A Life-Threatening Complication During the Fourth Pregnancy Due to Acute Promyelocytic Leukemia: A Case Report.

Incidents of leukemia in pregnancy are infrequent with only one case found from 75,000 to 100,000 pregnancies. The pathophysiological mechanism of leukemia during pregnancy is still unclear. Leukemia which occurs in pregnancy is usually acute and predominantly the myeloid type.A 35-year-old woman in her fourth pregnancy with a gestational age of 38-39 weeks, came to the emergency department (ED) with complaints of contractions since 4.5 hours before admission. The contraction was not accompanied by discharge, mucus, or blood, and fetal movements was still active. She denied complaints of fever, nausea, vomiting, dizziness, shortness of breath, weakness, fatigue, lethargy, and bleeding. Physical examination results, both palpebral conjunctiva were pale. Laboratory examination results of a complete blood count, white blood cell count were 2,930/uL, hemoglobin 8.3 g/dL, Hct 24.10%, erythrocytes 2.78x106/µL, platelets 62,000/µL. Bone Marrow Aspiration (BMA) revealed Acute Promyelocytic Leukemia (APL).APL is a subtype of Acute Myelogenous Leukemia (AML). Persistent fatigue, recurrent infections, and bleeding are common manifestations of APL. The diagnosis of APL is made by bone marrow aspiration examination, and it is safe for pregnancy. APL therapy in pregnancy uses All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO). ATRA and ATO are highly teratogenic, but recent studies have reported no fetal abnormalities.Accuracy and speed in diagnosing and initiating APL therapy in pregnancy are essential in preventing serious complications.

The influence of hospital volume and physician volume on early mortality in acute promyelocytic leukemia patients.

Acute promyelocytic leukemia (APL) is a highly curable hematologic malignancy in the era of all-trans retinoic acid (ATRA) combination treatment. However, only a modest change in early mortality rate has been observed despite the wide availability of ATRA. In addition to the clinical characteristics of APL patients, studies on the hospital volume-outcome relationship and the physician volume-outcome relationship remained limited. We aim to evaluate the association between hospital and physician volume and the early mortality rate among APL patients. The patients were collected from Taiwan's National Health Insurance Research Database (NHIRD). Early mortality is defined as death within 30 days of diagnosis. Patients were categorized into four groups according to individual cumulative hospital and physician volume. The risk of all-cause mortality in APL patients with different cumulative volume groups was compared using a Cox proportional hazard model. The probability of overall survival was estimated using the Kaplan-Meier method. All 741 patients were divided into four quartile volume groups. In the multivariate analysis, only physician volume was significantly associated with early mortality rate. The physician volume of the highest quartile was a protective factor for early mortality compared with the physician volume of the lowest quartile (HR 0.10, 95% CI 0.02-0.65). Hospital characteristics were not associated with early mortality. In the sensitivity analyses, the results remained consistent using two other different definitions of early mortality. Higher physician volume was independently associated with lower early mortality, while hospital volume was not. Enhancing the clinical expertise of low-volume physicians may ensure better outcomes.

Dysregulated hemostasis in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is associated with a high incidence of early death, which occurs within 30 days of diagnosis. The major cause of early death in APL is severe bleeding, particularly intracranial bleeding. Although APL is known to be associated with activation of coagulation, hyperfibrinolysis, and thrombocytopenia, the precise mechanisms that cause bleeding have not yet been elucidated. I propose that a combination of four pathways may contribute to bleeding in APL: (1) tissue factor, (2) the urokinase plasminogen activator/urokinase plasminogen activator receptor, (3) the annexin A2/S100A100/tissue plasminogen activator, and (4) the podoplanin/C-type lectin-like receptor 2. A better understanding of these pathways will identify new biomarkers to determine which APL patients are at high risk of bleeding and allow the development of new treatments for APL-associated bleeding.

Disseminated intravascular coagulation score evolution in 48 h predicts early death in acute promyelocytic leukemia patients.

INTRODUCTION: Early death (ED) is the unsolved issue of acute promyelocytic leukemia (APL). The disseminated intravascular coagulation (DIC) score has been proposed as a marker of bleeding and death in APL; whether its temporal evolution predicts outcomes in APL is unknown. We evaluated whether an increasing score 48 h after diagnosis associates with ED. METHODS: Retrospective, single-center study, including patients with newly diagnosed APL between 2000 and 2023, treated with all-transretinoic acid (ATRA) plus anthracycline or arsenic trioxide (ATO). "DIC score worsening" was defined as ≥1 point increase in the score after 48 h, and ED as death within 30 days of diagnosis. RESULTS: Eighty-six patients were included, with median age of 46 years (17-82). ED patients (26.7%) more frequently had age >60 years and worsening DIC score after 48 h. These were also the only predictors of ED identified in both univariate and multivariate (OR 4.18, p = .011; OR 7.8, p = .005, respectively) logistic regression analysis. CONCLUSION: This is the first study on DIC score evolution in APL-a worsening DIC score 48 h after diagnosis is a strong independent predictive factor of ED. We propose a reduction of the DIC score from diagnosis as a new treatment goal in APL care.

Disseminated Intravascular Coagulation in Acute Promyelocytic Leukemia Patients: A Retrospective Analysis of Outcomes and Healthcare Burden in US Hospitals

Objective: Acute promyelocytic leukemia (APL) is associated with an elevated risk of developing disseminated intravascular coagulation (DIC). The purpose of this study was to assess the outcomes of hospitalizations related to DIC in APL and their impact on healthcare. Materials and Methods: This study entailed a cross-sectional and retrospective analysis of the US National Inpatient Sample database. We identified adults with APL and categorized them into groups of patients with and without DIC. Our focus areas included in-hospital mortality, length of stay, charges, and complications associated with DIC. Unadjusted odds ratios/coefficients were computed in univariate analysis, followed by adjusted odds ratios (aOR)/coefficients from multivariate analysis that accounted for confounding factors. Results: Our analysis revealed that APL patients with DIC had a substantially higher aOR for mortality (aOR: 6.68, 95% confidence interval [CI]: 4.76-9.37, p<0.001) and a prolonged length of stay (coefficient: 10.28 days, 95% CI: 8.48-12.09, p<0.001) accompanied by notably elevated total hospital charges (coefficient: $215,512 [95% CI: 177,368-253,656], p<0.001), thereby emphasizing the reality of extended medical care and economic burden. The presence of DIC was associated with increased odds of sepsis, vasopressor support, pneumonia, acute respiratory failure, intubation/mechanical ventilation, and acute kidney injury, reflecting heightened vulnerability to these complications. Patients with DIC demonstrated significantly higher odds ratios for major bleeding, intracranial hemorrhage, gastrointestinal bleeding, red blood cell transfusion, platelet transfusion, fresh frozen plasma transfusion, and cryoprecipitate transfusion, highlighting the pronounced hematological risks posed by DIC. Conclusion: This study has revealed the significant associations between DIC in APL and various outcomes, underscoring the clinical and economic implications of these conditions. The hematological risks further increase patients' vulnerability to bleeding events and the need for transfusions.

Acute kidney injury in acute promyelocytic leukemia: a possible adverse effect of high dose arsenic trioxide in obese patients.

Arsenic trioxide (ATO)-based regimens are standard in acute promyelocytic leukemia (APL). ATO-related nephrotoxicity has not been reported. We reviewed APL patients treated with ATO to identify cases of acute kidney injury (AKI). Clinically significant cases were characterized. Multivariate analysis was performed to identify predictors of idiopathic, clinically significant AKI. One hundred and eight patients were included. ATO dose was 0.15 mg/kg/day using actual body weight with no dose cap. Thirty-one (28.7%) AKI cases were identified, 10 (32.3%) clinically significant. Six were idiopathic; five required dialysis. The proportion with significant, idiopathic AKI was 15.8% in patients receiving >15mg ATO versus 0% in those receiving ≤15mg (p = 0.001). On multivariate analysis, only ATO dose was a significant predictor of clinically significant AKI (odds ratio of 1.91, 95%CI, 1.19-3.07, p = 0.007). High-dose ATO may be associated with significant nephrotoxicity. We recommend that ATO dose be capped at 15 mg to minimize toxicity for this curable disease.

How to avoid early mortality in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL), a phenotypically and genotypically unique subtype of acute myeloid leukemia, has seen unprecedented advances in its management since the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide. However, the phenomenal pharmacologic conversion of this once highly fatal disease to one with a long-term survival exceeding 90% among patients who survive induction remains impaired by the significant incidence of early death (ED) reaching 30% in some real-world studies. The key driver for ED in APL is catastrophic hemorrhage with a proclivity for cranial sites. Most EDs in APL are currently considered preventable. Here, we discuss the concept of early death in APL and its characteristics. Importantly, we outline implementable strategies to reduce the incidence of ED. Early recognition of APL underpins these preventive measures as significant delays in the diagnosis increase the likelihood of ED. While early administration of ATRA is often taught to all hematology trainees, this lifesaving intervention is only possible if providers, including those in emergency departments and urgent/immediate care settings, are trained to have a high index of suspicion and competence to recognize the morphologic and clinical characteristics of the disease. Other proposed strategies tackle the complications that can be present at diagnosis or arise during induction therapy and address the issues of expert consultation and protocol adherence in the management of these patients. While some of these measures appear intuitive and others aspirational, widespread adoption could bring about an era of cure for almost every patient with APL.

[Acute promyelocytic leukemia with asymptomatic cerebral hemorrhage].

A 43-year-old man presenting with oral bleeding was diagnosed with acute promyelocytic leukemia (APL). Induction chemotherapy consisting of all-trans retinoic acid and idarubicin was initiated, and disseminated intravascular coagulation (DIC) was treated with fresh frozen plasma and recombinant thrombomodulin infusions. The patient was free from neurological symptoms throughout the clinical course. However, cerebral hemorrhagic lesions were detected incidentally on magnetic resonance imaging performed to screen for leukemic central nervous system invasion at 2 weeks after treatment initiation. Imaging findings suggested subacute or later-phase cerebral hemorrhage. Platelet transfusions and other supportive care was provided. Serial imaging evaluations confirmed reduction of the hemorrhagic lesions. Hematological remission was achieved after induction chemotherapy, and no symptoms due to cerebral hemorrhage developed during the subsequent consolidation therapy. As patients with APL characteristically experience hemorrhagic events due to bleeding tendency caused by DIC, physicians should be aware of the possibility of asymptomatic cerebral hemorrhage in these patients.

Emergence of acute promyelocytic leukemia in a patient with granulomatosis with polyangiitis during treatment with cyclophosphamide: a rare case report.

Granulomatosis with polyangiitis (GPA) is a rare autoimmune disease that affects multiple organs and causes inflammation, necrosis, and vasculitis in small blood vessels. Treatment for GPA involves achieving and maintaining remission. In recent studies, cyclophosphamide-based regimens have been linked to comorbidity hazards, including an increased risk of malignancies, especially hematological ones. Acute myeloid leukemia is the main hematologic malignancy that can complicate GPA. In this context, we report the case of a middle-aged woman with GPA who developed acute promyelocytic leukemia (APL) during maintenance with cyclophosphamide. She was treated with all-trans retinoic acid at 50 mg/day and arsenic trioxide at 10 mg/day, along with steroids. This case highlights the unique emergence of APL in a GPA patient during cyclophosphamide therapy. A single case has previously been reported on the development of APL in a patient with GPA while using azathioprine monotherapy for 2 years.

[Correlation between D-Dimer/Fibrinogen Ratio and Bleeding in Patients with Newly Diagnosed Acute Promyelocytic Leukemia].

OBJECTIVE: To further explore the better indicators for predicting the degree of bleeding associated with newly diagnosed acute promyelocytic leukemia (APL). METHODS: A total of 131 patients with newly diagnosed APL were classified according to WHO bleeding scales before treatment and divided into two groups: scales 0, 1 and 2 were included in no severe bleeding group, scales 3 and 4 were included in severe bleeding group. The information of the patients were collected, including sex, age, hemoglobin (Hb), white blood cell (WBC) count and platelet (PLT) count, peripheral blood lymphocyte percentage (LYMPH%), peripheral blood monocyte percentage (MONO%), percentage of leukemic cells in pripheral blood and bone marrow, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB) levels, D-dimer (D-D), D-dimer/fibrinogen ratio (DFR). RESULTS: Among 131 patients, 110 were classified as no severe bleeding, and 21 were severe bleeding. The results of univariate analysis showed that patients with severe bleeding had significantly higher percentage of leukemic cells in pripheral blood, WBC, D-D, and DFR, as well as longer PT and lower LYMPH%, compared to those with no severe bleeding. Multivariate analysis revealed that DFR (OR =1.054, 95%CI : 1.024-1.084, P < 0.001) and percentage of peripheral blood leukemic cells (OR=1.026, 95%CI: 1.002-1.051, P =0.033) were independent risk factors for severe bleeding. The area under ROC curve (AUC) of peripheral blood leukemic cells, D-D and DFR were 0.748, 0.736 and 0.809, respectively. There was no statistical difference between the peripheral blood leukemic cells and D-D in diagnostic efficacy (P =0.8708). Compared with D-D, DFR had a higher predictive value (P =0.0302). The optimal cut-off value of DFR was 16.50, with a sensitivity of 90.5% and a specificity of 70.0%. CONCLUSION: DFR has a significant advantage in predicting the degree of bleeding associated with newly diagnosed APL. The greater the DFR value, the heavier the degree of bleeding. The risk of severe or fatal bleeding increases when DFR is greater than 16.50.

Factors associated with thrombo-hemorrhagic deaths in patients with Acute Promyelocytic leukemia treated with Arsenic Trioxide and all-trans retinoic acid.

Acute Promyelocytic Leukemia (APL) is associated with excellent long-term outcomes. However, early mortality due to coagulopathy remains a challenge. In this study we examined the bleeding and thrombotic manifestations, as well as incidence of Early Death secondary to thrombosis/hemorrhage (ED-TH) in patients with APL. Early death (ED) was defined as death occurring within 30 days of induction therapy. Two-hundred forty-eight patients were included in the study. Overall, 57 patients had evidence of a major bleed/thrombosis at presentation or during induction therapy, including 44 patients with a major bleed, 8 patients with thrombosis and 5 patients with both evidence of thrombosis and a major bleed. Forty patients (16.1%) had ED, of which 21 had ED-TH. The cumulative incidence of death due to thrombo-hemorrhagic complications at 30 days was 8.4%. On univariate analysis, increasing Prothrombin time (PT)(p-<0.001), white blood cell count (p < 0.001) and activated Partial thromboplastin time (aPTT) (p < 0.001) were statistically significantly associated with increased risk of ED-TH. However, on multivariate analysis, only increasing PT (p-0.025) and aPTT (p-0.041) were significantly associated with increased risk of ED-TH.

Could Acute Myeloid Leukemia Have Presented Even Worse? "Uncommon Cause of Concurrently Multivessel Thrombosis". / A Leucemia Mieloide Aguda Poderia ter se Apresentado Ainda Pior? "Causa Incomum de Trombose Multiarterial Concomitante".

Acute promyelocytic leukemia (APL) is a subgroup of acute myeloid leukemia (AML). Although it is known that hemorrhagic complications are common, thrombotic complications are not as rare as thought. However, myocardial infarction and ischemic stroke incidence are very rare during AML. Here, we present the astonishing case of APL diagnosed with pancytopenia in its presentation with acute myocardial infarction and ischemic stroke.

A leucemia promielocítica aguda (LPA) é um subgrupo da leucemia mieloide aguda (LMA). Embora se saiba que as complicações hemorrágicas são comuns, as complicações trombóticas não são tão raras quanto se pensa. No entanto, infarto do miocárdio e incidência de acidente vascular cerebral isquêmico são muito raros durante a LMA. Aqui, apresentamos o caso surpreendente de LPA diagnosticada com pancitopenia em sua apresentação com infarto agudo do miocárdio e acidente vascular cerebral isquêmico.

Influence of cytokines on early death and coagulopathy in newly diagnosed patients with acute promyelocytic leukemia.

Introduction: Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) with a better prognosis. But early death (ED) rate remains high. APL patients are simultaneously accompanied by coagulopathy and hyperinflammation at the onset. It is not known what effects cytokines have on ED and coagulopathy in these patients. Therefore, the purposes of this study are to explore the clinical differences between APL and other types of AML, the link between cytokines and coagulopathy in newly diagnosed APL, and their roles in the ED for APL. Methods: This study retrospectively collected the information of 496 adult patients with AML (age ≥14 years at admission) newly diagnosed in the First People's Hospital of Yunnan Province between January 2017 to February 2022, including 115 APL patients. The difference of clinical manifestations between two groups [APL and AML (non-APL)] was statistically analyzed. Then, the factors affecting ED in APL patients were screened, and the possible pathways of their influence on ED were further analyzed. Results: The results indicate APL at the onset have a younger age and higher incidence of ED and DIC than other types of AML. Intracranial hemorrhage (ICH), age, and PLT count are found to be independent factors for ED in newly APL, among which ICH is the main cause of ED, accounting for 61.54% (8/13). The levels of cytokines in newly APL are generally higher than that in AML (non-APL), and those in the group of ED for APL were widely more than the control group. IL-17A and TNF-ß are directly related to the ED in newly APL, especially IL-17A, which also affects ICH in these patients. Moreover, the increase of IL-17A and TNF-ß cause the prolongation of PT in APL patients, which reflected the exogenous coagulation pathway. However, they have no effect on APTT prolongation and FIB reduction. Thus, it is speculated that IL-17A leads to early cerebral hemorrhage death in newly APL by inducing tissue factor (TF) overexpression to initiate exogenous coagulation and further leading to excessive depletion of clotting factors and prolongation of PT. Conclusions: In conclusion, compared with other types of AML, APL patients have a younger age of onset and high inflammatory state, and are more likely to develop into DIC and die early. Age, and PLT count at diagnosis are independent factors for ED of APL, especially ICH. IL-17A is confirmed to be an independent risk factor for ED and ICH of newly APL. Hence, IL-17A may serve as a predictor of ED in newly diagnosed APL patients, and controlling its expression probably reduce ED in these patients.