly diagnosed AML patients 75 years and older and/or for those with comor- bidities that preclude IC.71 Full FDA approval followed in 2020 based on the findings of a phase III study in which 431 patients were randomized to either 7 days of azaciti- dine and 28 days of venetoclax 400 mg daily or azacitidine and placebo.3 The OS was 14.7 months in the azaciti- dine/venetoclax arm and 9.6 months in the azacitidine/placebo arm with a composite CR (CR/CRi) of 66.4% versus 28.3%, respectively.3 By molecular sub- groups, CR/CRi was achieved in 75.4% versus 10.7% of IDH1/2-mutated patients, 72.4% versus 36.4% of FLT3- mutated patients, 66.7% versus 23.5% of NPM1-mutated patients, and 55.3% versus 0% of TP53-mutated patients, respectively. The median OS for patients with intermedi- ate-risk cytogenetics treated with azacitidine/venetoclax or azacitidine/placebo, was 20.8 months versus 12.4 months, respectively, whereas it was 7.6 months versus 6.0 months for those with poor-risk cytogenetics (patients with CBF-AML were excluded from the study). Febrile neutropenia occurred in 42% of patients treated with the
combination. Thirty-day mortality was 7% in the azaciti- dine/venetoclax group and 6% in the control group.3
Alongside its approval in combination with HMA, vene- toclax received accelerated approval in combination with LDAC based on a study of 82 patients aged 63-90 years who were treated with LDAC at 20 mg/m2 per day on days 1-10 in combination with venetoclax 600 mg daily.72 LDAC/venetoclax was associated with a 30-day mortality of 6%, a CR/CRi rate of 44%, and a median OS of 10.1 months. In patients not previously exposed to HMA, the CR/CRi rate was 62% with a median OS of 13.5 months.72 Full approval was granted when subsequent phase III data from patients aged 36-93 years old demonstrated a 25% reduction in risk of death in the LDAC/venetoclax versus LDAC/placebo with a CR/CRi rate of 48% versus 13%, respectively.73 Rates of CR/CRi were 72% in FLT3-mutat- ed, 71% for IDH1/2-mutated, 91% for NPM1-mutated, and 47% for TP53-mutated AML. The median survival after LDAC/venetoclax for patients with the correspon- ding mutations was not reached, 24.4 months, not reached, and 7.2 months. Rates of febrile neutropenia were 32%. These data are particularly promising for AML patients with NPM1 mutations and hint at a high response rate for NPM1-mutated patients treated with cytotoxic chemotherapy and venetoclax, discussed further below.
While not FDA-approved in combination, another lower-intensity option that is being explored is a combina- tion of cytarabine, cladribine, and venetoclax. Phase II data showed a 58% CR rate with cladribine and LDAC alternating with HMA in older AML patients unfit for intensive induction.74 In a subsequent trial, the addition of venetoclax to the prior regimen produced a 94% CR/CRi rate and is being explored as a moderate-intensity option.75
Venetoclax high-intensity combination therapies
Given its success in combination with lower intensity therapies, venetoclax has also been explored in patients 65 years and older who were fit for intensive chemotherapy. In this trial, venetoclax was given as a 7-day pre-phase ramp up, followed by idarubicin on days 2 and 3 (5+2), infusional cytarabine on days 2-7, then 7 additional days of venetoclax. Patients in the study were 63-80 years old and had a CR/CRi rate of 72% (97% in those with de novo AML and 43% in those with secondary AML).76 Interestingly, a ≥50% reduction in blasts after just the pre- phase venetoclax was documented in patients with NPM1, IDH2, or SRSF2 mutations. A few interesting points can be gleaned from this study: i) that secondary AML likely responds at least as well if not better to HMA/venetoclax than to 5+2/venetoclax; and ii) a strong signal exists that venetoclax is associated with high response rates in NPM1- and IDH-mutated AML, which might point towards the addition of this agent either to cytotoxic or HMA-based therapy, respectively, to improve outcomes in the future. Venetoclax is also being explored in combination with fludarabine, ara-C, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) induction. Among ten newly diagnosed patients treated with this regimen the CR/CRh rate was 91% with a high rate of minimal residual disease negativitiy.77 Other inten- sive combinations such as venetoclax with cladribine, ara- C, and idarubicin induction are also showing promise.78
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