br Role of the funding

Role of the funding source
Contributions
Conflicts of interest
Acknowledgments The authors would like to thank the patients who participated in this study and their families. The authors would also like to acknowledge the writing assistance of Stephen Mosley, Ph.D., of Knowledge Point 360, in the development of this manuscript, which was funded by Millennium: The Takeda Oncology Company, and Jeff Klko, MD, for providing photomicrographs.
Introduction Acute promyelocytic leukemia (APL) is an aggressive myeloid malignancy defined by the presence of the PML-RARα fusion gene produced by a translocation between chromosomes 15 and 17. Through risk stratification and incorporation of tretinoin (all-trans-retinoic acid; ATRA) into treatment, patient outcomes have drastically improved with complete response (CR) rates reaching >90% when combined with chemotherapy [1–3]. Most recently, dual differentiation therapy with ATRA and arsenic trioxide (ATO) (Table 1), has become a recommended first-line regimen by the National Comprehensive Cancer Network for the management of patients with low/intermediate risk APL (white blood cell (WBC) count <10×109/L), or patients with high risk disease who are unable to receive anthracycline-based chemotherapy [4]. ATO binds to the PML end of the fusion protein resulting in apoptosis of APL Lomerizine HCl [5]. A randomized controlled trial by Lo-Coco et al. [6] demonstrated complete remission rates of 100% with dual differentiation therapy, proving non-inferiority of the ATO-ATRA combination over ATRA plus chemotherapy in the management of low/intermediate risk APL. Pseudotumor cerebri (PTC), also known as idiopathic intracranial hypertension, is a condition characterized by an increase in intracranial pressure, without cerebrospinal fluid (CSF) abnormalities or radiological evidence of other intracranial pathology (hydrocephalus, mass, structural or vascular lesion) [7]. PTC following ATRA administration for APL has been well described [8–26]. However, reports of PTC resulting specifically from dual differentiation therapy are currently lacking, and there is a paucity of evidence describing management of this condition specifically in patients with APL, where continuation of therapy is necessary for optimal clinical outcomes. Although the exact mechanism of ATRA induced PTC is currently unknown, a variety of medications are used in its management including carbonic anhydrase inhibitors, diuretics, corticosteroids, and analgesics. Acetazolamide, a carbonic anhydrase inhibitor, is the most commonly used agent in the management of non-drug induced PTC and is thought to work through reduction of CSF production. More recently, the anticonvulsant topiramate has been viewed as an attractive treatment option for idiopathic PTC given its activity as a carbonic anhydrase inhibitor (mostly at receptor subtypes II and IV) and its efficacy as a migrainolytic [27–29]. The precise mechanism of both migrainolysis and anti-epileptic efficacy is unknown, however the drug is known to antagonize sodium channels, augment the effect of gamma-aminobutyrate (GABA) at receptor subtype A, and antagonize the AMPA/kainate subtypes of the glutamate receptors [30]. From November 2012, through January 2014, ten patients with low or intermediate risk APL received upfront dual differentiation therapy with the ATO–ATRA combination [4]. Out of these ten patients, we describe five (50%) cases of PTC which occurred following the initiation of dual differentiation therapy and their clinical courses, with an emphasis on our experience with the substitution of topiramate in place of acetazolamide in non-responders.
Case 1 A 54 year old African American male was transferred to RPCI where workup revealed a diagnosis of APL (Table 2) and dual differentiation therapy was subsequently initiated (Table 1). That same evening, he complained of severe headache that was out of the ordinary for him with no other symptoms. Of note, he was also receiving concomitant diltiazem CD 180mg daily, a medication known to inhibit CYP3A4 [31]. A head CT scan was without any abnormalities, and a lumbar puncture (LP) revealed an elevated intracranial pressure (ICP) of 35cm H20. ATRA was interrupted, and acetazolamide was started at 250mg orally twice daily. After two days, his headache resolved and ATRA was restarted with an 80% dosage reduction. Headaches resumed upon ATRA reintroduction. However, therapy was continued, and acetazolamide was increased to 500mg orally twice daily.