The clinical examination was unremarkable, except for pallor and confirmed rectorrhagia, without other active hemorrhages – ECOG 3.

The laboratory tests revealed pancytopenia: moderate leucopenia – white blood cells (WBC) 2,900/mm³, severe normocytic anemia – hemoglobin (HGB) 7 g/dl, medium cell volume 95 fl, and severe thrombocytopenia – platelet count 7,000/mm³. Peripheral blood smear (Figure 1) identified atypical promyelocytes 30%, blasts 1%, neutrophils 2%, lymphocytes 26%, and monocytes 41%. Uric acid and creatinine were slightly increased. Also, aspartate aminotransferase was slightly increased, but viral markers were negative for hepatitis B and C, and for HIV infection. 

The patient presented a decreased fibrinogen level (160 mg/dl), with slightly prolonged prothrombin time (international normalized ratio; PT INR) and normal activated partial thromboplastin time (aPTT).

The bone marrow aspiration revealed 66% atypical promyelocytes: large cells, with irregular nucleus, fine chromatin, some of them with nucleoli, basophilic cytoplasm with multiple granules. They expressed myeloperoxidase. Flowcytometry of bone marrow aspirate showed the presence of 39% precursor cells CD33+ cMPO+ CD117+ CD 34+ CD9+ CD123+ CD45RA+ CD2+/- CD10- CD3- CD7- cCD79a- CD19- CD56+/- CD11b- HLA-DR- and 31% precursor cells CD34+ CD117+ HLA-DR+ CD14- CD300e-/+ CD13- CD33++ CD11b+ CD36+ CD64+ CD4+ CD2+ CD9+. Thus, immunophenotyping showed two cell populations – one with 39% precursor cells of the myeloid lineage with a phenotype comparable to the atypical promyelocyte, and another with 31% precursor cells of the monocytoid lineage.

Fluorescence in situ hybridization identified the presence of t(15;17)(q24;q21) translocation. Molecular biology tests were positive for PML-RARa and for FLT3-ITD, and negative for NPM1.

Based on these findings, we established the positive diagnosis of APL with PML/RARa fusion, and FLT3-ITD positive (according to World Health Organization 2016 criteria), with intermediate risk.

The patient developed perirectal abscess complicated with fistula. We started intravenous broad-spectrum antibiotics, including for anti-anaerobe bacteria. He was also periodically evaluated by the surgeon. The evolution was favorable due to local (conservative) and systemic treatment.

Before the hematological treatment was started, an echocardiography was performed which revealed a left ventricular ejection fraction (LVEF) of 35% and kinetic impairment – akinesis of the apex, two apical thirds of the anterior wall and septum, and the apical third of the lateral wall.

According to the guidelines, we started specific treatment – namely, induction treatment with all-trans retinoic acid (ATRA), 45 mg/m²/day, in two divided doses, and arsenic trioxide (ATO) 0.3 mg/kg/d, days 1-5 in the first week, then two days a week, in weeks 2-8. Along with hematologic treatment, the patient received supportive treatment: transfusions with platelets and packed red blood cells, hemostatic agents, allopurinol, antibiotics and herpes zoster prophylaxis with acyclovir.

After the first two days of treatment with arsenic trioxide, the patient started to have severe anterior chest pain radiating in both arms and jaw, associated with difficulty in breathing and diaphoresis. An electrocardiogram revealed ST-segment elevation in leads V1-V3 (Figure 2). Laboratory analysis showed an increase of troponin-T from 29.6 ng/l initially to 400 ng/l (normal upper limit: 29 ng/l). The echocardiography showed decreased LVEF from 35% (at admission) to 25-30% and extended akinesia. A diagnosis of acute coronary syndrome and dilated cardiomyopathy was established.

The complete blood count showed leukocytosis (WBC 32,800/mm³), severe anemia (HGB 6.4 g/dl) and severe thrombocytopenia (platelet count 9,000/mm³). Coagulation panel revealed decreased fibrinogen (94 mg/dl) and increased prothrombin time of 22.3 seconds, INR 2.

The patient received oxygen, nitroglycerine and transfusion with packed red blood cells, taking into account that the severe anemia could aggravate the pain and the heart condition.

In this situation, the initial management includes the administration of antiplatelet agents and performing a coronary angiography. But, in our patient, neither of those could be accomplished because of the severe thrombocytopenia and coagulopathy. Thus, we completed his cardiology medication with angiotensin-converting enzyme inhibitor, beta-blocker, nitrates and statin. The patient was periodically evaluated by the cardiologist.

We decided to stop the arsenic trioxide administration and to continue the induction treatment with all-trans retinoic acid as a single agent, associated with steroids for the prevention of differentiation syndrome. Unfortunately, the diabetes decompensated and, besides the antidiabetic medication, the patient required insulin therapy during hospitalization.

We also continued the supportive treatment with intravenous broad-spectrum antibiotics, transfusions with platelets, packed red cells, fresh frozen plasma and cryoprecipitate, hemostatic agents and allopurinol.

The patient’s evolution was favorable. After the hematological features improved, we performed a bone marrow aspiration which revealed 3% normal promyelocytes, without any blasts, so the patient obtained complete hematological remission after induction therapy. He continued with consolidation treatment for intermediate-risk acute promyelocytic leukemia, with four courses of all-trans retinoic acid, 45 mg/m²/day for two weeks every 28 days, for seven cycles, and arsenic trioxide, 0.15 mg/kg/day, daily for five days per week, during weeks 1-4 of each eight-week cycle. Taking into account the recent history of acute coronary syndrome developed during induction, a complete evaluation was performed before every cycle of arsenic trioxide. Thus, besides hematologic specific tests, we evaluated the renal and hepatic function, the serum electrolytes, and made a complete cardiac evaluation – echocardiography before every cycle and electrocardiogram before and after every dose of arsenic trioxide to monitor QT interval. The patient was stable and did not develop any complication during the consolidation treatment. The remission was stable – molecular examination for PML-RARa was negative after induction and also after the consolidation treatment. He continued with maintenance treatment, preserving the complete molecular remission.

Discussion

A unique pathology among acute leukemias, acute promyelocytic leukemia differs from other subtypes of the class to which it belongs by its particular biology and cytogenetic features, targeted treatment and high curability. However, hemorrhagic complications and differentiation syndrome confer a high risk for early mortality in patients diagnosed with APL.

Approximately 95% of APL cases are characterized by t(15;17)⁽⁷⁾, leading to PML-RARa fusion protein⁽⁸⁾, which causes a dominant negative mutation⁽⁷⁾, but it also has a gain-of-function effect^(9,10). This blocks cell differentiation and prevents apoptosis, thus favoring leukemic cells proliferation⁽⁷⁾.

Like any disease associated with medullary failure, most of the complications appear secondary to cytopenias⁽¹¹⁾, but some of them can be emphasized in the context of other processes. As an example, hemorrhagic complications are often out of proportion compared to the degree of thrombocytopenia⁽¹¹⁾.

The most feared and frequent complication of APL⁽¹²⁾ is bleeding diathesis, representing the main cause of death, particularly at presentation^(13,14), along with infections and differentiation syndrome⁽¹⁵⁾. Early death remains the major cause of treatment failure in this type of highly curable acute leukemia^(16,17). In APL, primary fibrinolysis is the main cause of hemorrhagic events, but it can also be triggered in the context of disseminated intravascular coagulation and secondary fibrinolysis⁽¹⁸⁾. Rectal bleeding is rare among the initial signs of acute leukemia, but also represents a sign of severity⁽¹⁹⁾.

Our patient presented with rectorrhagia, which was thought to be a consequence of hemorrhoids, thrombocytopenia and coagulopathy. While the rectal bleeding resolved, the patient quickly developed another complication, an infectious one – namely, perirectal abscess associated with fistula, those two representing the acute and chronic manifestation of the same disease, an infected anal gland⁽²⁰⁾. With careful surgical evaluation and proper treatment, the evolution was favorable.

In APL, due to unique mechanisms of coagulopathy, there is an increased risk of both hemorrhagic and thrombotic complications, the last one being underrecognized^(12,21). Thrombotic events can occur either as a consequence of the expression of tissue factor and cancer procoagulant on the surface of leukemic promyelocytes, or as a component of the DIC spectrum^(22,23). Thus, we can consider that activation of the fibrinolytic system is useful to some extent, as it breaks down the fibrin thrombus⁽¹⁸⁾.

APL is the first hematological malignancy that benefits from molecular-targeted based therapy. Current guidelines recommend approaching the pathology as an emergency and ATRA initiation from the slightest suspicion of diagnosis^(24,25). The standard of care for non-high-risk APL patients (WBC count ≤10,000/mm³) is ATRA plus ATO, this regimen being noninferior and possible superior to standard ATRA-idarubicin (AIDA) protocol⁽²⁵⁾.

In the case of our patient, considering the cardiac pathology, the history of myocardial infarction and the decreased LVEF, idarubicin could not be administered because of the cardiotoxicity of anthracyclines. Thus, according to guidelines, we decided for the combination between ATRA and arsenic trioxide, even though the last one also has potential cardiotoxicity. ATO treatment can cause QT interval prolongation, torsade de pointes and sudden cardiac death⁽²⁶⁾. 

Major risk factors for acute coronary syndrome include male gender, smoking, hypertension, diabetes, dyslipidemia, obesity and family history of ACS^(27-29).

Our patient’s risk for suffering an acute coronary syndrome was increased both by the hematological pathology and the underlying thrombotic risk, by severe anemia secondary to bone marrow failure, and worsened by rectal bleeding, as well as by cardiovascular risk factors, such as the personal history of acute myocardial infarction, hypertension, dyslipidemia, diabetes and obesity.

Several possible mechanisms of acute coronary syndrome in the context of APL have been described in literature.

During induction treatment for APL, the risk of thrombotic events is 5-20%⁽¹²⁾. By impairing the balance between coagulation and fibrinolysis, it is possible that ATRA initially leads to a hypercoagulable status⁽³⁰⁾. Shortly after the initiation of ATRA, hyperfibrinolysis is corrected, but normalization of thrombotic markers usually occurs two weeks after the initiation of treatment⁽³⁰⁾. Thus, after starting the treatment, if fibrinolysis is disabled, there is an additional risk of thrombotic complications⁽¹⁸⁾. Also, ATRA can cause coronary vasospasm^(31,32).

The study of Chang from 2013 indicated one case of AMI out of ten patients with thrombotic events, who also associated gastrointestinal hemorrhage⁽²¹⁾. Another study revealed that cardiac thrombotic events were among the most common thrombotic events before and during induction⁽²³⁾.

Also, directly related to the treatment with differentiation agents and as a possible mechanism of the ACS, we emphasize the differentiation syndrome⁽³³⁾, characterized by endothelial damage produced both by the release of IL-1b, IL-6, IL-8 and TNF-a by promyelocytes, following differentiation⁽³⁴⁾ and by cathepsin G, which increases vascular permeability⁽³⁴⁾. ATRA enhances the expression of certain adhesion molecules, which induces neoplastic cells aggregation⁽³⁵⁾. Endothelial lesions are precipitated by increased aggregation of blast cells and adhesion between blast cells and the endothelium⁽³⁴⁾. The clinical picture of differentiation syndrome implies dyspnea, pulmonary infiltrates, pleuro-pericardial effusion, peripheral edema, weight gain, fever and hypotension^(36,37). The laboratory tests reveal leukocytosis and coagulopathy, and in severe cases, acute renal failure and hepatocytolysis⁽³⁸⁾. Our patient presented dyspnea, but we consider it in the context of acute pain and myocardial ischemia.

Disseminated intravascular coagulation leads to microthrombi in peripheral branches of the coronary arteries, which can cause severe cardiac dysfunction⁽³¹⁾. This may be a possible mechanism of ACS in our patient, considering the increased INR and the low fibrinogen at the time of angina.

Another mechanism for acute coronary syndrome that leads to microthrombi formation through less activation of secondary fibrinolysis is elevated fibrinogen levels⁽³⁹⁾. It also plays a role in increasing clot stiffness, fiber density, platelet binding and blood viscosity⁽⁴⁰⁾.

Leukocytosis (white blood cells >10,000/mm³), CD2 expression of atypical promyelocytes, FLT3-ITD mutation and bcr3 isoform of the PML-RARa transcript are also associated with an increased risk for thrombosis in APL patients⁽⁴¹⁾. Furthermore, related to leukocytosis, tissue infiltration by leukemic promyelocytes could be involved in the process⁽²⁶⁾. Our patient presented CD2 on the surface of leukemic promyelocytes and FLT3-ITD mutation.

A meta-analysis published in 2019 revealed that patients with FLT3-ITD have a higher risk of induction death and lower overall survival rates than those without mutation⁽⁴²⁾. Recent studies indicated that FLT3-ITD mutation did not confer a worse prognosis and did not influence the survival outcome in adult APL treated with ATO and ATRA-based therapeutic regimen^(43-45).

Monotherapy with ATRA has been associated with frequent relapses, as continuous treatment with ATRA is characterized by a decrease in the plasma concentration of the drug secondary to accelerated clearance⁽⁴⁶⁾. Although our patient only received ATRA as induction therapy, he achieved complete remission and has maintained the response. An important aspect for maintaining the favorable response was applying consolidation treatment according to the guidelines.

Conclusions

Acute coronary syndrome is a rare complication associated with APL. In a patient presenting both conditions, choosing the best treatment option is challenging. Our case emphasizes the importance of close collaboration with other medical specialties in the management of a hematological patient with multiple comorbidities and complications secondary to the underlying pathology and treatment.
 

 

Conflict of interest: none declared

Financial support: none declared

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