Intensive induction in older patients with acute myeloid leukemia: an initial struggle with later rewards?

Sustained remission is a realistic goal of therapy in older adults presenting with acute myeloid leukemia (AML). Despite the fact that no prospective comparison has demonstrated its superiority, the use of an azacitidine-venetoclax combination has become popular even among patients who were previously considered “fit” and would have been offered intensive chemotherapy.^1,2 The high burden of potentially associated devastating adverse events, as well as the unpleasant side effects (e.g., anorexia and alopecia) swayed people away from intensive chemotherapy, particularly considering existing alternatives. It seems that with non-intensive regimens, the risks of tumor lysis syndrome, acute kidney injury and severe infections are sightly lessened. However, many patients with AML are already neutropenic at diagnosis and at risk of infections or other complications due to the leukemia, regardless of therapy. One popular consideration supporting the azacitidine-venetoclax combination over intensive chemotherapy in patients of advanced age is the benefit of the amount of time spent at home (“home stay”) compared to the prolonged admission to hospital that is essential following intensive chemotherapy induction.

In this issue of Haematologica, Jensen and colleagues from the University of North Carolina publish a simple but provocative analysis questioning the common wisdom that the azacitidine-venetoclax combination is associated with a longer home stay than intensive chemotherapy.³ Apparently, calculating the burden of all hospital visits and stays for any leukemia-associated reason, as well as the need for repeated subsequent cycles of azacitidine infusions, leads to a surprising insight. The actual numbers are not in favor of what seems obvious when only the first month following the diagnosis is considered. Reviewing Jensen’s data, it is important to separate patients treated with palliative aims from those who were targeting remission. For the purpose of the current discussion, data regarding patients with AML who were offered azacitidine alone or supportive care are excluded, on the assumption that palliation was the main goal of therapy in these cases. Assuming that patients treated with intensive chemotherapy or the azacitidine-venetoclax combination shared a goal of achieving sustained remission and a lasting period with good quality of life, prolonged home stay was desired for patients in both groups. Surprisingly, and counterintuitively, the data reveal an enormous difference in the length of home stay between the two groups. The mean time patients treated with intensive chemotherapy stayed at home was 7.6 months longer (13.1 vs. 5.5 months) than the home stay of patients assigned to azacitidine-venetoclax. Similar results were reported even when an age-adjusted model was applied, with a 2.4-fold difference in favor of intensive chemotherapy. Moreover, despite identical remission rates, survival with intensive chemotherapy was significantly longer with a median overall difference of more than a year (19.9 vs. 7.7 months) compared to survival with azacitidine-venetoclax. In conclusion, in older adults with AML, accepting some loss of time at home upfront, right after diagnosis, should be carefully considered in many patients as a worthwhile ultimate investment that is a feature of intensive chemotherapy induction. This will often be rewarded when reaching a sustained remission with a prolonged home-time with lesser need for repeat hospital visits. Of note, the feasibility of long-term remission in older adults treated with intensive chemotherapy was demonstrated in a prospective ECOG-ARIN study, E2906. In this prospective trial allogeneic stem cell transplantation was utilized in only 26% of patients and the median disease-free survival of FLT3-wildtype patients (in whom the rate of allogeneic stem cell transplantation was even lower) reached 24 months.⁴

The work by Jensen et al. is a call for physicians to re-evaluate the way they present treatment options to patients debating which route of induction to take (Figure 1). A frequently heard argument guiding treatment selection is to favor home stay over hospitalization. While this is definitely an important parameter essential for good quality of life, the whole anticipated life period should be considered globally, not only the first month of treatment. The burden of adverse events during remission, considering the required repeat cycles of azacitidine infusions and the often-resulting cytopenia, must not be neglected.

Figure 1.Time at home during treatment for acute myeloid leukemia. Fitness for intensive chemotherapy in patients with comorbidities is multifactorial and remaining time at home may serve as one of the arguments for or against a certain treatment. Contrary to the immediate period of induction, in the long run, intensive chemotherapy is associated with longer home stay than treatment with a combination of hypomethylation and venetoclax.

Notably, former research⁵ by the same group, highlights how surprising and worthwhile is a discussion on their current findings. Preliminary assumptions on anticipated outcome may lead to misjudgment and suboptimal clinical decisions. In their former research, the authors asked patients for their views regarding home stay and demonstrated that patients greatly appreciate the value of home stay. Patients even declared that they are “willing to accept some reduction in treatment efficacy in exchange for increased home time” but as physicians our duty is to provide our patients the whole landscape of short- and long-term data regarding home-time so that they, and us, can make the best educated decision. Intensive chemotherapy is not easy, particularly in older adults. Yet, the outcome with intensive chemotherapy has improved significantly over the years with a reduction of induction mortality and morbidity due to improvements in supportive care. The quality of life recorded within the E2906, a recent, large, prospective study of intensive chemotherapy in patients 60 years and older, confirmed that the patients experienced significant improvement in quality of life after recovering from nadir.⁶ The current, important study by Jensen et al. emphasizes the importance of systematically collecting data even on what may apparently look obvious. With a wide perspective supported by comparative data, the jury are still out, not only concerning efficacy, but also regarding the burden of adverse influence on quality of life between intensive and non-intensive therapies for AML.

Footnotes

• Received January 16, 2024
• Accepted January 25, 2024

Correspondence

Y. Ofran yofran@szmc.org.il

Disclosures

No conflicts of interest to disclose.