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Differentiation Syndrome in a Patient With Promyelocytic Leukemia Treated With All-trans Retinoic Acid

Ariel Perez Perez, MD; Gary J. Hardoon, MD; and Jorge Parellada, MD
Orlando Regional Medical Center, Orlando, Florida

Volume 56 - Issue 11 - November 2016

AUTHOR:
Ariel Perez Perez, MD; Gary J. Hardoon, MD; and Jorge Parellada, MD
Orlando Regional Medical Center, Orlando, Florida

CITATION:
Perez AP, Hardoon GJ, Parellada J. Differentiation syndrome in a patient with promyelocytic leukemia treated with all-trans retinoic acid. Consultant. 2016;56(12):1040-1042.

 

The patient is a 64-year-old woman who presented with concern for easily bruising for 1½ weeks and 1 episode of epistaxis that had resolved with compression. She also reported having developed “ulcers” in her mouth.

History. She had visited her primary care provider, who had started acyclovir for a presumed herpes simplex virus infection. Three days later, the patient developed oropharyngeal thrush for which she returned to her primary care provider, who prescribed nystatin suspension and ordered further laboratory tests. Results of a complete blood cell count showed severe pancytopenia, and the patient was immediately referred for hospital admission.

Physical examination. At presentation, a review of systems was significant for dyspnea, weakness, dizziness that worsened with movement, and feeling faint. The patient had a past medical history of hypertension and insomnia. She reported previous surgical interventions for a benign tumor of the right breast and total abdominal hysterectomy for uterine leiomyoma. Her social history was significant for secondhand smoke exposure and occasional alcohol use.

She was afebrile and hemodynamically stable. Physical examination findings were remarkable for multiple petechiae and ecchymosis on the patient’s extremities and torso, a crusted 5-mm lesion on her upper lip, and trace pedal edema bilaterally. No oral thrush was present. Examination findings were otherwise benign.

Diagnostic tests. Initial laboratory test findings showed pancytopenia with a white blood cell (WBC) count of 2900/µL, a hemoglobin level of 7 g/dL, a platelet count of 7000/µL, and 15% promyelocytes. Her creatinine level was mildly elevated at 1.37 mg/dL, with a calculated glomerular filtration rate of 41 mL/min. Liver function test results, the total protein level, and the albumin level were within normal range.

Results of a peripheral smear showed 50% blasts, some with irregular nuclear contours, abundant cytoplasmic granules, and occasional Auer rods. Myeloperoxidase stain on the peripheral blood showed dense positivity in the cytoplasmic granules of the blast cells. Additional blood work showed an elevated D-dimer level and hypofibrinogenemia.

Chest radiographs showed no acute cardiopulmonary process. A bone marrow biopsy was performed, with findings of 86% blasts and the presence of Auer rods (Figure 1).


Figure 1. Bone marrow smear showing a blast with an irregular nuclear contour, along with abundant cytoplasmic granules with Auer rods.

 

Acute promyelocytic leukemia (APL) was diagnosed, with normal cytogenetic test results and positive polymerase chain reaction test results for promyelocytic leukemia/retinoic acid receptor α (PML/RARA) bcr3 transcript mutation. She was classified as having low-risk APL, given her WBC count of less than 10,000/µL.

Hospital course. Induction therapy with all-trans retinoic acid (ATRA) was started on hospital day 2, along with intravenous (IV) fluids and allopurinol for tumor lysis syndrome prophylaxis. On hospital day 3, her temperature spiked overnight to 38°C with a calculated absolute neutrophil count of 407. Empiric antibiotic therapy with IV cefepime, 2 g every 8 hours, was initiated for neutropenic fever. The patient remained afebrile and hemodynamically stable during hospital days 4 and 5.

On hospital day 6, she again started to spike fevers with a maximum temperature of 38.5°C, accompanied by dyspnea and a WBC count that trended up to 32,500/µL. Results of laboratory studies to rule out infection were negative, including 2 blood cultures with no growth, a normal urinalysis result, and negative urine Streptococcus and Legionella antigens. However, a chest computed tomography (CT) angiography showed a pleural effusion and interstitial infiltrates (Figure 2). An echocardiogram showed normal systolic and diastolic function, a left ventricular ejection fraction of 55%, and no pericardial effusion.


Figure 2. CT angiogram demonstrating bilateral pleural effusions and interstitial infiltrates.

 

The patient was started on dexamethasone, 10 mg twice daily, for suspected differentiation syndrome, with clinical improvement noted at 12 hours and full resolution of symptoms at 24 hours. ATRA was continued, and therapy with arsenic trioxide (ATO) was initiated on day 10 as planned, without further complication.

Discussion. APL is considered a hematologic emergency. Early institution of treatment is key to avoiding severe complications and mortality. The mainstay of therapy is the combination of ATRA and chemotherapy, achieving cure rates of as high as 80%.1-4 A recent phase 3 trial including more than 150 patients concluded that ATRA plus ATO is noninferior to and may even be superior to ATRA plus chemotherapy in low- to intermediate-risk APL.5

Differentiation syndrome is a potentially fatal complication of the treatment of APL with differentiation agents such as ATRA and ATO that act by inducing the differentiation of promyelocytic blast cells. This syndrome occurs in approximately 25% of patients undergoing induction therapy with ATRA and ATO.6,7 The pathophysiology is not completely understood, but its proposed underlying mechanisms are cytokine release–mediated systemic inflammatory response syndrome and endothelium damage through serine proteases such as cathepsin G.8,9

Presentation. The main clinical manifestations are dyspnea, pulmonary infiltrates, unexplained fever, weight gain of more than 5 kg, pleural and/or pericardial effusions, hypotension, and kidney failure.10 Diagnosis is made on a clinical basis, and early suspicion is essential, since none of the clinical signs or symptoms are pathognomonic. The criteria used for diagnosis in several clinical trials have been variable, leading to differences in the reported incidence and outcome data. The PETHEMA group definition6,7 requires 2 of the aforementioned clinical findings to be present in order to make the diagnosis, and other potential causes must have been ruled out. Another frequently observed finding is an elevated WBC count, and although it is not a part of the criteria, it may help support the diagnosis.11-13 Differentiation syndrome usually presents in the second week of induction, but it may occur as early as day 2 or as late as day 46.14-16

No specific diagnostic test is required, since diagnosis is clinical in a patient on ATRA and ATO. Radiologic features can include cardiomegaly, widening of the vascular pedicle, increased pulmonary blood volume, peribronchial cuffing, ground-glass opacity, septal lines, and pleural effusions.17 Davis and colleagues18 reported CT findings of peripheral nodules, reticular and ground-glass opacities, and pleural effusions in patients with differentiation syndrome.

An echocardiogram to assess ventricular function and microbiologic studies to rule out infectious processes may be indicated; however, treatment for all possible complications should be initiated given that positive findings do not exclude concomitant differentiation syndrome.

Treatment. Dexamethasone, 10 mg twice daily, should be initiated as early as possible and continued until clinical resolution. The preemptive use of corticosteroids has been adopted as the standard management of differentiation syndrome, according to recommendations of an expert panel on behalf of the European LeukemiaNet.19 ATRA should not be discontinued unless severe differentiation syndrome is diagnosed, and even in those cases, the differentiating agent should be restarted immediately after resolution of symptoms. In some patients, a second occurrence of differentiation syndrome has been reported.20 One of the main controversial areas in the management of this syndrome is the possible benefit of preventive strategies, and although scientific evidence is lacking, many groups have incorporated prophylactic corticosteroids into their induction protocols.5,7 

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