ALBERT

Description: Background With an aging population, the burden of comorbidity in AML patients is expected to increase. Evidence on how to integrate comorbidity and functional status into clinical decision making is sparse and prior studies have been predictive and limited by single center study design, and small sample sizes. Objectives To examine the impact of comorbidity and WHO Performance Status (PS) on intent of treatment in Danish AML patients. Secondary, to determine the prognostic impact of comorbidity and PS on achievement of complete remission, short- and long-term mortality in AML patients treated with curative intent. Methods In a nationwide cohort study, we identified all AML (non-promyelocytic leukemia) patients diagnosed in Denmark from 2000-2013 using a population-based leukemia registry (n=2785) which prospectively collects clinical data. We excluded patients with unknown intent of treatment (n=25). We identified comorbid conditions through the Danish National Registry of Patients. Comorbidity was evaluated according to presence of 17 of the 19 chronic diseases (HIV and leukemia excluded) in the Charlson Comorbidity Index with separate adjustment for all diseases associated with secondary AML (modified CCI (mCCI)). Crude and adjusted odds ratios (OR) and corresponding 95% confidence intervals (CI) for receiving treatment with curative intent were estimated. We used Cox proportional hazards regression to assess the influence of comorbidity and performance status on 90-day and 90-day to 3-year mortality in patients treated with curative intent (n=1444) by estimating crude and adjusted mortality ratios (MRs) and corresponding 95% CIs. We adjusted for age, gender, leukocyte count, prior chemo-/radiotherapy, and prior hematological diseases. Results Of 2760 patients 52% were treated with curative intent. Median age was 69 years (palliative intent: 78 vs. curative intent: 58). Overall, 60% of patients did not have any comorbidity, 26% had 1 comorbid disease, and 13% had 2 or more comorbidities. In patients treated with curative intent, the corresponding prevalences were 76%, 19%, and 6%. Overall, 26% of patients had PS=0, 42% had PS=1, and 32% had PS ≥2. The corresponding figures in patients treated with curative intent were 33%, 47%, and 20%. Dementia and heart failure were the two individual comorbid diseases most strongly associated with opting-out of intensive treatment (prevalence ratio 0.11 (95%CI 0.01-0.67) and 0.24 (95%CI 0.15-0.37). In patients treated with curative intent, those with comorbidity had lower complete remission rate than those without comorbidity, 66% (95%CI 60.7-70.7) vs. 74% (95%CI 70.8-76.9) whereas choice of chemotherapy regimen and dose did not differ. Compared to patients without comorbidity (mCCI=0), the adjusted ORs for treatment with curative intent were 0.57 (95%CI 0.41-0.73) for patients with 1 comorbid disease and 0.32 (95%CI 0.22-0.47) for 2 or more. Compared to patients with PS=0, the adjusted ORs of treatment with curative intent were 0.80 (95%CI 0.58-1.09) for PS 1, 0.45 (95%CI 0.31-0.65) for PS 2, and 0.09 (95%CI 0.05-0.14) for PS≥3. Crude survival curves according to comorbidity and PS are shown below. Crude and adjusted MRs are listed in table 1. Conclusions The chance of being allocated to intensive chemotherapy decreased dramatically with increasing number of comorbid diseases and increasing PS. Surprisingly, among patients treated with curative intent presence of comorbidity was not associated with an increase in short-term mortality, and if any, only a slight increase in long-term mortality. High PS was strongly associated with both short- and long-term mortality. Our findings may be explained by the selection process before treatment with curative intent and raises the question whether more patients with comorbidity and low PS at time of diagnosis may benefit from intensive treatment. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1477 Previous studies have documented the underrepresentation of women and elderly patients in American clinical trials of leukemia. If, characteristics of patients included in clinical protocols differ markedly from the characteristics of the majority of patients treated outside protocols the external validity of clinical trials may be threatened. Methods: The Danish National Acute Leukaemia Database (ALDB) includes detailed data on a large well-defined non-selected population of 2729 AML patients (covering 〉95% of AML patients diagnosed since Jan 2000). Since 2000 Danish AML patients have been included in 3 different British protocols (AML15, 16 and 17). We analysed a cohort of 2624 patients diagnosed with AML in Denmark since Jan. 2000 (105 APL-patients were excluded). We compared patients treated with curative intent according to the British protocols with patients treated with curative intent off-protocol with regard to characteristics, possible prognostic factors, CR-rate, and survival. For comparable groups we divided patients into 2 age groups (

Description: BACKGROUND Treatment of acute myeloid leukemia (AML) is widely centralized at specialized centers. Longer distances to a specialized treatment facility may affect patients' access to curative-intended treatment and ultimately survival. Few studies have focused on the potential distance decay association in hematological cancers and limitations include small sample size and lack of individual-level socioeconomic, clinical, and treatment information. AIM We designed a large national population-based cohort study of all AML patients diagnosed in Denmark between 2000-2014 (followup ending 2017) to investigate the effect of distance on treatment intensity and outcome considering individual-level clinical and socioeconomic factors. METHODS Demographics, clinical, and outcome data were obtained from the Danish National Acute Leukemia Registry (DNLR). Socioeconomic information was retrieved from registries at Statistics Denmark (Figure 1). Distance to specialized treatment centres was calculated using shortest route (Google Maps) from city center of habitation and categorized into groups. We investigated effects of distance to nearest specialized treatment center on chance of receiving intensive chemotherapy using logistic regression analysis (odds ratios; ORs). In intensive therapy patients, we calculated chance of complete remission (CR [ORs]) and in allogeneic transplantation (HSCT) candidates; we estimated chance of HSCT (ORs). Overall survival was calculated for all patients and in intensive therapy patients only using cox regression (Hazard Ratios; HRs). All results were adjusted for sex, age, and individual-level socioeconomic (ethnicity, income, education, and occupation) and disease-related factors (WBC, secondary or therapy-related AML, cytogenetics, performance status, and comorbidity). Results were given crude and adjusted with 95% confidence intervals (CI), and stratified by age (

Description: Abstract 3542 The prognosis of acute promyelocytic leukemia (APL) has improved markedly over the last two decades. Clinical trials have demonstrated excellent survival of patients receiving anthracycline-based chemotherapy in combination with all-trans-retinoid acid (ATRA). It is not clear whether the excellent survival results demonstrated in clinical trials during recent years, also do apply to unselected patients including elderly and frail patients for whom a clinical trial may not be available. In order to investigate survival and death rates in APL over the course of treatment, we conducted a retrospective analysis of survival in 105 consecutive APL-patients diagnosed in Denmark January 2000 through June 2012. Data were retrieved from the Danish National Acute Leukemia Registry which covers 95 – 100 % of all acute leukemia cases diagnosed in Denmark since January 2000 (not including children). A diagnosis of APL was confirmed in 105 (3.9 %) of 2726 adult patients (age ≥ 15 years) with acute myeloid leukemia (AML) diagnosed in Denmark during the 12½ year period. This corresponds to an incidence rate of 1.53 APL cases per million inhabitants per year. The diagnosis of APL was based upon cytogenetic analysis (performed in 96 (91 %) of cases), and/or interphase FISH (iFISH), and/or RT-PCR in a total of 100 cases. In 5 cases clinical signs and morphological changes in bone marrow were highly suggestive of APL and these cases were, thus, deemed to have APL. Median age at diagnosis of APL was 50 years (range 15 to 83 years) and median leukocyte count was 2.65 (range 0.2 to 99.0 × 109/L). In 104 patients with data available for analysis, very early death (VED, within the first week from the date of diagnostic bone marrow) occurred in 10 cases (9.6 %), and early death (ED, death within 30 day from diagnosis) occurred in 22 (21 %) cases. Death between day 30 and 5 years from diagnosis occurred in 11 cases. No deaths were seen after 5 years from diagnosis. For all patients, estimated overall survival at 10 years was 65 % (Figure 1). Patients surviving beyond day 30 from day of diagnosis (82 cases) had an excellent overall survival of greater than 80 % at 10 years (Figure 2). Survival of patients were strongly correlated with WHO-performance status whereas age over 50 years and presenting leukocyte count greater than 10 × 109/L could not be definitely associated with inferior survival (Table 1 and Figure 3). Table 1. Factors of importance to survival in unselected APL-patients Probability of overall survival (Univariate Cox Regression, nevaluable= 104) Probability of overall survival (multivariate Cox Regression, nevaluable= 101) Variable Hazard ratio 95% CI of HR P value Hazard ratio 95% CI of HR P value Age (≤50 vs. 〉50 years) 2.17 1.07–4.42 0.03 1.44 0.67–3.09 NS WHO performance status (0–1 vs. ≥2) 5.20 2.57–10.5 〈 10−4 4.06 1.88–8.78 〈 10−4 WBC (≤10 × vs.〉10 × 109/L) 1.76 0.86–3.61 NS 1.62 0.79–3.33 NS From this population-based analysis we conclude that early death continues to be the predominant hazard to patients with APL. Two thirds of deaths in APL-patients do occur during the first month from diagnosis. Patients with a poor performance status at disease presentation carry a particularly dismal prognosis. For all APL-patients, every possible effort should be made to facilitate prompt diagnosis and speedy initiation of treatment with ATRA and anthracycline-based chemotherapy. When timely applied, currently available treatments are highly effective and result in cure in a high proportion of patients including elderly patients and patients with high leukocyte count at time of disease presentation. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2003 The prognosis of patients suffering from AML with manifestations of accompanying extramedullary leukemia (EML) including myeloid sarcoma (MS) compared to that of AML patients not exhibiting EML manifestations is still an open question as results from previous studies have been contradictory most likely due to selection bias. Here we present an analysis performed in a cohort of 2261 patients representing 〉90% of all AML patients diagnosed and treated in Denmark during the eleven-year period January 2000 through December 2010. The goal was to investigate the prognostic impact of presence of EML at time of AML diagnosis by a retrospective population- and registry-based analysis Of these patients, 219 (9.7%) showed signs of EML at time of AML presentation. Anatomic sites of EML were: lymph nodes (3.0%), skin (2.7%), spleen (1.7%), oral (1.3%), CNS (0.4%), testes (0.2%), other sites (1.1%), and two or more anatomical sites (0.5%). In 27 cases myeloid sarcoma was not accompanied by AML in the bone marrow and, thus, presented as isolated MS. In total, 1168 of the 2261 (52 %) patients were treated with curative intention. Allogeneic stem cell transplantation (Standard allo in 105 cases, and reduced intensity conditioning (RIC) transplant in 90 cases) was conducted in a total of 195 patients (118 in CR1, 65 in CR2, and 12 during other disease stages). Overall the frequencies of allogeneic transplantations in curatively treated patients were 13.7% in patients with EML and 8.5% in patients without EML. The presence of EML at time of leukemia diagnosis had no statistical significance to probability of obtaining complete remission (CR), nor to duration of overall survival (OS) (Table 1. and Fig. 1). By contrast, well-established prognostic parameters such as presenting cytogenetic abnormalities (categorized according to revised MRC-criteria, D. Grimwade et al. Blood, 2010), age, leukocyte count, and type of leukemia (secondary vs de novo) were all found to be statistically significant to probability of attainment of (CR) and to duration of OS in uni- as well as multivariate analyses. Gender was of borderline statistical significance with respect to probability of attainment of CR and to OS (Table 1).Figure 1Years from AML diagnosisPatients with EML(n = 132)Patients without EML(n = 1007)p-value (log-rank test) = 0.51Figure 1. Years from AML diagnosis. / Patients with EML. / (n = 132). / Patients without EML. / (n = 1007). / p-value (log-rank test) = 0.51Table 1.Factors of significance to probability of attainment of CR and to overall survival (OS)Probability of CR (Logistic regression, nevaluable = 927)Probability of overall survival (Cox regression, nevaluable = 958)VariableOdds ratio (OR)95% CI of ORP valueHazard ratio95% CI of HRP valueEML––0.82––0.54Age1.061.04–1.08

Description: Abstract 3586 The prognosis of leukemia patients suffering from secondary AML (sAML) compared to that of patients with de novo AML is dismal. The group of sAMLs is heterogeneous and includes AML arising from an antecedent myelodysplastic (MDS) or myeloproliferative neoplasm (MPN), and AML caused by cytotoxic therapy (tAML). In the present retrospective population- and national registry-based analysis we identified 612 (27%) patients as having some form of sAML. Cytogenetic risk group patterns and clinical outcomes among the different categories of sAML were compared to those of 1635 de novo AML cases identified in a total population of 2261 patients (data missing in 14 cases). The cohort represents 〉90% of all AML patients diagnosed and treated in Denmark during the eleven-year period January 2000 through December 2010. The following groups of sAMLs were identified: A. Patients with an antecedent MDS or chronic myelomonocytic leukemia (324 cases), B. Patients with antecedent MPN (excluding chronic myeloid leukemia, 108 cases), C. Patients previously treated with chemo- and/or radiotherapy for another hematological neoplasm (113 cases), and D. Patients previously treated with chemo- and/or radiotherapy for another non-hematological neoplasm or disease (67 cases). For all 1168 curatively treated patients in the total cohort, presenting cytogenetic abnormalities (categorized according to revised MRC-criteria, D. Grimwade et al. Blood, 2010), age, leukocyte count, and type of leukemia (secondary vs. de novo) were all prognostic parameters found to be highly statistically significant to probability of attainment of complete remission (CR) and to overall survival (OS) in univariate as well as multivariate analyses, data not shown. There were strikingly fewer patients showing favorable cytogenetic abnormalities among sAMLs. Focusing on the above defined 4 categories of sAML, patterns of cytogenetic risk group distribution were strikingly and statistically significantly different (nevaluable= 418, p-value, Chi-square