Retrospective analysis of a novel molecular genetic risk score, “MRplus”, in BCR-ABL1 negative pediatric B-ALL: A single-center experience.
Authors: Gupta Sanjeev Kumar , Bakhshi Sameer , Gupta Ritu , Sharma Preity , Pushpam Deepam , Sahoo Ranjit Kumar , Sharma Atul 
Published: June 2021

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Background: Currently, the molecular risk scoring is variably used in the management algorithms of B-ALL across various clinical cohorts. Unlike AML, the usage of molecular genetic abnormalities in the risk-stratification of B-ALL is limited and a consensus is yet to be reached. We have retrospectively analyzed the utility of molecular genetic risk criteria, previously described by Moorman et al. (2014), and Stanulla et al. (2018), in our cohort and hereby propose a novel molecular risk score, “MRplus”, obtained by combining both criteria, as a useful way to improve the risk-stratification of BCR-ABL1 negative pediatric B-ALL. Methods: In this retrospective observational study, the genomic DNA of untreated BCR-ABL1 negative pediatric B-ALL cases was analyzed at baseline for copy number alterations of IKZF1, PAX5, CDKN2A/B, BTG1, RB1, ETV6, EBF1, ERG, pseudoautosomal region (PAR) genes– (CRLF2, CSF2RA, IL3RA), using multiplex ligation-dependent probe amplification (MLPA)- P335, P202 and P327 kits (MRC Holland). The cases were assigned a score- 0 for low and 1 for high genetic-risk as per the criteria by Moorman et al., and another score as per the criteria by Stanulla et al., 1 for IKZF1plus cases and 0 for other cases. The final “MRplus” risk-score of 0 (low), 1 (intermediate) or 2 (high) was given by adding both these scores. All patients were treated using Indian Childhood Collaborative Leukemia Group protocol (ICICLE). The post-induction remission status, overall survival (OS) and event free survival (EFS) was noted for all patients. Results: Out of 320 cases with median age of 6 years (1-18 years), 141 (44.1%) cases had high genetic-risk (score 1) as per the Moorman’s criteria. Thirty-two (10%) cases fulfilled the criteria of IKZF1plus (score 1) as per the criteria of Stanulla et al. The final “MRplus” score of 0, 1 and 2 was obtained in 179 (55.9%), 109 (34.1%) and 32 (10%) cases respectively. Out of these, 284 received treatment including 160, 101, and 23 cases with “MRplus” score 0, 1, and 2 respectively. The follow up period was upto 80 months with a median of 34.6 months. The post-induction remission rate was 90.6%, 78.2%, 73.9% (p = 0.008); 4-year OS 68%, 48%, 27% (p < 0.001); and 4-year EFS 57%, 36%, 19% (p < 0.001) in cases with “MRplus” score 0,1, and 2 respectively. Conclusions: The proposed novel “MRplus” scoring at baseline could identify three distinct risk- groups-low, intermediate and high, in BCR-ABL1 negative pediatric B-ALL. This may help in better identification of patients for alternative treatment approaches and also triage patients for further detailed genomic analysis for disease biology; with particular emphasis on those with intermediate and high “MRplus” score. Acknowledgement: Institute Research Grants [A-193 (2013-15), A-413 (2016-18) and A-600 (2018-20)] from All India Institute of Medical Sciences (AIIMS), New Delhi, INDIA.