Arsenic trioxide is a new and investigational agent for the treatment of relapsed or refractory acute promyelocytic leukemia (APL). Leukocytosis has been commonly noted with its use; however, this side effect usually resolves spontaneously and is generally not treated. To date, no deaths have been reported from the complications of leukocytosis associated with the use of arsenic trioxide. We report on a patient who died from the complications of a cerebral vascular event secondary to hyperleukocytosis and probable cerebral leukostasis, which occurred while the patient was receiving arsenic trioxide for relapsed APL.
A 27-year-old female was diagnosed with APL in May 1998. She was initially treated with all-trans-retinoic acid (ATRA), followed by consolidation chemotherapy with idarubicin, high-dose cytarabine, and ATRA. She presented to our clinic 6 months after completion of ATRA consolidation treatment with a white blood cell (WBC) count of 21.2 × 103/μL (50% promyelocytes and myeloblasts) and a platelet count of 19 × 103/μL. There was no disseminated intravascular coagulation (DIC), as evidenced by a normal fibrinogen level (248 ng/dL) and a normal activated partial thromboplastin time (PTT) (24.1 seconds). A bone marrow biopsy and aspirate confirmed the diagnosis of relapsed APL, and fluorescence in situ hybridization (FISH) analysis was positive for t(15;17). After the patient signed informed consent, treatment with daily intravenous arsenic trioxide 0.15 mg/kg was started. Arsenic trioxide was obtained from the National Cancer Institute under a compassionate individual patient special exception protocol. The patient's WBC count at the initiation of treatment with arsenic trioxide was 8.2 × 103/μL, and her platelet count was 41 × 103/μL. After 2 doses of arsenic trioxide, the WBC count had increased to 15.1 × 103/μL. After 3 doses, the patient was febrile at 38.2°C, and her WBC count had increased to 20.9 × 103/μL, but she was otherwise asymptomatic. Corticosteroid therapy was initiated at this time.
The patient's WBC count continued to rise, and on the seventh day of treatment she was asymptomatic, with a WBC of 101 × 103/μL and a platelet count of 61 × 103/μL. Following the eighth dose, the WBC count increased to 212.6 × 103/μL (89% myeloblasts) with a platelet count of 30 × 103/μL, and the arsenic trioxide was discontinued. Evidence of DIC included schistocytes on the blood smear, prothrombin time (PT) of 16.1 seconds, PTT of 23 seconds, decreasing fibrinogen (101 mg/dL), and increasing fibrinogen degradation products (FDP 8 mcg/dL). Later that day, the patient was found confused with slurred speech and right-sided weakness. A CT scan of the head was consistent with an early left middle cerebral artery (MCA) territorial infarct with no evidence of hemorrhage, mass effect, or midline shift. The patient was transferred to an intensive care unit and received high doses of decadron and platelet transfusions. Twelve hours later the patient had a generalized seizure. Another CT scan of the head showed an acute left MCA territorial infarct with diffuse cerebral edema and signs indicative of central herniation. The patient's WBC count was now 292.2 × 103/μL, and chemotherapy with idarubicin and cytarabine was started. The patient continued to deteriorate and expired on the fifteenth hospital day. The family declined an autopsy.
We report here for the first time death associated with hyperleukocytosis secondary to treatment with arsenic trioxide for relapsed APL. Leukocytosis is a well-documented effect of treatment with arsenic trioxide. Most patients experience a gradual increase in the WBC, which peaks between 2 and 3 weeks after starting treatment with arsenic trioxide. Soignet et al1 reported on 12 patients treated with arsenic trioxide for relapsed APL. Six patients (50%) experienced a leukocytosis with WBC counts ranging from 20.8 to 144.2 × 103/μL. None of the patients received therapy for the leukocytosis, and all continued on treatment. The leukocytosis resolved in all patients without treatment or complications. More recently, Niu et al2 presented toxicity and follow-up data on 47 patients with relapsed APL treated with arsenic trioxide. Leukocytosis was observed in 55% of patients treated, with WBC counts ranging from 11.9 × 103/μL to 167 × 103/μL. The WBC counts in 42% of these patients returned to normal after chemotherapy, and 54% of them normalized spontaneously. One patient with leukocytosis died from cerebral hemorrhage with a low platelet count and low fibrinogen. Interestingly, Niu et al alluded to leukocytosis as possibly being causative in the treatment failure and death of one patient treated with arsenic trioxide with newly diagnosed APL, but no details were given. Camacho et al3 presented data on 26 patients with relapsed or refractory APL treated with arsenic trioxide. They observed a 58% incidence of leukocytosis with no associated deaths. Leukocytosis with a WBC count as high as 260 × 103/μL resolved in all cases without administration of cytotoxic therapy or discontinuation of the arsenic trioxide (R. P. Warrell, personal communication, 1999).
Current protocols and clinical practice do not advocate cessation of arsenic trioxide in the setting of hyperleukocytosis. Recent reports indicate that leukocytosis during treatment with arsenic trioxide has an incidence of 50% to 60%, with the majority of cases resolving spontaneously. The treatment of ATRA-associated leukocytosis with chemotherapy is controversial and potentially harmful, and the role of chemotherapy in arsenic trioxide–associated hyperleukocytosis is unknown.4 Our case highlights that arsenic trioxide–associated hyperleukocytosis may be associated with central nervous system sequelae and can be fatal. This case is unusual due to the rapid rise in leukocytosis, which continued during the duration of the patient's treatment. The WBC count at which a cerebral event occurred was lower than the peak level of other reported cases in which there were no sequelae or discontinuation of drug. In conclusion, this case illustrates the need for a cautionary approach to the management of hyperleukocytosis associated with the administration of arsenic trioxide.
