Hematological Oncology Hematol Oncol 2016; 34: 22–27 Published online 16 February 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/hon.2188
Original Research Article
Serum beta-2 microglobulin as a prognostic biomarker in patients with mantle cell lymphoma Changhoon Yoo1, Dok Hyun Yoon1, Shin Kim1, Jooryung Huh2, Chan-Sik Park2, Chan-Jeong Park3, Sang-Wook Lee4 and Cheolwon Suh1* 1
Department Department 3 Department 4 Department 2
of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
*Correspondence to: Cheolwon Suh, MD, PhD, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. E-mail: [email protected]
Received 15 November 2014 Revised 9 December 2014 Accepted 17 December 2014
Abstract Although serum beta-2 microglobulin (B2M) has been suggested as a prognostic factor for mantle cell lymphoma (MCL), additional data are necessary to confirm its role. Between November 2005 and July 2014, a total of 52 patients with MCL were identified from the database of Asan Medical Center, Seoul, Korea. Pretreatment serum B2M information was available in 50 patients (96%). Overall survival (OS) was compared according to the serum B2M level with a cut-off value of 2.5 mg/L. The median MCL international prognostic index (MIPI) score was 5.84 (range 4.72–7.80), and the median biologic MIPI (MIPI-b) score was 6.27 (4.93–8.47). Pretreatment serum B2M was elevated in 30 patients (60%) and was significantly related to advanced stage (p = 0.02) and high MIPI (p = 0.03) and MIPI-b (p = 0.03) scores. With median follow-up duration of 29.8 months (range 0.8–87.0 months), the median OS was 56.2 months [95% confidence interval (CI) 36.6-75.9 months] in all patients, and serum B2M was significantly associated with OS (p = 0.001). In multivariate analyses adjusted for MIPI or MIPI-b scores and rituximab, elevated serum B2M was significantly associated with poor OS (when adjusting MIPI, hazard ratio = 26.4, 95% CI 2.9–241.3, p = 0.004; when adjusting MIPI-b, hazard ratio = 20.1, 95% CI 2.4–170.1, p = 0.006). Thus, pretreatment serum B2M may be an independent and significant prognostic factor in patients with MCL. Copyright © 2015 John Wiley & Sons, Ltd. Keywords: beta-2 microglobulin; mantle cell lymphoma; prognosis
Introduction Mantle cell lymphoma (MCL), a distinct subtype of B-cell non-Hodgkin lymphoma (NHL), represents 5%–10% of all malignant lymphomas [1]. In addition to classical histology, immunohistochemical assessment of cyclin D1 overexpression is pathognomonic for the diagnosis of MCL [2]. Most patients are diagnosed with disseminated disease. MCL is also characterized by male predominance and frequent involvement of the gastrointestinal tract and bone marrow. Mantle cell lymphoma is considered a heterogeneous disease in terms of biology and prognosis [3,4]. Although most patients with MCL show aggressive clinical features, a subset of patients with MCL has a more indolent clinical course, with a previous observational study based on population-based registries showing favourable survival outcomes in a subgroup of patients, even without anticancer treatment [5]. Hence, risk stratification for prognosis may be important for planning the therapeutic strategy Copyright © 2015 John Wiley & Sons, Ltd.
and conducting clinical trials more efficiently. The MCL international prognostic index (MIPI) is a prognostic index specific for patients with MCL that was initially developed based on the databases of randomized trials and was recently validated [6,7]. Ki-67 expression is well established as a biological marker for cell proliferation in MCL, and its incorporation into MIPI—biologic MIPI (MIPI-b)—also shows good correlation with the prognosis of patients with MCL [6,7]. However, there remains an unmet medical need for better prognostic prediction through the identification of further prognostic factors for MCL because better risk stratification of patients would allow tailored riskadapted therapy. Beta-2 microglobulin (B2M) is synthesized in all nucleated cells and forms the light chain subunit of the major histocompatibility class I antigen[8]. Free soluble B2M is detected in body fluids, such as blood, urine, and cerebrospinal fluid, following its release from the cell surface or cytoplasm. Since the identification of B2M in the early 1970s, the serum B2M level has been widely investigated
Beta-2 microglobulin in MCL
23
for its prognostic value in multiple hematological disorders, including multiple myeloma and lymphomas [9–11]. Prognostic relevance of serum B2M has been investigated in previous studies for patients with MCL [12–15]. However, additional data are still necessary to confirm its role in MCL. We therefore investigated the prognostic relevance of pretreatment serum B2M in patients with MCL.
used to estimate hazard ratios (HRs) for OS. In multivariate analysis, prognostic models (i.e. MIPI and MIPI-b), rituximab and autologous stem cell transplantation (ASCT) were included to evaluate the relevance of serum B2M. All statistical analyses were performed using the Statistical Package for the Social Sciences (IBM SPSS, Chicago, IL, USA) version 20.0, and all tests were two sided with 5% defined as the level of significance.
Methods
Results
Between November 2005 and July 2014, a total of 52 patients with MCL were identified in the database of the Asan Lymphoma Registry, Asan Medical Center, Seoul, Korea. Among them, baseline serum B2M was measured in 50 patients (96%) at the time of diagnosis. Diagnosis of MCL was based on the World Health Organization classification, and detection of cyclin D1 overexpression by immunohistochemistry was mandatory [16]. The Ki-67 index was assessed according to the published guideline [17]. Data for patient baseline characteristics and survival outcomes were retrieved from the prospectively collected database. This study was approved by the Institutional Review Board of Asan Medical Center. Initial staging evaluation included the taking of history; physical examination; complete blood count; blood chemistry, including electrolyte levels; serum lactate dehydrogenase (LDH); computed tomography of the neck, chest, abdomen, and pelvis; esophagogastroduodenoscopy; colonoscopy; and bone marrow aspiration and biopsy. According to the revised response criteria for malignant lymphoma [6], the response was assessed during and after treatment or when progressive disease was suspected. Serum B2M was measured using a radioimmunoassay kit (Immunotech, Inc., Prague, Czech Republic). The kit manufacturer defined the upper normal limit (UNL) of serum B2M at 2.5 mg/L. Patients were categorized by the level of the UNL for the analysis of the relationship between B2M levels and survival outcomes. MCL international prognostic index scores were calculated using the formula presented in the original paper for MIPI with inclusion of baseline values for age, Eastern Cooperative Oncology Group performance status, and LDH. For the calculation of MIPI-b, Ki-67 expression was added to the formula in addition to MIPI factors. Baseline values of all MIPI factors and Ki-67 expression were available in our study cohort. Overall survival (OS) was calculated by the dates between diagnosis and death from any cause. Data were censored if patients were alive at last follow-up. Categorical variables were evaluated using chi-square or Fisher’s exact tests, as appropriate. The Kaplan–Meier method was used to estimate OS, and survival curves were compared by the log-rank test. The Cox proportional hazard model was
The baseline characteristics of the study patients are presented in Table 1. The median age was 66 years (range 42–82 years), and 39 patients (78%) were male. Most patients (n = 46, 92%) had advanced disease with stage III–IV. Median absolute monocyte count (AMC) at the time of diagnosis was 0.51 × 109/L (range, 0.13–1.27). The median MIPI score was 5.84 (range 4.72–7.80), and the median MIPI-b score was 6.27 (range 4.93–8.47). As the primary therapy, all patients were treated with chemotherapy, 30 (60%) with rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone); 9 (18%) with CHOP-like regimens (combination with bortezomib or ibritumomab in two); 4 (8%) with etoposide, methylprednisolone, cytarabine, and cisplatin; 3 (6%) with bendamustine plus rituximab, 2 (4%) with R-hyper-CVAD (rituximab, cyclophosphamide, vincristine, doxorubicine, and dexamethasone); 1 (2%) with combination of rituximab, bortezomib, cyclophosphamide, doxorubicin and prednisolone; and 1 (2%) with combination of rituximab, cyclophosphamide, and fludarabine. In three patients (6%), radiotherapy was given for residual disease after primary chemotherapy. Rituximab-containing combination regimens were used in 37 patients (74%). Five patients (10%) underwent high-dose chemotherapy followed by ASCT as primary therapy. As salvage therapy for refractory disease, ASCT was given in two patients. With median follow-up duration of 29.8 months (range 0.8–87.0 months) in surviving patients, 18 patients (36%) died, and the median OS was 56.2 months [95% confidence interval (CI) 36.6–75.9 months] in all patients. The 3 and 5-year OS rates were 71.0% (95% CI 56.9%–85.1%) and 42.7% (95% CI 19.4%–66.0%) respectively. As a continuous variable, the MIPI score showed a marginal relationship with OS (HR = 2.0 by +1 of score, 95% CI 0.9–4.6, p = 0.09), and MIPI-b was significantly associated with OS (HR = 1.8 by +1 of score, 95% CI 1.0–3.1, p = 0.04). When analysed using the risk groups stratified by MIPI and MIPI-b, there were no significant differences between groups in terms of OS (p = 0.59 and p = 0.32 respectively). ASCT was marginally associated with better OS (p = 0.07) In addition, OS did not differ significantly according to gender (p = 0.63), AMC (≤0.5 × 109/L vs >0.5 × 109/L; p = 0.31), or rituximab (p = 0.37).
Copyright © 2015 John Wiley & Sons, Ltd.
Hematol Oncol 2016; 34: 22–27 DOI: 10.1002/hon
C Yoo et al.
24
Table 1. Baseline patient characteristics Total (n = 50)
Age ≤60 years >60 years Gender Male Female Serum LDH level Normal Elevated ECOG performance status 0–1 2–3 Stage I–II III–IV B symptoms No Yes WBC count (109/L), median (range) Ki-67 index, median (range) Absolute monocyte counts (n = 48) ≤0.5 × 109/L >0.5 × 109/L Rituximab ASCT MIPI score, median (range) MIPI-b score, median (range) MIPI risk groups Low risk Intermediate risk High risk MIPI-b risk groups Low risk Intermediate risk High risk
B2M
Original Research Article
Serum beta-2 microglobulin as a prognostic biomarker in patients with mantle cell lymphoma Changhoon Yoo1, Dok Hyun Yoon1, Shin Kim1, Jooryung Huh2, Chan-Sik Park2, Chan-Jeong Park3, Sang-Wook Lee4 and Cheolwon Suh1* 1
Department Department 3 Department 4 Department 2
of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
*Correspondence to: Cheolwon Suh, MD, PhD, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. E-mail: [email protected]
Received 15 November 2014 Revised 9 December 2014 Accepted 17 December 2014
Abstract Although serum beta-2 microglobulin (B2M) has been suggested as a prognostic factor for mantle cell lymphoma (MCL), additional data are necessary to confirm its role. Between November 2005 and July 2014, a total of 52 patients with MCL were identified from the database of Asan Medical Center, Seoul, Korea. Pretreatment serum B2M information was available in 50 patients (96%). Overall survival (OS) was compared according to the serum B2M level with a cut-off value of 2.5 mg/L. The median MCL international prognostic index (MIPI) score was 5.84 (range 4.72–7.80), and the median biologic MIPI (MIPI-b) score was 6.27 (4.93–8.47). Pretreatment serum B2M was elevated in 30 patients (60%) and was significantly related to advanced stage (p = 0.02) and high MIPI (p = 0.03) and MIPI-b (p = 0.03) scores. With median follow-up duration of 29.8 months (range 0.8–87.0 months), the median OS was 56.2 months [95% confidence interval (CI) 36.6-75.9 months] in all patients, and serum B2M was significantly associated with OS (p = 0.001). In multivariate analyses adjusted for MIPI or MIPI-b scores and rituximab, elevated serum B2M was significantly associated with poor OS (when adjusting MIPI, hazard ratio = 26.4, 95% CI 2.9–241.3, p = 0.004; when adjusting MIPI-b, hazard ratio = 20.1, 95% CI 2.4–170.1, p = 0.006). Thus, pretreatment serum B2M may be an independent and significant prognostic factor in patients with MCL. Copyright © 2015 John Wiley & Sons, Ltd. Keywords: beta-2 microglobulin; mantle cell lymphoma; prognosis
Introduction Mantle cell lymphoma (MCL), a distinct subtype of B-cell non-Hodgkin lymphoma (NHL), represents 5%–10% of all malignant lymphomas [1]. In addition to classical histology, immunohistochemical assessment of cyclin D1 overexpression is pathognomonic for the diagnosis of MCL [2]. Most patients are diagnosed with disseminated disease. MCL is also characterized by male predominance and frequent involvement of the gastrointestinal tract and bone marrow. Mantle cell lymphoma is considered a heterogeneous disease in terms of biology and prognosis [3,4]. Although most patients with MCL show aggressive clinical features, a subset of patients with MCL has a more indolent clinical course, with a previous observational study based on population-based registries showing favourable survival outcomes in a subgroup of patients, even without anticancer treatment [5]. Hence, risk stratification for prognosis may be important for planning the therapeutic strategy Copyright © 2015 John Wiley & Sons, Ltd.
and conducting clinical trials more efficiently. The MCL international prognostic index (MIPI) is a prognostic index specific for patients with MCL that was initially developed based on the databases of randomized trials and was recently validated [6,7]. Ki-67 expression is well established as a biological marker for cell proliferation in MCL, and its incorporation into MIPI—biologic MIPI (MIPI-b)—also shows good correlation with the prognosis of patients with MCL [6,7]. However, there remains an unmet medical need for better prognostic prediction through the identification of further prognostic factors for MCL because better risk stratification of patients would allow tailored riskadapted therapy. Beta-2 microglobulin (B2M) is synthesized in all nucleated cells and forms the light chain subunit of the major histocompatibility class I antigen[8]. Free soluble B2M is detected in body fluids, such as blood, urine, and cerebrospinal fluid, following its release from the cell surface or cytoplasm. Since the identification of B2M in the early 1970s, the serum B2M level has been widely investigated
Beta-2 microglobulin in MCL
23
for its prognostic value in multiple hematological disorders, including multiple myeloma and lymphomas [9–11]. Prognostic relevance of serum B2M has been investigated in previous studies for patients with MCL [12–15]. However, additional data are still necessary to confirm its role in MCL. We therefore investigated the prognostic relevance of pretreatment serum B2M in patients with MCL.
used to estimate hazard ratios (HRs) for OS. In multivariate analysis, prognostic models (i.e. MIPI and MIPI-b), rituximab and autologous stem cell transplantation (ASCT) were included to evaluate the relevance of serum B2M. All statistical analyses were performed using the Statistical Package for the Social Sciences (IBM SPSS, Chicago, IL, USA) version 20.0, and all tests were two sided with 5% defined as the level of significance.
Methods
Results
Between November 2005 and July 2014, a total of 52 patients with MCL were identified in the database of the Asan Lymphoma Registry, Asan Medical Center, Seoul, Korea. Among them, baseline serum B2M was measured in 50 patients (96%) at the time of diagnosis. Diagnosis of MCL was based on the World Health Organization classification, and detection of cyclin D1 overexpression by immunohistochemistry was mandatory [16]. The Ki-67 index was assessed according to the published guideline [17]. Data for patient baseline characteristics and survival outcomes were retrieved from the prospectively collected database. This study was approved by the Institutional Review Board of Asan Medical Center. Initial staging evaluation included the taking of history; physical examination; complete blood count; blood chemistry, including electrolyte levels; serum lactate dehydrogenase (LDH); computed tomography of the neck, chest, abdomen, and pelvis; esophagogastroduodenoscopy; colonoscopy; and bone marrow aspiration and biopsy. According to the revised response criteria for malignant lymphoma [6], the response was assessed during and after treatment or when progressive disease was suspected. Serum B2M was measured using a radioimmunoassay kit (Immunotech, Inc., Prague, Czech Republic). The kit manufacturer defined the upper normal limit (UNL) of serum B2M at 2.5 mg/L. Patients were categorized by the level of the UNL for the analysis of the relationship between B2M levels and survival outcomes. MCL international prognostic index scores were calculated using the formula presented in the original paper for MIPI with inclusion of baseline values for age, Eastern Cooperative Oncology Group performance status, and LDH. For the calculation of MIPI-b, Ki-67 expression was added to the formula in addition to MIPI factors. Baseline values of all MIPI factors and Ki-67 expression were available in our study cohort. Overall survival (OS) was calculated by the dates between diagnosis and death from any cause. Data were censored if patients were alive at last follow-up. Categorical variables were evaluated using chi-square or Fisher’s exact tests, as appropriate. The Kaplan–Meier method was used to estimate OS, and survival curves were compared by the log-rank test. The Cox proportional hazard model was
The baseline characteristics of the study patients are presented in Table 1. The median age was 66 years (range 42–82 years), and 39 patients (78%) were male. Most patients (n = 46, 92%) had advanced disease with stage III–IV. Median absolute monocyte count (AMC) at the time of diagnosis was 0.51 × 109/L (range, 0.13–1.27). The median MIPI score was 5.84 (range 4.72–7.80), and the median MIPI-b score was 6.27 (range 4.93–8.47). As the primary therapy, all patients were treated with chemotherapy, 30 (60%) with rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone); 9 (18%) with CHOP-like regimens (combination with bortezomib or ibritumomab in two); 4 (8%) with etoposide, methylprednisolone, cytarabine, and cisplatin; 3 (6%) with bendamustine plus rituximab, 2 (4%) with R-hyper-CVAD (rituximab, cyclophosphamide, vincristine, doxorubicine, and dexamethasone); 1 (2%) with combination of rituximab, bortezomib, cyclophosphamide, doxorubicin and prednisolone; and 1 (2%) with combination of rituximab, cyclophosphamide, and fludarabine. In three patients (6%), radiotherapy was given for residual disease after primary chemotherapy. Rituximab-containing combination regimens were used in 37 patients (74%). Five patients (10%) underwent high-dose chemotherapy followed by ASCT as primary therapy. As salvage therapy for refractory disease, ASCT was given in two patients. With median follow-up duration of 29.8 months (range 0.8–87.0 months) in surviving patients, 18 patients (36%) died, and the median OS was 56.2 months [95% confidence interval (CI) 36.6–75.9 months] in all patients. The 3 and 5-year OS rates were 71.0% (95% CI 56.9%–85.1%) and 42.7% (95% CI 19.4%–66.0%) respectively. As a continuous variable, the MIPI score showed a marginal relationship with OS (HR = 2.0 by +1 of score, 95% CI 0.9–4.6, p = 0.09), and MIPI-b was significantly associated with OS (HR = 1.8 by +1 of score, 95% CI 1.0–3.1, p = 0.04). When analysed using the risk groups stratified by MIPI and MIPI-b, there were no significant differences between groups in terms of OS (p = 0.59 and p = 0.32 respectively). ASCT was marginally associated with better OS (p = 0.07) In addition, OS did not differ significantly according to gender (p = 0.63), AMC (≤0.5 × 109/L vs >0.5 × 109/L; p = 0.31), or rituximab (p = 0.37).
Copyright © 2015 John Wiley & Sons, Ltd.
Hematol Oncol 2016; 34: 22–27 DOI: 10.1002/hon
C Yoo et al.
24
Table 1. Baseline patient characteristics Total (n = 50)
Age ≤60 years >60 years Gender Male Female Serum LDH level Normal Elevated ECOG performance status 0–1 2–3 Stage I–II III–IV B symptoms No Yes WBC count (109/L), median (range) Ki-67 index, median (range) Absolute monocyte counts (n = 48) ≤0.5 × 109/L >0.5 × 109/L Rituximab ASCT MIPI score, median (range) MIPI-b score, median (range) MIPI risk groups Low risk Intermediate risk High risk MIPI-b risk groups Low risk Intermediate risk High risk
B2M
