Researchers have found that patients with psychiatric or substance use disorders may have an increased risk of experiencing poorer outcomes such as early mortality following treatment for acute myeloid leukemia (AML) with venetoclax combination therapies compared with those without a recent history of these disorders, according to new findings presented by Lee et al at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 388). The new research may help explain why venetoclax combination therapies have led to worse outcomes in real-world populations than in clinical trials.
Background
AML accounts for about 1% of new cancer cases per year. The disease is often associated with a relatively poor survival rate; however, it can be cured with a hematopoietic stem cell transplant for patients who are healthy enough to undergo this intensive treatment.
First-line therapies include induction chemotherapy or combination therapies with the oral BCL2 inhibitor venetoclax. Venetoclax combination therapies can offer a less intensive treatment option for patients who are ineligible for chemotherapy, but they show less favorable outcomes in real-world populations compared with clinical trials.
“Psychiatric diagnoses and a history of substance dependence are prevalent problems, not only among veterans but also in the general public,” explained lead study author Michelle Hyunju Lee, MD, Instructor of Medicine at Harvard Medical School and a hematologist at Massachusetts General Hospital. “We have to pay closer attention to these potentially intervenable comorbidities, and we need to get to the root of why [patients] with these disorders are not doing as well. Perhaps early intervention with proper support and resources may improve outcomes,” she added.
Study Methods and Results
In the new study, the researchers analyzed the health records of 452 U.S. veterans with AML who received front-line venetoclax combination therapies, with the goal of determining whether psychiatric and substance use disorders may play a role in the poor survival rates. The researchers noted that the patients involved in the study had a high rate of psychiatric and substance use disorders—which tend to be more common among veterans than among the general population. They reported that 46% of them had at least one psychiatric diagnosis, 19% of them had a substance use disorder, and 11% of them had both. Additionally, 20% of patients died within 60 days of initiating venetoclax combination therapies, and the median overall survival was just over 7 months.
The researchers found that the patients who experienced a psychiatric disorder within 3 years prior to treatment were nearly twice as likely to die within 60 days of initiating venetoclax combination therapies and 28% more likely to die overall compared with those who did not have a psychiatric disorder. Similarly, having a substance use disorder was associated with a lower rate of achieving complete remission.
Only 3% of the patients underwent stem cell transplants, which the researchers characterized as a strikingly low proportion given that nearly 50% of the study participants were young enough to be eligible for this curative treatment. Other real-world studies in adult patients treated with venetoclax combination therapies have shown transplant rates of 8% to 18%. Psychiatric disorders were also significantly more common among younger patients, and no patients with a substance use disorder received a transplant, although it was unclear whether the presence of these disorders had a direct role in determining the number of patients who underwent stem cell transplants.
The association between early mortality and psychiatric disorders was independent of age, sociodemographics, markers of disease risk, and the particular venetoclax combination therapy used. Although the study was not designed to determine the mechanisms involved, the researchers suggested that psychiatric disorders could potentially contribute to biological differences in the response to treatment or pose barriers for medication adherence. A new cancer diagnosis could also potentially trigger a resurgence or worsening of mental health issues.
Conclusions
“While venetoclax combinations have increased the number of patients who can be treated, we still have much to learn in the real world about who can tolerate these regimens well, especially in patients with mental health and other medical comorbid conditions,” emphasized Dr. Lee.
The researchers noted that the association between psychiatric and substance use disorders and negative AML outcomes may partially explain the disparities between the results from clinical trials and real-world practice—especially because many patients are excluded from participating in clinical trials if they have preexisting psychiatric disorders. With rising numbers of mental health comorbidities diagnosed in U.S. individuals, they stressed the significance of finding ways to expand clinical trial access for patients with AML.
The researchers plan to conduct further studies to determine whether the timing or delivery of treatment, the number of doctor visits or rate of appointments not attended, or the timing of active psychiatric or substance use disorders could play a role in the correlations. They concluded that insights into these factors could help pinpoint the optimal strategies to intervene and better support patients affected by psychiatric and substance use disorders during AML treatment.
Disclosure: For full disclosures of the study authors, visit ash.confex.com.
