Differentiation (retinoic acid) syndrome

INTRODUCTION

The differentiation syndrome, formerly known as the retinoic acid syndrome, is a distinct complex of symptoms that has been reported among patients receiving all-trans retinoic acid (ATRA) therapy for acute promyelocytic leukemia [1,2]. Acute promyelocytic leukemia is currently defined in molecular genetic terms by the presence of a reciprocal translocation between the long arms of chromosomes 15 and 17 [3], with the creation of a fusion gene product identified as PML/RAR-alpha. (See "Molecular biology of acute promyelocytic leukemia".)

Among patients with the appropriate cytogenetic profile, ATRA has demonstrated efficacy as an alternative to cytotoxic chemotherapy [4]. By inducing the differentiation of malignant cells into phenotypically mature myeloid cells, ATRA has produced complete remissions in a large proportion of patients treated [1,4-6]. There are also ongoing clinical trials regarding its use in myelodysplastic syndromes [7,8], metastatic non-small cell lung cancer [9], neural tumors, and prostate cancer.

CLINICAL PRESENTATION

As the number of patients treated with ATRA has grown, a constellation of signs and symptoms, now identified as the differentiation syndrome, has been identified. This syndrome consists of fever, dyspnea, weight gain, pulmonary infiltrates, pleural or pericardial effusions, episodic hypotension, renal dysfunction, and leukocytosis [10,11]. There have also been case reports of the differentiation syndrome associated with Sweet's syndrome (acute febrile neutrophilic dermatosis) [12,13]. Pulmonary hemorrhage is a well-described complication; however, its incidence is unclear [14,15].

The differentiation syndrome has also been described in patients with relapsed acute promyelocytic leukemia who received induction therapy with arsenic trioxide [16,17]. One patient developed this syndrome after initial induction therapy with ATRA in combination with chemotherapy. At relapse 3 years later, she was treated with arsenic trioxide and developed the identical syndrome, which was relieved by administration of glucocorticoids [17]. As with ATRA, both the leukocytosis and the differentiation syndrome following induction therapy with arsenic trioxide are believed related to the ability of these agents to induce differentiation of APL cells [16]. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults".)

EPIDEMIOLOGY

The frequency of the differentiation syndrome ranges between 6 and 26 percent in patients treated with standard doses of ATRA [2,10,14]. Most cases of the syndrome develop during the first 30 days of therapy; one series of 64 patients found that the median timing of onset was 7 days after ATRA treatment was begun [2].