Prognostic role of controlling nutritional status score in hematological malignancies

ABSTRACT Background Controlling nutritional status (CONUT) score, based on three indexes including serum albumin (ALB), total cholesterol (CHO), and absolute lymphocyte count (ALC), has been closely associated with the prognosis of cancer patients. Multiple studies revealed the significance of CONUT score in hematological malignancies, including diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma (PTCL), multiple myeloma (MM), and leukemia. Objective This review aimed to explore the prognostic role of CONUT score in hematological malignancies. Methods We conducted this review through Pubmed to summarize the published studies on the CONUT score in hematological malignancies, using the terms: Controlling nutritional status, CONUT score, hematological malignancy, lymphoma, multiple myeloma, and leukemia. Result CONUT score can reflect not only the nutritional status but also the inflammatory status of patients with hematological malignancies. It can assist in predicting the survival of patients with DLBCL, PTCL, MM, adult T-cell leukemia (ATL), myelodysplastic syndrome (MDS), and acute myeloid leukemia with myelodysplasia related changes (AML-MRC). Conclusion CONUT score plays an important role in predicting the prognosis of patients with hematological malignancies.


Background
Malnutrition conditions have been found to be closely associated with the treatment response and survival of patients with cancers, such as gastric cancer, colorectal cancer, and non-Hodgkin lymphomas [1][2][3][4][5]. Currently, multiple nutritional indexes were found to have prognostic value in various hematological malignancies, such as controlling nutritional status (CONUT) score, prognostic nutrition index (PNI) and geriatric nutritional risk index (GNRI). PNI and GNRI have been widely reported as nutritional indexes to be related to prognosis in patients with malignant tumors [6,7]. CONUT score has attracted growing attention as an immuno-nutritional index to detect undernourished patients in the hospitalized population. According to a study by Matsukawa et al. [6], they were the first to compare prognostic values of GNRI, PNI, and CONUT scores in newly diagnosed DLBCL. The result showed that GNRI and CONUT scores were independent risk factors, which indicated that the CONUT score was a meaningful nutritional indicator. Thus, we focused on CONUT score.
It is based on three indexes: serum albumin (ALB), total cholesterol (CHO), and absolute lymphocyte count (ALC) [8,9]. Several studies have demonstrated that CONUT score can be applied in predicting the outcomes of many diseases [10,11], and studies have revealed its prognostic values in solid tumors such as colorectal cancer [12,13], small hepatocellular carcinoma [14,15], gastric cancer [16,17], renal cell carcinoma [18], and urological cancers [19]. Besides, many studies have analyzed the clinical values of CONUT score in hematological malignancies [20][21][22][23][24][25][26][27][28]. Recent studies have suggested that CONUT score might be a parameter that influences prognosis in lymphoma, multiple myeloma, and leukemia [20,23,26]. However, whether the CONUT score can be a prognostic parameter in hematological malignancies and how it affects prognosis are not clearly discussed. This review focuses on the clinical importance and the potential mechanisms of CONUT score as a prognostic tool for hematological diseases. study involving patients from 33 hospitals in 1986. Based on the study of Kamath et al., Ulíbarri et al. [9] developed a new tool named CONUT score to assess the nutritional status of patients. It was initially used to screen outpatients at risk of malnutrition. The CONUT scores were identified to be related to the clinical outcomes of patients with solid tumor and hematological malignancies.
Most of the previous research focused on the CONUT score of patients with solid tumors who received no treatments or operations. For instance, Ahiko et al. [12]. used CONUT score as a preoperative risk assessment index for older patients with colorectal cancer. The results showed that patients with higher CONUT score (≥4) had shorter 5-year OS (CONUT scores of 0-1, 2-3, ≥4 were 77.7%, 73.2%, and 49.7%, respectively, p < 0.0001) and preoperative CONUT score was an independent factor in short-term outcomes of older patients with colorectal cancer. Similarly, Song et al. [29]. focused on the role of preoperative CONUT score in the prognosis of patients with non-metastatic renal cell carcinoma. The result showed that patients with high preoperative CONUT score (>3) had worse survival (5-year OS: >3 vs. ≤3, 93.7% and 67.8%, p < 0.001). Multivariate analysis manifested that a high preoperative CONUT score was an independent factor for OS (HR = 3.36, 95% CI: 1.73-6.56, p < 0.001). In addition, some researchers assessed the CONUT score of postoperative patients to predict their survival. Peng et al. [14] enrolled patients with small hepatocellular carcinoma and analyzed the relationship between postoperative CONUT score and prognosis. They found that the 1-, 3-, and 5-year OS rates of patients in the low postoperative CONUT score group (≤2) were significantly higher than those of the high postoperative CONUT score group (≥3) (≤2 vs. ≥3, 96.7%, 83.6% and 72.8% respectively, and 91.3%, 64.7% and 48.2%, p < 0.001). Multivariate analysis manifested that postoperative CONUT scores were an independent factor for OS (HR = 1.708, 95% CI: 1.091-2.676, p = 0.019).
Previous research proved the adequacy of using the CONUT score to evaluate cancer patients who received no treatments (including surgery and chemotherapy). CONUT score was associated with postoperative complications and long-term prognosis and could assist physicians in choosing treatment regimes. Postoperative CONUT score was found relevant to the immunological and nutritional status of cancer patients after the removal of the cancer cells [29].
The CONUT score was also closely associated with the disease stages. Most cancer patients with higher CONUT scores tended to be in higher disease stages. Based on ALB, CHO, and ALC, the prognostic value of the CONUT score in cancer patients might be clarified by the function of these three variables. ALB is a parameter to assess both nutritional status and liver synthesis capacity. In the field of immunity, ALB can reflect aggressive tumor behavior and inflammatory status. Inflammation cytokines such as interleukin-6 (IL-6) secreted by the myeloma microenvironment may lead to low ALB [30]. It has been widely considered that hypoalbuminemia predicts an inferior outcome in cancer patients [31][32][33][34]. CHO plays an important role in assembling cell membranes. As cholesterol synthesis, accumulation and demand increase in cancer cells, the cell turnover rate tends to raise, particularly in hematological malignancies [35]. CHO is also related to nutritional status. Hypocholesterolemia is associated with worse clinical survival in cancers, including hematologic malignancies, lung cancer, and renal cell carcinoma [36][37][38][39][40]. Low lymphocyte count is not only associated with malnutrition but also impaired immune status in patients with hematological malignancies. ALC serves as a surrogate marker in hosting immunological incompetence [41]. Lymphocytes can control the cancer cell proliferation, invasion, and migration. Increasing evidence has shown that low ALC leads to poor survival in cancer patients [42][43][44][45][46]. Some research demonstrates that patients in low ALC are insensitive to chemotherapeutic drugs. The possible mechanism is that lymphocytes are important mediators of some chemotherapeutic drugs, such as anti-CD 20 monoclonal antibodies [47].

Lymphoma
Lymphoma is a group of heterogeneous hematological malignancies with more than 90 types. It is traditionally classified into Hodgkin and non-Hodgkin lymphomas.  So far, the prognostic role of CONUT score has been discussed only in the fields of DLBCL and PTCL. DLBCL is the most common type of non-Hodgkin lymphoma. The first-line therapy is R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). About 60 percent of patients can receive complete remission (CR) or long-term survival, with the other 40 percent relapsed or refractory [49]. Hence, it is necessary to find an easy-to-use tool to assess the prognosis of DLBCL patients. The International Prognostic Index (IPI), revived IPI (R-IPI), and the National Comprehensive Cancer Network IPI (NCCN-IPI) have been broadly used to predict the prognosis of DLBCL patients [50]. Some previous studies revealed that nutritional status affected the prognosis of DLBCL patients [1,6,20]. However, IPI, R-IPI, and NCCN-IPI lack in assessing their nutritional status. Emerging evidence has suggested that CONUT score, as a nutritional index, plays an important role in the prognosis of DLBCL patients. Nagata et al. [20] first reported that a high-CONUT score was associated with poor overall survival (OS) of DLBCL patients. They retrospectively analyzed 476 DLBCL patients and divided them into two groups according to their CONUT scores. The results showed that patients with high-CONUT scores (≥4) had poorer 5-year OS (49.0% vs. 83.2%, p < 0.001) and 5-year progression-free-survival (PFS) (46.1% vs. 73.1%, p < 0.001) compared with those with low-CONUT scores (<4). They believed that CONUT score was an convenient tool to identify patients with malnutrition and sarcopenia, which had been recognized as prognostic factors in DLBCL patients. Similarly, Matsukawa et al. [6] found that newly diagnosed DLBCL patients with poor nutritional status were associated with poor 5-year OS (>4 vs. ≤4, 53.1% vs. 77.1%, p < 0.001). Baysal et al. [21] found in a recent study that the CONUT score was an independent prognostic factor in DLBCL patients. More intriguing was that the cutoff value of CONUT score was four in all of the above-mentioned three studies, which indicated DLBCL patients in normal and mild nutritional status had better survival.
PTCL is a rare subtype of non-Hodgkin lymphoma. Most PTCL patients are treated with CHOP or CHOPlike chemotherapy with an inferior prognosis than DLBCL [51]. Malnutrition leads to poorer survival in cancer patients. Though IPI and the Prognostic Index for PTCL-U (PIT) are widely applied in prognostic risk stratification, they lack nutritional index. Nakamura et al. [52] enrolled 99 cases and analyzed their CONUT score at diagnosis. Based on their survival status, those PTCL patients were divided into non-survivor group (n = 55) and survivor group (n = 44). The median CONUT score of the non-survivor group was significantly higher than survivor group (5 scores vs. 3 scores, p = 0.026). Judging from the cutoff value of CONUT score of the two groups, the median OS of high-CONUT score group (≥5) was significantly shorter than that of the low-CONUT score group (0.85 years vs. 6.97 years, p < 0.001). Multivariate analysis showed that CONUT score was an independent factor for PTCL patients [hazard ratio (HR): 1.119, 95%; confidence interval (CI): 1.021-1.227; p = 0.017 ].
Till the date when this paper has been finished, the prognostic value of CONUT score in other types of lymphoma (such as FL and MZL) has not been researched. The current research was mainly carried out from one single center, and the number of participants was rather small. We hope that more studies and multiple-center clinical trials will be performed to prove the prognostic impact of CONUT score in patients with lymphoma in the future.

Multiple myeloma
Multiple myeloma (MM) is a hematological malignancy with clonal plasma cells [53]. According to M protein type, MM are divided into IgM, IgG, IgA, IgD, IgE, light chain, double clone and non-secretory subtypes. The prognosis of MM patients varies depending on their biologic and genetic characteristics. International Staging System (ISS) and revised ISS (R-ISS) are valid risk stratification tools for estimating the prognosis of MM patients [54,55]. With the development of proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), monoclonal antibodies, antibody-drug conjugates, chimeric antigen receptor T cells(CAR-T), and autologous hematopoietic stem cell transplantation (auto-HSCT), the survival of MM patients have significantly improved [56]. Nevertheless, not all MM patients received a better prognosis. Some researchers supposed that poor nutritional status was closely related to worse clinical survival. Although ALB served as a parameter in ISS, it could be easily interfered with by inflammation cytokines such as interleukin-6 (IL-6) secreted by the myeloma microenvironment and changes in body fluid volume [57]. Consequently, the CONUT score was used as a nutritional tool in predicting the prognosis of MM patients. Okamoto et al. [23] retrospectively analyzed the CONUT score in 64 MM patients and divided them into two groups: high score group (CONUT score >4) and low score group (CONUT score ≤ 4). They found that transplant-eligible MM patients with high-CONUT scores showed worse OS than those with low scores (median OS, not reached vs. 64.1 months, p = 0.011), and high-CONUT score (>4) was an independent prognostic factor in MM patients, particularly in younger transplant-eligible patients. Kamiya et al. [24] explored the relationship between CONUT score and MM prognosis. They found that MM patients with higher CONUT scores (≥5) had significantly shorter median OS than those with low-CONUT scores (≤4) (33 months vs. 57 months, p < 0.001). The study demonstrated that a higher CONUT score was an independent prognostic factor in MM patients, especially in lower-ISS-score (ISS ≤ 2) cases. Similarly, Zhou et al. [22] enrolled 245 MM patients to investigate the role of CONUT score in predicting OS. They divided MM patients into three groups: low-CONUT group (≤3), mid-CONUT group (4)(5)(6)(7)(8)(9), and high-CONUT group (>9). The 5-year OS of three groups were respectively 65.1%, 38.9%, and 16.6%. They concluded that a high-CONUT score (≥4) was an independent prognostic risk factor for OS in MM patients. The two studies mentioned above proved that the CONUT score had a significant prognostic value in MM. The same conclusion was then confirmed in a study by Li et al. [58] Liang et al. [59] found that the CONUT score had a significantly prognostic value in MM patients but it was not an independent factor. They claimed that age and plasma cell ratio were independent factors in MM.
We are looking forward to getting more results about the prognostic impact of CONUT score on MM prognosis from multi-center studies.

Leukemia
Leukemia is a group of hematological malignancies, mainly classified as acute or chronic (by the degree of cell differentiation) and as myelocytic or lymphocytic (by type of cells) [60]. Data from The Surveillance, Epidemiology, and End Results (SEER), and the National Center for Health Statistics show that leukemia is the 10th most incident cancer in the United States and the 7th leading cause of cancer death. Treatments for leukemia include chemotherapy, target therapy, and hematopoietic stem cell transplantation (HSCT). With the development of bio-immunity, targeted medicine like Bruton tyrosine kinase (BTK) inhibitors, B-cell lymphoma 2 (BCL-2) inhibitors have increased the treatment response and the survival of leukemia patients [61]. Factors affecting curative effects need further exploration. Among relevant research, Ureshino et al. [26] found that a low-CONUT score (≤3) was correlated with better OS in younger patients (n = 25, <70 years old) with adult T-cell leukemia (ATL) (≤3 vs. ≥4, median OS: 562 and 321 days, p = 0.036). Among 14 younger patients who received allo-HSCT, low-CONUT score group had better OS than high group (≤3 vs. ≥4, median OS:1685.5 and 184.5 days, p = 0.017). The result indicated that the CONUT score could be a prognostic tool for transplant-eligible ATL patients. Senjo et al. [27] enrolled 174 elderly(≥65 years old) AML patients. In the study, they found that a modified CONUT score (CONUT score omitting ALC) could predict prognosis in elderly AML patients. Patients in the high modified CONUT group demonstrated a salient lower 5-year OS compared with those in the low group (26.5% vs. 9.97%, p = 0.00145). Among patients treated with chemotherapy, the low modified CONUT group had a longer 2-year OS than the high group (42.1% vs. 21.6%, p = 0.0315). In multivariable analysis, modified CONUT score was found independently associated with 2-year OS (HR 1.76; 95% CI: 1.11-2.78, p = 0.0163). Additionally, patients treated without chemotherapy were mostly in high modified CONUT groups. The result showed that the modified CONUT score was a prognostic factor affecting the treatment choice of physicians and predicting the prognosis of AML patients treated with chemotherapy. Sakurai et al. [28] found that a high-CONUT score indicated poor outcomes in myelodysplastic syndrome (MDS) and acute myeloid leukemia with myelodysplasia related changes (AML-MRC) treated with azacitidine. In this study, 1-year OS of patients with high-CONUT scores (≥5) were 15.3%, and the 1-year OS of patients with low-CONUT scores were 62.6% (p < 0.001). In multivariate analysis, the CONUT score was an independent factor (HR 3.244; 95% CI: 1.904-5.525, p < 0.001) in patients with MDS and AML-MRC treated with azacitidine.
All of the studies mentioned above are, however, conducted through retrospective data collection and have a limited sample size. Sufficient cases are needed for future investigation. The clinical impacts of CONUT score on acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL) still remain unclear. We advocate that more research should be done on clarifying the relationships between CONUT scores and different types of leukemia.

Conclusion
The CONUT score is composed of three components, namely, ALB, CHO, and ALC. In this paper, several research studies have been reviewed, all of which prove that the CONUT score is an easy-to-use tool to assess whether patients suffer from malnutrition. Nutritional status plays an important role in the treatment response and survival of patients with hematological malignancies. Poor nutritional status can decrease patients' tolerance to chemotherapy and increase their risk of secondary infection. Besides, the CONUT score can reflect inflammatory status. It can assist in predicting the survival of patients with DLBCL, PTCL, MM, ATL, AML or MDS. Judging from the literature, it is highly possible and meaningful to promote CONUT score into predicting the prognosis of patients with hematological malignancies.
So far, no study has been found to explore the relationship between CONUT score and benign hematological diseases such as immunologic thrombocytopenia, aplastic anemia and so on, and the mechanisms underlying the relationship between CONUT scores and clinical outcomes in hematological malignant patients have not been clarified. We call on more research results in the field of CONUT scores in hematological diseases.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.