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Introduction
Acute promyelocytic leukemia (APL) is a distinct category of acute myeloid leukemia (AML-M3 according to the FAB classification), characterized by a blockage of granulopoiesis at the promyelocyte stage, caused by the chromosomal translocation t(15;17) that results in the PML::RARA fusion gene(1). It accounts for 5% to 20% of the acute myeloid leukemia (AML) cases among adult patients, with a median age of 47 years old and a slight male predominance(2).
The onset is characterized by symptoms that are secondary to pancytopenia or to the associated coagulopathy (characteristically disseminated intravascular coagulation), which can turn it into a hematological emergency(3).
Based on morphological examination, two APL forms are distinguished: hypergranular or classic (75% of cases, promyelocytes with intensely granular cytoplasm and multiple Auer bodies) and microgranular or variant (25% of cases, promyelocytes with hypogranular cytoplasm, rare Auer bodies and bilobed nucleus)(3).
According to the PETHEMA working group, three risk categories have been identified, depending on the leukocyte (WBC) and platelet (PLT) counts at diagnosis: low risk (WBC ≤10,000/µL; PLT >40,000/µL), intermediate risk (WBC ≤10,000/µL; PLT ≥40,000/µL) and high risk (WBC >10,000/ µL)(3).
According to both clinical studies and case series publications, the evolution of APL patients is contrastly marked by either early mortality or good long-term survival. Early mortality (defined as death within the first 30 days after diagnosis) is most often caused by hemorrhagic complications (e.g., intracranial hemorrhage), but sepsis or complications of the induction therapy such as differentiation syndrome or intraparenchymal hemorrhage (e.g., diffuse alveolar hemorrhage) are also involved(2). Long-term survival is mainly due to prompt treatment with a differentiation agent (all-trans retinoic acid – ATRA) from the moment of suspected diagnosis, arsenic trioxide (ATO), chemotherapy (cytarabine, idarubicin), or gemtuzumab ozogamicin (GO) being added after obtaining a definitive diagnosis, in accordance with national and international guidelines. Thanks to targeted and supportive therapeutic measures, APL has become the AML subtype with the most favorable prognosis, exhibiting a significant incidence of curability(2-4).
The differentiation syndrome is a life-threatening complication of the treatment with differentiation agents(5). With an incidence of 2% to 30%, it most commonly occurs within the first 7-12 days after initiating the treatment. It is characterized by acute organ injury, most commonly manifesting as fever, weight gain, peripheral edema, hypotension, dyspnea, oliguria, musculoskeletal pain, pleural effusion or, more rarely, pericardial effusion(6,7). It requires prompt therapeutic measures, with discontinuation of the differentiation agent, initiation of corticosteroid therapy, empirical antibiotic therapy and supportive measures.
Case presentation
A 60-year-old hypertensive patient presented to the emergency department with anterior chest pain, fever and chills. Clinical examination revealed: fever (39°C), purpura on both lower limbs, oxygen therapy need (SaO2=94% with O2 via nasal cannula, FiO2 4 L/min) and tachycardia.
The complete blood count indicated leukocytosis (WBC = 20,000/µL) with monocytosis (18,480/µL), macrocytic anemia (Hb = 9.6 g/dl; MCV = 113 fL), and severe thrombocytopenia (PLT = 26,000/µL).
Peripheral blood smear: 82% atypical promyelocytes with bilobed nucleus, moderately granular cytoplasm and rare Auer rods. Interestingly, a few neutrophils with multiple Auer rods were also observed (usually seen after granulocyte maturation induced by the differentiation agent) – Figure 1.
Coagulation studies: prolonged prothrombin time and INR (16.2 s, 1.47, respectively), normal activated partial thromboplastin time (29.9 s) and fibrinogen levels (335 mg/dL).
Imaging on thoraco-abdominal-pelvic CT scan: pericardial fluid accumulation with a thickness of 11 mm, cardiomegaly, hepatomegaly (craniocaudal diameter 20 cm).
Cardiological evaluation: sinus rhythm on electrocardiogram (ECG), heart rate 99 bpm, narrow QRS, PR depression in DII, DIII, aVF, concave 1 mm elevation in DII, DIII, aVF, V5, V6. Echocardiography – left ventricular ejection fraction (LVEF) 60%, pericardium with thin fluid layer, 4 mm lateral in the right cavities. Elevated serum levels of cardiac markers: troponin = 1121 ng/L, NT-proBNP = 3288 pg/mL.
Based on clinical symptoms and morphologic findings, APL was highly suspected. At the same time, acute myopericarditis/acute coronary syndrome represented a cardiologic emergency that required specific treatment (beta-blocker, nitrate, SGLT2 inhibitor, mineralocorticoid receptor antagonist). From the hematologic point of view, it was decided to initiate ATRA treatment (45 mg/m2). There was also an indication for prophylactic anticoagulant treatment, but this was postponed due to thrombocytopenia.
Morphological examination of the bone marrow aspirate revealed the presence of 90% atypical promyelocytes, predominantly with a bilobed nucleus, moderately granular, basophilic cytoplasm, with Auer bodies in some cells.
Multiparametric flow cytometry analysis of bone marrow aspirate described the presence of 59% cells with atypical promyelocyte immunophenotype.
Molecular examination by RT-PCR detected the presence of PML::RARA fusion transcript.
A definitive diagnosis of high-risk APL was established according to WHO 2022 criteria. The previously administered differentiation agent (ATRA) in combination with cytoreduction agent (hydroxyurea), corticosteroid therapy (dexamethasone 8 mg every 12 hours) and cardiovascular treatment was continued, considering also the presence of spontaneous differentiation syndrome.
Forty-eight hours after starting ATRA treatment, the chest pain was alleviated, but the patient experienced dyspnea, polypnea, tachycardia, hypotension, oliguria and weight gain of approximately 3 kg; biologically, slightly progressive leukocytosis, nitrogen retention and troponin with stable values were detected.
CT scan of the brain, chest, abdomen and pelvis showed circumferential pericardial fluid (maximum thickness 15 mm), bilateral pleural fluid, bilateral posterior-basal alveolar-interstitial pulmonary densification and hepatomegaly (Figures 2 and 3).
Thus, the highly suspected differentiation syndrome, which most likely appeared at the time of diagnosis, was confirmed, and it was decided to discontinue ATRA administration, increase the corticosteroid dose to 10 mg dexamethasone every 12 hours and initiate chemotherapy, the combination of cytarabine 100 mg/m2 on days 1-5 and idarubicin 12 mg/m2 on days 2, 4, 6 and 8 being chosen.
However, the short-term evolution was unfavorable, with the exacerbation of respiratory failure, leukocytosis and anemia in the following hours. Corticosteroid therapy was escalated to 10 mg dexamethasone every 8 hours, anticoagulant treatment was associated (prophylactic-dose low-molecular-weight heparin LMWH), and cardiological reevaluation was performed. ECG aspect and troponin value were stable, serum NT-pro BNP displayed increasing values (12,930 pg/mL), echocardiography indicated LVE >55% and pericardial fluid 8 mm. An increase in the diuretic dose and postponement of beta-blocker administration were recommended by cardiologists. Chemotherapy was continued, and ATRA administration was temporarily postponed.
On days 2 and 3 of chemotherapy, respiratory failure symptoms persisted, being associated with progressive leukocytosis, coagulopathy and increased NT-pro BNP values.
Starting on day 4, the patient’s outcome was slowly favorable, both clinically (improvement of dyspnea until its disappearance and discontinuation of oxygen therapy, absence of chest pain, resumption of diuresis) and biologically (remission of leukocytosis, decreasing values of troponin and NT-pro BNP until normalization).
The therapeutic management continued with chemotherapy in combination with supportive measures, including corticosteroid therapy (dexamethasone with slowly decreasing doses) and prophylactic anticoagulant therapy (adjusted to PLT count).
On day 23, the patient presented with unilateral edema of the left calf; a venous Doppler ultrasound was performed, and deep vein thrombosis was detected, for which anticoagulant treatment with LMWH at a therapeutic dose was escalated.
The evolution was favorable with morphological remission after induction and molecular response after consolidation, the latter being maintained up to date.
Discussion and conclusions
Acute promyelocytic leukemia is a particular and heterogeneous hematological neoplasm, being at the same time the only type of acute leukemia with curative potential after induction treatment and a real hematological emergency due to hemorrhagic or thrombotic complications. Hemostasis complications may occur at onset or during disease evolution and treatment administration.
We discussed the case of a patient with no significant personal medical history who was diagnosed with high-risk microgranular APL, following an atypical onset with manifestations suggestive for differentiation syndrome.
Pericardial effusions have been described as manifestations of the differentiation syndrome (originally called “retinoic acid syndrome”), since its first descriptions, along with other cardiac signs, such as QT prolongation(8). Myopericarditis, however, is an extremely rare complication, reported in literature in isolated cases of differentiation syndrome and, most often, fatal(9). It also raises the issue of differential diagnosis with chemotherapy-associated cardiac toxicity(10). In the presented case, this was part of the initial picture, becoming a challenge for the decision on therapeutic conduct.
Given the unfavorable prognosis associated with this case, it was decided to promptly initiate treatment with both supportive and specific hematological therapy (ATRA), which was discontinued after four doses due to the worsening of differentiation syndrome. At this point, chemotherapy with cytarabine was started, followed by idarubicin administration. Although on days 1 and 2 of treatment the clinical and biological status was deteriorated, the subsequent evolution was slowly favorable. However, on day 20, a new complication was detected, this time of a thrombotic nature: deep vein thrombosis of the right calf in a patient undergoing prophylactic anticoagulant treatment with LMWH (administered with dosage adjustments according to PLT count).
In conclusion, acute myopericarditis is a rare complication of acute promyelocytic leukemia, being previously described in a few cases as a component of the differentiation syndrome which, even more rarely, can occur at the disease onset. It represents a challenge for the management, as patients may have a favorable outcome with correct and prompt APL treatment, but at the same time, there is a high risk of serious hemorrhagic and thrombotic complications.
Corresponding author: Patricia-Mihaela Pîrvan E-mail: patricia.pirvan@yahoo.com
Conflict of interest: none declared.
Financial support: none declared.
This work is permanently accessible online free of charge and published under the CC-BY licence.
