Effect of time of admission to treatment initiation on outcomes of patients with acute myeloid leukemia: a tertiary care referral center experience
Background The time from diagnosis of acute myeloid leukemia (AML) to initiation of treatment could affect patient outcomes, but findings from previous studies have been mixed.
Objective To analyze the impact of the time from adm ission to treatment initiation (TAT) on overall survival (OS) and event-free survival (EFS) in patients who are newly diagnosed with AML.
Methods A retrospective review of the records of all newly diagnosed AML patients treated at the Oklahoma University Health Sciences Center from January 2000 through June 2015 was conducted. Inclusion criteria also included age ≥18 years and available insurance data. Data on patient characteristics, laboratory values, pathology, treatment, response, and survival were obtained from the electronic medical records.
Results In all, 154 patients were divided into 2 groups: those with a TAT of 0-4 days (n = 109) and those with a TAT of >4 days (n = 45). The median OS of the TAT 0-4 days group and the TAT >4 days group was 1.3 years and 0.57 years, respectively(P = .0207), and the median EFS for the groups was 1.21 years and 0.57 years, respectively (P = .0392). That association remained significant in a multivariate analysis adjusting for age, white blood cell count, molecular risk group, and undergoing allogeneic stem cell transplant.
Limitations Study limitations include a small sample size and a short median follow-up time.
Conclusion Patients with AML who are treated more than 4 days after admission have a lower OS and EFS compared with patients treated within 0-4 days of admission.
Funding/sponsorship None
Accepted for publication September 13, 2018
Correspondence Sami Ibrahimi, MD; Sami-Ibrahimi@ouhsc.edu
Disclosures Cherry is on the advisory board of Gilead. The remaining authors report no disclosures or conflicts of interest.
Citation JCSO 2018;16(5):e188-e193
©2018 Frontline Medical Communications
doi https://doi.org/10.12788/jcso.0428
The median OS for all patients was 10.9 months (95% CI, 8.3-15.1), and the median EFS was 9.1 months (95% CI, 7.4-13.8). Median follow-up time was 8.6 months (95% CI, 6.7-11). We found a significant association between TAT and both OS and EFS without any adjustment (Table 2).
The median OS for the TAT 0-4 days group was 15.6 months, and for the TAT >4 days group, it was 6.8 months (P = .0207; Figure 1). The median EFS for the TAT 0-4 days group was 14.5 months, and for the TAT >4 days group, it was 6.8 months (P = .0240; Figure 2).
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We found no association between the day of admission to hospital (Monday-Thursday vs Friday-Sunday) and either OS or EFS. After adjusting for age, WBC count, molecular risk status, and undergoing AlloSCT, the OS was shorter for those who received treatment >4 days after admission compared with those who received treatment within 0 to 4 days, with a hazard ratio (HR) of 1.59 (95% CI, 1.02-2.49; P = .0427; Table 3).
There was no association between day of admission with OS in the multivariable analysis. Similarly, after adjusting for age, WBC count, molecular risk status, and undergoing AlloSCT, EFS was shorter in patients who received treatment >4 days after admission compared with those who received treatment within 0 to 4 days (HR, 1.64; 95% CI, 1.06-2.54; P = .0268). There was no association between day of admission with EFS in the multivariable model. Although there was a trend for a higher CR rate with earlier treatment, this was not statistically significant (Table 4).
Discussion
Treatment outcomes for patients with AML are known to be affected by several patient- and disease-related factors. Patient-related factors can include age, performance status, comorbidities, and availability of a stem cell donor. Examples of disease-related factors include molecular alterations and site of disease involvement. Little is known about whether the timing of treatment initiation affects patient outcomes. Short-term treatment delays after the diagnosis of leukemia are not uncommon. Generally, patients are treated with anthracycline-based induction chemotherapy, but the response rate and survival are particularly poor in the older age group.12 Moreover, increasing comorbidities with aging are expected to lead to lower treatment tolerability.13 Therefore, elderly patients are particularly prone to treatment delays while providers await the results of the molecular studies to guide the use of less intensive targeted therapies.10 Other reasons for treatment delays may also include transfers between hospitals, suspected or documented infections, and evaluation of chronic illnesses. Our analysis also indicates that admission to the hospital on the weekend contributes to a delay in therapy compared with admission on a weekday.
We found a decreased OS and EFS in patients who received treatment >4 days after admission to the hospital compared with patients who received treatment within 0 to 4 days of admission. This association was statistically significant in a bivariate analysis as well as in a multivariable analysis with adjustment for age, WBC count on presentation, molecular risk group, and undergoing AlloSCT. A previous large retrospective study showed that the time from diagnosis to treatment initiation predicts survival in younger, but not older, patients with AML.10 This remained true after adjusting for age, performance status, WBC count, and the type of AML in a multivariable analysis. In our study, the declines in overall survival and event-free survival were evident after a delay of more than 4 days.
Another retrospective study that included 599 newly diagnosed AML patients, with a median time from diagnosis to treatment of 8 days, did not show any impact of treatment delay on overall survival, early death, or response rate.11 These differences in the effect of treatment delay on outcomes could be related to the differences in baseline characteristics of patients in these studies. Our study had a higher proportion of patients younger than 60 years, for example. We hypothesize that treatment delays, especially in patients with a high WBC count on presentation, might lead to further organ compromise and poorer outcomes with chemotherapy.
In our study, a higher proportion of patients were admitted over the weekend in the >4 days TAT group, but when we analyzed the day of admission to hospital separately, it was not associated with OS or EFS. Admission over the weekend was also not associated with clinical outcomes including 30-day mortality in a larger study that included 422 patients treated at a large teaching referral hospital.14
Limitations of our study include a small sample size and a short median follow-up time. Most of our patients were young and white, which may not be representative of the general population.
In conclusion, we found that treatment delays are associated with inferior outcomes in AML patients. It remains to be elucidated whether the benefit gained from using targeted and less-intensive chemotherapy, especially in elderly patients, outweighs the potential harm from delaying treatment. Additional studies are needed to confirm our findings in different settings and patient populations.
