PS1190 R-INTERFERON TREATMENT BEFORE TKI START IMPROVES TREATMENT FREE REMISSION RATE (TFR) PARTICULARLY IN CHRONIC MYELOID LEUKEMIA (CML) PATIENTS WITH THE LESS FAVORABLE E13A2 BCR-ABL1 TRANSCRIPT TYPE
Authors: M. D’Adda, M. Farina, A. Passi, D. Gramegna, R. Daffini, S. Ferrari, C. Bottelli, E. Borlenghi, E. Cerqui, D. Bertoli, S. Archetti, M. Marini, G. Rossi
Journal: HemaSphere (2019)

Background: Imatinib is administered at a fixed dose regimen for the treatment of chronic myeloid leukemia in chronic phase (CP-CML) regardless of patient's body size. However, increasing evidence support the impact of body size on efficacy (e.g., molecular response [MR]) and safety (e.g., dose limiting toxicity [DLT]). Hence, a weight-based initial dosing strategy of imatinib is worth assessing. Aims: Using extensive data retrieved retrospectively from electronic medical records (EMR), the dose-response relationships of imatinib along with DLTs and MRs were analyzed to determine the optimal dose of imatinib. Methods: Clinical data were collected from the patients newly diagnosed with CP-CML and treated initially with imatinib at Seoul St. Mary's Hospital. The evaluated primary efficacy endpoints were the achievement of MR1 at 3 months, MR2 at 6 months, and major molecular response (MMR) at 12 months. The transcript levels of BCR-ABL1/ABL1 were measured at screening, and at 3, 6 and 12 months after imatinib initiation. Safety responses were measured as the occurrence of DLTs by 12 months that required an interruption or discontinuation of imatinib. The time span between the administration of imatinib and the occurrence of first DLT (i.e., time-to-first DLT) was explored along with the relative occurrence of various DLTs. The efficacy and safety responses were analyzed in association with the initial dose of imatinib adjusted for body weight (Dose/BW). Patients were divided into 5 quantile groups (Q1-Q5) based on Dose/BW and graphically aligned in an ascending manner. The slopes of the graphs were statistically assessed using the chi-squared test for trend. Results: From 2001 to 2018 the clinical data were collected from a total of 1,003 Asian patients whose median BW was 64.0 kg (range, 37.8 to 106.0 kg) and Dose/BW 6.3 mg/kg (range, 3.8 to 10.6 mg/kg). Safety. Hematological DLTs occurred earlier than non-hematological DLTs with the median time-to-first DLT of 35 days (range, 3 to 277 days) and 58 days (range, 2 to 355 days), respectively. The frequent DLTs were thrombocytopenia (41.2%), dermatological reactions (12.1%) and neutropenia (10.6%); median time-to-first DLT for the toxicities were 35 days (range, 7 to 270 days), 78 days (range, 8 to 272 days) and 42 days (range, 4 to 270 days), respectively. As the Dose/BW of patients increased from Q1 to Q5 (4.9, 5.7, 6.2, 6.9 and 8.1 mg/kg, respectively), the probability of DLT occurrence by 12 months demonstrated a statistically significant increasing trend (p < 0.001) with Q1 having the lowest rate of 32% and Q5 having the highest of 65%. The differences in DLT occurrence between Q1 and other groups were all statistically significant except for Q2. The ideal dose with the lowest occurrence of DLT was 312.3 mg. As determined by mean Dose/BW of Q1 multiplied by median BW. Efficacy. Neither decreasing nor increasing trend between Dose/BW and MR1, MR2 or MMR achievements were detected in a statistical trend analysis; 39%, 37%, 36%, 47% and 38% of MMR achievements in groups Q1 to Q5 respectively. Summary/Conclusion: Based on the results, we recommend that the initial dose of imatinib be lowered not to exceed 4.9 mg/kg (300 mg once daily), particularly for Asian patients with smaller BW (<64 kg) to minimize DLTs without compromising efficacy.