Excellent outcomes for patients with B-cell precursor acute lymphoblastic leukaemia with late bone marrow relapses
Authors: David T Teachey
Journal: The Lancet Haematology (2019)

The prognosis for children with acute lymphoblastic leukaemia has improved substantially during the past 50 years. The improved survival results from the use of multi-agent, multiblock chemotherapy regimens that have been studied in randomised cooperative group clinical trials. Most gains have occurred in newly diagnosed patients, as the outcome for children with relapsed acute lymphoblastic leukaemia remains relatively poor. In this issue of The Lancet Haematology, Catriona Parker and colleagues present long-term outcome data for patients with B-cell precursor acute lymphoblastic leukaemia with late bone marrow relapses who were enrolled in the ALLR3 clinical trial.1Parker C Krishnan S Hamadeh L et al.Outcomes of patients with childhood B-cell precursor acute lymphoblastic leukaemia with late bone marrow relapses: long-term follow-up of the ALLR3 open-label randomised trial.Lancet Haematol. 2019; (published Feb 27.)http://dx.doi.org/10.1016/S2352-3026(19)30003-1Summary Full Text Full Text PDF PubMed Scopus (26) Google Scholar ALLR3 was an international, open-label, randomised trial for patients aged 1–18 years with relapsed acute lymphoblastic leukaemia treated at 31 Children's Cancer and Leukaemia (CCLG) cooperative group centres. Patients were randomly assigned to receive an idarubicin-based or mitoxantrone-based remission induction regimen. The initial results of the ALLR3 trial were published in 2010, showing improved 3-year progression-free survival and overall survival in the mitoxantrone group.2Parker C Waters R Leighton C et al.Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial.Lancet. 2010; 376: 2009-2017Summary Full Text Full Text PDF PubMed Scopus (239) Google Scholar 3-year overall survival was 69%, leading other cooperative groups to adopt the ALLR3 backbone. 228 patients with late bone marrow relapses occurring more than 6 months after completion of front-line therapy were included in the long-term follow-up. Patients who had low minimal residual disease at end of induction (<10−4 cells, at timepoint 1) measured by real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements were non-randomly assigned to receive chemotherapy without haemopoietic stem-cell transplantation (HSCT). Those with extramedullary disease at relapse also received site-directed radiation. Patients with high minimal residual disease (≥10−4 cells) were non-randomly assigned to undergo HSCT. This study found a post-induction minimal residual disease at a cutoff of 1×10−4 cells to be highly prognostic for patients with late bone marrow relapses. With a median follow-up of 84 months, progression-free survival was 72% (95% CI 60–81) in patients with low minimal residual disease and 56% (46–65) in those with high minimal residual disease (p=0·0078). Notably, 30 (14%) of 211 patients were not able to follow the recommended treatment plan of stratification according to minimal residual disease level. Progression-free survival was higher in the mitoxantrone group, but unlike the overall cohort, 5-year overall survival did not differ significantly between the mitoxantrone and idarubicin groups among patients with late bone marrow relapses (75% [67–81] vs 63% [49–74]; p=0·10). Duration of first complete remission has been shown to be one of the best predictors of survival in patients with acute lymphoblastic leukaemia who relapse.3Bhojwani D Pui CH Relapsed childhood acute lymphoblastic leukaemia.Lancet Oncol. 2013; 14: e205-e217Summary Full Text Full Text PDF PubMed Scopus (281) Google Scholar Patients who relapse earlier, especially those who relapse while on therapy, have worse outcomes than those who have late relapses. Differences in the definition of early versus late relapse exist between different cooperative groups, indicating that the risk of relapse relative to the duration of first complete remission is not a purely dichotomous variable. Nevertheless, as major therapeutic decisions are made on the basis of the duration of remission, lines need to be drawn, and various studies have shown that the biology of blasts differs in patients who have early relapses versus those who have late relapses.4Pierro J Hogan LE Bhatla T Carroll WL New targeted therapies for relapsed pediatric acute lymphoblastic leukemia.Expert Rev Anticancer Ther. 2017; 17: 725-736Crossref PubMed Scopus (30) Google Scholar Additional variables that have been shown to predict outcomes in relapsed patients with acute lymphoblastic leukaemia in other trials are quantification of minimal residual disease after re-induction therapy, site of relapse (medullary vs extramedullary vs combined), and immunophenotype (B cell vs T cell).3Bhojwani D Pui CH Relapsed childhood acute lymphoblastic leukaemia.Lancet Oncol. 2013; 14: e205-e217Summary Full Text Full Text PDF PubMed Scopus (281) Google Scholar, 5Pui CH, Teachey DT. Comparative features and outcome between paediatric T- and B-acute lymphoblastic leukaemia. Lancet Oncol (in press).Google Scholar Arguably, one of the most important observations in the study by Parker and colleagues is the high survival rates for patients with low minimal residual disease at end of induction and no extramedullary disease who were treated with chemotherapy without prophylactic cranial radiation. Outcomes for patients with combined and isolated late bone marrow relapses were similar in this trial. Given the toxicities of site-directed radiation, studies showing that it can be safely eliminated in certain populations are noteworthy. Patients who were assigned to undergo HSCT had repeat minimal residual disease (timepoint 2) immediately before transplantation. Progression-free survival and overall survival of patients with low minimal residual disease versus those with high minimal residual disease at timepoint 2 did not differ significantly. This is in stark contrast to various studies that have shown that positive minimal residual disease immediately before transplantation portends worse survival.6Eapen M Relapsed acute lymphoblastic leukemia: is it crucial to achieve molecular remission prior to transplant?.Best Pract Res Clin Haematol. 2017; 30: 317-319Crossref PubMed Scopus (2) Google Scholar The authors acknowledge that the results at timepoint 2 are likely to be due to the small sample size and the fact that the outcome for patients with low minimal residual disease at timepoint 2 was worse than expected. Other studies have shown that worse outcome found in patients who have positive minimal residual disease immediately before transplantation can be mitigated by the development of graft-versus-host disease, presumably from the graft-versus-leukaemia effect.7Pulsipher MA Bader P Klingebiel T Cooper LJ Allogeneic transplantation for pediatric acute lymphoblastic leukemia: the emerging role of peritransplantation minimal residual disease/chimerism monitoring and novel chemotherapeutic, molecular, and immune approaches aimed at preventing relapse.Biol Blood Marrow Transplant. 2009; 15: 62-71Summary Full Text Full Text PDF PubMed Scopus (55) Google Scholar Data about rates of acute and chronic graft-versus-host disease, donor chimerism after HSCT, transplant conditioning regimen, immune suppression after HSCT, and minimal residual disease after HSCT were not provided, making it difficult to interpret the data at timepoint 2. Finally, the study investigated the prognostic significance of disease biology in patients with B-cell precursor acute lymphoblastic leukaemia and late bone marrow relapses. Although several studies have explored this for newly diagnosed patients with B-cell precursor acute lymphoblastic leukaemia, prognostic data for those with relapses are sparse and inconsistent. As the biology of relapsed disease is strikingly different, studies focusing on relapse biology are important. In addition to standard cytogenetics, the investigators looked at copy number status or for mutations or deletions in a panel of more than 15 genes, including IKZF1, TP53, and NRAS. 132 (60%) of 228 patients had favourable cytogenetics (ETV6-RUNX1 or high hyperdiploid), which correlated with favourable outcome. Unfavourable cytogenetics such as hypodiploid were rare in the cohort with late bone marrow relapses and patients had poor outcomes. Patients with IZKF1 deletions were more likely to have intermediate or unfavourable cytogenetics and positive minimal residual disease at end of induction. Various mutations, deletions, and copy number alterations correlated with progression-free survival and minimal residual disease in univariate analyses, but only NRAS mutations were found to be independently prognostic. Although NRAS mutations were rare (detected in 11% of patients), patients with these mutations had worse progression-free survival and overall survival, regardless of minimal residual disease at end of induction. NRAS mutations can be subclonal and are often enriched at relapse.8Ma X Edmonson M Yergeau D et al.Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia.Nat Commun. 2015; 6: 6604Crossref PubMed Scopus (236) Google Scholar Data about variant allele frequency and the presence or absence of NRAS mutations at original diagnosis were not provided. These results need to be validated in future trials. In conclusion, as the outcome data from the ALLR3 trial continue to mature, key observations that affect clinical practice continue to be revealed. With the advent of novel immunotherapies and improvements in HSCT, including haplo-identical transplantation, the therapeutic landscape for acute lymphoblastic leukaemia is markedly different in 2019 than it was when ALLR3 opened to accrual in 2003. Nevertheless, the importance of carefully designed randomised trials such as ALLR3 that ask salient clinical and biological questions will continue to influence the standard of care for patients with B-cell precursor acute lymphoblastic leukaemia. I report no relevant competing interests. I have served on advisory boards for La Roche and Amgen. Outcomes of patients with childhood B-cell precursor acute lymphoblastic leukaemia with late bone marrow relapses: long-term follow-up of the ALLR3 open-label randomised trialPatients with B-cell precursor acute lymphoblastic leukaemia with late bone marrow relapses and low minimal residual disease at end of induction had favourable outcomes with chemotherapy without undergoing stem-cell transplantation. Patients with high minimal residual disease benefited from stem-cell transplantation, and targeted therapies might offer further improvements in outcomes for these patients. Full-Text PDF Open Access