- Email: [email protected]
The Prognostic Significance of Elevated Levels of Serum Ferritin Before Chemotherapy in Patients With Non-Hodgkin Lymphoma
Original Study
The Prognostic Significance of Elevated Levels of Serum Ferritin Before Chemotherapy in Patients With Non-Hodgkin Lymphoma Kyung Ah Yoh,1 Ho Sup Lee,1 Lee Chun Park,1 Eun Mi Lee,1 Seong Hoon Shin,1 Dae Jin Park,2 Byeong Jin Ye,3 Yang Soo Kim1 Abstract A total of 267 patients who were newly diagnosed with NHL and who received chemotherapy between September 1999 and April 2012 were retrospectively analyzed. Elevated levels of serum ferritin of 500 ng/ml or more may be an important marker for predicting poor survival outcomes. Background: Elevated levels of serum ferritin have been documented to be an adverse prognostic factor in patients with hematologic malignancies undergoing hematopoietic stem cell transplantation. The purpose of this study was to estimate the correlation between elevated levels of serum ferritin and survival outcomes in patients with non-Hodgkin lymphoma (NHL). Patients and Methods: A total of 267 patients who were newly diagnosed with NHL and who received chemotherapy between September 1999 and April 2012 were retrospectively analyzed. Results: In multivariate analysis, other chemotherapy regimens excluding CHOP-like chemotherapy regimens (cyclophosphamide, adriamycin, vincristine, prednisolone) and RCHOP (rituximab plus CHOP), a high level of b2-microglobulin, a high-intermediate/high risk according to the international prognostic index (IPI), and elevated levels of serum ferritin were all significant independent prognostic factors for 5-year progression-free survival rates. RCHOP and other chemotherapy regimens, a high level of b2-microglobulin, a high-intermediate/high IPI risk, and high levels of serum ferritin were significant independent prognostic factors for 5-year overall survival rates. Conclusion: Elevated levels of serum ferritin of 500 ng/mL or more as well as the use of chemotherapy regimens besides CHOP-like or RCHOP, a high-intermediate/high risk IPI, and a high level of beta2-microglobulin in NHL may be an important marker for predicting poor survival outcomes. Clinical Lymphoma, Myeloma & Leukemia, Vol. 14, No. 1, 43-9 ª 2014 Elsevier Inc. All rights reserved. Keywords: Chemotherapy, Ferritin, Lymphoma, Prognosis, Survival
Introduction Serum ferritin has frequently been used as a surrogate marker for systemic iron stores, but might also be elevated in specific circumstances without excess iron stores, such as in inflammation. Elevated levels of serum ferritin might occur with certain infectious disease and rheumatic disorders, but can also act as a key marker for malignancy.1-3 Some studies have shown that serum ferritin levels correlated with tumor mass and closely followed disease activity in 1
Department of Internal Medicine Department of Pharmacology Department of Occupational and Environmental Medicine Kosin University College of Medicine, Busan, South Korea 2 3
Submitted: Jul 18, 2013; Revised: Sep 12, 2013; Accepted: Sep 24, 2013; Epub: Oct 1, 2013 Address for correspondence: Ho Sup Lee, MD, PhD, Division of Hematology/ Oncology, Department of Internal Medicine, Kosin University College of Medicine, Kosin University Gospel Hospital, 34 Amnam-Dong, Seo-Gu, Busan 602-703, Korea Fax: þ82-51-990-5820; e-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.09.008
patients with hematologic malignancies such as malignant lymphoma and acute leukemia.4-7 Studies have also shown that elevated serum ferritin levels in cancer patients are associated with a poor prognosis. One study pointed out that elevated levels of serum ferritin at the time of diagnosis of pancreatic cancer indicated a bad prognosis for the patient.8 In patients with squamous cell carcinoma of the head and neck, ferritin levels also showed a tendency to increase or remain at high levels in patients with a poor prognosis.9 Moreover, recent studies suggest that elevated pretransplantation serum ferritin levels are associated with increased mortality and a lower transplantation-related survival after allogeneic hematopoietic stem cell transplantation.10-13 In addition, other studies have demonstrated an association between elevated levels of serum ferritin and overall survival (OS) or relapse-free survival after autologous hematopoietic stem cell transplantation for malignant lymphoma.14-17 There are many clinical and molecular factors used to predict outcomes in patients with malignant lymphomas.18 The
Clinical Lymphoma, Myeloma & Leukemia February 2014
- 43
Prognostic Significance of Serum Ferritin in NHL documented negative clinical prognostic factors for malignant lymphoma are old age (> 60 years), Ann Arbor stage III, Eastern Cooperative Oncology Group (ECOG) performance status 2, elevated lactate dehydrogenase (LDH) levels, more than 1 extranodal site of disease, the presence of bone marrow involvement, presence of B symptoms, a bulky mass ( 10 cm), hemogloblin levels < 12 g/dL, above upper normal b2-microglobulin levels, low absolute lymphocyte counts (ALC) < 1.0 109/L, etc, and there are some meaningful prognostic molecular markers such as Bcl-2, MYC proto-oncogene, cyclin D2, CD5, CD10, survivin, vascular endothelial growth factor, anaplastic lymphoma kinase, and others.18-20 Few studies have reported correlations between serum ferritin and prognosis in malignant lymphoma. Disease remission was associated with the normalization of serum ferritin levels, which suggests that serum ferritin measurements might be of clinical usefulness in the initial evaluation and assessment of therapy response in patients with acute leukemia and malignant lymphoma.6 A study of biochemical markers in non-Hodgkin lymphoma (NHL) stages III and IV showed that serum ferritin had a significant relationship with survival.21 Based on these data, it appears that serum ferritin levels might be associated with prognosis or therapeutic outcomes in malignant lymphoma. However, there are no studies about the prognostic role of serum ferritin in malignant lymphoma in patients who have not yet received chemotherapy. The aim of this study was to determine the relationship between baseline serum ferritin levels in patients who were newly diagnosed with NHL and survival outcomes after conventional chemotherapy.
Patients and Methods Patients A total of 267 consecutive adult patients treated with conventional chemotherapy for NHL at the Kosin University Gospel Hospital between September 1999 and June 2012 were analyzed. This retrospective study included all patients who matched specified inclusion and exclusion criteria. Patients were included only if their NHL was confirmed using pathology. They were newly diagnosed with NHL and underwent initial chemotherapy. Enrolled patients had baseline serum ferritin levels measured at least 2 weeks before chemotherapy. Patients who had not had their serum ferritin levels checked before chemotherapy were excluded. Patients who had received chemotherapy for less than 3 cycles for other reasons without disease progression were also excluded. Most of the enrolled patients initially received CHOP-like (CHOP [cyclophosphamide, adriamycin, vincristine, prednisolone], CVP [cyclophosphamide, vincristine, prednisolone], and CEOP [cyclophosphamide, etoposide, vincristine, prednisolone]) chemotherapy, RCHOP (rituximab plus CHOP), or others such as MINE (mitoxantrone, ifosfamide, etoposide), IMVP (ifosfamide, methotrexate, etoposide), ESHAP (etoposide, cytarabine, cisplatin, methylprednisolone), ProMACE-CytaBOM (cyclophosphamide, doxorubicin, etoposide, mechlorethamine, vincristine, prednisone, procarbazine, cytarabine, bleomycin and methotrexate with leucovorin).
Laboratory Analyses
44
-
Baseline serum ferritin levels were measured at least 2 weeks before beginning first-line chemotherapy. Blood samples were obtained
Clinical Lymphoma, Myeloma & Leukemia February 2014
before treatment and basic biochemical and hematological parameters, inflammatory markers, and tumor markers were measured. Serum ferritin levels were measured using a 2-site chemiluminometric sandwich immunoassay (ADVIA Centaur Ferritin analyzer). The 95th percentile range of serum ferritin for healthy men is 22 to 322 ng/mL and for healthy women is 10 to 291 ng/mL. Because the focus of this study was to assess the prognostic effects of elevated serum ferritin levels, the cutoff value for the high ferritin levels was 500 ng/mL, a number that has been used for hyperferritinemia criteria for hematologic disease in other studies.22,23
Analysis In this study, we assessed prognostic factors that are known to predict the outcome of treatment in patients with NHL. We investigated whether elevated serum ferritin levels at baseline before chemotherapy could be an independent predictor for survival in patients with NHL. The following clinical and demographic parameters were analyzed in this study: age, sex, Ann Arbor stage, LDH, ECOG performance status, international prognostic index (IPI), bone marrow involvement, extranodal involvement, bulky mass, C-reactive protein (CRP), b2-microglobulin, ALC, ferritin, and chemotherapy received. We could not estimate the relationship between cytogenetic or molecular abnormalities and survival outcomes because this retrospective study did not have enough medical records on cytogenetic or molecular markers.
Statistical Analysis OS was calculated from the date of diagnosis to the date of death from any cause, or to the final follow-up date. Progression-free survival rate (PFS) was calculated from the date of starting chemotherapy to the date of disease progression or relapse. Survival was estimated from Kaplan-Meier curves and compared using a log-rank test. To identify which factors might have independent significance in influencing survival, a Cox proportional hazard model was fitted with some variables used for the univariate studies. In multivariate analysis, age, LDH, ECOG, stage, and extranodal involvement were excluded because these factors were included in the IPI criteria.24,25 Approval for these studies was obtained from the institutional review board.
Results The patient characteristics are summarized in Table 1. The median patient age was 56 years (range, 14-84 years), with 40.4% of patients being older than 60 years. The female-to-male ratio was 1 to 1.4. Enrolled patients were diagnosed with diffuse large B-cell lymphoma (n ¼ 163, 61.0%), T cell lymphoma (n ¼ 48, 18.0%), and other lymphomas (n ¼ 56, 21.0%) including mantle cell lymphoma, marzinal zone B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, and Burkitt’s lymphoma. The studied group was comprised of 63 patients in stage I, 63 patients in stage II, 74 patients in stage III, and 67 patients in stage IV disease according to the Ann Arbor classification. Among these, 89 (33.3%), 63 (23.6%), 54 (20.2%), and 61 (22.8%) patients were classified in IPI low, low-intermediate, high-intermediate, and high-risk groups, respectively. Most patients were treated with anthracycline-based standard CHOP-like chemotherapy (n ¼ 157; 58.8%) and RCHOP chemotherapy
Kyung Ah Yoh et al Table 1 Patient Characteristics (n [ 267) Characteristic Median Age (Range), Years
Table 2 Univariate Analysis of Prognostic Factors for Survival in Patients With NHL Value 56 (14-84)
Sex Male
157 (58.8)
Female
110 (41.2)
Diagnosis DLBCL
Age, Years
163 (61.0) 56 (21.0)
T-cell NHL
48 (18.0)
Chemotherapy
P
5-Year OS (%)
<60
54.6
60
43.2
60.9 36.9 .967
Male
49.7
Female
50.7
Diagnosis
.894 51.8 51.0
.007
B-cell NHL
53.5 36.1
.025 53.8
157 (58.8)
T-cell NHL
RCHOP
94 (35.2)
Chemotherapy
Others
16 (6.0)
CHOP-Like
48.4
50.8
RCHOP
59.5
57.9
Others
11.4
IPI Low
89 (33.3)
Low-intermediate
63 (23.6)
High-intermediate
54 (20.2)
High Mean LDH (Range), IU/L
61 (22.8) 605.67 (163.00-4438.00)
ECOG PS 0-1 2
99 (37.1) 168 (62.9)
Stage
126 (47.2)
III
141 (52.8)
Extranodal Involvement <2
208 (77.9)
2
59 (22.1)
Bulky Mass
Low/low-intermediate
63.0
High-intermediate/high
30.8
<450
63.6
450
32.8
ECOG PS <2
54.4
2
47.3
Stage
60.2
III
40.9
Extranodal Involvement <2
53.8
2
37.1
<10 cm
52.1
10 cm
41.6
Present
49 (18.4)
Absent
218 (81.6)
Mean ALC (Range), 1.0 3 103/mL Mean Ferritin (Range), ng/mL
2783.11 (140.00-197,300.00) 259.98 (1.70-6562.00)
Data are presented as n (%) except where otherwise noted. Abbreviations: ALC ¼ absolute lymphocyte counts; BM ¼ bone marrow; CHOP-like ¼ cyclophosphamide, adriamycin, vincristine and prednisolone; CRP ¼ C-reactive protein; DLBCL ¼ diffuse large B-cell lymphoma; ECOG PS ¼ Eastern Cooperative Oncology Group performance status; IPI ¼ International Prognostic Index; LDH ¼ lactate dehydrogenase; NHL ¼ non-Hodgkin lymphoma; RCHOP ¼ rituximab plus CHOP.
29.4 .001 68.8 42.0 .004 62.5 41.1 .046 55.3 37.2 .114
.001 56.6 31.6
<.001
CRP, mg/dL <5
55.0
5
18.6
b2-Microglobulin, mg/L
<.001 59.4 24.6
<.001
<3.5
54.8
3.5
26.6
<.001 58.7 14.9
<.001
BM Involvement (%) Present
35.8
Absent
53.5
ALC, 1.0 3 103/mL
.013 37.8 54.6
.001
<1000
36.3
1000
54.6
.001 32.2 57.7
<.001
Ferritin, ng/mL
(n ¼ 94; 35.2%), and others including multidrug combination chemotherapy (n ¼ 16; 6.0%). The mean level of serum ferritin at baseline before chemotherapy was 259.98 ng/mL (range, 1.70-6562.00 ng/mL). Of the 267 patients with NHL, 36 (13.9%) were categorized as having high levels of ferritin (500 ng/mL or more).
<.001 69.5
.020
49 (18.4)
BM Involvement
29.7
.001
10 cm
2.78 (0.01-147.95)
<.001 67.5
.144
Bulky Mass
2.48 (0.71-24.01)
9.8
<.001
LDH, IU/L
217 (81.3)
Mean b2-Microglobusslin (Range), mg/L
.001
<.001
<10 cm Mean CRP (Range), mg/dL
42.1 .002
IPI
P <.001
.053
Sex
Other B-cell NHL
CHOP-like
5-Year PFS (%)
Value
<.001
<500
57.5
56.5
500
11.0
18.1
Abbreviations: ALC ¼ absolute lymphocyte counts; BM ¼ bone marrow; CHOP-like ¼ cyclophosphamide, adriamycin, vincristine and prednisolone; CRP ¼ C-reactive protein; ECOG PS ¼ Eastern Cooperative Oncology Group performance status; IPI ¼ International Prognostic Index; LDH ¼ lactate dehydrogenase; NHL ¼ non-Hodgkin lymphoma; OS ¼ overall survival; PFS ¼ progression-free survival; RCHOP ¼ rituximab plus CHOP.
Clinical Lymphoma, Myeloma & Leukemia February 2014
- 45
Prognostic Significance of Serum Ferritin in NHL Table 3 Multivariate Analysis of Independent Prognostic Factors for Survival in Patients With NHL PFS
OS
RR
95% CI
P
RR
95% CI
0.784
0.444-1.385
.402
0.648
0.369-1.137
.130
0.606
0.375-0.979
.041
0.558
0.350-0.888
.014
RCHOP
0.554
0.261-1.176
.124
0.466
0.239-0.909
.025
Others
0.309
0.135-0.979
.005
0.382
0.187-0.780
.008
0.947
0.580-1.545
.827
Factor
P
Diagnosis, % B-cell NHL vs. T-cell NHL IPI, % Low and low-intermediate vs. high-intermediate and high Chemotherapy, % CHOP-like
Bulky Mass, % <10 cm vs. 10 cm CRP, mg/dL <5 vs. 5
0.660
0.389-1.121
.124
0.687
0.415-1.135
.143
0.442
0.264-0.739
.002
0.401
0.250-0.645
<.001
1.419
0.857-2.350
.174
0.888
0.528-1.492
.653
0.810
0.470-1.395
.447
1.277
0.775-2.105
.337
0.426
0.253-0.716
.001
0.583
0.350-0.970
.038
b2-Microglobulin, mg/L <3.5 vs. 3.5 BM involvement, % Present vs. absent ALC, 1.0 3 103/mL <1000 vs. 1000 Ferritin, ng/mL <500 vs. 500
Abbreviations: ALC ¼ absolute lymphocyte counts; CHOP-like ¼ cyclophosphamide, adriamycin, vincristine and prednisolone; CRP ¼ C-reactive protein; IPI ¼ international prognostic index; NHL ¼ non-Hodgkin lymphoma; OS ¼ overall survival; PFS ¼ progression-free survival; RCHOP ¼ rituximab plus CHOP; RR ¼ relative risk.
Analysis of Prognostic Factors in NHL
46
-
In univariate analysis, the differences in 5-year PFS and OS rates are shown in Table 2. Factors documented to have significant differences in 5-year PFS rates were the chemotherapy regimen (P ¼ .002; 48.4% in the CHOP-like regimen vs. 59.5% in RCHOP vs. 11.4% in other regimens), diagnosis (P ¼ .012; 54.1% in B-cell NHL vs. 37.5% in T-cell NHL), IPI ranking (P < .001; 63.0% in low/low-intermediate vs. 30.8% in high-intermediate/high risk group), LDH (P < .001; 63.6% in less than normal limit vs. 32.8% in greater than normal limit), stage (P ¼ .001; 60.2% in less than stage III vs. 40.9% in stage III or higher), extranodal involvement (P ¼ .020; 53.8% in less than 2 sites vs. 37.1% in 2 sites or more), CRP (P < .001; 55.0% in less than 5 mg/dL vs. 18.6% in 5 mg/dL or more), b2-microglobulin (P < .001; 54.8% in less than 3.5 mg/L vs. 26.6% in 3.5 mg/L or more), bone marrow (BM) involvement (P < .001; 35.8% in present vs. 53.5% in absent), ALC (P ¼ .001; 36.3% in less than 1.0 103/mL vs. 54.6% in 1.0 103/mL or more), and serum ferritin (P < .001; 57.5% in less than 500 ng/mL vs. 11.0% in 500 ng/mL or more). Factors with documented significant differences in 5-year OS rates were age (P < .001; 60.9% in younger than 60 years vs. 36.9% in 60 years or older), chemotherapy regimen (P ¼ .001; 50.8% in CHOP-like regimen vs. 57.9% in RCHOP vs. 9.8% in other regimens), IPI rank (P < .001; 67.5% in low/low-intermediate vs. 29.7% in high-intermediate/high risk group), LDH (P < .001; 69.5% in less than normal limit vs. 29.4% in higher than normal limit), ECOG performance status (P ¼ .001; 68.8% in less than 2 scores vs. 42.0% in 2 or more scores), stage
Clinical Lymphoma, Myeloma & Leukemia February 2014
(P ¼ .004; 62.5% in less than stage III vs. 41.1% in stage III or more), a bulky mass (P ¼ .001; 56.6% in tumor diameter less than 10 cm vs. 31.6% in 10 cm or more), CRP (P < .001; 59.4% in less than 5 mg/dL vs. 24.6% in 5 mg/dL or more), b2-microglobulin (P < .001; 58.7% in less than 3.5 mg/L vs 14.9% in 3.5 mg/L or more), BM involvement (P ¼ .013; 37.8% in present vs. 54.6% in absent), ALC (P ¼ .001; 32.2% in less than 1.0 103/mL vs. 57.7% in 1.0 103/mL or more), and serum ferritin (P < .001; 56.5% in less than 500 ng/mL vs. 18.1% in 500 ng/mL or more). In multivariate analysis, other chemotherapy regimens that were not CHOP-like or RCHOP (relative risk [RR] ¼ 0.309; 95% confidence interval [CI], 0.135-0.979; P ¼ .005 in other regimens), a high level of b2-microglobulin (RR ¼ 0.442; 95% CI, 0.264-0.739; P ¼ .002), high-intermediate/high risk IPI (RR ¼ 0.606; 95% CI, 0.375-0.979; P ¼ .041) and high levels of serum ferritin (RR ¼ 0.426; 95% CI, 0.253-0.716; P ¼ .001) were significant independent prognostic factors for 5-year PFS. RCHOP and other chemotherapy regimens (RR ¼ 0.466; 95% CI, 0.239-0.909; P ¼ .025 in RCHOP and RR ¼ 0.382; 95% CI, 0.187-0.780; P ¼ .008 in other regimens), a high level of b2-microglobulin (RR ¼ 0.401; 95% CI, 0.250-0.645; P < .001), high-intermediate/high risk IPI (RR ¼ 0.558; 95% CI, 0.3500.888; P ¼ .014), and high levels of serum ferritin (RR ¼ 0.583; 95% CI, 0.350-0.970; P ¼ .038) were significant independent prognostic factors for OS. These results are shown in Table 3. Survival curves according to serum levels of ferritin are shown in Figures 1 and 2.
Kyung Ah Yoh et al Figure 1 Progression-Free Survival. In Patients With Non-Hodgkin’s Lymphoma, the 5-Year Progression Free Survival Rate was Superior in the High Serum Ferritin Level Group Compared to that of the Low Level Group (56.9% vs 22.3%, P < .001)
Discussion Elevated levels of serum ferritin are the most widely used surrogate marker for iron overload. However, in other clinical situations such as inflammation, infectious disease, and malignancy, increased serum ferritin might be found without excess iron stores.1-3 Moreover, there are some reports that high levels of serum ferritin at the time of diagnosis are associated with the prognosis of several solid cancers and that high levels of serum ferritin before transplantation are associated with mortality and survival in several hematologic malignancies.8,9,12,15 In our study, the 5-year PFS rates were 57.5% and 11.6% in the groups with low levels of serum ferritin (< 500 ng/mL) and high levels ( 500 ng/mL), respectively (Fig. 1). The 5-year OS rates were 56.9% and 22.3% in the groups with low levels and high revels, respectively (Fig. 2). With these data, patients with high
levels of serum ferritin had a lower PFS and OS rate than those with low levels of ferritin, although the results of OS were shown to be lower than those of PFS because the definition of OS included death from any cause. In multivariate analysis, having elevated levels of serum ferritin and a high/high-intermediate IPI, a high level of b2-microglobulin, and chemotherapy regimens that were not CHOP-like were independent poor prognostic factors for PFS and OS in patients with NHL. Until now, the RCHOP regimen has been the standard treatment for patients with CD20-positive NHL, and the CHOP regimen has been the standard of care for younger and older patients with NHL who could not use rituximab or other new agents.26,27 In this study, the number of patients treated with RCHOP, CHOP-like, and others were 94, 157, and 16, respectively (Table 1). The reasons that some patients could not use rituximab were: patients who were diagnosed with NHL before
Figure 2 Overall Survival. In Patients With Non-Hodgkin’s Lymphoma, the 5-Year Overall Survival Rate was Superior in the High Serum Ferritin Level Group Compared to that of the Low Level Group (57.5% vs 11.6%, P < .001)
Clinical Lymphoma, Myeloma & Leukemia February 2014
- 47
Prognostic Significance of Serum Ferritin in NHL 2004 could not be supplied rituximab in Korea and patients who were diagnosed as CD20-negative NHL in tumor tissue could not. In the same context, patients in this study who could not be treated with CHOP or RCHOP because of several individual conditions such as comorbidities including cardiomyopathy, etc, might have had poor survival outcomes. IPI had been the widely accepted prognostic factor index for patients with malignant lymphomas before the rituximab era25 and a standard IPI has been confirmed as valid for predicting survival outcomes in patients treated with RCHOP.24 In our study, IPI was shown to be one of the most significant prognostic factors. In some reports, serum b2microglobulin levels were also shown to be significant variables for predicting survival outcomes in NHL.28-30 However, serum ferritin levels have not been documented as a prognostic marker in NHL. There have been some reports about mechanisms of how ferritin plays a role for prognosis in NHL by cell line research. Ferritin might be a regulator of lymphoid cell proliferation and could induce cell damage by inflammation or immune function in malignant lymphoma. The expression of the H-ferritin receptor is associated with the proliferative status of the T-lymphoid cell, suggesting that the receptor might mediate a putative regulatory role of H-ferritin.31 Specific binding sites for H-ferritin on human lymphocytes have also behaved as proliferation markers.32 Increased levels of serum ferritin found in patients with malignancy could exert adverse effects on the host immune response and perhaps have an inhibitory effect on hematopoiesis.33 Other studies have suggested that high ferritin expression in tumor tissues and elevated serum levels were the result of inflammation and oxidative stress and improved resistance to oxidative stress by interfering with the cellular antioxidant system. Malignant tumors might manipulate the body’s inflammation process to promote their own angiogenic growth, which could lead to disease progression in NHL.34,35 Other studies have suggested that high ferritin expression in tumor tissues and elevated serum levels were the result of inflammation and oxidative stress and improved resistance to oxidative stress by interfering with the cellular antioxidant system. Malignant tumors might manipulate the body’s inflammation process to promote their own angiogenic growth, which could lead to disease progression in NHL.
Conclusion Elevated levels of serum ferritin of 500 ng/mL or more might be an important marker for predicting poor survival outcomes in NHL. Further studies are needed to recognize the reasons that elevated levels of serum ferritin is correlated with prognosis in NHL.
Clinical Practice Points Serum ferritin has often been used as a surrogate marker for
48
-
systemic iron stores, but may be elevated in cases even without excess iron stores, such as during inflammation. Elevated levels of serum ferritin have been documented to be an adverse prognostic factor in patients with several solid tumors undergoing hematopoietic stem cell transplantation with hematologic malignancies. Several studies have suggested that elevated levels of serum ferritin are associated with worse outcomes in malignant lymphoma. The purpose of this study was to estimate the correlation between elevated levels of serum
Clinical Lymphoma, Myeloma & Leukemia February 2014
ferritin and survival outcomes in patients with non-Hodgkin’s lymphoma (NHL). A total of 267 patients who were newly diagnosed with NHL and who received chemotherapy between September 1999 and April 2012 were retrospectively enrolled in the study. In multivariate analysis, non-CHOP-like chemotherapy regimens (cyclophosphamide, adriamycin, vincristine, prednisolone), RCHOP (rituximab plus CHOP), a high level of b2-microglobulin a high-intermediate/high risk according to the international prognostic index (IPI), and elevated levels of serum ferritin were all significant independent prognostic factors for 5-year progression free survival rates (PFS). RCHOP and other chemotherapy regimens, a high level of b2-microglobulin, and high levels of serum ferritin were significant independent prognostic factors for 5-year overall survival rates (OS). Elevated levels of serum ferritin of 500 ng/ml or more may be an important marker for predicting poor survival outcomes and the use of chemotherapy regimens besides CHOP-like or RCHOP, a high-intermediate/high risk IPI, and a high level of beta2-microglobulin in NHL.
Acknowledgments Kyung Ah Yoh and Ho Sup Lee designed the study, analyzed the clinical data and wrote the manuscript. Dae Jin Park, Lee Chun Park, Eun Mi Lee, Seong Hoon Shin and Yang Soo Kim contributed to conception of the study. Byeong Jin Ye supported statistical analysis of our data. Ho Sup Lee was involved in revising the manuscript critically for intellectual content and all authors gave final approval for the submission of the manuscript.
Disclosure This study was supported by a grant from Kosin University College of Medicine.
References 1. Dayer E, Dayer J-M, Roux-Lombard P. Primer: the practical use of biological markers of rheumatic and systemic inflammatory diseases. Nat Clin Pract Rheum 2007; 3:512-20. 2. Bagnari V, Colina M, Ciancio G, et al. Adult-onset Still’s disease. Rheumatol Int 2010; 30:855-62. 3. Petelin A, Cunha BA. Fever of unknown origin (FUO) attributable to large B-cell lymphoma: the diagnostic significance of highly elevated alkaline phosphatase and serum ferritin levels. Heart Lung 2013; 42:67-71. 4. Aulbert E, Fromm H, Hornemann H. Ferritin in acute leukemia. Serum ferritin concentration as a nonspecific tumor marker for M1 and M2 myeloid leukemia [in German]. Med Klin (Munich) 1991; 86:297-304. 5. Aulbert E, Steffens O. Serum ferritinea tumor marker in malignant lymphomas? [in German]. Onkologie 1990; 13:102-8. 6. Matzner Y, Konijn AM, Hershko C. Serum ferritin in hematologic malignancies. Am J Hematol 1980; 9:13-22. 7. Eshhar Z, Order SE, Katz DH. Ferritin, a Hodgkin’s disease associated antigen. Proc Natl Acad Sci U S A 1974; 71:3956-60. 8. Kalousová M, Krechler T, Jáchymová M, et al. Ferritin as an independent mortality predictor in patients with pancreas cancer. Results of a pilot study. Tumour Biol 2012; 33:1695-700. 9. Maxim PE, Veltri RW. Serum ferritin as a tumor marker in patients with squamous cell carcinoma of the head and neck. Cancer 1986; 57:305-11. 10. Lim ZY, Fiaccadori V, Gandhi S, et al. Impact of pre-transplant serum ferritin on outcomes of patients with myelodysplastic syndromes or secondary acute myeloid leukaemia receiving reduced intensity conditioning allogeneic haematopoietic stem cell transplantation. Leuk Res 2010; 34:723-7. 11. Alessandrino EP, Porta MGD, Bacigalupo A, et al. Prognostic impact of pre-transplantation transfusion history and secondary iron overload in patients with myelodysplastic syndrome undergoing allogeneic stem cell transplantation: a GITMO study. Haematologica 2010; 95:476-84.
Kyung Ah Yoh et al 12. Armand P, Kim HT, Cutler CS, et al. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood 2007; 109:4586-8. 13. Storey JA, Connor RF, Lewis ZT, et al. The transplant iron score as a predictor of stem cell transplant survival. J Hematol Oncol 2009; 2:44. 14. Sucak GT, Yegin ZA, Özkurt ZN, et al. Iron overload: predictor of adverse outcome in hematopoietic stem cell transplantation. Transplant Proc 2010; 42: 1841-8. 15. Mahindra A, Bolwell B, Sobecks R, et al. Elevated ferritin is associated with relapse after autologous hematopoietic stem cell transplantation for lymphoma. Biol Blood Marrow Transplant 2008; 14:1239-44. 16. Altès A, Remacha AF, Sureda A, et al. Iron overload might increase transplantrelated mortality in haematopoietic stem cell transplantation. Bone Marrow Transplant 2002; 29:987-9. 17. McKay PJ, Murphy JA, Cameron S, et al. Iron overload and liver dysfunction after allogeneic or autologous bone marrow transplantation. Bone Marrow Transplant 1996; 17:63-6. 18. Sehn LH. Optimal use of prognostic factors in non-Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program 2006; 2006:295-302. 19. Lossos IS, Morgensztern D. Prognostic biomarkers in diffuse large B-cell lymphoma. J Clin Oncol 2006; 24:995-1007. 20. Perry AM, Cardesa-Salzmann TM, Meyer PN, et al. A new biologic prognostic model based on immunohistochemistry predicts survival in patients with diffuse large B-cell lymphoma. Blood 2012; 120:2290-6. 21. Hagberg H, Glimelius B, Gronowitz S, et al. Biochemical markers in nonHodgkin’s lymphoma stages III and IV and prognosis: a multivariate analysis. Scand J Haematol 1984; 33:59-67. 22. Verbsky JW, Grossman WJ. Hemophagocytic lymphohistiocytosis: diagnosis, pathophysiology, treatment, and future perspectives. Ann Med 2006; 38:20-31. 23. Fardet L, Coppo P, Kettaneh A, et al. Low glycosylated ferritin, a good marker for the diagnosis of hemophagocytic syndrome. Arthritis Rheum 2008; 58: 1521-7.
24. Ziepert M, Hasenclever D, Kuhnt E, et al. Standard International Prognostic Index remains a valid predictor of outcome for patients with aggressive CD20þ B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28:2373-80. 25. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 1993; 329: 987-94. 26. Coiffier B, Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346:235-42. 27. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 1993; 328:1002-6. 28. Swan F, Velasquez WS, Tucker S, et al. A new serologic staging system for largecell lymphomas based on initial beta 2-microglobulin and lactate dehydrogenase levels. J Clin Oncol 1989; 7:1518-27. 29. Conconi A, Zucca E, Roggero E, et al. Prognostic models for diffuse large b-cell lymphoma. Hematol Oncol 2000; 18:61-73. 30. Rodriguez J, Cabanillas F, McLaughlin P, et al. A proposal for a simple staging system for intermediate grade lymphoma and immunoblastic lymphoma based on the ‘tumor score’. Ann Oncol 1992; 3:711-7. 31. Moss D, Powell LW, Arosio P, et al. Effect of cell proliferation on H-ferritin receptor expression in human T lymphoid (MOLT-4) cells. J Lab Clin Med 1992; 120:239-43. 32. Fargion S, Fracanzani AL, Brando B, et al. Specific binding sites for H-ferritin on human lymphocytes: modulation during cellular proliferation and potential implication in cell growth control. Blood 1991; 78:1056-61. 33. Cazzola M, Arosio P, Bellotti V, et al. Immunological reactivity of serum ferritin in patients with malignancy. Tumori 1985; 71:547-54. 34. Alkhateeb AA, Connor JR. Nuclear ferritin: a new role for ferritin in cell biology. Biochim Biophys Acta 2010; 1800:793-7. 35. Recalcati S, Invernizzi P, Arosio P, et al. New functions for an iron storage protein: the role of ferritin in immunity and autoimmunity. J Autoimmun 2008; 30:84-9.
Clinical Lymphoma, Myeloma & Leukemia February 2014
- 49
The Prognostic Significance of Elevated Levels of Serum Ferritin Before Chemotherapy in Patients With Non-Hodgkin Lymphoma Kyung Ah Yoh,1 Ho Sup Lee,1 Lee Chun Park,1 Eun Mi Lee,1 Seong Hoon Shin,1 Dae Jin Park,2 Byeong Jin Ye,3 Yang Soo Kim1 Abstract A total of 267 patients who were newly diagnosed with NHL and who received chemotherapy between September 1999 and April 2012 were retrospectively analyzed. Elevated levels of serum ferritin of 500 ng/ml or more may be an important marker for predicting poor survival outcomes. Background: Elevated levels of serum ferritin have been documented to be an adverse prognostic factor in patients with hematologic malignancies undergoing hematopoietic stem cell transplantation. The purpose of this study was to estimate the correlation between elevated levels of serum ferritin and survival outcomes in patients with non-Hodgkin lymphoma (NHL). Patients and Methods: A total of 267 patients who were newly diagnosed with NHL and who received chemotherapy between September 1999 and April 2012 were retrospectively analyzed. Results: In multivariate analysis, other chemotherapy regimens excluding CHOP-like chemotherapy regimens (cyclophosphamide, adriamycin, vincristine, prednisolone) and RCHOP (rituximab plus CHOP), a high level of b2-microglobulin, a high-intermediate/high risk according to the international prognostic index (IPI), and elevated levels of serum ferritin were all significant independent prognostic factors for 5-year progression-free survival rates. RCHOP and other chemotherapy regimens, a high level of b2-microglobulin, a high-intermediate/high IPI risk, and high levels of serum ferritin were significant independent prognostic factors for 5-year overall survival rates. Conclusion: Elevated levels of serum ferritin of 500 ng/mL or more as well as the use of chemotherapy regimens besides CHOP-like or RCHOP, a high-intermediate/high risk IPI, and a high level of beta2-microglobulin in NHL may be an important marker for predicting poor survival outcomes. Clinical Lymphoma, Myeloma & Leukemia, Vol. 14, No. 1, 43-9 ª 2014 Elsevier Inc. All rights reserved. Keywords: Chemotherapy, Ferritin, Lymphoma, Prognosis, Survival
Introduction Serum ferritin has frequently been used as a surrogate marker for systemic iron stores, but might also be elevated in specific circumstances without excess iron stores, such as in inflammation. Elevated levels of serum ferritin might occur with certain infectious disease and rheumatic disorders, but can also act as a key marker for malignancy.1-3 Some studies have shown that serum ferritin levels correlated with tumor mass and closely followed disease activity in 1
Department of Internal Medicine Department of Pharmacology Department of Occupational and Environmental Medicine Kosin University College of Medicine, Busan, South Korea 2 3
Submitted: Jul 18, 2013; Revised: Sep 12, 2013; Accepted: Sep 24, 2013; Epub: Oct 1, 2013 Address for correspondence: Ho Sup Lee, MD, PhD, Division of Hematology/ Oncology, Department of Internal Medicine, Kosin University College of Medicine, Kosin University Gospel Hospital, 34 Amnam-Dong, Seo-Gu, Busan 602-703, Korea Fax: þ82-51-990-5820; e-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.09.008
patients with hematologic malignancies such as malignant lymphoma and acute leukemia.4-7 Studies have also shown that elevated serum ferritin levels in cancer patients are associated with a poor prognosis. One study pointed out that elevated levels of serum ferritin at the time of diagnosis of pancreatic cancer indicated a bad prognosis for the patient.8 In patients with squamous cell carcinoma of the head and neck, ferritin levels also showed a tendency to increase or remain at high levels in patients with a poor prognosis.9 Moreover, recent studies suggest that elevated pretransplantation serum ferritin levels are associated with increased mortality and a lower transplantation-related survival after allogeneic hematopoietic stem cell transplantation.10-13 In addition, other studies have demonstrated an association between elevated levels of serum ferritin and overall survival (OS) or relapse-free survival after autologous hematopoietic stem cell transplantation for malignant lymphoma.14-17 There are many clinical and molecular factors used to predict outcomes in patients with malignant lymphomas.18 The
Clinical Lymphoma, Myeloma & Leukemia February 2014
- 43
Prognostic Significance of Serum Ferritin in NHL documented negative clinical prognostic factors for malignant lymphoma are old age (> 60 years), Ann Arbor stage III, Eastern Cooperative Oncology Group (ECOG) performance status 2, elevated lactate dehydrogenase (LDH) levels, more than 1 extranodal site of disease, the presence of bone marrow involvement, presence of B symptoms, a bulky mass ( 10 cm), hemogloblin levels < 12 g/dL, above upper normal b2-microglobulin levels, low absolute lymphocyte counts (ALC) < 1.0 109/L, etc, and there are some meaningful prognostic molecular markers such as Bcl-2, MYC proto-oncogene, cyclin D2, CD5, CD10, survivin, vascular endothelial growth factor, anaplastic lymphoma kinase, and others.18-20 Few studies have reported correlations between serum ferritin and prognosis in malignant lymphoma. Disease remission was associated with the normalization of serum ferritin levels, which suggests that serum ferritin measurements might be of clinical usefulness in the initial evaluation and assessment of therapy response in patients with acute leukemia and malignant lymphoma.6 A study of biochemical markers in non-Hodgkin lymphoma (NHL) stages III and IV showed that serum ferritin had a significant relationship with survival.21 Based on these data, it appears that serum ferritin levels might be associated with prognosis or therapeutic outcomes in malignant lymphoma. However, there are no studies about the prognostic role of serum ferritin in malignant lymphoma in patients who have not yet received chemotherapy. The aim of this study was to determine the relationship between baseline serum ferritin levels in patients who were newly diagnosed with NHL and survival outcomes after conventional chemotherapy.
Patients and Methods Patients A total of 267 consecutive adult patients treated with conventional chemotherapy for NHL at the Kosin University Gospel Hospital between September 1999 and June 2012 were analyzed. This retrospective study included all patients who matched specified inclusion and exclusion criteria. Patients were included only if their NHL was confirmed using pathology. They were newly diagnosed with NHL and underwent initial chemotherapy. Enrolled patients had baseline serum ferritin levels measured at least 2 weeks before chemotherapy. Patients who had not had their serum ferritin levels checked before chemotherapy were excluded. Patients who had received chemotherapy for less than 3 cycles for other reasons without disease progression were also excluded. Most of the enrolled patients initially received CHOP-like (CHOP [cyclophosphamide, adriamycin, vincristine, prednisolone], CVP [cyclophosphamide, vincristine, prednisolone], and CEOP [cyclophosphamide, etoposide, vincristine, prednisolone]) chemotherapy, RCHOP (rituximab plus CHOP), or others such as MINE (mitoxantrone, ifosfamide, etoposide), IMVP (ifosfamide, methotrexate, etoposide), ESHAP (etoposide, cytarabine, cisplatin, methylprednisolone), ProMACE-CytaBOM (cyclophosphamide, doxorubicin, etoposide, mechlorethamine, vincristine, prednisone, procarbazine, cytarabine, bleomycin and methotrexate with leucovorin).
Laboratory Analyses
44
-
Baseline serum ferritin levels were measured at least 2 weeks before beginning first-line chemotherapy. Blood samples were obtained
Clinical Lymphoma, Myeloma & Leukemia February 2014
before treatment and basic biochemical and hematological parameters, inflammatory markers, and tumor markers were measured. Serum ferritin levels were measured using a 2-site chemiluminometric sandwich immunoassay (ADVIA Centaur Ferritin analyzer). The 95th percentile range of serum ferritin for healthy men is 22 to 322 ng/mL and for healthy women is 10 to 291 ng/mL. Because the focus of this study was to assess the prognostic effects of elevated serum ferritin levels, the cutoff value for the high ferritin levels was 500 ng/mL, a number that has been used for hyperferritinemia criteria for hematologic disease in other studies.22,23
Analysis In this study, we assessed prognostic factors that are known to predict the outcome of treatment in patients with NHL. We investigated whether elevated serum ferritin levels at baseline before chemotherapy could be an independent predictor for survival in patients with NHL. The following clinical and demographic parameters were analyzed in this study: age, sex, Ann Arbor stage, LDH, ECOG performance status, international prognostic index (IPI), bone marrow involvement, extranodal involvement, bulky mass, C-reactive protein (CRP), b2-microglobulin, ALC, ferritin, and chemotherapy received. We could not estimate the relationship between cytogenetic or molecular abnormalities and survival outcomes because this retrospective study did not have enough medical records on cytogenetic or molecular markers.
Statistical Analysis OS was calculated from the date of diagnosis to the date of death from any cause, or to the final follow-up date. Progression-free survival rate (PFS) was calculated from the date of starting chemotherapy to the date of disease progression or relapse. Survival was estimated from Kaplan-Meier curves and compared using a log-rank test. To identify which factors might have independent significance in influencing survival, a Cox proportional hazard model was fitted with some variables used for the univariate studies. In multivariate analysis, age, LDH, ECOG, stage, and extranodal involvement were excluded because these factors were included in the IPI criteria.24,25 Approval for these studies was obtained from the institutional review board.
Results The patient characteristics are summarized in Table 1. The median patient age was 56 years (range, 14-84 years), with 40.4% of patients being older than 60 years. The female-to-male ratio was 1 to 1.4. Enrolled patients were diagnosed with diffuse large B-cell lymphoma (n ¼ 163, 61.0%), T cell lymphoma (n ¼ 48, 18.0%), and other lymphomas (n ¼ 56, 21.0%) including mantle cell lymphoma, marzinal zone B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, and Burkitt’s lymphoma. The studied group was comprised of 63 patients in stage I, 63 patients in stage II, 74 patients in stage III, and 67 patients in stage IV disease according to the Ann Arbor classification. Among these, 89 (33.3%), 63 (23.6%), 54 (20.2%), and 61 (22.8%) patients were classified in IPI low, low-intermediate, high-intermediate, and high-risk groups, respectively. Most patients were treated with anthracycline-based standard CHOP-like chemotherapy (n ¼ 157; 58.8%) and RCHOP chemotherapy
Kyung Ah Yoh et al Table 1 Patient Characteristics (n [ 267) Characteristic Median Age (Range), Years
Table 2 Univariate Analysis of Prognostic Factors for Survival in Patients With NHL Value 56 (14-84)
Sex Male
157 (58.8)
Female
110 (41.2)
Diagnosis DLBCL
Age, Years
163 (61.0) 56 (21.0)
T-cell NHL
48 (18.0)
Chemotherapy
P
5-Year OS (%)
<60
54.6
60
43.2
60.9 36.9 .967
Male
49.7
Female
50.7
Diagnosis
.894 51.8 51.0
.007
B-cell NHL
53.5 36.1
.025 53.8
157 (58.8)
T-cell NHL
RCHOP
94 (35.2)
Chemotherapy
Others
16 (6.0)
CHOP-Like
48.4
50.8
RCHOP
59.5
57.9
Others
11.4
IPI Low
89 (33.3)
Low-intermediate
63 (23.6)
High-intermediate
54 (20.2)
High Mean LDH (Range), IU/L
61 (22.8) 605.67 (163.00-4438.00)
ECOG PS 0-1 2
99 (37.1) 168 (62.9)
Stage
126 (47.2)
III
141 (52.8)
Extranodal Involvement <2
208 (77.9)
2
59 (22.1)
Bulky Mass
Low/low-intermediate
63.0
High-intermediate/high
30.8
<450
63.6
450
32.8
ECOG PS <2
54.4
2
47.3
Stage
60.2
III
40.9
Extranodal Involvement <2
53.8
2
37.1
<10 cm
52.1
10 cm
41.6
Present
49 (18.4)
Absent
218 (81.6)
Mean ALC (Range), 1.0 3 103/mL Mean Ferritin (Range), ng/mL
2783.11 (140.00-197,300.00) 259.98 (1.70-6562.00)
Data are presented as n (%) except where otherwise noted. Abbreviations: ALC ¼ absolute lymphocyte counts; BM ¼ bone marrow; CHOP-like ¼ cyclophosphamide, adriamycin, vincristine and prednisolone; CRP ¼ C-reactive protein; DLBCL ¼ diffuse large B-cell lymphoma; ECOG PS ¼ Eastern Cooperative Oncology Group performance status; IPI ¼ International Prognostic Index; LDH ¼ lactate dehydrogenase; NHL ¼ non-Hodgkin lymphoma; RCHOP ¼ rituximab plus CHOP.
29.4 .001 68.8 42.0 .004 62.5 41.1 .046 55.3 37.2 .114
.001 56.6 31.6
<.001
CRP, mg/dL <5
55.0
5
18.6
b2-Microglobulin, mg/L
<.001 59.4 24.6
<.001
<3.5
54.8
3.5
26.6
<.001 58.7 14.9
<.001
BM Involvement (%) Present
35.8
Absent
53.5
ALC, 1.0 3 103/mL
.013 37.8 54.6
.001
<1000
36.3
1000
54.6
.001 32.2 57.7
<.001
Ferritin, ng/mL
(n ¼ 94; 35.2%), and others including multidrug combination chemotherapy (n ¼ 16; 6.0%). The mean level of serum ferritin at baseline before chemotherapy was 259.98 ng/mL (range, 1.70-6562.00 ng/mL). Of the 267 patients with NHL, 36 (13.9%) were categorized as having high levels of ferritin (500 ng/mL or more).
<.001 69.5
.020
49 (18.4)
BM Involvement
29.7
.001
10 cm
2.78 (0.01-147.95)
<.001 67.5
.144
Bulky Mass
2.48 (0.71-24.01)
9.8
<.001
LDH, IU/L
217 (81.3)
Mean b2-Microglobusslin (Range), mg/L
.001
<.001
<10 cm Mean CRP (Range), mg/dL
42.1 .002
IPI
P <.001
.053
Sex
Other B-cell NHL
CHOP-like
5-Year PFS (%)
Value
<.001
<500
57.5
56.5
500
11.0
18.1
Abbreviations: ALC ¼ absolute lymphocyte counts; BM ¼ bone marrow; CHOP-like ¼ cyclophosphamide, adriamycin, vincristine and prednisolone; CRP ¼ C-reactive protein; ECOG PS ¼ Eastern Cooperative Oncology Group performance status; IPI ¼ International Prognostic Index; LDH ¼ lactate dehydrogenase; NHL ¼ non-Hodgkin lymphoma; OS ¼ overall survival; PFS ¼ progression-free survival; RCHOP ¼ rituximab plus CHOP.
Clinical Lymphoma, Myeloma & Leukemia February 2014
- 45
Prognostic Significance of Serum Ferritin in NHL Table 3 Multivariate Analysis of Independent Prognostic Factors for Survival in Patients With NHL PFS
OS
RR
95% CI
P
RR
95% CI
0.784
0.444-1.385
.402
0.648
0.369-1.137
.130
0.606
0.375-0.979
.041
0.558
0.350-0.888
.014
RCHOP
0.554
0.261-1.176
.124
0.466
0.239-0.909
.025
Others
0.309
0.135-0.979
.005
0.382
0.187-0.780
.008
0.947
0.580-1.545
.827
Factor
P
Diagnosis, % B-cell NHL vs. T-cell NHL IPI, % Low and low-intermediate vs. high-intermediate and high Chemotherapy, % CHOP-like
Bulky Mass, % <10 cm vs. 10 cm CRP, mg/dL <5 vs. 5
0.660
0.389-1.121
.124
0.687
0.415-1.135
.143
0.442
0.264-0.739
.002
0.401
0.250-0.645
<.001
1.419
0.857-2.350
.174
0.888
0.528-1.492
.653
0.810
0.470-1.395
.447
1.277
0.775-2.105
.337
0.426
0.253-0.716
.001
0.583
0.350-0.970
.038
b2-Microglobulin, mg/L <3.5 vs. 3.5 BM involvement, % Present vs. absent ALC, 1.0 3 103/mL <1000 vs. 1000 Ferritin, ng/mL <500 vs. 500
Abbreviations: ALC ¼ absolute lymphocyte counts; CHOP-like ¼ cyclophosphamide, adriamycin, vincristine and prednisolone; CRP ¼ C-reactive protein; IPI ¼ international prognostic index; NHL ¼ non-Hodgkin lymphoma; OS ¼ overall survival; PFS ¼ progression-free survival; RCHOP ¼ rituximab plus CHOP; RR ¼ relative risk.
Analysis of Prognostic Factors in NHL
46
-
In univariate analysis, the differences in 5-year PFS and OS rates are shown in Table 2. Factors documented to have significant differences in 5-year PFS rates were the chemotherapy regimen (P ¼ .002; 48.4% in the CHOP-like regimen vs. 59.5% in RCHOP vs. 11.4% in other regimens), diagnosis (P ¼ .012; 54.1% in B-cell NHL vs. 37.5% in T-cell NHL), IPI ranking (P < .001; 63.0% in low/low-intermediate vs. 30.8% in high-intermediate/high risk group), LDH (P < .001; 63.6% in less than normal limit vs. 32.8% in greater than normal limit), stage (P ¼ .001; 60.2% in less than stage III vs. 40.9% in stage III or higher), extranodal involvement (P ¼ .020; 53.8% in less than 2 sites vs. 37.1% in 2 sites or more), CRP (P < .001; 55.0% in less than 5 mg/dL vs. 18.6% in 5 mg/dL or more), b2-microglobulin (P < .001; 54.8% in less than 3.5 mg/L vs. 26.6% in 3.5 mg/L or more), bone marrow (BM) involvement (P < .001; 35.8% in present vs. 53.5% in absent), ALC (P ¼ .001; 36.3% in less than 1.0 103/mL vs. 54.6% in 1.0 103/mL or more), and serum ferritin (P < .001; 57.5% in less than 500 ng/mL vs. 11.0% in 500 ng/mL or more). Factors with documented significant differences in 5-year OS rates were age (P < .001; 60.9% in younger than 60 years vs. 36.9% in 60 years or older), chemotherapy regimen (P ¼ .001; 50.8% in CHOP-like regimen vs. 57.9% in RCHOP vs. 9.8% in other regimens), IPI rank (P < .001; 67.5% in low/low-intermediate vs. 29.7% in high-intermediate/high risk group), LDH (P < .001; 69.5% in less than normal limit vs. 29.4% in higher than normal limit), ECOG performance status (P ¼ .001; 68.8% in less than 2 scores vs. 42.0% in 2 or more scores), stage
Clinical Lymphoma, Myeloma & Leukemia February 2014
(P ¼ .004; 62.5% in less than stage III vs. 41.1% in stage III or more), a bulky mass (P ¼ .001; 56.6% in tumor diameter less than 10 cm vs. 31.6% in 10 cm or more), CRP (P < .001; 59.4% in less than 5 mg/dL vs. 24.6% in 5 mg/dL or more), b2-microglobulin (P < .001; 58.7% in less than 3.5 mg/L vs 14.9% in 3.5 mg/L or more), BM involvement (P ¼ .013; 37.8% in present vs. 54.6% in absent), ALC (P ¼ .001; 32.2% in less than 1.0 103/mL vs. 57.7% in 1.0 103/mL or more), and serum ferritin (P < .001; 56.5% in less than 500 ng/mL vs. 18.1% in 500 ng/mL or more). In multivariate analysis, other chemotherapy regimens that were not CHOP-like or RCHOP (relative risk [RR] ¼ 0.309; 95% confidence interval [CI], 0.135-0.979; P ¼ .005 in other regimens), a high level of b2-microglobulin (RR ¼ 0.442; 95% CI, 0.264-0.739; P ¼ .002), high-intermediate/high risk IPI (RR ¼ 0.606; 95% CI, 0.375-0.979; P ¼ .041) and high levels of serum ferritin (RR ¼ 0.426; 95% CI, 0.253-0.716; P ¼ .001) were significant independent prognostic factors for 5-year PFS. RCHOP and other chemotherapy regimens (RR ¼ 0.466; 95% CI, 0.239-0.909; P ¼ .025 in RCHOP and RR ¼ 0.382; 95% CI, 0.187-0.780; P ¼ .008 in other regimens), a high level of b2-microglobulin (RR ¼ 0.401; 95% CI, 0.250-0.645; P < .001), high-intermediate/high risk IPI (RR ¼ 0.558; 95% CI, 0.3500.888; P ¼ .014), and high levels of serum ferritin (RR ¼ 0.583; 95% CI, 0.350-0.970; P ¼ .038) were significant independent prognostic factors for OS. These results are shown in Table 3. Survival curves according to serum levels of ferritin are shown in Figures 1 and 2.
Kyung Ah Yoh et al Figure 1 Progression-Free Survival. In Patients With Non-Hodgkin’s Lymphoma, the 5-Year Progression Free Survival Rate was Superior in the High Serum Ferritin Level Group Compared to that of the Low Level Group (56.9% vs 22.3%, P < .001)
Discussion Elevated levels of serum ferritin are the most widely used surrogate marker for iron overload. However, in other clinical situations such as inflammation, infectious disease, and malignancy, increased serum ferritin might be found without excess iron stores.1-3 Moreover, there are some reports that high levels of serum ferritin at the time of diagnosis are associated with the prognosis of several solid cancers and that high levels of serum ferritin before transplantation are associated with mortality and survival in several hematologic malignancies.8,9,12,15 In our study, the 5-year PFS rates were 57.5% and 11.6% in the groups with low levels of serum ferritin (< 500 ng/mL) and high levels ( 500 ng/mL), respectively (Fig. 1). The 5-year OS rates were 56.9% and 22.3% in the groups with low levels and high revels, respectively (Fig. 2). With these data, patients with high
levels of serum ferritin had a lower PFS and OS rate than those with low levels of ferritin, although the results of OS were shown to be lower than those of PFS because the definition of OS included death from any cause. In multivariate analysis, having elevated levels of serum ferritin and a high/high-intermediate IPI, a high level of b2-microglobulin, and chemotherapy regimens that were not CHOP-like were independent poor prognostic factors for PFS and OS in patients with NHL. Until now, the RCHOP regimen has been the standard treatment for patients with CD20-positive NHL, and the CHOP regimen has been the standard of care for younger and older patients with NHL who could not use rituximab or other new agents.26,27 In this study, the number of patients treated with RCHOP, CHOP-like, and others were 94, 157, and 16, respectively (Table 1). The reasons that some patients could not use rituximab were: patients who were diagnosed with NHL before
Figure 2 Overall Survival. In Patients With Non-Hodgkin’s Lymphoma, the 5-Year Overall Survival Rate was Superior in the High Serum Ferritin Level Group Compared to that of the Low Level Group (57.5% vs 11.6%, P < .001)
Clinical Lymphoma, Myeloma & Leukemia February 2014
- 47
Prognostic Significance of Serum Ferritin in NHL 2004 could not be supplied rituximab in Korea and patients who were diagnosed as CD20-negative NHL in tumor tissue could not. In the same context, patients in this study who could not be treated with CHOP or RCHOP because of several individual conditions such as comorbidities including cardiomyopathy, etc, might have had poor survival outcomes. IPI had been the widely accepted prognostic factor index for patients with malignant lymphomas before the rituximab era25 and a standard IPI has been confirmed as valid for predicting survival outcomes in patients treated with RCHOP.24 In our study, IPI was shown to be one of the most significant prognostic factors. In some reports, serum b2microglobulin levels were also shown to be significant variables for predicting survival outcomes in NHL.28-30 However, serum ferritin levels have not been documented as a prognostic marker in NHL. There have been some reports about mechanisms of how ferritin plays a role for prognosis in NHL by cell line research. Ferritin might be a regulator of lymphoid cell proliferation and could induce cell damage by inflammation or immune function in malignant lymphoma. The expression of the H-ferritin receptor is associated with the proliferative status of the T-lymphoid cell, suggesting that the receptor might mediate a putative regulatory role of H-ferritin.31 Specific binding sites for H-ferritin on human lymphocytes have also behaved as proliferation markers.32 Increased levels of serum ferritin found in patients with malignancy could exert adverse effects on the host immune response and perhaps have an inhibitory effect on hematopoiesis.33 Other studies have suggested that high ferritin expression in tumor tissues and elevated serum levels were the result of inflammation and oxidative stress and improved resistance to oxidative stress by interfering with the cellular antioxidant system. Malignant tumors might manipulate the body’s inflammation process to promote their own angiogenic growth, which could lead to disease progression in NHL.34,35 Other studies have suggested that high ferritin expression in tumor tissues and elevated serum levels were the result of inflammation and oxidative stress and improved resistance to oxidative stress by interfering with the cellular antioxidant system. Malignant tumors might manipulate the body’s inflammation process to promote their own angiogenic growth, which could lead to disease progression in NHL.
Conclusion Elevated levels of serum ferritin of 500 ng/mL or more might be an important marker for predicting poor survival outcomes in NHL. Further studies are needed to recognize the reasons that elevated levels of serum ferritin is correlated with prognosis in NHL.
Clinical Practice Points Serum ferritin has often been used as a surrogate marker for
48
-
systemic iron stores, but may be elevated in cases even without excess iron stores, such as during inflammation. Elevated levels of serum ferritin have been documented to be an adverse prognostic factor in patients with several solid tumors undergoing hematopoietic stem cell transplantation with hematologic malignancies. Several studies have suggested that elevated levels of serum ferritin are associated with worse outcomes in malignant lymphoma. The purpose of this study was to estimate the correlation between elevated levels of serum
Clinical Lymphoma, Myeloma & Leukemia February 2014
ferritin and survival outcomes in patients with non-Hodgkin’s lymphoma (NHL). A total of 267 patients who were newly diagnosed with NHL and who received chemotherapy between September 1999 and April 2012 were retrospectively enrolled in the study. In multivariate analysis, non-CHOP-like chemotherapy regimens (cyclophosphamide, adriamycin, vincristine, prednisolone), RCHOP (rituximab plus CHOP), a high level of b2-microglobulin a high-intermediate/high risk according to the international prognostic index (IPI), and elevated levels of serum ferritin were all significant independent prognostic factors for 5-year progression free survival rates (PFS). RCHOP and other chemotherapy regimens, a high level of b2-microglobulin, and high levels of serum ferritin were significant independent prognostic factors for 5-year overall survival rates (OS). Elevated levels of serum ferritin of 500 ng/ml or more may be an important marker for predicting poor survival outcomes and the use of chemotherapy regimens besides CHOP-like or RCHOP, a high-intermediate/high risk IPI, and a high level of beta2-microglobulin in NHL.
Acknowledgments Kyung Ah Yoh and Ho Sup Lee designed the study, analyzed the clinical data and wrote the manuscript. Dae Jin Park, Lee Chun Park, Eun Mi Lee, Seong Hoon Shin and Yang Soo Kim contributed to conception of the study. Byeong Jin Ye supported statistical analysis of our data. Ho Sup Lee was involved in revising the manuscript critically for intellectual content and all authors gave final approval for the submission of the manuscript.
Disclosure This study was supported by a grant from Kosin University College of Medicine.
References 1. Dayer E, Dayer J-M, Roux-Lombard P. Primer: the practical use of biological markers of rheumatic and systemic inflammatory diseases. Nat Clin Pract Rheum 2007; 3:512-20. 2. Bagnari V, Colina M, Ciancio G, et al. Adult-onset Still’s disease. Rheumatol Int 2010; 30:855-62. 3. Petelin A, Cunha BA. Fever of unknown origin (FUO) attributable to large B-cell lymphoma: the diagnostic significance of highly elevated alkaline phosphatase and serum ferritin levels. Heart Lung 2013; 42:67-71. 4. Aulbert E, Fromm H, Hornemann H. Ferritin in acute leukemia. Serum ferritin concentration as a nonspecific tumor marker for M1 and M2 myeloid leukemia [in German]. Med Klin (Munich) 1991; 86:297-304. 5. Aulbert E, Steffens O. Serum ferritinea tumor marker in malignant lymphomas? [in German]. Onkologie 1990; 13:102-8. 6. Matzner Y, Konijn AM, Hershko C. Serum ferritin in hematologic malignancies. Am J Hematol 1980; 9:13-22. 7. Eshhar Z, Order SE, Katz DH. Ferritin, a Hodgkin’s disease associated antigen. Proc Natl Acad Sci U S A 1974; 71:3956-60. 8. Kalousová M, Krechler T, Jáchymová M, et al. Ferritin as an independent mortality predictor in patients with pancreas cancer. Results of a pilot study. Tumour Biol 2012; 33:1695-700. 9. Maxim PE, Veltri RW. Serum ferritin as a tumor marker in patients with squamous cell carcinoma of the head and neck. Cancer 1986; 57:305-11. 10. Lim ZY, Fiaccadori V, Gandhi S, et al. Impact of pre-transplant serum ferritin on outcomes of patients with myelodysplastic syndromes or secondary acute myeloid leukaemia receiving reduced intensity conditioning allogeneic haematopoietic stem cell transplantation. Leuk Res 2010; 34:723-7. 11. Alessandrino EP, Porta MGD, Bacigalupo A, et al. Prognostic impact of pre-transplantation transfusion history and secondary iron overload in patients with myelodysplastic syndrome undergoing allogeneic stem cell transplantation: a GITMO study. Haematologica 2010; 95:476-84.
Kyung Ah Yoh et al 12. Armand P, Kim HT, Cutler CS, et al. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood 2007; 109:4586-8. 13. Storey JA, Connor RF, Lewis ZT, et al. The transplant iron score as a predictor of stem cell transplant survival. J Hematol Oncol 2009; 2:44. 14. Sucak GT, Yegin ZA, Özkurt ZN, et al. Iron overload: predictor of adverse outcome in hematopoietic stem cell transplantation. Transplant Proc 2010; 42: 1841-8. 15. Mahindra A, Bolwell B, Sobecks R, et al. Elevated ferritin is associated with relapse after autologous hematopoietic stem cell transplantation for lymphoma. Biol Blood Marrow Transplant 2008; 14:1239-44. 16. Altès A, Remacha AF, Sureda A, et al. Iron overload might increase transplantrelated mortality in haematopoietic stem cell transplantation. Bone Marrow Transplant 2002; 29:987-9. 17. McKay PJ, Murphy JA, Cameron S, et al. Iron overload and liver dysfunction after allogeneic or autologous bone marrow transplantation. Bone Marrow Transplant 1996; 17:63-6. 18. Sehn LH. Optimal use of prognostic factors in non-Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program 2006; 2006:295-302. 19. Lossos IS, Morgensztern D. Prognostic biomarkers in diffuse large B-cell lymphoma. J Clin Oncol 2006; 24:995-1007. 20. Perry AM, Cardesa-Salzmann TM, Meyer PN, et al. A new biologic prognostic model based on immunohistochemistry predicts survival in patients with diffuse large B-cell lymphoma. Blood 2012; 120:2290-6. 21. Hagberg H, Glimelius B, Gronowitz S, et al. Biochemical markers in nonHodgkin’s lymphoma stages III and IV and prognosis: a multivariate analysis. Scand J Haematol 1984; 33:59-67. 22. Verbsky JW, Grossman WJ. Hemophagocytic lymphohistiocytosis: diagnosis, pathophysiology, treatment, and future perspectives. Ann Med 2006; 38:20-31. 23. Fardet L, Coppo P, Kettaneh A, et al. Low glycosylated ferritin, a good marker for the diagnosis of hemophagocytic syndrome. Arthritis Rheum 2008; 58: 1521-7.
24. Ziepert M, Hasenclever D, Kuhnt E, et al. Standard International Prognostic Index remains a valid predictor of outcome for patients with aggressive CD20þ B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28:2373-80. 25. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 1993; 329: 987-94. 26. Coiffier B, Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346:235-42. 27. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 1993; 328:1002-6. 28. Swan F, Velasquez WS, Tucker S, et al. A new serologic staging system for largecell lymphomas based on initial beta 2-microglobulin and lactate dehydrogenase levels. J Clin Oncol 1989; 7:1518-27. 29. Conconi A, Zucca E, Roggero E, et al. Prognostic models for diffuse large b-cell lymphoma. Hematol Oncol 2000; 18:61-73. 30. Rodriguez J, Cabanillas F, McLaughlin P, et al. A proposal for a simple staging system for intermediate grade lymphoma and immunoblastic lymphoma based on the ‘tumor score’. Ann Oncol 1992; 3:711-7. 31. Moss D, Powell LW, Arosio P, et al. Effect of cell proliferation on H-ferritin receptor expression in human T lymphoid (MOLT-4) cells. J Lab Clin Med 1992; 120:239-43. 32. Fargion S, Fracanzani AL, Brando B, et al. Specific binding sites for H-ferritin on human lymphocytes: modulation during cellular proliferation and potential implication in cell growth control. Blood 1991; 78:1056-61. 33. Cazzola M, Arosio P, Bellotti V, et al. Immunological reactivity of serum ferritin in patients with malignancy. Tumori 1985; 71:547-54. 34. Alkhateeb AA, Connor JR. Nuclear ferritin: a new role for ferritin in cell biology. Biochim Biophys Acta 2010; 1800:793-7. 35. Recalcati S, Invernizzi P, Arosio P, et al. New functions for an iron storage protein: the role of ferritin in immunity and autoimmunity. J Autoimmun 2008; 30:84-9.
Clinical Lymphoma, Myeloma & Leukemia February 2014
- 49