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On February 25, 2019, Andrew Wei from the Alfred Hospital and Monash University, Melbourne, Australia, presented at the Acute Leukemias XVII Biology and Treatment Strategies biennial symposium, in Munich, Germany on the topic of novel treatment combinations for acute myeloid leukemia (AML), particularly focusing on venetoclax.1
Treatment options for elderly patients with AML are limited, with few new drug approvals over the last decade. Since this patient population has poor survival outcomes and are often ineligible for intensive chemotherapy, there is an unmet need for novel therapies in this setting.
BCL-2 and MCL1 are anti-apoptotic proteins, making them targets for inhibitory agents. Inhibiting these proteins leads to cell apoptosis and negates the need for upstream inhibitors such as p53, which are commonly mutated or silenced in tumor cells. On November 21, 2018, venetoclax, a BCL-2 inhibitor was approved by the U.S. Food & Drug Administration (FDA), as was glasdegib, a selective hedgehog pathway inhibitor.
Since venetoclax only inhibits BCL-2, it has limited activity in AML. In a phase II study by Konopleva et al., 2016, an overall response rate of 19% and median overall survival (OS) of 4.7 months was achieved with venetoclax alone.2 Therefore, it is plausible that combining venetoclax with chemotherapy, may increase response rates.
In a phase I/II study (NCT02287233) by Wei et al., 2018, venetoclax was combined with low-dose cytarabine (LDAC) in patients with treatment naïve AML who were considered unfit for intensive chemotherapy. In this study, LDAC was administered subcutaneously at a dose of 20 mg/m2 daily on days 1–10, with venetoclax in a dose-escalation stage starting at 50 mg or 100 mg and increasing to 600 mg and then at 600 mg onwards.3
There are currently no results available from randomized trials comparing venetoclax + LDAC to LDAC alone. However, there are trials conducted with the same LDAC regimen, which may provide evidence of the efficacy of this regimen. Table 1 shows the venetoclax + LDAC study compared to a study by Kantarjian et al., 2012, investigating LDAC alone, and Cortes et al., 2018, comparing LDAC to LDAC + glasdegib.4,5
Table 1.
Complete remission (CR), complete remission with incomplete blood count recovery (CRi), hypomethylating agent (HMA) |
||||
|
LDAC + Venetoclax3 |
LDAC4 |
LDAC5 |
LDAC + glasdegib5 |
---|---|---|---|---|
N |
82 |
243 |
38 |
78 |
Median age |
74 (63–90) |
73 (64–91) |
75 (58–83) |
77 (63–92) |
ECOG >1 |
29% |
24% |
52% |
53% |
Prior HMA |
29% |
- |
18% |
17% |
CR/CRi |
54% |
11% |
5.2% |
24% |
In a recent study by Wei et al., 2019, in the Journal of Clinical Oncology, the survival outcomes of LDAC with venetoclax were found to be promising, with an average 13.5-month median overall survival (OS) in patients without prior HMA. There was a 62% CR/CRi rate in patients without prior HMA, compared to 33% in patients with prior HMA exposure.6 In the Kantarjian et al., 2012, study of LDAC alone, a median OS of 5 months was achieved.4
The survival was especially prominent in patients who achieved a CR, with 100% (100–100) of patients alive at 12 months, compared to 73% (62–90) who achieved CR/CRi and 5% (0–19) who did not respond. This was at a median follow-up of 20 months. There was also a short time to first response of 1.4 months (median). Patients who were long-term survivors have also ceased therapy.
In patients who did not respond, it is important to understand the mechanism of resistance in order to find viable alternative options. When analyzing cytogenetics (Wei et al., 2017)7:
Combining a BCL-2 inhibitor with an MCL1 inhibitor is another route to explore. There are four MCL1 inhibitors currently in clinical development. Targeting both BCL-2 and MCL1 with respective inhibitors has been shown to be effective in treatment naïve AML as well as relapsed/refractory AML by Moujallad et al., 2018, in preclinical models.8 This is interesting as the primary AML cells utilized would likely have had diverse molecular abnormalities, yet showed a promising overall response, showing these abnormalities may not affect the effectiveness of the combination.
The BCL-2 and MCL1 combination has been shown to be effective in multiple settings; including primary AML, diverse genotype primary AML, chemoresistant AML samples and, venetoclax/LDAC resistant samples. Since effectiveness is shown in venetoclax/LDAC resistant samples, this indicates resistance is to the cytotoxic component of treatment meaning that the combination of venetoclax with a novel agent such as an MCL1 inhibitor can restore the potential for sensitivity.
Colony assays on normal CD34 cells show combining BCL-2 and MCL1 is well-tolerated. In preclinical toxicity experiments in humanized MCL knock-in mice models, monocytes and B-cells are suppressed when an MCL1 inhibitor is used, but no gross organ toxicity was been reported. Trials are underway investigating the BCL-2 and MCL1 combinations.
There are many potential applications for venetoclax in AML treatment, including combination therapy with targeted drugs such as IDH, FLT3, MCL1 inhibitors, or drugs which are more active against p53 mutant AML. Understanding the resistance mechanisms involved may assist in developing the optimal combinations, and the dual-targeting of BCL-2 and MCL1 is showing strong results so far. There may also be a role for these drugs in the maintenance setting. The treatment of elderly patients with AML is becoming more feasible and effective with these novel agents.
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