Impact of Comorbidities at Diagnosis of Acute Myeloid Leukemia on One-Year Mortality
Authors: Sorror Mohamed L , Storer Barry E. , Elsawy Mahmoud , Fathi Amir T , Brunner Andrew , Gerds Aaron T. , Sekeres Mikkael A. , Mukherjee Sudipto , Medeiros Bruno C. , Shami Paul , Peña Esteban , Wardyn Shylo , Whitten Jennifer , Frenkel Hannah , McCune Jeannine , Lee Stephanie J. , Estey Elihu H. 
Published: October 2019

Abstract
The hematopoietic cell transplantation comorbidity index (HCT-CI) was specifically developed to assign weighted scores to comorbidities existing prior to allogeneic HCT; thus stratifying post-HCT mortality risks. The utility of comorbidities assessed prior to treatment for AML is unknown. Here, we a) investigated the impact of each comorbidity on 1-year overall mortality of patients (pts) with newly diagnosed AML, b) designed and validated a new comorbidity score (AML-CI) comparing its performance to that of the HCT-CI, and c) identified other relevant risk factors for AML outcomes.
We retrospectively collected comorbidities and laboratorydata from 1079 pts with newly diagnosed AML who received therapy at 5 institutions from 2008- 2012. Pts were aged ≤49 (29%), 50-59 (25%), 60-69 (26%), and ≥70 (20%) years old. Cytogenetic-risks were favorable (21%), intermediate (36%), or unfavorable (43%). Regimen intensity was low in 18%, intermediate in 63%, and high in 19%. HCT-CI comorbidities were evaluated per HCT-CI standard comorbidity definitions with the exception that renal comorbidity was defined per serum creatinine and/or creatinine clearance. Newly evaluated comorbiditiesincluded including hyperlipidemia, hypertension, deep venous thrombosis, gastroesophageal reflux disease, hypothyroidism, hypoalbuminemia, thrombocytopenia, neutropenia, anemia, elevated lactate dehydrogenase (LDH), smoking, and alcohol intake. Pts were randomly divided into a training (n=710) and a testing set (n=369). In the training set, the unadjusted hazard ratios (HRs) for 1-year overall mortality were calculated for each comorbidity as well as all adjustment factors: gender, age, race, cytogenetic-risks, regimen intensity, WBC, blast count, and marrow blast percentages. Only factors that were associated with overall mortality at a significance level of P <.10 proceeded to the multivariate model. Each comorbidity that entered the multivariate model was then adjusted for the effect of other comorbidities as well as gender, age, cytogenetic-risks, and regimen intensity (Table 1). The adjusted HRs were employedas weights for individual comorbidities. In the validation set, the new AML-CI incorporating comorbidities had comparable power of prediction for 1-year overall mortality as the HCT-CI (c-statistic estimates of 0.6 for each). Augmenting the HCT-CI with the three new covariates: platelets, albumin, and LDH yielded c-statistic estimate of 0.61. Other than comorbidities, age (c-statistic of 0.65) and cytogenetic-risks (c-statistic of 0.62) independently predicted overall mortality (Table 2).
Comorbidities at diagnosis of AML heavily influenced the survival of pts over the year following diagnosis. The new AML-CI has similar predictive power as the HCT-CI suggesting appropriateness of using the HCT-CI at diagnosis of AML given its familiarity to physicians. The augmented HCT-CI, age, and cytogenetic-risks independently stratified for risks of 1-year mortality. In the future, studying physical, cognitive, and social health might further clarify the prognostic role of increasing age. Targeting health limitations with interventions alongside specific AML-therapy might improve survival of patients.
Table 1. Components of a new AML-CI based on multivariate evaluation of impact of comorbidities on 1-year mortality after diagnosis of AML Comorbidities HR Assigned score for AML-CI Arrhythmia* 1.0 ─ Coronary Artery* 1.1 ─ Valvular* 1.3 1 Cerebrovascular * 1.3 1 Hepatic* Mild 1.2 ─ Moderate/severe 1.2 ─ Renal* Mild 1.1 ─ Moderate/severe .8 ─ Pulmonary* Mild .9 ─ Moderate/severe 1.1 ─ Diabetes* 1.3 1 Tumor* 1.7 1 Peptic Ulcer* 1.3 1 Psychiatric* 1.3 1 Hyperlipidemia 1.0 ─ HTN 1.2 ─ Albumin <4 - 3.5 1.3 1 <3.5 - 3 1.2 1 <3 1.7 1 Platelets <100 - 50 1.2 ─ <50 - 20 1.4 1 <10 1.7 1 LDH >200 - 500 1.5 1 >500 - 1000 1.4 1 >1000 2.2 2 Smoking Former 1.2 ─ Current 1.1 ─ *included comorbidities within HCT-CI
Table 2. Probabilities of 1-year survival per 6 different models in the validation set AML-CI HCT-CI Augmented HCT-CI* Score % OS Score % OS Score % OS 0-1 18 69 0 20 72 0-2 24 70 2 28 68 1-2 35 61 3-4 28 63 3 30 56 3-4 28 57 5-7 33 58 ≥4 23 45 ≥5 18 42 ≥8 15 34 Age Cytogenetic-risks Augmented HCTCI* + age + cyto Group % OS Group % OS Score % OS 0-49 27 81 Favorable 19 87 2-4 17 86 50-69 51 60 Intermediate 36 63 5-7 37 67 70+ 22 31 Unfavorable 45 45 8-10 27 54 ≥11 19 28 *included HCT-CI + albumin, platelet counts and LDH

Disclosures
Fathi: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy; Exelexis: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding. Sekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Lee:Kadmon: Consultancy; Bristol-Myers Squibb: Consultancy.