Hypercalcemia in Pediatric Malignancies

Retinoic Acid Differentiation Syndrome in Acute Promyelocytic LeukemiaSean Green

Doctor of Pharmacy Candidate, 2013

Massachusetts College of Pharmacy and Health Sciences

Childrens Hospital Boston

December 10, 2012Pathophysiology: Acute promyelocytic leukemia (APL) is a subtype of acute myelocytic leukemia (AML) characterized by translocation t(15;17) which causes fusion of the PML gene on chromosome 15 with the retinoic acid receptor gene on chromosome 17. Studies have shown that treatment of APL with all-trans retinoic acid (ATRA) has improved the survival rate of adult APL patients to 70-80%.1,2 However, in 15-25% of ATRA-treated APL patients, a process known as retinoic (or ATRA) differentiation syndrome has developed. Though the pathogenesis is largely unknown, it is hypothesized that ATRA-responsive differentiating myeloid precursors and granulocytes undergo changes in their adhesion ability and cytokine release leading to tissue infiltration and microvascular damage. Ultimately this uncontrolled endothelial injury leads to edema, hemorrhage, fibrinous exudates, fever, hypotension and eventually renal and respiratory failure.3 Despite a lack of any significant risk factors, a trend directly correlating severity of ATRA differentiation syndrome with initial WBC on presentation has been seen.2Presentation: ATRA differentiation syndrome usually presents approximately 10 days after initiating ATRA therapy, although reports have demonstrated patients with symptomatic onset within 2 days of starting ATRA. Respiratory distress and fever are found in 80% of patients, 50% have pulmonary infiltrates, 30% have pleural or pericardial effusions and 10% develop renal failure. Hypotension, bone pain, headache, and acute-onset congestive heart failure are also common manifestations.3Treatment: Due to the high mortality rate (~30%), prompt recognition and treatment is paramount to survival. Because the presentation of ATRA differentiation syndrome resembles many other conditions such as iatrogenic fluid overload, pneumonia and sepsis, many of these patients are inappropriately placed on antibiotics to while cultures are pending. The mainstay of therapy is discontinuation of ATRA until symptoms resolve along with steroids leading to an 80-90% survival rate after 3-26 days.2 ATRA should be held and dexamethasone should be started 10mg/m2 from the onset of symptoms to their resolution. Patients may be re-challenged with ATRA following disappearance of symptoms, however, they should be closely monitored for re-development. References:

1. Tallman, M. Best Research and Practice 16(3); 2003: 453-461 2. Patatanian, E. Journal of Clinical Pharmacy and Therapeutics 33; 2008: 331-3383. De Botton, S. Blood 92(8); 1998: 2712-2718