Weighing the benefits of hematopoietic stem cell transplantation for older and medically infirm patients with acute myeloid leukemia

From the Sorror Group, Clinical Research Division

Acute myeloid leukemia (AML), a cancer that begins in the bone marrow, is often treated with allogeneic (from a donor) hematopoietic stem cell transplantation (HCT) to re-establish healthy bone marrow function, and utilize the donor immune cells to prevent relapse of the AML. While HCT procedures continue to advance and survival outcomes continue to improve, older populations – those patients aged 65 years and older – remain at greater risk of poorer outcomes. This is further compounded by the fact that older populations are more likely to receive a diagnosis of AML, and to be living with co-morbidities that may preclude their eligibility for HCT. A recent novel study led by Dr. Mohamed Sorror, an Associate Professor in Fred Hutch’s Clinical Research Division, sought to better elucidate the potential benefits of HCT in older patients with AML. Dr. Sorror and colleagues designed an observational study, recently published in Blood, that over the course of 8 years assessed overall survival and the impact on quality life after receiving HCT in patients with AML, a majority of whom were >60 years of age. Their use of an observational study design allowed for a more comprehensive review of ‘real world’ patient scenarios, that were not limited by clinical trial eligibility criteria that often exclude a wide range of co-morbidities reflected in the general population. The authors designed their study to start from diagnosis of AML hence encompassing a wide range of participants, reflecting those who did and did not receive HCT, and those who had favorable, intermediate, and adverse risk according to European LeukemiaNet (ELN) diagnostic guidelines, among other clinical characteristics. Describing the study in further detail and the impact it will have for older patients with AML, Dr. Sorror said “the study set the stage for the need for randomized trials specific for older and medically infirm patients with AML and comparing HCT versus non-HCT therapies to clarify which patient subgroups could benefit the most from the procedure. The study also highlights the importance of accounting for patient-risk factors and geriatric assessments, in both the clinic and research studies, to better calibrate the impact of patients’ health on treatment decisions and outcomes.”

At the study outset, participants were asked to rank their treatment goals and an overwhelming majority (80%) stated that cure was their primary goal. Cure remained the primary goal for participants at later study timepoints, regardless of whether they received HCT or not. However, much lower percentages of physicians estimated a strong possibility of cure with/without HCT. “The discordance between patient and physician opinions with respect to cure is alarming and not necessarily totally new as it has been pointed out in previous AML studies. Our study is unique to show that patients who received or did not receive HCT had similar expectations for cure and similar goals of cure versus quality of life while the physicians who made the treatment decisions for their patients expected higher cure chances for those selected to receive HCT. This highlights a possible disconnect between patients and their physicians in understanding the treatment decision-making process, the prognostic tools used to make these decisions, and the impact of different treatments offered to the patients at the time. A room for improvement exists where better education tools about AML therapies, their impacts and outcomes can be explored to narrow the gap between physicians and their patients in expectations for cure especially when complex procedures like HCT are being discussed,” explained Dr. Sorror.

Multivariable models determined no improvement in overall survival rates in older or medically infirm patients who received an allogeneic hematopoietic stem cell transplant (HCT) compared to those who did not suggesting the need for randomized trials.
Multivariable models determined no improvement in overall survival rates in older or medically infirm patients who received an allogeneic hematopoietic stem cell transplant (HCT) compared to those who did not suggesting the need for randomized trials. CR1 – First complete remission, ELN – European LeukemiaNet diagnostic guidelines, HR - Hazard ratio Figure adapted from the original publication.

Overall survival was the primary outcome and the authors started by analyzing the data in a univariate model. They noted that patients who received HCT had a reduction in mortality risk compared to those who did not receive HCT. This mortality risk reduction was also observed in the subgroup analysis of patients with intermediate and adverse ELN risk. However, in their multivariate model, that accounted for co-morbidities and other health measures, these findings did not remain constant. In fact, the authors described no significant improvement in overall survival in patients who received HCT, in analysis of the entire cohort and in defined subgroups (older patients, those with comorbidities, those with intermediate ELN diagnostic risk, and those in their first complete remission from AML), compared to those who did not receive HCT. When accounting for quality-of-life (QOL) outcomes in their multivariate model as a secondary outcome, the authors observed better QOL scores in patients who were selected for HCT compared to those who never received HCT which highlights “the possible selection bias in offering allogeneic HCT to the healthiest candidates (regardless of the aggressiveness of AML),” commented Dr. Sorror. Further, as analysis accounted for changes over time, these two groups performed similarly, with no significant differences being observed between the post-HCT and never received HCT subgroups. The authors hypothesize that although patients with better QOL scores were more often selected for HCT, the lack of difference observed in the post-HCT and never received HCT groups suggests that this health benefit is often lost after receipt of HCT further highlighting “the need for randomized trials to make the best possible decision about an individual patient’s suitability for allogeneic HCT,” said Dr. Sorror.  

The results from this study “raise questions whether we can improve our current process to select patients for allogeneic HCT by performing randomized studies to ask the question about the role of HCT for three distinctive groups of older patients 1) those who are medically fit and have intermediate risk AML, 2) those who are medically fit and have measurable residual disease, 3) and those who are medically unfit and have advanced risk AML. These randomized studies could help direct the best candidates to benefit from HCT to receive the transplant and avoid HCT for those who might not receive benefit,” stated Dr. Sorror. “This is particularly important as there has been a surge lately in the number of older patients receiving allogeneic HCT in the nation with the oldest patient given a transplant aged 88 years old. It is important to ensure that we are doing benefit and no harm by offering such an important procedure but also making sure we do not exclude patients who might benefit from HCT,” he concluded.  

This work was funded by awards from the Patient-Centered Outcomes Research Institute, the American Cancer Society, and the American Society of Hematology.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Dr. Mohamed L. Sorror, Dr. Ted Gooley, Dr. Wendy Leisenring, Dr. Stephanie Lee, Dr. Brenda M. Sandmaier, Dr. Frederick R. Appelbaum and Dr. Elihu Estey contributed to this work.

Sorror ML, Gooley TA, Storer BE, Gerds AT, Sekeres MA, Medeiros BC, Wang ES, Shami PJ, Adekola K, Luger S, Baer MR, Rizzieri DA, Wildes TM, Koprivnikar J, Smith J, Garrison M, Kojouri K, Schuler TA, Leisenring WM, Onstad LE, Becker PS, McCune JS, Lee SJ, Sandmaier BM, Appelbaum FR, Estey EH. An 8-year pragmatic observation evaluation of the benefits of allogeneic HCT in older and medically infirm patients with AML. Blood. 2023 Jan 19;141(3):295-308. doi: 10.1182/blood.2022016916. PMID: 36260765.