Value of flow cytometry for MRD-based relapse prediction in B-cell precursor ALL in a multicenter setting
Signe Modvig, Heléne Hallböök, Hans O. Madsen, Sanna Siitonen, Susanne Rosthøj, Anne Tierens, Vesa Juvonen, Liv Osnes, Helen Vålerhaugen, Magnus Hultdin, Rėda Matuzevičienė, Mindaugas Stoškus, Millaray Marincevic, Aili Lilleorg, Mats Ehinger, Ulrika Norén‐Nyström, N. Toft, Mervi Taskinen, Ólafur G. Jónsson, Kaie Pruunsild, Goda Vaitkevičienė, Kim Vettenranta, Bendik Lund, Jonas Abrahamsson, Anna Porwit, Kjeld Schmiegelow, Hanne Vibeke Marquart
Abstract
Abstract PCR of TCR/Ig gene rearrangements is considered the method of choice for minimal residual disease (MRD) quantification in BCP-ALL, but flow cytometry analysis of leukemia-associated immunophenotypes (FCM-MRD) is faster and biologically more informative. FCM-MRD performed in 18 laboratories across seven countries was used for risk stratification of 1487 patients with BCP-ALL enrolled in the NOPHO ALL2008 protocol. When no informative FCM-marker was available, risk stratification was based on real-time quantitative PCR. An informative FCM-marker was found in 96.2% and only two patients (0.14%) had non-informative FCM and non-informative PCR-markers. The overall 5-year event-free survival was 86.1% with a cumulative incidence of relapse (CIR 5y ) of 9.5%. FCM-MRD levels on days 15 (HzR 4.0, p < 0.0001), 29 (HzR 2.7, p < 0.0001), and 79 (HzR 3.5, p < 0.0001) associated with hazard of relapse adjusted for age, cytogenetics, and WBC. The early (day 15) response associated with CIR 5y adjusted for day 29 FCM-MRD, with higher levels in adults (median 2.4 × 10 −2 versus 5.2 × 10 −3 , p < 0.0001). Undetectable FCM- and/or PCR-MRD on day 29 identified patients with a very good outcome (CIR 5y = 3.2%). For patients who did not undergo transplantation, day 79 FCM-MRD > 10 −4 associated with a CIR 5y = 22.1%. In conclusion, FCM-MRD performed in a multicenter setting is a clinically useful method for MRD-based treatment stratification in BCP-ALL.