The European journal of neuroscience · 2002
The lemniscal-cuneate recurrent excitation is suppressed by strychnine and enhanced by GABAA antagonists in the anaesthetized cat.
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Gupta Prakhar, Ghosh Shouriyo, Roy Sabyasachi, Das Poonam, Poddar Dibakar, Chattopadhyay Debranjani, Kumar Jeevan, Nag Arijit, Ghara Niharendu, Nair Reena, Rath Asish, Vinarkar Sushant, Parihar Mayur, Mishra Deepak Kumar
Аннотация
INTRODUCTION: Acute promyelocytic leukemia (APL) is defined by the PML-RARα fusion gene, which serves as a key biomarker for pathogenesis, diagnosis, and measurable residual disease (MRD) monitoring. The incorporation of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has markedly transformed treatment outcomes. However, treatment-related toxicities frequently lead to treatment interruptions that may lead to persistent MRD post-induction therapy. This study investigates whether variations in doses are associated with persistent MRD. Additionally, statistical modelling is utilized to find the ideal dose and duration of ATRA for induction, to balance drug toxicity and response.
MATERIAL AND METHOD: A retrospective cohort of APL patients treated at Tata Medical Centre, Kolkata, between January 2019 and July 2024 was analysed. All patients received ATRA-ATO-based induction regimens, with chemotherapy added as per risk stratification. Post-induction MRD status was assessed via digital droplet PCR for PML-RARα on bone-marrow samples. Cumulative ATRA dose, body surface area (BSA) and treatment duration were calculated, considering variations in dose and exposure duration. Binary logistic regression and receiver operating characteristic (ROC) analysis were used to identify dose thresholds predictive of MRD negativity.
RESULTS: Of Thirty-seven patients, 54 % (n=20) exhibited detectable PML-RARAα transcripts post-induction. Seventeen patients experienced drug therapy disruptions due to adverse effects. ATRA dose reduction was significantly associated with MRD positivity (p=0.025). Among the dosing metrics evaluated, Cumulative ATRA Dose Adjusted For BSA showed the strongest predictive value for MRD status (AUC=0.710, p=0.029), with a Youden-optimized (index=0.338) threshold of 1844.8 mg/m² achieving the best response. The ideal daily ATRA dose was estimated at 41 mg/m²/day, accounting for variability in treatment duration, close to the recommended dose.
CONCLUSION: Post-induction MRD persistence in APL is significantly associated with ATRA dose disruptions. A Cumulative ATRA Dose Adjusted For BSA of 1844.8 mg/m² appears optimal for balancing MRD clearance and minimizing toxicity rather than a fixed daily dose. This highlights the importance of personalized ATRA dosing strategies, reinforces the recommendations, and provides a data-driven threshold to guide clinical practice.
SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s12288-025-02230-5.
MATERIAL AND METHOD: A retrospective cohort of APL patients treated at Tata Medical Centre, Kolkata, between January 2019 and July 2024 was analysed. All patients received ATRA-ATO-based induction regimens, with chemotherapy added as per risk stratification. Post-induction MRD status was assessed via digital droplet PCR for PML-RARα on bone-marrow samples. Cumulative ATRA dose, body surface area (BSA) and treatment duration were calculated, considering variations in dose and exposure duration. Binary logistic regression and receiver operating characteristic (ROC) analysis were used to identify dose thresholds predictive of MRD negativity.
RESULTS: Of Thirty-seven patients, 54 % (n=20) exhibited detectable PML-RARAα transcripts post-induction. Seventeen patients experienced drug therapy disruptions due to adverse effects. ATRA dose reduction was significantly associated with MRD positivity (p=0.025). Among the dosing metrics evaluated, Cumulative ATRA Dose Adjusted For BSA showed the strongest predictive value for MRD status (AUC=0.710, p=0.029), with a Youden-optimized (index=0.338) threshold of 1844.8 mg/m² achieving the best response. The ideal daily ATRA dose was estimated at 41 mg/m²/day, accounting for variability in treatment duration, close to the recommended dose.
CONCLUSION: Post-induction MRD persistence in APL is significantly associated with ATRA dose disruptions. A Cumulative ATRA Dose Adjusted For BSA of 1844.8 mg/m² appears optimal for balancing MRD clearance and minimizing toxicity rather than a fixed daily dose. This highlights the importance of personalized ATRA dosing strategies, reinforces the recommendations, and provides a data-driven threshold to guide clinical practice.
SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s12288-025-02230-5.