Inferior Outcomes with Intensive AML Induction Therapy in Patients Age 70 or Greater Compared to Age 60-69

Background: The median age of diagnosis for acute myeloid leukemia (AML) is between age 65 and 70.  While advances in therapy and supportive care in the past several decades has significantly improved outcomes in younger patients, the prognosis in elderly AML patients, defined as age 60 or greater,  remains dismal.  In addition, many elderly patients are unable to receive such aggressive therapy due to increased treatment-related mortality and poorer clinical response.  There remains great interest in identifying factors that are associated with both beneficial and detrimental outcomes in this patient population.   

Methods: This was a retrospective analysis conducted at Moffitt Cancer Center.  The primary study objective was to compare the incidence of 30-day mortality of patients aged 60-69 years vs. patients 70 years or older with newly diagnosed AML who received intensive remission induction chemotherapy.  Secondary endpoints included 60-day mortality, overall survival (OS), complete response rate (CR), receipt of allogeneic hematopoietic stem cell transplant, rate of infection, cardiac complications, major organ failure, ICU transfer, and any other treatment-related complications.  Baseline patient characteristics at diagnosis were summarized using descriptive statistics including mean, median, standard deviation, and range for continuous measures and proportions and frequencies for categorical measures.  The primary outcome was assessed via chi-squared analysis.  Assuming treatment-related mortality is 5% in the younger patients and 15% in patients > 70 years old, with a 2-sided p-value of 0.05, a sample size of 300 would provide a power of 0.83 to detect this 10% difference in mortality.  Overall survival was estimated using the Kaplan-Meier method, and compared using a log-rank test.  Univariate and multivariate analyses using Cox-Regression models were conducted to identify factors affecting OS.

Results: A total of 246 patients with newly diagnosed AML between age 60-69 (n=132) and 70 or greater (n=114) who underwent initial remission-induction chemotherapy between July 2009 and July 2014 were identified and included in this analysis.  Background characteristics and known factors that affect CR and OS such as overall risk category and performance status were well matched between groups. Sixty-four (56%) patients in the older and 62 (47%) patients in the younger group received 7+3 induction chemotherapy, whereas 41 (36%) in the older and 50 (38%) in the younger group received cladribine-based regimens. The remainder of patients received clinical trial induction chemotherapy.  Twenty-three (17.4%) of patients in the younger patient group underwent immediate re-induction chemotherapy, compared to 8 (7%) patients in the older group (p=0.02).  

Thirty day mortality rate was 6.8% (9) in the younger group and 14% (16) in the older group (p=0.062).   By day 60 after initiation of induction chemotherapy, 13.6% (18) and 23.7% (27) of patients in the younger and older cohorts, respectively, were deceased (p=0.031).  No difference was noted in infection rate, ICU transfer, major organ failure, percentage of patients intubated, incidence of tumor lysis syndrome, or initiation of parenteral nutrition.

Seventy-nine (59.8%) patients in the younger arm achieved CR, compared to 51 (44.7%) patients in the older arm (p=0.003).    Median OS was 10.4 months and 8.3 months in the younger and older group respectively (p=0.002). Significantly more patients in the younger group went on to receive stem cell transplant. Multivariate analysis of the composite group revealed age >75, risk category, prior therapy with hypomethylating agents, and number of comorbidities were predictors of poorer survival.

Conclusions: The presented study demonstrates that intensively-treated patients age ≥70 have an increased early treatment-related mortality, similar treatment-related morbidity, and a lower incidence of CR and OS compared to patients age 60-69.  Additionally, prior hypomethylator use, risk category and comorbidities contribute to poorer survival. These observations give further insight into the role of intensive remission chemotherapy in an elderly AML patient population. 

Table 1. Multivariable Analysis Overall Survival (p = <0.05)

	Hazard Ratio	95% CI
Age >75	1.5	1.06-2.20
Risk Category	1.1	1.01-1.16
Prior Hypomethylator	1.6	1.17-2.12
No. of Comorbidities	1.1	1.04-1.20