Minimal Residual Disease Assessment and Risk-based Therapy in Acute Lymphoblastic Leukemia

Bassan, Renato; Intermesoli, Tamara; Scattolin, Annamaria; Viero, Piera; Maino, Elena; Sancetta, Rosaria; Carobolante, Francesca; Gianni, Francesca; Stefanoni, Paola; Tosi, Manuela; Spinelli, Orietta

doi:10.1016/j.clml.2017.02.019

Cited by 21 publications

(22 citation statements)

References 39 publications

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“…MRD is increasingly being used in clinical practice as an independent prognostic marker for the duration of CR and long-term outcomes in patients with ALL, and for informing treatment decisions. 19–22 The European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network clinical practice guidelines for adult patients with ALL recommend the quantification of MRD whenever possible, 6,23,24 but it is not yet clear whether MRD status alone is sufficient to predict prognosis, or whether it should be combined with other parameters, such as patient-related (e.g., age) or disease-related (e.g., cytogenetics) risk factors. In drug development, MRD response has been considered as an early marker of efficacy in clinical studies, with potential use as a surrogate endpoint in registration studies for accelerated drug approval.…”

Section: Introductionmentioning

confidence: 99%

“…A large number of studies have shown that achievement of MRD-negative status correlates positively with CR duration, reduced risk of relapse, and HSCT success. 22,27 The use of MRD testing is individualized within a given study protocol, and hence there is wide variation in the test method used, the timing and sensitivity of MRD assessment, the characteristics of the patients, and the treatments used before and after MRD was assessed. We conducted a systematic review to capture the evidence supporting the clinical significance of MRD on clinical outcomes and used this evidence to inform a meta-analysis with the aim of quantifying the impact of MRD status on relapse-free survival (RFS) and overall survival (OS).…”

Section: Introductionmentioning

confidence: 99%

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A systematic literature review and meta-analysis of minimal residual disease as a prognostic indicator in adult B-cell acute lymphoblastic leukemia

et al. 2019

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Minimal (or ‘measurable’) residual disease in acute lymphoblastic leukemia appears to be a prognostic indicator, with potential value in informing individualized treatment decisions. Complete understanding of the strength of the association between minimal residual disease and long-term outcomes is, however, lacking. A systematic literature review and meta-analysis were performed to elucidate the clinical significance of minimal residual disease with respect to relapse-free survival and overall survival in precursor B-cell acute lymphoblastic leukemia. A total of 23 articles and abstracts, most published between 2012 and 2016, were identified for inclusion in the primary meta-analysis. Typically, patients were in their first complete remission at the time of minimal residual disease assessment; in two studies, all patients were in their second, or later, complete remission. The primary analysis revealed improved relapse-free survival across all studies for patients who achieved minimal residual disease negativity (random effects hazard ratio, 2.34; 95% confidence interval, 1.91–2.86). Improved overall survival for patients who achieved minimal residual disease negativity was also observed (hazard ratio, 2.19; 95% confidence interval, 1.63–2.94). There was no observed difference in the impact of minimal residual disease status in subgroups based on disease stage, minimal residual disease sensitivity threshold level, Philadelphia chromosome status, histological phenotype, risk group, minimal residual disease testing location, minimal residual disease timing after induction, or minimal residual disease detection method. Despite heterogeneity in study design and patient populations between the contributing studies, these data provide a compelling argument for minimal residual disease as a clinical tool for assessing prognosis and guiding treatment decisions in precursor B-cell acute lymphoblastic leukemia.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A systematic literature review and meta-analysis of minimal residual disease as a prognostic indicator in adult B-cell acute lymphoblastic leukemia

et al. 2019

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“…Advances in the field of subset recognition, risk stratification, chemotherapy, targeted therapy, and immunotherapy have led to significant therapeutic progress in adult acute lymphoblastic leukemia (ALL) over the past 20 years 1,2 . In the frontline setting, outcomes were improved by the use of pediatric-inspired chemotherapy 3,4 , minimal residual disease (MRD) to optimize risk classification and guide treatments 5,6 , targeted therapy in Philadelphia chromosome-positive (Ph+) ALL 7 , and monoclonal antibody therapy in B-precursor ALL (B-ALL) 8 . Pediatric-based chemotherapy together with the assessment of postinduction MRD has been used in Ph− ALL as a primary risk classifier and indicator for riskoriented allogeneic hematopoietic cell transplantation (HCT) [9][10][11][12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

Updated risk-oriented strategy for acute lymphoblastic leukemia in adult patients 18–65 years: NILG ALL 10/07

et al. 2020

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An updated strategy combining pediatric-based chemotherapy with risk-oriented allogeneic hematopoietic cell transplantation (HCT) was evaluated in Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph− ALL) and compared with a published control series. Following induction–consolidation chemotherapy, responsive patients were assigned to receive maintenance chemotherapy or undergo early HCT according to the risk stratification criteria and minimal residual disease (MRD) status. Of the 203 study patients (median age 41 years, range 17–67), 140/161 with Ph− ALL achieved complete remission (86.9%; 91.6% ≤55 years, P = 0.0002), with complete MRD clearing in 68/109; 55 patients were assigned to maintenance chemotherapy, and 85 to HCT due to very high-risk characteristics (hyperleukocytosis, adverse genetics, early/mature T-precursor ALL, and MRD persistence). The 5-year relapse incidence was 36%, and the treatment-related mortality rate was 18%. Median overall and relapse-free survival were 7.4 and 6.2 years, with rates of 54 and 53% at 5 years, respectively, which were significantly better than those obtained with the historical protocol (P = 0.001 and P = 0.005, respectively), without significant differences between maintenance and HCT cohorts. In prognostic analysis, MRD negativity and age ≤55 years were the most favorable independent prognostic factors. A reduction in treatment toxicity and further improvements in the risk definitions and risk-oriented design are the focuses of this ongoing research.

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“…Testing for measurable ('minimal') residual disease (MRD) in people with acute leukaemias and other haematologic cancers has gained popularity [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Results of these tests are now often included as an endpoint in reports of clinical trials outcomes and increasingly used in clinical practice with haematopoietic cell transplantation no exception.…”

Section: Introductionmentioning

confidence: 99%

Statistics and measurable residual disease (MRD) testing: uses and abuses in hematopoietic cell transplantation

Othus

Gale

Hourigan

et al. 2019

Bone Marrow Transplant

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Series Editors' NoteThe decision whether to recommend a transplant to someone with acute leukemia in first remission is complex and challenging. Diverse, often confounded co-variates interact to influence one's recommendation. Briefly, the decision metric can be viewed in three spheres: (1) subject-; (2) transplant-; and (3) disease-related co-variates. Subject-related co-variates include items such as age and comorbidities. Transplant-related co-variates include items such as donor-types, graft source, proposed conditioning and pre-and post-transplant immune suppression.But what of disease-related variables? Previously haematologists relied on co-variates such as WBC at diagnosis, chemotherapy cycles to achieve first remission, cytogenetics and most recently, mutation topography. However, these covariates have largely been replaced by results of measurable residual disease (MRD)-testing. Many chemotherapy-only and transplant studies report strong correlations between results of MRD-testing on therapy outcomes such as cumulative incidence of relapse (CIR), leukemia-free survival (LFS) or survival. (CIR makes biological sense in a transplant context whereas LFS and survival do not give competing causes of death such as transplant-related mortality (TRM), graft-versushost disease and interstitial pneumonia unrelated to relapse probability).This raises the question of how useful results are of MRD-testing in predicting CIR after transplants. Elsewhere we discussed accuracy and precision of MRD-testing in predicting outcomes of therapy of acute myeloid leukemia (Estey E, Gale RP. . Briefly put, not terribly good. Although results of MRD-testing are often the most powerful predictor of CIR in multivariable analyses, the C-statistic (a measure of prediction accuracy) is often only about 0.75. This is much better than flipping a fair coin but far from ideal.In the typescript which follows, Othus and colleagues discuss statistical issues underlying MRD-testing in the context of haematopoietic cell transplants. We hope readers, especially haematologists who often need to make transplant recommendations to people with acute leukemia in first remission, will read it carefully and critically. The bottom line is MRD-test data are useful but considerable uncertainty is unavoidable with substantial false-positive and -negative rates. We need to acknowledge this uncertainty to ourselves and to the people we counsel. The authors quote Voltaire who said: Doubt is not a pleasant condition, but certainty is an absurd one. Sadly so, but we do the best we can.

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Minimal Residual Disease Assessment and Risk-based Therapy in Acute Lymphoblastic Leukemia

Cited by 21 publications

References 39 publications

A systematic literature review and meta-analysis of minimal residual disease as a prognostic indicator in adult B-cell acute lymphoblastic leukemia

A systematic literature review and meta-analysis of minimal residual disease as a prognostic indicator in adult B-cell acute lymphoblastic leukemia

Updated risk-oriented strategy for acute lymphoblastic leukemia in adult patients 18–65 years: NILG ALL 10/07

Statistics and measurable residual disease (MRD) testing: uses and abuses in hematopoietic cell transplantation

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