Work

High-risk Combinations of Additional Chromosomal Abnormalities in Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia: JALSG Ph+ALL TKI-SCT Study

Year: 2023

Type: article

Abstract: Additional chromosomal abnormalities (ACAs) are found in 60%–70% of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) cases. Although some high-risk chromosomal and genetic abnormalities have recently been reported,1,2 they have not been established as risk factors.3 The purpose of this study was to explore the prognostic importance of ACAs for Ph+ALL. This study combined 3 Japan Adult Leukemia Study Group (JALSG) prospective studies in the era of tyrosine kinase inhibitors (TKIs): 77 registered in the Ph+ALL202 study, 55 registered in the Ph+ALL208 study, and 74 registered in the Ph+ALL213 study. The detailed treatment schedules for each study are described elsewhere.4-6 The Ph+ALL202 study was the first JALSG study using imatinib for Ph+ALL. In the Ph+ALL208 study, imatinib was also used as a TKI, but the emphasis was on the combination of chemotherapy and imatinib, and the duration of imatinib monotherapy was shorter compared with the Ph+ALL202 study. In the Ph+ALL213 study, dasatinib was used instead of imatinib, and the induction phase was separated into 2 steps (Supplemental Methods). In this study, we used chromosomal data reviewed in the final analysis of each study. A complex karyotype was defined by the presence of at least 3 abnormalities (ie, t[9;22] and 2 or more additional aberrations) as previously described.7-9 We analyzed data from 206 de novo adult Ph+ALL patients (Suppl. Table S1). The median age at diagnosis was 45 years, white blood cell count at diagnosis was 23,510/μL, and the TKI of initial treatment was imatinib in 132 patients (64.1%) and dasatinib in 74 patients (35.9%). An ACA was identified in 63.6% of all patients; the most common structural chromosomal abnormality was +der(22)t(9;22) (32.8% of patients with an ACA). A complex karyotype was observed in 48.1% of patients with an ACA. Of 152 evaluable patients, 121 (79.6%) achieved molecular complete remission (CR) at 3 months. Allogeneic stem cell transplantation (allo-SCT) in the first CR (CR1) was performed in 138 (67.0%) of 206 patients. Regarding the overlap of ACAs, the pairwise analysis showed significant cooccurrence of +der(22)t(9;22) with both abnormal 9p and a complex karyotype (Figure 1; Suppl. Figure S1). Among 43 patients with +der(22)t(9;22), 67.4% also had a complex karyotype. On the contrary, +der(22)t(9;22) was observed in 46.0% of 63 patients with a complex karyotype.Figure 1.: Landscape of additional chromosomal abnormalities. *Monosomal karyotype means 1 or more autosomal monosomy in addition to t(9;22) (−7 and −9 described above were also counted as monosomal). **Complex karyotype means 2 or more additional aberrations in addition to t(9;22) (ACAs described earlier were also counted as complex when there were at least 2 aberrations in addition to t[9;22]). ACA = additional chromosomal abnormalities.At 5 years, the overall survival (OS) was 58.8% (95% confidence interval [CI], 51.4%-65.4%) in all 206 patients. OS was significantly higher in patients treated with dasatinib compared with those treated with imatinib (dasatinib: 74.2% [95% CI, 61.7%-83.1%] versus imatinib: 50.6% [95% CI, 41.6%-59.0%] at 5 y; P = 0.002). OS with a landmark at 3 months was significantly different between patients who achieved molecular CR at 3 months and those who did not (molecular CR(+): 65.7% [95% CI, 56.6%-73.4%] versus molecular CR(−): 43.5% [95% CI, 24.8%-60.9%] at 5 y; P = 0.02). At 5 years, leukemia-free survival (LFS) was 51.0% (95% CI, 43.6%-57.9%) in 198 patients who achieved CR1. LFS tended to be higher in patients treated with dasatinib compared with those treated with imatinib (dasatinib: 55.7% [95% CI, 42.6%-66.9%] versus imatinib: 47.6% [95% CI, 38.5%-56.2%] at 5 y; P = 0.07). LFS with a landmark at 3 months was significantly different between patients who achieved molecular CR at 3 months and those who did not (molecular CR(+): 55.5% [95% CI, 46.3%-63.8%] versus molecular CR(−): 32.6% [95% CI, 15.7%-50.8%] at 5 y; P = 0.02). When divided into 4 groups of chromosomal abnormalities, (1) both +der(22)t(9;22) and a complex karyotype; (2) +der(22)t(9;22) alone; (3) a complex karyotype alone; and (4) others, OS and LFS were worse in patients with both +der(22)t(9;22) and complex karyotype (Suppl. Figure S2). In multivariate analysis, while coexistence of +der(22)t(9;22) and a complex karyotype was a significant risk factor for both OS and LFS, +der(22)t(9;22) alone or a complex karyotype alone were not significant risk factors (Figure 2A).Figure 2.: Risk of additional chromosomal abnormalities. (A) Forest plots for the adjusted hazard ratios and 95% confidence intervals in the multivariate analysis. (B). Survival according to the risk of ACAs. All covariates other than karyotype included in multivariate models were age, WBC, and TKI. ACA = additional chromosomal abnormalities; TKI = tyrosine kinase inhibitor; WBC = white blood cell.When the coexistence of +der(22)t(9;22) and a complex karyotype were considered high risk and the others are considered standard risk, both OS and LFS were significantly worse in high-risk patients compared with standard-risk patients (Figure 2B). Patient characteristics by chromosomal risk are shown in Suppl. Table S2. There were no significant differences in baseline characteristics between the standard- and high-risk patients. The CR1 achievement rate was not significantly different between the standard- and high-risk patients (95.1% versus 100%; P = 0.22). In addition, the molecular CR rate at 3 months was not significantly different between the standard- and high-risk patients (79.8% versus 78.2%; P = 0.86). However, among patients who relapsed after achieving CR1, CR duration was significantly shorter in high-risk patients compared with standard-risk patients (0.68 versus 1.1 y; P = 0.046). The OS of high-risk patients was worse than that of low-risk patients, even when censored at the time of allo-SCT (1-y adjusted OS: 73.3% [95% CI, 54.6%-98.3%] versus 95.7% [95% CI, 92.0%-99.5%]). Regarding the type of TKIs, although OS was significantly higher in standard-risk patients treated with dasatinib compared with standard-risk patients treated with imatinib (dasatinib: 85.2% [95% CI, 72.5%-92.3%] versus imatinib: 51.9% [95% CI, 41.7%-61.2%] at 5 y; P < 0.001), no significant differences in OS were observed between high-risk patients treated with dasatinib and high-risk patients treated with imatinib when post hoc analyses were performed (dasatinib: 33.7% [95% CI, 9.5%-60.4%] versus imatinib: 31.3% [95% CI, 11.4%-53.7%] at 5 y; P = 0.55). Similarly, although LFS tended to be higher in standard-risk patients treated with dasatinib compared with standard-risk patients treated with imatinib (dasatinib: 65.4% [95% CI, 49.8%-77.2%] versus imatinib: 49.3% [95% CI, 38.9%-58.9%] at 5 y; P = 0.06), no significant differences in LFS were observed between high-risk patients treated with dasatinib and high-risk patients treated with imatinib when post hoc analyses were performed (dasatinib: 19.2% [95% CI, 3.3%-45.0%] versus imatinib: 25.0% [95% CI, 7.8%-45.0%] at 5 y; P = 0.54). Although it has been reported that +der(22)t(9;22) is an ACA with a poor prognosis1, we clarified that prognoses differ depending on the coexistence of a complex karyotype. It is known that an ACA is often observed in Ph+ALL patients, but reports of whether ACAs affect prognosis are inconsistent: some studies have reported that ACAs were a poor prognostic factor7,9 whereas others have reported that ACAs were not a poor prognostic factor.10-12 Considering the types and combinations of ACAs, we were able to clarify a subgroup of ACAs with poor prognosis in Ph+ALL. The cooccurrence of +der(22)t(9;22) and a complex karyotype was associated with a poor prognosis. In this high-risk combination of chromosomal abnormalities, not only hematological CR but also molecular CR could be achieved with the same probability as patients with standard risk, but the risk was characterized by early recurrence. In addition, improved survival with dasatinib instead of imatinib, which was observed in standard-risk patients, was not observed in high-risk patients. In this study, a complex karyotype was defined as the presence of at least 3 abnormalities, which meant that high-risk patients had 1 or more other abnormalities in addition to Ph of the main cell lineage and +der(22)t(9;22). It has been reported that ponatinib, a third-generation TKI, and/or blinatumomab, a bispecific T-cell engager, improves treatment results for Ph+ALL patients.13,14 Because ponatinib is a multikinase inhibitor and blinatumomab is an immunotherapy drug, both of which act in addition to BCR-ABL1 kinase, they may be effective for Ph+ALL patients with high-risk chromosomal abnormalities. As ponatinib was approved in 2016 for relapsed/refractory Ph+ALL and blinatumomab was approved in 2018 for relapsed/refractory ALL in Japan, the effects of these new drugs will be clarified in future clinical trials. Recently, the effect of genetic aberrations on prognosis has been reported by clinical studies of Ph+ALL. The presence of additional copy number alterations (CNAs) with the cooccurrence of IKZF1 plus CDKN2A/B and/or PAX5 has been associated with poor survival.2,14 In another study, we are conducting genetic analysis using preserved specimens from clinical studies of Ph+ALL conducted at JALSG. Considering that several chromosomal abnormalities are reported to be associated with CNAs in ALL,15 there may be genetic aberrations associated with the high-risk combination of ACAs identified in this study. The elucidation of associated genetic abnormalities may lead to new targeted therapies. Data from 3 prospective studies conducted at JALSG in the TKI era were analyzed in this study. Although some treatment improvements have been made between the studies, the principals of the chemotherapy regimens remained the same. Therefore, pooling data from the 3 studies was considered suitable for identifying leukemias with high-risk biological characteristics using a large number of cases that are difficult to accumulate in a single clinical study. As a result, we were able to identify a high-risk ACA combination that was less frequent (14%) by analyzing >200 de novo Ph+ALL patients. In conclusion, the coexistence of +der(22)t(9;22) and a complex karyotype was identified as a high-risk combination of ACAs in Ph+ALL. Multiple ACAs are often observed in Ph+ALL, leading to identifying this subgroup with a poor prognosis. It was characterized by early relapse, although remission could be achieved at the same rate as standard-risk Ph+ALL. Further molecular genetic elucidation and the establishment of effective therapeutic strategies are warranted. PARTICIPATING INSTITUTION - ID Name of Institution 1001 Hematology and Rheumatology, Nihon University Itabashi Hospital 1005 Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital 1006 Department of Hematology, Nagoya University Hospital 1012 Department of Hematology, Komaki City Hospital 1013 Department of Hematology/Oncology, Nagoya ekisaikai hospital 1014 Department of Hamatology and Oncology, JA Aichi Konan Kosei Hospital 1015 Department of Hematology, Okazaki City Hospital 1017 Hematology, Yokkaichi Municipal Hospital 1018 Division of Hematology and Oncology, Toyohashi Municipal Hospital 1023 Ichinomiya Municipal Hospital 1026 Department of Hematology and Cell Therapy, Aichi Cancer Center 1027 Department of Hematology, Japanese Red Cross Nagoya First Hospital 1028 Department of Hematology, Fujita Health University Hospital 1029 Department of Hematology, Mie University Hospital 1030 Division of Hematology/Oncology, Suzuka General Hospital 1031 Department of Hematology, Suzuka Kaisei Hospital 1034 Department of Hematology, Japanese Red Cross Ise Hospital 1036 Department of Hematology and Rheumatology, Kindai University Hospital 1037 Department of Hematology, Osaka International Cancer Institute 1038 Hematology, Hiroshima Red Cross and Atomic-bomb Suvivors Hospital 1040 Department of hematology, Nagasaki University Hospital 1041 Department of Hematology, Sasebo City General Hospital 1042 Department of Hematology, Kumamoto University Hospital 1044 Dep of Hematology and oncology, Kumamoto City hospital 1046 Clinical Hematology branch, Jichi Medical University Hospital 1050 Department of Hematology and Oncology, Okayama University Hospital 1052 Department of Haematology, National Hospital Organization Okayama Medical Centre 1053 Department of Medicine, Okayama Rosai Hospital 1054 Dept. of Hematology/Oncology, Okayama City Hospital 1056 Department of Hematology, Chugoku Central Hospital 1057 Division of Hematology, Gunma University Hospital 1061 Department of Hematology, National Hospital Organization Shibukawa Medical Center 1062 Department of Hematology, Fujioka Genaral Hospital 1063 Department of Hematology and Oncology, University of Fukui Hospital 1064 Department of Hematology/Oncology, Kurashiki Central Hospital (Ohara HealthCare Foundation) 1065 Internal Medicine, Japanese Red Cross Fukui Hospital 1069 Department of Hematology, National Cancer Center Hospital 1072 Department of Hemato-Oncology, Saitama Medical University International Medical Center 1073 Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine. 1075 Department of Hematology, Kawasaki Medical School Hospital 1077 Department of Hematology and Blood Transfusion, Kochi Health Sciences Center 1078 Division of Hematology, Ehime Prefectural Central Hospital 1079 Department of Hematology, Chiba University Hospital 1080 Internal Medicine, Japan Community Health care Organization Funabashi Central Hospital 1081 Department of Hematology, Chiba Aoba Municipal Hospital 1082 Department of Hematology, Chibaken Siseikai Narashino Hospital 1083 Department of Respiratory Medicine, Allergology and Hematology, Nara Medicai University Hospital 1085 Division of Clinical Oncology/ Hematology, Department of Internal Medicine, The Jikei University Daisan Hospital 1086 Hematology and Oncology, Dokkyo Medical University Hospital 1087 Hematology, National Hospital Organization Nagoya Medical Center 1089 Department of Hematology, Ohta Nishinouchi Hospital, Ohta General Hospital Foundation 1090 Department of hematology, Kochi Medical School Hospital 1092 Hematology, Shiga University of Medical Science 1099 Department of Hematology, National Cancer Center Hospital East 1100 Department of Hematology and Oncology, Anjo Kosei Hospital 1101 Division of Hematology and Oncology, St. Marianna University School of Medicine 1102 Department of Internal Medicine, Division of Hematology, Yokohama City Seibu Hospital, St. Marianna University School of Medicine 1104 Department of Hematology, JCHO Kyoto Kuramaguchi Medical Center 1105 Internal Medichine, Japan Community Health care Organization Kobe Central Hospital 1109 Department of Hematology, Shinshu University Hospital 1110 Department of Hematology, Nagano Red Cross Hospital 1111 Department of Hematology, Tokyo Women’s Medical University 1113 Division of Hematology, Internal Medicine 3, Hamamatsu Univesity School of Medicine 1116 Department of Hematology and Rheumatology, Kagoshima University Hospital 1119 Division of Hematology, Kanazawa University Hospital 1121 Internal Medicine, Keiju Medical Center 1122 Keiju Kanazawa Hospital 1124 Division of Hematology, Toyama City Hospital 1126 Department of Hematology, Ishikawa Prefectural Central Hospital 1128 Department of Hematology, Tokyo Medical University Hospital 1129 Department of Hematology, Kyorin University Hospital 1130 Department of Hematology, Hokkaido University Hospital 1132 Blood Disorders Center, Aiiku Hospital 1133 Department of Hematology, Sapporo Hokuyu Hospital Institute for Artificial Organs, Transplantation & Cell Therapy 1137 Dept. of Hematology, Asahikawa City Hospital 1144 Divison of Hematology, Saiseikai Maebashi Hospital 1145 Hematology and Oncology, Nagoya City University Hospital 1148 Hematology and Oncology, Tokai University School of Medicine 1149 Department of Hematology, EBINA GENERAL HOSPITAL 1150 Third Department of Internal Medicine, Yamaguchi University School of Medicine 1152 Department of Hematology, Yamaguchi Grand Medical Center 1153 Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo 1156 Department of Hematology, Hematopoietic Cell Transplantation, Osaka City University Hospital 1157 Department of Hematology, Fuchu Hospital, Osaka 1160 Hematology and Oncology, Osaka University Hospital 1161 Department of Hematology and Oncology, The University of Tokyo Hospital 1163 Department of Hematology, Niigata University Medical and Dental General Hospital 1164 Department of Hematology, Oita University Hospital 1165 Hematology, Oita Prefectural Hospital 1166 National Hospital Organization Kyushu Cancer Center 1168 Division of Hematology, Department of Internal Medicine, Aichi Medical University Hospital 1169 Department of Hematology, Kitasato University Hospital 1170 Division of Hematology, Yamagata University Hospital 1171 Hematology, Almeida Memorial Hospital 1172 Hematology, Oitaken Kouseiren Tsurumi Hospital 1173 Department of Hematology, Kumamoto Shinto General Hospital 1178 Department of Hematology, Kyushu Medical Center 1181 Department of Hematology, Iizuka Hospital 1183 Division of Hematology, Department of Medicine, Keio University School of Medicine 1184 Department of Hematology, Aomori Prefectural Central Hospital 1186 Department of Hematology, Hyogo Cancer Center 1187 Department of Hematology, Kyoto Prefectural University of Medicine 1191 Department of Hematology, Osaka City General Hospital 1192 Division of Hematology, National Defense Medical College Hospital 1193 Hematology, Akita University Hospital 1194 department of hematology, Kanazawa medical center 1195 Department of Hematology, Ogaki Municipal Hospital 1196 Hematology, Hakodate Municipal Hospital 1197 Department of Hematology, NTT Medical Center Tokyo 1198 Department of Hematology and Clinical Immunology, Yokohama City University Hospital 1199 Department of Hematology and Rheumatology, Tohoku University Hospital 1200 Department of Hematology, Hiroshima University Hospital 1203 Department Of Hematology, Yokohama City University Medical Center 1204 Department of Hematology/Oncology, Kanagawa Cancer Center 1206 Department of Hematology, Fujisawa City Hospital 1210 Dept. of Hematology, Shizuoka Red Cross Hospital 1212 Division of Hematology, Kagawa University 1213 Department of Hematology, Juntendo University School of Medicine 1214 Department of Hematology & Immunology, Kanazawa Medical University Hospital 1215 Department of Hematology, National Hospital Organization Nagasaki Medical Center 1216 Department of Hematology, National Hospital Organization Osaka Minami Medical Center 1223 Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Hospital 1225 Department of Hematology, Imamura General Hospital 1227 Department of Hematology, Miyagi Cancer Center 1228 Hematology, Ehime University Hospital 1229 Internal Medicine, Tokyo Metropolitan Bokutoh Hospital 1230 Department of Hematology, Takarazuka Municipal Hospital 1231 Division of Hematology, National Hospital Organization, Matsumoto Medical Center 1232 Hematology Division, Internal Medicine, Kagawa Prefectural Central Hospital 1236 Department of Hematology, sakaide city hospital 1237 Department of Hematology and Immunology, Ohtsu Red Cross Hospital 1240 Department of Hematology, Osaki Citizen Hospital 1241 Department of Hematology, Tokyo Medical and Dental University Hospital 1242 Division of Hematology, Saitama Medical Center, Jichi Medical University 1243 Division of Hematology and Stem Cell Transplantation, Shizuoka Cancer Center 1244 Division of Hematology, National Center for Global Health and Medicine 1245 Department of Hematology, National Hospital Organization Hokkaido Cancer Center 1246 Department of Internal Medicine, Uegahara Hospital 1248 Department of Hematology, Tokyo Metropolitan Health and Medical Treatment Corporation, Tama-Hokubu Medical Center 1251 Department of Hematology, Yokohama City Minato Red Cross Hospital 1253 department of Hematology, National Hospital Organization Kure Medical Center 1254 Department of Hematology and Oncology, Japanese Red Cross Nagoya Daini Hospital 1255 Department of Hematology/Oncology, University of Yamanashi 1256 department of hematology, Heartlife hospital 1257 Hematologic oncology, NHO Shikoku Cancer Center 1258 Department of Hematology, Japanese Red Cross Musashino Hospital 1259 Department of Hematology, Kagawa Rosai Hospital 1260 Department of Hematology, Saitama Medical Center, Saitama Medical University 1261 Department of Hematology, PL General Hospital 1262 Internal Medicine (Hematology), Toyama Prefectural Central Hospital 1265 Osaka Saiseikai Nakatsu Hospital 1266 Matsusaka Chuo General Hospital 1267 Department of Hematology, National Hospital Organization Disaster Medical Center 1268 Hematologu/Oncology, Yamato Municipal Hospital 1269 Department of Hematology NHO Hiroshimanishi Medical Center 1270 Department of oncology/hematology, Shimane university hospital 1271 Department of Hematology, Otemae Hospital 1272 hematology, Tokyo Medical University Hachioji Medical Center 1273 Hematology/Oncology, Nakagami Hospital 1274 Department of Hematology, Matsushita memorial hospital 1275 Department of Hematology, University of Tsukuba Hospital 1277 Department of Hematology, Tottori Prefectural Central Hospital 1278 Department of Hematology, Ibaraki Prefectural Central Hospital 1279 Division of Hematology and Blood transfusion, Tokyo Metropolitan Ohtsuka Hospital 1280 Department of Hematology, Toyota Kosei Hospital 1281 Department of Hematology and Oncology, Tosei General Hospital 1282 Department of Hematology, National Hospital Organization Mito Medical Center 1283 Department of Hematology, Tsuchiura Kyodo General Hospital Division of Hematology and Oncology, Department of Internal Medicine, University Hospital Department of Hematology and Oncology, hospital Department of Hematology, Yamanashi hospital Department of Hematology and Oncology, Fukui Prefectural Hospital Dept. General Hospital Department of Hematology, National Center for and of Hematology, Medical Center, National Hospital Organization Internal Medicine, Japan Community Health care Organization Kyushu Hospital Hematology, of Medicine, University of Hospital Medicine and Science, Kyushu University Hospital Department of Hematology, Medical University Hospital Department of Medical Oncology, Hematology and Infectious University Hospital Department of Hematology and Oncology, Nagoya City Medical Center Department of Hematology, Yokohama Municipal hospital Hematology, JA Medical Center Department of Internal University of Hospital Department of Hematology, Saiseikai Yokohama Hospital Department of Hematology, Municipal hospital Department of Hematology, Japanese Red Cross Osaka Hospital Department of Hematology, Sapporo Medical University Hospital Department of Hematology, Japanese Red Cross Kyoto Hospital Hematology/Oncology, Medical University Hospital Division of Hematology, General Hospital Department of Hematology, Kyoto University Hospital Department of Internal Medicine (Hematology), hospital Department of Hematology, Hospital Division of Hematology, Department of Internal Medicine, Hospital Department of Hematology and Rheumatology, Saiseikai Hospital Department of Hematology and Oncology, Red Cross Hospital Medical Oncology/Hematology, Central City Hospital Department of Hematology, Kobe City Medical Center General Hospital Department of Hematology, Toyama Red Cross Hospital Department of Hematology, Medical School Hospital Department of Hematology, Japanese Red Kyoto Daini Hospital Department of Hematology, Red Cross Hospital Department of Internal Medicine (Hematology), Niigata Prefectural Central Hospital Department of Hematology/Oncology, Tokai University Hachioji Hospital Department of Hematology, Kyoto City Hospital Department of Hematology, Memorial Hospital Department of Hematology, General Medical Center Department of Hematology, Red Cross Okayama Hospital Department of Hematology, General Hospital Department of Hematology, Osaka General Hospital of Japan Division of Hematology Oncology, Japanese Red Cross Hospital Department of Hematology and Oncology, Nagoya City East Medical Center Division of Hematology, Department of Medicine, University School of Medicine Hematology, Kindai University Nara Hospital Department of Hematology, Tottori University Hospital Division of Hematology, Medical Center Division of Clinical Oncology/ Hematology, Department of Internal Medicine, The Jikei University Hospital Division of Clinical Oncology/ Hematology, Department of Internal Medicine, The Jikei University Hospital University Of Japan Department of Hematology and Oncology, Nagoya Memorial Japan Department of Hematology, Tokyo Metropolitan Hospital, Japan The all of the and of the in the study, as as all of JALSG and the Japanese Data Center for Hematopoietic Cell and the performed the analysis, the and the and the data of patients. and the data of patients the data of patients JALSG All reviewed and approved the final reports from and and from reports from Japan and and from & and reports from and reports from and and from reports from and and reports from and reports from reports from Corporation, and and from and reports from from & Japan and and from Japan and reports from and and from All the other have no of to This was in by Japan for the of Science and the Japan for Medical Research and and

Source: HemaSphere

DOI: 10.1097/hs9.0000000000000899