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

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.

High-sensitivity next-generation sequencing MRD assessment in ALL identifies patients at very low risk of relapse.

Measurable residual disease (MRD) is highly prognostic for relapse and overall survival (OS) in acute lymphoblastic leukemia (ALL), although many patients with apparent "MRD negativity" by standard assays still relapse. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay in 74 adults with ALL undergoing frontline therapy. Among remission samples that were MRD negative by multiparameter flow cytometry (MFC), 46% were MRD+ by the NGS assay. After 1 cycle of induction chemotherapy, MRD negativity by MFC at a sensitivity of 1 × 10-4 and NGS at a sensitivity of 1 × 10-6 was achieved in 66% and 23% of patients, respectively. The 5-year cumulative incidence of relapse (CIR) among patients who achieved MRD negativity by MFC at complete remission (CR) was 29%; in contrast, no patients who achieved early MRD negativity by NGS relapsed, and their 5-year OS was 90%. NGS MRD negativity at CR was associated with significantly decreased risk of relapse compared with MRD positivity (5-year CIR, 0% vs 45%, respectively; P = .04). Among patients who were MRD negative by MFC, detection of low levels of MRD by NGS identified patients who still had a significant risk of relapse (5-year CIR, 39%). Early assessment of MRD using a highly sensitive NGS assay adds clinically relevant prognostic information to standard MFC-based approaches and can identify patients with ALL undergoing frontline therapy who have a very low risk of relapse and excellent long-term survival.

Tyrosine Kinase Inhibitors Early in the Disease Course: Lessons From Chronic Myelogenous Leukemia.

The landscape of chronic myeloid leukemia (CML) management has changed with the advent of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 oncoprotein. Imatinib mesylate, followed by nilotinib and dasatinib, has been approved for newly diagnosed patients. Since none of these TKIs show survival superiority, the drug choice is a challenge. Even so, the rate of deeper and earlier responses is higher with second-generation TKIs than it is with imatinib, and, in general, better response is associated with a survival advantage, regardless of TKI type being used. Patients should be monitored carefully for response, and treatment failure should prompt a timely switch to another TKI. Side effect profile and drug cost are other important considerations in therapy choice. In several clinical studies, achieving undetectable and durable disease status allowed some patients to discontinue the TKI and enjoy long-term treatment-free remission. Cure for CML may be possible with TKIs alone or TKIs in combination with other investigational therapies. However, due to lack of long-term outcome data and absence of consensus for the definition of optimal response and time to stop TKIs, discontinuation is discouraged outside of a clinical trial.