Superior Therapy Response Predictions for Patients with Myelodysplastic Syndrome (MDS) Using Cellworks Singula™: Mycare-020-02

Background: Therapy selection for MDS patients is often based on information considering only cytogenetics and single molecular aberrations and ignoring other patient-specific omics data that could potentially enable more effective treatments. In turn, despite using cytogenetic and molecular-risk stratification and precision medicine, the current overall outcome of MDS patients remains relatively poor. The Cellworks Singula™ report predicts response for physician prescribed treatments using the novel Cellworks Omics Biology Model (CBM) to simulate downstream molecular effects of cell signaling, drugs, and radiation on patient-specific in silico diseased cells.

Methods: The performance of Singula™ was evaluated in an independent, randomly selected, retrospective cohort of 144 MDS patients aged 28 to 89 years (median 69). The pre-defined Singula™ Classifier utilizes an individual's genomics profile to provide a dichotomous prediction of response or non-responses to a given physician prescribed treatment (PPT). Outcome data for these subjects, including measurement of complete response (CR), were obtained from 42 PubMed publications, each including patient genomics data of either karyotyping, targeted gene panels, and/or whole exome sequencing. Blinded to clinical outcomes, Cellworks utilized these data to generate a Singula™ classifier of responder vs non-responder in this MDS cohort. Statistical analyses, including assessments of accuracy, sensitivity, specificity, negative (NPV) and positive predictive (PPV) values were performed on the merged data to compare the Singula™ predicted response with the actual observed CR. Multivariate logistic regression models of complete response were performed incorporating covariates for patient age, PPT, and the Singula™ Classifier.

Results: Table 1 reveals that the pre-defined Singula™ classifier had 90.3% (Exact 95% CI: 84.2%, 94.6%) accuracy in predicting observed patient response from the physician prescribed treatment. In this study, Singula™ was able to accurately identify responders with 90.0% (81.2%, 95.6%) sensitivity. Importantly, Singula™ had 90.6% (80.7%, 96.5%) specificity for the subset of 64 patients (44.4%) that had a non-response. For 32% (17/54) of the non-responders patients, Singula™ provided an alternative Standard of Care treatment therapy, as shown in Table 2. The remaining 37 patients were predicted to be non-responders to all remaining Standard of Care options, so did not have alternate treatment predictions. Assuming at least 4% of these non-responding patients would have responded to the alternative Singula™ prescribed therapy, then these data support that Singula™ improves prediction of CR compared to the original PPT (McNemar's p-value < 0.05). In multivariate logistic regression models of CR that included patient age and prescribed drug therapy, the Singula™ Classifier remained an independent, significant predictor of CR (OR > 100, p-value < 0.0001), while both patient age (p = 0.372) and drug therapy (p = 0.720) fell off the model.

Conclusions: Cellworks Singula™ has high accuracy and sensitivity in predicting CR for MDS patient response to physician prescribed therapies. Singula™ also has high specificity in identifying patients who are unlikely to respond to physician prescribed therapies and provides alternative treatment recommendations for these patients. The Singula™ Classifier is an independent and superior predictor of CR compared with other clinical (age) or therapeutic (PPT) factors.

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