Early death rates remain high in high-risk APL: update from the Swedish Acute Leukemia Registry 1997–2013

Lehmann, Sören; Deneberg, Stefan; Antunović, Petar; Rangert-Derolf, Åsa; Garelius, Hege; Lazarevic, Vladimir; Myhr‐Eriksson, Kristina; Möllgård, Lars; Uggla, Bertil; Wåhlin, Anders; Wennström, Lovisa; Höglund, Martin; Juliusson, Gunnar

doi:10.1038/leu.2017.71

Cited by 50 publications

(57 citation statements)

References 9 publications

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“…5,6,22,23 In contrast, EDRs of 17 to 35% have been reported in non-clinical trial subjects with APL treated with ATRA and chemotherapy. [24][25][26][27][28] We found that the overall EDR in our population-based national APL cohort was 18% without signifi- are strikingly similar to our results and those reported in the Netherlands. 29 In contrast, a US SEER-based cohort had a median age of 44 years and an annual incidence of 0.23 per 100 000, 26 while the mean age at diagnosis was 47.9 years and the age-adjusted incidence rate was 0.083 per 100 000 in a Canadian population-based cohort.…”

Section: Discussionsupporting

confidence: 91%

“…Early death rates in APL treated with the ATRA‐ATO combination in clinical trials have been reported to range between 2% and 9% . In contrast, EDRs of 17 to 35% have been reported in non‐clinical trial subjects with APL treated with ATRA and chemotherapy . We found that the overall EDR in our population‐based national APL cohort was 18% without significant variation throughout the study period.…”

Section: Discussionmentioning

confidence: 51%

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Addressing the room for improvement in management of acute promyelocytic leukemia

Nørgaard

Friis

Kristensen

et al. 2019

European J of Haematology

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Acute promyelocytic leukemia (APL) is highly curable. To achieve high cure rates, targeted therapy with retinoic acid (ATRA) must be started promptly at time of suspected diagnosis. Early death rates (EDRs, ≤30 days from diagnosis) differ markedly in patients treated on clinical trials compared to the general population. Objectives and methods: We used the comprehensive Danish National AcuteLeukemia Registry (DNLR) to investigate the incidence, treatment, EDR, and longterm clinical outcome in APL between 2000 and 2014.Results: Twenty-two of 41 deaths occurring in 122 APL patients were EDs which were primarily caused by intracranial hemorrhage, disseminated intravascular coagulation (DIC), sepsis, and multiorgan failure. The overall EDR was 18.0%, whereas clinical trial participants had an EDR of 6.7%. Fifteen patients recruited to the NCRI AML17 APL trial from 2010 to 2013 were younger and had decreased mortality (HR 0.18, CI 0.04-0.86, P = 0.02) compared to contemporarily treated patients (n = 15) not recruited to a clinical trial. Performance status, leukemia origin, and Sanz-score were independent prognostic variables. Conclusions:The very low EDR for on-trial patients is not observed in the general cohort of APL patients. Diagnostic awareness emerges as the greatest clinical challenge in management of APL. K E Y W O R D Sacute promyelocytic leukemia, diagnostic awareness, early death, prognosis

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 51%

Addressing the room for improvement in management of acute promyelocytic leukemia

Nørgaard

Friis

Kristensen

et al. 2019

European J of Haematology

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“…Similarly, elderly patients have been mostly investigated after the introduction of ATO in a scattered and retrospective fashion [43,52]. Older patients with APL (aged >70 years) treated with chemotherapy are more prone to develop toxicities and experience up to 60% early death rates [53], making the milder toxicity profile of ATO combinations attractive to treat these fragile patients. A large retrospective study analyzed data from 475 patients (median age 73.4 years, range 70-89 years) derived from different multinational registries.…”

Section: Special Situations In Aplmentioning

confidence: 99%

When Poisons Cure: The Case of Arsenic in Acute Promyelocytic Leukemia

Gurnari¹,

Bellis²,

Divona³

et al. 2019

Chemotherapy

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Arsenic has been known for centuries for its double-edged potential: a poison and at the same time a therapeutic agent. The name "arsenikon," meaning "potent," speaks itself for the pharmaceutical properties of this compound, questioned and analyzed for at least 2000 years. In the last decades, acute promyelocytic leukemia (APL) has evolved from a highly fatal to a curable disease, due to the use of all-transretinoic acid and, more recently, arsenic trioxide combinations. The success of these entirely chemo-free regimens increased the awareness of APL and reduced the prevalence of early deaths, which was an impending issue in this disease. Further improvements are expected with the next use of oral arsenic formulations, which will allow a complete outpatient approach, at least in the post-induction settings, further improving patients' quality of life. The wide use of standardized approaches in APL will also help unravel long-standing open questions, including the pathogenesis, prevention, and treatment of the differentiation syndrome and of short-term organ toxicities. In the long term, the study of survivorship issues, such as fertility and organ-related and psychological damages, in the increasing number of survivors will help further improve their life after APL.

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“…Acute promyelocytic leukaemia (APL) is a disease characterized by catastrophic bleeding. Treatment with all- trans retinoic acid (ATRA) or arsenic trioxide (ATO) leads to complete remission in up to 90% of patients [1] , [2] , [3] . However, bleeding events remain a leading cause of early death (25–29% incidence rate) in APL and account for 40–65% of the mortality of this disease [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Endothelial damage and a thin intercellular fibrin network promote haemorrhage in acute promyelocytic leukaemia

Wang

Zhou

et al. 2020

EBioMedicine

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Background The role of vascular endothelium in acute promyelocytic leukaemia (APL) remains unknown. We aimed to investigate the mechanisms by which APL cells interact with endothelial cells (ECs) and to further explore how the endothelium affects bleeding as well as therapeutic interventions. Method APL cells and an original APL cell line, NB4 cells, were used for experiments. The effects of leukaemic cells on ECs were analyzed in vitro and in vivo. Moreover, the endothelial barrier function and procoagulant activity were detected. An APL mouse model was established for in vivo studies. Findings APL cells interacted with ECs via ICAM-1 and VCAM-1 receptors to disrupt endothelial integrity. This binding activated MLCK signaling, resulting in the trans-endothelial passage of protein and red blood cells (RBCs). Combined treatment with asiatic acid or anti-adhesion receptor antibody inhibited the response of ECs to APL cells, thereby preventing APL-associated haemorrhage in vitro and in vivo. Activated ECs exhibited a procoagulant phenotype after phosphatidylserine exposure. Plasma from APL patients formed a thin fibrin network between procoagulant ECs, and this intercellular fibrin decreased the passage of albumin and RBCs. Ex vivo addition of fibrinogen further enhanced this barrier function in a dose-dependent manner. Interpretation Endothelial damage induced by leukaemic cell adherence promotes haemorrhaging in APL. Stabilization of ECs, decreasing adhesion receptor expression, and increasing fibrinogen transfusion levels may be a new therapeutic avenue to alleviate this fatal bleeding complication. Funding National Science Foundation of China (81670128, 81873433).

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Early death rates remain high in high-risk APL: update from the Swedish Acute Leukemia Registry 1997–2013

Cited by 50 publications

References 9 publications

Addressing the room for improvement in management of acute promyelocytic leukemia

Addressing the room for improvement in management of acute promyelocytic leukemia

When Poisons Cure: The Case of Arsenic in Acute Promyelocytic Leukemia

Endothelial damage and a thin intercellular fibrin network promote haemorrhage in acute promyelocytic leukaemia

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