Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia

Abstract

IMPORTANCE Minimal residual disease (MRD) refers to the presence of disease in cases deemed to be in complete remission by conventional pathologic analysis. Assessing the association of MRD status following induction therapy in patients with acute lymphoblastic leukemia (ALL) with relapse and mortality may improve the efficiency of clinical trials and accelerate drug development.OBJECTIVE To quantify the relationships between event-free survival (EFS) and overall survival (OS) with MRD status in pediatric and adult ALL using publications of clinical trials and other databases.DATA SOURCES Clinical studies in ALL identified via searches of PubMed, MEDLINE, and clinicaltrials.gov.STUDY SELECTION Our search and study screening process adhered to the PRISMA Guidelines. Studies that addressed EFS or OS by MRD status in patients with ALL were included; reviews, abstracts, and studies with fewer than 30 patients or insufficient MRD description were excluded. CONCLUSIONS AND RELEVANCE The value of having achieved MRD negativity is substantial in both pediatric and adult patients with ALL. These results are consistent across therapies, methods of and times of MRD assessment, cutoff levels, and disease subtypes. Minimal residual disease status warrants consideration as an early measure of disease response for evaluating new therapies, improving the efficiency of clinical trials, accelerating drug development, and for regulatory approval. A caveat is that an accelerated approval of a particular new drug using an intermediate end point, such as MRD, would require confirmation using traditional efficacy end points.

A pediatric regimen for adolescents and young adults with Philadelphia chromosome‐negative acute lymphoblastic leukemia: Results of the ALLRE08 PETHEMA trial

“…Overall, the CR rate observed was high and similar to that reported for most full pediatric or pediatric‐inspired protocols focused on AYA with ALL . and those without a pediatric basis .…”

Clinical benefit of a high‐throughput sequencing approach for minimal residual disease in acute lymphoblastic leukemia

“…For this significant group, it is imperative that HTS is utilized to identify suitable MRD targets. Advantages/disadvantages of HTS screening and MRD monitoring have been discussed previously, particularly in tandem with flow cytometry MRD monitoring . HTS MRD monitoring may lead to assessment at different time points post treatment as well as potentially in blood samples .…”

Day 15 bone marrow minimal residual disease predicts response to blinatumomab in relapsed/refractory paediatric B‐ALL

“…CD19 is stably expressed in B‐ALL and is a rational target for immunotherapy (Raponi et al ., Topp et al ., ). Effector memory T cells have the potential to kill autologous tumour cells, and deep molecular remission [i.e., elimination of minimal residual disease (MRD)] has been shown to predict outcomes for patients with B‐ALL (von Stackelberg et al ., ; Berry et al ., ).…”

“…CD19 is stably expressed in B-ALL and is a rational target for immunotherapy (Raponi et al, 2011Topp et al, 2012. Effector memory T cells have the potential to kill autologous tumour cells, and deep molecular remission [i.e., elimination of minimal residual disease (MRD)] has been shown to predict outcomes for patients with B-ALL (von Stackelberg et al, 2016;Berry et al, 2017). Blinatumomab (Blincyto â , Amgen Inc., Thousand Oaks, CA, USA) is a bispecific CD19/CD3 T-cell engager (BiTE â ) immunotherapy that has been shown to induce MRD-negative remissions in adults with relapsed B-ALL or MRD-positive primary B-ALL (Topp et al, 2011;Topp et al, 2012).…”