A 28-year-old man presented to the emergency department with a fever and a red, warm, tender left leg. His symptoms began four days earlier, and had been worsening since then. He called his primary care physician the day before, and had scheduled an outpatient DVT ultrasound, which had not yet been performed. He denied abrasion, laceration, and other trauma to his leg. His only other symptom was mild fatigue for a month.
He was febrile to 39.1°C, and tachycardic with a heart rate of 142 bpm. He had an area of confluent erythema to his left inner thigh, which was blanching and moderately tender. He had no crepitance or tenderness outside the margins of the erythema. He had no knee effusion, could range all joints of his lower extremities, and could ambulate without difficulty.
A DVT ultrasound showed superficial thrombophlebitis of the left lower extremity but no DVT. Lactate was 3.0, BMP was unremarkable, and an HIV test was negative. Empiric antibiotics were started, and the patient was prepared for admission when the laboratory called with critical results: platelets of 8, absolute neutrophil count of 440, and Auer rods seen on peripheral smear. (Photo.) What is the diagnosis?
Find the diagnosis and case discussion on p. 15.
Diagnosis: Acute Promyelocytic Leukemia
Acute promyelocytic leukemia (APL) is a subset of acute myeloid leukemia. It has an average 30-day untreated mortality rate of 20 percent, and is a true hematologic emergency. (Haematologica 2012;97:133.)
Its name refers to the type of deranged cells found in the bone marrow and circulating blood. (Blood 2016;127:2391.) Promyelocytes in normal white blood cell differentiation go on to become granulocytes, such as neutrophils, basophils, and eosinophils. Cell differentiation is halted at the promyelocyte stage because of one of a number of characteristic mutations. This leads to proliferation of promyelocytes. Auer rods are common in the hypergranular form of APL, which represents approximately 75 percent of cases. (Blood 2000;96:1287.)
The most common genetic abnormality leading to APL is a reciprocal translocation between chromosomes 15 and 17, denoted as t(15;17)(q24.1;q21.2);PML-RARA. (Blood 2016;127:2391.) In simple terms, the long arms of these two chromosomes switch with each other. The result is a fusion gene that contains parts of two previously separate genes. Normally, the RARA gene works to regulate differentiation of hematopoietic cells such as promyelocytes. The resultant RARA fusion protein blocks differentiation when fused with the PML gene rather than inducing differentiation. Promyelocytes are then stuck in an intermediate stage and accumulate in the marrow and the blood.
Morbidity and mortality result primarily from downstream effects related to pancytopenia and coagulopathy. Symptoms including fatigue and generalized weakness (related to anemia), infections (related to neutropenia), and bleeding and bruising (related to thrombocytopenia) are common, alone or in combination. (Cancer 2005;104:788.) Coagulopathy results from not only thrombocytopenia but also disseminated intravascular coagulation and primary hyperfibrinolysis. (Curr Opin Hematol 2016;23:121.) Hemorrhagic complications, particularly intracranial and pulmonary hemorrhages, cause the majority of early mortality in APL. (Haematologica 2010;95:853.)
Rather than targeting the leukemic cells, as in most other cancer therapies, treatment revolves around inducing differentiation of the deranged promyelocytes. All-trans retinoic acid (ATRA), which causes the differentiation of promyelocytes into mature neutrophils, is the hallmark of APL therapy. (Lancet Oncol 2000;1:101.) Expert consensus recommends initiation of ATRA when the diagnosis is suspected, even before it is confirmed, given APL's high mortality rate and ATRA's relatively safe risk profile. Arsenic trioxide or chemotherapy are often used as adjuvants. (Blood 2006;107:3469.)
This patient was transferred to a dedicated oncology ICU, and started on ATRA and arsenic trioxide. He did well and was ultimately discharged with outpatient treatment.