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Analysis of risk factors for early death in patients with acute promyelocytic leukaemia treated with arsenic trioxide

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Abstract

To date, no specific studies have evaluated early death (ED) in patients with acute promyelocytic leukaemia (APL) homogeneously treated with arsenic trioxide induction therapy and investigated according to the white blood cell (WBC) count at onset. Such patients were retrospectively analysed in this study, including 314 patients with a WBC count ≤ 10 × 109/L (standard-risk (SR) group) and 144 with a WBC count > 10 × 109/L (high-risk (HR) group). The baseline clinical characteristics and risk factors for ED were compared between the two groups. The incidence of fibrinogen < 1.0 g/L and elevated serum uric acid, aspartate aminotransferase and creatinine levels were higher in the HR group than in the SR group (P = 0.001; P < 0.001; P < 0.001; P = 0.044, respectively). The ED rate was significantly higher in the HR group than in the SR group (29.17% vs. 10.83%, P < 0.001). The main cause of ED was bleeding, followed by infection and differentiation syndrome (DS) in the HR group, while it was bleeding, followed by DS and infection in the SR group. Male sex, age > 50 years old, and fibrinogen < 1.0 g/L were independent risk factors for ED in the SR group. Increased serum creatinine levels, decreased albumin levels, and fibrinogen < 1.0 g/L were independent risk factors for ED in the HR group. Overall, the incidence of ED was higher in the HR group, and the baseline clinical characteristics, causes, times, and predictors of ED in the HR group differed from those in the SR group.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code availability

The code used for the analysis of data in this study is available from the corresponding author upon reasonable request.

References

  1. Guru Murthy GS, Szabo A, Michaelis L, Carlson KS, Runaas L, Abedin S, Atallah E (2020) Improving outcomes of Acute promyelocytic leukemia in the current era: analysis of the SEER database. J Natl Compr Canc New 18:169–175. https://doi.org/10.6004/jnccn.2019.7351

    Article  Google Scholar 

  2. Lou Y, Ma Y, Suo S, Ni W, Wang Y, Pan H, Tong H, Meng H, Mai W, Huang J, Yu W, Wei J, Mao L, Jin J (2015) Prognostic factors of patients with newly diagnosed acute promyelocytic leukemia treated with arsenic trioxide-based frontline therapy. Leuk Res 39:938–944. https://doi.org/10.1016/j.leukres.2015.05.016

    Article  CAS  PubMed  Google Scholar 

  3. Lehmann S, Ravn A, Carlsson L, Antunovic P, Deneberg S, Möllgård L, Derolf AR, Stockelberg D, Tidefelt U, Wahlin A, Wennström L, Höglund M, Juliusson G (2011) Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia 25:1128–1134. https://doi.org/10.1038/leu.2011.78

    Article  CAS  PubMed  Google Scholar 

  4. Sun J, Zhu J, Zhou D, Zhu L, Yang X, Xie M, Li L, Huang X, Zhu M, Zheng Y, Xie W, Ye X (2019) Factors affecting early death and survival of patients with acute promyelocytic leukemia treated with ATRA - based therapy regimens. Clin Lymphoma Myeloma Leuk 19:e63–e70. https://doi.org/10.1016/j.clml.2018.08.001

    Article  PubMed  Google Scholar 

  5. Hassan IB, Zaabi MRA, Alam A, Hashim MJ, Tallman MS, Kris-tensen J (2017) Characteristics features and factors influencing early death in acute promyelocytic leukemia; experience from United Arab Emirates (UAE). Int J Hematol 106:90–98. https://doi.org/10.1007/s12185-017-2211-7

    Article  PubMed  Google Scholar 

  6. Rashidi A, Riley M, Goldin TA, Sayedian F, Bayerl MG, Aguilera NS, Vos JA, Goudar RK, Fisher SI (2014) Delay in the administration of all-trans retinoic acid and its effects on early mortality in acute promyelocytic leukemia: final results of a multicentric study in the United States. Leuk Res 38:1036–1040. https://doi.org/10.1016/j.leukres.2014.06.011

    Article  CAS  PubMed  Google Scholar 

  7. Sanz MA, Lo Coco F, Martín G, Avvisati G, Rayón C, Barbui T, Díaz-Mediavilla J, Fioritoni G, González JD, Liso V, Esteve J, Ferrara F, Bolufer P, Bernasconi C, Gonzalez M, Rodeghiero F, Colomer D, Petti MC, Ribera JM, Mandelli F (2000) Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 96:1247–1253

    CAS  PubMed  Google Scholar 

  8. Burnett AK, Grimwade D, Solomon E, Wheat-ley K, Goldstone AH (1999) Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the Randomized MRC Trial. Blood 93:4131–4143

    Article  CAS  Google Scholar 

  9. Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U, GruppoItalianoMalattieEmatologichedell’Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia (2013) Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 369:111–121. https://doi.org/10.1056/NEJMoa1300874

    Article  CAS  PubMed  Google Scholar 

  10. de la Serna J, Montesinos P, Vellenga E, Rayón C, Parody R, León A, Esteve J, Bergua JM, Milone G, Debén G, Rivas C, González M, Tormo M, Díaz-Mediavilla J, González JD, Negri S, Amutio E, Brunet S, Lowenberg B, Sanz MA (2008) Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood 111:3395–3402. https://doi.org/10.1182/blood-2007-07-100669

    Article  CAS  PubMed  Google Scholar 

  11. Kim DY, Lee JH, Lee JH, Kim SD, Lim SN, Choi Y, Lee YS, Kang YA, Seol M, Jeon M, Kim JY, Lee KH, Lee YJ, Lee KH (2011) Significance of fibrinogen, D-dimer, and LDH levels in predicting the risk of bleeding in patients with acute promyelocytic leukemia. Leuk Res 35:152–158. https://doi.org/10.1016/j.leukres.2010.05.022

    Article  CAS  PubMed  Google Scholar 

  12. Lou Y, Ma Y, Sun J, Suo S, Tong H, Qian W, Mai W, Meng H, Jin J (2017) Effectivity of a modified Sanz risk model for early death prediction in patients with newly diagnosed acute promyelocytic leukemia. Ann Hematol 96:1793–1800. https://doi.org/10.1007/s00277-017-3096-5

    Article  CAS  PubMed  Google Scholar 

  13. Fenaux P, Chevret S, Guerci A, Fegueux N, Dombret H, Thomas X, Sanz M, Link H, Maloisel F, Gardin C, Bordessoule D, Stoppa AM, Sadoun A, Muus P, Wandt H, Mineur P, Whittaker JA, Fey M, Daniel MT, Castaigne S, Degos L (2000) Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. European APL group. Leukemia 14:1371–1377. https://doi.org/10.1038/sj.leu.2401859

    Article  CAS  PubMed  Google Scholar 

  14. Iland HJ, Bradstock K, Seymour J, Hertzberg M, Grigg A, Taylor K, Catalano J, Cannell P, Horvath N, Deveridge S, Browett P, Brighton T, Chong L, Springall F, Ayling J, Catalano A, Supple S, Collins M, Di Iulio J, Reynolds J, Australasian Leukaemia and Lymphoma Group (2012) Results of the APML3 trial incorporating all-trans- retinoic acid and idarubicin in both induction and consolidation as initial therapy for patients with acute promyelocytic leukemia. Haematologica 97:227–234. https://doi.org/10.3324/haematol.2011.047506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R, Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF, Australasian Leukaemia and Lymphoma Group (2012) All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 120:1570–1580. https://doi.org/10.1182/blood-2012-02-410746

    Article  CAS  PubMed  Google Scholar 

  16. McClellan JS, Kohrt HE, Coutre S, Gotlib JR, Majeti R, Alizadeh AA, Medeiros BC (2012) Treatment advances have not improved the early death rate in acute promyelocytic leukemia. Haematologica 9:133–136. https://doi.org/10.3324/haematol.2011.046490

    Article  Google Scholar 

  17. Altman JK, Rademaker A, Cull E, Weitner BB, Ofran Y, Rosenblat TL, Haidau A, Park JH, Ram SL, Orsini JM Jr, Sandhu S, Catchatourian R, Trifilio SM, Adel NG, Frankfurt O, Stein EM, Mallios G, Deblasio T, Jurcic JG, Nimer S, Peterson LC, Kwaan HC, Rowe JM, Douer D, Tallman MS (2013) Administration of ATRA to newly diagnosed patients with acute promyelocytic leukemia is delayed contributing to early hemorrhagic death. Leuk Res 37:1004–1009. https://doi.org/10.1016/j.leukres.2013.05.007

    Article  CAS  PubMed  Google Scholar 

  18. Ciftciler R, Haznedaroglu IC, Aksu S, Ozcebe O, Sayınalp N, Malkan UY, Buyukasık Y (2019) The factors affecting early death in newly diagnosed APL patients. Open Med (Wars) 14:647–652. https://doi.org/10.1515/med-2019-0074

    Article  CAS  Google Scholar 

  19. Hou W, Zhang Y, Jin B, Cao W, Lu M, Yan L, Yang H, Tian X, Hou J, Fu J, Zhao H, Li H, Zhou J (2019) Factors affecting thrombohemorrhagic early death in patients with acute promyelocytic leukemia treated with arsenic trioxide alone. Blood Cells Mol Dis 79:102351. https://doi.org/10.1016/j.bcmd.2019.102351

    Article  CAS  PubMed  Google Scholar 

  20. Jácomo RH, Melo RA, Souto FR, de Mattos ER, de Oliveira CT, Fagundes EM, Bittencourt HN, Bittencourt RI, Bortolheiro TC, Paton EJ, Bendlin R, Ismael S, ChauffailleMde L, Silva D, Pagnano KB, Ribeiro R, Rego EM (2007) Clinical features and outcomes of 134 Brazilians with acute promyelocytic leukemia who received ATRA and anthracyclines. Haematologica 92:1431–1432. https://doi.org/10.3324/haematol.10874

    Article  PubMed  Google Scholar 

  21. Jin B, Zhang Y, Hou W, Cao F, Lu M, Yang H, Tian X, Wang Y, Hou J, Fu J, Li H, Zhou J (2020) Comparative analysis of causes and predictors of early death in elderly and young patients with acute promyelocytic leukemia treated with arsenic trioxide. J Cancer Res Clin Oncol 146:485–492. https://doi.org/10.1007/s00432-019-03076-x

    Article  CAS  PubMed  Google Scholar 

  22. Jeddi R, Ghédira H, Menif S, Ben Neji H, Ben Amor R, Kacem K, Aissaoui L, Bouteraâ W, Abdennebi Y, Raihane BL, Gouider E, Raouf H, Hèla BA, Saad A, Zaher B, Meddeb B (2010) Treatment of acute promyelocytic leukemia with PETHEMA LPA 99 protocol: a Tunisian single center experience. Hematology 15:204–209. https://doi.org/10.1179/102453309X12583347114176

    Article  CAS  PubMed  Google Scholar 

  23. Ghavamzadeh A, Alimoghaddam K, Rostami S, Ghaffari SH, Jahani M, Iravani M, Mousavi SA, Bahar B, Jalili M (2011) Phase II study of single-agent arse-nic trioxide for the front-line therapy of acute promyelocytic leukemia. J Clin Oncol 29:2753–2757. https://doi.org/10.1200/JCO.2010.32.2107

    Article  CAS  PubMed  Google Scholar 

  24. Breccia M, Lo Coco F (2014) Thrombo-hemorrhagic deaths in acute promyelocytic leukemia. Thromb Res 133(Suppl 2):S112–S116. https://doi.org/10.1016/S0049-3848(14)50019-9

    Article  CAS  PubMed  Google Scholar 

  25. Falanga A, Russo L, Tartari CJ (2011) Pathogenesis and treatment of thrombohemorrhagic diathesis in acute promyelocytic leukemia. Mediterr J Hematol Infect Dis 3:e2011068. https://doi.org/10.4084/MJHID.2011.068

    Article  PubMed  PubMed Central  Google Scholar 

  26. Mitrovic M, Suvajdzic N, Bogdanovic A, Kurtovic NK, Sretenovic A, Elezovic I, Tomin D (2013) International Society of Thrombosis and Hemostasis Scoring System for disseminatedintravascular coagulation ≥ 6: a new predictor of hemorrhagic early death in acute promyelocytic leukemia. Med Oncol 30:478. https://doi.org/10.1007/s12032-013-0478-y

    Article  CAS  PubMed  Google Scholar 

  27. Gurnari C, Breccia M, Di Giuliano F, Scalzulli E, Divona M, Piciocchi A, Cicconi L, De Bellis E, Venditti A, Del Principe MI, Arcese W, Lo-Coco F, Garaci F, Voso MT (2021) Early intracranial haemorrhages in acute promyelocytic leukaemia: analysis of neuroradiological and clinico-biological parameters. Br J Haematol 193:129–132. https://doi.org/10.1111/bjh.17018

    Article  CAS  PubMed  Google Scholar 

  28. Yanada M, Matsushita T, Asou N, Kishimoto Y, Tsuzuki M, Maeda Y, Horikawa K, Okada M, Ohtake S, Yagasaki F, Matsumoto T, Kimura Y, Shinagawa K, Iwanaga M, Miyazaki Y, Ohno R, Naoe T (2007) Severe hemorrhagic complications during remission induction therapy for acute promyelocytic leukemia: incidence, risk factors, and influence on outcome. Eur J Haematol 78:213–219. https://doi.org/10.1111/j.1600-0609.2006.00803.x

    Article  PubMed  Google Scholar 

  29. Mantha S, Goldman DA, Devlin SM, Lee JW, Zannino D, Collins M, Douer D, Iland HJ, Litzow MR, Stein EM, Appelbaum FR, Larson RA, Stone R, Powell BL, Geyer S, Laumann K, Rowe JM, Erba H, Coutre S, Othus M, Park JH, Wiernik PH, Tallman MS (2017) Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era. Blood 129:1763–1767. https://doi.org/10.1182/blood-2016-10-747170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gill H, Yung Y, Chu HT, Au WY, Yip PK, Lee E, Yim R, Lee P, Cheuk D, Ha SY, Leung RYY, Ma ESK, Kumana CR, Kwong Y (2021) Characteristics and predictors of early hospital deaths in newly diagnosed APL: a 13-year population-wide study. Blood Adv 5:2829–2838. https://doi.org/10.1182/bloodadvances.2021004789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the graduate practice and innovation project of Harbin Medical University (No. YJSCX2020-82HYD).

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Authors and Affiliations

  1. Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China

    Yuan Wang, Wenyi Hou, Haitao Li, Jinqiao Li, Tianming Hu & Deli Shi

  2. Department of Oncology, The Yuechi People’s Hospital, Guangan, 638373, People’s Republic of China

    Xuanyu Tian

  3. Department of Central Laboratory, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, People’s Republic of China

    Yingmei Zhang

  4. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China

    Yingmei Zhang

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  1. Yuan Wang
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Contributions

YW conceived and designed the study, analysed the data, and wrote the manuscript. YZ conceived and designed the study, participated in data analysis, revised the manuscript, and is the corresponding author. WH, HL, XT, JL, TH, and DS participated in data collection. All authors reviewed the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yingmei Zhang.

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This study was approved by the Ethics Committee of the First Affiliated Hospital of Harbin Medical University, who waived the requirement for patient informed consent for this retrospective analysis.

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Wang, Y., Hou, W., Li, H. et al. Analysis of risk factors for early death in patients with acute promyelocytic leukaemia treated with arsenic trioxide. Ann Hematol 101, 1039–1047 (2022). https://doi.org/10.1007/s00277-022-04788-w

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