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    • br Case A year old Caucasian male

    2019-05-20


    Case 4 A 59 year old Caucasian male with a history of chronic renal insufficiency was transferred to our intensive care unit from an outside hospital, intubated secondary to respiratory failure and severe mucositis. He arrived on multiple broad spectrum aldehyde dehydrogenase inhibitor for treatment of healthcare associated pneumonia and possible invasive fungal infection. He was found to have APL (Table 2) and was started on ATO–ATRA induction (Table 1). ATRA was administered as a compounded suspension down a nasogastric tube during intubation. He continued to be intubated for the first week of the dual differentiation therapy and was extubated on day ten of his admission. Due to renal failure of unclear etiology requiring hemodialysis, ATO was dosed every 48h for the first two weeks of therapy until normalization of renal function. At day 28, a bone marrow biopsy revealed persistent disease, and a repeat marrow was planned for one week later. Thirty one days after initiation of induction, this patient began to experience 8/10 intensity headaches accompanied by nausea. Pain was unrelieved by oxycodone. A diagnostic LP revealed an elevated ICP (Table 1) without CSF abnormalities. ATRA was held and acetazolamide started at 500mg orally twice daily. After holding three doses of ATRA, headaches completely resolved and ATRA was then restarted at 50% of the original dosage. His ATRA was able to be titrated up to 67% of the original dose, which he continued for the remainder of induction. He was discharged with a prescription for acetazolamide 250mg orally twice daily to take during ATRA consolidation. After initiation of consolidation cycle 1, he was admitted for renal insufficiency and metabolic acidosis secondary to acetazolamide treatment. Since then, he has been taking sodium bicarbonate tablets 650mg orally twice daily with acetazolamide. At the time of this writing, he is currently receiving cycle 2 of consolidation and remains in CR.
    Case 5 A 62 year old Caucasian male with a history of thyroid cancer was transferred to RPCI for further workup of pancytopenia, fevers, and flu-like symptoms. Work up revealed APL (Table 2). He successfully completed induction with dual differentiation therapy without interruption or development of PTC. A bone marrow biopsy on day 28 met criteria for drug discontinuation, and the patient was discharged home. Two weeks later, upon obtaining CR, he began consolidation (Table 1). Three days into his first cycle of consolidation, the patient presented with complaints of headaches that were unrelieved by oxycodone. The patient was initiated on acetazolamide 250mg orally twice daily to be taken with ATRA, which led to minimal headache relief. A diagnostic LP revealed PTC (Table 1). As a result, ATRA was held, acetazolamide discontinued, and topiramate 50mg orally twice daily initiated. He continued topiramate for ten days until complete resolution of headaches. At the start of his next two-week ATRA period, his ATRA was reinitiated at 50% of his original dose, and topiramate switched back to acetazolamide 250mg orally twice daily for headache prophylaxis. Four weeks later, on the first day of cycle three, the patient began to develop headaches again that failed to respond to oxycodone and acetazolamide 500mg orally twice daily. Again, his ATRA was held, acetazolamide discontinued, and topiramate reinitiated at 50mg orally twice daily. After complete resolution of his headaches, ATRA was reinitiated at 50% of his previous dose and continued, along with topiramate, for the remainder of his consolidation. Of note, the patient was receiving omeprazole, a CYP3A4 inhibitor, throughout the duration of his consolidation therapy. He currently remains in remission four months after completion of consolidation therapy.
    Discussion Dual differentiation therapy has revolutionized the management of APL with comparable CR rates to ATRA plus chemotherapy with decreased risk of many adverse events typically associated with anthracyclines [6]. Despite the reduction shown in oral, hematologic, and infectious complications, the combination of ATO–ATRA is by no means risk free. Treatment with dual differentiation has been associated with significantly higher rates of QTc prolongation and hepatotoxicity compared to ATRA with idarubicin [6]. Although PTC has gone unreported in studies demonstrating the efficacy of the ATO–ATRA combination [6,32,33], our report suggests a significant incidence of PTC amongst APL patients being managed with this combination. Of the ten patients identified as having received dual differentiation therapy, five developed PTC, making our incidence 50%, an alarming rate. It is unclear why our patient population developed such a high incidence of PTC. We report the management of our first 10 patients receiving dual differentiation therapy, however it is possible that the incidence may become diluted once we have treated a larger number of patients. In addition, our team may have become more vigilant in screening for PTC and had a lower threshold for doing a LP upon symptom development given our previous patient׳s experiences with PTC from ATO-ATRA. A third possible reason may be related to under reporting of this complication of dual differentiation therapy.