# Consistency Test between Scoring Systems for Predicting Outcomes of Chronic Myeloid Leukemia in a Saudi Population Treated with Imatinib

Authors: Haneen R. Banjar; Enaam Alsobhi
Journal: International Scholarly Research Notices
 (2017)

---

## Abstract

Inconsistency in prognostic scores occurs where two different risk categories are applied to the same chronic myeloid leukemia (CML) patient. This study evaluated common scoring systems for identifying risk groups based on patients’ molecular responses to select the best prognostic score when conflict prognoses are obtained from patient profiles. We analyzed 104 patients diagnosed with CML and treated at King Abdulaziz Medical City, Saudi Arabia, who were monitored for major molecular response (achieving aBCR-ABL1 transcript level equal to or less than 0.1%) by Real-Time Quantitative Polymerase Chain Reaction (RQ-PCR), and their risk profiles were identified using Sokal, Hasford, EUTOS, and ELTS scores based on the patients’ clinical and hematological parameters at diagnosis. Our results found that the Hasford score outperformed other scores in identifying risk categories for conflict groups, with an accuracy of 63%.


---

## Body

## 1. Introduction

The Australian Institute of Health and Welfare (AIHW) classified myeloid cancers as the ninth most commonly diagnosed cancer in 2016, with more than 3,600 cases in Australia [1]. Chronic myeloid leukemia (CML) is also known as chronic myelogenous leukemia or chronic granulocytic leukemia. The bone marrow produces an unusual number of white blood cells. The bone marrow could produce an excessive number of immature white blood cells and lead to progressive disease. Consequently, the bone marrow cannot make enough red cells, normal white cells, and platelets [2].Prognostic scores in patients with CML are used to stratify CML patients according to risk profile to ensure appropriate treatment. Historically, the science of prognostication has evolved rapidly, and various scoring systems have been developed to optimize the use of clinical experience in CML treatment. These scores were developed using logistic regression with the selection of the patients’ clinical and hematological parameters at diagnosis. The common prognostic scores have shown variable correlation with complete cytogenetic response (CCyR) [3–8] and major molecular response (MMR) [9–12]. Although the investigation compared the prognostic value of the validated scoring systems in overall survival (OS), event free survival (EFS) or optimal response in CML patients who receive frontline imatinib, applying the established prognostic scores in a comparative fashion and questioning the value of scoring systems, especially with regard to inconsistency in risk category, has not been considered in previous studies.The European LeukemiaNet (ELN) current recommendations for the management of CML are basically addressed to the goal of achieving an at least MMR [13]. As newly diagnosed CML patients should be stratified based on the available prognostic scoring systems, we considered the risk groups might be studied based on the MMR outcomes. This is needed to evaluate the clinical impact of the existing prognostic scores by comparison of prognostic risk groups with primary concern on consistency in prognostic scores outcomes. Inconsistency occurs when two different risk categories are applied to the same CML patient; that is, one prognostic score classifies the patient in one group and the other score contradicts the first classification. Consistency in prognostic scores used to estimate the risk group of CML patients before therapy commencement can increase clinician trust in the treatment decision and play important role in modern medicine for CML changing treatment modalities [14, 15]. However, conflict between prognostic scores is observed in some CML patients. Thus, it is important to study consistency between prognostic score categories used to allocate CML patients to risk groups in order to support clinician decision-making.Our analysis evaluated the different scores outcomes with the long-term molecular response in patients treated with imatinib to determine which was the best prognostic score to apply where a conflict prognosis was generated by prognostic scores.


## 2. Materials and Methods

### 2.1. Study Population

Participants in this study were members of the Saudi population diagnosed with CML and treated at King Abdulaziz Medical City, Jeddah [16]. A total of 104 CML patients received 400 mg imatinib as the initial therapy. Patient characteristics are described in Table 1. All of the patients monitored their MMR in time points defined by ELN [13] where MMR is defined as achieving aBCR-ABL1 transcript level equal to or less than 0.1% at 12 months by RQ-PCR.Table 1
Characteristics of 95 patients with CML at diagnosis.
Factor Median Range SD Age (yrs) 40.21 18–74 15.13 Spleen size (cm, BCM) 8.33 0–25 7.53 Platelet count (×109/L) 510.97 4.42–2876 439.88 Basophils (%) 1.32 0–7 1.10 Eosinophils (%) 0.83 0–0.07 1.24 Peripheral blast (%) 1.50 0–10 1.39 SD = standard deviation; BCM = below costal margin.


### 2.2. Scoring Systems in CML

Four common prognostic scoring systems are available for CML patients prior to commencing therapy: (1) the Sokal score [17], (2) the Hasford score [14], (3) the European Treatment and Outcome Study (EUTOS) score [15], and (4) the EUTOS long-term survival (ELTS) score [18]. These four scores ascertain the level of risk for CML patients by running multivariable regression analysis. Prognostic scores were calculated using formulas in Table 2, based on the patients’ clinical and hematological parameters at diagnosis.Table 2
The current methods used to identify risk in CML.
Scoring systems Study Factors Equation Method Risk categories Target prediction Data and results Sokal score, Sokal et al. [17] Age, spleen size (cm), blast (%), and platelets (109/L) exp(0.0116 × (age [years] − 43.4)) + 0.0345 × (spleen size [cm] − 7.51) + (0.188 × ((platelets [109/L]/700)2 − 0.563)) + (0.0887 × (blasts [%] − 2.10)) Multivariate analysis of survival Low-risk score < 0.8, of patients, intermediate-risk in 0.8–1.2, and high-risk > 1.2 Risk groups for chemotherapy Six European and American sources (n=813), low 39%, intermediate 38%, and high 23%  Hasford score, Hasford et al. [14] Age, spleen size (cm), blasts (%), eosinophils (%), basophils (%), and platelets (109/L) (0.6666 × age [0 when age < 50 years; 1 otherwise]) + (0.0420 × spleen size [cm]) + (0.0584 × blasts [%]) + (0.0413 × eosinophils [%]) + (0.2039 × basophils [0 when basophils < 3%; 1 otherwise]) + (1.0956 × platelet count [0 when platelets < 1500 × 109/L; 1 otherwise]) × 1000 Multivariate analysis of survival Low-risk score ≤ 780, intermediate-risk in 781–1480, and high-risk ≥ 1481 Risk groups for interferon alpha alone 14 studies (n=981), low 40.6%, intermediate 44.7%, and high 14.6%  EUTOS score, Hasford et al. [15] Basophils (%) and spleen size (cm) (7 × basophil [%]) + (4 × spleen [cm]) Multivariate analysis of response Low-risk score < 87 and high-risk ≥ 87 CCgR at 18 months to imatinib Five national study groups (n=2,060), low 79% and high 21%  ELTS score, Pfirrmann et al. [18] Age, spleen size (cm), blast (%), and platelets (109/L) 0.0025 × (age in completed years/10)3 + 0.0615 × spleen size below costal margin + 0.1052 × blasts in peripheral blood + 0.4104 × (platelet count/1000)−0.5 Multivariate analysis of response Low-risk score ≤ 1.5680, intermediate-risk in 1.5680–2.2185, and high-risk > 2.2185 Long-term survival (n=2,205), low 61%, intermediate 27%, and high 12%The analysis is conducted in two steps: (1) studying the prognostic index using combined groups and (2) consistency analysis between the risk categories obtained from the scoring systems. First, from Table2, the EUTOS score is the only score that classifies CML patients into low risk and high risk. The number of categories in comparative prognostic scores in Sokal, Hasford, EUTOS, and ELTS was three, three, two, and three, respectively. Accuracy was measured on prognostic score data by assuming two different combined groups: (1) low and intermediate risk in Sokal, Hasford, and ELTS scores as low risk and (2) intermediate and high risk in Sokal, Hasford, and ELTS scores as high risk.Secondly, in consistency analysis, the combined category is selected based on the higher-accuracy results from combined groups to study the inconsistency between scoring systems. We are dealing with two models advising on the same patient. Each score may provide an index that conflicts with the other. The patients were classified into a consistency group or an inconsistency group. The consistency group included patients who observed consistent risk categorization from scoring systems, while the inconsistency group included patients who observed inconsistent risk categorization from scoring systems. The possible combination of risk categories forS scoring systems is N (number of the risk categories) raised to S power. The number of patients belongs to each molecular response groups is included to calculate the accuracy and determine which is the most accurate scoring system that can be used in a conflict group.


## 2.1. Study Population

Participants in this study were members of the Saudi population diagnosed with CML and treated at King Abdulaziz Medical City, Jeddah [16]. A total of 104 CML patients received 400 mg imatinib as the initial therapy. Patient characteristics are described in Table 1. All of the patients monitored their MMR in time points defined by ELN [13] where MMR is defined as achieving aBCR-ABL1 transcript level equal to or less than 0.1% at 12 months by RQ-PCR.Table 1
Characteristics of 95 patients with CML at diagnosis.
Factor Median Range SD Age (yrs) 40.21 18–74 15.13 Spleen size (cm, BCM) 8.33 0–25 7.53 Platelet count (×109/L) 510.97 4.42–2876 439.88 Basophils (%) 1.32 0–7 1.10 Eosinophils (%) 0.83 0–0.07 1.24 Peripheral blast (%) 1.50 0–10 1.39 SD = standard deviation; BCM = below costal margin.


## 2.2. Scoring Systems in CML

Four common prognostic scoring systems are available for CML patients prior to commencing therapy: (1) the Sokal score [17], (2) the Hasford score [14], (3) the European Treatment and Outcome Study (EUTOS) score [15], and (4) the EUTOS long-term survival (ELTS) score [18]. These four scores ascertain the level of risk for CML patients by running multivariable regression analysis. Prognostic scores were calculated using formulas in Table 2, based on the patients’ clinical and hematological parameters at diagnosis.Table 2
The current methods used to identify risk in CML.
Scoring systems Study Factors Equation Method Risk categories Target prediction Data and results Sokal score, Sokal et al. [17] Age, spleen size (cm), blast (%), and platelets (109/L) exp(0.0116 × (age [years] − 43.4)) + 0.0345 × (spleen size [cm] − 7.51) + (0.188 × ((platelets [109/L]/700)2 − 0.563)) + (0.0887 × (blasts [%] − 2.10)) Multivariate analysis of survival Low-risk score < 0.8, of patients, intermediate-risk in 0.8–1.2, and high-risk > 1.2 Risk groups for chemotherapy Six European and American sources (n=813), low 39%, intermediate 38%, and high 23%  Hasford score, Hasford et al. [14] Age, spleen size (cm), blasts (%), eosinophils (%), basophils (%), and platelets (109/L) (0.6666 × age [0 when age < 50 years; 1 otherwise]) + (0.0420 × spleen size [cm]) + (0.0584 × blasts [%]) + (0.0413 × eosinophils [%]) + (0.2039 × basophils [0 when basophils < 3%; 1 otherwise]) + (1.0956 × platelet count [0 when platelets < 1500 × 109/L; 1 otherwise]) × 1000 Multivariate analysis of survival Low-risk score ≤ 780, intermediate-risk in 781–1480, and high-risk ≥ 1481 Risk groups for interferon alpha alone 14 studies (n=981), low 40.6%, intermediate 44.7%, and high 14.6%  EUTOS score, Hasford et al. [15] Basophils (%) and spleen size (cm) (7 × basophil [%]) + (4 × spleen [cm]) Multivariate analysis of response Low-risk score < 87 and high-risk ≥ 87 CCgR at 18 months to imatinib Five national study groups (n=2,060), low 79% and high 21%  ELTS score, Pfirrmann et al. [18] Age, spleen size (cm), blast (%), and platelets (109/L) 0.0025 × (age in completed years/10)3 + 0.0615 × spleen size below costal margin + 0.1052 × blasts in peripheral blood + 0.4104 × (platelet count/1000)−0.5 Multivariate analysis of response Low-risk score ≤ 1.5680, intermediate-risk in 1.5680–2.2185, and high-risk > 2.2185 Long-term survival (n=2,205), low 61%, intermediate 27%, and high 12%The analysis is conducted in two steps: (1) studying the prognostic index using combined groups and (2) consistency analysis between the risk categories obtained from the scoring systems. First, from Table2, the EUTOS score is the only score that classifies CML patients into low risk and high risk. The number of categories in comparative prognostic scores in Sokal, Hasford, EUTOS, and ELTS was three, three, two, and three, respectively. Accuracy was measured on prognostic score data by assuming two different combined groups: (1) low and intermediate risk in Sokal, Hasford, and ELTS scores as low risk and (2) intermediate and high risk in Sokal, Hasford, and ELTS scores as high risk.Secondly, in consistency analysis, the combined category is selected based on the higher-accuracy results from combined groups to study the inconsistency between scoring systems. We are dealing with two models advising on the same patient. Each score may provide an index that conflicts with the other. The patients were classified into a consistency group or an inconsistency group. The consistency group included patients who observed consistent risk categorization from scoring systems, while the inconsistency group included patients who observed inconsistent risk categorization from scoring systems. The possible combination of risk categories forS scoring systems is N (number of the risk categories) raised to S power. The number of patients belongs to each molecular response groups is included to calculate the accuracy and determine which is the most accurate scoring system that can be used in a conflict group.


## 3. Results and Discussion

This study presents the analysis of each scoring system for distinguishing patients. We evaluated scoring systems in CML for identifying risk categories based on patients’ molecular responses to determine which was the best prognostic score to apply where a conflict prognosis was generated by prognostic scores.Of the 104 CML patients included in this study, the data of 9 patients were removed due to incomplete MMR data, to improve overall data quality. Of the 95 patients with complete data, 33 (34%) did not achieve MMR, while 62 (65%) did achieve MMR. The number of CML patients per prognostic score included in the two different combined methods is shown in Table3.Table 3
The number of patients in different risk groups as per calculated scores.
n Not achieving MMR Achieving MMR Accuracy ⁢Combined groups (1) Sokal score risk group High 25 11 14 62.10 Low and intermediate 70 22 48 Hasford score risk group High 6 4 2 67.37 Low and intermediate 89 29 60 EUTOS score risk group High 10 4 6 63.15 Low 85 29 56 ELTS score risk group High 17 7 10 62.10 Low and intermediate 78 26 52  ⁢Combined groups (2) Sokal score risk group Intermediate and high 62 23 39 48.42 Low 33 10 23 Hasford score risk group Intermediate and high 46 20 26 58.94 Low 49 13 36 EUTOS score risk group High 10 4 6 63.15 Low 85 29 56 ELTS score risk group Intermediate and high 42 19 23 61.05 Low 53 14 39It is clearly observed that the combined method of low and intermediate risk in Sokal, Hasford, and ELTS score as low risk achieved higher accuracy than the second combined method of intermediate and high risk in Sokal, Hasford, and ELTS score as high risk. Comparison of the accuracies in Sokal was 62.10% versus 48.42%, Hasford was 67.37% versus 58.94%, and ELTS was 62.10% versus 61.05%. Indeed, the ELN [13] recommended dividing patients into low-risk (including intermediate) and high-risk populations in the management of CML. Basically, there is insufficient evidence to prove intermediate risk patients behave differently from low-risk patients. A study used the combined method of low and intermediate in one risk group to evaluate Sokal and EUOS to predict optimal response [12]. Therefore, we used the first combined method in the consistency analysis.In Table4, there will be sixteen rows in our analysis (24=16). The consensus group involved 65 (68.42%) patients, and there were 30 (31.58%) patients in the conflict group. To identify the most appropriate prognostic score to use when there is conflict between prognostic scores, we compared the number of patients belonging to each group. Table 4 shows that, in the consensus group, both prognostic scores incorrectly predict CML risk group in 21% (19 patients did not achieve MMR, while all scores classified them in the low-risk group, and 1 achieved MMR, while all scores classified this patient in the high-risk group) of cases. In the conflict group, the Sokal and ELTS scores predicted MMR accurately in 46.67% (14 of 30) of patients, while the EUTOS score predicted MMR accurately in 50% (15 of 30) of patients. The highest accuracy of 63.33% (19 of 30) of patients was obtained by the Hasford score for predicting the risk category. However, the accuracy achieved by the Hasford score in both groups (consensus and conflict groups) was the lowest (58.95%) among the other scores (Sokal’s accuracy: 62.11%, EUTOS’s accuracy: 63.16%, and ELTS’s accuracy: 62.11%).Table 4
The consistency/inconsistency of prognostic scores for predicting major molecular response.
Analysis groups ⁢Score prediction MMR Total Sokal Hasford EUTOS ELTS Achieving MMR,n=62 Not achieving MMR,n=33 Conflict group Low and intermediate Low and intermediate Low High 5 2 30 Low and intermediate Low and intermediate High Low and intermediate 0 0 Low and intermediate Low and intermediate High High 0 1 Low and intermediate High Low Low and intermediate 0 0 Low and intermediate High Low High 0 0 Low and intermediate High High Low and intermediate 0 0 Low and intermediate High High High 0 0 High Low and intermediate Low Low and intermediate 7 5 High Low and intermediate Low High 0 1 High Low and intermediate High Low and intermediate 1 1 High Low and intermediate High High 4 0 High High Low Low and intermediate 1 1 High High Low High 0 1 High High High Low and intermediate 0 0  Consensus group Low and intermediate Low and intermediate Low Low and intermediate 43 19 65 High High High High 1 2  Single score in consensus group and conflict group Low and intermediate    48 22 95 High    14 11 Low and intermediate   36 13 High   26 20 Low  56 29 High  6 4 Low and intermediate 52 26 High 10 7  Single score in conflict group Low and intermediate    5 3 30 High    13 9 Low and intermediate   17 10 High   1 2 Low  13 10 High  5 2 Low and intermediate 9 7 High 9 5Although the results show that the Hasford performance in the consensus and conflict groups was not recommended, the Hasford score accuracy percentage (63%) shows that Hasford may be useful in identifying risk group in conflict CML patients. In the conflict group, the Hasford prognostic score identified more low-risk categories for CML patients and few high-risk patients, while the Sokal score identified more high-risk patients and few low-risk patients. Only one study [3] reported conflict in 22 CML patients. This study also supports our finding as they found that a majority of patients corroborated better with the Hasford score [14] than the Sokal and EUTOS scores. Previous studies compared and assessed the Sokal, Hasford, and EUTOS but not ELTS scores in investigating consistency between the scoring systems. Our study is the first to investigate the conflict and compare the four validated scoring systems. Comparison of prognostic scores shows the diversity in scoring, but in future work, we intend to implement advanced methods from computer science to resolve conflict. Thus, a new scoring system combining the power of currently available prognostic scores may further help increase accuracy of identifying risk groups.



---

*Source: 1076493-2017-02-13.xml*