A previously healthy 10-year-old girl presented to the emergency department (ED) with a headache and vomiting which resolved with oral NSAIDs. The patient returned two days later unable to ambulate with mental slowing and lower extremity bruising. Labs demonstrated marked leukocytosis, severe anemia and thrombocytopenia, and disseminated intravascular coagulation (DIC). Brain MRI showed multiple intracranial hemorrhages. A peripheral blood smear demonstrated blasts with many Auer rods. A diagnosis of acute promyelocytic leukemia (APL) was made and therapy including all-transretinoic acid (ATRA) was initiated. Neurologic status returned to baseline within 1 week in the pediatric intensive care unit.
Acute promyelocytic leukemia (APL) is a rare form of acute myeloid leukemia (AML) representing less than 10% of
A previously healthy 10-year-old Asian girl presented to the emergency department with headache, vomiting, and one week of mild nonproductive cough. Her headache started the evening prior to presentation, was gradual in onset and frontotemporal in location, and improved with acetaminophen but subsequently woke her from sleep. It was accompanied by two episodes of emesis. On presentation to the ED, the patient described her headache pain as 3 out of 10 in severity. She denied photophobia, had no further nausea, and denied abdominal pain. She reported that the headache worsened with standing and improved with lying down. Review of systems was significant only for pallor.
The patient was otherwise healthy with no prior medical issues and taking no regular medications. She was fully vaccinated and had no known allergies. Her family history was significant for frequent headaches in her mother and maternal aunt. She was living with her parents and brother and attending
Vital signs demonstrated blood pressure 111/56, pulse 104, temperature 37.1°C, respiratory rate 22, and oxygen saturation 100% on room air. Initial exam revealed a well-appearing female and was unremarkable including a normal fundoscopic exam and a normal complete neurologic exam.
The patient received ibuprofen and oral rehydration and her headache further improved. A presumptive diagnosis of migraine headache was made and was discharged with primary care follow-up the following day.
Two days after her initial emergency department visit, the patient returned to the ED with worsening headache, myalgia, subjective fever, and diffuse weakness. The patient’s mother reported that the patient was unable to stand or walk and as a result her mother had been carrying her, including to and from the bathroom. The patient endorsed nausea but no further vomiting.
Vital signs demonstrated blood pressure 105/49, pulse 123, temperature 36.9°C, respiratory rate 30, and oxygenation saturation of 97% on room air. On exam, the patient was moderately ill appearing, lying in bed responding slowly to questions. Her lips were noted to be cracked and with some oozing blood. No oral lesions were noted in the mouth. Pupils were equal, round, and sluggishly reactive bilaterally. Neck was supple with no adenopathy noted. Cardiovascularly, she was noted to be tachycardic with a regular rhythm and II/VI flow murmur. Her respiratory exam was normal. Her abdominal exam was benign with no organomegaly. Neurologically the patient was noted to be slow to respond to questions and moving slowly but without focal deficits. She was, however, unable to walk without assistance. Skin exam revealed diffuse ecchymoses on the lower extremities bilaterally.
Laboratory studies were ordered along with a rapid brain MRI, and pediatric neurology was consulted.
Laboratory results were as follows: hemoglobin 2.6 g/dL, hematocrit 8.3%, platelets 10K/uL, and WBC 60.5K/uL with 83% blasts in the differential. CRP was 15.7 mg/L, and ESR was 125 mm/h. Electrolytes showed sodium 139 mmol/L, potassium 4.0 mmol/L, chloride 100 mmol/L, carbon dioxide 24 mmol/L, BUN 11mg/dL, creatinine 0.56 mg/dL, glucose 129, magnesium 2.5mg/dL, and phosphorus 3.6 mg/dL. LDH was 359 U/L, uric acid was 2.3mg/dL. PTT was 29.4 seconds, PT was 19.5 seconds, and INR was 1.7. Fibrinogen was 117 mg/dL and D-dimer was >10,000 ng/mL. Review of peripheral blood smear (Figure
Peripheral blood smear demonstrating many primitive cells with round and lobated nuclei and moderately abundant cytoplasm with numerous cytoplasmic granules. Auer rods were readily identified; some cells had multiple Auer rods. A classic appearance for APL.
Rapid MRI Brain (Figure
MRI Brain FLAIR images demonstrating multicompartmental hemorrhages and leptomeningeal enhancement.
Pediatric Oncology was consulted and treatment initiated emergently with ATRA, dexamethasone, allopurinol, cefepime, and blood products including packed red blood cells, platelets, and cryoprecipitate. The patient was subsequently admitted to the pediatric intensive care unit.
In the pediatric ICU the patient received several transfusions with platelets, cryoprecipitate, and fresh frozen plasma to manage DIC. She was continued on an induction course of chemotherapy including ATRA, dexamethasone, idarubicin, and arsenic trioxide. Molecular analysis of the peripheral blood was positive for PML-RARA, confirming the diagnosis of APL. After the coagulopathy improved and the patient stabilized, lumbar puncture was performed with administration of intrathecal chemotherapy. The cerebrospinal fluid was notable for the presence of leukemia cells, confirming the involvement of the central nervous system. The patient’s encephalopathy gradually improved and she returned to her baseline mental status by day 7 of treatment. The patient was noted to have elevated opening pressure on lumbar punctures, which worsened over the course of induction, attributed to pseudotumor cerebri secondary to ATRA.
Upon completion of the first 28 days of induction therapy, repeat lumbar puncture and bone marrow studies demonstrated no morphologic evidence of acute promyelocytic leukemia, consistent with remission.
There are a total of 600-800 new cases of APL diagnosed each year in the United States, the majority of which occur in adults [
On peripheral blood smear, APL blasts have a characteristic appearance with abundant cytoplasmic granules, bilobed nuclei, and prominent Auer rods (Figure
Children with APL usually present with the signs and symptoms of cytopenias common to other leukemias. Fatigue, pallor, bruising, and fevers are frequent complaints [
The central distinguishing feature of APL, as compared to other forms of leukemia, is its propensity to cause disseminated intravascular coagulopathy (DIC). 80-90% of patients with APL will have evidence of bleeding diathesis on initial presentation [
All-transretinoic acid (ATRA), a vitamin A derivative, binds to the RARA site of the PML-RARA fusion protein in APL cells and allows the leukemic promyelocytes to differentiate into mature granulocytes. This leads to a rapid improvement in coagulopathies [
In conjunction with therapy for suspected APL with ATRA, aggressive therapy of DIC should be undertaken. Fresh frozen plasma and/or cryoprecipitate should be transfused to maintain fibrinogen levels over 150 g/dL and platelets should be transfused to maintain platelet counts over 50 x109/liter. Heparin has not been demonstrated to have a clear benefit and is not recommended for DIC related to APL [
The overall prognosis of APL is excellent, with more than 90% of patients achieving complete remission and 5-year overall survival rates in excess of 80%. On average, coagulopathy in APL corrects within a median time of 4 days after the initiation of ATRA [
While ATRA avoids many of the side effects associated with traditional cytotoxic drugs, it does have some significant associated adverse reactions including pseudotumor cerebri and differentiation syndrome. ATRA toxicity, including pseudotumor cerebri, appears to be more common in children as compared to adults [
APL is a rare disease in children, and its characteristic presentation of typical leukemia signs and symptoms accompanied by DIC/bleeding and its characteristic morphology on peripheral blood smear are important to recognize because initiation of disease-targeted therapy is associated with decreased mortality from hemorrhagic complications. Pediatric emergency providers should have a high index of suspicion for APL in pediatric patients presenting with pancytopenia accompanied by DIC. ATRA therapy, in consultation with a pediatric oncologist, accompanied by platelet and fibrinogen replacement to manage DIC should be initiated as soon as APL is suspected based on clinical presentation and/or peripheral blood smear.
The authors declare that there are no conflicts of interest regarding the publication of this paper.
The authors would like to acknowledge Dr. Judith Ferry and Dr. Aaron Paul for their assistance in providing pathology and radiographic images, respectively, for this manuscript.