Go with the flow: simplified MRD in LMIC ALL

In this issue of Blood, Pedrosa et al¹  provide long-term results of a pilot study in children with precursor B-cell ALL conducted in a Brazilian center in a limited-resource setting. This pilot study incorporated a previously described simplified flow cytometric methodology for minimal residual disease (MRD) assessment in B-lineage ALL adapted for use in limited-resource settings to assess response at days 19 and 26.^2,3 

Children diagnosed with acute lymphocytic leukemia (ALL) in low- and middle-income countries (LMICs) do not enjoy the outstanding outcomes presently available to children with ALL in first-world countries. Factors contributing to this disparity in outcomes include abandonment of care (ie, patients who drop out of treatment prior to completion),⁴  limited access to essential medications,⁵  and limitations in supportive care measures contributing to excessive toxicity and poor outcomes associated with the use of intensive chemotherapy regimens employed in the first world setting.⁶  Optimal management of childhood ALL in first-world countries also includes the use of diagnostic tests, such as immunophenotyping by flow cytometry, fluorescence in situ hybridization (FISH) to detect common recurring cytogenetic abnormalities associated with favorable or unfavorable outcomes, and assessment of MRD by flow cytometry.⁷ 

End-induction MRD assessment is the single strongest prognostic factor in predicting outcome in childhood ALL.⁸  However, the sophisticated equipment and complex technical requirements for multiparametric flow cytometry as used in resource-rich settings, together with limited resources for personnel and reagents, place routine MRD assessment beyond the reach of many pediatric cancer programs in limited-resource settings. The lack of advanced diagnostic testing capabilities in many LMICs precludes optimal risk-stratification and therapy refinement for children with ALL, contributing to unnecessary overtreatment of some children with lower-risk ALL and a corresponding increased risk of treatment-related toxicity and mortality. Thus, the validation of a simplified MRD assay as feasible in the LMIC setting with sufficient predictive power to achieve clinically relevant risk stratification in childhood ALL would represent a significant step forward.

MRD results obtained with this simplified flow cytometry approach were combined with clinical features, immunophenotype, and a limited genetic analysis to identify a population of patients predicted to be at very low risk (VLR) of disease recurrence. These patients, representing about one-fifth of the total ALL population at the treating center, received a reduced-intensity, antimetabolite-based treatment protocol, which minimized myelosuppressive agents commonly used in first-world protocols, such as cyclophosphamide and cytarabine, that contribute to infections and other treatment-related toxicities.

The outcomes achieved with this risk-stratified, reduced-intensity approach for VLR patients enrolled in the Recife RELLA05 pilot study were outstanding, with a very high rate of remission induction, estimated 5-year event-free and overall survival rates of 92% and 96%, respectively, and a 5-year cumulative relapse risk of only 4%. These results rival or surpass those previously reported in similar settings. Importantly, the toxicity associated with this approach was also remarkably low, with an overall toxic death rate of <1%. Abandonment of therapy was not an issue, as all patients completed treatment.

Many challenges remain in improving outcomes for childhood ALL in LMICs. The approach used in the Recife RELLA05 is relevant for only about one-quarter of the childhood ALL population in LMICs; more effective, less toxic approaches are needed for children with higher-risk disease, for whom greater treatment intensity, with its risks of treatment-related toxicities and morbidity, is presently required. It must also be acknowledged that even the simplified MRD assessment approach used in this study may be beyond the reach of some LMIC centers treating childhood ALL, as may the polymerase chain reaction–based genetic analyses used to identify common gene fusions with prognostic significance; FISH analysis may be more attainable for this purpose in the LMIC setting. Nevertheless, these results clearly document that a simplified MRD assessment is feasible in the LMIC setting and informs a risk-adapted approach that identifies a very low-risk subset of the childhood ALL population with excellent outcomes following minimally intensive chemotherapy. Pedrosa and colleagues have established a new benchmark of success for LMIC pediatric cancer programs and their twinning collaborators in improving outcomes for their children with low-risk ALL.