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Subclonal Mutations Predict Poor Outcomes After Relapse in ALL

Study findings posit that although subclonal NT5C2 mutations are rapidly eradicated by relapse therapy, they independently prognosticate inferior outcomes post-relapse in patients with acute lymphoblastic leukemia (ALL; Blood. 2020;135[12]:921-933).

“Activating mutations in [NT5C2] are considered to drive relapse formation in [ALL] by conferring purine analog resistance,” explained Malwine J. Barz, PhD, Department of Pediatric Oncology/Hematology, Charité–Universitätsmedizin Berlin, Germany, and colleagues, who evaluated the clinical effects of NT5C2 mutations in 455 patients with relapsed B-cell precursor ALL in the ALL-REZ BFM 2002 relapse trial. These patients were treated with sequencing and sensitive allele-specific real-time polymerase chain reaction.

Dr Barz et al identified 110 NT5C2 mutations in 75 (16.5%) overall, with approximately 67% and 33% of relapses harboring subclonal and clonal mutations, respectively.

Furthermore, post-relapse event-free survival was inferior in patients with relapses with clonal and subclonal NT5C2 mutations versus those without either mutation (19% and 25% vs 53%, respectively; P <.001).

Of note, subclonal NT5C2 mutations were tied to reduced event-free survival in multivariable analysis whereas clonal mutations were not (hazard ratio, 1.89; 95% CI, 1.28-2.69; P = .001). Subclonal NT5C2 mutations were also associated with a higher rate of nonresponse to relapse therapy (subclonal 32%, clonal 12%, wild type 9%, P <.001).

That said, 27 (82%) of 33 subclonal NT5C2 mutations turned out to be undetectable as of the point of nonresponse or second relapse, and in 10 (71%) of 14 patients had subclonal NT5C2 mutations that couldn’t be detected after relapse induction treatment.

“These results show that subclonal NT5C2 mutations define relapses associated with high risk of treatment failure in patients and at the same time emphasize that their role in outcome is complex and goes beyond mutant NT5C2 acting as a targetable driver during relapse progression,” Dr Barz and colleagues said.

“Sensitive, prospective identification of NT5C2 mutations is warranted to improve the understanding and treatment of this aggressive ALL relapse subtype,” they concluded.—Hina Porcelli

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