Ultrasensitive NGS MRD assessment in Ph+ ALL: Prognostic impact and correlation with RT‐PCR for BCR::ABL1

Abstract Reverse transcription polymerase chain reaction (RT‐PCR) for BCR::ABL1 is the most common and widely accepted method of measurable residual disease (MRD) assessment in Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ ALL); however, RT‐PCR may not be an optimal measure of MRD in many cases of Ph+ ALL. We evaluated the clinical impact of a highly sensitive next‐generation sequencing (NGS) MRD assay (sensitivity of 10 −6 ) and its correlation with RT‐PCR for BCR::ABL1 in patients with Ph+ ALL. Overall, 32% of patients had a discordance between MRD assessment by RT‐PCR and NGS, and 31% of patients who achieved NGS MRD negativity were PCR+ at the same timepoint. Among eight patients with long‐term detectable BCR::ABL1 by PCR, six were PCR+/NGS−. These patients generally had stable PCR levels that persisted despite therapeutic interventions, and none subsequently relapsed; in contrast, patients who were PCR+/NGS+ had more variable PCR values that responded to therapeutic intervention. In a separate cohort of prospectively collected clinical samples, 11 of 65 patients (17%) with Ph+ ALL who achieved NGS MRD negativity had detectable BCR::ABL1 by PCR, and none of these patients relapsed. Relapse‐free survival and overall survival were similar in patients who were PCR+/NGS− and PCR−/NGS−, suggesting that PCR for BCR::ABL1 did not provide additional prognostic information in patients who achieved NGS MRD negativity. NGS‐based assessment of MRD is prognostic in Ph+ ALL and identifies patients with low‐level detectable BCR::ABL1 who are unlikely to relapse nor to benefit from therapeutic interventions.