Relapsed Acute Lymphoblastic Leukemia

Abstract

Outcomes for children with acute lymphoblastic leukemia (ALL) have improved worldwide to >85%. For those who relapse, outcomes have remained static at ~50% making relapsed acute lymphoblastic leukemia one of the leading causes of death in childhood cancers. Those relapsing within 18 mo in the bone marrow have a particularly dismal outcome. The mainstay of treatment is chemotherapy, local radiotherapy with or without hematopoietic stem cell transplantation (HSCT). Improved biological understanding of mechanisms of relapse and drug resistance, use of innovative strategies to identify the most effective and least toxic treatment regimens and global partnerships are needed to improve outcomes in these patients. Over the last decade, new therapeutic options and strategies have been developed for relapsed ALL including immunotherapies and cellular therapies. It is imperative to understand how and when to use these newer approaches in relapsed ALL. Increasingly, integrated precision oncology strategies are being used to individualize treatment of patients with relapsed ALL, especially in patients with poor response disease.

Keywords: Chemotherapy; Childhood ALL; Relapse; Transplant.

Fig. 1

(a) Evolution of subclones at relapse (b) Mechanisms of drug tolerance of relapse-fated clones. Adapted from [3, 4]

Fig. 2

Treatment schema of the InPOG-ALL-R1 treatment protocol for patients with untreated first relapse of acute lymphoblastic leukemia (InPOG-ALL-19–02-ALL R1; Clinical Trials Registry-India CTRI/2019/10/021758). Upper panel: Patients with medullary (bone marrow) ALL relapse, either isolated or combined (marrow relapse combined with relapse at extramedullary sites); Lower panel: Patients with isolated extramedullary relapse. High risk cytogenetics include Philadelphia chromosome-positive ALL, other ABL-class ALL, KMT2A-rearranged ALL, ALL with intrachromosomal amplification of chromosome 21 (iAMP21), TCF3-rearranged ALL, ALL with hypodiploidy (modal chromosome number <40) and ALL with select gene copy number alterations (such as TP53 deletion). BCP-ALL B cell precursor-ALL, BM Bone marrow, CR2 Complete remission second, EOI MRD End of induction minimal residual disease, HSCT Hematopoietic stem/progenitor cell transplantation, MPAL Mixed phenotype acute leukemia