Minimal residual disease in peripheral blood at day 15 identifies a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with superior prognosis

Abstract

The online version of this article has a Supplementary Appendix. BackgroundMost minimal residual disease-directed treatment interventions in current treatment protocols for acute lymphoblastic leukemia are based on bone marrow testing, which is a consequence of previous studies showing the superiority of bone marrow over peripheral blood as an investigational material. Those studies typically did not explore the prognostic impact of peripheral blood involvement and lacked samples from very early time points of induction. Design and MethodsIn this study, we employed real-time quantitative polymerase chain reaction analysis to examine minimal residual disease in 398 pairs of blood and bone marrow follow-up samples taken from 95 children with B-cell precursor acute lymphoblastic leukemia treated with the ALL IC-BFM 2002 protocol. ResultsWe confirmed the previously published poor correlation between minimal residual disease in blood and marrow at early treatment time points, with levels in bone marrow being higher than in blood in most samples (median 7.9-fold, range 0.04-8,293-fold). A greater involvement of peripheral blood at diagnosis was associated with a higher white blood cell count at diagnosis (P=0.003) and with enlargement of the spleen (P=0.0004) and liver (P=0.05). At day 15, a level of minimal residual disease in blood lower than 10 -4 was associated with an excellent 5-year relapse-free survival in 78 investigated patients (100% versus 69±7%; P=0.0003). Subgroups defined by the level of minimal residual disease in blood at day 15 (high-risk: ≥10 ) partially correlated with bone marrowbased stratification described previously, but the risk groups did not match completely. No other time point analyses were predictive of outcome in peripheral blood, except for a weak association at day 8. ConclusionsMinimal residual disease in peripheral blood at day 15 identified a large group of patients with an excellent prognosis and added prognostic information to the risk stratification based on minimal residual disease at day 33 and week 12.Key words: acute lymphoblastic leukemia, peripheral blood, minimal residual disease, day 15, childhood.Citation: Volejnikova J, Mejstrikova E, Valova T, Reznickova L, Hodonska L, Mihal V, Sterba J, Jabali Y, Prochazkova D, Blazek B, Hak J, Cerna Z, Hrusak O, Stary J, Trka J, and Fronkova E. Minimal residual disease in peripheral blood at day 15 identifies a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with superior prognosis. Haematologica 2011;96(12):1815-1821. doi:10.3324/haematol.2011 This is an open-access paper. Minimal residual disease in peripheral blood at day 15 identifies a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with superior prognosis

Early (Day 15 Post Diagnosis) Peripheral Blood Assessment of Measurable Residual Disease in Flow Cytometry is a Strong Predictor of Outcome in Childhood B‐Lineage Lymphoblastic Leukemia

“…Another interesting point is the high applicability of MFC-MRD observed in our study where all samples were informative, as reported in BM (17) but also in rare PB studies (20,21). At variance with RT-PCR which is only informative for 80-95% of the patients (18), MFC also does not require diagnosis material to be preserved, since diagnosis data remain available at all times in silico for comparison with MRD samples.…”

Isocitrate dehydrogenase 1 and 2 mutations, 2‐hydroxyglutarate levels, and response to standard chemotherapy for patients with newly diagnosed acute myeloid leukemia

“…With our growing understanding of the prognostic significance of early responses and the clearance of minimal residual disease in other hematologic malignancies, we found that, among those with IDH1/2 mutations receiving induction chemotherapy, a decrease in serum 2HG levels on day 14 with respect to the baseline was associated with significantly improved EFS and OS, even when we accounted for transplantation. This time point is relevant because many patients will have an ablated marrow, and other markers of residual disease may be less sensitive in that state.…”

Flow‐cytometric minimal residual disease monitoring in blood predicts relapse risk in pediatric B‐cell precursor acute lymphoblastic leukemia in trial AIEOP‐BFM‐ALL 2000

“…Our results on patients treated with BFM‐type therapy are partially in line with these data, although in terms of chemotherapy intensity, the COG protocol day 8 better compares with day 15 in BFM. A first hint toward the usefulness of PB‐MRD for BFM‐type protocols came from Czech authors, who considered that PCR is not the right method for rapid result turnaround contrary to what is feasible using FCM. Our results now broaden the view on this matter.…”

“…Some authors therefore reasoned that PB is not appropriate for MRD‐based outcome prognostication in B‐ALL. However, quantifying MRD in PB of children with B‐ALL does correlate with outcome and might even allow separating different risk groups, if respective time points and/or thresholds of MRD in PB differ from those used in BM …”