Prognostic significance of novel ALL subtypes: adding to the framework of MRD-directed therapy

Childhood acute lymphoblastic leukemia (ALL) has a favorable prognosis, with 5-year survival rates of over 80%. Minimal residual disease (MRD)-directed therapy has been a significant factor in the survival of children with ALL, allowing for a tailored approach to treatment based on risk: patients with persistent MRD following induction therapy can be treated with augmented postremission therapy, while patients with early MRD can be treated with a reduced-intensity regimen.

The risk of relapse, however, is multifactorial, as patients with early MRD clearance have a relative risk of relapse that differs between subtypes; therefore, reduced-intensity treatment may not be appropriate or successful for all patients. In a retrospective analysis, Jeha, et al.¹ evaluated the clinical significance of novel ALL subtypes in children treated with MRD-directed therapy and we discuss the results of this study here.

Study design 

There were 598 eligible patients aged between 0.12 and 18.9 years (median, 6.04 years) with newly diagnosed ALL from St. Jude Total Therapy Study 16 who were included and were subtyped using genetic and transcriptomic analyses. Patients were consecutive and were treated using a contemporary risk-based protocol based on well-recognized genetic abnormalities and MRD, which was assessed at three timepoints during remission induction.

Results 

Risk assignment and genomic classification

Of the 598 evaluable patients, 260 were classified as having low risk ALL, 280 were classified as standard-risk, and 58 as high-risk; risk stratification was based on presenting clinical features and MRD levels on Days 15 and 42 of remission induction. Genomic analyses identified 16 B-ALL subtypes, nine of which required transcriptomic sequencing analysis for accurate identification: BCL2/MYC, BCR-ABL1-like, DUX4-rearranged, ETV6-RUNX1-like, MEF2D-rearranged, NUTM1-rearranged, PAX5alt, PAX5 P80R, and ZNF384-rearranged. Risk groups based on subtypes are shown in Table 1.

Table 1. Risk groups by subtype*

Treatment outcome by subtype

• For the entire cohort of patients, 5-year event-free survival (EFS) was 88.8%, overall survival  was 94.0%, and cumulative risk of any relapse was 7.4%.
• ETV6-RUNX1, high-hyperdiploid, and DUX4-rearranged B-ALL were categorized as favorable and had the highest overall survival rates and lowest relapse rates (Table 2).
• BCR-ABL1, BCR-ABL1-like, ETV6-RUNX1-like, KMT2A-rearranged, and MEF2D-rearranged ALL had high levels of MRD but were categorized as unfavorable due to their worst EFS rates.
• The remaining subtypes were considered to have intermediate risk.

Table 2. Clinical outcome according to subtype*

Impact of MRD levels

• Day 8 peripheral blood MRD levels were <0.01% in 142 of the 572 patients with available data (24.8%), and all but three of these patients remained in continuous complete remission.
  • The Day 8 MRD finding wasn’t significantly correlated with any outcome within individual subtypes except for high-hyperdiploid ALL.
• Bone marrow (BM) MRD levels on Day 15 were <0.01% in 187 (31.7%), 0.01% to <1% in 226 (38.3%), and ≥1% in 177 (30.0%) of the 590 patients who were tested.
  • Patients with a Day 15 MRD ≥1% had significantly worse 5-year EFS and higher cumulative risk of relapse (CRR) than patients with lower or undetectable MRD levels (p < 0.001), though high MRD on Day 15 was associated with a significantly poorer 5-year EFS only in patients with high-hyperdiploid ALL (p = 0.05), and B other ALL (p < 0.001) subtypes. In patients with other subtypes, there was no prognostic impact noted with Day 15 MRD ≥1%.

• BM MRD levels on Day 42 were 0.01% to <1% in 60 (10.2%) of the patients and ≥1% in 15 (2.6%) patients; those with a Day 42 MRD <0.01% had significantly better outcomes compared with those with Day 42 MRD levels of 0.01% to <1%, who had better outcomes than patients with Day 42 MRD ≥1% (p < 0.001).
  • There were 279 patients with favorable genotypes who had Day 42 MRD levels of <0.01%; two of these patients relapsed with a 5-year CRR of 1.3%. Notably, of the 184 patients with intermediate- or high-risk subtypes and Day 42 MRD <0.01%, 20 relapsed (p < 0.001).

Outcome of T-ALL subgroups

Most patients in the T-cell acute lymphoblastic leukemia (T-ALL) subgroups were treated in the standard risk group, though higher proportions of patients in the HOXA and LMO1/2 subgroups had Day 42 MRD ≥1% and were therefore treated in the high-risk group. Patients in these two subgroups also had higher 5-year CRR (25.1% and 40%, respectively) and poor EFS (60.6% and 60.0%, respectively). Interestingly, most alterations observed in typical T-ALL cases were not seen in early T-cell precursor ALL, and there were no significant differences between patients with T-ALL and early T-cell precursor in 5-year EFS (81.3% vs 80.0%) or 5-year CRR (12.0% vs 20.0%).

Conclusion 

In this retrospective study, Jeha et al. highlighted the importance of genomic analysis together with MRD determination during remission induction as prognostic indicators that have therapeutic implications for pediatric patients with ALL. Day 8 MRD <0.01% in PB predicted a positive outcome, with only three relapses among the 142 patients in this subgroup, while Day 15 MRD in BM was useful in identifying patients who had a poor early response who may have otherwise been classified as low risk. Regarding Day 42 MRD in BM, not all patients who achieved undetectable MRD at this time point avoided relapse: those with intermediate- or high-risk subtypes were still at risk for relapse. The results of this study suggest that both genomic analysis and MRD analysis are needed to accurately stratify children with ALL into risk groups for tailored therapy.