ViewpointChoosing between intensive and less intensive front-line treatment approaches for older patients with newly diagnosed acute myeloid leukaemia
Section snippets
The challenges and controversies of treating older patients with acute myeloid leukaemia
Acute myeloid leukaemia is predominantly a disease of older age, with a median age of 68 years at the time of diagnosis.1 The outcomes of older patients with acute myeloid leukaemia (herein defined as 60 years or older, unless otherwise specified) are inferior to their younger counterparts. Adults aged 65 years or older account for approximately 60% of new cases, but comprise 75% of deaths related to acute myeloid leukaemia.1 The worse survival in older patients is multifactorial and is driven
The rationale for intensive chemotherapy
The use of intensive chemotherapy for older patients with acute myeloid leukaemia is supported by several large retrospective studies showing that outcomes with intensive chemotherapy are superior to palliation or supportive care alone.3, 10, 11 In one analysis of Surveillance, Epidemiology, and End Results data from 2000 to 2007, anti-leukaemia treatment resulted in a significant improvement of median overall survival in patients up to the age of 80 years.11 Similar findings were also reported
Potential risks of intensive chemotherapy
Although intensive chemotherapy offers a potential chance for cure in a small subset of older patients with acute myeloid leukaemia, it is also associated with substantial risks, including treatment-related morbidity and mortality, both of which are generally due to myelosuppression-related infectious complications. Even in large, well controlled studies of highly selected patients treated with intensive chemotherapy, early mortality of 10–25% has been reported in older patients.12, 17, 18
Intensive chemotherapy versus hypomethylating agents
Most analyses supporting the use of intensive chemotherapy in older patients with acute myeloid leukaemia were done before wide availability of hypomethylating agents. Several retrospective analyses have compared outcomes of those treated with intensive chemotherapy and hypomethylating agents, with mixed results. Although some studies have shown similar outcomes among patients who received intensive chemotherapy or a hypomethylating agent,26, 27, 28 other studies have shown superiority of
Intensive chemotherapy versus low-intensity venetoclax-based regimens
The incorporation of venetoclax into front-line regimens for older or unfit patients with acute myeloid leukaemia has revolutionised the treatment of this population. In the phase 3 VIALE-A study,8 patients with newly diagnosed acute myeloid leukaemia who were deemed ineligible for intensive chemotherapy (ie, aged ≥75 years, a clinically significant comorbidity, or ECOG performance status of 2 or more) were randomly assigned to receive to azacitidine plus either venetoclax or placebo.
Improving on the hypomethylating agent plus venetoclax treatment backbone
Although the front-line use of a hypomethylating agent plus venetoclax has improved outcomes for older, unfit patients with acute myeloid leukaemia, the 2-year overall survival with this approach is only 30–50%.8, 44 Fortunately, new advances are already improving upon the outcomes achieved with a hypomethylating agent plus venetoclax.45 Building upon promising results with a regimen of cladribine plus low-dose cytarabine, alternating with decitabine, in patients aged 60 years or older with
The MD Anderson Cancer Center approach to front-line treatment selection in older or unfit patients with acute myeloid leukaemia
Our treatment approach for older patients with newly diagnosed acute myeloid leukaemia is informed primarily by patient age and cytomolecular features (figure). Given the available data suggesting that hypomethylating agents plus venetoclax-based regimens might result in similar or even superior outcomes to intensive chemotherapy in older patients with acute myeloid leukaemia, our approach is to treat nearly all patients aged 65 years or older with a low-intensity venetoclax-based regimen,
Conclusions and future directions
Effective, yet tolerable, therapy for older patients with acute myeloid leukaemia has historically been a major unmet need in the field. The development of low-intensity venetoclax-based regimens has greatly improved the outlook for these patients, although their long-term outcomes remain largely unsatisfactory. Novel strategies that build upon the successes of the hypomethylating agent plus venetoclax backbone will hopefully further improve response rates and survival for these patients, as
Declaration of interests
NJS has served as a consultant for Takeda Oncology and AstraZeneca, reports receiving research grants from Takeda Oncology and Astellas Pharma, and has received honoraria from Amgen. HK declares no competing interests.
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