Title: Clinical features of patients with acute myeloid leukaemia and the <i>NUP98::NSD1</i> fusion gene
Abstract: International Journal of Laboratory HematologyEarly View LETTER TO THE EDITOROpen Access Clinical features of patients with acute myeloid leukaemia and the NUP98::NSD1 fusion gene An Wu, An Wu Department of Hematology, Ningbo First Hospital, Ningbo Clinical Research Center for Hematologic malignancies, Ningbo, ChinaSearch for more papers by this authorYuntao Liu, Yuntao Liu State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorShuning Wei, Shuning Wei State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorYan Li, Yan Li State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorKaiqi Liu, Kaiqi Liu orcid.org/0000-0002-1532-0301 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorQiuyun Fang, Qiuyun Fang State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorDong Lin, Dong Lin State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorBenfa Gong, Benfa Gong State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorGuangji Zhang, Guangji Zhang State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorXiaoyuan Gong, Xiaoyuan Gong orcid.org/0000-0002-8938-3081 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorBingcheng Liu, Bingcheng Liu State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorYing Wang, Ying Wang State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorYingchang Mi, Yingchang Mi State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorHui Wei, Corresponding Author Hui Wei [email protected] State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China Correspondence Hui Wei and Jianxiang Wang, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China. Email: [email protected] and [email protected]Search for more papers by this authorJianxiang Wang, Corresponding Author Jianxiang Wang [email protected] State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China Correspondence Hui Wei and Jianxiang Wang, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China. Email: [email protected] and [email protected]Search for more papers by this author An Wu, An Wu Department of Hematology, Ningbo First Hospital, Ningbo Clinical Research Center for Hematologic malignancies, Ningbo, ChinaSearch for more papers by this authorYuntao Liu, Yuntao Liu State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorShuning Wei, Shuning Wei State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorYan Li, Yan Li State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorKaiqi Liu, Kaiqi Liu orcid.org/0000-0002-1532-0301 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorQiuyun Fang, Qiuyun Fang State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorDong Lin, Dong Lin State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorBenfa Gong, Benfa Gong State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorGuangji Zhang, Guangji Zhang State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorXiaoyuan Gong, Xiaoyuan Gong orcid.org/0000-0002-8938-3081 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorBingcheng Liu, Bingcheng Liu State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorYing Wang, Ying Wang State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorYingchang Mi, Yingchang Mi State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, ChinaSearch for more papers by this authorHui Wei, Corresponding Author Hui Wei [email protected] State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China Correspondence Hui Wei and Jianxiang Wang, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China. Email: [email protected] and [email protected]Search for more papers by this authorJianxiang Wang, Corresponding Author Jianxiang Wang [email protected] State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China Correspondence Hui Wei and Jianxiang Wang, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China. Email: [email protected] and [email protected]Search for more papers by this author First published: 07 February 2023 https://doi.org/10.1111/ijlh.14032 An Wu and Yuntao Liu are co-first authors. Funding information: The National Key Research and Development Program, Grant/Award Number: 2021YFC2500300; CAMS Innovation Fund for Medical Science, Grant/Award Number: No.2020-I2M-C&T-A-019 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Dear Editors, The NUP98::NSD1 fusion, frequently associated with FLT3-ITD mutation, is often detected in cytogenetically normal acute myeloid leukaemia (CN-AML) patients and predicts poor outcomes in children.1, 2 However, the clinical features of the NUP98::NSD1 fusion in adult AML remain unclear. We retrospectively investigated 11 adult patients with the NUP98::NSD1 fusion gene at the Institute of Hematology and Blood Diseases Hospital of the Chinese Academy of Medical Sciences from 2020 to 2021. Informed consent was obtained from the patients, and the study was conducted according to the Declaration of Helsinki. Five patients were male, and six were female, with a median age of 30 years (range, 14–59 years). Based on the 5th WHO classification, all patients were classified as acute myeloid leukaemia with defining genetic abnormalities. Table 1 shows the clinical characteristics of the patients. TABLE 1. Laboratory features of 11 acute myeloid leukaemia patients with NUP98::NSD1 fusion VALUE Age, years Median (range) 30 (14–59) Male/Female, n 5/6 BM blast, % Median (range) 77.0 (22.0–91.0) Peripheral blood WBC, ×109/L Median (range) 69.3 (2.8–203.2) HB, g/dl Median (range) 8.3 (4.9–11.2) PLT, ×109/L Median (range) 71.0 (44.0–128.0) LDH, IU/L Median (range) 728.8 (262.0–2175.1) Abbreviation: BM, bone marrow; HB, hemoglobin; LDH, lactate dehydrogenase; PLT, platelet; WBC, white blood cell. Chromosomes were identified from bone marrow (BM) cells using the reverse banding (R-banding) method, and karyotypes were classified according to the International System for Human Cytogenetic Nomenclature (2016) (ISCN2016).3 The chromosomal analysis at initial diagnosis showed a normal karyotype in most patients (cases 1–4, 6–10). Cases 5 and 11 showed trisomy 8 and del(9q13), respectively. With disease progression, a complex karyotype (CK) was observed in two patients (case 3, 7) who were CN-AML at diagnosis. This phenomenon suggests that NUP98::NSD1 positive patients have highly unstable chromosomes and genomes, resulting in disease progression.1, 4, 5 Trisomy 8 has also appeared frequently from disease onset to progression in our cohort. The relationship between an extra copy of the 8th chromosome and NUP98::NSD1 fusion remains to be further studied. Table 2 shows the karyotype data. TABLE 2. Genetic characteristics and clinical outcomes of 11 acute myeloid leukaemia patients with NUP98::NSD1 fusion Cases FLT3-ITD mutation Karyotype at diagnose Karyotype at disease progression or relapsing Target drugs CR HSCT Total FU (months) Outcome 1 Y CN 47,+XY,+8[17]/47, idem,+X,-7[1]/46,XY [2] SOR + VEN; GIL Y Y 14 Alive 2 Y CN / SOR + VEN Y Y 10 Alive 3 Y CN 49,XX,+8,+13,+15[4]/46,XX[16] SOR + VEN; GIL N Y 12 Alive 4 Y CN 47,XX,+8[19]/46,XX [1] DAS + VEN N N 6 DOD 5 Y 47,+XY,+8[10]/46,XY[10] 46,XY, del(9)(q13q12)[20] DAS + VEN; SOR N Y 13 Alive 6 Y CN / VEN N Y 10 DOD 7 Y CN 46,XX,t(5;19)(p10;p10) [4]/46,XX,t(11;19)(p10;p10) [1]/46,XX,t(14;19)(q32;q13.1) [1]/47,XX,+mar[I]/46,XX[13] SOR N Y 6 Alive 8 N CN / / Y N 6 Alive 9 N CN CN / N N 4 DOD 10 N CN CN / N N 3 Alive 11 N 46,XY,del(9)(q14,q22) [5]/46,XY,del(12)(p13p11.2) [5]/46,XY[10] 46,XY,del(9)(q14,q22) [5]/46,XY,del(12)(p13p11.2) [5]/46,XY[10] DAS N N 4 – Abbreviations: CN, cytogenetically normal; DAS, dasatinib; DOD, died of disease; F, female; FU, follow-up; GIL, gilteritinib; M, male; SOR, sorafenib; VEN, venetoclax; −, lost follow-up. Consistent with previous studies,4, 6 the FLT3-ITD mutation appeared the most in our cohort (63.6%), followed by the WT1 mutation (27.3%) and the CEBPA single mutation (27.3%). Five of seven patients harboring the FLT3-ITD mutation had an allelic ratio (AR) of ≥0.5. It is worth noting that none of the 11 patients acquired an NPM1 mutation. In the early stage of AML, this should prompt us to look for an NUP98::NSD1 fusion when an FLT3-ITD mutation exists or an NPM1 mutation is absent. All patients in our cohort completed at least one cycle of induction therapy, including daunorubicin (DNR) and cytarabine (Ara-C) (DA), idarubicin (IDA), Ara-C and cyclophosphamide (CTX) (IAC), homoharringtonine (HHT), Ara-C and aclacinomycin (Acla) (HAA) and a therapeutic regimen of Ara-C, azacitidine (AZA) plus a targeted drugs combination, and the clinical curative effect was evaluated. Consolidation therapy included high-dose Ara-C and a therapeutic regimen of AZA, fms-like tyrosine kinase 3 (FLT3) inhibitors, and B-cell lymphoma-2 (BCL-2) inhibitors. Salvage therapy included the chemotherapy drugs fludarabine (Flu), Ara-C and granulocyte colony-stimulating factor (G-CSF) (FLAG), Acla, Ara-C and G-CSF (CAG), HHT, Ara-C and etoposide (VP-16) (HAE), HHT, Ara-C and CTX (HAC) and HAA with or without hypomethylating drugs (AZA and decitabine (DCA)) and targeted drugs (FLT3 inhibitors and BCL-2 inhibitors). The complete response (CR) rate for 11 patients was 27.3% (3/11). The CR rate was 9.1% (1/11) in one cycle and 18.2% (2/11) in two cycles. Three patients (cases 1,2,8) who achieved CR after induction therapy were alive at the last follow-up. Of them, one patient (case 1) had a CR after one course of DA, although there were two relapses during the following five courses of treatment. The patient eventually had a durable remission for 4 months after allogeneic hematopoietic stem cell transplantation (allo-HSCT). One patient (case 2) had a sustained remission for 8 months after induction therapy, including one course of HAA followed by a course of Ara-C, AZA, FLT3 inhibitor and BCL-2 inhibitor. Another patient (case 8) had sustained remission for 4 months after DA and IAC. Both cases 2 and 8 underwent four consolidation therapy courses, and one also received allo-HSCT. Eight patients (3–7, 9–11) without CR had a median overall survival (OS) of 10 months. These patients had completed two cycles of induction chemotherapy with DA, followed by IAC. Of them, two patients (case 9, 10) only received induction chemotherapy. Case 9 died 2 months later, while the case 10 was waiting for the next course of therapy. Four patients (case 3, 5–7) received several courses (range 1–3) of salvage therapy before rescue allo-HSCT was done and had already survived more than 6 months, while one patient (case 6) died of pulmonary infection with an OS of 10 months. The remaining two patients both withdrew treatment after one course of salvage therapy, one of them (case 4) died 1 month later, and the other (case 11) was lost to follow-up (Table 2). The median follow-up time of 11 patients was 10 months, and the 1-year OS rate was approximately 54.5%. On the other hand, all seven patients with the FLT3-ITD mutation received chemotherapy agents concomitantly with targeted drugs, namely, FLT3 inhibitors or BCL-2 inhibitors. The median course of therapy was 4 (range, 3–6). Three patients (cases 1–3) received both BCL-2 inhibitors and FLT3 inhibitors, and two achieved CR. One patient (case 5) received BCL-2 inhibitor followed by FLT3 inhibitor during the next course. Cases 6 and 7 received BCL-2 inhibitor and FLT3 inhibitor, respectively. The CR rate was 28.6% (2/7), and the one-year OS rate was 68.6%. Of four patients without FLT3-ITD mutations, none underwent FLT3 inhibitor nor BCL-2 inhibitor therapy. The median course of treatment was 4.5 (range, 2–6). The CR rate was 25% (1/4), and one-year OS could not be determined in newly diagnosed FLT3-ITD-negative patients (Table 2). It has been reported that AML patients positive for NUP98::NSD1 and FLT3-ITD mutations have a worse outcome than those who are FLT3-ITD negative,1 which is contrary to our results. The difference may be due to the small number of cases in this study. All patients positive for NUP98::NSD1 and FLT3-ITD mutations received allo-HSCT. We assume that allo-HSCT played an essential role in their survival. It is worth noting that all patients positive for NUP98::NSD1 and FLT3-ITD mutations received targeted drugs, which might partly explain their better outcomes than those who were FLT3-ITD negative. In conclusion, AML with NUP98::NSD1 fusion is a distinct disease. It is difficult to achieve complete remission in patients with this fusion gene. Our results need to be verified in a larger cohort of patients with a longer duration of follow-up. AUTHOR CONTRIBUTIONS An Wu and Yuntao Liu equally contributed to this work including collecting and analyzing data and writing the manuscript. Shuning Wei, Yan Li, Kaiqi Liu, Qiuyun Fang, Dong Lin, Benfa Gong, Guangji Zhang, Xiaoyuan Gong, Bingcheng Liu, Ying Wang, and Yingchang Mi collected data. Hui Wei and Jianxiang Wang designed research and reviewed the manuscript. All authors read and approved the final manuscript. ACKNOWLEDGMENTS We thank the patients and their caregivers, and the study teams who made this study possible. The authors are fully responsible for all content and editorial decisions for this manuscript. FUNDING INFORMATION This research was supported by National Key Research and Development Program of China. (2021YFC2500300) and the CAMS Innovation Fund for Medical Science (No. 2020-I2M-C&T-A-019). CONFLICT OF INTEREST STATEMENT The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. PATIENT CONSENT STATEMENT All patients signed an informed consent approved by the institutional Review Board. Open Research DATA AVAILABILITY STATEMENT Data openly available in a public repository. REFERENCES 1Ostronoff F, Othus M, Gerbing RB, et al. NUP98/NSD1 and FLT3/ITD coexpression is more prevalent in younger AML patients and leads to induction failure: a COG and SWOG report. Blood. 2014; 124(15): 2400- 2407. 2Niktoreh N, Walter C, Zimmermann M, et al. Mutated WT1, FLT3-ITD, and NUP98::NSD1 fusion in various combinations define a poor prognostic Group in Pediatric Acute Myeloid Leukemia. J Oncol. 2019; 2019:1609128. 3McGowan-Jordan J, Simons A, Schmid M. ISCN 2016: An International System for Human Cytogenomic Nomenclature (2016). Karger AG; 2016. 4Hollink IH, van den Heuvel-Eibrink MM, Arentsen-Peters STCJM, et al. NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern. Blood. 2011; 118(13): 3645- 3656. 5Wang T, Ni JB, Wang XY, et al. Genetic characteristics and clinical outcomes of pediatric acute myeloid leukemia with NUP98::NSD1 fusion gene. Zhonghua Yi Xue Za Zhi. 2019; 99(36): 2820- 2825. 6Akiki S, Dyer SA, Grimwade D, et al. NUP98::NSD1 fusion in association with FLT3-ITD mutation identifies a prognostically relevant subgroup of pediatric acute myeloid leukemia patients suitable for monitoring by real time quantitative PCR. Genes Chromosomes Cancer. 2013; 52(11): 1053- 1064. Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation