Progressive hyperleukocytosis associates with differential syndrome in acute promyelocytic leukemia patients treated with all-trans retinoic acid and arsenic trioxide

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Conference Proceeding

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Background: The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) as first line treatment has drastically transformed acute promyelocytic leukemia (APL) management. The chemotherapy-free regimen is superior to ATRA plus chemotherapy with improved event-free survival and lower relapse rate. However progressive leukocytosis leading to differentiation syndrome (DS) has been an increasing concern.

Aims: Our retrospective study compared the incidence of hyperleukocytosis- related DS in APL patients treated with ATRA plus ATO versus anthracycline chemotherapy during induction. We also aimed to determine the predictive factors for developing DS in patients treated with ATRA plus ATO regimen.

Methods: 28 APL patients in our metropolitan tertiary center over a 10-year period (2009-2019) were included in our study. Diagnosis of APL was confirmed by FISH/cytogenetics and/or PML-RARA PCR upon hospitalization. 16 patients were treated with ATRA plus chemotherapy, while ATRA/ATO group consisted of 12 patients. Multiple parameters were analyzed in each group, including age, sex, BMI, maximum WBC counts, WBC doubling time, LDH, creatinine, DS events and patient outcomes after induction.

Results: Compared with ATRA plus chemotherapy, ATRA/ATO combination had fewer pancytopenia, neutropenic fever, and anthracycline-induced heart failure. Nonetheless addition of ATO led to frequent peripheral leukocytosis (WBC > 10X109/L, 11 out of 12 patients) rather than myelosuppression as seen with chemotherapy. Furthermore, ATRA/ATO associated with hyperleukocytosis (WBC > 50X109/L), resulted in DS in the high risk patient and 3 out of 8 intermittent risk patients, causing multi-organ dysfunction/failure. Among those patients, short WBC doubling time ( < 3 days, p value = 0.0019) correlated with hyperleukocytosis in contrast to longer WBC doubling time ( > 7 days) (Table 1). Rapid WBC doubling was followed by significantly elevated LDH, acute kidney injury (AKI), progression to tumor lysis syndrome, and eventually DS. Age > 60 years old and male gender were also possible risk factors for hyperleukocytosis (Table 1). Cytoreduction with Hydroxyurea, aggressive hydration and diuretics use, as well as prompt Dexamethasone initiation at the first sign of DS are essential to improve patient outcomes.

Summary/Conclusion: Dual differentiation agents ATRA plus ATO frequently induce hyperleukocytosis, which contribute to differentiation syndrome in high and intermittent risk APL patients during induction. Short WBC doubling time ( < 3 days), accompanied by elevated LDH and AKI, are the major risk factors leading to hyperleukocytosis. High awareness of hyperleukocytosis and early recognition of DS are crucial for management of those potentially life-threatening complications in this otherwise highly curable APL.



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