한국임상약학회지제 23 권제 3 호 Kor. J. Clin. Pharm., Vol. 23, No. 3. 2013 Korean Journal of Clinical Pharmacy Official Journal of Korean College of Clinical Pharmacy Available online at http://www.kccp.or.kr pissn: 1226-6051 Rituximab 주입관련부작용발생및위험인자분석 이은정 1,3 김영주 3 이정연 1,2 * 1 이화여자대학교임상보건과학대학원, 2 이화여자대학교약학대학생명약학부, 3 국립암센터약제부 (2013 년 8 월 27 일접수 2013 년 9 월 9 일수정 2013 년 9 월 10 일승인 ) Rituximab Infusion-related Adverse Events and Risk Factors Eun Jung Lee 1,3, Young Joo Kim 3, and Sandy J Rhie 1,2 * 1 Graduate School of Clinical Health Sciences, Ewha Womans University, Seoul, Korea 120-750 2 College of Pharmacy & Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea 120-750 3 Department of Pharmacy, National Cancer Center, Gyeonggi-do 410-769 (Received August 27, 2013 Revised September 9, 2013 Accepted September 10, 2013) Objective: This study aimed to identify the status and risk factors of rituximab infusion-related adverse events (ADE) in rituximab-naïve patients with cancer diseases. Method: A retrospective analysis using electronic medical records review was conducted. Inclusions were patients with a diagnosis of cancer disease with the initiation of rituximabincluded treatment who were naïve to rituximab during January 2011 to March 2013 at National Cancer Center (NCC) in Korea. Result: Total 110 patients, 582 cases of rituximab administrations, were reported in the study. About 57.2% of patients were 51-70 years old and evenly distributed between two genders and 72.7% were BMI less than 25 kg/m 2. All of study patients were diagnosed with non-hodgkin lymphoma. Fifty patients (45.4%) and 54 cases (9.3%) were experienced rituximab infusion-related AEs even with conservative administration protocol at NCC. The most frequently occurring AEs were shivering followed by rash and itching. In single variant analysis, we found that the early stage of NHL, low exposure to rituximab administrations, high white blood cell counts, high lymphocyte counts, high absolute neutrophil count and low lactate dehydrogenase were associated with infusion-related AEs (p<0.05). The early stage of disease, high lymphocyte counts, low exposure to rituximab administrations were also related significantly with AEs in multiple variants analysis (p<0.05). Conclusion: Rituximab infusion-related AEs for patients who were naïve to rituximab were still a concern with conservative administration protocol. The adverse drug reactions were significantly associated with early stage of NHL, higher lymphocyte counts and low exposure to rituximab administrations. The factors need to be considered with close monitoring to prevent rituximab infusion-related AE. Key words - Monoclonal antibodies, Rituximab, Adverse reactions, Risk factors Rituximab은 1997년승인받은최초의인간화단일클론항체 (Humanized monoclonal antibody) 항암치료제이다. 국내에서는재발성또는화학요법내성여포형림프종 (follicular lymphoma) 인 B세포비호지킨림프종 (non-hodgkin s lymphoma, NHL), CD20 양성의미만형대형 B세포비호지킨림프종 (diffuse large B cell lymphoma, DLBCL), 만성림프구성백혈병 (chronic lymphocytic leukemia, CLL) 등에적응증이있다. 악성종양질환외에도류마티스성관절염, 베게너육아종증, 현미경적다발혈관염등의면역질환치료에도적응증을받아 Correspondence to : Sandy (Jeong Yeon) Rhie College of Pharmacy & Division of Life and Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil Seodaemun-gu, Seoul 120-750, Korea Tel: +82-2-3277-3023, Fax: +82-2-3277-2851 E-mail: sandy.rhie@ewha.ac.kr 사용중이다. 1,2) 그러나 Rituximab은주입관련부작용발생이빈번하고특히항암치료목적으로 rituximab을투여한경우 77% 의환자에게서주입관련부작용이발생했다는보고가있다. 3) 대표적인주입관련부작용은홍조, 발진, 발열, 경직, 오한, 호흡곤란, 경미한저혈압등경미한부작용과 (grade 1 or 2), 기관지경련, 치료를요하는저혈압, 심기능장애, 아나필락시스등심각한 (grade 3 or 4) 부작용이보고된바있으며, 이러한심각한부작용은적절한처치가수행되지않는경우사망에까지이를수도있다. 3,4) 이러한부작용의증상과강도의정의에대한기준은 Common terminology criteria for adverse events v.4.03 (CTCAE) 의정의를참고할수있다 (Table 1). 5) Rituximab 에의한주입관련부작용을줄이기위하여 rituximab의주입속도를제한하거나점적투여 30-60분전 acetaminophen 650 mg 등의해열제및 diphenhydramine 50 mg 223
224 Kor. J. Clin. Pharm., Vol. 23, No. 3, 2013 등의항히스타민제의투여가권고되고있다. 2,6) 이러한예방적인해열제및항히스타민제투여이외에도경우에따라 H 2 -수용체차단제인 ranitidine 50 mg 정맥주사를포함하기도하며스테로이드제제를사용하기도한다. 7) Rituximab 의주입에따른부작용감소를위한노력의일환으로주입속도제한에관한연구는흔히볼수있다. 8,9) 여러선행연구에서실행기관의프로토콜과환자군의특성차이로결과해석에어려움을보이고있다. 국립암센터도동일한의도로항암치료로 rituximab을사용하는경우주입속도를국내허가사항에기재된주입속도보다감소시킨프로토콜을적용하고있다. 반면 rituximab 투여에참여하는의료진의인력투여절감효과와환자치료에요구되는시간적부담을줄이고, 환자가병원에오고가는편의를도모하고자 rituximab 주입시간을단축한연구도있다. 이연구결과에서기본주입속도시와비교하여동등한안정성과비용절감의효과를나타냈으며, 대부분의환자에서사용시바람직한결과를기대할수있음을발표하기도하였다. 9,10) 이러한선행연구에서결과는실행기관의프로토콜과환자군의특성차이로결과해석에어려움을보이고있는것이사실이다. 이에본연구는현재국립암센터프로토콜에서적용하고있는 rituximab 주입속도를기본으로항암치료에함께투여되는 rituximab의주입관련부작용발생현황을살펴보고자하였다. 또한이전에 rituximab을투여받은경험이없는환자를대상환자로제한하고기존에보고된연구보다경증의부작용을경험한환자들을분석에포함하여주입관련부작용발현의위험인자를확인하고자하였다. 그리고이를통하여 rituximab의안전한투약을위한참고자료로활용하고자하였다. 연구방법 연구대상및자료수집 2011년 1월 1일부터 2013년 3월 31일까지국립암센터에서항암치료를목적으로 rituximab을처방받은환자중이전에 rituximab을투여받은경험이없는 18세이상성인환자 110명을대상으로하였다. 대상환자의성별, 나이 (rituximab 투여시작당시의나이 ), 키, 체중, 체질량지수, 진단명, 병기, 기저질환의유무 ( 당뇨, 알러지관련질환, 심혈관계질환 ), rituximab의투여횟수, 항암치료 regimen의종류, 과거항암치료여부, 혈액검사결과, 주입관련부작용발현여부및증상에관한정보에대하여전자의무기록을후향적으로수집하였다. 혈액검사결과는 rituximab 투여개시전 7일이내또는투여당일의결과를사용하였다 (Table 2와 3). 통계분석방법 Rituximab 주입관련부작용의위험인자를알아보기위하여 generalized estimating equation (GEE) 분석을시행하였다. 반응변수가주입관련부작용의유무이기때문에 logit 연결함수를이용하였고, 반복횟수 ( 투여횟수 ) 가서로다르기때문에 variance structure은 unstructure로설정하였다. 우선 GEE를각각의독립변수로적합시켜 multiple GEE analysis를시행하였다. 유의한것으로확인되는변수만을선택하기위해 forward selection을이용한양측검정을시행하였으며, 기준은 p-value 0.05 미만으로하였다. 모든통계분석은 Rx64 2.15.3 버전을이용하였다. 연구결과 환자특성연구기간동안항암치료목적으로 rituximab을처음사용하는 18세이상성인환자는총 110명이었으며총 582건의 rituximab이환자에따라서는 1회에서수회에걸쳐투여되었다. 연구대상환자의평균연령은 59.3세, 연령분포는 51-60세가 27명 (24.5%), 61-70세는 36명 (32.7%) 으로 51-70세의환자가 57.3% 이었다. 성별은남성이 61명 (55.5%), 여성이 49명 (44.5%) 이었다. 체질량지수는 25 kg/m 2 미만인환자가 80명 (72.7%) 으로나타났다. 연구대상환자중 103명 (93.6%) 은항암 Table 1. Grading of hypersensitivity-infusion reactions by National Cancer Institute common terminology criteria for adverse events (CTCAE). Adverse event Hypersensitivity (allergic reaction) Acute infusion reaction (Cytokine release syndrome) Grade 1 2 3 4 5 Transient flushing or rash; drug fever<38 o C Mild reaction: infusion interruption not indicated; intervention not indicated Rash; flushing; urticaria; dyspnea; drug fever 38 o C Require therapy or infusion interruption but responds promptly to symptomatic treatment (e.g. antihistamines, nonsteroidal anti-inflammatory drugs, narcotics, i.v. fluids); prophylactic medication indicated for 24 hours Symptomatic bronchospasm, with or without urticaria; parenteral medication(s) indicated; allergy-related edema, angioedema; hypotension Prolonged (i.e., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for other clinical impairment (e.g. renal impairment, pulmonary infiltrates) Anaphylaxis Life-threatening; pressor or ventilatory support indicated Death Death
Rituximab 주입관련부작용발생및위험인자분석 225 치료를처음받는환자들이였으며그외 7명 (6.4%) 은과거 rituximab 이외의항암치료를받은경험이있었다. 진단명은모두비호지킨림프종에해당되었고, 그중미만형대형 B세포비호지킨림프종이 88명 (80%) 으로가장많았다. 이에항암 regimen 은 R-CHOP(rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) 요법이 93건 (83.8%) 으로가장많았다. 대상환자의병기에따른분포는, 1기가 29명 (26.4%), 2기가 10명 (9.1%), 3기가 9명 (8.2%), 그리고 4기가 45명 (40.9%) 으로 4기가상대적으로많았다 (Table 2). 전체 rituximab 처방중 95.4%(555건 ) 가 rituximab과스테로이드를동시처방받았으며, 스테로이드가항암 regimen에포함되어있는경우가 534건으로전체투여중 91.8 % 에해당되었다 (Table 4). Rituximab 주입관련부작용발생현황 Rituximab 투여 24시간이내부작용발생건수를조사한결과, 전체 110명의대상환자중 50명 (45.4%), 총투여 582건중 54건 (9.3%) 의부작용이발생하였다. 증상이보고된주입 Table 2. Characteristics of patients demographics (n=110). Characteristic Number of patients % Age (yrs) 31-40 10 9.1 41-50 16 14.5 51-60 27 24.5 61-70 36 32.7 71 21 19.1 Sex Male 61 55.5 Female 49 44.5 BMI (kg/m 2 ) <25 80 72.7 25 30 27.3 Diagnosis Non-Hodgkin lymphoma Diffuse large B cell lymphoma 88 80.0 Burkitt lymphoma 7 6.4 Mantle cell lymphoma 6 5.5 Marginal zone B cell lymphoma 5 4.5 Follicular lymphoma 4 3.6 Regimen R-CHOP 93 83.8 R-Hyper CVAD/R-HD MTX/AraC 9 8.1 R-CVP 7 6.3 R alone 2 1.8 Stage I 29 26.4 II 10 9.1 III 9 8.2 IV 45 40.9 No stage given 17 15.5 Comorbidity related to Cardiac disease 46 41.8 Diabetes 28 25.5 Allergy 15 13.6 Prior chemotherapy None 103 93.6 1 7 6.4 Cycle 1-3 23 20.9 4-6 65 59.1 7 22 20.0 Steroid use Yes 83 95.4 None 27 4.6 R: rituximab, CHOP: cyclophosphamide, doxorubicin, vincristine, prednisolone, CVAD: cyclophosphamide, vincristine, doxorubicin, dexamethasone, HD MTX/AraC: high dose methotrexate, cytarabine (cytosine arabinoside) CVP: cyclophosphamide, vincristine, prednisolone 관련부작용은총 109건이었다 (Fig. 1). 한환자에게두가지이상부작용이발생한경우그빈도를각각계산하였으며, 가장빈번하게보고된증상은오한및전율로총 109건중 24 건 (22%) 이었으며, 가려움증 17건 (15.6%), 두드러기및발진 16건 (14.7%) 순이었다. The National cancer institute common terminology criteria for adverse events version 4.03의분류에따라부작용을분류했을때보고된부작용은 grade 1 또는 grade 2에해당되었고전체 54건의부작용발생중 grade 1 증상은 8건 (1.4%), grade 2의증상은 46건 (7.9%) 이었다. 부작용발현과약물의투여회차와의연관성분석시초회투여 110건중 46건 (41.8%), 2회약물을투여한 102건의경우중 2.9%, 3회투여시 94건중에는 1.1%, 4회투여 90건중 4.4%, 5회및 6회투여시부작용발현보고가없었으며, 7회투여시 9.1% 의보고가있엇다. 그러나 8회이후의투여에서는주입관련부작용이보고되지않았다. 위험인자분석기존문헌에서보고된약물과민반응위험인자및 rituximab
226 Kor. J. Clin. Pharm., Vol. 23, No. 3, 2013 Table 4. Demographics of using steroid of each cycle (n=582). Route of steroid administration Object of use steroid Number of cases % Oral only Regimen 515 88.5 Other treatment a 5 0.9 IV only Regimen 6 1.0 Regimen + Premedication 5 0.9 Regimen + Other treatment 3 0.5 Premedication 4 0.7 Other treatment a 12 2.1 Fig. 1. Type of adverse events and frequency. Table 3. Baseline patients' blood counts based on each cycle (total number of cases=582). Blood counts Number of results % Total white blood cell counts( 10 6 /L) <4000 216 37.1 4000-11000 (reference) 341 58.6 >11000 25 4.3 Platelet counts( 10 9 /L) <130 33 5.7 130-400 (reference) 514 88.3 >400 35 6.0 Absolute neutrophil counts ( 10 6 /L) <1800 127 21.8 1800-7500 (reference) 425 73.0 >7500 30 5.2 Lymphocyte counts ( 10 6 /L) <1000 228 39.2 1000-3500 (reference) 346 59.5 >3500 8 1.4 Lactate dehydrogenase (U/L) a <110 5 0.9 110-230 (reference) 407 73.5 >230 142 25.6 a Information is not auailable for all cycles. 부작용발생의위험인자로알려져있는환자정보를취합하여분석하였다. 병기, 백혈구수, 림프구수, 절대호중구수, 젖산탈수소효소, 투여차수, 항암치료경험, 성별, 나이, 체질량지수, 환자의기저질환 ( 당뇨, 심혈관계질환, 알러지관련질환 ), 그 Oral + IV Regimen + Premedication 4 0.7 Regimen + Other treatment a 1 0.2 Not using 27 4.6 a It indicates that using steroid regardless of rituximab infusion. or chemotherapy (e.g. using steroid for other reasons related to patient's treatment). 리고진단암종등을분석에이용하였다. 병기는높을수록주입관련부작용발생률이통계적으로유의하게감소하였다 (Odd Ratio (OR) 0.7915, 95% CI 0.6544 0.9573, p=0.0159). 백혈구수의경우, 정상치보다수치가낮은경우 (<4,000 10 6 cells/l) 부작용발생률이감소하였고 (OR 0.2594, 95% CI 0.1143-0.5887, p=0.0013), 높은경우 (>11,000 10 6 cells/l) 에부작용발생률은증가하였다 (OR 3.6440, 95 % CI 1.5501-8.5663, p=0.0030). 림프구도수치가높은경우 (>3,500 10 6 cells/l) 에부작용발생이증가하는경향을보였다 (OR 17.8571, 95% CI 4.2212-75.5427, p=0.0001). 절대호중구수는낮을수록 (<1,800 10 6 cells/l) 부작용발생률의감소를보였고 (OR 0.2095, 95% CI 0.0653-0.6720, p=0.0001), 정상치이상인경우 (>7,500 10 6 cells/l) 에부작용발생률이증가하는결과를보였다 (OR 2.6354, 95% CI 1.0561-6.5763, p=0.0378). 반대로젖산탈수소효소의경우는정상치보다낮을때 (<110 U/L) 주입관련부작용이증가하였으나 (OR 7.8125, 95% CI 1.9834-30.7727, p=0.0033), 높은경우 (>230 U/L) 에는유의한차이가없었다. Rituximab의누적투여차수와주입관련부작용의관계는투여차수가낮을수록주입관련부작용발생률이높아지는유의관계를보였다 (OR 0.2717, 95% CI 0.1347-0.5479, p=0.0003). 그러나과거항암치료경험여부와는통계적으로유의하지않았다. 그리고, 성별, 나이, 체질량지수, 환자의기저질환 ( 당뇨, 심혈관계질환, 알러지관련질환 ), 진단암종을선별하여주입관련부작용의발생률과의연관성에대하여단변량분석을하였으나, 통계적으로유의한차이가없었다 (Table 5). 앞서시행한단변량분석결과통계적으로유의하게주입관련부작용발생의위험인자로밝혀진환자의병기, 백혈구수, 림프구수, 절대호중구수, 젖산탈수소효소, rituximab 의투여차
Rituximab 주입관련부작용발생및위험인자분석 227 Table 5. Single variant analysis. Factor Variable Estimate S.E. z Lower C.I Upper C.I Odds p-value Sex Female 0.2641 0.2505 1.0543-0.2268 0.7550 1.3022 [0.7970-2.1276] 0.2917 Male 1.0000 Age <65 0.1455 0.2582 0.5635-0.3606 0.6517 1.1566 [0.6972-1.9188] 0.5731 65 1.0000 BMI <25 1.0000 25 0.2031 0.2528 0.8034-0.2925 0.6987 1.2252 [0.7464-2.0111] 0.4218 DM Yes 0.0932 0.2569 0.3628-0.4103 0.5968 1.0977 [0.6634-1.8162] 0.7167 No 1.0000 Allergy Yes 0.3365 0.3072 1.0952-0.2657 0.9386 1.4000 [0.7667-2.5564] 0.2734 No 1.0000 Cardiac Yes -0.2084 0.2438-0.8545-0.6863 0.2696 0.8119 [0.5034-1.3094] 0.3928 No 1.0000 Disease DLBCL 0.0168 0.3038 0.0552-0.5787 0.6123 1.0169 [0.5606-1.8446] 0.9560 Others 1.0000 Stage -0.2338 0.0970-2.4102-0.4240-0.0437 0.7915 [0.6544-0.9573] 0.0159 * WBC <4000-1.3496 0.4183-3.2266-2.1694-0.5298 0.2594 [0.1143-0.5887] 0.0013 * 4000-11000 1.0000 >11000 1.2931 0.4361 2.9652 0.4383 2.1478 3.6440 [1.5501-8.5663] 0.0030 * Platelet <130 0.3875 0.4974 0.7791-0.5874 1.3625 1.4734 [0.5557-3.9061] 0.4359 130-400 1.0000 >400 0.7930 0.5286 1.5002-0.2431 1.8291 2.2100 [07842-6.2282] 0.1336 Lymphocyte 3500 1.0000 >3500 2.8824 0.7359 3.9170 1.4401 4.3247 17.8571 [4.2212-75.5427] 0.0001 * ANC <1800-1.5631 0.5947-2.6284-2.7286-0.3975 0.2095 [0.0653-0.6720] 0.0086 * 1800-7500 1.0000 >7500 0.9690 0.4666 2.0770 0.0546 1.8835 2.6354 [1.0561-6.5763] 0.0378 * LDH <110 2.0557 0.6994 2.9391 0.6848 3.4266 7.8125 [1.9834-30.7727] 0.0033 * 110-230 1.0000 >230 0.2482 0.3334 0.7444-0.4053 0.9018 1.2817 [0.6668-2.4640] 0.4566 Use of steroid a -0.8531 0.6801-1.2544-2.1861 0.4799 0.4261 [0.1124-1.6159] 0.2097 Prior chemotherapy b -0.7293 0.6359-1.1469-1.9756 0.5170 0.4822 [0.1387-1.6770] 0.2514 Cycle -1.3032 0.3579-3.6408-2.0047-0.6016 0.2717 [0.1347-0.5479] 0.0003 * Age (yr), BMI (mg/m 2 ), body mass index, DM, diabetes mellitus, DLBCL, diffuse large B cell lymphoma, S.E, standard error, C.I, confidence interval, WBC (x10 6 /L), white blood cell, Platelet ( 10 9 /L), lymphocyte ( 10 6 /L), ANC ( 10 6 /L), absolute neutrophil counts, LDH (U/L), lactate dehydrogenase, a it was coded "using steroid : 1, not using steroid : 0" b it was coded "none prior chemotherapy : 0, prior chemotherpy : 1" * p < 0.05 (significant) 수를포함하여다변량 GEE를시행하였다. 그결과최종모형으로채택된인자는림프구수, 병기, rituximab의사용차수, 그리고스테로이드의사용이었다. 그중, 스테로이드의사용은단변량분석시에는유의성있는차이를발견하지못했으나, 다변량분석에서스테로이드를사용한경우주입관련부작용이통계적으로유의하게감소하였음을확인할수있었다 (OR 0.3100, 95% CI 0.0985-0.9755, p = 0.0452) (Table 6 과 7).
228 Kor. J. Clin. Pharm., Vol. 23, No. 3, 2013 Table 6. Multiple variants analysis for occurrence of adverse. Factor Variable Estimate S.E z Lower C.I Upper C.I Odds p-value (Intercept) 3.2233 1.9828 1.6256-0.6630 7.1095 25.1099 [0.5153-1223.5397] 0.1040 Age <65 0.4395 0.4322 1.0168-0.4077 1.2866 1.5519 [0.6652-3.6203] 0.3093 Sex Female 0.4310 0.3602 1.1964-0.2751 1.1370 1.5387 [0.7595-3.1174] 0.2315 BMI 25 0.1074 0.4576 0.2347-0.7895 1.0042 1.1133 [0.4541-2.7297] 0.8145 DM Yes 0.4212 0.4309 0.9774-0.4234 1.2658 1.5238 [0.6548-3.5458] 0.3284 Cardiac Yes -0.4385 0.3948-1.1109-1.2123 0.3352 0.6450 [0.2975-1.3982] 0.2666 Disease DLBCL -0.0953 0.6475-0.1473-1.3644 1.1737 0.9091 [0.2555-3.2338] 0.8829 Stage -0.3739 0.1851-2.0207-0.7367-0.0112 0.6880 [0.4787-0.9888] 0.0433 * WBC1 <4000 0.7358 0.4536 1.6221-0.1533 1.6249 2.0872 [0.8579-5.0779] 0.1048 WBC2 >11000-0.3971 1.1189-0.3549-2.5901 1.7959 0.6723 [0.0750-6.0246] 0.7226 PLT1 <130 0.4885 0.8984 0.5437-1.2725 2.2494 1.6298 [0.2801-9.4820] 0.5867 PLT2 >400 0.7696 0.5881 1.3086-0.3831 1.9223 2.1590 [0.6818-6.8370] 0.1907 Lymphocyte >3500 2.2071 0.9237 2.3895 0.3967 4.0175 9.0891 [1.4869-55.5595] 0.0169 * ANC1 <1800-1.1871 0.8639-1.3741-2.8803 0.5062 0.3051 [0.0561-1.6590] 0.1694 ANC2 >7500 0.9876 1.1742 0.8411-1.3139 3.2892 2.6849 [0.2688-26.8201] 0.4003 LDH1 <110 0.7839 0.8448 0.9280-0.8718 2.4397 2.1901 [0.4182-11.4694] 0.3534 LDH2 >230 0.1113 0.5250 0.2119-0.9177 1.1403 1.1177 [0.3994-3.1276] 0.8322 Use of steroid a -1.5946 0.6960-2.2911-2.9587-0.2305 0.2030 [0.0519-0.7942] 0.0220 * Prior chemotherapy b -0.8518 0.8364-1.0184-2.4911 0.7876 0.4267 [0.0828-2.1981] 0.3085 Cycle -1.2465 0.4613-2.7024-2.1506-0.3424 0.2875 [0.1164-0.7100] 0.0069 * Age (yr), BMI (mg/m 2 ), body mass index, DM, diabetes mellitus, DLBCL, diffuse large B cell lymphoma, WBC ( 10 6 /L), white blood cell, PLT ( 10 9 /L), platelet, Lymphocyte ( 10 6 /L), ANC ( 10 6 /L), absolute neutrophil counts, LDH (U/L), lactate dehydrogenase, S.E, standard error, C.I, confidence interval, * p = 0.05 (significant) a it was coded "using steroid : 1, not using steroid : 0" b it was coded "none prior chemotherapy : 0, prior chemotherpy : 1 Table 7. Multiple variants analysis for occurrence of adverse events after stepwise selection. Factor Variable Estimate S.E z Lower C.I Upper C.I Odds p-value (Intercept) 2.2077 1.0439 2.1149 0.1617 4.2538 9.0951 [1.1755-70.3711] 0.0344 Lymphocyte >3500 1.7213 0.6864 2.5077 0.3759 3.0666 5.5915 [1.4564-21.4679] 0.0122 * Stage -0.2677 0.1205-2.2218-0.5038-0.0315 0.7652 [0.6042-0.9690] 0.0263 * Use of steroid a -1.1713 0.5849-2.0024-2.3178-0.0248 0.3100 [0.0985-0.9755] 0.0452 * Cycle -1.2228 0.3838-3.1861-1.9751-0.4706 0.2944 [0.1388-0.6246] 0.0014 * Lymphocyte ( 10 6 /L), S.E, standard error, C.I, confidence interval, * p = 0.05 (significant) a it was coded "using steroid : 1, not using steroid : 0" 고찰및결론 Rituximab은단일클론항체중주입관련부작용보고가많은약물중의하나로암환자의경우초회투여시투여환자의약 77% 정도의주입관련부작용을경험하였다고보고된바있다. 2,11-17) 본연구기간중 rituximab이항암치료이외에시신경척수염 (neuromyelitis optica) 치료나간이식전처치로사 용된사례도있었으나 rituximab을항암치료목적으로사용한환자의진단명은모두비호지킨림프종환자들이었다. 투여누적차수와부작용발생률의관계분석결과부작용발생의 41.8% 가초회투여시에발생하였는데, 이는 2차투여시 5.6% 그리고 3차투여시 1.8% 등으로부수적인투여시발생한부작용발생률보다월등히높았다. 초회투여가부수적인투여차수보다부작용발생과연관이깊다는결과는
Rituximab 주입관련부작용발생및위험인자분석 229 다른보고들과유사하나, 본연구에서의초회투여시의발생빈도가다른연구보고보다낮은빈도로발생되었음을알수있었다. 2,18) 그리고주입관련부작용의증상을조사한결과, 오한및전율그리고얼굴이나상체의가려움증이나두드러기및발진으로모두경증의 grade 1과 grade 2에해당되었다. 대부분의증상은 rituximab의투여를중단하고 chlorpheniramine 정맥주사등의항히스타민제나스테로이드정맥주사제제의투약으로충분히조절이가능하였다. 산소포화도저하가나타난경우도보고되었으나, 약물투여의중단과휴식으로회복이가능하였으며, 산소공급을통해회복하기도하였다. Rituximab은고혈압또는저혈압증상을나타낼수있어, 일반적으로환자가혈압약을복용하는경우에는 rituximab투여 12시간전부터혈압약을복용하지않도록권고하고있다. 2) 그러나본연구에서는항암치료시환자가복용하고있는고혈압약제의중단등의제한없이 vital sign 등을모니터링하면서치료가진행되었다. 연구대상환자중저혈압증상을호소한경우가 1건 (0.9%) 보고되었으나, 특별한처치는요구되지않았다. 그리고고혈압을호소하는경우는 4건 (3.7%) 으로 nicardipine 정맥주사제제나 nifedipine과같은경구약물을투여하여증상을조절하면서항암치료를진행하였으며, 부수적인유의할만한상황은발견되지않았다. 이와같이본연구대상자들의부작용발생률과증상의심각도가기존의보고에비하여심하지않았으며이는 rituximab의투여속도를제한하고있기때문이라사료되었다. 본의료기관의경우, rituximab투여시주입관련부작용의발현을조기에발견하고적절한대응을하기위하여, 특히초회투여시에는, 입원하여약물투여를진행하고있으며, 본연구대상 110명중 102명 (92.7%) 가입원하여 rituximab을투여받았다. 국내허가사항에서권장하는투여속도는 rituximab 초기투여시에는 50 mg/hr로시작하여 30분간격으로주입속도를 50 mg/hr씩높여최대 400 mg/hr 로투여하는것이다. 또한이후에주입하는경우는주입속도를시간당 100 mg에서시작하여 30분마다 100 mg/h씩증가시켜최고시간당 400 mg까지높일수있는것으로되어있다. 이에비교하여본연구에서는에서는 50 mg/hr 로시작한것은동일하나 1 시간마다 100 mg/hr 증량하여 1시간동안투여, 1시간이후부터투여종료까지 200 mg/hr로속도를유지하는프로토콜로진행이되기때문에허가사항에비해천천히투여되었다. 이러한투여방법이주입관련부작용의발생률을저하시키는데긍정적인영향을끼쳤을것으로사료된다. 그러나, 향후주입속도및주입용량과부작용발현의연관성을연구할수있는잘고안된전향적인연구가체계적으로진행될필요가있겠다. 또한본연구에서는과민반응에연관이있는위험인자를조사하였는데, 백혈구, 림프구, 절대호중구수가 rituximab주입에관련한부작용발현과유의적인관계가있었으며, 이는 rituximab주입과관련하여사이토카인분비에의한혈중표 적세포의증가에기인한다고사료된다. 18,21-24) 일반적으로젖산탈수소효소는종양부하가많을수록종양용해증후군의위험이커지고, 그만큼주입관련부작용발현가능성도함께높아진다고알려져있으며, 비호지킨림프종에서예후를정할때사용되는 International prognostic index (IPI) 에서도젖산탈수소효소수치를반영한다. 3) 본연구에서는이와는상충되는결과를보였는데, 이는종양용해증후군의위험성에주의를요하는젖산탈수소효소수치는약 1500 U/L이상이지만, 이번연구에서반영된젖산탈수소효소의수치기준는 220 U/L정도이었다. 그리고연구대상중 1500 U/L이상인환자가 2명있었으나, 2명모두주입관련부작용이보고되지않았다. 그리고종양용해증후군의증상은젖산탈수소효소수치의증가뿐만아니라고뇨산혈증, 고칼륨혈증, 저칼슘혈증, 고인산혈증, 급성신부전등의증상이동반되면서나타나는데이번연구에서는단순히투여전혈액검사결과자료로만분석을하였으므로정확한상관관계를알기는어렵다고판단된다. 성별, 나이, 천식과같은알러지성질환이나알러지력의유무, 심혈관계질환의유무는통계적유의성을나타내지않았다. 이는다른연구에서도성별, 나이, 심혈관계또는호흡기계질환의유무에관련해서통계적으로유의한차이가없었던결과와유사하였다. 18-20) Rituximab과관련된대부분의연구에서는 1기의환자가연구대상에서제외된채진행이되는경구가많았다. 본연구에서는 1기에해당하는환자가전체환자의 4분의 1이상을차지하고있었으며병기각각을구분하여분석을시도하였고, 그결과병기가낮을수록부작용발생률이높아진다는통계적인유의성이나왔다. 스테로이드사용은대부분의환자가전처치나항암치료요법에포함하여사용하고있었다. 그럼에도불구하고 8.6% 의환자에서부작용이보고되었다. 반면스테로이드를사용하지않은경우에서부작용이발현된경우는 18.5% 이었다. 그러므로주입관련부작용을예방하기위한스테로이드를사용하는것이부작용예방에도움이된다는것은위의자료를토대로예측해볼수있다. 따라서주입관련부작용이발현가능성이높은환자에게는항히스타민제와해열제의사용뿐만아니라스테로이드를투여하는것이주입관련부작용예방에도움이된다고사료된다. 그러나스테로이드를사용함에도불구하고심각한강도의주입관련부작용이나타났다는연구결과가있다. 25) 따라서주입관련부작용발생률을낮추기위하여스테로이드를사용할때, 약의선택과투여경로그리고용량의선택이중요하며, 면밀한임상관찰이필요로한다고사료된다. 본연구는한계점을살펴보면, 우선연구대상자의수가통계적으로유의성을감지하기에적었다. 포함한환자에있어서도항암요법, 병기, 진단명등의범주의각각속하는환자수가적어분석에어려움이있었다. 그리고후향적의무기록을검토한연구이므로예방적으로사용된약물의종류와용량을조절할수없었으며, 자료수집에서어려움이있었고보
230 Kor. J. Clin. Pharm., Vol. 23, No. 3, 2013 고되지않은부작용사례도있으리라보인다. 이러한이유로연구의결과를일반화하기는어렵다고보이지만, 본연구는허가사항보다천천히주입되고있는 rituximab과관련된부작용발생의현황과관련인자를찾았다는데의의를두겠으며, 본연구결과가앞으로약물의주입속도관련한무작위전향적연구를위한기초연구로서그의미가있다고하겠다. 국내허가사용보다제한적인투여하의부작용발현의여부를살피는것은의미가있다고사료되며, 이에약사업무에서고려하여야하는사항을찾아보고자한다. 결론 본연구는 rituximab에의한주입관련부작용의발생현황을파악하고위험인자를알아보기위해서진행되었다. 연구결과로부터현재 rituximab을투여받는대부분의환자가전처치로아세타아미노펜이나항히스타민제를사용과더불어, rituximab관련부작용발현의확률이높은경우방지를위한조치의필요성을강조할수있다. 그리고그위험성이높은환자군으로는약물을처음으로투여받는경우, 환자의혈액수치가높거나병기가낮은경우이며, 대체방법으로주입속도를낮추거나정맥주사스테로이드제를추가로사용하는것을고려해볼수있겠다. 이는향후대규모전향적연구를통한검증이필요하겠으나, rituximab 투여를받는암환자에게안전한투여계획을수립할수있도록참고자료로활용될수있으리라사료된다. 참고문헌 1. Cheson BD, Leonard JP. Monoclonal antibody therapy for B-cell non-hodgkin's lymphoma. The NEJM 2008; 359(6): 613-26. 2. Roche (2012) Mabthera, Roche Products Pty Limited [updated 21 April 2012]; Available from : http://www.roche. co.kr/fmfiles/re7198001/product/insertpaper/mabthera_inj.pdf. Last accessed on 22 April 2013. 3. Dillman RO. Infusion reactions associated with the therapeutic use of monoclonal antibodies in the treatment of malignancy. Cancer metastasis reviews 1999; 18(4): 465-71. 4. Lenz HJ. Management and preparedness for infusion and hypersensitivity reactions. The oncologist 2007; 12(5): 601-9. 5. Institute NC. Common Terminology Criteria for Adverse Events(CTACE) v4.03. 2010. 6. Kimby E. Tolerability and safety of rituximab (MabThera). Cancer treatment reviews 2005; 31(6): 456-73. 7. Kang SP, Saif MW. Infusion-related and hypersensitivity reactions of monoclonal antibodies used to treat colorectal cancer--identification, prevention, and management. The journal of supportive oncology 2007; 5(9): 451-7. 8. Czuczman MS, Grillo-López AJ, White CA, et al., Treatment of patients with low-grade B-cell lymphoma with the combination of chimaeric anti CD-20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 1999; 17: 268-76. 9. Tuthill M, Crook T, Corbet T, et al., Rapid infusion of rituximab over 60 min. Eur J Haematol 2009; 82(4): 322-5. 10. Al Zahrani A, Ibrahim N, Al Eid A. Rapid infusion rituximab changing practice for patient care. J Oncol Pharm Pract 2009; 15(3): 183-6. 11. Atmar J. Review of the safety and feasibility of rapid infusion of rituximab. Journal of oncology practice. American Society of Clinical Oncology 2010; 6(2): 91-3. 12. Davis TA, Grillo-Lopez AJ, White CA, et al., Rituximab anti-cd20 monoclonal antibody therapy in non-hodgkin's lymphoma: safety and efficacy of re-treatment. Journal of clinical oncology 2000; 18(17): 3135-43. 13. Maloney DG, Grillo-Lopez AJ, White CA, et al., IDEC- C2B8 (Rituximab) anti-cd20 monoclonal antibody therapy in patients with relapsed low-grade non-hodgkin's lymphoma. Blood 1997; 90(6): 2188-95. 14. Maloney DG, Liles TM, Czerwinski DK, et al., Phase I clinical trial using escalating single-dose infusion of chimeric anti-cd20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 1994; 84(8): 2457-66. 15. Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et al., IDEC- C2B8: results of a phase I multiple-dose trial in patients with relapsed non-hodgkin's lymphoma. Journal of clinical oncology 1997; 15(10): 3266-74. 16. McLaughlin P, Grillo-Lopez AJ, Link BK, et al., Rituximab chimeric anti-cd20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. Journal of clinical oncology 1998; 16(8): 2825-33. 17. Piro LD, White CA, Grillo-Lopez AJ, et al., Extended Rituximab (anti-cd20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non- Hodgkin's lymphoma. Annals of oncology 1999; 10(6): 655-61. 18. Dillman RO, Hendrix CS. Unique aspects of supportive care using monoclonal antibodies in cancer treatment. Supportive cancer therapy 2003; 1(1): 38-48.
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