correspondence
Prognostic significance of serum immunoglobulin paraprotein in patients with diffuse large B cell lymphoma
Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Despite some common features, DLBCL is a heterogeneous disease with long-term survival rates ranging between 30‒90% (Ziepert et al, 2010). Immunoglobulin (Ig) paraproteinemia is a well-recognized finding in patients with multiple myeloma, lymphoplasmacytic lymphoma/Waldenstr€ om macroglobulinaemia (LPL/ WM), etc., and can also be detected in various lymphoid malignancies (Owen et al, 2000; Lin et al, 2005). Serum Ig paraprotein has been detected in some DLBCL patients, although there is little data regarding the prevalence of Ig paraproteinemia in DLBCL populations and its prognostic influence. To better describe this, we conducted a retrospective study. Records at the Department of Haematology in the First Affiliated Hospital of Nanjing Medical University were searched for all cases tested for serum Ig paraprotein and diagnosed with DLBCL according to the 2008 World Health Organization classification, between September 2006 and April 2015. A total of 599 patients were diagnosed with DLBCL, of which 245 patients had been tested for serum monoclonal Ig. We conducted v2 test between these 245 patients and the 354 other patients with regard to International Prognostic Index (IPI) and b2-microglobulin (b2-MG). No significant difference was found, indicating that there was no selection bias in this population. All patients provided informed consent according to the Declaration of Helsinki. Baseline clinical characteristics and their associations with Ig paraprotein are shown in Table I. Median age at diagnosis was 57 years (range, 14–88) and median follow-up time from initial diagnosis was 28 months (range, 2–114). Strong correlations of serum Ig paraproteinemia with MUM1 and b2MG were observed. Other risk factors showed no significant relationship with the occurrence of Ig paraproteinemia. The distribution of Ig paraprotein types is shown in Table SI. Survival analysis regarding the association of Ig paraprotein with both progression-free survival (PFS) and overall survival (OS) is shown in Table SII. Univariate analysis was used to assess associations between survival and potential risk factors, including Ig paraprotein. All the factors were entered into multivariate analysis to determine whether they had prognostic independence. Ig paraprotein, Ann Arbor stage, Eastern Cooperative Oncology Group performance status (ECOG-PS), serum lactate dehydrogenase (LDH), number of extranodal sites involved (ESI), b2-MG, serum albumin (ALB) and Hans ª 2017 John Wiley & Sons Ltd, British Journal of Haematology
Table I. Baseline characteristics and their associations with Ig paraprotein in 245 DLBCL patients.
Characteristics
Cases n (%)
Sex (n = 245) Male 135 (551) Female 110 (449) Age (n = 245) ≤60 years 149 (608) >60 years 96 (392) Stage (n = 245) I–II 86 (351) III–IV 159 (649) ECOG-PS (n = 245) 0–1 199 (812) 2–4 46 (188) LDH (n = 245) Normal 148 (604) >ULN 97 (396) ESI (n = 245) 0–1 185 (755) >1 60 (245) IPI (n = 245) 0–1 103 (420) >1 142 (580) Hans classification (n = 231) GCB 102 (442) nGCB 129 (558) MUM1 (n = 224) Positive 157 (701) Negative 67 (299) B2-MG (n = 241) Normal 129 (535) >ULN 96 (392) ALB (n = 244) 1), age (younger than 60 years, older than 60 years), LDH (normal, >upper normal limit) and survival time of PFS and OS (Figures S1–S5). Almost all subgroup analyses showed statistical differences, except PFS for the IPI
2–5 and ESI > 1 subgroups, although we observed a distinguishable trend from the survival curve. These subgroup analyses demonstrated that Ig paraprotein is a prognostic factor for the entire DLBCL population, instead of certain specific subgroups. Ig paraprotein was determined to be an independent prognostic predictor for both PFS and OS, thus we included IPI and Ig paraprotein to generate a modified prognostic index (MPI) and compared its predictive abilities with IPI alone and Ig paraprotein alone for PFS and OS. MPI was generated by the sum of IPI and 26 additional points for Ig paraproteinemia according to the hazard ratio (HR: MPI = IPI + 26 9 Ig), if it exists. It was shown that the areas under the curve (AUCs) for MPI were significantly more than those of IPI (P = 00009 for OS) (Figure S6), indicating that MPI had better prognostic value than IPI for DLBCL. Unfortunately, our research population is too small for independent validation (Molica et al, 2016). Via this simplified model construction, we intended to preliminarily prove the prognostic significance of Ig in DLBCL. We hope to perform an independent validation in the future in a larger number of cases. Further external validations from other database will be very welcome.
Figure 1. Survival curves. (A) PFS of DLBCL patients with and without Ig paraprotein. (B) OS of DLBCL patients with and without Ig paraprotein for OS. (C) PFS of DLBCL patients with IgG paraprotein and without Ig paraprotein. (D) OS of DLBCL patients with IgG paraprotein and without Ig paraprotein. (E) PFS of DLBCL patients with IgM paraprotein and without Ig paraprotein. (F) OS of DLBCL patients with IgM paraprotein and without Ig paraprotein. DLBCL, diffuse large B cell lymphoma; Ig, immunoglobulin; OS, overall survival; PFS, progression-free survival. [Colour figure can be viewed at wileyonlinelibrary.com]
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ª 2017 John Wiley & Sons Ltd, British Journal of Haematology
Correspondence Mechanism of why these subgroups of DLBCL present with inferior prognosis remains undetermined, but has been hypothesized. The MYD88 L265P mutation has been reported in 65% and 17% of unselected DLBCL cases and this mutation was prevalent in IgM-secreting WM (Kraan et al, 2013; Xu et al, 2013). There may be certain relationships between DLBCL with IgM and MYD88 L265P mutation that accelerates disease progression. Furthermore, other molecular pathways, such as somatically mutated monoclonal IGHV4-34 rearrangement, was also demonstrated to be involved in globulin-associated lymphoproliferative diseases (Randen et al, 2014). There is dispute about the relationship between Ig paraprotein and survival in chronic lymphocytic leukaemia (Bernstein et al, 1992; Yin et al, 2005). For DLBCL, Gavrilina et al (2016) reported 93 patients with newly diagnosed DLBCL, among whom 21 (226%) were found to secrete monoclonal Ig. Survival rate analysis indicated that the patients had a poor prognosis versus those with non-Igsecreting DLBCL. Further detailed research may enable this parameter to be included in the prognostic index for DLBCL. Our results are consistent with those of Gavrilina et al (2016), but due to the small number of patients and limited relative literature, the prognostic impact of Ig paraproteinemia in DLBCL still cannot be thoroughly ruled out. In conclusion, DLBCL patients with Ig paraproteinemia represent a subgroup with inferior clinical outcome. Serum Ig paraprotein might be applied for the assessment of prognosis in patients with DLBCL. The explicit relationship between DLBCL survival and different types of Ig paraprotein still remains unclear and needs further study.
Acknowledgements This study was supported by National Natural Science Foundation of China (30971296, 81170485, 81170488, 81370657, and 81470328), the project of National Key Clinical Specialty, the National Science & Technology Pillar Programme (2014BAI09B12), and a project funded by Jiangsu Provincial Special Programme of Medical Science (BL2014086).
Author Contributions Yue Li, Li Wang performed the research, analysed the data and wrote the paper. Hua-Yuan Zhu, Jin-Hua Liang performed research and analysed the data. Yi Xia, Jia-Zhu Wu contributed essential reagents or tools. Wei Wu and Lei Fan analysed the data. Jian-Yong Li and Wei Xu designed the research.
References Bernstein, Z.P., Fitzpatrick, J.E., O’Donnell, A., Han, T., Foon, K.A. & Bhargava, A. (1992) Clinical significance of monoclonal proteins in
Conflict of interest The authors declare that they have no conflict of interest. Yue Li1 Li Wang1 Hua-Yuan Zhu1 Jin-Hua Liang1 Wei Wu1 Jia-Zhu Wu1 Yi Xia1 Lei Fan1 Jian-Yong Li1,2 Wei Xu1 1
Department of Haematology, the First Affiliated Hospital of Nanjing
Medical University, Jiangsu Province Hospital, Nanjing 210029, China and 2Collaborative Innovation Centre for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 210029, China. E-mail:
[email protected] Yue Li and Li Wang contributed equally to this work.
Keywords: diffuse large B paraprotein, prognosis centre
lymphoma,
immunoglobulin
Supporting Information Additional Supporting Information may be found in the online version of this article: Fig S1. Subgroup survival analyses of IPI for DLBCL patients with and without Ig paraprotein. Fig S2. Subgroup survival analyses of ESI for DLBCL patients with and without Ig paraprotein. Fig S3. Subgroup survival analyses of stage for DLBCL patients with and without Ig paraprotein. Fig S4. Subgroup survival analyses of age for DLBCL patients with and without Ig paraprotein. Fig S5. Subgroup survival analyses of LDH for DLBCL patients with and without Ig paraprotein. Fig S6. Comparison of ROC curves of IPI, MPI and Ig paraprotein for PFS and OS. Table SI. Distribution of different types of Ig paraprotein. Table SII. Correlations between survival and risk factors (including Ig paraprotein).
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