Leucocytosis during induction therapy with all-trans-retinoic acid and arsenic trioxide in acute promyelocytic leukaemia predicts differentiation syndrome and treatment-related complications.
ATO
ATRA
acute promyelocytic leukaemia
leucocytosis
Journal
British journal of haematology
ISSN: 1365-2141
Titre abrégé: Br J Haematol
Pays: England
ID NLM: 0372544
Informations de publication
Date de publication:
14 Sep 2024
14 Sep 2024
Historique:
received:
11
07
2024
accepted:
27
08
2024
medline:
14
9
2024
pubmed:
14
9
2024
entrez:
14
9
2024
Statut:
aheadofprint
Résumé
All-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) represent the standard of care for low-intermediate risk acute promyelocytic leukaemia (APL). Leucocytosis during induction with ATRA-ATO represents a common complication with an incidence of up to 60%. To identify predictive factors for this complication, we studied a cohort of 65 low-intermediate risk APL patients treated with ATRA-ATO in three highly specialized Italian centres. Overall, 39/65 (60%) patients developed leucocytosis, with a peak in leucocyte count being most frequent in the second week from diagnosis. All cases were successfully managed with hydroxyurea. Predictive factors for leucocytosis in univariate analysis were lower platelet counts (odds ratio [OR] 0.98, 0.97-1.00, p = 0.018), lower fibrinogen levels (OR 0.36, 0.17-0.66, p = 0.003), higher bone marrow blast infiltration (OR 1.03, 1.01-1.07, p = 0.021) and CD117 expression by flow (OR 1.04, 1.01-1.08, p = 0.012). Multivariate analysis confirmed lower levels of fibrinogen at diagnosis as the strongest predictive factor for the development of leucocytosis (OR 0.36, 0.15-0.72, p = 0.009). Differentiation syndrome (DS) occurred only in patients developing leucocytosis showing a strict correlation with rising leucocytes counts (16/39 vs. 0/26, p < 0.001). In addition, other treatment-related complications including QTc prolongation, cardiac events, liver, and haematological toxicities were significantly more frequent in patients experiencing leucocytosis (22/39 vs. 3/26, p < 0.001). In conclusion, APL patients undergoing ATRA-ATO therapy with lower fibrinogen levels and platelet counts at diagnosis and with a massive bone marrow blast infiltrate should be carefully monitored for the development of leucocytosis during induction. DS and other treatment-related complications seem to occur almost exclusively in patients developing leucocytosis, who should necessarily receive DS prophylaxis and more intensive monitoring and supportive therapy to prevent treatment complications.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024 British Society for Haematology and John Wiley & Sons Ltd.
Références
Lo‐Coco F, Cicconi L, Voso MT. Progress and criticalities in the management of acute promyelocytic leukemia. Oncotarget. 2017;8:992221.
Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, et al. Leukemia long‐term results of all‐trans retinoic acid and arsenic trioxide in non‐high‐risk acute promyelocytic leukemia: update of the APL0406 Italian‐German randomized trial. Leukemia. 2020;34(3):914–918.
Russell N, Burnett A, Hills R, Betteridge S, Dennis M, Jovanovic J, et al. Attenuated arsenic trioxide plus ATRA therapy for newly diagnosed and relapsed APL: long‐term follow‐up of the AML17 trial. Blood. 2018;132(13):1452–1454.
Sanz MA, Fenaux P, Tallman MS, Estey EH, Löwenberg B, Naoe T, et al. Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood. 2019;133(15):1630–1643.
Wang F, Jia J, Wang J, Zhao T, Jiang Q, Jiang H, et al. The kinetics of white blood cell and the predictive factors of leucocytosis under oral or intravenous arsenic as the first‐line treatment for acute promyelocytic leukemia. Leuk Res. 2017;61:84–88.
Lo‐Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111–121.
Lo‐Coco F, Ammatuna E. The biology of acute promyelocytic leukemia and its impact on diagnosis and treatment. Hematol Am Soc Hematol Educ Program. 2006;2006:156–161.
Sanz MA, Lo Coco F, Martín G, Avvisati G, Rayòn C, Barbui T, et al. 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. 2000;96(4):1247–1253.
Frankel SR, Eardley A, Lauwers G, Weiss M, Warrell RP. The “retinoic acid syndrome” in acute promyelocytic leukemia. Ann Intern Med. 1992;117:292–296.
Montesinos P, Bergua JM, Vellenga E, Rayon C, Parody R, de la Serna J, et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all‐trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood. 2009;113:775–783.
Mantha S, Tallman MS, Soff GA. What's new in the pathogenesis of the coagulopathy in acute promyelocytic leukemia? Curr Opin Hematol. 2016;23(2):121–126.
Falanga A, Rickles FR. Pathogenesis and management of the bleeding diathesis in acute promyelocytic leukaemia. Best Pract Res Clin Haematol. 2003;16:463–482.
Mantha S, Goldman DA, Devlin SM, Lee JW, Zannino D, Collins M, et al. Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era. Blood. 2017;129(13):1763–1767.
Abla O, Ribeiro RC, Testi AM, Montesinos P, Creutzig U, Sung L, et al. Predictors of thrombohemorrhagic early death in children and adolescents with t(15;17)‐positive acute promyelocytic leukemia treated with ATRA and chemotherapy. Ann Hematol. 2017;96(9):1449–1456.
Yoon JH, Kim HJ, Min GJ, Park SS, Jeon YW, Lee SE, et al. Progressive hyperleukocytosis is a relevant predictive marker for differentiation syndrome, early death, and subsequent relapse in acute promyelocytic leukemia. Sci Rep. 2019;9:11935.
Sanz MA, Montesinos P. How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood. 2014;123(18):2777–2782.