Elderly patients with acute myeloid leukemia who only receive supportive care in the Surveillance, Epidemiology and End Results-Medicare database: demographics, treatment patterns and outcomes

Acute myeloid leukemia (AML) is a rapidly progressing malignant disorder of the blood and bone marrow. In AML, there is a block in myeloid differentiation and uncontrolled proliferation of abnormal myeloid progenitors that accumulate in the bone marrow and blood [1]. It is the second most commonly diagnosed leukemia in adults and children, but most cases occur in adults [2]. It is often observed in elderly patients with a median age of 68 years at diagnosis in the USA [2] and 63–71 years in the UK, Canada, Australia and Sweden [3]. Although the 5-year overall survival (OS) is estimated to be 28.3% for all patients with AML, it is 3–8% for patients ≥60 years old [4]. Without antileukemic treatment, most AML patients die within a few months [5,6].

Administration of optimal antileukemic treatment can be challenging in elderly AML patients due to their general health condition. Consequently, these undertreated elderly patients often have inferior outcomes [5]. Several biological and clinical factors among the AML patient population affect their treatment and prognosis, including comorbidity and performance status, organ dysfunction and cytogenetic abnormalities [5,7,8]. The choice of therapy for these patients is determined by their treatment status i.e., if a patient has or has not received prior treatment, or has relapsed. This in turn impacts their prognosis. Disease-related factors including etiology (de novo, secondary, or therapy-related AML) and baseline bone marrow blast percentage, among others, influence the disease course, treatment and outcomes of AML patients [5,9,10]. Therefore, it is often difficult to balance treatment benefits and associated risks (mortality and side effects) in these patients. This is particularly challenging in the elderly AML patient population as they are often unable to tolerate intensive antileukemic therapy and hematopoietic stem cell transplant [5,11].

In 2020, the American Society of Hematology guidelines for treating newly diagnosed AML in older adults supported the utilization of antileukemic treatment over best supportive care [12]. Among the treatment options for elderly patients with AML, intensive therapy (e.g., anthracyclines and cytarabine, gemtuzumab ozogamicin, FLT3 inhibitors, or CPX-351) or low-intensity treatment (e.g., hypomethylating agents [HMA] like decitabine or azacytidine, venetoclax-containing regimens, venetoclax with HMA, venetoclax with low-dose cytarabine [LDAC], glasdegib with LDAC, gemtuzumab ozogamicin, or ivosidenib and enasidenib) have been used as treatment approaches that depend on age and cytogenetic risk [4]. Best supportive care or palliative treatment has been utilized to ameliorate the symptoms of the disease and for managing the side effects of treatments [4,13]. Supportive care options include transfusion therapy during remission induction treatment, growth factors (e.g., colony-stimulating factors, erythropoiesis-stimulating agents, and thrombopoietin mimetics) and antimicrobial therapy [13].

Among patients with AML ≥60 years who are not suitable for intensive remission induction therapy or those who decline therapy and do not have actionable mutations, National Comprehensive Cancer Network (NCCN) guidelines outline best supportive care as an ‘other recommended’ option using hydroxyurea and/or transfusion support [14]. Best supportive care is also considered as a treatment option after standard induction for patients ≥60 years with residual disease. For those who have had post-induction therapy, best supportive care can be considered after previous intensive therapy and induction failure or after previous lower-intensity therapy with no response or progression. After completion of consolidation therapy, AML surveillance and therapy for relapsed/refractory disease with supportive therapy is recommended for patients ≥18 years. In remission, growth factors are considered as part of supportive care for post-remission therapy. According to NCCN guidelines, supportive care is advised as a treatment option for patients whose condition has deteriorated to a point where active treatment can no longer be considered, or for the prevention of deterioration of their general health that makes the patient intolerant to standard AML therapy [14]. However, until intolerable, intensive therapy is recommended over low-intensity therapy and antileukemic therapy is recommended over best supportive care based on moderate evidence from American Society of Hematology 2020 guidelines [12]. When patients experience side effects of treatment such as neutropenia or are at high risk of functional and cognitive declines due to the disease or treatment, supportive care options are generally recommended. Granulocyte-colony stimulating factor are used, although not routinely, during consolidation therapy when remission has been achieved. However, Granulocyte-colony stimulating factor in older patients has not conferred survival benefits [4].

A significant percent of elderly AML patients do not receive active antileukemic therapy due to their disease complexity despite the evidence that they greatly benefit from it [6,15,16]. A review of the literature describing the treatment characteristics of AML patients in the USA reported that the proportion of patients not receiving active antileukemic treatment was 10–61.4% (weighted average: 30%) [5]. It was assumed that these patients were given the best supportive care. AML patients included in the studies reviewed by Hubscher et al. did not receive active antileukemic therapy if they were of advanced age, had a higher comorbidity index, and an uncontrolled chronic comorbidity due to suboptimal therapy or non-adherence [5].

AML patients who did not receive active antileukemic treatment had inferior OS (median: 1.2–4.8 months; weighted average: 1.7 months) [5]. A retrospective study (2003–2011) using the National Cancer Database from the USA evaluated AML patients and reported nontreatment with active antileukemic therapy in 25.3% patients [17]. Explanation for why these patients were not treated was not provided for most patients (72.8%). Other reasons included presence of contraindications (11.4%), refusal of therapy (11.3%) and death before therapy (3.8%) [17].

The Surveillance, Epidemiology and End Results (SEER)-Medicare database has been utilized to characterize the elderly AML patient population in a few published studies. In a retrospective cohort study (1997–2007) using this database, the majority (57%) of the 4058 elderly AML patients were treated with supportive care only while 43% received chemotherapy. One-year mortality in chemotherapy-treated patients versus those treated with supportive care was 69.1 and 95%, respectively; their corresponding median survival was 7.0 months and 1.5 months [18]. A study conducted by Medeiros and colleagues evaluated data on 8336 patients with AML, during 2000 and 2009, who were 66 years and older [19]. In the 90 days post-diagnosis, 40% of these patients were treated with chemotherapy while 60% were not. Among patients not treated with chemotherapy, it was unknown if they received supportive care. The median unadjusted OS was longer for patients treated with intensive therapy (18.9 months) compared with those treated with HMA therapy (6.6 months) and those receiving no treatment (1.5 months) [19]. As a follow-up to their original publication, Medeiros et al. assessed data on 11,142 AML patients included in the SEER-Medicare database during 2000 and 2013, with Medicare enrollment data through 2015. Similar to their previous analysis and the study by Meyers and colleagues, in the 90 days post-diagnosis, 43% of these patients were treated with chemotherapy while 57% were not; their corresponding median survival was 5.3 months and 1.6 months, respectively [20].

In a recently published retrospective analysis of SEER-Medicare database using data from 2008–2015, Dharmani et al. showed that for elderly AML patients that do not have AML secondary to myelodysplastic syndrome (MDS), only 27.2% are treated with active antileukemic therapy, with an additional 41.9% of patients receiving supportive care only. A new mutually exclusive cohort of no treatment (no active antileukemic therapy and no supportive care) was identified in this analysis [6].

Consistent results from past SEER-Medicare analyses reveal a stagnant standard of care with a high disparity in treatment for elderly AML patients and a lack of understanding of the reasons for this disparity. Results from previously published studies provide evidence that a significant percent of elderly AML patients receive supportive care only; however, none of them have focused on clearly defining this cohort. The objective of this study is to analyze the demographics, comorbidities, survival and prognostic factors for survival of this unique cohort of elderly AML patients who are only treated with supportive care.

Materials & methods

Patient population

In this observational study, the SEER-Medicare database was used to retrospectively analyze data on a cohort of elderly AML patients that was treated with supportive care only. Two large, distinct and national databases in the USA, SEER and Medicare, are linked to form the SEER-Medicare database. This combined population-based database includes comprehensive data on cancer patients who are Medicare beneficiaries. SEER collects data on cancer patients from various locations and sources throughout the USA and provides their cancer statistics. SEER captures data on 47.9% of all cancer patients in the USA. The information collected on these cancer patients includes patient demographics, cancer identification (diagnosis date and diagnostic confirmation method, source of reporting and primary malignancy status), cancer details, course of initial treatment and death [21].

Medicare, a federal healthcare plan, covers qualifying individuals who are ≥65 years old and select adults with disability in the USA. Medicare database includes enrollment data, billing data submitted by providers (provider, service and treatment details), and claims data on prescriptions (for Medicare beneficiaries that opt for Part D) [22]. Data on all cancer patients captured by SEER registries is sent to the National Cancer Institute. This data is then linked with data collected in the Medicare database resulting in the combined SEER-Medicare database. Most recent SEER to Medicare linkage has reported match rates of 95.7% (range: 91.1–99.2%) for cancer patients who were ≥65 years of age. Individuals who have End Stage Renal Disease or have a disability, as they are Medicare eligible, are also captured in this database [23]. Previous studies have also described these databases [6].

Inclusion/exclusion criteria

In this study, data on AML patients included in the SEER-Medicare database was analyzed. Patient data from year 2008 to 2015 was assessed with a follow-up until 2016. The study cohort was defined by AML diagnosis using SEER recodes 35021 and 35031, patient age ≥65 years, continuous enrollment of ≥12 months pre-index date, and no diagnosis of any other malignant cancer. Index date was defined as a patient's first date of AML diagnosis during the study period.

Exclusion criteria included treatment with lenalidomide (for MDS), treatment with vincristine (for blastic plasmacytoid dendritic cell neoplasms), patients with secondary or therapy-related AML (to prevent confounding as these patients have a history of prior malignancy and treatment with various chemotherapy regimens, transplant and/or radiation). These patients are a different subset of AML patients as their survival and treatment is impacted by their prior history and exposure. Also, there was a likelihood of misclassification if stratification by AML type was attempted due to challenges associated with validation of these diagnosis codes in the SEER-Medicare database. Patients with disability or End Stage Renal Disease were excluded if it was the reason for their original enrollment. Enrollment in Medicare Part D was not required; however, the study identified drugs from it. Therefore, if a patient did not have enrollment in Medicare Part D, no outpatient drugs could be identified.

Using the AML treatment guidelines [24,25], a separate list of drugs was created for antileukemic treatments, transplant drugs and supportive care (Supplementary Tables 1–3). These were used to create three distinct buckets of AML patients resulting in three mutually exclusive patient cohorts: patients treated with antileukemic drugs and/or transplant (AML treated cohort), patients only treated with supportive care (supportive care only cohort) and patients who did not receive any treatment, neither antileukemic therapy nor supportive care (no treatment cohort; Figure 1). If an AML patient was treated with an antileukemic drug (Supplementary Tables 1 & 3 [24–26]) or had a transplant (confirmed by International Classification of Diseases [ICD] procedure codes, Healthcare Common Procedure Coding System codes, Diagnosis-Related Group codes, and ICD diagnosis codes; or use of transplant drugs listed in Supplementary Table 4), it was included in the ‘AML treated’ cohort. These patients were excluded from this analysis.

A list of supportive care treatments (Supplementary Table 2) was developed by using both AML treatment guidelines and palliative care guidelines [24,25]. If an AML patient received a drug on this list post-index and did not receive AML treatment or transplant, it was included in the supportive care only cohort. AML patients who were treated with supportive care on a post-index date with drugs listed in Supplementary Table 2 and those patients that had evidence of no treatment but may have a history of treatment with drugs listed in Supplementary Table 2 were temporally stratified. These criteria have also been described previously [6]. Patients without evidence of AML treatment, transplant, or supportive care were excluded from this analysis. This study focuses on the analysis of supportive care only cohort. Analysis of the ‘No treatment cohort’ has been previous published [6]; evaluation of the ‘AML treated’ cohort will be published subsequently.

Statistical analysis

SEER recodes 35021 and 35031 were used to identify diagnosis of AML in the database; the date of first AML diagnosis was defined as the index date. Availability of the full diagnosis date (day/month/year) was necessary for a patient to be included in this analysis. As SEER only reports the month and year of diagnosis of a patient, patients were excluded if the month or year was missing. When they were available, first day of the month was assigned as the diagnosis date [6].

Descriptive statistics were calculated for assessing patient demographics and evaluating comorbidities and mortality. In addition, summary statistics of survival of these patients were calculated (30-day, 60-day and 90-day; >1-year vs ≤1-year analyses). Frequencies of various supportive care therapies were estimated for patients included in this cohort by their duration of survival. Also, frequencies of relapse and remission codes populated for patients included in this cohort were calculated.

Medicare provides a list of 24 preselected and validated comorbidities that are predefined for any analysis. For this study, 22 of these comorbidities were analyzed (Table 2). The two comorbidities that were excluded were colorectal cancer and lung cancer as per the requirements of exclusion criteria of this study. The prevalence of these 22 comorbidities was evaluated in this cohort at baseline and at the end of follow-up (until 2016). The dataset has an onset date for each comorbidity which was used to compare with the diagnosis index date for each patient to categorize the onset of comorbidity (before, on/after) relative to the index AML diagnosis date. Kaplan-Meier was used to analyze survival of patients included in this cohort. Prognostic factors for survival were assessed using a multivariate Cox proportional hazards model.

Results

Patient population

The analysis identified a total of 7665 elderly AML patients in the SEER-Medicare database during 2008–2015. Of these, 3209 (41.9%) patients received supportive care only during follow-up period (Figure 1). At the index date, patients included in the supportive care cohort had a mean age of 79.0 (±7.5) years. Half of the patients included in this cohort were males (50.5%; n = 1622); more than 81% were white. Remaining patients were black (7%) and other races (11%). The largest proportion of these patients (48.6%) was from the Western region of the USA (California, Washington and Hawaii). Table 1 provides detailed statistics on patient demographics and their geographical distribution.

Comorbidities

The comorbidities with highest prevalence at baseline included anemia (68.9%), hypertension 66.6%), hyperlipidemia (58.7%), cataract (52.7%) and ischemic heart disease (IHD; 47.2%). On/after AML diagnosis, anemia (16.2%), chronic kidney disease (CKD; 15.6%), congestive heart failure ( 9.6%) and IHD (5.7%) were the most prevalent comorbidities in these patients (Table 2).

Survival

By the end of study follow-up period, 95.4% patients of this cohort died. Of these, 48.2 and 82.2% died within 90 days and one-year of their index date, respectively. The attributable cause of death was reported as AML for 77.9% patients and it was other diseases for 10.1% patients. Table 3 provides detailed survival statistics for this cohort.

At the end of study follow-up period, only 9.9% patients who were 65 to 74 years old survived; 90.1% died. AML was reported as the attributable cause of death in 79.2% of these patients. Similarly, 97.3 and 98.6% of the 75–84 and 85+ year olds died, respectively; AML was listed as the attributable cause of death in 79.1 and 74.2% of these patients. For 368 (12%) patients in this cohort, the attributable cause of their death was not listed (Table 4).

Kaplan-Meier plots were generated for assessing the survival of patients included in the overall cohort (Figure 2) and comparing survival of patients by various age-groups (Figure 3). Their respective 95% Hall-Wellner Bands are also presented. The plots highlight that most patients of this cohort die within the first few months of their index date and their survival probability decreases sharply over time.

Of the entire cohort, only 13.2% patients were alive after one year of their index date. When stratified by age, 28.9, 15.3 and only 7% of the patients in the 65–74-, 75–84-, and 85+-year age group were alive after 1 year, respectively. After 2 years of the index date, only 2.6% patients in the 85+ year age group were alive. The proportion of patients that were alive after 5 years of the index date in the 65–74- and 75–84-year age groups was <4.3 and <1.7%, respectively (Table 5). All patients in this cohort died within 108 months (9 years) of their index date.

Survival: 30-day, 60-day & 90-day analyses

Of this cohort, 12.5, 34 and 48.2% patients died within the first 30 days, 60 days, and 90 days, respectively. Demographics of this cohort that died within the 30-, 60- and 90-days of the index date are presented in Table 6. Analysis of these 1546 AML patients estimated their mean age as 80.7 (±7.4) years. Of these, 9.4% were 65–69 years old, followed by 14.4, 20.4, 24.3, and 31.6% in the 70–74-, 75–79-, 80–84-, and 85+-year age groups, respectively. Also, 51.4% were females; distribution of their race was White: 83.8%, Black: 6.5%, and other: 9.7% (Table 6).

Supportive care treatments received by patients that died within 30 days, 60 days and 90 days of the index date are presented in Table 7. Higher proportion of AML patients were treated with various supportive care therapies who survived 60–90 days when compared with those AML patients who died in <60 days and in <30 days. Only 20.7% of AML patients that died within 90 days received red blood cells, and 11.8% received platelets. Most common supportive care therapies in patients dying within 90 days were levofloxacin (quinolone antibiotic: to prevent infection), acetaminophen (non-steroidal anti-inflammatory drug to manage mild cancer pain), ondansetron (serotonin 5-HT₃ receptor antagonist: to prevent nausea and vomiting), morphine (opioid: to manage chronic cancer pain of moderate to severe intensity), allopurinol (xanthine oxidase inhibitor: to decrease uric acid levels) and furosemide (loop diuretic: to manage edema and hypertension); however, only 10–16.2% AML patients who died within 90 days received them.

Survival: >1 year versus ≤1 year

Of this cohort, 82.2% patients died within 1 year of their index date. The mean age of 572 patients (17.8%) who survived more than one year was 75.3 (±6.4) years (range: 65.0–96.3 years). These patients were predominantly of white race (79.9%) and male gender (51.2%). When compared with patients who died during the first year, patients surviving more than a year had a lower mean age (79.8 vs 75.3 years). When compared with white patients included in this cohort, a greater percent of black and other race patients were alive after one year (18.2 vs 20.1%). The percent of male patients that died within the first year and who were alive after one year was 50.4 and 51.2%, respectively.

When compared with patients who died within the first year, those that were alive after one year had fewer comorbidities at baseline: anemia (71.3 vs 57.5%), hypertension (69.2 vs 54.2%), hyperlipidemia (60.7 vs 49.8%), cataract (55.2 vs 41.1%), IHD (49.7 vs 35.7%), arthritis (46.9 vs 36.2%), congestive heart failure (37.8 vs 25.3%), CKD (37.2 vs 25.0%), diabetes (35.5 vs 29.0%), chronic obstructive pulmonary disease (COPD; 30.5 vs 17.7%), depression (26.4 vs 20.1%), benign prostatic hyperplasia (21.0 vs 16.6%), hypothyroidism (20.7 vs 15.9%), glaucoma (19.1 vs 14.0%), atrial fibrillation (18.7 vs 11.4%) and stroke (16.5 vs 11.7%). In addition, at baseline, a higher proportion of patients that died within the first year had comorbid dementia (16.8 vs 8.4%), asthma (13.8 vs 8.7%), acute myocardial infarction (AMI; 6.6 vs 2.4%), Alzheimer's disease (6.3 vs 2.8%) and hip fracture (3.5 vs 2.6%).

When compared with AML patients who died within one year, a smaller percent of patients who died after one year during follow-up received red blood cells (26.2 vs 13.7%), platelets (16.1 vs 10.9%), allopurinol (13.3 vs 10.9%), prochlorperazine (12.2 vs 11.1%), morphine (11.8 vs 8.5%), hydroxyurea (11.1 vs 9%), lorazepam (7.9 vs 7.6%) and diphenhydramine (7.3 vs 6.6%). However, a higher proportion of these patients received levofloxacin (21.7 vs 26.5%), acetaminophen (16.3 vs 22.5%), ciprofloxacin (14.4 vs 22.7%), acyclovir (14.1 vs 22.2%), fluconazole (12.4 vs 18.7%), ondansetron (16.2 vs 17%), furosemide (14.2 vs 15.4%), pantoprazole (6.6 vs 10.4%), lidocaine (6 vs 10.4%), prednisone (6.7 vs 10.2%) and megestrol (6 vs 8.3%; Table 8). In addition, 5–10% of the AML patients who did not die within the first year received oxycodone, metronidazole, hydrocortisone, vancomycin, zolpidem, methylprednisolone, triamcinolone, tramadol, dexamethasone and fentanyl compared with <5% of the patients who died within 1 year (Table 8).

When compared with AML patients who died after 1 year, patients who survived more than 1 year and did not die during follow-up, a lower proportion received levofloxacin, ciprofloxacin, acetaminophen, acyclovir, fluconazole, furosemide, red blood cells, omeprazole, prochlorperazine, platelets, allopurinol, pantoprazole and lidocaine for supportive care. A higher proportion of survivors received ondansetron and prednisone for supportive care (Table 9).

Prognostic factors for survival

The results of the Cox proportional hazards model identified that following as prognostic factors for survival in this cohort: older age, concurrent CKD, AMI, hypertension, diabetes and COPD (Table 10).

ICD code tabulation for relapse & remission status

When crosstabulation of ICD codes for relapse (20502, C9202, C9242, C9252) and remission (20501, C9201, C9251) status was conducted for patients included in this cohort (n = 3209), the proportion of patients with relapse, remission and both codes was 6.3, 8.4 and 4.8%, respectively. Similarly, crosstabulation of relapse and remission codes for patients that were alive after 1 year (n = 572) yielded the proportion of patients with relapse, remission and both codes to be 10.3, 23.1 and 14.9%, respectively (Table 11). Based on the available codes, it can be inferred that of the patients that were alive after the first year, 38% were in remission. Assuming that all the patients that survived past 1 year were in remission, based on the available codes, it can be inferred that at least 39.2% of these patients relapsed during follow-up.

Advantages & limitations

Data on cancer patients from an estimated 48% of the population in the USA is captured by SEER registries and is included in the SEER database. When this SEER data is linked with Medicare data, the resulting SEER-Medicare becomes a unique and large database with valuable data on elderly individuals who have cancer, including the ones who have AML. In this study cohort, the evidence of limited missing data validates the quality of data and accuracy of this analysis. Additionally, data on patient diagnoses and their mortality is collected by SEER registries, assuring its accuracy. This is an important advantage of using this database for this study. Using both, the National Drug Codes (NDC) and Healthcare Common Procedure Coding System codes, ensured collection of complete data on treatments given to these AML patients. Another advantage of this study was the availability of data for a long duration providing sufficient follow-up data on these patients for survival analysis. Finally, Medicare provides data on a list of preselected comorbidities that are validated and can be utilized for research. This list was used for analyzing this study cohort.

In this study cohort, the completeness of ICD codes for relapse and remission status of patients was inadequate; it did not match in frequency with patients potentially in remission or those that had relapsed. However, neither relapse nor remission codes were used to assess demographics, comorbidities, survival, or prognostic factors in this analysis. All patients that survived past 1 year with only supportive care are expected to be in remission, yet less than 40% of these had remission codes populated. There were an additional 10% of patients that had relapse codes only, which raises serious questions regarding the completeness of these codes in the database.

As patients included in this cohort were ineligible for Medicare before turning 65 years, it is not possible to ascertain their medical history including their treatments before their entry in the SEER-Medicare database. Certain patients may have been covered by private insurance besides Medicare, data from their additional coverage cannot be captured for inclusion in this research. Also, it is not possible to ascertain the etiology of a comorbidity in AML patients in the SEER-Medicare database. For example, anemia could be a sequela of a patient's leukemia, or it could result from CKD or another chronic disease. Another limitation of this study is that the data included in this analysis only spanned 2008–2016. There have been many changes in the treatment landscape of AML, particularly since 2018, with the emergence of targeted therapies e.g., FLT3 inhibitors, isocitrate dehydrogenase (IDH) inhibitors, anti-CD33 drugs. These were not included in this analysis due to the prespecified end date of the data.

Discussion

A large proportion (41.9%) of the patients diagnosed with AML in the SEER-Medicare database (2008–2015) received supportive care only. This cohort was mutually exclusive from the previously described untreated (no antileukemic therapy, transplant, or supportive care) cohort of elderly AML patients [6]. Adding together both cohorts, an estimated 73% of the entire AML population ≥65 years old are not treated with active antileukemic therapy and/or transplant. This is significantly higher than previously described in the published literature [5,18,19].

There is a strong possibility that the patients included in this cohort either received antileukemic therapy or fully exhausted all treatment avenues prior to entry into the database. They may be ineligible to receive antileukemic therapy once they entered the database due to preexisting medical conditions or may have been in remission. Also, some of these patients may have declined antileukemic therapy due to personal or family reasons. Likely, the reasonings would be similar to those previously described [6]. However, why some patients only receive supportive care while others receive no treatment at all are unclear.

Under the NCCN guidelines, best supportive care is generally reserved for patients who are unable to tolerate non-intensive chemotherapy and do not have actionable mutations, or patients who decline therapy. Best supportive care is also an option after induction failure and after relapse of AML [14]. As these patients did not receive antileukemic treatment over the study period, the likelihood of induction failure is low. These elderly patients would likely have an unacceptable quality of life under chemotherapy, so they may have chosen to decline antileukemic therapy to preserve their quality of life. Additionally, given their unknown treatment history prior to becoming Medicare eligible, patients could have relapsed after being in remission for a number of years. These patients could have been initially diagnosed with AML before the age of 65 years and been successfully treated; however, due to database limitations, prior history would not be captured. After entry into the SEER-Medicare database, they could have subsequently relapsed. Patients with active AML disease due to the aforementioned reasons would be expected to die within a few months with best supportive care only. Indeed, in this study, 48.2% of the supportive care only cohort died within the first 90 days after AML diagnosis. However, an additional 34.0% died between 90 and 365 days postdiagnosis and 17.8% of the cohort survived past 1 year postdiagnosis. Decline of therapy, relapse of AML and exhaustion of available treatments do not fully explain the proportion of patients that survived past 90 days and even 1 year. There seems to be another group of patients within this cohort that do not have active AML disease. Likely, they are in remission and are continuing to receive supportive care treatments only.

The majority (67.3%) of patients receiving supportive care only died within 180 days and 82.2% died within 365 days postdiagnosis, respectively. This was in line with expectations and is consistent with previous findings [18]. When compared with those who received no treatment [6], elderly AML patients that received supportive care survived much longer regardless of age group. Around 18% of patients receiving supportive care only survived past 12 months versus 2% of those who received no treatment at all [6]. Very likely, these patients are in remission as they would not be alive with active disease unless they are treated with antileukemic therapy. In addition, results of the crosstabulation show that ICD codes for patients' relapse and remission status were inadequately entered in the SEER-Medicare database. This is validated by the fact that only 37.9% of the 572 patients surviving longer than 12 months had ICD remission codes populated.

In a review including assessment of data from 12 studies, Hubscher et al. found that elderly patients with AML were less likely to be treated with antileukemic therapy [5]. This was consistent with the findings from our study. Another important factor associated with nontreatment with active antileukemic therapy was the presence of a higher comorbidity index or an uncontrolled chronic comorbidity in these patients [5]. Similar to Hubscher et al., the findings of this analysis show that the patients included in the current study cohort had a high comorbidity burden which impacted their likelihood of receiving active antileukemic therapy. Hubscher et al. reported that AML patients who were not treated with active antileukemic therapy had worse OS compared with those who received it [5]. The median survival (range: 1.2–4.8 months) for patients that did not receive any antileukemic therapy [5] was comparable to current findings, with a median survival of around 90 days for those that received supportive care only.

In an observational study including 8336 AML patients >66 years old who were analyzed retrospectively, 40% received chemotherapy within 3 months of AML diagnosis in the SEER-Medicare database [19]. Treated patients were more likely to be younger, male and married, and less likely to have secondary AML, poor performance indicators, and comorbidity scores compared with untreated patients [19]. Within 30 days of diagnosis, 24% of patients died while that number increased to 47% by 60 days. Stratifying by treatment status, 9% of treated patients and 31% untreated patients died within 30 days of diagnosis. Compared with the Medeiros et al. analysis, our study found a smaller proportion (27%) of patients treated with active antileukemic therapy and a higher proportion of untreated patients (73%). Additionally, our analysis excluded prior MDS patients as well as examined specific agents used in best supportive care. For survival, a previous analysis of those treated with no active antileukemic therapy nor supportive care found that 46.6% of patients died within 30 days and 79.7% by 60 days [6], much higher than that reported by Medeiros et al. under best supportive care, 12.5% of patients died within 30 days and 34% died within 60 days, which was much lower than that reported by the Medeiros et al. study.

When comparing elderly AML patients who received supportive care only and died within a year of their index date, a smaller proportion of patients that were alive after 1 year used certain supportive care agents. These included red blood cells, platelets and morphine. This could potentially be due to disease severity on presentation. Comparatively, those that survived more than 1 year had significantly more utilization of levofloxacin, acetaminophen, ciprofloxacin, acyclovir, fluconazole, prednisone, pantoprazole, lidocaine and omeprazole (Table 8).

Another important observation in our study was that the majority of AML patients captured in this analysis were white (81.5%); only 7.5% of the patients were black and 11% were of other races/ethnicities. Additionally, in the Medeiros et al. study, nonwhite races made up 12.6% of the AML sample [19]. This racial disparity over time raises questions regarding the distribution of AML in the broader population across ethnicities.

Implications of these findings & conclusion

Results of this analysis show that a significant percentage of elderly patients with AML are only given supportive care; they do not receive antileukemic treatment. The majority of these patients are over 78 years old. Various factors can explain their non-treatment with active antileukemic therapy, such as the patients' comorbidity status, fragile health condition, individual or caregiver preference and relapse after previous antileukemic therapy. In these patients, older age, concurrent AMI, CKD, COPD and hypertension were identified as prognostic factors associated with decreased odds of survival.

Most elderly patients with AML who are treated with supportive care only die within a few months, 48.2% during 3 months of the index date. Regardless of their age, most of these patients die due to disease progression (74.2% [85+ years] to 79.2% [64–74 years]). Patients who were alive 1 year following the index date without active antileukemic treatment (17.8%) are assumed to be in remission. Contrary to this finding, ICD codes for their remission status were inadequately entered in the database. Also, a significant percent of these patients would have received antileukemic therapy prior to entry into the database and would have subsequently relapsed. However, an ICD code for relapse status was entered in the database for 11.2% patients.

For elderly AML patients treated with supportive care only who were alive after 1 year (17.8%) without being treated with antileukemic therapy, it can be assumed that they were in remission. These patients constituted 28.9, 15.3 and 7% of the patients included in the 65–74, 75–84, and 85+ year age groups, respectively.

Several attributes of elderly patients with AML complicate their health condition in turn may prevent their treatment with intensive chemotherapy. However, these patients should ideally receive antileukemic therapy besides the best supportive care. As almost 50% of the elderly AML patients who receive supportive care only die within 90 days of their index date, there is opportunity for new antileukemic therapies for treating these patients, besides supportive care, for improving their survival. In addition, effective management of comorbidities, such as hypertension, COPD, CKD and AMI, in these elderly patients will increase their likelihood for receiving antileukemic therapy.

Recent clinical research has identified a few treatments that have been shown to be effective in elderly patients with AML, including those patients who have other comorbid conditions. As reported by Hubscher et al. [5], the proportion of elderly AML patients that are treated with antileukemic therapy has consistently increased since the year 2000.

In 2018, the US FDA approved the drug venetoclax for treatment of newly diagnosed elderly (≥75 years) patients with AML, and for those AML patients who were not eligible to receive intensive induction chemotherapy due to their comorbidity burden [27]. It was approved to be used in combination with azacitidine, decitabine, or LDAC for treating these patients. AML patients treated with venetoclax and azacitidine combination had a survival of 14.7 months compared with 3 months in those who did not receive active antileukemic treatment [27]. These results demonstrate the benefit of treating these elderly AML patients with non-intensive chemotherapy. However, these treatments do not account for the genetic profile of elderly AML patients, such as their FLT3 mutation status.

There is an urgent need for further research to develop alternate antileukemic therapies for treatment of elderly patients with AML, especially for those who have high comorbidity burden and poor overall health condition. Also, there is a need for a robust, multidisciplinary approach to correctly frame the elderly AML population. Paired with this approach, to help guide clinical decisions, there should be a standardized specification of factors that make elderly AML patients candidates for intensive or non-intensive chemotherapy, and supportive care.

Furthermore, efforts should be made to completely enter the ICD codes for relapse and remission status of these patients in the SEER-Medicare database. This will enable further characterization of the relapsed/refractory elderly AML patient population and enhance the assessment of the prognostic factors for their survival, leading to ultimately improving the quality and accuracy of research findings.