American Journal of Emergency Medicine 31 (2013) 1290.e1–1290.e2
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Case Report
Acute promyelocytic leukemia; early diagnosis is the key to survival
Abstract Acute promyelocytic leukemia, a subtype of acute myelogenous leukemia characterized by an abnormal accumulation of immature granulocytes called promyelocytes, is a feared oncologic emergency. Currently, management of acute promyelocytic leukemia with supportive transfusions, to correct underlying coagulopathy, and alltrans retinoic acid, in combination with chemotherapy, can lead to complete remission in 80% to 90% of cases. However, early mortality from pulmonary or intracranial hemorrhage remains high if cases are late presenting or treatment is delayed. We report the case of a 23-year-old woman who presented to her local emergency department (ED) with headache, chills, epistaxis, dry cough, and fever. The emergency physician diagnosed her with a “viral illness” and discharged her home on symptomatic treatment. One week later, she developed easy skin bruising and hemoptysis. In a second visit, she was diagnosed with acute leukemia based on these clinical features in addition to an abnormally elevated white blood cell count and admitted to the hospital. The following day the patient was transferred to our ED for expert cancer care; additional laboratory investigations revealed progressive anemia, thrombocytopenia, and coagulopathy. A review of her peripheral smear showed abundant promyelocytes consistent with a diagnosis of acute promyelocytic leukemia (APL), and treatment with supportive blood transfusions and all-trans retinoic acid (ATRA) was started. Given her complaints of headache in the setting of thrombocytopenia and coagulopathy, she underwent a computed tomographic (CT) scan of brain, and the scan results revealed an intracranial hemorrhage. The patient's condition progressively deteriorated, and on day 5 of her hospitalization, she died of complications from the intracranial hemorrhage. A 23-year-old Hispanic woman with no previous medical history presented to her local emergency center with a 1-week history of chills, dry cough, myalgia, fever, and frontal headache associated with nausea. She was considered to have a “viral illness” and was discharged home on symptomatic therapy and antipyretics. One week later, on a second visit, she stated that her symptoms were not improved, and she had developed skin bruising, hemoptysis, and worsening headache. After finding a significantly elevated white blood cell count (WBC), she was suspected to have acute leukemia. She was admitted to the local hospital while initiating transfer of care to our cancer center. The patient had no previous medical history and did not use tobacco, alcohol, or illicit drugs. Her family medical history was unremarkable. She was taking no medications but has an allergy to aspirin, which caused an anaphylactic reaction. Once in our emergency center, the initial physical examination showed a febrile patient in no acute distress. She had blood pressure 0735-6757/$ – see front matter © 2013 Elsevier Inc. All rights reserved.
of 130/80 mm Hg, pulse of 110 beats per minute, respiratory rate of 18 breaths per minute, and temperature of 38.2°C, and her oxygen saturation on ambient air was 96%. Her oropharynx had occasional petechiae, and her skin manifested scattered areas of atraumatic ecchymosis mostly at the abdominal wall and lower limbs. The remainder of her examination, including a detailed neurological assessment, was unremarkable. Laboratory investigations revealed a WBC of 186 000 cells/μL, hemoglobin level of 8.5 g/dL, and a platelet count of 14 000 cells/μL. The patient's fibrinogen level was 106 mg/dL, and prothrombin time was mildly elevated. Her chemistry panel results were normal. A review of her peripheral blood smear demonstrated immature, abnormal hematopoietic cells consistent with APL. A noncontrast brain CT scan was performed, demonstrating intraparenchymal hemorrhage in the right parietal lobe. The patient was immediately started on all-trans retinoic acid (ATRA) and supportive blood transfusions. The comprehensive management of her leukemia and coagulopathy was fruitless, and her neurologic condition deteriorated. Eight hours after the original CT scan of the brain, a repeat CT scan displayed interval increase in the hemorrhage, mass effect with midline shift, and a new focus of hemorrhage. On hospital day 2, cytogenetic and fluorescence in situ hybridization testing confirmed the diagnosis of APL. Unfortunately, her condition continued to deteriorate, and she died of complications from her intracranial hemorrhage 5 days after admission. Acute promyelocytic leukemia is a distinct subtype of acute myeloid leukemia (AML) that has unique molecular and clinical characteristics. It results from a chromosomal translocation between the retinoic acid receptor α gene on chromosome 17 and the promyelocytic gene on chromosome 15 [1], leading to an arrest of myeloid cell differentiation at the promyelocyte stage and abnormal proliferation of these cells. First described by Hillestad [2] in 1957, APL represents 5% to 8% of all AML cases [2,3]. In the United States, it accounts for 4% to 8% of AML in children and 10% to 15% in adults [3]. The incidence of APL reaches a plateau at age 20 years and remains constant until declining after age 60 years [4]. Other areas of the world have reported a 23% to 59% incidence of APL among pediatric AML [5]. Clinical manifestations are commonly a result of cytopenias, as seen in other leukemia patients, but some signs and symptoms are distinctive to APL. Acute promyelocytic leukemia has a unique propensity for inducing disseminated intravascular coagulation, which can manifest as bleeding from mucocutaneous membranes. Life-threatening pulmonary or intracranial hemorrhage is a common cause of early death [6]. Acute promyelocytic leukemia usually is associated lower WBC as compared with other AML subtypes [7]. Organomegaly or lymphadenopathy is also less commonly seen in APL as compared with other leukemias [8].
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The diagnosis of APL should be suspected in patients with new onset leukemia and evidence of early coagulopathy, such as cutaneous ecchymosis or petechiae. Laboratory investigations can reveal anemia, thrombocytopenia, leukocytosis or leukopenia, low fibrinogen, and elevated prothrombin or partial thromboplastin time. Examination of a peripheral blood smear will show promyelocytes, most often with abundant myeloperoxidase-positive cytoplasmic granules. Confirmation of APL requires testing to detect the retinoic acid receptor–promyelocytic fusion protein or translocation between chromosomes 15 and 17. Basic blood cell counts have recently been proposed as a method of risk stratifying adults with APL. A WBC of less than 10 000 cells/mL and a platelet count of greater than 40 000 cells/mL are correlated to low risk of relapse [9]. Unfortunately, there are scant data on prognostic features in pediatric APL. The treatment of APL should begin with appropriate resuscitation and symptom relief, followed by aggressive correction of coagulopathy, as pulmonary or intracranial hemorrhage is responsible for most of the early deaths in APL. Fresh frozen plasma, fibrinogen, and cryoprecipitate should be given to maintain fibrinogen concentration greater than 100 g/dL, and platelets should be transfused to a level greater than 30 000 cells/μL [10]. Definitive therapy for APL consists of ATRA in combination with chemotherapy. ATRA, a vitamin A derivative, has proven to be a highly safe and effective differentiating agent [11]. It leads to maturation and eventual apoptosis of the immature promyelocytes that cause APL. When used in combination with chemotherapy, it has increased the complete remission and 6-year disease-free survival rates of APL to 90% and 86%, respectively [12,13]. ATRA at a dose of 45 mg/m 2 per day in 2 divided doses needs to be started immediately once the diagnosis of APL is suspected [10]. The emergency physician should maintain a high index of suspicion for APL when newly diagnosed leukemia patients present with a bleeding diathesis, as this disease is curable if treated early. The emergency physician should not wait for peripheral blood smear confirmation. Aggressive correction of underlying coagulopathy followed by administration of ATRA in consultation with a hematologist should be prioritized while pending transfer to a facility experienced in treating APL.
Carlos J. Roldan MD Samir M. Haq MD Adam H. Miller MD, MSMM, MSCS Departments of Emergency Medicine The University of Texas Health Science Center Houston, TX, USA The University of Texas MD Anderson Cancer Center Houston Houston, TX, USA E-mail address:
[email protected] http://dx.doi.org/10.1016/j.ajem.2013.03.038 References [1] Rowley JD, Golomb HM, Dougherty C. 15/17 translocation, a consistent chromosomal change in acute promyelocytic leukaemia. Lancet 1977;1:549–50. [2] Hillestad L. Acute promyelocytic leukemia. Acta Med Scand 1957;159:189–94. [3] Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997-2002. Cancer Causes Control 2008;19:379–90. [4] Vickers M, Jackson G, Taylor P. The incidence of acute promyelocytic leukemia appears constant over most of a human lifespan, implying only one rate limiting mutation. Leukemia 2000;14:722–6. [5] Gomez SM, Schuttenberg V, Armendariz H, et al. Childhood acute leukemia: a single institution experience in La Plata, Argentina. Med Pediatr Oncol 2001;36:383–5. [6] Park JH, Qiao B, Panageas KS, et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood 2011;118:1248–54. [7] Mann G, Reinhardt D, Ritter J, et al. Treatment with all-trans retinoic acid in acute promyelocytic leukemia reduces early deaths in children. Ann Hematol 2001;80:417–22. [8] Carter M, Kalwinsky DK, Dahl GV, et al. Childhood acute promyelocytic leukemia: a rare variant of nonlymphoid leukemia with distinctive clinical and biologic features. Leukemia 1989;3:298–302. [9] Sanz MA, Lo Coco F, Martin G, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 2000;96:1247–53. [10] Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009;113:1875–91. [11] Fenaux P, Le Deley MC, Castaigne S, et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group. Blood 1993;82:3241–9. [12] Tallman MS, Nabhan C, Feusner JH, et al. Acute promyelocytic leukemia: evolving therapeutic strategies. Blood 2002;99:759–67. [13] Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 2008;111:2505–15.
