Differential Impact of CD34+ Cell Dose for Different Age Groups in Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia: A Machine Learning-Based Discovery

Authors:
raw_author_name: Yiyang Qu
raw_affiliation_string: Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON, Canada
raw_author_name: Aravind Subramanian
raw_affiliation_string: Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON, Canada
raw_author_name: Dionne Aleman
raw_affiliation_string: Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON, Canada
raw_author_name: Louis-Martin Rousseau
raw_affiliation_string: Department of Mathematical and Industrial Engineering, Polytechnique Montreal, Montreal, QC, Canada

Abstract: Allogeneic hematopoietic cell transplantation (alloHCT) is curative for hematologic malignancies; however, it is associated with risks and complications. Identification of risk factors remain the topic of ongoing investigation. Specifically, CD34+ cell dose impact on overall survival (OS) has been investigated in various studies with contradicting conclusions. We utilized machine learning (ML) techniques to predict alloHCT outcomes based on patient and transplant-related characteristics, using single-center data to identify critical and often overlooked variable interactions. Our predictive model improves on the conventional Cox regression analysis with the ability to capture complex high-dimensional relationships. The application of SHAP (SHapley Additive exPlanations), an explainable artificial intelligence (XAI) technique, allowed us to discern new and clinically relevant feature-outcome relationships. The cohort used for developing the machine learning model covers 1153 patients across different diagnoses, transplanted between 2010 to 2019. In particular, we chose XGBoost, a tree-based ML model, that is known for its high performance with tabular data. After further investigation by SHAP, we narrowed the study cohort to 674 acute leukemia patients (AML n=549, ALL n=125) with a median age of 54 (18-76), where we identified clear interaction between CD34+ cell dose of the peripheral blood stem cell (PBSC) grafts and patient age at alloHCT for acute leukemia patients (Figure 1). Three cell dose groups (low, medium and high) were determined using maximally selected rank statistics method, separately for the younger (≤45-years-old) and older (>45-year-old) patient age groups. On univariate analysis for OS, within the younger cohort, the group with a lower CD34+ dose resulted in the highest 2-year OS: low vs. medium vs. high dose, 84.6% vs. 48.2% vs. 59.1% (overall p-value=0.034, Figure 2a). For the older cohort, the group with a low CD34+ dose resulted in the lowest 2-year OS: low vs. medium vs. high dose, 33.3% vs. 48.8% vs. 55.1% (overall p-value=0.054, Figure 2b). Multivariable analysis affirmed the interaction effect: for younger acute leukemia patients, a cell dose no higher than 4.3 × 106 CD34+/kg was associated with improved OS against the medium (hazard ratio [HR] 0.22, p=0.004) and higher (HR 0.25, p=0.009) cell dose groups. Conversely, for older acute leukemia patients, low CD34+ cell dose <3.8 × 106/kg was associated with worse OS against a high dose ³6.1 × 106/kg (HR 1.73, p= 0.009). The high dose group in older patients retained superior OS compared to low and medium dose groups combined (HR 0.73, p=0.024). Our findings suggest that CD34+ cell dose should be tailored by patient age for acute leukemia patients undergoing alloHCT, and XAI showcases excellent proficiency in revealing such interactions.