Hemorrhagic stroke in acute promyelocytic leukemia

Introduction

Acute promyelocytic leukemia (APL) is a unique type of acute myeloid leukemia, having as a pathognomonic sign the presence of atypical promyelocytes and the translocation between chromosomes 15 and 17, resulting in the PML-RARA fusion gene⁽¹⁾. This genetic anomaly results in special clinical characteristics, mainly involving coagulation disorders⁽²⁾.

Hemorrhagic diathesis represents a fundamental characteristic of acute promyelocytic leukemia⁽³⁾, since the first description in the literature, but also the most common cause of early death⁽⁴⁾. The most frequent sites of fatal bleeding are cerebral and pulmonary⁽⁵⁾.

Atypical promyelocytes in the peripheral blood are directly involved in the imbalance between fibrinolysis, anticoagulant and procoagulant status⁽⁴⁾. All trans retinoic acid (ATRA) and arsenic trioxide (ATO) induce atypical promyelocytes differentiation and, as a consequence, the improvement of hemorrhagic complications, as well as loss of procoagulant and fibrinolytic properties of the leukemic cells⁽⁴⁾. Also, introducing differentiation agents in the APL treatment significantly increases survival and the complete response rates^(6-9). Delaying ATRA initiation increases the incidence of early hemorrhagic death⁽¹⁰⁾.

Materials and method

We conducted an observational study at the Emerge­ncy University Hospital Bucharest, Romania. The study included all 48 patients diagnosed with APL during the 2006-2024 period. We analyzed the clinical and biological parameters at diagnosis, the treatment modalities, the complications and outcomes. All data were collected from the medical records.

The diagnosis of APL patients was established according to the World Health Organization (WHO) criteria. The diagnosis based on the detection of the PML-RARA fusion gene or the t(15;17) correlated with the morphological aspects and immunophenotype of the atypical promyelocytes in the peripheral blood and bone marrow. The patients were classified based on the PETHEMA criteria, established by the Spanish Cooperative Group⁽¹¹⁾. Those with a white blood cell count (WBC) of 10 x10⁹/L or less were stratified into low-risk or intermediate-risk categories, based on platelet count (PLT>40 x10⁹/L for low-risk; PLT≤40 x10⁹/L for intermediate risk), while those with WBC exceeding 10 x10⁹/L were categorized as high-risk group.

The induction regimen included AIDA (ATRA+ida­ru­bi­cin), ATRA+ATO, ATRA monotherapy and different combinations of ATRA, cytosine arabino­side, idarubicin and/or hydroxyurea. In addition to APL-specific treatment, the patients received platelet concentrates to maintain the PLT levels above 20x10⁹/L, packed red blood cells to sustain hemoglobin levels above 8 g/dl, fresh frozen plasma, and cryoprecipitate to keep fibrinogen above 100 mg/dl.

The statistical analysis was performed using SPSS IBM Statistics version 25 (IBM Corp., Armonk, NY, USA). The categorical variables were expressed as numbers and percentages. The continuous variables were reported as medians. Odds ratio, 95% confidence intervals, and Chi-squared and Fisher’s exact tests were used to characterize the association between categorical variables. Independent Samples Median Test was used to evaluate the difference between the continuous variables.

Results

The study included 48 patients diagnosed with APL, 42 with the hypergranular variant and six patients with the microgranular variant. The age at diagnosis ranged from 18 to 78 years old, with an equal male-to-female ratio.

The most common complications at diagnosis were hemorrhagic (n=35; 72.9%) and infectious (n=13; 27.1%). The predominant hemorrhagic complication was cutaneous (n=23; 47.9%), followed by gum bleeding (n=7; 14.6%), retinal/subconjunctival hemorrhage (n=7; 14.6%), and epistaxis (n=6; 12.5%). One patient experienced an intracerebral hemorrhage due to an arteriovenous malformation rupture. Another patient was the only one with hemoperitoneum.

A quarter of patients (n=12) had disseminated intravascular coagulation (DIC). Those patients had a 5.5 higher risk (95% CI; 0.63-47.75) of associating bleeding at admission.

At diagnosis, most patients presented with pancytopenia. The microgranular form associated with higher counts of atypical promyelocytes in the peripheral blood than the hypergranular form (p=0.023). The morphological aspects of the hypergranular form are illustrated in Figure 1.
 

The patients with hemorrhagic complications at diagnosis presented with higher white blood cells and higher atypical promyelocytes in the peripheral blood compared to those without this complication (Figures 2 and 3). Also, the patients with bleeding presented lower platelets count and hypofibrinogenemia (Figures 4 and 5).
 

Platelets values at diagnosis were also predictive for associating hemorrhages after the induction treatment. In addition, the presence of DIC at diagnosis increased the risk of developing bleeding in the first period of aplasia by 16.72 times (95% CI; 1.85-150.89; p=0.001).

We registered thirteen early deaths within the first 30 days after diagnosis, six of which were caused by cerebral hemorrhage, and one patient presented concomitant pulmonary bleeding.

The time of death for the six patients who developed cerebral hemorrhage was in the first week from the diagnosis. Regarding the sites of bleeding, we observed intraparenchymal hemorrhage complicated with intraventricular hemorrhage (three patients), epidural and subdural (one patient), subarachnoid (one patient), and in the infratentorial and supratentorial regions (one patient).

Table 1 presents a comparison between patients who experienced fatal brain bleeding and those who did not associate this complication. All patients with hemorrhagic stroke presented with bleeding at diagnosis, and four of them (66.7%) had DIC. Association of coagulopathy at diagnosis increased by 5.5 times (95% CI; 1.02-29.64; p=0.031) the risk of hemorrhagic death. We observed statistically significant differences in the presence of DIC and LDH values between patients with hemorrhagic stroke and those who did not associate this complication.
 

Discussion

Hemorrhagic complications, both at diagnosis and during the follow-up, DIC and early death are the main challenges in the management of APL patients. The dominant feature of APL is the significant hemorrhagic diathesis, initially attributed to fibrinolysis⁽¹²⁾.

In our study, almost three quarters of the patients presented with bleeding at admission, while half developed hemorrhagic complications during follow-up.

The mechanisms underlying hemorrhages in APL remain incompletely understood. Several contributing factors have been identified. A significant factor is the consumption of coagulation factors, driven by elevated tissue factor activity. Additionally, the excessive generation of plasmin, induced by the activation of annexin A2/S100 complexes along with tissue plasminogen activator and urokinase/urokinase receptor complexes, plays a critical role. Another key mechanism involves the depletion of platelets due to the interaction between podoplanin and C-type lectin-like receptor-2 (CLEC-2) on platelets⁽¹³⁾.

The patients in our study who presented with bleeding had higher WBC and atypical promyelocytes in the peripheral blood, as well as lower platelet counts and hypofibrinogenemia. This emphasizes the involvement of leukemic cells, platelets and fibrinogen in the pathogenesis of hemorrhagic complications in APL.

In numerous reports, the predominant site of bleeding was cerebral^(14-17). This elevated incidence of cerebral hemorrhage can be attributed to heightened annexin II expression on endothelial cells within the cerebral microvasculature compared to those in other regions^(18,19). In our study, all patients with early hemorrhagic death had cerebral bleeding, one of them presenting concomitant pulmonary bleeding.

A study of the PETHEMA group reports that most of hemorrhagic death occurs in the first 10 days from the diagnosis, but fatal bleeding continued until the 23^rd day of induction⁽¹⁶⁾. Our patients with hemorrhagic stroke died in the first week after the diagnosis. Most of them (three patients) had intraparenchymal hemorrhage, which is the most common site described in an extensive study⁽²⁰⁾.

Conclusions

Hemorrhagic death continues to be one of the main causes of induction failure in APL patients. Also, disseminated intravascular coagulation and hemorrhagic diathesis are important challenges we face in clinical practice. Developing a protocol of personalized management, including early initiation of hematologic treatment and, also, aggressive supportive care, especially for patients with a high risk, could improve the outcome and increase even more the survival rate.  

Autori pentru corespondenţă: Andreea Spînu E-mail: andreeaspinu09@gmail.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

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