병원약사회지 (2014), 제 31 권제 6 호 J. Kor. Soc. Health-Syst. Pharm., Vol. 31, No. 6, 1110 ~ 1118 (2014) 회원학술보고 성인악성종양환자의고뇨산혈증에대한 Rasburicase 효능분석 정지운, 김영애, 조은정, 이용화, 이혜숙, 김향숙서울대학교병원약제부 Efficacy of Rasburicase on Hyperuricemia in Adult Patients with Malignant Tumor Jee Woon Cheong, Young Ae Kim, Eun Jeong Cho, Yong Hwa Lee, Hye Suk Lee and Hyang Suk Kim Department of Pharmacy, Seoul National University Hospital, 101 Daehak-ro, Jongro-gu, Seoul, 110-744, Korea Abstract : Rasburicase reduces uric acid levels by converting uric acid to allantoin. Allopurinol is the most used in TLS(tumor lysis syndrome). However, it has limitations such as slow onset and kidney toxicity. In Korea, a few research studies on rasburicase have been performed on pediatric patients under 18 years. However, efficacy study of rasburicase in adult patients is limited. In this study, we determined the efficacy of rasburicase on hyperuricemia in adult patients with malignant tumor and analyzed the factors that might have affected its ability to convert uric acid. From November 2006 to July 2012, a retrospective study was designed to analyze laboratory changes of patients administrated 0.2 mg/kg rasburicase in Seoul National University Hospital who had malignant tumor over the age of 18. A total of 21 patients was included. This study observed uric acid, creatinine, blood urea nitrogen etc. until 96 hours after the first administration of rasburicase. 투고일자 2014.11.11; 심사완료일자 2014.11.26; 게재확정일자 2014.12.12 교신저자정지운 Tel:02-2072-2872 E-mail:82043@snuh.org - 1110 -
정지운 : 성인악성종양환자의고뇨산혈증에대한 Rasburicase 효능분석 After 12 hours, uric acid levels of all patients were significantly (p<0.05) decreased. Average uric acid levels were decreased from 10.69±4.07 mg/dl to 1.94±3.13 mg/dl and maintained until 96 hours post the first administration of rasburicase. Regression analysis revealed that lower percentage of reduced degree of 96 hours-uric acid was associated with higher numbers of white blood cells (WBC) and higher plasma uric acid levels before administration. In conclusion, rasburicase reduced uric acid levels in Korean adult patients effectively. Therefore, a careful monitoring will be required for patients who have high white blood cells or uric acid levels because higher WBC and higher plasma uric acid levels before administration was associated with lower reduction of uric acid. [Key words] Rasburicase, Tumor Lysis Syndrome, Hyperuricemia 연구배경및목적고뇨산혈증과 tumor lysis syndrome은항암화학요법을받는혈액종양환자들의심각한합병증이다. 종양용해증후군 (tumor lysis syndrome: TLS) 은암세포의급작스런괴사로인해발생하는복합적인대사이상증후군으로, 1),2) 위험도에따라 3~22% 의암환자에게서유발된다. 질병의진행으로는고뇨산혈증, 고칼륨혈증, 고인산혈증, 저칼슘혈증의혈액학적이상이나타나는검사수치상종양용해증후군 (laboratory TLS) 로시작해서급성요산신증, 부정맥, 간질, 급성신부전 (25~38%), 사망 (5~17.5%) 등심각한증상을동반한임상적종양용해증후군 (clinical TLS) 으로 3)-5) 진행되기때문에예방및치료가반드시필요한증후군이다. 현재까지는 TLS 치료및예방에있어서 allopurinol이가장많이쓰이고있는약물이다. 2) 그렇지만 allopurinol은 xanthine oxidase inhibitor로서이미생성된요산의농도를낮출수없기때문에효과 발현이느리고, xanthine 축적으로인한신장병 (nephropathy), TLS 고위험환자에서는효과발현율이 57% 정도로낮다는한계점을가지고있다. 반면에 rasburicase는 urate oxidase 재조합효소로서이미생성된요산을, 요산보다 5배이상수용성이높은 allantoin으로변환하여요산배설을빠르게촉진할수있다. 6) 따라서 allopurinol을대체할만한약물로 rasburicase가각광받고있으며현재국내에서 Allopurinol 제제에의한전처치에도종양용해증후군 (TLS; Tumor Lysis Syndrome) 에의한고뇨산혈증이확진된경우 항암제치료에의한오심구토가심하여경구용 allopurinol 제제를사용할수없는사유가확인된경우에대해요양급여를인정하고있다. 7) Rasburicase에대한연구는허가용량 (0.2 mg/kg) 보다저용량인 3 mg 또는 6 mg 8),9) 단회투여시효과분석이나소아를 6),10) 대상으로한연구가주를이루고있으며, 국내에서는 rasburicase에대한논문및임상데이터자체가 - 1111 -
JKSHP, VOL.31, NO.6 (2014) 부족한실정이다. 11) 이에본연구를통해국내성인환자의 rasburicase 0.2 mg/kg 투여시효과및예후와관련된위험요인을분석하고자한다. 연구대상및방법 1. 대상환자및자료수집 2006년 11월 3일부터 2012년 7월 10일까지서울대학교병원을내원한환자중 rasburicase를투여받은 18세이상성인악성종양환자를대상으로후향적연구를진행하였다. 허가용량인 0.2 mg/kg 외의용량을투여받았거나 (N=5) 고뇨산혈증의원인이악성종양이아닌다른사유인환자 (N=1) 를제외하여연구에적합한환자는 26명이었다. 이중 rasburicase 효과검증을위해첫투여후96시간동안한번이상혈액검사를한 21 명을대상으로하였다. 자료수집은환자기본정보인성별, 나이, 기저질환및혈액학적수치, 연구약물투약정보를수집하였다. 혈액학적수치로는 tumor burden을나타내는 WBC, Fig. 1 Cairo-Bishop definition of tumor lysis syndrome - 1112 -
정지운 : 성인악성종양환자의고뇨산혈증에대한 Rasburicase 효능분석 Lactate Dehydrogenase(LDH), uric acid와 laboratory TLS 수치 (Fig. 1) 12) 인 calcium, phosphate, potassium, uric acid 그리고 clinical TLS의척도로신기능개선여부를보기위해 blood urea nitrogen(bun), creatinine이포함되었다. 연구약물투약정보로는첫 rasburicase 투약후혈액검사시행시간, 투약횟수, 약물용량 (mg/kg), allopurinol 병용여부를조사하였다. 2. 반응평가시점및환자군분류시간에따른혈액학적수치변화평가시, 처음 rasburicase 0.2 mg/kg를투여한시간을기준으로 12 시간마다 96시간경과시점까지의수치변화를연구하였다. 또한투여전수치는약물투여직전의수치를사용하였다. 약물사용평가기준으로 TLS risk 평가시 Cairo MS et. al 13) 이제시한기준을따랐다. 또한약물사용목적평가시 Cairo-Bishop definition (Fig. 1) 12) 에따라분류하였다. 환자군모두고뇨산혈증인상태이었으며 laboratory TLS 기준부적합시 TLS 예방목적으로 rasburicase를사용하였다고평가하였다. 연구결과 1. 대상환자의기본특성총 21 명을대상으로한연구로기존의연구들과마찬가지로대다수가혈액종양환자이었으며, 평균신기능도좋지않아환자군전체적으로 TLS risk가높았다 (Table 1). Tumor burden을나타내는 WBC, LDH, uric acid 세수치모두정상치보다높았으며특히 WBC, LDH 수치는전체환자군 TLS risk가혈액종양종류와관계없이중등도이상임을뜻한다. 전체적으로이미고뇨산혈증을가지고있었고 calcium, phosphate, potassium 수치는비교적정상치에근접한수치이다 (Table 1). 2. 치료에대한반응 Table.1 Baseline characteristics of patients Total number of patients(n) Median age (range) 50.19 (22-76) Sex Male (13) Female (8) Diagnosis Burkitt lymphoma 2 CMML 1 MM 2 ALL 6 NHL 7 Solid tumor 2 Other 1 Renal function BUN ( mg /dl) 40.48±18.35 Creatinine ( mg /dl) 2.07±0.77 Tumor burden WBC (x10 3 /μl) 42.13±61.12 LDH (IU/L) 3616±5482 Uric acid( mg /dl) 10.69±4.07 Laboratory TLS values Calcium ( mg /dl) 8.30±1.185 Phosphate ( mg /dl) 5.00±2.52 Potassium (mmol/l) 4.30±0.73 Uric acid ( mg /dl) 10.69±4.07 CMML ; Chronic myelomonocytic leukemia, MM ; multiple myeloma, ALL ; acute lymphocytic leukemia, NHL ; non-hodgkin's lymphoma Table.2 Patient population based on TLS progression and antihyperuricemic drugs administration history TLS risk 21 Number of patients(n) Intermediate 3 High 18 Combined therapy with allopurinol Monotherapy 8 Co-administration 13 The number of administration Single dose 9 Multiple dose 12 Purpose for use TLS prevention 7 TLS treatment 14 Purpose for use 21-1113 -
JKSHP, VOL.31, NO.6 (2014) 으로삼았다. TLS risk 분류결과 TLS 저위험환자는없었으며, 각기준마다 TLS 고위험환자및 allopurinol 병용투여, rasburicase 다회투여, TLS 치료목적으로 rasburicase를투여받은환자가과반수를차지해공격적인치료를받고있었음을알수있었다. 4가지분류별로다음과같은항목에대해효과를분석해보았다. Fig. 2 Combined therapy with allopurinol based on TLS risk Fig. 3 Times of administration based on TLS 1) 약물사용정보별효과분석 4가지분류에따라환자군을나누어 rasburicase 효과를비교해보았다 (Table 2). TLS risk, allopurinol 병용여부, 투여횟수, 약물사용목적을기준 [ 약물투여전수치 ] Tumor burden : WBC, LDH, uric acid [ 첫약물투여전및 96 hr 경과시점까지의수치 ] Renal function : BUN, creatinine Laboratory TLS : calcium, phosphate, pota ssium, uric acid TLS 고위험군에서 allopurinol 병용및투여횟수가많은환자가밀집되어있어 TLS 위험도가높을수록더공격적인치료를받았음을알수있었다 (Fig. 2, 3) 그러나 allopurinol 병용별효과비교및투여횟수별효과비교분석에서, rasburicase 1회투여외의추가치료가 rasburicase의효과에유의한영향을끼친다고보기는어려웠다. 또한첫 rasburicase 투여후 12 시간과 84시간경과시점에서 TLS 고위험군및중등도위험군간의유의한차이없이모두 plasma uric acid level이크게감소하였다 (Table 3). TLS risk와는상관없이 rasburicase 투여후유사한 plasma uric acid level을볼수있으며 rasburicase 1회투여후추가약물투여시그로인한치료적성과차이는없었다. Rasburicase 사용목적별효과분석역시두군간유의한차이가없는것으로나왔다. 이는앞서분석한 4가지분류기준에대해환자간의차이가있더라도 rasburicase 효과분석에영향을미치지않음을시사한다. 그러므로이후거론할혈액학적수치변화및예후관련인자에서는전체환자군을대상으로분석하였다. 2) 시간경과에따른혈액학적수치변화다음 6가지항목을대상으로 rasburicase 첫투여후시간에따른혈액학적수치변화를분석해보았다. - 1114 -
정지운 : 성인악성종양환자의고뇨산혈증에대한 Rasburicase 효능분석 Table 3. Plasma uric acid levels (mg/dl) based on TLS risk Hours after first dose Baseline 12hr 84hr Intermediate 9.73±0.81 1.57±2.54 2.43±1.54 High 10.85±4.38 2.04±3.38 1.85±2.67 Table 4. Plasma uric acid level (mg/dl) during 96hr after first dose of rasburicase Hours after first dose Plasma uric acid Deviation to baseline P-value 12hr 1.94±3.13 8.05± 5.19 <0.001 24hr 1.30±1.95 9.67± 4.89 <0.001 P-value 0.214 0.943 0.501 84hr 1.98±2.41 9.19± 5.12 <0.001 96hr 1.70±1.90 9.95± 6.26 0.001 Ca, P, K, Cr, Uric acid BUN 경과시간 (hr) Fig. 4 Tumor lysis syndrome laboratory values during 96hr after first dose of rasburicase 그중 plasma uric acid 수치만유의하게감소하였고그외다른수치에는영향을주지않아 rasburicase는고뇨산혈증치료외에 laboratory, clinical TLS 개선에는효과가없었음을알수있었다 (Fig. 4). Plasma uric acid는첫번째모니터링시점인 12시간경과후검사수치가급격히감소하여 36시간경과시점까지서서히감소하는경향을보였고, 96시간후까지유의하게감소된채수치가유지되었다 (Table 4, Fig. 5). 개별환자의 plasma uric acid 변화추이에서도, 평균그래프와유사한양상을볼수있었다 (Fig. 5). 3) Plasma uric acid 예후관련인자분석 Rasburicase 투여후의 plasma uric acid level을예상할수있는관련인자를분석하기위해, 마지막모니터링시점인 96시간경과시점의절대적수치 (uric acid 96hr) 와투여전수치대비 % 수치 (uric acid 96hr(%)) 로나누어분석해보았다. 대상인자로는나이및치료강도지표로서투여횟수, tumor burden 지표인 WBC, LDH, uric acid가분석되었다. 단일회귀분석결과, uric acid 96hr(%) 의경우 WBC, uric acid만이유의한인자로나왔다 (Table 5). 이는 rasburicase 투여전 WBC, uric acid 수치에따라 rasburicase 효능의차이가있을수있음을시사하는결과이다. 다만다중회귀분석은 WBC, uric acid 간의관련성이높아시행하지않았다. - 1115 -
JKSHP, VOL.31, NO.6 (2014) Uric acid (mg/dl) 경과시간 (hr) Fig. 5 Plasma uric acid levels (mg/dl) during 96hr after first dose of rasburicase for individual patients Table 5. Simple regression analysis of baseline characteristics on response Uric acid 96hr (mg/dl) Uric acid 96hr (%) R² P-value R² P-value Age (years) 0.145 0.151 0.052 0.256 Times of administration 0.010 0.350 0.016 0.315 TLS tumor burden values before first dose WBC (x10 3 /μl) 0.104 0.190 0.825 <0.001 LDH (IU/L) 0.234 0.106-0.141 0.917 Uric acid (mg/dl) 0.325 0.050 0.614 0.004 Uric acid 96hr을기준으로회귀분석시어떠한인자도관련이없다고나왔다. Uric acid 인자는 p-value 가 0.05로나와특히이부분에대해추후더많은환자군을확보한연구들이필요할것이다 (Table 5). 고찰및결론본연구는 rasburicase에대한연구가많이진행되지않은국내성인악성종양환자를대상으로한연구로, 허가용량인 0.2 mg/kg 투여시의효과를분석하였으며, 투여이후 plasma uric acid level에영향을미칠수있는인자를분석한연구이다. Rasburicase가 2001년 2월 23일 EMEA(European Medicines Agency) 에서소아환자를대상으로처음승인된이후성인환자까지허가사항이확장된약물로 rasburicase 관련국내연구가많이이루어지지않았으며성인환자에대한임상적경험이매우적기때문에국내성인환자를대상으로하였다는것에본연구의의의가있다. 더나아가약물의효과에영향을미칠수있는인자를분석하고자하였다. TLS risk, allopurinol 병용여부, 투여횟수, 약물사용목적, 이 4가지분류로각각환자군을나누어 rasburicase의효과를비교한결과, 4가지분류기준모두두환자군간의유의한약물효능적차이가없는 - 1116 -
정지운 : 성인악성종양환자의고뇨산혈증에대한 Rasburicase 효능분석 것으로나왔다. 이는 rasburicase를투여할경우, allopurinol 병용또는 rasburicase 추가투여가적절한약물요법인지에대해논의할필요가있다는것을의미한다. 이번연구를통해국내성인환자에서도기존연구와마찬가지로 rasburicase가단회투여만으로도효과적임을밝혀졌다. 또한 TLS risk 정도간 rasburicase의효과차이없이 plasma uric acid level이유의하게낮아졌기때문에고뇨산혈증이나타난 TLS 고위험환자에도효과적인약물임을알수있었다. Rasburicase 투여전, 후로혈액학적수치를비교분석한결과에서기존논문과마찬가지로 rasburicase는 uric acid에서만유의한효과가있었고신기능개선효과가없었다. 5),10),14) Uric acid는 rasburicase 반감기가약 18 시간이지만 96시간경과시점수치가가장수치가낮았던 36시간경과시점수치와비교시크게증가하지않은채유지되었다. 이는 rasburicase의약물기전이 uric acid 생성을억제하는것이아니라더수용성이높은 allantoin으로 uric acid을전환하여고뇨산혈증을개선하는것임을생각해보았을때, 주목할만한결과이다. 마지막으로 96시간경과시점의 uric acid(%) level 이투여전 WBC 또는 plasma uric acid 수치에영향을받을수있다는결과가나와투여전두수치가높은환자에대해서는주의깊은모니터링이필요할것으로생각된다. 이번연구는단일기관내환자를대상으로한연구로대규모의환자군확보에어려움이있었다. 따라서허가용량외의저용량 rasburicase를투여받은환자군에대해서는효과분석을하지못했다는것이이연구의한계이다. 외국에서발표된자료들에따르면 6 mg 같은저용량으로 rasburicase를사용하더라도고뇨산혈증치료에효과적이라는결과들 8),9) 이있었기때문에추후대규모의환자군을대상으로한연구가필요할것이다. 또한연구특성상모니터링이필요한시점의혈액검사가필요하지만후향적연구로그시점의혈액학적검사가누락된것들이있어서이를개선하기위해전향적연구또한이루어져야할것이다. 참고문헌 1) Cairo M.S. and Bishop M. : Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol, 127(1), 3-11 (2004) 2) Coiffier B., Altman A., Pui C.H., Younes A. and Cairo M.S. : Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol, 26(16), 2767-2778 (2008) 3) Pession A., Melchionda F. and Castellini C. : Pitfall, prevention, and treatment of hyperuricemia during tumor lysis syndrome in the era of rasburicase(recombinant urate oxidase). Biologics, 2(1),129-141 (2008) 4) Will A. and Tholouli E. : The clinical management of tumour lysis syndrome in haematological malignancies. Br J Haematol, 154(1), 3-13 (2011) 5) Knoebel R.W., Lo M. and Crank C.W. : Evaluation of a low, weight-based dose of rasburicase in adult patients for the treatment or prophylaxis of tumor lysis syndrome. J Oncol Pharm Pract, 17(3), 147-154 (2011) 6) Goldman S.C., Holcenberg J.S., Finklestein J.Z., Hutchinson R., Kreissman S., Johnson F.L., Tou C., Harvey E., Morris E. and Cairo M.S. : A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood, 97(10), 2998-3003 (2001) 7) Health Insurance Review & Assessment Service. http://www.hira.or.kr, Updated Sep 1, 2013 8) Trifilio S., Gordon L., Singhal S., Tallman M., Evens A., Rashid K., Fishman M., Masino K., Pi J. and Mehta J. : Reduceddose rasburicase(recombinant xanthine oxidase) in adult cancer patients with - 1117 -
JKSHP, VOL.31, NO.6 (2014) hyperuricemia. Bone Marrow Transplant, 37(11), 997-1001 (2006) 9) Trifilio S.M., Pi J., Zook J., Golf M., Coyle K., Greenberg D., Newman D., Koslosky M. and Mehta J. : Effectiveness of a single 3mg rasburicase dose for the management of hyperuricemia in patients with hematological malignancies. Bone Marrow Transplant, 46(6), 800-805 (2011) 10) Renyil I., Bardi E., Udvardi E., Kovacs G., Bartyik K., Kajtar P., Masat P., Nagy K., Galantai I. and Kiss C. : Prevention and treatment of hyperuricemia with rasburicase in children with leukemia and nonhodgkin s lymphoma. Pathol Oncol Res, 13(1), 57-62 (2007) 11) Ahn Y.H., Kang H.J., Shin H.Y., Ahn H.S., Choi Y. and Kang H.G. : Tumor lysis syndrome in children: experience of last decade. Hematol Oncol, 29(4), 196-201 (2011) 12) Howard S.C., Jones D.P. and Pui C.H. : The tumor lysis syndrome. N Engl J Med, 364(19), 1844-1854 (2011) 13) Cairo M.S., Coiffier B., Reiter A. and Younes A. : Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome(tls) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol, 149(4), 578-586 (2010) 14) Bosly A., Sonet A., Pinkerton C.R., McCowage G., Bron D., Sanz M.A. and Van den Berg H. : Rasburicase (recombinant urate oxidase) for the management of hyperuricemia in patients with cancer: report of an international compassionate use study. Cancer, 98(5), 1048-1054 (2003) - 1118 -