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

Manuela Tosi,Federico Lussana,Alessandro Rambaldi,Renato Bassan,Matteo Leoncin,Francesca Carobolante,Orietta Spinelli,Piera Viero,Giulia Perali,Cristina Skert,Luca Frison,Tamara Intermesoli,Roberta Cavagna,Chiara Pavoni

doi:10.3390/cancers13092108

Manuela Tosi, Federico Lussana + Show 12 more

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https://doi.org/10.3390/cancers13092108

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Abstract

Simple SummaryIn acute lymphoblastic leukemia (ALL), once a complete remission is achieved following induction chemotherapy, the study of submicroscopic minimal residual disease (MRD) represents a highly sensitive tool to assess the efficacy of early chemotherapy courses and predict outcome. Because of the significant therapeutic progress occurred in adolescent and young adult (AYA) ALL, the importance of MRD in this peculiar age setting has grown considerably, to refine individual prognostic scores within different genetic subsets and support specific risk and MRD-oriented programs. The evidence coming from the most recent MRD-based studies and the new therapeutic directions for AYA ALL are critically reviewed according to ALL subset and risk category.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

Highlights

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children, peaking at 7.6:100.000/year at 1–4 years of age and decreasing in adolescents and young adults (AYA), to an average incidence of 1.8 and 0.8 between 15 and 39 years of age [1,2].Therapeutic progress has been outstanding in childhood ALL over the past decades, reaching an 80–90% chance of cure [3,4]
The minimal residual disease (MRD)-based risk stratification was quite often unrelated to the initial risk profile (SR or HR) and motivated the choice of an allogeneic hematopoietic cell transplantation (HCT) in case of MRD persistence. In some of these trials, the MRD analysis was available for a limited proportion of patients, which is one half or less of all CR patients, and/or was not clearly or not always meant to guide a risk-oriented approach with HCT, left to the discretion of treating physicians or indicated for very high-risk conditions such as t (4;11)+ ALL, etc
65% or more of these patients may achieve cure. This represents an outstanding therapeutic achievement, not very far from the 85–90% cure rate documented in children and highly encouraging given the different prognostic patterns and the increasing treatment complexity of AYA compared to childhood ALL

Summary

Introduction

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children, peaking at 7.6:100.000/year at 1–4 years of age and decreasing in adolescents and young adults (AYA), to an average incidence of 1.8 and 0.8 between 15 and 39 years of age [1,2].Therapeutic progress has been outstanding in childhood ALL over the past decades, reaching an 80–90% chance of cure [3,4]. Therapeutic results are progressively less favorable with the increase of patient age, the case of AYA patients is unique. AYA patients share several diagnostic and clinical features in common with children and exhibit a higher tolerance to modern highly effective pediatric regimens, which makes them eligible to receive these pediatric-type treatments. The latter concept was explored in several clinical trials that eventually confirmed and provided an explanation for the therapeutic superiority of modern pediatric regimens compared to standard adult protocols in AYA ALL [6]

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