Complications Unique to APL Therapy

Pseudotumor cerebri. Pseudotumor cerebri is typically manifested by headache, papilledema, sixth nerve palsy, visual field cuts, and normal intracranial imaging in the face of an elevated opening lumbar puncture pressure (not often obtained in APL patients). Pseudotumor cerebri is known to be associated with tretinoin, presumably by the same mechanism of vitamin A toxicity that leads to increased production of cerebrospinal fluid.The incidence of pseudotumor cerebri has been reported to be as low as 1.7% with very strict definitions of the complication and as high as 6% to 16% in pediatric trials.[3,12,22,32,33] Pseudotumor cerebri is thought to be more prevalent in children receiving tretinoin, leading to lower dosing in contemporary pediatric APL clinical trials.[3,33] Pseudotumor cerebri most typically occurs during induction at a median of 15 days (range, 1–35 days) after starting tretinoin, but is known to occur in other phases of therapy as well.[32] Pseudotumor cerebri incidence and severity may be exacerbated with the concurrent use of azoles via inhibition of cytochrome P450 metabolism of tretinoin.When a diagnosis of pseudotumor cerebri is suspected, tretinoin is withheld until symptoms abate and then is slowly escalated to full dose as tolerated.[32]

Differentiation syndrome. Differentiation syndrome (also known as retinoic acid syndrome or tretinoin syndrome) is a life-threatening syndrome thought to be an inflammatory response–mediated syndrome manifested by weight gain, fever, edema, pulmonary infiltrates, pleuro-pericardial effusions, hypotension, and, in the most severe cases, acute renal failure.[34] In the COG AAML0631 (NCT00866918) study, it was present in 20% of patients during induction. It was more prevalent in high-risk children (31%) than in low-risk children (13%), a risk factor also seen in adults with APL.[22,35] There is a bimodal peak with this syndrome seen in the first and third weeks of induction therapy. Since differentiation syndrome occurs more often in high-risk patients, dexamethasone is given with tretinoin and/or arsenic trioxide to prevent this complication.[34] Prophylaxis with dexamethasone and hydroxyurea (for cytoreduction) is also administered to standard-risk patients if their WBC count rises to greater than 10 × 109/L after the start of tretinoin or arsenic. If differentiation syndrome occurs, the patient's dexamethasone dose may be escalated with temporary withholding of tretinoin and arsenic trioxide and, similar to pseudotumor cerebri, restarted at a lower dose and escalated as tolerated. When this approach was used in the COG AAML1331 (NCT02339740) trial, 24.5% of standard-risk patients and 30.4% of high-risk patients presented with differentiation syndrome. Only one standard-risk patient died of differentiation syndrome and coagulopathy.[3]Patients with standard-risk APL who are treated during induction with tretinoin and arsenic trioxide alone, without other cytotoxic chemotherapy, have a risk of hyperleukocytosis (WBC count >10 × 109/L). The differentiating effect of tretinoin and arsenic trioxide can cause a rapid and significant rise in the WBC count after initiation of therapy. While hyperleukocytosis is a risk factor for developing differentiation syndrome, it may occur without developing the signs or symptoms of differentiation syndrome. In the COG AAML1331 trial, 32 of 98 patients with standard-risk APL developed hyperleukocytosis. This was managed with the initiation of hydroxyurea for cytoreduction and prophylaxis with dexamethasone to prevent differentiation syndrome. Patients with high-risk APL did not require hydroxyurea because they received idarubicin doses in early induction, which were effective for cytoreduction.[3]

Coagulopathy. Along with differentiation syndrome, coagulopathy complications result in a higher risk of death during induction therapy (early death in APL). For more information about the diagnosis and management of coagulopathy, see the Clinical Presentation section.

QT interval prolongation. Arsenic trioxide is associated with QT interval prolongation that can lead to life-threatening arrhythmias (e.g., torsades de pointes).[36] It is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at mid-reference ranges, as well as to be cognizant of other agents known to prolong the QT interval.[37]