Minimal residual disease after induction is the strongest predictor of prognosis in intermediate risk relapsed acute lymphoblastic leukaemia - long-term results of trial ALL-REZ BFM P95/96.

TY - JOUR

T1 - Minimal residual disease after induction is the strongest predictor of prognosis in intermediate risk relapsed acute lymphoblastic leukaemia - long-term results of trial ALL-REZ BFM P95/96.

AU - Eckert, Cornelia

AU - von Stackelberg, Arend

AU - Seeger, Karl

AU - Groeneveld, Tom W L

AU - Peters, Christina

AU - Klingebiel, Thomas

AU - Borkhardt, Arndt

AU - Schrappe, Martin

AU - Escherich, Gabriele

AU - Henze, Günter

N1 - Copyright © 2012 Elsevier Ltd. All rights reserved.

PY - 2013

Y1 - 2013

N2 - PURPOSE: This blinded prospective study was performed to optimise the risk assessment of children with a late isolated, combined or an early combined bone marrow (BM) relapse of precursor B-cell acute lymphoblastic leukaemia (ALL). The aim was to develop a reliable tool to identify patients with an intermediate risk relapse who are in need of haematopoietic stem cell transplantation (HSCT).METHODS: Included were 80 children and adolescents with first intermediate risk BM relapse of ALL recruited in trial ALL-REZ BFM P95/96. We assessed the prognostic value of minimal residual disease (MRD) after induction therapy quantified by PCR using leukaemia clone-specific T-cell receptor/immunoglobulin gene rearrangements.RESULTS: Molecular good responders (MRD < 10(-3), n=46) had a probability of event-free survival (pEFS) at 10 years of 76% standard error (SE) ± 6% and a cumulative incidence of second relapse (CIR) at 10 years of 21% SE ± 6%; pEFS of molecular poor responders (MRD ≥ 10(-3), n=34) at 10 years was 18% SE ± 7% and CIR 61% SE ± 9% (p<0.001). Cox regression analysis revealed MRD after induction to be the strongest independent prognostic parameter with a 6.6-fold increased risk (95% confidence interval 3.3-13.5, p<0.001) for molecular poor responders to suffer a subsequent adverse event compared to good responders.CONCLUSION: In patients with intermediate risk BM relapse of ALL, low MRD after induction is associated with an excellent long-term prognosis with conventional chemo-/radiotherapy whereas patients with insufficient response have an extremely poor prognosis. Therefore, in the subsequent trial ALL-REZ BFM 2002, MRD is used to allocate molecular good responders to conventional post-induction therapy and molecular poor responders to allogeneic HSCT.

AB - PURPOSE: This blinded prospective study was performed to optimise the risk assessment of children with a late isolated, combined or an early combined bone marrow (BM) relapse of precursor B-cell acute lymphoblastic leukaemia (ALL). The aim was to develop a reliable tool to identify patients with an intermediate risk relapse who are in need of haematopoietic stem cell transplantation (HSCT).METHODS: Included were 80 children and adolescents with first intermediate risk BM relapse of ALL recruited in trial ALL-REZ BFM P95/96. We assessed the prognostic value of minimal residual disease (MRD) after induction therapy quantified by PCR using leukaemia clone-specific T-cell receptor/immunoglobulin gene rearrangements.RESULTS: Molecular good responders (MRD < 10(-3), n=46) had a probability of event-free survival (pEFS) at 10 years of 76% standard error (SE) ± 6% and a cumulative incidence of second relapse (CIR) at 10 years of 21% SE ± 6%; pEFS of molecular poor responders (MRD ≥ 10(-3), n=34) at 10 years was 18% SE ± 7% and CIR 61% SE ± 9% (p<0.001). Cox regression analysis revealed MRD after induction to be the strongest independent prognostic parameter with a 6.6-fold increased risk (95% confidence interval 3.3-13.5, p<0.001) for molecular poor responders to suffer a subsequent adverse event compared to good responders.CONCLUSION: In patients with intermediate risk BM relapse of ALL, low MRD after induction is associated with an excellent long-term prognosis with conventional chemo-/radiotherapy whereas patients with insufficient response have an extremely poor prognosis. Therefore, in the subsequent trial ALL-REZ BFM 2002, MRD is used to allocate molecular good responders to conventional post-induction therapy and molecular poor responders to allogeneic HSCT.

KW - Humans

KW - Male

KW - Female

KW - Risk Factors

KW - Adolescent

KW - Prospective Studies

KW - Child

KW - Prognosis

KW - Risk Assessment

KW - Disease-Free Survival

KW - Proportional Hazards Models

KW - Clinical Trials as Topic

KW - Child, Preschool

KW - Recurrence

KW - Hematopoietic Stem Cell Transplantation

KW - Gene Rearrangement

KW - Outcome Assessment (Health Care)/methods/statistics & numerical data

KW - Bone Marrow/pathology

KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use

KW - Immunoglobulins/genetics

KW - Induction Chemotherapy/methods

KW - Neoplasm, Residual/diagnosis

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics/surgery

KW - Receptors, Antigen, T-Cell/genetics

KW - Humans

KW - Male

KW - Female

KW - Risk Factors

KW - Adolescent

KW - Prospective Studies

KW - Child

KW - Prognosis

KW - Risk Assessment

KW - Disease-Free Survival

KW - Proportional Hazards Models

KW - Clinical Trials as Topic

KW - Child, Preschool

KW - Recurrence

KW - Hematopoietic Stem Cell Transplantation

KW - Gene Rearrangement

KW - Outcome Assessment (Health Care)/methods/statistics & numerical data

KW - Bone Marrow/pathology

KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use

KW - Immunoglobulins/genetics

KW - Induction Chemotherapy/methods

KW - Neoplasm, Residual/diagnosis

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics/surgery

KW - Receptors, Antigen, T-Cell/genetics

U2 - 10.1016/j.ejca.2012.11.010

DO - 10.1016/j.ejca.2012.11.010

M3 - SCORING: Journal article

C2 - 23265714

VL - 49

SP - 1346

EP - 1355

JO - EUR J CANCER

JF - EUR J CANCER

SN - 0959-8049

IS - 6

M1 - 6

ER -