Reduced-intensity therapy of paediatric lymphoblastic leukaemia

March 2021 Science Tom Feys

Results of an Egyptian study indicate that children with very low risk (VLR) acute lymphoblastic leukemia (ALL) can successfully be treated with decreased-intensity therapy. Moreover, the study underscores that the classification criteria for VLR can be further refined by using a more sensitive assay assessing minimal residual disease (MRD).

Expert opinion

In paediatric acute lymphoblastic leukemia (ALL), 5-year overall survival rates with contemporary risk-directed treatment exceed 90%. To further improve these results and diminish the toxicity associated with intensive therapy, current efforts focus on expanding the application of immunotherapy, identifying targetable genetic abnormalities, and improving the precision of risk assessment. Minimal residual disease (MRD) level determined during the early phases of treatment (remission induction or consolidation) has been an independent prognostic factor in all reported clinical trials for pediatric and adult ALL and also guides risk stratification and individualized therapy for children with ALL. This study confirms the importance of MRD in children with very low risk ALL who can successfully be treated with reduced-intensity therapy.

Sidhom, I., et al. Blood 2020; Epub ahead of print.

The overall survival (OS) rates for children with acute lymphoblastic leukaemia (ALL) receiving contemporary therapy currently exceeds 90%, largely due to the adoption of risk-adapted intensification of chemotherapy in conjunction with improved supportive care.1-3 Long-term follow-up of adult survivors of childhood cancer, including survivors of ALL, did reveal a range of late treatment-related adverse effects.4 This underscores the importance of strategies to prevent or mitigate late effects of childhood cancer treatment.

In this light, previous studies suggest that approximately 40-50% of patients with ALL can also be cured with less intensive chemotherapy regimens.5,6 Unfortunately, the identification of patients with very-low-risk (VLR) ALL remains challenging, resulting in frequent overtreatment of patients. In a study from the Children’s Cancer Hospital Egypt (CCHE)200 children (40%) with progenitor B-cell ALL classified as VLR and treated with a low-intensity regimen assessed the impact of minimal residual disease (MRD) levels early in remission on the treatment outcome.7,8

The investigators found an overall 5-year event-free survival (EFS) of 89.5%, with a corresponding OS rate of 95.5%. The 5-year cumulative incidence of relapse (CIR) was 7% and 1% for isolated central nervous system (CNS) relapse. Patients with detectable MRD levels (between 0.001% and <0.01% on day 19) had a significantly higher 5-year CIR than patients with undetectable residual leukaemia (17.2% vs. 5.3%; p= 0.02).  The CIR, treatment-related mortality, and 5-year OS in this study are comparable to what was reported for children treated with international protocols.

Treatment was generally well tolerated, although all patients did develop neutropenia. Of the 200 VLR patients, three died of infectious complications during induction treatment and 197 attained CR at a median of 30 days. A total of 21 adverse events (AEs) occurred to date; 3 early deaths, 14 relapses, one secondary AML, and 3 patients died in remission. There were significantly fewer toxic deaths among the VLR patients in this study compared to what is seen with institutional standard treatments in low-risk patients. Toxic death occurred in nine of the 309 low-risk patients (2.9%) during induction and in 14 patients (4.5%) in remission, with a cumulative incidence of 7.6% (95% CI, 5% – 11%; P = 0.017).  

An important contribution of the study was the validation of the simplified flow cytometric assay compared to standard assay to evaluate MRD after 19 days of remission induction therapy. They only found one case not correlating. However, it cannot be used to evaluate residual disease after remission induction and not all samples can be assessed on day 19 because of insufficient cellularity. Moreover, detecting residual disease at the level of <0.01% does require analytical expertise and alternative validation methods.9 Despite these limitations, monitoring for early response to therapy by the simplified MRD assay can be recommended for laboratories in low- and middle-income countries (LMICs).8

To conclude, this study revealed that approximately 40% of children classified as having VLR ALL had good outcomes when treated with a low-intensity therapy. These observations suggest opportunities to refine the stratification of children with ALL along with strategies to integrate decreased therapy regimens.8 Further studies are necessary to address the management of cases with detectable MRD levels of <0.01% at early time points.

References

  1. Hunger, S.P., et al. N Engl J Med, 2015
  2. Pui, C.H., et al. Blood, 2012
  3. Hunger, S.P., et al. Blood, 2015
  4. Oeffinger, K.C., N Engl J Med, 2016
  5. Gaynon, P.S., et al. Leukaemia, 2000
  6. Scharappe, M., et al. Leukaemia, 2000
  7. Pedrosa, F., et al. Blood, 2020
  8. Sithom, I., et al Blood, 2020
  9. Coustan-Smith, E., et al. Blood, 2006
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