Elsevier

The Lancet Haematology

Volume 9, Issue 7, July 2022, Pages e535-e545
The Lancet Haematology

Viewpoint
Choosing between intensive and less intensive front-line treatment approaches for older patients with newly diagnosed acute myeloid leukaemia

https://doi.org/10.1016/S2352-3026(22)00167-3Get rights and content

Summary

The outcomes of older patients with acute myeloid leukaemia are inferior to their younger counterparts, because, in part, of a more aggressive disease biology and poorer tolerance of cytotoxic chemotherapy. Although intensive chemotherapy was historically considered the only effective treatment for these patients, many older patients are not suitable for intensive chemotherapy owing to comorbidities or general frailty. Determination of patient fitness for intensive chemotherapy is imperfect, and even older patients who appear to be suitable (also known as fit) for intensive chemotherapy can have high rates of morbidity and early and late mortality with this approach. Fortunately, the outcomes of older or unfit patients with acute myeloid leukaemia have substantially improved with the use of a hypomethylating agent plus venetoclax in the front-line setting. Although the formal approval of this combination is limited to patients aged 75 years or older, or those with a clinically significant comorbidity, the high response rates and survival improvement in these patients have led many practitioners to consider this low-intensity regimen in older patients without significant comorbidities and even in younger patients with high-risk disease features for whom the expected outcomes with intensive chemotherapy are poor. Modifications to the hypomethylating agent plus venetoclax backbone might further improve the outlook for these patients, particularly in some acute myeloid leukaemia subsets with a targetable mutation. In this Viewpoint, we review the retrospective and prospective data supporting both intensive chemotherapy and low-intensity venetoclax-based approaches in older patients with acute myeloid leukaemia. We also discuss our own approach to the management of older or unfit patients with acute myeloid leukaemia, including how cytomolecular features have a role in establishing the optimal front-line therapy.

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.

References (69)

  • P Boddu et al.

    Treated secondary acute myeloid leukemia: a distinct high-risk subset of AML with adverse prognosis

    Blood Adv

    (2017)
  • EM Cherry et al.

    Venetoclax and azacitidine compared with induction chemotherapy for newly diagnosed patients with acute myeloid leukemia

    Blood Adv

    (2021)
  • J Grenet et al.

    Comparing outcomes between liposomal daunorubicin/cytarabine (CPX-351) and HMA+ venetoclax as frontline therapy in acute myeloid leukemia

    Blood

    (2021)
  • TM Kadia et al.

    Venetoclax plus intensive chemotherapy with cladribine, idarubicin, and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: a cohort from a single-centre, single-arm, phase 2 trial

    Lancet Haematol

    (2021)
  • VA Pullarkat et al.

    Preliminary results by age group of treatment with CPX-351 plus venetoclax in adults with newly diagnosed AML: subgroup analysis of the V-FAST phase 1b master trial

    Blood

    (2021)
  • CD DiNardo et al.

    10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial

    Lancet Haematol

    (2020)
  • TM Kadia et al.

    Cladribine and low-dose cytarabine alternating with decitabine as front-line therapy for elderly patients with acute myeloid leukaemia: a phase 2 single-arm trial

    Lancet Haematol

    (2018)
  • PK Reville et al.

    Phase II study of venetoclax added to cladribine (CLAD) and low dose AraC (LDAC) alternating with 5-azacytidine (AZA) in older and unfit patients with newly diagnosed acute myeloid leukemia (AML)

    Blood

    (2021)
  • NJ Short et al.

    A triplet combination of azacitidine, venetoclax and gilteritinib for patients with FLT3-mutated acute myeloid leukemia: results from a phase I/II study

    Blood

    (2021)
  • CA Lachowiez et al.

    Venetoclax combined with induction chemotherapy in patients with newly diagnosed acute myeloid leukaemia: a post-hoc, propensity score-matched, cohort study

    Lancet Haematol

    (2022)
  • RK Hills et al.

    Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials

    Lancet Oncol

    (2014)
  • NJ Short et al.

    Prognostic and therapeutic impacts of mutant TP53 variant allelic frequency in newly diagnosed acute myeloid leukemia

    Blood Adv

    (2020)
  • DA Sallman et al.

    Phase 1b/2 combination study of APR-246 and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML)

    Blood

    (2018)
  • N Daver et al.

    Phase I/II study of azacitidine (AZA) with venetoclax (VEN) and magrolimab (Magro) in patients (pts) with newly diagnosed older/unfit or high-risk acute myeloid leukemia (AML) and relapsed/refractory (R/R) AML

    Blood

    (2021)
  • J Sun et al.

    De novo acute myeloid leukemia with inv(3)(q21q26·2) or t(3;3)(q21;q26·2): a clinicopathologic and cytogenetic study of an entity recently added to the WHO classification

    Mod Pathol

    (2011)
  • Cancer stat facts: leukemia—acute myeloid leukemia (AML)

  • BC Medeiros et al.

    Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States

    Ann Hematol

    (2015)
  • HM Kantarjian et al.

    Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia

    J Clin Oncol

    (2012)
  • K Sasaki et al.

    De novo acute myeloid leukemia: a population-based study of outcome in the United States based on the Surveillance, Epidemiology, and End Results (SEER) database, 1980 to 2017

    Cancer

    (2021)
  • AH Wei et al.

    Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase ib/ii study

    J Clin Oncol

    (2019)
  • CD DiNardo et al.

    Azacitidine and venetoclax in previously untreated acute myeloid leukemia

    N Engl J Med

    (2020)
  • NJ Short et al.

    When less is more: reevaluating the role of intensive chemotherapy for older adults with acute myeloid leukemia in the modern era

    J Clin Oncol

    (2021)
  • B Oran et al.

    Survival for older patients with acute myeloid leukemia: a population-based study

    Haematologica

    (2012)
  • B Löwenberg et al.

    High-dose daunorubicin in older patients with acute myeloid leukemia

    N Engl J Med

    (2009)
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