Is the integration of lymphocyte/monocyte ratio and international prognostic score effective in predicting prognosis for hodgkin's lymphoma in the modern era? A prospective cohort study

Hasan Khalil; Firas Hussein; Suzan Samra

doi:10.4103/joah.joah_60_22

ORIGINAL ARTICLE

Year : 2022 | Volume : 13 | Issue : 4 | Page : 201-207

Is the integration of lymphocyte/monocyte ratio and international prognostic score effective in predicting prognosis for hodgkin's lymphoma in the modern era? A prospective cohort study

Hasan Khalil¹, Firas Hussein², Suzan Samra¹
¹ Department of Biochemistry and Microbiology, Faculty of Pharmacy, Tishreen University, Latakia, Syria
² Department of Internal Medicine (Clinical Hematology), Faculty of Medicine, Tishreen University, Latakia, Syria

Date of Submission	07-Jul-2022
Date of Decision	06-Aug-2022
Date of Acceptance	02-Sep-2022
Date of Web Publication	18-Oct-2022

Correspondence Address:
Dr. Hasan Khalil
Department of Biochemistry and Microbiology, Faculty of Pharmacy, Tishreen University, Latakia
Syria

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/joah.joah_60_22

Abstract

BACKGROUND: Determining the prognosis of Hodgkin's Lymphoma (HL) is crucial to avoid overtreatment and undertreatment, both of which have dangerous effects on the patient's health. This justifies the many studies to find prognostic factors, which in turn contribute to making the appropriate therapeutic decision. International Prognostic Score (IPS) and lymphocyte/monocyte ratio (LMR) are the most common prognostic indicator in HL, but they have some limitations in their application at some stages of the disease. The aim of this research was to study the efficiency of combining IPS and LMR to predict prognosis at both stages of the disease (early and advanced).
METHODS: This study included 84 newly classical HL patients treated by ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) with radiotherapy.
RESULTS: IPS showed a poor ability to predict 18-month progression-free survival (PFS) in both early-stage disease (P = 0.162) and advanced-stage disease (P = 0.191); LMR showed high performance in predicting 18-month PFS in early-stage patients treated with ABVD (HR = 5.456, confidence interval [CI] =1.04–28.715, P = 0.045). The combination of IPS and LMR was able to predict 18-month PFS in both early- and advanced-stage disease (HR = 12.21, CI = 1.24–120.1, P = 0.032) (HR = 2.84, CI = 1.04–5.04, P = 0.041), respectively.
CONCLUSIONS: The combination of IPS and LMR defines two important risk groups: the high-risk group (IPS ≥3 and LMR <2.9) and the low-risk group (IPS <3 and LMR ≥2.9); it can therefore be used to predict prognosis and adapt treatment to suit each patient's condition.

Keywords: ABVD, Hodgkin's lymphoma, International Prognostic Score, lymphocyte/monocyte ratio, prognosis, progression-free survival

How to cite this article:
Khalil H, Hussein F, Samra S. Is the integration of lymphocyte/monocyte ratio and international prognostic score effective in predicting prognosis for hodgkin's lymphoma in the modern era? A prospective cohort study. J Appl Hematol 2022;13:201-7

How to cite this URL:
Khalil H, Hussein F, Samra S. Is the integration of lymphocyte/monocyte ratio and international prognostic score effective in predicting prognosis for hodgkin's lymphoma in the modern era? A prospective cohort study. J Appl Hematol [serial online] 2022 [cited 2023 Oct 2];13:201-7. Available from: https://www.jahjournal.org/text.asp?2022/13/4/201/358714

Introduction

Hodgkin's lymphoma (HL) has characteristics distinct from other tumors such as high curability^[1] and high potential for treatment-induced toxicity after recovery. The latter is responsible for a large proportion of deaths.^[1] This makes it crucial to adapt the treatment to fit the severity of the disease in each patient.^[2] Prognostic factors for HL have been continuously investigated for a long time. The most widely used of these prognostic factors are those based on the Ann Arbor classification such as EORTC and GHSG and prognostic system like International Prognostic Score (IPS).^[3] However, there is still a significant proportion of patients who fail to respond to initial therapy because of undertreatment.^[4] In contrast, there are patients who have increased risks of serious infections, second malignancies, and cardiovascular diseases after overtreatment.^{[5],[6],[7],[8],[9],[10]} This confirms the need to investigate additional prognostic indicators that help reduce overtreatment and undertreatment. IPS includes seven factors: gender (male), age ≥45 years, white blood cell count >15,000 cells/mcL, lymphocyte count <600 cells/mcL or lymphocyte percentage <8%, hemoglobin value <10.5 g/dL, albumin value <4 g/dL, and the patient being in stage IV of the disease.^[3] IPS is widely used to classify patients according to risk, but many recent studies have indicated a decline in its efficiency in the modern era with the development of diagnostic techniques and treatment regimen.^[11],[12] Lymphocyte-to-monocyte ratio (LMR) has been studied by many researchers and all of them agreed on its prognostic importance, but there was an important difference in the cutoff points between the researchers,^{[13],[14],[15],[16],[17]} which is mainly due to the effect of ethnic differences on the manifestations of Hodgkin's lymphoma,^[18] and on the reference values of the differential leukocyte count.^[19],[20] This research aimed to study the efficiency of integration IPS and LMR in predicting prognosis, which helps in making the optimal treatment decision at the moment of disease diagnosis.

Methods

This research is a prospective cohort study included 84 newly diagnosed HL patients who were admitted to the Unit for Radio- and Chemotherapy of Tishreen University Hospital in Latakia and who have the following criteria: confirmed cases of classical HL using immunohistochemistry, ages greater or equal to 16 years, without previous history of immunodeficiencies or malignancy, HIV negative, they do not have not any previous treatment and they will be treated by ABVD (Adriamycin [a brand name of Doxorubicin], Bleomycin, Vinblastine and Dacarbazine) protocol with radiotherapy. Therapeutic decision was made based on the EORTC classification. Patients with early-stage favorable HL (stages I, II without risk factors) treated with 2 cycles of ABVD and radiotherapy (20–30 Gy), while patients with early-stage unfavorable HL (stages I, II with risk factors) treated with 4 cycles of ABVD and radiotherapy (20–30 Gy) and patients with advanced-stage HL (stages III, IV) treated with 6 cycles of ABVD and radiotherapy (20–30 Gy). Fluorodeoxyglucose-positron emission tomography (PET) scan was performed after two cycles of ABVD. Based on its outcome, the treatment was either escalated to BEACOPP in the case of PET + or Bleomycin was abolished in the case of PET- in order to avoid potential pulmonary toxicity to the patient. Brentuximab vedotin was used only in refractory patient. Patients who did not complete the course of treatment for reasons other than death were excluded. Data were collected prospectively between June 2020 and January 2021. Informed consent was obtained from all patients participating in this study. Complete blood count (CBC) was performed at the time of diagnosis and before receiving any treatment. The LMR was calculated based on the results of CBC. The IPS was calculated based on: clinical and radiographic findings, CBC test results, and plasma albumin results. The value of LMR = 2.9 was adopted as the most appropriate cutoff point based on a pilot study that we conducted before the start of this study. This pilot study was retrospective case-control study. It included 136 HL patients. Receiver operating characteristics curve analysis showed that the LMR of 2.9 represents the best cutoff point that separates the groups of good and bad prognosis. For IPS, We could not study the best cutoff point suitable for our patients because the pilot study data did not include albumin analysis results. Therefore, we relied on what is found in the medical literature. We considered that IPS of 3 represents the best cutoff point.^[11],[17] After completion of the treatment, all patients were followed up every 3 months for 18 months. Computed tomography scan was carried out every 3 months. The endpoints was progression-free survival (PFS). PFS was defined as the length of time during and after the treatment of HL that a patient lives with the disease without getting worse. PFS is a sufficient endpoint to predict the prognosis^[21]and overall survival in many cancers.^[22] For this reason, we only studied 18-month PFS in our research.

Statistical analysis

Chi-squared test (or Fisher's exact test, if indicated) was used for categorical variables; Cox proportional hazards model was used to estimate the HR and 95% confidence interval (CI) in order to study the ability of indicators to predict 18-month PFS. Data were analyzed using SPSS V.24 software (IBM SPSS statistical software package, SPSS version 24.0, Chicago, IL, USA); differences were considered statistically significant if the P < 0.05.

Results

The clinical and laboratory characteristics of the study sample are summarized in [Table 1].

Table 1: Clinical and laboratory characteristics of study sample according to disease groups

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IPS was calculated for the sample patients. The number of patients with IPS = 0 was 16 patients. 13 patients had IPS = 1, 12 patients had IPS = 2, 33 patients had IPS = 3, and 10 patients had IPS = 4, and no patients were enrolled with IPS >4.

Progression-free survival analysis

The mean follow-up was 21.54 months (min: 11 and max: 27 months). After the follow-up, there were 12 patients had progressive disease (7 patients from the early-stage group and 5 patients from the advanced-stage group). The efficacy of both IPS and LMR in predicting 18-month PFS is shown in [Table 2] and in [Figure 1], [Figure 2], [Figure 3], [Figure 4], respectively.

Table 2: Efficiency of lymphocyte/monocyte ratio and International Prognostic Score in predicting 18-month progression-free survival

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Figure 1: PFS survival according to IPS in advanced-stage disease. PFS = Progression-free survival, IPS = International Prognostic Score

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Figure 2: PFS survival according to LMR in advanced-stage disease. PFS = Progression-free survival, LMR = Lymphocyte/monocyte ratio

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Figure 3: PFS survival according to IPS in early-stage disease. PFS = Progression-free survival, IPS = International Prognostic Score

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Figure 4: PFS survival according to LMR in early-stage disease. PFS = Progression-free survival, LMR = Lymphocyte/monocyte ratio

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In early-stage patients, we found that LMR was a prognostic indicator for predicting 18-month PFS (HR = 5.465, CI = 1.04–28.715, P = 0.045). However, LMR did not show a prognostic significance in advanced-stage patients. For IPS, it did not show any prognostic significance in the prediction of 18-month PFS.

Integration of International Prognostic Score and lymphocyte/monocyte ratio

By combining IPS and LMR, we get 4 levels of prognostic classification: IPS <3 and LMR ≥2.9, IPS <3 and LMR <2.9, IPS ≥3 and LMR ≥2.9 and IPS ≥3 and LMR <2.9, and the survival curves for these groups with early and advanced disease are shown in [Figure 5] and [Figure 6], respectively.

Figure 5: PFS survival according to integration IPS with LMR in early-stage disease. PFS = Progression-free survival, IPS = International Prognostic Score, LMR = Lymphocyte/monocyte ratio

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Figure 6: PFS survival according to integration IPS with LMR in advanced-stage disease. PFS = Progression-free survival, IPS = International Prognostic Score, LMR = Lymphocyte/monocyte ratio

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Cox regression was carried out to compare the prognosis between (IPS <3 and LMR ≥2.9) group and (IPS ≥3 and LMR <2.9) group in both early-stage and advanced-stage disease as shown in [Table 3]; [Figure 7] and [Figure 8].

Table 3: Efficiency of integration International Prognostic Score and lymphocyte/monocyte ratio in predicting 18-month progression-free survival

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Figure 7: PFS survival for (IPS <3 and LMR ≥2.9) versus (IPS ≥3 and LMR <2.9) groups in early-stage disease. PFS = Progression-free survival, IPS = International Prognostic Score, LMR = Lymphocyte/monocyte ratio

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Figure 8: PFS survival for (IPS <3 and LMR ≥2.9) versus (IPS ≥3 and LMR <2.9) groups in advanced-stage disease. PFS = Progression-free survival, IPS = International Prognostic Score, LMR = Lymphocyte/monocyte ratio

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By studying the relationship between the four prognostic groups and the risk factors of HL, we found the results presented in the [Table 4].

Table 4: The relationship between the four prognostic groups and risk factors for Hodgkin's lym

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The proportion of males in the high-risk group (IPS ≥3 and LMR <2.9) was higher than in the low-risk group (IPS <3 and LMR ≥2.9) (P Value < 0.0001).

The proportion of patients with hemoglobin values ≥10.5 was higher in the low-risk group (IPS <3 and LMR≥2.9) than in the high-risk group (IPS ≥3 and LMR <2.9) (P = 0.013). The proportion of patients with albumin values ≥40 was higher in the low-risk group (IPS <3 and LMR ≥2.9) than in the rest of the groups (P < 0.00001).

Discussion

IPS did not show any prognosis significance in both early-stage and advanced-stage disease. This does not agree with Hasenclever and Diehl^[3] who found that IPS was only prognostic in advanced-stage disease. This can be explained by the difference in time between the two studies, and thus the large difference in the methods of diagnosing and treating the disease. Our result partially agrees with Wang et al. 2016,^[11] Moccia et al. 2012,^[12] who found less efficacy of IPS in distinguishing good prognosis patients from bad ones in the modern era. LMR showed a significant prognostic value only in early-stage disease. This is consistent with Romano et al. 2018^[13] who found that LMR does not have prognostic significance in case of advanced disease, but it has prognostic significance in case of early disease. By integration IPS and LMR we obtained a high performance indicator which is able to distinguish between good prognosis group (IPS <3 and LMR ≥2.9) and bad prognosis group (IPS ≥3 and LMR < 2.9) in both early-stage and advanced-stage disease (HR = 12.21 CI = 1.24–120.1, P = 0.032) and (HR = 2.84 CI = 1.04–5.04, P = 0.041) respectively. This increase in the efficiency of the two indicators when combined can be explained that the two indicators together reflect the general status of the patient, his immune state and tumor microenvironment that HL has. There was a significant association between prognostic classification according to the combination of IPS and LMR and established risk factors for HL such as gender, age, hemoglobin values, and albumin values. This indicates, in another way, the efficiency of this prognostic indicator.

Conclusions and Recommendations

The LMR was a prognostic indicator for predicting 18-month PFS after receiving ABVD in patients with early Hodgkin's disease. The combination of IPS and LMR defines two important groups: the high-risk group (IPS ≥3 and LMR <2.9) and the low-risk group (IPS <3 and LMR ≥2.9); it can therefore be used to predict prognosis and adapt treatment to suit each patient's condition. However, we recommend further studies in this field with larger sample size.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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