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Early predictor for differentiation syndrome in newly diagnosed acute promyelocytic leukaemia patients treated with single-agent arsenic trioxide

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Abstract

Differentiation syndrome (DS) is the second leading cause of death in acute promyelocytic leukaemia (APL) patients. Few studies have tested predictors of DS events. This study aimed to identify optimized predictors of DS events related to APL. The data of 298 consecutive patients who were newly diagnosed with APL between December 2012 and June 2023 were retrospectively investigated. A systematic review of computer-based patient medical records was conducted to obtain clinical data, including baseline characteristics, routine blood examination findings, biochemical indices and clinical manifestations of DS. Among the 298 patients, 158 were classified into the no-DS group, while 140 had DS. Compared with those of patients without DS, the peripheral blast count, age, and WBC count at each time point were significantly different in patients with DS (P < 0.05 for all time points). Generalized linear mixed models (GLMMs) revealed that WBC Double (Coeff. 0.442, P = 0.000) and WBCPeak (Coeff. 0.879, P = 0.000) were independent risk factors for DS. The frequencies of clinical manifestations of unexplained fever (P = 0.003), dyspnoea (P = 0.002), weight gain of more than 5 kg (P = 0.006), pleural effusion (P = 0.001), pulmonary infiltrates (P < 0.001), pericardial effusion (P = 0.002) and renal failure (P = 0.006) were considerably lower in moderate DS patients than in severe DS patients. The WBCDouble occurs earlier than the WBCpeak occurrence, so WBC Double might be a new indicator of DS.

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References

  1. Stahl M, Tallman MS (2019) Differentiation syndrome in acute promyelocytic leukaemia [J]. Br J Haematol 187(2):157–162. https://doi.org/10.1111/bjh.16151

    Article  CAS  PubMed  Google Scholar 

  2. Frankel SR, Eardley A, Lauwers G, Weiss M, Warrell RP Jr. (1992) The “retinoic acid syndrome” in acute promyelocytic leukaemia [J]. Ann Intern Med 117(4):292–296. https://doi.org/10.7326/0003-4819-117-4-292

    Article  CAS  PubMed  Google Scholar 

  3. Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A, Shepherd L, Willman C, Bloomfield CD, Rowe JM, Wiernik PH (1997) All-trans-retinoic acid in acute promyelocytic leukaemia [J]. N Engl J Med 337(15):1021–1028. https://doi.org/10.1056/nejm199710093371501

    Article  CAS  PubMed  Google Scholar 

  4. 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 leukaemia with PETHEMA LPA 99 protocol: a Tunisian single centre experience [J]. Haematology 15(4):204–209. https://doi.org/10.1179/102453309x12583347114176

    Article  CAS  Google Scholar 

  5. Leblebjian H, DeAngelo DJ, Skirvin JA, Stone RM, Wadleigh M, Werner L, Neuberg DS, Bartel S, McDonnell AM (2013) Predictive factors for all-trans retinoic acid-related differentiation syndrome in patients with acute promyelocytic leukaemia [J]. Leuk Res 37(7):747–751. https://doi.org/10.1016/j.leukres.2013.04.011

    Article  CAS  PubMed  Google Scholar 

  6. Vahdat L, Maslak P, Miller WH Jr., Eardley A, Heller G, Scheinberg DA, Warrell RP Jr. (1994) Early mortality and the retinoic acid syndrome in acute promyelocytic leukaemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR-alpha isoform, and CD13 expression in patients treated with all-trans retinoic acid [J]. Blood 84(11):3843–3849. https://doi.org/10.1016/S0950-3536(05)80122-2

    Article  CAS  PubMed  Google Scholar 

  7. Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A, Shepherd L, Rowe JM, François C, Larson RS, Wiernik PH (2000) Clinical description of 44 patients with acute promyelocytic leukaemia who developed the retinoic acid syndrome [J]. Blood 95(1):90–95. https://doi.org/10.1016/S1083-8791(00)70031-0

    Article  CAS  PubMed  Google Scholar 

  8. Sanz MA, Martín G, Rayón C, Esteve J, González M, Díaz-Mediavilla J, Bolufer P, Barragán E, Terol MJ, González JD, Colomer D, Chillón C, Rivas C, Gómez T, Ribera JM, Bornstein R, Román J, Calasanz MJ, Arias J, Alvarez C, Ramos F, Debén G (1999) A modified AIDA protocol with anthracycline-based consolidation results in high antileukaemic efficacy and reduced toxicity in newly diagnosed PML/RARalpha-positive acute promyelocytic leukaemia. PETHEMA group [J]. Blood 94(9):3015–3021

    CAS  PubMed  Google Scholar 

  9. Yoon JH, Kim HJ, Min GJ, Park SS, Jeon YW, Lee SE, Cho BS, Eom KS, Kim YJ, Lee S, Min CK, Cho SG, Lee JW (2019) Progressive hyperleukocytosis is a relevant predictive marker for differentiation syndrome, early death, and subsequent relapse in acute promyelocytic leukaemia [J]. Sci Rep 9(1):11935. https://doi.org/10.1038/s41598-019-47937-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. de Botton S, Chevret S, Coiteux V, Dombret H, Sanz M, San Miguel J, Caillot D, Vekhoff A, Gardembas M, Stamatoulas A, Conde E, Guerci A, Gardin C, Fey M, Cony Makhoul D, Reman O, de la Serna J, Lefrere F, Chomienne C, Degos L, Fenaux P (2003) Early onset of chemotherapy can reduce the incidence of ATRA syndrome in newly diagnosed acute promyelocytic leukaemia (APL) with low white blood cell counts: results from APL 93 trial [J]. Leukaemia 17(2):339–342. https://doi.org/10.1038/sj.leu.2402807

    Article  CAS  Google Scholar 

  11. Rego EM, Kim HT, Ruiz-Argüelles GJ, Undurraga MS, UriarteMdel R, Jacomo RH, Gutiérrez-Aguirre H, Melo RA, Bittencourt R, Pasquini R, Pagnano K, Fagundes EM, ChauffailleMde L, Chiattone CS, Martinez L, Meillón LA, Gómez-Almaguer D, Kwaan HC, Garcés-Eisele J, Gallagher R, Niemeyer CM, Schrier SL, Tallman M, Grimwade D, Ganser A, Berliner N, Ribeiro RC, Lo-Coco F, Löwenberg B, Sanz MA (2013) Improving acute promyelocytic leukaemia (APL) outcome in developing countries through networking, results of the International Consortium on APL [J]. Blood 121(11):1935–1943. https://doi.org/10.1182/blood-2012-08-449918

    Article  CAS  PubMed  Google Scholar 

  12. Serefhanoglu S, Buyukasik Y, Goker H, Sayinalp N, Haznedaroglu IC, Aksu S, Ozcebe OI, Turgut M, Aslan R, Ozdemir E (2010) Clinical features and outcomes of 49 Turkish patients with acute promyelocytic leukaemia who received ATRA and anthracyclines (PETHEMA protocol) therapy [J]. Leuk Res 34(12):e317-319. https://doi.org/10.1016/j.leukres.2010.07.027

    Article  PubMed  Google Scholar 

  13. Sobas M, Czyż A, Montesinos P, Armatys A, Helbig G, Hołowiecka A, Pluta A, Zarzycka E, Piątkowska-Jakubas B, Majcherek M, Lewandowski K, Gołos A, Paluszewska M, Podhorecka M, Oleksiuk J, Skręt A, Hawrylecka D, Guzicka-Kazimierczak RE, Wątek M, Gromek T, Charliński G, Grosicki S, Holojda J, Miśkiewicz W, Martinez-Cuadrón D, Sanz MA, Wróbel T, Wierzbowska A, Giebel S (2020) Outcome of a Real-Life Population of Patients With Acute Promyelocytic Leukaemia Treated According to the PETHEMA Guidelines: The Polish Adult Leukaemia Group (PALG) Experience [J]. Clin Lymphoma Myeloma Leuk 20(2):105–113. https://doi.org/10.1016/j.clml.2019.09.616

    Article  PubMed  Google Scholar 

  14. Wang F, Jia JS, Wang J, Zhao T, Jiang Q, Jiang H, Zhu HH (2017) The kinetics of white blood cell and the predictive factors of leukocytosis under oral or intravenous arsenic as the first-line treatment for acute promyelocytic leukaemia [J]. Leuk Res 61:84–88. https://doi.org/10.1016/j.leukres.2017.09.006

    Article  CAS  PubMed  Google Scholar 

  15. Montesinos P, Bergua JM, Vellenga E, Rayón C, Parody R, de la Serna J, León A, Esteve J, 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 (2009) Differentiation syndrome in patients with acute promyelocytic leukaemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors [J]. Blood 113(4):775–783. https://doi.org/10.1182/blood-2008-07-168617

    Article  CAS  PubMed  Google Scholar 

  16. De Botton S, Dombret H, Sanz M, Miguel JS, Caillot D, Zittoun R, Gardembas M, Stamatoulas A, Condé E, Guerci A, Gardin C, Geiser K, Makhoul DC, Reman O, de la Serna J, Lefrere F, Chomienne C, Chastang C, Degos L, Fenaux P (1998) Incidence, clinical features, and outcome of all trans-retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukaemia The European APL Group [J]. Blood 92(8):2712–2718. https://doi.org/10.1006/bcmd.1998.0212

    Article  PubMed  Google Scholar 

  17. Patatanian E, Thompson DF (2008) Retinoic acid syndrome: a review [J]. J Clin Pharm Ther 33(4):331–338. https://doi.org/10.1111/j.1365-2710.2008.00935.x

    Article  CAS  PubMed  Google Scholar 

  18. Wen J, Xu F, Zhou Q, Hu H, Liu Y, Su J, Zhang Y, Qu W, Shi L (2021) Dynamic changes and multiplication rate of white blood cell count may direct the timing of cytoreduction chemotherapy during induction treatment in newly diagnosed acute promyelocytic leukaemia with low-intermediate risk [J]. Mol Clin Oncol 14(6):112. https://doi.org/10.3892/mco.2021.2274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chen ZX, Xue YQ, Zhang R, Tao RF, Xia XM, Li C, Wang W, Zu WY, Yao XZ, Ling BJ (1991) A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukaemia patients [J]. Blood 78(6):1413–1419. https://doi.org/10.1046/j.1537-2995.1991.31892023514.x

    Article  CAS  PubMed  Google Scholar 

  20. Zhou J, Meng R, Sui X, Meng L, Jia J, Yang B (2005) Effects of administration styles of arsenic trioxide on intracellular arsenic concentration, cell differentiation and apoptosis [J]. Haematologica 90(9):1277–1279. https://doi.org/10.1016/j.exphem.2005.06.025

    Article  CAS  PubMed  Google Scholar 

  21. Sanz MA, Fenaux P, Tallman MS, Estey EH, Löwenberg B, Naoe T, Lengfelder E, Döhner H, Burnett AK, Chen SJ, Mathews V, Iland H, Rego E, Kantarjian H, Adès L, Avvisati G, Montesinos P, Platzbecker U, Ravandi F, Russell NH, Lo-Coco F (2019) Management of acute promyelocytic leukaemia: updated recommendations from an expert panel of the European LeukaemiaNet [J]. Blood 133(15):1630–1643. https://doi.org/10.1182/blood-2019-01-894980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Román J, Barragán E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P (2004) Risk-adapted treatment of acute promyelocytic leukaemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicentre study by the PETHEMA group [J]. Blood 103(4):1237–1243. https://doi.org/10.1182/blood-2003-07-2462

    Article  CAS  PubMed  Google Scholar 

  23. Bono R, Alarcón R, Blanca MJ (2021) Report Quality of Generalized Linear Mixed Models in Psychology: A Systematic Review [J]. Front Psychol 12:666182. https://doi.org/10.3389/fpsyg.2021.666182

    Article  PubMed  PubMed Central  Google Scholar 

  24. Tang L, Chai W, Ye F, Yu Y, Cao L, Yang M, Xie M, Yang L (2017) HMGB1 promotes differentiation syndrome by inducing hyperinflammation via MEK/ERK signalling in acute promyelocytic leukaemia cells [J]. Oncotarget 8(16):27314–27327. https://doi.org/10.18632/oncotarget.15432

    Article  PubMed  PubMed Central  Google Scholar 

  25. Bi KH, Jiang GS (2006) Relationship between cytokines and leukocytosis in patients with APL induced by all-trans retinoic acid or arsenic trioxide [J]. Cell Mol Immunol 3(6):421–427. https://doi.org/10.1016/j.cellimm.2007.01.008

    Article  CAS  PubMed  Google Scholar 

  26. Jin B, Hou KZ, Liu YP, Yu P (2006) Leukocytosis and retinoic acid syndrome in patients with acute promyelocytic leukaemia treated with arsenic trioxide [J]. Chin Med Sci J 21(3):171–174. https://doi.org/10.1007/PL00008489

    Article  CAS  PubMed  Google Scholar 

  27. Sanz MA, Montesinos P (2014) How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukaemia [J]. Blood 123(18):2777–2782. https://doi.org/10.1182/blood-2013-10-512640

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank all members of the study team, the patients and their families.

Funding

This work was supported by the First Affiliated Hospital of Harbin Medical University Foundation of China (No. 2024B06).

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  1. Yujuan Gao and Yuanyuan Xi contributed equally to the manuscript. They should be regarded as the co-first authors.

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  1. The First Affiliated Hospital of Harbin Medical University, Long Jiang Road, Harbin, 150007, Heilongjiang Province, China

    Yujuan Gao, Yuanyuan Xi, Wenqi Chen, Yanfen Meng & Yanhua Su

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Contributions

All authors contributed to the study's conception and design. Yujuan Gao and Yuanyuan Xi conceived and designed the study. Yuanyuan Xi, Wenqi Chen, and Yanfen Meng performed the data acquisition, analyses, and interpretation. Yuanyuan Xi drafted the manuscript. Yujuan Gao and Yanhua Su critically revised the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Yanhua Su.

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Gao, Y., Xi, Y., Chen, W. et al. Early predictor for differentiation syndrome in newly diagnosed acute promyelocytic leukaemia patients treated with single-agent arsenic trioxide. Ann Hematol (2024). https://doi.org/10.1007/s00277-024-05776-y

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