We aimed to investigate the prognostic value of serum β2-microglobulin for patients with Burkitt lymphoma (BL) and to propose a risk-stratifying classification system.
A prospective registry-based cohort study of BL patients treated with dose-intensive or effective dose-adjusted chemotherapies (n=81) was conducted. Survival outcomes were compared based on previously reported risk groups and/or serum β2-microglobulin levels. A risk-stratifying classification system incorporating serum β2-microglobulin levels was proposed and validated in an independent validation cohort (n=60).
The median age was 47 years, and 57 patients (70.4%) were male. Patients with high serum β2-microglobulin levels (> 2 mg/L) had significantly worse progression-free survival (PFS) and overall survival (OS) (p < 0.01 for both). Serum β2-microglobulin levels further stratified patients in the low-risk and high-risk groups in terms of PFS (p=0.010 and p=0.044, respectively) and OS (p=0.014 and p=0.026, respectively). Multivariate analyses revealed that a high serum β2-microglobulin level (> 2 mg/L) was independently associated with a shorter PFS (hazards ratio [HR], 3.56; p=0.047) and OS (HR, 4.66; p=0.043). The new classification system incorporating the serum β2-microglobulin level allowed the stratification of patients into three distinct risk subgroups with 5-year OS rates of 100%, 89.5%, and 62.5%. In an independent cohort of BL, the system was validated by stratifying patients with different survival outcomes.
Serum β2-microglobulin level is an independent prognostic factor for BL patients. The proposed β2-microglobulin–based classification system could stratify patients with distinct survival outcomes, which may help define appropriate treatment approaches for individual patients.
Burkitt lymphoma (BL) is a rare type of non-Hodgkin lymphoma of B cell origin that features highly aggressive biological and clinical behavior [
Despite the highly aggressive biological behavior of BL, the patterns of disease involvement and clinical course show substantial heterogeneity [
β2-microglobulin is a small protein that is an essential part of major histocompatibility complex class I molecules, and its serum levels can be elevated under various pathologic conditions. Elevated serum β2-microglobulin levels have been shown to be associated with poor clinical outcomes in various types of lymphoma [
In this study, using two independent BL cohorts, we aimed to investigate the prognostic value of β2-microglobulin and to propose a risk-stratifying classification based on serum β2-microglobulin levels.
The study patients were identified from a prospective registry of lymphoma patients at Asan Medical Center (Seoul, Korea) (Asan Lymphoma Registry). Between May 2004 and March 2020, 103 patients were diagnosed as having BL based on both histologic and immunophenotypic findings. After excluding patients with no baseline serum β2-microglobulin value (n=10) and those who did not receive dose-intensive or effective dose-adjusted chemotherapies (n=12), 81 patients were included as the main study population (training cohort). Data such as patient characteristics and survival outcomes were obtained from the prospectively collected database and electronic medical record system of the institution.
The validation cohort was constructed based on 60 BL patients who were treated with intensive chemotherapy regimens and had a baseline serum β2-microglobulin value recorded at Samsung Medical Center between February 2000 and December 2019.
The diagnosis of BL was confirmed by experienced pathologists from each institution (C.S.P., J.H., and Y.H.K) based on morphological characteristics and immunohistochemical features, including CD10, CD20, Bcl-6, Bcl-2, and Ki-67 expression. Chromosomal translocations such as t(8;14), t(8;22), and t(2;8), and c-Myc overexpression, were assessed based on karyotyping and fluorescence
The dose-intensive or dose-adjusted chemotherapy regimens used were as follows: (1) brief-duration high-intensity chemotherapy regimen consisting of one cycle of cyclophosphamide and prednisone followed by cycles containing ifosfamide; high-dose methotrexate, vincristine, dexamethasone, and either doxorubicin or etoposide/cytarabine; or intrathecal triple therapy (B-NHL) [
Serum β2-microglobulin values were obtained as part of regular clinical practice for lymphoma staging work-up. Serum β2-microglobulin was measured using a radioimmunoassay kit (Immunotech, Inc., Prague, Czech Republic). The kit manufacturer defined the upper normal limit of serum β2-microglobulin as 2.5 mg/L.
The low-risk group was defined as patients having stage I/II disease, normal LDH levels, ECOG PS of ≤ 1, and non-bulky disease (tumor mass with a diameter of < 7 cm) [
Statistical analyses were performed using R software ver. 3.4.1 (R Foundation for Statistical Computing, Vienna, Austria). Progression-free survival (PFS) was defined as the time interval from the time of initial diagnosis (index date) to the date of disease progression [
The baseline characteristics of 81 study patients with BL in the training cohort are summarized in
Patients in the validation cohort had comparable baseline characteristics. The chemotherapy regimens used for the patients in the validation cohort were as follows: R-HyperCVAD (n=29, 48.3%), LMB protocol (n=25, 41.7%), COPADM (n=4, 6.7%), and HyperCVAD (n=2, 3.3%).
We first compared the clinical outcomes of the study patients according to risk groups. There was no significant difference in the treatment regimens between the low-risk and high-risk groups (p=0.239) (
We examined the clinical characteristics and outcomes of the subgroups of BL patients according to their serum β2-microglobulin levels (
A comparison of the survival outcomes of the entire cohort revealed the significantly shorter PFS and OS of the high-B2MG group (p=0.002 and p=0.001, respectively) compared with the low-B2MG group (
In the low-risk group, 12 patients (75.0%) had low serum β2-microglobulin levels (≤ 2 mg/L), whereas four patients (25.0%) had high serum β2-microglobulin levels (> 2 mg/L). In the high-risk group, 46 patients (70.8%) had low serum β2-microglobulin levels, whereas 19 patients (29.2%) had high serum β2-microglobulin levels. In the low-risk group, patients with β2-microglobulin levels of > 2 mg/L had significantly shorter PFS and OS (
We performed Cox regression analyses for PFS and OS (
Considering the ability of serum β2-microglobulin levels to stratify BL patients with distinct clinical outcomes, we proposed a new risk stratification classification system with distinct survival outcomes (
To validate the generalizability of our classification system, we used it for patients in the validation cohort (
In the current study, we investigated the clinical value of serum β2-microglobulin for the risk stratification of BL patients. To the best of our knowledge, this study is the first to highlight the level of serum β2-microglobulin as a robust prognosticator for patients with BL. Our β2-microglobulin-based stratification of risk subgroups raises an important question regarding the application of dose adjustment of chemotherapy for patients with BL. The clinical value of this study is considerably improved by the validation of our risk-stratifying system in an independent cohort.
The prognostic value of serum β2-microglobulin has been widely investigated in various types of lymphoproliferative disorders such as extranodal natural killer/T cell lymphoma [
The exact mechanism linking β2-microglobulin to the poor clinical outcomes of patients with various lymphoproliferative diseases remains poorly understood. In our analyses, high serum β2-microglobulin levels were associated with a more advanced disease status and reflected a higher tumor burden represented by elevated serum LDH. This is consistent with the findings of previous studies showing an association between elevated serum β2-microglobulin levels and a higher tumor burden [
Importantly, our study demonstrated the ability of serum β2-microglobulin levels to further stratify the clinical outcomes of patients in addition to known risk stratification criteria that were originally developed for selecting different chemotherapeutic dose intensities [
Our results showed that patients in the low-risk group with elevated serum β2-microglobulin levels exhibited clinical outcomes comparable to those of patients in the high-risk group, suggesting that extreme caution should be taken when treating these patients. Therefore, additional studies are required to confirm whether serum β2-microglobulin levels are elevated in low-risk group patients with poor clinical outcomes in other BL cohorts. This is important given that a fair proportion (25%) of patients in our study in the low-risk group had elevated serum β2-microglobulin levels. On the other hand, serum β2-microglobulin was able to significantly stratify patients in the high-risk group in terms of PFS and OS. This suggests that high-risk group patients with low serum β2-microglobulin levels may be treated with less intense chemotherapeutic regimens, which may lead to reduced acute treatment-related morbidities such as severe myelosuppression or long-term sequelae such as cognitive dysfunction, secondary malignancy, and disabling neuropathy [
Considering the strong prognostic impact of serum β2-microglobulin levels, we proposed a new classification system that could stratify patients into three distinct risk subgroups with 5-year OS rates of 100%, 89.5%, and 62.5%. Importantly, the risk-stratifying ability of our system was well validated in an independent cohort, with 5-year OS rates of 100%, 92.9%, and 53.9% for the risk subgroups. Our newly proposed risk-stratifying system should be further investigated in the context of risk-adapted therapy with dose adjustment. The optimization of therapeutic strategies, including the chemotherapeutic regimen and dose intensity for the re-classified patients (i.e., the low-risk group with elevated serum β2-microglobulin levels and the high-risk group with low serum β2-microglobulin levels) is a topic of particular interest. From a practical point of view, the level of serum β2-microglobulin is easily determined with excellent reproducibility, and our results suggest that serum β2-microglobulin level measurements in daily practice may guide treatment decisions and the prediction of clinical outcomes. However, the retrospective nature of our study and the relatively small number of patients, may limit the interpretation and generalizability of our data.
In conclusion, the serum β2-microglobulin level is an independent prognostic factor, which allows for further risk stratification of BL patients. This risk-stratifying classification system incorporating the serum β2-microglobulin level may be useful in stratifying BL patients with distinct survival outcomes. This classification system warrants further investigation in future studies dealing with the issue of applying risk-adapted treatment approaches with dose adjustment.
Supplementary materials are available at Cancer Research and Treatment website (
This study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Institutional Review Board (IRB) (No.2020-1229). Informed consent from the patients was waived.
Conceived and designed the analysis: Kim HD, Suh C.
Collected the data: Kim HD, Cho H, Kim S, Lee K, Kang EH, Park JS, Park CS, Huh J, Ryu JS, Lee SW, Yoon DH, Kim SJ, Ko YH, Kim WS, Suh C.
Contributed data or analysis tools: Kim HD, Cho H, Suh C.
Performed the analysis: Kim HD, Suh C.
Wrote the paper: Kim HD, Suh C.
Conflict of interest relevant to this article was not reported.
Survival outcomes according to risk groups and serum β2-microglobulin (B2M) levels: progression-free survival and overall survival according to risk groups (A) and serum B2M levels (B).
Survival outcomes of patients with different serum β2-microglobulin (B2M) levels in different risk groups. Progression-free survival and overall survival according to the serum B2M levels in the low-risk group (A) and high-risk group (B). (C) Survival outcomes were compared between low-risk group patients with serum B2M levels of > 2.0 mg/L and high-risk group patients.
Survival outcomes in subgroups determined by a novel serum β2-microglobulin (B2M)–based risk stratification system. Progression-free survival and overall survival of low-risk group patients with serum B2M levels of ≤ 2 mg/L, high-risk group patients with serum B2M levels of ≤ 2 mg/L, and any-risk group patients with serum B2M levels of > 2 mg/L in the training cohort (A) and validation cohort (B).
Clinical characteristics of the patients
Variable | Training cohort (n=81) | Validation cohort (n=60) |
---|---|---|
47 (16–82) | 52.5 (18–84) | |
13 (16.0) | 10 (16.7) | |
57 (70.4) | 42 (70) | |
0 | 9 (11.1) | 10 (16.7) |
1 | 56 (61.5) | 31 (51.7) |
2 | 14 (17.3) | 19 (31.6) |
3/4 | 2 (2.5) | 0 |
2 (2.5) | 2 (3.6) | |
I | 10 (12.3) | 6 (10.0) |
II | 8 (9.9) | 9 (15.0) |
III | 1 (1.2) | 5 (8.3) |
IV | 62 (76.5) | 40 (66.7) |
7 (8.6) | 1 (1.7) | |
Low | 16 (19.8) | 9 (15.0) |
High | 65 (80.2) | 51 (85.0) |
55 (67.9) | 45 (75.0) | |
2.3 (0.76–22.2) | 2.7 (1.11–22.5) |
Values are presented as median (range) or number (%). ECOG, Eastern Cooperative Oncology Group; HIV, human immunodeficiency virus; LDH, lactate dehydrogenase; PS, performance status; UNL, upper normal limit.
Data of 56 patients were available.
Clinical characteristics according to serum B2MG levels
Variable | Low-B2MG group (n=31) | High-B2MG group (n=50) | p-value |
---|---|---|---|
38.5 (28.5–47.5) | 53.0 (30.0–64.0) | 0.014 | |
20 (64.5) | 37 (74.0) | 0.510 | |
2 (6.5) | 5 (10.0) | 0.844 | |
0.002 | |||
Low | 12 (38.7) | 4 (8.0) | |
High | 19 (61.3) | 46 (92.0) | |
14 (45.2) | 41 (82.0) | 0.001 | |
1 (3.2) | 15 (30.0) | 0.008 | |
16 (51.6) | 46 (92.0) | < 0.001 |
Values are presented as median (interquartile range) or number (%). B2MG, β2-microglobulin; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PS, performance status; UNL, upper normal limit.
Factors associated with progression-free survival and overall survival
Variable | Progression-free survival | Overall survival | ||||||
---|---|---|---|---|---|---|---|---|
|
| |||||||
Univariate | Multivariate | Univariate | Multivariate | |||||
|
|
|
| |||||
HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | |
B2MG > 2 mg/dL | 5.65 (1.69–18.90) | 0.005 | 3.56 (1.02–12.45) | 0.047 | 7.66 (1.79–32.82) | 0.006 | 4.66 (1.04–20.85) | 0.043 |
| ||||||||
Age > 65 yr | 2.68 (1.11–6.45) | < 0.001 | 2.43 (0.98–6.01) | 0.055 | 3.33 (1.34–8.26) | 0.010 | 3.02 (1.17–7.79) | 0.021 |
| ||||||||
Male sex | 0.91 (0.39–2.12) | 0.833 | - | - | 0.77 (0.32–1.83) | 0.548 | - | - |
| ||||||||
Stage III/IV | 4.50 (10.06–19.11) | 0.042 | - | - | 3.80 (0.89–16.27) | 0.072 | - | - |
| ||||||||
LDH > UNL | 2.33 (0.87–6.20) | 0.092 | - | - | 2.64 (0.89–7.81) | 0.080 | - | - |
| ||||||||
Bulky disease | 0.95 (0.22–4.03) | 0.095 | - | - | 1.10 (0.26–4.72) | 0.896 | - | - |
| ||||||||
ECOG PS ≥ 2 | 5.64 (2.54–12.53) | < 0.001 | 4.35 (1.89–10.02) | < 0.001 | 5.90 (2.52–13.82) | < 0.001 | 4.50 (1.84–10.99) | < 0.001 |
B2MG, β2-microglobulin; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazards ratio; LDH, lactate dehydrogenase; PS, performance status; UNL, upper normal limit.