Minimal Residual Disease (MRD) Analysis in Non-MRD Based ALL IC-BFM 2002 Protocol for Childhood ALL: Is It Possible To Omit Minimal Residual Disease in Risk Stratification?.
Authors: Fronkova Eva , Avigad Smadar , Wai Chik Ki , Castillo Luis , Sigal Manor , Reznickova Leona , Zdrahalova Katerina , Skocovska Tatana , Schrappe Martin , Conter Valentino , Izraeli Shai , Li Chi Kong , Stark Batia , Hrusak Ondrej , Mejstrikova Ester , Stary Jan , Trka Jan 
Published: October 2019

Abstract
More than 800 children with acute lymphoblastic leukaemia (ALL) are treated every year according to ALL IC-BFM 2002 protocol, which was designed by the International-BFM Group as a parallel to MRD-based ALL/AIEOP BFM 2000 study. The ALL-IC BFM 2002 risk group stratification comprises blast proportion in peripheral blood (PB) after 7 days of prednisone and one IT-MTX (prednisone response) and bone marrow (BM) morphology evaluation at days 15 and 33 of therapy together with age, initial WBC and presence of BCR/ABL and MLL/AF4 fusion. One of the aims of the ALL IC-BFM 2002 study is the comparison of this risk group assessment to the MRD-based criteria used in ALL-BFM 2000. We analyzed a total of 203 patients treated according to the ALL IC-BFM 2002 in the Czech Republic, Israel, Hong Kong and Uruguay for the presence of clonal antigen receptor rearrangements. MRD was evaluated in 175 patients at several time-points of therapy including mandatory points at week 5 and 12, which are used in the ALL/AIEOP BFM 2000 stratification. In total, 654 follow-up BM specimens and 80 PB samples were tested. In the univariate analysis, a good molecular response defined as MRD negativity at both week 5 and 12 was associated with the age of 1–6 years (p=0.0001), WBC<20,000/mm3 (p=0.0002), non-T immunophenotype (p<0.0001), good prednisone response (p=0.0006), presence of TEL/AML1 fusion (p=0.003) and non-M3 morphology (≤25% blasts in BM) at day 15 (p=0.02). There was no significant association of MRD negativity with sex and hyperdiploidy; non-M3 BM morphology at day 8 was significant only when analyzing non-T ALL (p=0.02). Patients with BCP ALL had significantly lower MRD levels at day 15 (p=0.03) and at day 33 (p=0.001) than T-ALL patients; the difference was no more significant at week 12. Patients stratified to standard risk group (SRG) according to the ALL IC-BFM 2002 criteria had a significantly better molecular response defined as MRD negativity at week 5 and 12 than intermediate risk group (IRG) patients (p=0.009). However, in 24 of 69 SRG patients (34.7%), MRD positivity at week 5 and/or at week 12 was observed (ranging from borderline positivity to 1.5x10(-2)), thus identifying patients who would not qualify to MRD-based SRG in ALL/AIEOP BFM 2000. Within ALL IC SRG, patients with slow molecular response did not differ significantly from those with good MRD response in age, sex, WBC, BM morphology at day 15 and presence of hyperdiploidy or TEL/AML1 fusion. The only difference was in a higher proportion of M3 BM at day 8 in MRD slow-responders (p=0.04). Our findings revealed a significant divergence between the stratification results of ALL IC-BFM 2002 and ALL-BFM 2000. A fast morphological response to treatment (M1 or M2 bone marrow at day 15) together with other low-risk features does not necessarily correspond with rapid MRD clearance. Supported by MSM0021620813, Israel Cancer Association and Children’s Cancer Foundation Hong Kong.