Abstract 6181: Dynamic changes in monocyte and reticulocyte counts predict mechanism-based anemia development and recovery during ATR inhibitor treatment in phase I/II trials
Authors: Ngoi Natalie Y. , Lin Heather Y. , Dumbrava Ecaterina , Fu Siqing , Karp Daniel D. , Naing Aung , Pant Shubham , Piha-Paul Sarina A. , Rodon Jordi , Subbiah Vivek , Tsimberidou Apostolia M. , Campbell Erick , Urrutia Samuel , Hong David S. , Meric-Bernstam Funda , Yuan Ying , Yap Timothy A. 
Published: April 2023

Abstract
Introduction: Clinical trials are exploring ATR inhibitors (ATRi) in genomically selected contexts. However, dose-dependent anemia has limited the therapeutic index of this class. We hypothesized that monocytes and reticulocytes are more vulnerable to ATRi due to their lack of base excision repair and high levels of oxidative stress, respectively. We sought to examine the kinetics of decline and recovery of red blood cell (RBC) and reticulocyte indices, in relation to hemoglobin (Hb), in the first 28 days after ATRi initiation.
Methods: We retrospectively retrieved peripheral blood cell indices from complete blood count (CBC) reports of patients (pts) pre- and during treatment with an oral ATRi on phase I/II trials at our center. Pts received ATRi monotherapy or in combination with a PARP inhibitor (ATRi+PARPi) in dose-escalation and expansion cohorts, which included ATRi at potentially toxic doses. We applied linear mixed effect models to evaluate the joint evolution of Hb and other RBC or reticulocyte indices over time via bivariate analysis. A random intercept was included in the model to account for the longitudinal nature of the data and a variance component option for the covariance structure was specified to model a different variance component for each index of interest. To assess if Hb decline was preceded by decline in the index of interest from baseline, piecewise regression models were used to estimate break points, defined as the time point where the fitted functions intersect, of each index. Log transformed data with a base of 2, were noted to have more symmetric distributions, and were used in the analyses. The time variable assessed was days from cycle 1 day 1 of ATRi. A two-sided p value &lt;0.05 was considered statistically significant.
Results: 35,007 indices from 1,843 CBC of 119 pts treated with an ATRi from 10/2017 to 1/2022 were analyzed. 110 (92.4%) pts received ATRi, 9 (7.6%) received ATRi+PARPi. Monocytes (-0.120 vs -0.022, p &lt;0.0001) and reticulocytes (-0.140 vs -0.022, p &lt;0.0001) declined at a faster rate compared with Hb. Time to monocyte and reticulocyte nadir after ATRi initiation was 8.9 and 5.8 days, respectively, while time to Hb nadir was 19.5 days. Conversely, RBC (-0.020 vs -0.023, p=0.410), MCV (-0.002 vs -0.022, p &lt;0.0001) and MCH (-0.001 vs -0.022, p&lt;0.0001) declined at a slower rate than Hb. Time to RBC, MCV and MCH nadir after ATRi initiation was 26.3, 18.7 and 15.0 days, respectively. After reaching their individual index nadir, monocytes (0.004 vs 0.001, p &lt;0.0001) and reticulocytes (0.005 vs 0.0005, p &lt;0.0001) increased more quickly than Hb.
Conclusions: Charting the kinetics of CBC index evolution in relation to Hb identified peripheral monocytes and reticulocytes as relevant blood indices that herald Hb decline. Our findings may inform patient monitoring strategies to mitigate hematologic toxicity on future ATRi trials.
Citation Format: Natalie Y. Ngoi, Heather Y. Lin, Ecaterina Dumbrava, Siqing Fu, Daniel D. Karp, Aung Naing, Shubham Pant, Sarina A. Piha-Paul, Jordi Rodon, Vivek Subbiah, Apostolia M. Tsimberidou, Erick Campbell, Samuel Urrutia, David S. Hong, Funda Meric-Bernstam, Ying Yuan, Timothy A. Yap. Dynamic changes in monocyte and reticulocyte counts predict mechanism-based anemia development and recovery during ATR inhibitor treatment in phase I/II trials. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6181.