Risk adjustment ‘negates benefit’ of stem cell transplant for acute myeloid leukemia
SAN DIEGO — The addition of a transplant-specific comorbidity score to risk stratification appeared to negate the survival benefit of hematopoietic stem cell transplantation among older patients with acute myeloid leukemia, according to results of a prospective, multicenter, longitudinal study presented at ASH Annual Meeting and Exposition.
Survival rates following allogeneic HSCT have continued to improve for older patients with AML, according to Mohamed L. Sorror, MD, MSc, associate professor of medicine in the division of oncology at University of Washington School of Medicine, associate member in the clinical research division at Fred Hutchinson Cancer Research Center, and physician at Seattle Cancer Care Alliance.
“Patients aged 61 to 70 years seem to have the biggest improvement in survival over the last decade,” he said, stressing that the population of individuals aged older than 60 years who undergo transplantation is small.
The fundamental question clinicians face when they have a patient in remission is whether they should receive a transplant, Elihu Estey, MD, professor in the division of hematology at University of Washington School of Medicine, member of Fred Hutchinson Cancer Research Center and hematologist at Seattle Cancer Care Alliance, told HemOnc Today.
“For many years, transplants were restricted to people who were relatively young,” he said. “It was felt that the procedure was too intense for older individuals, and that they would die from it. In the last 20 or 25 years, the idea of a reduced-intensity transplant has been developed, permitting transplantation in people even in their 70s.
“Now, the question becomes, if you have a patient in that older age, and they are reasonably fit, should they undergo transplant in their first remission?” he added. “The goal is to decrease the likelihood of relapse, which is the principle reason why people with AML are not cured.”
The issue remains controversial, Estey added. Patients in first remission should get a transplant under the assumption that the results are better; however, there are many factors other than whether they do or don’t undergo transplant that influence outcome, he said.
Researchers sought to develop a transplant-specific comorbidity index to help untangle complicated factors that impact quality of life after HSCT.
“In reality, comorbidity is just one piece of the puzzle, but we also have to include other forms of patient health in order to understand the burden of patient health, especially when it comes to questions about the benefit of transplant in older patient populations,” Sorror said during his presentation. “It’s unclear how much transplantation is actually contributing to global outcomes.”
Researchers followed 705 patients treated at 12 academic institutions from diagnosis of AML through treatment and HSCT.
“We didn’t want to be limited by the exclusion criteria of randomized trials,” Sorror said. “We just wanted to observe clinical practice at different institutions. Our goal is to focus on vulnerable patients.”
Researchers gathered longitudinal data on physical function, quality of life, frailty, gait speed, cognitive function, socioeconomic factors, geriatric syndromes, and depression and anxiety.
“It was a very comprehensive way of assessing these patients at different time intervals,” Sorror said.
The analysis included 24 months of follow-up from the time of diagnosis, from induction to postinduction, and on to transplant, if necessary.
“Transplant, in most cases, was offered in a median time of 3 to 4 months after diagnosis,” Sorror said.
The analysis included two steps — the first was to identify which factors were most important to mortality after AML diagnosis, and the second was to use those risk factors to determine the benefit of transplant.
In the unadjusted analysis, HSCT demonstrated a time-dependent association with overall mortality for the full cohort (HR = 0.62; P = .0003), in vulnerable patients (HR = 0.54; P < .0001), in European Leukemia Net (ELN) response-intermediate patients (HR = 0.53; P = .0005), and ELN adverse-risk patients (HR = 0.3; P < .0001).
However, when the researchers conducted an adjusted analysis accounting for the various factors in their risk score, the survival benefit disappeared. This occurred for all patients (HR = 1.21), vulnerable patients (HR = 1.12), ELN-intermediate patients (HR = 1.2), and ELN adverse-risk patients (HR = 0.85).
Other findings showed that patients with higher comorbidity scores at the time of transplantation had increased risk for mortality, as did patients aged 70 years or older (P < .0001).
“In the adjusted analysis, the benefit of transplant was negated,” Sorror said.
Previous research that adjusted for these factors continued to show benefit of transplant, Estey said.
“But, one thing that Dr. Sorror has put on map is the importance of comorbidities,” he told HemOnc Today. “It’s common sense that someone age 70 years with few comorbidities may be a better transplant candidate than some who is age 62 years with comorbidities, like diabetes or obesity. This study accounts for these comorbidities and, for example, we looked at frailty measured by how fast someone can walk a certain distance. It turns out that if you look at people the same age, those who can walk a certain distance faster than others are likely to live longer.”
It remains difficult to determine if patients who demonstrated benefit did so because they are less frail in general, or because they underwent transplant, Estey said.
“The only way this could be addressed is to do a randomized controlled trial to try to balance out these biases,” he said. “Then we can determine how much of the survival benefit of transplant has to do with frailty and how much has to do with the transplant itself. But, conducting a randomized controlled trial will also have its complications.”
These results may be due, in part, to improvements in both supportive care and non-HSCT therapies, according to Sorror. Still, he stressed that there is work to be done.
“There is a huge gap of knowledge in making therapy choices for this patient population,” he said.
The clinical implications of the findings are “probably nothing,” Sorror said, but the data
may provide information about the way transplant is delivered.
“New trials need to focus on vulnerable patients,” he said. “We need to utilize measures of geriatric health.” – by Rob Volansky
Sorror ML, et al. Abstract 207. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures : Sorror and Estey report no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.