All-trans-retinoic acid syndrome

All-trans-retinoic acid (ATRA) syndrome, is the more common cause of differentiation syndrome ⁸. Acute promyelocytic leukemia (APL) cells respond to therapeutic levels of this normal plasma derivative of vitamin A by maturating into normal granulocytes which can cause capillary leakage and organ damage ¹.

Terminology

Differentiation syndrome is the preferred term as other anti-leukemia drugs are implicated. Arsenic trioxide (ATO) is often used in combination with ATRA and contributes to the development of this syndrome.

Isocitrate dehydrogenase (IDH) inhibitors cause this syndrome in acute myeloid leukemia (AML) patients.

Epidemiology

Incidence is approximately 25% in APL patients treated with ATRA +/- ATO and 20% in AML patients treated with IDH inhibitors.

Pathology

Differentiation syndrome is related to the rapid increase in mature granulocytes over several days resulting in vascular adherence and organ infiltration. Cytokine release can cause capillary leak, hemorrhage and organ failure and these effects can be blocked by corticosteroids. Mortality can be as high as 25% and is commonly due to heart failure, acute respiratory distress syndrome, pulmonary hemorrhage and renal failure ¹.

Clinical presentation

Differentiation syndrome occurs approximately 7 days after treatment initiation with features of fever, congestive heart failure, fluid-retention, respiratory distress, hemorrhage, thrombosis and renal failure.

Radiographic features

Cardio-pulmonary disease dominates the radiographic picture.

Plain radiograph

Imaging appearances are non-specific but can help to confirm the clinical suspicion of differentiation syndrome: 

• increased cardiothoracic ratio

• increased vascular pedicle width

• widespread ground-glass opacities, consolidation, il-defined nodules

• peribronchial cuffing

• septal lines

• pleural effusion(s) 

CT

Chest CT may show features of congestive heart failure, acute lung injury and pulmonary hemorrhage:

• cardiomegaly due to myocardial damage and pericardial effusion

• systemic venous distension

• pleural effusions

• lung opacity due to diffuse alveolar damage and hemorrhage

Treatment and prognosis

Without prompt treatment with corticosteroids, the mortality of all-trans-retinoic acid syndrome is about 25% ¹. Early intervention with high dose corticosteroids is effective, and those most at risk are given steroid prophylaxis. Acute myeloid leukemia treated with differentiation agents has a lower mortality rate compared to acute promyelocytic leukemia treated with ATRA.

History and etymology

All-trans-retinoic acid syndrome was first described in 1991 by Frankel et al. ^1-3,7.

Differential diagnosis

• congestive heart failure

• acute lung injury

• fluid overload

See also

• leukemia

• pulmonary manifestations of leukemia