Acute myeloid leukemia (AML) predominantly affects older patients, and the median age at diagnosis is 68 years. In older patients, AML has an adverse outcome due to the combined effects of high-risk genetic and molecular aberrations, the presence of comorbidities, and reduced biological reserve — a fact that has limited the use of approaches with curative intent such as intensive induction chemotherapy and allogeneic stem cell transplantation. This has motivated the search for lower-toxicity treatments that retain therapeutic efficacy. The DNA methyl-transferase inhibitor azacitidine has demonstrated efficacy in older patients with low blast count AML (≤ 30% blasts), leading to improved survival when compared to conventional care approaches (best supportive care, low-dose cytarabine, or intensive chemotherapy).1 However, in older patients with higher blast counts (> 30%), azacitadine outcomes were more modest, with a low rate of clinical responses (< 30%) and 10.4 months median survival.2 BCL2 is an antiapoptotic protein that is overexpressed in AML blasts, and high levels of BCL2 are associated with resistance to chemotherapy. Venetoclax, a first in class BCL2 inhibitor, has limited single agent activity in AML; however, synergy with azacitidine and cytotoxic agents was demonstrated in preclinical studies. Early-phase clinical trials have shown high response rates and acceptable tolerability when venetoclax is combined with either azacitidine3 or low-dose cytarabine.4 These studies informed the phase III clinical trial designed to determine whether venetoclax plus azacitidine (Ven/Aza) is superior to azacitidine (Aza) alone in untreated AML patients for whom intensive chemotherapy is not suitable.
In the VIALE-A study, Dr. Courtney D. DiNardo and colleagues examined whether the Ven/Aza combination was able to prolong overall survival (OS) compared to Aza plus placebo. The study included 431 patients with AML who were deemed unfit for chemotherapy by virtue of age (> 75 years), or by the presence of defined comorbidities including cardiac or respiratory impairment, or an Eastern Cooperative Oncology Group performance status of 2-3. Patients who had previously received chemotherapy and patients with favorable-risk cytogenetics (as defined by the National Comprehensive Cancer Network guidelines) were excluded from this trial. Patients were randomized in a 2:1 fashion in favor of Ven/Aza and were matched for cytogenetic and molecular risk, as well as the percentage of patients with de novo (75%) or secondary (25%) disease. Prior exposure to hypomethylating agents was not allowed, nor were cases evolving from a myeloproliferative neoplasm. Patients received a rapid ramp up of venetoclax to the target dose of 400 mg within three days, and there was a remarkably low rate of tumor lysis syndrome (n=3, 1%) manifesting as transient biochemical changes that resolved with simple measures. It is possible that the study’s exclusion criteria of a white blood cell count greater than 25 × 103/µL helped to mitigate tumor lysis risk.
After a median follow-up of 20.5 months, the patients who received Ven/Aza showed prolonged survival compared to Aza (14.7 months vs. 9.6 months; hazard ratio, 0.66; p<0.001) with a 34 percent reduction in the risk of death. Secondary endpoints included composite complete remission (CCR), representing complete remission and complete remission with incomplete blood count recovery. CCR was 66.4 percent with Ven/Aza versus 28.3 percent with Aza (p<0.001). The greatest benefit was seen in the molecular subgroup of patients with mutations in IDH1 or IDH2 (CCR, 75.4% vs. 10%; hazard ratio for survival, 0.34). Intermediate-risk patients notably experienced greater benefits. Additionally, patients who achieved a deep response (minimal residual disease [MRD] < 1:1000 cells) seemed to show a strong benefit although this subgroup was small. Hematologic adverse events were more common in the Ven/Aza group and included febrile neutropenia (though infections occurred at a similar rate) and thrombocytopenia. Gastrointestinal toxicities (nausea, diarrhea, and constipation) were common and similar in both groups. Unfortunately, these are toxicities that appear to be inescapable in modern AML therapies. Thirty-day mortality was low in both groups (7% and 6%).
A complimentary phase III study examining venetoclax in combination with low-dose cytarabine (VIALE-C) has also reported positive results, improving on the very modest outcomes achieved with low-dose cytarabine alone. However, patient populations differed between these two studies, and therefore, direct comparisons are not possible.5
We are rapidly entering a new era in the treatment of older patients with AML, where highly active and relatively well tolerated novel therapies are providing realistic therapeutic options for the majority of patients and are improving survival in this poor-prognosis disease (Figure). The VIALE-A study sets a new standard of care for older patients or patients unfit for intensive chemotherapy because of comorbidities, with high response rates and improved OS. Further follow-up will be critical to define the longer-term outcomes of the small group of patients remaining in remission beyond 24 months at the time of this analysis. Challenges remain, however, particularly for patients with poor-risk cytogenetics and TP53 mutations who had improved but suboptimal response rates that were often transient on the venetoclax combination. Understanding resistance mechanisms and exploring novel therapies to augment and prolong responses will be important avenues of future research. Conversely, differential outcomes were seen in specific molecular subsets, raising questions such as whether combinations with molecularly targeted therapies such as IDH1 and IDH2 inhibitors, or FLT3 inhibitors, can further improve responses beyond Ven/Aza combinations. Furthermore, in patients who receive intensive chemotherapy, will there be a role for venetoclax combinations in the eradication of MRD and could this be an opportunity to cure more patients?
The VIALE-A study represents a paradigm shift in the management of patients with AML who are older or unsuitable for intensive induction chemotherapy. The study sets a new standard of care and opens the door to future exploration of highly active combinations or drug sequencing strategies, with the ultimate goal of improving cure rates in AML.
Dr. Lane has participated in advisory boards for Celgene. Dr. Marlton has participated in advisory boards for Celgene and Abbvie.