Acute lymphoblastic leukemia (ALL) responds well to initial multiagent chemotherapy, with 90% of adults and 95% of children experiencing complete remission.^1,2 However, attainment of complete remission does not always translate to long-term disease-free survival. Conventional morphologic assessment methods for complete remission determination may miss minimal residual disease (MRD),3 in which large numbers of leukemic cells remain in the bone marrow.4 Indeed, most adults and 15% to 20% of children with ALL experience relapse following complete remission due to MRD.³

In recognition of the prognostic importance of MRD, current clinical practice guidelines from the National Comprehensive Cancer Network indicate that MRD assessment is necessary for adults and children with ALL over the course of therapy.^4,5 The presence of MRD correlates strongly with risk of relapse,^4,5 with event-free survival and overall survival being dramatically improved among adults and children who experience MRD negativity.^3,6 For patients with precursor B-cell ALL, the most common immunologic subtype of ALL,⁷ relapse-free survival and overall survival are more than twice as high for those with MRD negativity compared with those with MRD positivity.⁷

Assessment of MRD can be conducted at multiple points throughout ALL treatment using one of several different methods. At a minimum, testing is performed upon completion of initial induction, but may also be needed with the use of certain regimens, for patients with molecular relapse or persistence of low-level disease, and at baseline for some techniques.^4,5 Three methods are commonly used to assess MRD status: (1) at least 6-color flow cytometry assays to detect abnormal MRD immunophenotypes; (2) real-time quantitative PCR assays to detect fusion genes (eg, BCR-ABL1); and (3) next-generation sequencing–based assays to detect clonal rearrangements in immunoglobulin heavy chain genes and/or T-cell receptor genes.^4,5 These methods vary with respect to sensitivity, specificity, applicability, turnaround time, and cost.⁸

Results from MRD evaluations have important implications at multiple points in ALL treatment. National Comprehensive Cancer Network treatment guidelines provide different treatment pathways for adults and children with ALL based on MRD positivity or negativity following induction therapy, during monitoring for MRD, and for relapsed/refractory disease.^4,5 For example, in adults with the Philadelphia chromosome, MRD negativity may indicate that multiagent chemotherapy should be continued, whereas MRD positivity may indicate the need to switch to blinatumomab.⁴ For children, MRD negativity may indicate that risk-stratified therapy should be continued, whereas MRD positivity may indicate the need to initiate therapies such as blinatumomab or tisagenlecleucel.⁵ In the setting of relapsed/refractory disease, knowledge of MRD status is also used to select which therapeutic agents should be used for consolidation therapy.⁵

References

1. 1. Texas Oncology. Adult acute lymphoblastic leukemia remission induction. www.texasoncology.com/types-of-cancer/leukemia/adult-acute-lymphoblastic-leukemia/adult-acute-lymphoblastic-leukemia-remission-induction. Accessed November 10, 2021.
2. 2. Texas Oncology. Childhood leukemia remission induction. www.texasoncology.com/types-of-cancer/leukemia/childhood-acute-lymphoblastic-leukemia/childhood-acute-lymphoblastic-leukemia-remission-induction. Accessed November 10, 2021.
3. 3. Deeren D, Balabanov S, Nickel K, et al. Management of patients with acute lymphoblastic leukemia in routine clinical practice: minimal residual disease testing, treatment patterns and clinical outcomes in Belgium, Greece and Switzerland. Leuk Res. 2020;91:106334.
4. 4. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: acute lymphoblastic leukemia. Version 2.2021. July 19, 2021. www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed November 10, 2021.
5. 5. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: pediatric acute lymphoblastic leukemia. Version 1.2022. October 1, 2021. www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf. Accessed November 10, 2021.
6. 6. Berry DA, Zhou S, Higley H, et al. Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis. JAMA Oncol. 2017;3:e170580.
7. 7. Bassan R, Brüggemann M, Radcliffe HS, et al. A systematic literature review and meta-analysis of minimal residual disease as a prognostic indicator in adult B-cell acute lymphoblastic leukemia. Haematologica. 2019;104:2028-2039.
8. 8. Correia RP, Bento LC, de Sousa FA, et al. How I investigate minimal residual disease in acute lymphoblastic leukemia. Int J Lab Hematol. 2021;43:354-363.