MRD-Based Therapeutic Decisions in Genetically Defined Subsets of Adolescents and Young Adult Philadelphia-Negative ALL

Abstract

In many clinical studies published over the past 20 years, adolescents and young adults (AYA) with Philadelphia chromosome negative acute lymphoblastic leukemia (Ph- ALL) were considered as a rather homogeneous clinico-prognostic group of patients suitable to receive intensive pediatric-like regimens with an improved outcome compared with the use of traditional adult ALL protocols. The AYA group was defined in most studies by an age range of 18-40 years, with some exceptions (up to 45 years). The experience collected in pediatric ALL with the study of post-induction minimal residual disease (MRD) was rapidly duplicated in AYA ALL, making MRD a widely accepted key factor for risk stratification and risk-oriented therapy with or without allogeneic stem cell transplantation and experimental new drugs for patients with MRD detectable after highly intensive chemotherapy. This combined strategy has resulted in long-term survival rates of AYA patients of 60-80%. The present review examines the evidence for MRD-guided therapies in AYA's Ph- ALL, provides a critical appraisal of current treatment pitfalls and illustrates the ways of achieving further therapeutic improvement according to the massive knowledge recently generated in the field of ALL biology and MRD/risk/subset-specific therapy.

Keywords: acute lymphoblastic leukemia; adolescents and young adults; minimal residual disease; risk stratification; risk-oriented therapy.

Figure 1

The ALLTogether MRD-based, mixed risk stratification system for risk-oriented therapy in patients with Ph− ALL 1–45 years. The master trial consisted of chemotherapy (chemo) of increasing intensity for SR, IR and HR patients, respectively, along with other risk-specific randomized or non-randomized interventions as indicated. TKI denotes tyrosine kinase inhibitor (imatinib) for cases with ABL-class fusions and CAR-T and BCP denote chimeric antigen receptor T-cell therapy and B-cell precursor ALL, respectively.

Figure 2

Leukemia specific assay design. An allele-specific oligonucleotide (ASO) primer is designed on the N-region between the V/D or D/J gene junction and used in combination with a family-specific primer and fluorescent probe. The fluorescence emission detected by the instrument is directly proportional to the amount of target DNA in the sample.

Figure 3

MRD-related incidence of relapse and duration of CR from NILG trial 10/07 in 61 AYA patients aged 10–40 years with Ph− ALL: (Left) cumulative incidence of relapse; and (Right) comparative CR duration in subsets with MRD < 0.01%/10⁻⁴ at EOI/Week 4 and Week 10 vs. others (non-significant p value due to small patient number).