New insights in clinical outcomes of patients with ALL and Down Syndrome

November 2021 Clinical trials Jolien Blokken

A recent cohort study addressed minimal residual disease (MRD) and long-term clinical outcomes in Down syndrome and non-Down syndrome patients with acute lymphocytic leukaemia (ALL), matched according to clinical risk factors and genetics. Results demonstrated that MRD levels at the end of induction are similar between individuals with and without Down syndrome. Furthermore, findings show that Down syndrome itself provides an additional risk of relapse in patients with IKZF1 deletion.

Acute lymphocytic leukaemia (ALL) occurs more frequently in children with Down syndrome than in those without. Unfortunately, patients with Down syndrome and ALL are at an increased risk of treatment-related mortality (TRM) and relapse, which is influenced by unfavourable genetic aberrations (e.g., IKZF1 deletion). It however remains unclear whether the poor outcome of children and adolescents with Down syndrome was due to a higher frequency of high risk genetics, or whether Down syndrome itself negatively affects clinical outcome. A large multinational study now addressed both minimal residual disease (MRD) and long-term clinical outcome in Down syndrome and non-Down syndrome patients with ALL, matched according to clinical risk factors and genetics.

STUDY DESIGN

This matched cohort study enrolled patients (aged 1 – 23 years) with ALL with or without Down syndrome who were treated between 2002 and 2018 in eight trials (DCOG ALL10 and ALL11, ANZCHOG ALL8, AIEOP-BFM ALL2009, UKALL2003, NOPHO ALL2008, CoALL 07-03, and CoALL 08-09) across different countries. Only trials with MRD-guided protocols were selected. A total of 251 and 8,426 patients were enrolled in the experimental and matched group, respectively.  Each patient with Down syndrome and ALL was matched to three non-Down syndrome patients with ALL (matched controls). Matching was done according to the type of induction treatment, cytogenetic subtype, IKZF1 status (deleted vs. not deleted), age at diagnosis (<10 vs. 10–23 years), and white blood cell count at diagnosis (<50 × 109 vs. ≥ 50 × 109 cells per L). For MRD analyses, matching was based on induction treatment. For long-term outcome analyses, matching was based on induction treatment and MRD-guided treatment group. The primary endpoint was the comparison of MRD levels (absolute MRD levels were categorised into two groups, low [<0.0001] and high [≥0.0001]) between patients with Down syndrome and ALL and matched controls, and the secondary outcomes were comparison of long-term outcomes (event-free survival, overall survival, relapse, and TRM) between ALL patients with Down syndrome and matched controls.

RESULTS

During induction treatment, 6% of ALL patients with Down syndrome and 0.8% of matched controls died. Induction deaths and patients with missing data on IKZF1 deletion or MRD were excluded from the analysis. Matching was done for 136 ALL patients with Down syndrome to study differences in MRD levels, and for 119 ALL patients with Down syndrome to analyse long-term clinical outcomes.

The proportion of patients with high MRD at the end of induction treatment ((38% vs. 39%, p= 0.88) and at the end of consolidation (6% vs. 7%, p= 0.76) was similar for ALL patients with Down syndrome and their matched controls. Furthermore, in patients with and without IKZF1 deletion, the percentage of patients in the higher MRD category was similar for patients in the experimental group and their matched controls at both end of induction and at the end of consolidation. After a median follow-up time of  7.2 years,  event-free survival  and overall survival was worse for ALL patients with Down syndrome than for matched controls (HR[95%CI]: 2.5[1.6-3.9]; p <0.0001, and HR[95%CI]: 3.8[2.2-6.3]; p<0.0001), respectively).Patients with Down syndrome had a higher relapse at 5 years (37.1%) than the matched controls (13.2%) in the IKZF1 deleted group (HR[95%CI]: 4.3 [1.6–11.0]; p= 0.0028), but not in the IKZF1 wild-type group (5.8% vs. 8.1%, HR[95%CI]: 1.0[0.5-2.1]; p= 0.99). In addition to the increased induction deaths (6% vs. 0.8%), post-induction TRM at 5 years was also higher in the group with Down syndrome than in the matched control (12.2% vs. 2.7%, HR[95%CI: 5.0[2.3-10.8]; p< 0.0001).

CONCLUSIONS

MRD levels of ALL patients with Down syndrome were similar to those of matched controls, indicating that the current induction schedules are also effective in eradicating leukaemia for patients with Down syndrome and acute lymphocytic. However, more ALL patients with Down syndrome died during induction, in comparison with matched controls, emphasising the need for alternative treatment strategies to reduce early toxicity. Furthermore, Down syndrome itself provides an additional risk in individuals with IKZF1 deletions, suggesting an interplay between the germline environment and this poor risk somatic aberration.

Reference

Michels M, Boer JM, Enshaei A, et al. Minimal residual disease, long-term outcome, and IKZF1 deletions in children and adolescents with Down syndrome and acute lymphocytic leukaemia: a matched cohort study. Lancet Haematol. 2021;8(10):e700–10.

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