At the time of diagnosis of their acute myeloid leukemia (AML), approximately 57 percent of patients are older than 65 years, with 33 percent older than 75 years per the SEER database. This epidemiology presents challenges to treatment given other comorbidities in these patients. Additionally, AML in older patients often responds poorly to standard induction regimens owing to a presumed lifetime of acquired genetic insults enhancing resistance properties in their leukemic stem cells (LSCs).1,2 Given historically poor clinical results in this context, novel therapies are much needed.
The hypomethylating agents (HMAs) decitabine (DAC) and azacitidine (AZA) have long been a mainstay of myeloid therapies.3 Recently, the B-cell lymphoma 2 (BCL-2) protein was shown to play an important role in the survival of leukemia blasts as a key regulator of cell death in AML.4 Venetoclax, a potent, selective oral inhibitor of BCL-2, has previously demonstrated single-agent clinical activity in refractory AML.5
Dr. Courtney D. DiNardo and colleagues have recently published results of a phase Ib dose-escalation and expansion study with the previously mentioned drugs for eligible patients 65 years or older with treatment-naïve AML, ineligible for intensive chemotherapy by age or comorbidities.6 Oral venetoclax was administered daily as part of the dose escalation in combination with HMAs, dosed in the standard fashions.
Among all 145 treated patients, the median age was 74 years (range, 65-86), with poor-risk cytogenetics in 49 percent of patients and white blood counts (WBCs) 25 × 109/L or less. Common adverse events were mostly gastrointestinal or hematologic (nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased WBC). No tumor lysis syndrome was observed. Dose delays for neutropenia were required. With a median time on study of 8.9 months, 67 percent of patients (all doses) achieved complete remission (CR) or CR with incomplete count recovery. Thus, the combined response rate published was 73 percent for the combination. Patients with poor-risk cytogenetics and those 75 years or older had responses of 60 percent and 65 percent, respectively. The median duration of response was 11.3 months, and median overall survival was 17.5 months in all patients, but this metric has not been reached for the 400 mg venetoclax cohort. Treatment discontinuation owing to progressive disease was seen in 101 patients with lower rates in the AZA arm (22%) compared with the DAC arm (34%). Multiple subgroup analyses were done, but notably, patients with de novo AML had the same CR rates as patients with secondary AML (both 67%), and there were reasonable responses in patients with unfavorable molecular genetics such as mutations in TP53 or FLT3ITD.
Similarly, Dr. Daniel A. Pollyea and colleagues recently provided rational data from the bench to explain these clinical results. Their group looked at an LSC-directed mechanism of AZA plus venetoclax in pre- and post-treatment samples from 33 patients who were treatment analogous to the aforementioned study by Dr. DiNardo and colleagues.6 These results were later compared with data from historical patients who received intensive induction. The authors were able to demonstrate deep and durable clinical remissions correlated with in vitro measurements of blast clearance. Through mass cytometry methods, the phenotypically defined AML blast cell population was rapidly reduced, and specifically the LSC population demonstrated prompt eradication, correlating with clinical response. Robust data show that with this HMA plus BCL2 inhibitor treatment combination, there were decreases in oxidative phosphorylation via disruption of electron transport chain in a glutathione-dependent fashion. This resulted in the selective targeting of the LSC population to gain bedside hematologic responses and CRs. Treatment with AZA plus venetoclax compared quite favorably with the lesser outcomes in the older induction cohort.
In Brief
These two articles demonstrate how and why older patients with AML can have improved outcomes with the venetoclax-HMA combination. In November 2018, the U.S. Food and Drug Administration granted an accelerated approval to venetoclax for use in combination with AZA or DAC at 400 mg daily for the treatment of patients with newly diagnosed AML who are 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy. The articles by Dr. DiNardo, Dr. Pollyea, and their colleagues describe clinical and laboratory data to support the reduction in LSC burden leading to CRs. Given the potential for outpatient treatment with this regimen in an older patient population, this will likely and rapidly be the induction of choice over intensive induction chemotherapy. Additional familiarity with the regimen in clinical use will allow further understanding of toxicity management as well as reasons for dose discontinuations in these patients. Future developments in therapy for AML will require hematologists to adapt to the rapidly changing therapeutic landscape as we minimize toxicity and optimize benefit for our patients while we gain improved biologic understanding of the disease.
References
Competing Interests
Dr. Dezern indicated no relevant conflicts of interest.
