Jpn J Clin Oncol 2014;44(5)435– 441 doi:10.1093/jjco/hyu017 Advance Access Publication 23 March 2014
Rapid Progression of Anemia Related to Tumor-lysis Syndrome Associated with Bortezomib Treatment in Myeloma Patients Kazuhito Suzuki1,2, Yasuhito Terui1, Noriko Nishimura1, Kyoko Ueda1, Yuko Mishima1, Sakura Sakajiri1, Masahiro Yokoyama1, Keisuke Aiba2 and Kiyohiko Hatake1,* 1
Department of Medical Hematology/Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo and 2Department of Internal Medicine, Division of Clinical Oncology/Hematology, The Jikei University School of Medicine, Tokyo, Japan
Received September 3, 2013; accepted February 1, 2014
Objective: Tumor-lysis syndrome is a rare complication in patients with multiple myeloma. However, bortezomib treatment for myeloma is often associated with tumor-lysis syndrome. Methods: We developed an index called the rapid anemia progression index, which represents the duration and progression of anemia, to evaluate risk factors for tumor-lysis syndrome. We retrospectively reviewed 35 relapsed or refractory myeloma patients treated with bortezomibcontaining treatment in our institution. We analyzed various parameters, including albumin, lactase dehydrogenase, b2-microglobulin and creatinine, similar to the rapid anemia progression index, and evaluated the risk factors for tumor-lysis syndrome associated with bortezomib by the Cairo – Bishop definition. Results: Clinical tumor-lysis syndrome occurred in six patients (17.1%). Tumor-lysis syndrome occurred during the first course of bortezomib-containing treatment among all the patients. The result of the area under the receiver operating characteristic curve for the rapid anemia progression index was 0.759 (P ¼ 0.049). The rapid anemia progression index was more accurate than the index of lactate dehydrogenase, b2-microglobulin, albumin and creatinine according to the receiver operating characteristic curve. For a cut-off point of 21.12 for the rapid anemia progression index, the sensitivity and specificity were 66.7 and 82.8%, respectively. Conclusions: The rapid anemia progression index is related to clinical tumor-lysis syndrome associated with bortezomib treatment for multiple myeloma patients with a cut-off point of 21.12 g/dl/month. Key words: hematol-leukemia/lymphoma – prognostic factors – supportive care
INTRODUCTION Tumor-lysis syndrome (TLS) is characterized by a group of metabolic disturbances caused by the massive and abrupt release of cellular components into the blood after the rapid lysis of malignant cells (1). TLS is a potentially lifethreatening complication of massive cellular lysis in rapidly proliferating, bulky or highly chemo-radiosensitive cancers (2 – 5) that include non-Hodgkin’s lymphoma such as
Burkitt’s lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia and chronic lymphoblastic leukemia. On the other hand, TLS is a rare complication among patients with indolent lymphoid malignancies such as multiple myeloma. TLS seems to occur more frequently in myeloma patients receiving bortezomib than in those receiving other cytotoxic agents such as dexamethasone or thalidomide (6). In particular,
# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://jjco.oxfordjournals.org/ at Universite Laval on June 16, 2014
* For reprints and all correspondence: Kiyohiko Hatake, Department of Medical Hematology/Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan. E-mail: [email protected]
436
Anemia related to tumor-lysis in myeloma
TLS more often occurs among myeloma patients who have a high tumor burden, rapidly proliferating disease and unfavorable cytogenetics (7). However, in multiple myeloma patients, the exact risk factors for TLS are controversial. We found that TLS occurred more often among myeloma patients with rapid progressive anemia. We developed an index (rapid anemia progression: RAP index) representing the duration and progression of anemia to evaluate risk factors for TLS. We retrospectively investigated the utility of this index among the patients in our institute.
calcium 1.75 mmol/l, or if they change by 25% within 3 days before or 7 days after the initiation of treatment. Clinical TLS (CTLS) requires the presence of LTLS in addition to one or more of the following significant clinical complications: renal insufficiency (serum creatinine 1.5 upper normal limit), cardiac arrhythmias/sudden death and seizures. LTLS is considered to be either present or absent, whereas the grade of CTLS is defined by the maximal grade of the clinical manifestation. PROGNOSTIC FACTORS
PATIENTS AND METHODS PATIENTS
RAP INDEX FLUCTUATION The RAP index was obtained by the following calculation:
TREATMENT AND ASSESSMENT OF RESPONSE All patients received bortezomib 1.3 mg/m2 twice a week every 3 weeks by intravenous infusion as salvage therapy. We generally combined bortezomib with dexamethasone 40 mg/body on days 1 through 4, 9 through 12 and 17 through 20. We administered TLS prophylaxis such as hydration, alkalinization, allopurinol and rasbricase as chosen by the attending doctors. Evaluations were carried out based on the following criteria. Complete response (CR) was defined as negative immunofixation on the serum and urine as well as the disappearance of any soft tissue plasmacytomas and 5% plasma cells in bone marrow. Very good partial response (VGPR) was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% greater reduction in serum M-protein plus urine M-protein ,100 mg/24 h. Partial response (PR) was defined as 50% reduction in serum M-protein and reduction in 24 h urinary M-protein by 90% or to ,200 mg/24 h. Progressive disease (PD) was defined as .25% increase in M-protein on two separate measurements at 4-week intervals. Stable disease (SD) did not meet the criteria for CR, VGPR, PR or PD (8). CLASSIFICATION OF TLS We evaluated TLS associated with bortezomib by the Cario – Bishop grading classification (9). According to this classification, laboratory TLS (LTLS) is considered to be present if levels of two or more serum values of uric acid, potassium, phosphate or calcium satisfy the following criteria: serum uric acid 476 mmol/l (or 8 mg/dl), serum potassium 6.0 mmol/ l (or 6.0 mg/dl), serum phosphate 1.45 mmol/l and serum
RAP index ¼
Hb(day 0Þ Hbðday 30Þ 30 day 0 day 30
where day 0 is the nearest day just before bortezomib is first administered. If the patient receives red blood cell concentrate transfusion before bortezomib starts, Day 0 is the nearest day before transfusion. Day 30 is the nearest day to day 0. Hb(day 0) and Hb(day 30) are hemoglobin concentrations on Day 0 and Day 30. We analyzed the relationship between CTLS and the RAP index. Moreover, we analyzed the levels of LDH, b2M, Alb and Cr fluctuation by the same method. STATISTICAL ANALYSIS The primary endpoint was to evaluate laboratory parameters that cause CTLS in patients with relapsed or refractory multiple myeloma treated with regimens containing bortezomib. First, correlations between CTLS and characteristics were examined by the x 2 test. Second, overall survival analysis was performed by the Kaplan – Meier method, and the curves were compared by the log-rank test. Finally, in order to assess the ability of the RAP index to predict clinical TLS, we analyzed sensitivity and specificity using receiver operating characteristic (ROC) curves. We evaluated the area under the ROC curve (AUC) to assess the diagnostic accuracy of a test and to compare the usefulness of tests (10). Moreover, we evaluated the cut-off with best sensitivity and specificity. We calculated post-test probability using positive results and pre-test probability, which was 3.9% (11). We performed multivariate analysis for the evaluation of predictive factors for TLS by a
Downloaded from http://jjco.oxfordjournals.org/ at Universite Laval on June 16, 2014
We retrospectively reviewed 35 relapsed or refractory myeloma patients who started to receive a regimen containing bortezomib in our institution from December 2006 to December 2010. This study was approved by the Independent Ethics Committees/Institutional Review Boards at our institute. Patients provided written informed consent before entering the studies, which were performed in accordance with the Declaration of Helsinki.
The following parameters when bortezomib started were recorded and evaluated for prognosis: serum hemoglobin (Hb) concentration, serum lactate dehydrogenase (LDH), serum b2-microglobulin (b2M), serum albumin (Alb) and serum creatinine (Cr). The cut-off levels of LDH, b2M, CRP, Cr and UA were the upper normal limit. The cut-off levels of Hb and Alb were the lower normal limit. The lower normal limit of serum Hb is 12.5 g/dl in men and 11.0 g/dl in women.
Jpn J Clin Oncol 2014;44(5)
logistic regression model. All P values reported were twosided, and statistical significance was defined at P , 0.05. The statistical analyses were computed with SPSS statistical software (SPSS, Inc., Chicago, IL, USA). All figures were described with EZR (Saitama Medical Center, Jichi Medical University), which is a graphical user interface for R (the R Foundation for Statistical Computing) in order to clear the figures. More precisely, it is a modified version of R commander designed to add statistical functions frequently used in biostatistics.
RESULTS PATIENTS
RESULTS OF BORTEZOMIB-CONTAINING REGIMEN
Table 1. Patient characteristics for the CTLS-positive arm and the CTLS arm Characteristic
TLS arm (n ¼ 6)
no-TLS arm (n ¼ 29)
P value
Age
65.5 (62–70)
64 (49– 82)
0.614
Gender Male
3
9
Female
3
20
1
1
11
2
2
14
0.392
ISS
3
3
4
0.080
PS 3
2
1
0.070
del 13 positive
1
2
0.442
Plasmacytoma
2
10
0.329
M-protein type IgG
1
16
0.101
IgA
2
6
0.420
IgD
0
1
0.829
IgM
0
1
0.829
BJP
3
8
0.269
3 treatments
1
2
2 treatments
0
11
1 treatment
5
16
0.541
Hydration
3
11
0.456
No-hydration
3
18
Alkalinization
3
3
No-alkalinization
3
26
Allopurinol
4
3
No-allopurinol
2
26
Pre-treatment
Prophylaxis
The CR rate and overall response rate of all patients were 5.7 and 71.4%, respectively. The median cycles of bortezomib treatment were 2.5 (1 – 8) cycles in the TLS arm and 5 (1 – 21) cycles in the no-TLS arm, respectively. The overall response rates in the TLS arm and no-TLS arm were 60.0 and 78.6%, respectively (P ¼ 0.296). The median overall survival was not significantly different between the TLS arm and no-TLS arm [not applicable vs 25.9 months; 95% confidence interval (CI), 23.7 – 28.0 months; P ¼ 0.574]. The 2-year overall survival rates in the TLS arm and no-TLS arm were 16.7 and 20.7%, respectively. PROGNOSTIC FACTORS FOR CTLS The patients’ characteristics in the TLS arm and no-TLS arm are shown in Table 1. Well-known predictive factors for TLS, such as elevated serum LDH, presence of plasmacytoma and deletion of 13q, were not correlated with TLS in our model. The analysis of prognostic factors influencing CTLS is shown in Table 1. Anemia, elevated LDH, elevated b2M and decreased Alb were not associated with CTLS significantly (P ¼ 0.634, 0.608, 0.612 and 0.200, respectively). The results of AUC for the RAP index, and the indexes of LDH, b2M, Alb and Cr are shown in Table 2. The RAP index was more accurate than the indexes of LDH, b2M, Alb and Cr
0.049
0.009
b2MG . UNL
2
9
0.612
Alb , 3.5 g/dl
4
11
0.200
Hb , 10 g/dl
5
13
0.101
LDH . UNL
2
10
0.608
UA . 4.0 mg/dl
4
16
0.299
Cr . 1.5 UNL
2
1
0.128
High-risk chromosomes were all del13q by G-banding methods. CTLS, clinical tumor-lysis syndrome; ISS, international staging score; PS, performance status; BJP, Bence Jones protein; b2MG, b2-microglobulin; Alb, albumin; Hb, hemoglobin; LDH, lactic dehydrogenase; UA, uric acid; Cr, creatinine.
(AUC 0.759, 0.757, 0.743, 0.729 and 0.604, respectively). The median RAP index of all patients was 20.789 (95% CI: 22.05 to 0.38). The mean RAP indexes in the TLS arm and no-TLS arm were 23.80 and 20.47, which were significantly different (P ¼ 0.009). As shown in Fig. 1, the ROC curve
Downloaded from http://jjco.oxfordjournals.org/ at Universite Laval on June 16, 2014
Thirty-five patients were entered into this study. Seven patients received bortezomib monotherapy. Prophylaxes for TLS were 14 hydration, 6 alkalinization and 7 allopurinol. No patient received rasbricase as prophylaxis for TLS. Six patients were diagnosed with CTLS at first cycle. The main characteristics of the TLS arm and no-TLS arm are shown in Table 1 and were not significantly different. Most patients received one to two regimens before bortezomib started. Pre-treatments were 20 MP, 18 VAD, 7 high-dose dexamethasone, 4 thalidomide and dexamethasone, 2 highdose melphalan followed with autologous stem cell transplantation and 1 radiation therapy.
437
438
Anemia related to tumor-lysis in myeloma
Table 2. Sensitivity, specificity and post-test probability of the rapid anemia progression (RAP) index regarding Hb and LDH
Table 3. Factors for the anemia progression arm and the no-anemia progression arm by the t-test
Prognostic factors
Factors
RAP index RAP index of LDH LDH . UNL LDH . 2 UNL
Cut-off
1.12 31.1 230 460
Sensitivity (%)
Specificity (%)
Post-test probability (%)
66.7
82.8
13.6
66.7
73.4
9.24
33.3
69.0
4.18
16.7
96.6
16.6
Hct (%)
Anemia progression (n ¼ 9) 26.2 + 4.54
No-anemia progression (n ¼ 26) 29.8 + 5.64
P value
0.099
MCV (fl)
94.9 + 5.36
98.7 + 5.75
0.092
b2MG (mg/dl)
5.47 + 5.59
3.47 + 2.47
0.162
Alb (mg/dl)
3.46 + 0.56
3.67 + 0.57
0.326
CRP (mg/dl)
2.52 + 3.55
0.65 + 1.22
0.237
LDH (IU/l)
383.6 + 389.1
217.1 + 262.3
0.237
UA (mg/dl)
4.31 + 1.26
4.42 + 1.27
0.830
Cr (mg/dl)
1.00 + 0.42
0.82 + 0.47
0.330
demonstrated that the RAP index was a significant predictor of TLS (hazard ratio 9.600; 95% CI, 1.363 – 67.596; P ¼ 0.023). Overall survival in the anemia progression arm and the no-anemia progression arm is shown in Fig. 2. After a median follow-up time of 17.6 months, anemia progression predicted shorter survival than no-anemia progression significantly by the Kaplan – Meier method (1-year overall survival rate; 22.2 vs 76.2%, respectively, P ¼ 0.010).
DISCUSSION
Figure 1. Receiver operating characteristic curves comparing the rapid anemia progression (RAP) index, serum lactate dehydrogenase (LDH), and the rate of increase in LDH. The receiver operating characteristic (ROC) curve showed better sensitivity and specificity for the RAP index. For a cut-off point of 21.12 g/dl/month for the RAP index, the area under the ROC curve of the RAP index was 0.759. The sensitivity and specificity were 66.7 and 82.8%, respectively. The RAP index predicted tumor-lysis syndrome as much as 3.8-fold that of post-test probability.
showed better sensitivity and specificity for the RAP index. For a cut-off point of 21.12 g/dl/month for the RAP index, the sensitivity and specificity were 66.7 and 82.8%, respectively. The post-test probabilities of positive and negative results were 13.6% (positive likelihood ratio 3.88) and 1.61% (negative likelihood ratio 0.402), respectively. The correlations between anemia and the other factors are shown in Tables 3 and 4. Anemia progression was not associated significantly with LDH, b2M, Alb and Cr according to the t-test (P ¼ 0.237, 0.162, 0.326 and 0.330, respectively). Multivariate analysis of five prognostic factors, such as RAP index positive, elevated serum LDH, plasmacytoma .7 cm and hydration as prevention for TLS, in this model
Our study showed that the anemia progression curve, in the form of the RAP index, was associated with CTLS. Hemoglobin concentration at some points does not, by itself, show proliferation and activity of the disease. We assumed that anemia was more progressive among patients with highly aggressive disease than indolent disease. Therefore, in order to predict the proliferation and activity of disease, we calculated the tendency toward anemia progression for 1 month, just before bortezomib was started. The calculation necessary to obtain the RAP index is mathematically simple and requires only the absolute hemoglobin concentration. CTLS occurs in 3.9% patients with multiple myeloma, which is an indolent hematological malignancy (11). Disease-specific therapy varies according to tumor type among patients with multiple myeloma (11). TLS occurred more frequently in multiple myeloma patients receiving bortezomib than in multiple myeloma patients receiving other chemotherapeutic agents, dexamethasone alone or thalidomide (6). TLS was reported in 1% of myeloma patients receiving high-dose chemotherapy with autologous stem cell transplantation (12). The rate of TLS was reported as 1.4% within 3 weeks of starting bortezomib therapy, during Phase II trials (6). No reports of TLS were observed in the large cohort involved in a Phase III trial, APEX study (13). Recently,
Downloaded from http://jjco.oxfordjournals.org/ at Universite Laval on June 16, 2014
Hct, hematocrit; MCV, mean corpuscular hemoglobin; CRP, C-reactive protein.
Jpn J Clin Oncol 2014;44(5)
439
Table 4. Factors for the anemia progression arm and the no-anemia progression arm by the x 2 test Factors
Anemia progression arm (n ¼ 9)
No-anemia progression arm (n ¼ 26)
P value
Age . 65
6
11
0.192
Male
4
9
Female
5
17
1
2
10
2
5
11
Gender
0.443
ISS
2
5
0.594
2
1
0.443
High-risk chromosome
2
1
0.156
Plasmacytoma
4
8
0.361
Plasmacytoma . 7 cm
3
1
0.044
IgG
3
14
0.251
IgA
3
5
0.330
IgD
0
1
0.743
IgM
0
1
0.743
BJP
3
8
0.597
3 treatments
1
16
2 treatments
5
8
M-protein type
Pre-treatment
1 treatment
3
2
0.526
b2MG . UNL
4
8
0.691
Alb , 3.5 mg/dl
5
10
0.306
Hb , 10 g/dl
6
12
0.251.
Hct , 36%
9
22
0.286
MCV . 100
1
13
0.045
LDH . UNL
5
8
0.177
UA . 4.0 mg/dl
5
15
0.572
Cr . 1.5 UNL
1
3
0.732
CRP . UNL
5
7
0.126
High-risk chromosomes were all del13q by G-banding methods.
a Japanese group reported that the rates of LTLS and CTLS were 3.4 and 29.0% in refractory or relapsed multiple myeloma patients who were treated with bortezomibcontaining chemotherapy (14). In this study, the anemia progression arm predicted a significantly poorer response rate than the non-anemia progression arm by the x 2 test (P ¼ 0.047). Therefore, TLS did not depend on the efficacy of bortezomib-containing therapies in the anemia progression arm. We suggested that the lower response rate in the anemia progression arm was a result of
Figure 2. Overall survival curve among the anemia progression arm and the no-anemia progression arm. After a median follow-up time of 17.6 months, anemia progression predicted shorter survival significantly more than no-anemia progression by the Kaplan – Meier method (1-year overall survival; 22.2 vs 76.2%, P ¼ 0.010).
fewer cycles of bortezomib therapies than in the non-anemia progression arm. The risk factors for TLS have been reported as bulky disease, elevated serum LDH, pre-existing renal failure, oliguria and high serum/plasma uric acid (11, 14). Moreover, TLS among multiple myeloma patients was associated with poor prognostic features such as high tumor mass, immature morphology, high proliferative activity of plasma cells, poor cytogenetics, secondary plasma cell leukemia and extramedullary plasmacytoma (11, 14). We analyzed various risk factors of anemia progression, such as hematocrit, mean corpuscular hemoglobin (MCV), LDH, b2M, Alb and CRP, by the t-test, and evaluated the relationship between high tumor volume and anemia progression. The anemia progression arm was accompanied by plasmacytoma of 7 cm more often than the no-anemia progression arm (P ¼ 0.044). Moreover, we analyzed serum LDH in the anemia progression arm and no-anemia progression arm by the t-test because high serum LDH was identified in a group of patients with poor prognosis and aggressive disease (15 – 17). Both serum LDH and the LDH index in the anemia progression arm were similar to those in the no-anemia progression arm by the t-test (P ¼ 0.237 and 0.165, respectively). The plasma cell percentage of bone marrow was similar in both the anemia progression arm and the no-anemia progression arm by the t-test (P ¼ 0.232). We suggested that anemia progression showed a high tumor volume according to the relationship between anemia progression and plasmacytoma. We could not evaluate poor cytogenetics in detail because we evaluated chromosome abnormality in most patients only by the G-banding method. Therefore, we suggested that anemia progression was related to a large tumor mass and high proliferation of myeloma cells
Downloaded from http://jjco.oxfordjournals.org/ at Universite Laval on June 16, 2014
3 PS 3
440
Anemia related to tumor-lysis in myeloma
prospectively analyzing the RAP index and including Ki-67 and thymidine kinase.
Acknowledgements We thank our attending doctors, dedicated fellows and nurses at the Cancer Institute Hospital, Japanese Foundation for Cancer Research. We offer special thanks to our multiple myeloma patients and their families.
Conflict of interest statement None declared.
References 1. Seegmiller JE, Laster L, Howell RR. Biochemistry of uric acid and its relation to gout. N Engl J Med 1963;268:712 –6. 2. Chasty RC, Liu-Yin JA. Acute tumor lysis syndrome. Br J Hosp Med 1993;49:7– 12. 3. Altman A. Acute tumor lysis syndrome. Semin Oncol 2001;28:3–8. 4. Ribeiro RC, Pui CH. Hyperuricemia in patients with cancer. Am J Cancer 2002;1:409 –22. 5. Hochberg J, Cairo MS. Tumor lysis syndrome: current perspective. Haematologica 2008;93:9–13. 6. Mehta J, Jakob C, Singhal S, et al. Bortezomib causes tumor lysis syndrome in approximately 1% of patients with myeloma. Blood 2003;102 (Suppl 2):386b (abstr). 7. Jaskiewicz AD, Herrington JD, Wong L. Tumor lysis syndrome after bortezomib therapy for plasma cell leukemia. Pharmacotherapy 2005;25:1820– 925. 8. Blade J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation: Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998;102:1115–23. 9. Cario MS, Bishiop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 2004;127:3– 11. 10. Akobeng AK. Understanding diagnostictests 3: receiver operating characteristic curves. Acta Paediatr 2007;96:644– 7. 11. Coiffier B, Alterman A, Pui CH, Younes A, Cario MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008;26:2767– 78. 12. Fassas AB, Desikan KR, Siegel D, et al. Tumour lysis syndrome complicating high-dose treatment in patients with multiple myeloma. Br J Haematol 1999;105:938 –41. 13. Richardson P, Sonneveld P, Schuster M, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352:2487–98. 14. Tanimura A. Tumor-lysis syndrome after bortezomib treatment in refractory/relapsed myeloma patients. Haematologica 2011;96(Suppl 1):S130. 15. Simmonsson B, Brenning G, Kallander C, Ahre A. Prognostic value of serum lactic dehydrogenase (S-LDH) in multiple myeloma. Eur J Clin Invest 1987;17:336– 9. 16. Barlogie B, Smallwood L, Smith T, Alexanian R. High serum level of lactic dehydrogenase identify a high-grade lymphoma-like myeloma. Ann Intern Med 1989;110:521– 5. 17. Dimopoulos MA, Barogie B, Smith TL, Alexanian R. High serum lactic dehydrogenase level as a marker for drug resistance and short survival in multiple myeloma. Ann Intern Med 1991;115:931– 5. 18. Fossa A, Brandhorst D, Myklebust JH, Seeber S, Nowrousian MR. Relation between S-phase fraction of myeloma cells and anemia in patients with multiple myeloma. Exp Hematol 1999;27:1621– 6. 19. Drach J, Gattringer C, Glassl H, Drach D, Huber H. The biological and clinical significance of the Ki-67 growth fraction in multiple myeloma. Hematol Oncol 1992;10:125–34.
Downloaded from http://jjco.oxfordjournals.org/ at Universite Laval on June 16, 2014
without a relationship between anemia and the other parameters. Prophylaxis using alkalization and allopurinol were poor predictors of TLS. We performed prophylaxis for TLS according to the physicians’ choice. Prophylactic administration for TLS was not correlated significantly with serum Cr and serum UA levels. We considered that patients with potential renal damage and high serum urinary acid might receive alkalization and allopurinol more frequently. We examined the relationship between anemia progression and high proliferation. Anemia progression was not correlated with the rate of increase in M-protein according to Pearson’s product moment correlation coefficient (correlation coefficient, r ¼ 0.054). We considered that the rate of increase in M-protein was not correlated with the proliferation speed of myeloma cells because patients with several subtypes of M-protein were included. Fossa et al. (18) reported that the hemoglobin concentration was related to the percentage of myeloma cells in S phase. Ki-67 immunohistochemical staining (19, 20), plasma cell labeling index (21) and serum thymidine kinase level (22) are known as methods of determining proliferation. However, they were not analyzed in this. We found that anemia progression predicted shorter survival significantly more than no-anemia progression by the Kaplan – Meier method. The patients with anemia progression may have received fewer cycles of bortezomib-containing therapies and achieved less response because anemia progression was related to a large tumor mass and high proliferation of myeloma cells. Anemia is a common clinical feature of multiple myeloma, with hemoglobin concentration below 12 g/dl occurring in 40 – 73% at present (23 – 25). Anemia is normocytic in most patients, but macrocytosis may be observed as well. However, MCV and hematocrit tended to be lower in the anemia progression arm (P ¼ 0.092 and 0.092, respectively). Low hematocrit might predict high serum M-protein. Anemia is related partially to the direct infiltration and replacement of bone marrow. In anemic multiple myeloma patients, reported causes include cytokines, such as tumour necrosis factor-a and interleukin-1, possibly inhibiting erythropoiesis (26); increased Fas ligand-mediating erythroid apoptosis (27) and relative erythropoietin deficiency from myeloma related to renal damage leading to erythropoiesis. Serum creatinine was similar in both the anemia progression arm and the no-anemia progression arm by the t-test (P ¼ 0.330). We suggest that anemia progression was not related with renal damage. In this study, the sensitivity and specificity with regard to hemoglobin used by the RAP index method were better than those using the index of the serum LDH levels. This was because only 7 – 11% of newly diagnosed multiple myeloma patients have high serum LDH in their sera, leading to the very low sensitivity of the index to serum LDH level. In conclusion, we reported that in multiple myeloma patients, anemia progression was related to TLS. According to the RAP index, anemia progression, which is 21.12 g/dl/ month, predicts TLS as much as 3.8-fold that of post-test probability. As this was a retrospective study, we will be
Jpn J Clin Oncol 2014;44(5)
20. Girino M, Riccardi A, Luoni R, Ucci G, Cuomo A. Monoclonal antibody Ki-67 as a marker of proliferative activity in monoclonal gammopathies. Acta Haematol 1991;85:26 –30. 21. Grippe PR, Katazmann JA, O’Fallon WM, Kyle RA. Value of beta-2 microglobulin level and plasma cell labeling indices as prognostic factors in patients with newly diagnosed multiple myeloma. Blood 1988;72:219–23. 22. Brown RD, Joshua DE, Nelson M, Gibson J, MacLennan IC. Serum thymidine kinase as a prognostic indicator for patients with multiple myeloma: results from the MRC (UK) V trial. Br J Haematol 1993; 84:238–41. 23. Kyle RA. Multiple myeloma: review of 869 cases. Mayo Clinic Proc 1975;50:29 –40.
441
24. Riccardi A, Gobbi PG, Ucci G, et al. Changing clinical presentation of multiple myeloma. Eur J Cancer 1991;27:1401– 5. 25. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003;78: 21– 33. 26. Musto P, Falcone A, D’ Arena G, et al. Clinical recombinant erythropoietin in transfusion-dependent patients with refractory multiple myeloma: role of cytokine and monitoring of erythropoiesis. Eur J Haematol 1997;58:314– 9. 27. Silvestris F, Cafforio P, Tucci M, Dammacco F. Negative regulation of erythroblast maturation by Fas-L(þ)/TRAIL(þ) highly malignant plasma cells: a major pathogenetic mechanism of anemia in multiple myeloma. Blood 2002;99:1305 –13.
Downloaded from http://jjco.oxfordjournals.org/ at Universite Laval on June 16, 2014
Rapid Progression of Anemia Related to Tumor-lysis Syndrome Associated with Bortezomib Treatment in Myeloma Patients Kazuhito Suzuki1,2, Yasuhito Terui1, Noriko Nishimura1, Kyoko Ueda1, Yuko Mishima1, Sakura Sakajiri1, Masahiro Yokoyama1, Keisuke Aiba2 and Kiyohiko Hatake1,* 1
Department of Medical Hematology/Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo and 2Department of Internal Medicine, Division of Clinical Oncology/Hematology, The Jikei University School of Medicine, Tokyo, Japan
Received September 3, 2013; accepted February 1, 2014
Objective: Tumor-lysis syndrome is a rare complication in patients with multiple myeloma. However, bortezomib treatment for myeloma is often associated with tumor-lysis syndrome. Methods: We developed an index called the rapid anemia progression index, which represents the duration and progression of anemia, to evaluate risk factors for tumor-lysis syndrome. We retrospectively reviewed 35 relapsed or refractory myeloma patients treated with bortezomibcontaining treatment in our institution. We analyzed various parameters, including albumin, lactase dehydrogenase, b2-microglobulin and creatinine, similar to the rapid anemia progression index, and evaluated the risk factors for tumor-lysis syndrome associated with bortezomib by the Cairo – Bishop definition. Results: Clinical tumor-lysis syndrome occurred in six patients (17.1%). Tumor-lysis syndrome occurred during the first course of bortezomib-containing treatment among all the patients. The result of the area under the receiver operating characteristic curve for the rapid anemia progression index was 0.759 (P ¼ 0.049). The rapid anemia progression index was more accurate than the index of lactate dehydrogenase, b2-microglobulin, albumin and creatinine according to the receiver operating characteristic curve. For a cut-off point of 21.12 for the rapid anemia progression index, the sensitivity and specificity were 66.7 and 82.8%, respectively. Conclusions: The rapid anemia progression index is related to clinical tumor-lysis syndrome associated with bortezomib treatment for multiple myeloma patients with a cut-off point of 21.12 g/dl/month. Key words: hematol-leukemia/lymphoma – prognostic factors – supportive care
INTRODUCTION Tumor-lysis syndrome (TLS) is characterized by a group of metabolic disturbances caused by the massive and abrupt release of cellular components into the blood after the rapid lysis of malignant cells (1). TLS is a potentially lifethreatening complication of massive cellular lysis in rapidly proliferating, bulky or highly chemo-radiosensitive cancers (2 – 5) that include non-Hodgkin’s lymphoma such as
Burkitt’s lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia and chronic lymphoblastic leukemia. On the other hand, TLS is a rare complication among patients with indolent lymphoid malignancies such as multiple myeloma. TLS seems to occur more frequently in myeloma patients receiving bortezomib than in those receiving other cytotoxic agents such as dexamethasone or thalidomide (6). In particular,
# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://jjco.oxfordjournals.org/ at Universite Laval on June 16, 2014
* For reprints and all correspondence: Kiyohiko Hatake, Department of Medical Hematology/Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan. E-mail: [email protected]
436
Anemia related to tumor-lysis in myeloma
TLS more often occurs among myeloma patients who have a high tumor burden, rapidly proliferating disease and unfavorable cytogenetics (7). However, in multiple myeloma patients, the exact risk factors for TLS are controversial. We found that TLS occurred more often among myeloma patients with rapid progressive anemia. We developed an index (rapid anemia progression: RAP index) representing the duration and progression of anemia to evaluate risk factors for TLS. We retrospectively investigated the utility of this index among the patients in our institute.
calcium 1.75 mmol/l, or if they change by 25% within 3 days before or 7 days after the initiation of treatment. Clinical TLS (CTLS) requires the presence of LTLS in addition to one or more of the following significant clinical complications: renal insufficiency (serum creatinine 1.5 upper normal limit), cardiac arrhythmias/sudden death and seizures. LTLS is considered to be either present or absent, whereas the grade of CTLS is defined by the maximal grade of the clinical manifestation. PROGNOSTIC FACTORS
PATIENTS AND METHODS PATIENTS
RAP INDEX FLUCTUATION The RAP index was obtained by the following calculation:
TREATMENT AND ASSESSMENT OF RESPONSE All patients received bortezomib 1.3 mg/m2 twice a week every 3 weeks by intravenous infusion as salvage therapy. We generally combined bortezomib with dexamethasone 40 mg/body on days 1 through 4, 9 through 12 and 17 through 20. We administered TLS prophylaxis such as hydration, alkalinization, allopurinol and rasbricase as chosen by the attending doctors. Evaluations were carried out based on the following criteria. Complete response (CR) was defined as negative immunofixation on the serum and urine as well as the disappearance of any soft tissue plasmacytomas and 5% plasma cells in bone marrow. Very good partial response (VGPR) was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% greater reduction in serum M-protein plus urine M-protein ,100 mg/24 h. Partial response (PR) was defined as 50% reduction in serum M-protein and reduction in 24 h urinary M-protein by 90% or to ,200 mg/24 h. Progressive disease (PD) was defined as .25% increase in M-protein on two separate measurements at 4-week intervals. Stable disease (SD) did not meet the criteria for CR, VGPR, PR or PD (8). CLASSIFICATION OF TLS We evaluated TLS associated with bortezomib by the Cario – Bishop grading classification (9). According to this classification, laboratory TLS (LTLS) is considered to be present if levels of two or more serum values of uric acid, potassium, phosphate or calcium satisfy the following criteria: serum uric acid 476 mmol/l (or 8 mg/dl), serum potassium 6.0 mmol/ l (or 6.0 mg/dl), serum phosphate 1.45 mmol/l and serum
RAP index ¼
Hb(day 0Þ Hbðday 30Þ 30 day 0 day 30
where day 0 is the nearest day just before bortezomib is first administered. If the patient receives red blood cell concentrate transfusion before bortezomib starts, Day 0 is the nearest day before transfusion. Day 30 is the nearest day to day 0. Hb(day 0) and Hb(day 30) are hemoglobin concentrations on Day 0 and Day 30. We analyzed the relationship between CTLS and the RAP index. Moreover, we analyzed the levels of LDH, b2M, Alb and Cr fluctuation by the same method. STATISTICAL ANALYSIS The primary endpoint was to evaluate laboratory parameters that cause CTLS in patients with relapsed or refractory multiple myeloma treated with regimens containing bortezomib. First, correlations between CTLS and characteristics were examined by the x 2 test. Second, overall survival analysis was performed by the Kaplan – Meier method, and the curves were compared by the log-rank test. Finally, in order to assess the ability of the RAP index to predict clinical TLS, we analyzed sensitivity and specificity using receiver operating characteristic (ROC) curves. We evaluated the area under the ROC curve (AUC) to assess the diagnostic accuracy of a test and to compare the usefulness of tests (10). Moreover, we evaluated the cut-off with best sensitivity and specificity. We calculated post-test probability using positive results and pre-test probability, which was 3.9% (11). We performed multivariate analysis for the evaluation of predictive factors for TLS by a
Downloaded from http://jjco.oxfordjournals.org/ at Universite Laval on June 16, 2014
We retrospectively reviewed 35 relapsed or refractory myeloma patients who started to receive a regimen containing bortezomib in our institution from December 2006 to December 2010. This study was approved by the Independent Ethics Committees/Institutional Review Boards at our institute. Patients provided written informed consent before entering the studies, which were performed in accordance with the Declaration of Helsinki.
The following parameters when bortezomib started were recorded and evaluated for prognosis: serum hemoglobin (Hb) concentration, serum lactate dehydrogenase (LDH), serum b2-microglobulin (b2M), serum albumin (Alb) and serum creatinine (Cr). The cut-off levels of LDH, b2M, CRP, Cr and UA were the upper normal limit. The cut-off levels of Hb and Alb were the lower normal limit. The lower normal limit of serum Hb is 12.5 g/dl in men and 11.0 g/dl in women.
Jpn J Clin Oncol 2014;44(5)
logistic regression model. All P values reported were twosided, and statistical significance was defined at P , 0.05. The statistical analyses were computed with SPSS statistical software (SPSS, Inc., Chicago, IL, USA). All figures were described with EZR (Saitama Medical Center, Jichi Medical University), which is a graphical user interface for R (the R Foundation for Statistical Computing) in order to clear the figures. More precisely, it is a modified version of R commander designed to add statistical functions frequently used in biostatistics.
RESULTS PATIENTS
RESULTS OF BORTEZOMIB-CONTAINING REGIMEN
Table 1. Patient characteristics for the CTLS-positive arm and the CTLS arm Characteristic
TLS arm (n ¼ 6)
no-TLS arm (n ¼ 29)
P value
Age
65.5 (62–70)
64 (49– 82)
0.614
Gender Male
3
9
Female
3
20
1
1
11
2
2
14
0.392
ISS
3
3
4
0.080
PS 3
2
1
0.070
del 13 positive
1
2
0.442
Plasmacytoma
2
10
0.329
M-protein type IgG
1
16
0.101
IgA
2
6
0.420
IgD
0
1
0.829
IgM
0
1
0.829
BJP
3
8
0.269
3 treatments
1
2
2 treatments
0
11
1 treatment
5
16
0.541
Hydration
3
11
0.456
No-hydration
3
18
Alkalinization
3
3
No-alkalinization
3
26
Allopurinol
4
3
No-allopurinol
2
26
Pre-treatment
Prophylaxis
The CR rate and overall response rate of all patients were 5.7 and 71.4%, respectively. The median cycles of bortezomib treatment were 2.5 (1 – 8) cycles in the TLS arm and 5 (1 – 21) cycles in the no-TLS arm, respectively. The overall response rates in the TLS arm and no-TLS arm were 60.0 and 78.6%, respectively (P ¼ 0.296). The median overall survival was not significantly different between the TLS arm and no-TLS arm [not applicable vs 25.9 months; 95% confidence interval (CI), 23.7 – 28.0 months; P ¼ 0.574]. The 2-year overall survival rates in the TLS arm and no-TLS arm were 16.7 and 20.7%, respectively. PROGNOSTIC FACTORS FOR CTLS The patients’ characteristics in the TLS arm and no-TLS arm are shown in Table 1. Well-known predictive factors for TLS, such as elevated serum LDH, presence of plasmacytoma and deletion of 13q, were not correlated with TLS in our model. The analysis of prognostic factors influencing CTLS is shown in Table 1. Anemia, elevated LDH, elevated b2M and decreased Alb were not associated with CTLS significantly (P ¼ 0.634, 0.608, 0.612 and 0.200, respectively). The results of AUC for the RAP index, and the indexes of LDH, b2M, Alb and Cr are shown in Table 2. The RAP index was more accurate than the indexes of LDH, b2M, Alb and Cr
0.049
0.009
b2MG . UNL
2
9
0.612
Alb , 3.5 g/dl
4
11
0.200
Hb , 10 g/dl
5
13
0.101
LDH . UNL
2
10
0.608
UA . 4.0 mg/dl
4
16
0.299
Cr . 1.5 UNL
2
1
0.128
High-risk chromosomes were all del13q by G-banding methods. CTLS, clinical tumor-lysis syndrome; ISS, international staging score; PS, performance status; BJP, Bence Jones protein; b2MG, b2-microglobulin; Alb, albumin; Hb, hemoglobin; LDH, lactic dehydrogenase; UA, uric acid; Cr, creatinine.
(AUC 0.759, 0.757, 0.743, 0.729 and 0.604, respectively). The median RAP index of all patients was 20.789 (95% CI: 22.05 to 0.38). The mean RAP indexes in the TLS arm and no-TLS arm were 23.80 and 20.47, which were significantly different (P ¼ 0.009). As shown in Fig. 1, the ROC curve
Downloaded from http://jjco.oxfordjournals.org/ at Universite Laval on June 16, 2014
Thirty-five patients were entered into this study. Seven patients received bortezomib monotherapy. Prophylaxes for TLS were 14 hydration, 6 alkalinization and 7 allopurinol. No patient received rasbricase as prophylaxis for TLS. Six patients were diagnosed with CTLS at first cycle. The main characteristics of the TLS arm and no-TLS arm are shown in Table 1 and were not significantly different. Most patients received one to two regimens before bortezomib started. Pre-treatments were 20 MP, 18 VAD, 7 high-dose dexamethasone, 4 thalidomide and dexamethasone, 2 highdose melphalan followed with autologous stem cell transplantation and 1 radiation therapy.
437
438
Anemia related to tumor-lysis in myeloma
Table 2. Sensitivity, specificity and post-test probability of the rapid anemia progression (RAP) index regarding Hb and LDH
Table 3. Factors for the anemia progression arm and the no-anemia progression arm by the t-test
Prognostic factors
Factors
RAP index RAP index of LDH LDH . UNL LDH . 2 UNL
Cut-off
1.12 31.1 230 460
Sensitivity (%)
Specificity (%)
Post-test probability (%)
66.7
82.8
13.6
66.7
73.4
9.24
33.3
69.0
4.18
16.7
96.6
16.6
Hct (%)
Anemia progression (n ¼ 9) 26.2 + 4.54
No-anemia progression (n ¼ 26) 29.8 + 5.64
P value
0.099
MCV (fl)
94.9 + 5.36
98.7 + 5.75
0.092
b2MG (mg/dl)
5.47 + 5.59
3.47 + 2.47
0.162
Alb (mg/dl)
3.46 + 0.56
3.67 + 0.57
0.326
CRP (mg/dl)
2.52 + 3.55
0.65 + 1.22
0.237
LDH (IU/l)
383.6 + 389.1
217.1 + 262.3
0.237
UA (mg/dl)
4.31 + 1.26
4.42 + 1.27
0.830
Cr (mg/dl)
1.00 + 0.42
0.82 + 0.47
0.330
demonstrated that the RAP index was a significant predictor of TLS (hazard ratio 9.600; 95% CI, 1.363 – 67.596; P ¼ 0.023). Overall survival in the anemia progression arm and the no-anemia progression arm is shown in Fig. 2. After a median follow-up time of 17.6 months, anemia progression predicted shorter survival than no-anemia progression significantly by the Kaplan – Meier method (1-year overall survival rate; 22.2 vs 76.2%, respectively, P ¼ 0.010).
DISCUSSION
Figure 1. Receiver operating characteristic curves comparing the rapid anemia progression (RAP) index, serum lactate dehydrogenase (LDH), and the rate of increase in LDH. The receiver operating characteristic (ROC) curve showed better sensitivity and specificity for the RAP index. For a cut-off point of 21.12 g/dl/month for the RAP index, the area under the ROC curve of the RAP index was 0.759. The sensitivity and specificity were 66.7 and 82.8%, respectively. The RAP index predicted tumor-lysis syndrome as much as 3.8-fold that of post-test probability.
showed better sensitivity and specificity for the RAP index. For a cut-off point of 21.12 g/dl/month for the RAP index, the sensitivity and specificity were 66.7 and 82.8%, respectively. The post-test probabilities of positive and negative results were 13.6% (positive likelihood ratio 3.88) and 1.61% (negative likelihood ratio 0.402), respectively. The correlations between anemia and the other factors are shown in Tables 3 and 4. Anemia progression was not associated significantly with LDH, b2M, Alb and Cr according to the t-test (P ¼ 0.237, 0.162, 0.326 and 0.330, respectively). Multivariate analysis of five prognostic factors, such as RAP index positive, elevated serum LDH, plasmacytoma .7 cm and hydration as prevention for TLS, in this model
Our study showed that the anemia progression curve, in the form of the RAP index, was associated with CTLS. Hemoglobin concentration at some points does not, by itself, show proliferation and activity of the disease. We assumed that anemia was more progressive among patients with highly aggressive disease than indolent disease. Therefore, in order to predict the proliferation and activity of disease, we calculated the tendency toward anemia progression for 1 month, just before bortezomib was started. The calculation necessary to obtain the RAP index is mathematically simple and requires only the absolute hemoglobin concentration. CTLS occurs in 3.9% patients with multiple myeloma, which is an indolent hematological malignancy (11). Disease-specific therapy varies according to tumor type among patients with multiple myeloma (11). TLS occurred more frequently in multiple myeloma patients receiving bortezomib than in multiple myeloma patients receiving other chemotherapeutic agents, dexamethasone alone or thalidomide (6). TLS was reported in 1% of myeloma patients receiving high-dose chemotherapy with autologous stem cell transplantation (12). The rate of TLS was reported as 1.4% within 3 weeks of starting bortezomib therapy, during Phase II trials (6). No reports of TLS were observed in the large cohort involved in a Phase III trial, APEX study (13). Recently,
Downloaded from http://jjco.oxfordjournals.org/ at Universite Laval on June 16, 2014
Hct, hematocrit; MCV, mean corpuscular hemoglobin; CRP, C-reactive protein.
Jpn J Clin Oncol 2014;44(5)
439
Table 4. Factors for the anemia progression arm and the no-anemia progression arm by the x 2 test Factors
Anemia progression arm (n ¼ 9)
No-anemia progression arm (n ¼ 26)
P value
Age . 65
6
11
0.192
Male
4
9
Female
5
17
1
2
10
2
5
11
Gender
0.443
ISS
2
5
0.594
2
1
0.443
High-risk chromosome
2
1
0.156
Plasmacytoma
4
8
0.361
Plasmacytoma . 7 cm
3
1
0.044
IgG
3
14
0.251
IgA
3
5
0.330
IgD
0
1
0.743
IgM
0
1
0.743
BJP
3
8
0.597
3 treatments
1
16
2 treatments
5
8
M-protein type
Pre-treatment
1 treatment
3
2
0.526
b2MG . UNL
4
8
0.691
Alb , 3.5 mg/dl
5
10
0.306
Hb , 10 g/dl
6
12
0.251.
Hct , 36%
9
22
0.286
MCV . 100
1
13
0.045
LDH . UNL
5
8
0.177
UA . 4.0 mg/dl
5
15
0.572
Cr . 1.5 UNL
1
3
0.732
CRP . UNL
5
7
0.126
High-risk chromosomes were all del13q by G-banding methods.
a Japanese group reported that the rates of LTLS and CTLS were 3.4 and 29.0% in refractory or relapsed multiple myeloma patients who were treated with bortezomibcontaining chemotherapy (14). In this study, the anemia progression arm predicted a significantly poorer response rate than the non-anemia progression arm by the x 2 test (P ¼ 0.047). Therefore, TLS did not depend on the efficacy of bortezomib-containing therapies in the anemia progression arm. We suggested that the lower response rate in the anemia progression arm was a result of
Figure 2. Overall survival curve among the anemia progression arm and the no-anemia progression arm. After a median follow-up time of 17.6 months, anemia progression predicted shorter survival significantly more than no-anemia progression by the Kaplan – Meier method (1-year overall survival; 22.2 vs 76.2%, P ¼ 0.010).
fewer cycles of bortezomib therapies than in the non-anemia progression arm. The risk factors for TLS have been reported as bulky disease, elevated serum LDH, pre-existing renal failure, oliguria and high serum/plasma uric acid (11, 14). Moreover, TLS among multiple myeloma patients was associated with poor prognostic features such as high tumor mass, immature morphology, high proliferative activity of plasma cells, poor cytogenetics, secondary plasma cell leukemia and extramedullary plasmacytoma (11, 14). We analyzed various risk factors of anemia progression, such as hematocrit, mean corpuscular hemoglobin (MCV), LDH, b2M, Alb and CRP, by the t-test, and evaluated the relationship between high tumor volume and anemia progression. The anemia progression arm was accompanied by plasmacytoma of 7 cm more often than the no-anemia progression arm (P ¼ 0.044). Moreover, we analyzed serum LDH in the anemia progression arm and no-anemia progression arm by the t-test because high serum LDH was identified in a group of patients with poor prognosis and aggressive disease (15 – 17). Both serum LDH and the LDH index in the anemia progression arm were similar to those in the no-anemia progression arm by the t-test (P ¼ 0.237 and 0.165, respectively). The plasma cell percentage of bone marrow was similar in both the anemia progression arm and the no-anemia progression arm by the t-test (P ¼ 0.232). We suggested that anemia progression showed a high tumor volume according to the relationship between anemia progression and plasmacytoma. We could not evaluate poor cytogenetics in detail because we evaluated chromosome abnormality in most patients only by the G-banding method. Therefore, we suggested that anemia progression was related to a large tumor mass and high proliferation of myeloma cells
Downloaded from http://jjco.oxfordjournals.org/ at Universite Laval on June 16, 2014
3 PS 3
440
Anemia related to tumor-lysis in myeloma
prospectively analyzing the RAP index and including Ki-67 and thymidine kinase.
Acknowledgements We thank our attending doctors, dedicated fellows and nurses at the Cancer Institute Hospital, Japanese Foundation for Cancer Research. We offer special thanks to our multiple myeloma patients and their families.
Conflict of interest statement None declared.
References 1. Seegmiller JE, Laster L, Howell RR. Biochemistry of uric acid and its relation to gout. N Engl J Med 1963;268:712 –6. 2. Chasty RC, Liu-Yin JA. Acute tumor lysis syndrome. Br J Hosp Med 1993;49:7– 12. 3. Altman A. Acute tumor lysis syndrome. Semin Oncol 2001;28:3–8. 4. Ribeiro RC, Pui CH. Hyperuricemia in patients with cancer. Am J Cancer 2002;1:409 –22. 5. Hochberg J, Cairo MS. Tumor lysis syndrome: current perspective. Haematologica 2008;93:9–13. 6. Mehta J, Jakob C, Singhal S, et al. Bortezomib causes tumor lysis syndrome in approximately 1% of patients with myeloma. Blood 2003;102 (Suppl 2):386b (abstr). 7. Jaskiewicz AD, Herrington JD, Wong L. Tumor lysis syndrome after bortezomib therapy for plasma cell leukemia. Pharmacotherapy 2005;25:1820– 925. 8. Blade J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation: Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998;102:1115–23. 9. Cario MS, Bishiop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 2004;127:3– 11. 10. Akobeng AK. Understanding diagnostictests 3: receiver operating characteristic curves. Acta Paediatr 2007;96:644– 7. 11. Coiffier B, Alterman A, Pui CH, Younes A, Cario MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008;26:2767– 78. 12. Fassas AB, Desikan KR, Siegel D, et al. Tumour lysis syndrome complicating high-dose treatment in patients with multiple myeloma. Br J Haematol 1999;105:938 –41. 13. Richardson P, Sonneveld P, Schuster M, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352:2487–98. 14. Tanimura A. Tumor-lysis syndrome after bortezomib treatment in refractory/relapsed myeloma patients. Haematologica 2011;96(Suppl 1):S130. 15. Simmonsson B, Brenning G, Kallander C, Ahre A. Prognostic value of serum lactic dehydrogenase (S-LDH) in multiple myeloma. Eur J Clin Invest 1987;17:336– 9. 16. Barlogie B, Smallwood L, Smith T, Alexanian R. High serum level of lactic dehydrogenase identify a high-grade lymphoma-like myeloma. Ann Intern Med 1989;110:521– 5. 17. Dimopoulos MA, Barogie B, Smith TL, Alexanian R. High serum lactic dehydrogenase level as a marker for drug resistance and short survival in multiple myeloma. Ann Intern Med 1991;115:931– 5. 18. Fossa A, Brandhorst D, Myklebust JH, Seeber S, Nowrousian MR. Relation between S-phase fraction of myeloma cells and anemia in patients with multiple myeloma. Exp Hematol 1999;27:1621– 6. 19. Drach J, Gattringer C, Glassl H, Drach D, Huber H. The biological and clinical significance of the Ki-67 growth fraction in multiple myeloma. Hematol Oncol 1992;10:125–34.
Downloaded from http://jjco.oxfordjournals.org/ at Universite Laval on June 16, 2014
without a relationship between anemia and the other parameters. Prophylaxis using alkalization and allopurinol were poor predictors of TLS. We performed prophylaxis for TLS according to the physicians’ choice. Prophylactic administration for TLS was not correlated significantly with serum Cr and serum UA levels. We considered that patients with potential renal damage and high serum urinary acid might receive alkalization and allopurinol more frequently. We examined the relationship between anemia progression and high proliferation. Anemia progression was not correlated with the rate of increase in M-protein according to Pearson’s product moment correlation coefficient (correlation coefficient, r ¼ 0.054). We considered that the rate of increase in M-protein was not correlated with the proliferation speed of myeloma cells because patients with several subtypes of M-protein were included. Fossa et al. (18) reported that the hemoglobin concentration was related to the percentage of myeloma cells in S phase. Ki-67 immunohistochemical staining (19, 20), plasma cell labeling index (21) and serum thymidine kinase level (22) are known as methods of determining proliferation. However, they were not analyzed in this. We found that anemia progression predicted shorter survival significantly more than no-anemia progression by the Kaplan – Meier method. The patients with anemia progression may have received fewer cycles of bortezomib-containing therapies and achieved less response because anemia progression was related to a large tumor mass and high proliferation of myeloma cells. Anemia is a common clinical feature of multiple myeloma, with hemoglobin concentration below 12 g/dl occurring in 40 – 73% at present (23 – 25). Anemia is normocytic in most patients, but macrocytosis may be observed as well. However, MCV and hematocrit tended to be lower in the anemia progression arm (P ¼ 0.092 and 0.092, respectively). Low hematocrit might predict high serum M-protein. Anemia is related partially to the direct infiltration and replacement of bone marrow. In anemic multiple myeloma patients, reported causes include cytokines, such as tumour necrosis factor-a and interleukin-1, possibly inhibiting erythropoiesis (26); increased Fas ligand-mediating erythroid apoptosis (27) and relative erythropoietin deficiency from myeloma related to renal damage leading to erythropoiesis. Serum creatinine was similar in both the anemia progression arm and the no-anemia progression arm by the t-test (P ¼ 0.330). We suggest that anemia progression was not related with renal damage. In this study, the sensitivity and specificity with regard to hemoglobin used by the RAP index method were better than those using the index of the serum LDH levels. This was because only 7 – 11% of newly diagnosed multiple myeloma patients have high serum LDH in their sera, leading to the very low sensitivity of the index to serum LDH level. In conclusion, we reported that in multiple myeloma patients, anemia progression was related to TLS. According to the RAP index, anemia progression, which is 21.12 g/dl/ month, predicts TLS as much as 3.8-fold that of post-test probability. As this was a retrospective study, we will be
Jpn J Clin Oncol 2014;44(5)
20. Girino M, Riccardi A, Luoni R, Ucci G, Cuomo A. Monoclonal antibody Ki-67 as a marker of proliferative activity in monoclonal gammopathies. Acta Haematol 1991;85:26 –30. 21. Grippe PR, Katazmann JA, O’Fallon WM, Kyle RA. Value of beta-2 microglobulin level and plasma cell labeling indices as prognostic factors in patients with newly diagnosed multiple myeloma. Blood 1988;72:219–23. 22. Brown RD, Joshua DE, Nelson M, Gibson J, MacLennan IC. Serum thymidine kinase as a prognostic indicator for patients with multiple myeloma: results from the MRC (UK) V trial. Br J Haematol 1993; 84:238–41. 23. Kyle RA. Multiple myeloma: review of 869 cases. Mayo Clinic Proc 1975;50:29 –40.
441
24. Riccardi A, Gobbi PG, Ucci G, et al. Changing clinical presentation of multiple myeloma. Eur J Cancer 1991;27:1401– 5. 25. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003;78: 21– 33. 26. Musto P, Falcone A, D’ Arena G, et al. Clinical recombinant erythropoietin in transfusion-dependent patients with refractory multiple myeloma: role of cytokine and monitoring of erythropoiesis. Eur J Haematol 1997;58:314– 9. 27. Silvestris F, Cafforio P, Tucci M, Dammacco F. Negative regulation of erythroblast maturation by Fas-L(þ)/TRAIL(þ) highly malignant plasma cells: a major pathogenetic mechanism of anemia in multiple myeloma. Blood 2002;99:1305 –13.
Downloaded from http://jjco.oxfordjournals.org/ at Universite Laval on June 16, 2014
