AtypicAl complicAtion in Acute promyelocytic leukemiA

minodora onisai1,2, mD, phD, Ana-maria Vladareanu1,2 mD, phD, iuliana iordan1,2, mD, Andreea Spinu1,2 mD, Ana-maria neagu1,2, mD, phD, Adrian Alexandru1,3, mD, phD 1 „Carol Davila“ University of Medicine and Pharmacy, Bucharest, Romania 2 Hematology Department, Emergency University Hospital, Bucharest, Romania 3 Plastic and Reconstructive Surgery Clinic, Emergency University Hospital, Bucharest, Romania


INTRODUCTION
Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) characterized by potentially severe hemorrhagic complications due to coagulopathy (1). It accounts for approximately 5-20% of AML cases (2). In APL patients requiring surgery, the risks and benefits must be carefully evaluated, especially at diagnosis, as coagulopathy and thrombocytopenia may increase the risk of fatal bleedings.
We present the case of a young patient with APL, with an infectious complication with indication for surgical resection, namely herpetic lesion complicated with infection and necrosis.

CASE PRESENTATION
A young female patient, 34 years old, with no relevant medical history, presented to the Emergency Department for persistent menorrhagia for about a month and weight loss of approximately 5 kg in a few weeks. She had no exposure to a toxic environment, she was not a smoker, and she had had three normal pregnancies. She had no brothers or sisters and no familial medical history.
The clinical examination was unremarkable except for pallor and confirmed genital bleeding, without other active hemorrhages; ECOG 0. The pregnancy test was negative.
We also observed a decreased fibrinogen level, 120 mg/dl, with normal coagulation times.
We thus established the positive diagnosis of APL with PML/RARα fusion (according to World Health Organization 2016 criteria).
On the second day of treatment, the patient developed a small herpetic lesion on her lower lip, without any other symptoms. We supplemented antiviral medication with both local and systemic Acyclovir.
After ten days of treatment, full aplasia was installed: WBC 500/mm³ with 4% neutrophils, hemoglobin 6.2 g/dl, PLT 20,000/ mm³; coagulation studies were normal. Infection and necrosis complicated the herpetic lesion (Figure 2), and the patient began to develop high fever. We started intravenous broad-spectrum antibiotics, including anti-anaerobe bacteria and anti-Staphylococcus; blood cultures were drawn, which were negative. The local evolution was not favorable due to the extension of the lesion, spontaneous bleeding, and persistent and aggravating fever. The patient maintained the severe aplasia despite transfusion support and specific treatment: WBC 1,500/mm³ with 30% neutrophils, HGB 6.7 g/dl, PLT 5,000/mm³.

FIGURE 2. Herpetic lesion of the lower lip
We requested a plastic surgery consult. Because of the lack of response to conservative treatment, surgical intervention was recommended. The lesion resection was performed in a V shape, full-thickness excision with free margins. The lip defect was almost a third of the lip, which was closed primarily. Primary repair allowed us to reduce the duration of the surgery and risk of a potential bleeding and also provided a good outcome with minimal donor-site morbidity and the best color and texture match for the lip.
Thus, excision of the lesion was performed, with minimal bleeding during surgery, even though the patient presented severe thrombocytopenia. The evolution was rapidly favorable: no signs of inflammation or infection, minimal defect, and the fever resolved. Also, hematological features improved: WBC 2,000/mm³ with 50% neutrophils, HGB 10.5 g/dl, PLT 295,000/ mm³. Meanwhile, we continued the hematological treatment and the patient had semi-solid food for two weeks. Ten days after surgery, the lesion had a favorable evolution, without bleeding or signs of infection ( Figure 3).

FIGURE 3. Herpetic lesion of the lower lip after ten days since surgical excision
Regarding hematological evaluation, the patient obtained complete hematological remission after induction therapy, with 2% (normal) promyelocytes in the bone marrow and no blasts. She continued with consolidation treatment for intermediate-risk acute promyelocytic leukemia (three courses in total, without any complications), and remission was stable -molecular examination for PML-RARα was negative after induction and also after the three cycles of consolidation treatment. She has also finished maintenance treatment, preserving complete molecular remission.

DISCUSSION
At presentation, the most severe findings in our patient were thrombocytopenia and menorrhagia, which was thought to be secondary to thrombocytopenia. We excluded pregnancy and other frequent causes, which can associate thrombocytopenia (3,4).
APL is a subtype of AML, which has particular morphologic and cytogenetic features, as well as specific treatment and better prognosis and survival compared to the other subtypes (1).
APL is characterized by a pathognomonic cytogenetic anomaly, namely the t(15;17) translocation, which translates into PML-RARα mutation. Translocation t(15;17) is a reciprocal translocation between chromosomes 15 and 17 that blocks the cell's response to retinoic acid (normal growth factor), the cell remaining in an immature stage, as a promyelocyte (1). There are two main subtypes of APL -hypergranular (typical) and hypogranular (microgranular) variants. Also, there are other different cytogenetic anomalies found in other subtypes of APL with different prognostic implications (5). In less than 5% of APL cases, the RARα gene fusions with other genes like PLZF, NPM1, NUMA1, and STAT5B (6). Some of these fusions have a negative impact on the treatment response and, as a consequence, on survival.
The morphological aspect is also characteristic. In the hypergranular variant, large atypical promyelocytes are found, with large, round, or incised nuclei, with visible, large nucleoli. The cytoplasm is abundant and contains a high number of azurophilic granules and Auer rods. In the microgranular variant, with a less favorable prognosis, granules are absent or rare, and nuclei are bilobed; patients also usually present leukocytosis, also an unfavorable prognosis feature (1).
APL is characterized by frequent hemorrhagic complications at debut, which appear with a higher prevalence compared to the other AML subtypes (7). The coagulopathy represents the principal cause of early mortality in APL (8). The most frequent ones are disseminated intravascular coagulation with secondary fibrinolysis and primary fibrinolysis. These are generated by the release of tissue factor from the granule content of the atypical promyelocytes (7,8).
The specific treatment includes ATRA in high doses. It is immediately initiated at the first suspicion of APL, because it overlaps the maturation blockage and induces cell differentiation, thus preventing coagulation complications. ATRA is associated with chemotherapy in protocols such as AIDA, or with arsenic trioxide (9,10), depending on the risk classification. Remission is achieved for a high percentage of patients, 85-90% being able to obtain complete remission (11). Afterward, the treatment is continued with risk-adapted consolidation treatment and two-years maintenance treatment (10).
Hemorrhage and infection are among the most common causes of induction failure (11). More frequently, infection is encountered in older male patients (13). Even though our patient developed both hemorrhage and infection, she responded to induction therapy and also maintained the response. One of the reasons this happened is the correct treatment applied promptly at the occurrence of complications.
The prognosis of our patient was intermediate. She had APL (a good prognosis subtype of AML) with t(15;17), which has chemosensitivity. Also, she had a de novo disease, was young and without comorbidities, had a favorable ECOG, and a low WBC (14). However, she presented with a hemorrhagic complication and also with severely decreased platelet count.
The bleeding risk in our patient was very high. The most critical period for APL patients is the time until complete remission when severe bleedings may occur. Afterward, we can talk about healing, taking into account that, except for the severe thrombocytopenia, she had only good prognostic factors.
We would like to underline the very fragile status of our patient. She had severe aplasia, severe leucopenia with increased sepsis risk, severe thrombocytopenia with increased bleeding risk, and also a history of bleeding complications. She is not a typical patient to undergo surgery. The intervention was a risk, but conservative treatment was not successful.
Therefore, taking into account both risks and benefits, we decided in favor for the surgery. Usually, an initial abnormal coagulation profile has a stronger correlation with severe bleeding episodes than initial thrombocytopenia (14), partially explaining the favorable evolution.

CONCLUSIONS
In the setting of APL with coagulopathy and surgery-requiring infection, it is difficult to decide whether the benefits of surgery will outweigh the risks. Sometimes, it is better to choose a more aggressive approach, assume the risks, and try to prevent possible complications. This case sustains the importance of teamwork in hematologic patients.