the Charlson Comorbidity Index Predicts Survival Following Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukemia Patients
Authors: Imataki Osamu , Uchida Shumpei , Oku Maki , Yokokura Shigeyuki , Uemura Makiko , Kadowaki Norimitsu 
Published: October 2019

Abstract
Background: Comorbidity may influence the treatment and long-term quality of life of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). The Charlson Comorbidity Index (CCI) assesses comorbidity by taking into account the severity of 19 precedent comorbid conditions [J Chron Dis 1987; 40: 373]. The CCI was originally introduced as a measure of the mortality risk of general hospitalized patients, and it can estimate the risk of morbidity in a patient with any medical background. The CCI has been validated to predict patients' life expectancy in various underlying diseases, and it is widely used for both hospitalized patients and outpatients. We evaluated the risk of comorbidity at the diagnosis of CML to determine whether treatment with tyrosine kinase inhibitors (TKIs) results in longer survival in a cohort of Japanese patients.
Patients and method: We used a chart review to survey CML patients diagnosed between November 2001 and December 2012 in Kagawa, Japan, where we collected all of the patients based on their registration in another population-based study. Inclusion criteria were (1) diagnosis of CML in the chronic phase during the study period and (2) treatment by TKIs at any point of the study period. Patients of all ages were included. The available TKIs were imatinib, nilotinib and dasatinib. We did not exclude patients treated with two or more TKIs. We used the CCI to evaluate concomitant underlying disease at diagnosis, and we calculated the Sokal and Hasford scores to compare the predictability of prognosis with the CCI at diagnosis. We used the Sokal and Hasford scores as the standard reference.
Results: Eighty (47 male, 33 female) cases were enrolled (median age 56 yrs, range 6-89 yrs). The distribution of CCI scores at diagnosis were 2-11 (median 2). The initial treatment was started in 73 cases by imatinib, two cases by nilotinib, and four by dasatinib (one is unknown). Only one patient underwent stem cell transplantation after 2-yr treatment by imatinib, because of the development of myelodysplastic syndrome (this case was not censored.) As of the last follow-up, the treatment responses were 46 major molecular responses (MMRs), 12 complete cytogenetic responses (CCyRs) and 14 complete hematological responses (CHRs). Seventy-five percent of the cases (60/80) achieved CCyR at 12 mos after TKI administration. We observed only five deaths during the 55.5-mos median follow-up period (0.3-217 mos; 3 pneumonia, 1 cancer and 1 unknown cause). The number of patients according to the given CCI comorbidity risk categories are presented in Table 1. The patient numbers in the risk categories (low/intermediate/high) per the Sokal and Hasford scores were 33/27/7 and 21/43/3, respectively. The CCI scores were significantly correlated with the Sokal and Hasford scores (R >0.5). Twenty-seven cases with a CCI score ≥3 (52 cases had CCI <2) had significantly poor survival both from diagnosis (log rank, P=0.0136) and from TKI treatment (P =0.0025). The most common CCI comorbidity factor was 'diabetes without organ failure.' The most serious comorbidity was 'metastatic cancer,' seen in four cases. CCI scores were inversely associated with overall survival (R = −0.11).
Discussion: In CML, concomitant comorbidity at diagnosis is more strongly associated with survival, especially after TKI treatment compared to after diagnosis. This suggests that TKI treatment may influence patients' health conditions by contributing to the induction of adverse events. Thus, the clinical impact of CCI for CML patients treated with TKIs is supplemental, but CCI is useful to take care of the patient.
Table 1. Numbers of patients according to the given comorbidity risk categories of CCI A. Myocardial Infarction (1 point) 1 B. Congestive Heart Failure (1 point) 3 C. Peripheral Vascular Disease (1 point) 1 D. Cerebrovascular Disease (1 point) 1 E. Dementia (1 point) 5 F. COPD (1 point) 4 G. Connective Tissue Disease (1 point) 1 H. Peptic Ulcer Disease (1 point) 2 I. Diabetes Mellitus (1 point uncomplicated, 2 points if end-organ damage) 7 and 2 J. Moderate to Severe Chronic Kidney Disease (2 points) 2 K. Hemiplegia (2 points) 1 L. Leukemia (2 points) 80 M. Malignant Lymphoma (2 points) 0 N. Solid Tumor (2 points, 6 points if metastatic) 2 and 3 O. Liver Disease (1 point mild, 3 points if moderate to severe) 3 and 0 P. AIDS (6 points) 0

Disclosures
No relevant conflicts of interest to declare.