Evidence of the efficacy of topiramate in PTC

Evidence of the efficacy of topiramate in PTC has been reported in the literature [41,42]. The largest study, an open-label trial by Celebisoy and colleagues [41], demonstrated the non-inferiority of topiramate to acetazolamide in the management of idiopathic intracranial Sirtinol in a population consisting primarily of women of child-bearing age. Patients with secondary causes of PTC, such as medications, were excluded from this analysis. Although one of our five cases was successfully managed with ATRA interruption and acetazolamide treatment alone, the remaining four experienced symptom relief only after topiramate was utilized. Three of four patients receiving topiramate were being closely monitored in the inpatient setting. Additionally, three patients were able to safely receive topiramate as outpatients with regularly scheduled follow-up. Metabolism of ATRA occurs through the CYP450 system. Co-administration of agents that inhibit CYP3A4, CYP2C8, and CYP2C9 has been implicated to increase serum ATRA levels [43]. Theoretically, these interactions could potentiate PTC in patients managed with differentiation therapy. ATO is primarily metabolized through methylation. Methyltransferases responsible for this reaction are not members of the CYP450 system, and formal drug interaction studies with this agent have not been conducted [44].Standard protocol at our institute dictates that neutropenic patients receiving dual differentiation therapy are to receive fungal prophylaxis with micafungin. Although azole antifungals were not used in the patients included in our report, two cases were receiving CYP3A4 inhibitors (diltiazem and omeprazole) during ATO–ATRA therapy and at onset of PTC symptoms. No other interacting medications were noted.
Introduction Clinically, CNL and aCML are rare leukemias characterized by varying degrees of leukocytosis, anemia, thrombocytopenia, splenomegaly, and constitutional symptoms. Key distinguishing pathologic features between CNL and aCML are summarized in Table 1[1]. No standard of care is established for CNL and aCML and the reported median overall survival is approximately two years [2]. Recently, Maxson, et al. reported CSF3R mutations in ~90% of patients with CNL and in ~40% of patients with aCML [3]. Subsequent studies confirmed this high frequency of CSF3R mutation in CNL while observing a lower frequency in aCML [4]. Mutations in CSF3R generally occur in the extracellular membrane proximal domain or result in premature truncation of the cytoplasmic tail. Of note, membrane proximal mutations are far more common [3]. These membrane proximal mutations cause significant activation of JAK/STAT signaling. Therefore, targeting of the JAK/STAT pathway may inhibit granulocytic proliferation and provide clinical benefit to patients with CNL or aCML. Ruxolitinib (Incyte Corporation) is the first FDA-approved JAK1/JAK2 inhibitor with a reported IC50 of 3.3nM and 2.8nM, respectively [5]. In preclinical studies, targeting JAK1/2 with ruxolitinib significantly suppressed CSF3R-T618I-induced malignant colony growth compared to no drug treatment controls [6]. Transplantation of T618I-CSF3R-expressing mouse bone marrow cells was sufficient to produce a highly penetrant, lethal neutrophilic leukemia in a mouse model. Treatment of experimental mice with ruxolitinib provided disease control and improved survival compared to untreated controls [6]. These studies suggest that targeting JAK1/2 may provide clinical benefit to patients with these rare types of leukemia.
Case study A 75 year old man with Parkinson׳s disease was diagnosed with aCML in April 2013 based on pathologic review of his bone marrow biopsy and on the finding of the CSF3R-T618I mutation. According to old records, leukocytosis (not otherwise specified) was present as far back as 2005. His CBC before he began taking hydroxyurea showed WBC 71.3×10e3/microliter, ANC 42.1×10e3/microliter, Hgb 9.8g/dL, MCV 98.3fL, and platelet 97×10e3/microliter. His peripheral blood showed 12% immature granulocytes and hypogranular neutrophils and rare pseudo-Pelger–Huet neutrophils. His bone marrow showed granulocytic hyperplasia (myeloid:erythroid ratio >15:1) and hypolobated megakaryocytes in 30% of megakaryocytes. Peripheral and marrow blasts were less than 1%. In addition to the CSF3R-T618I mutation (50% allele frequency), his disease also harbored CBL-I383T (70% allele frequency) and KDM6A-S114C (100% allele frequency on one X chromosome) mutations evaluated by massively parallel sequencing. SETBP1 was wildtype. His disease was characterized by progressive leukocytosis, anemia, thrombocytopenia, splenomegaly, and constitutional symptoms. Performance status was ECOG of 3. Physical exam revealed a chronically ill-appearing, cachectic male with massive splenomegaly. He began taking hydroxyurea in April 2013 at 1000mg three times per week and 500mg four times per week (total 5000mg per week).