doi:10.1182/blood-2009-10-248146 Prepublished online February 12, 2010; 2010 115: 3206-3214 Schrappe Bradtke, Rosanna Parasole, Rita Beier, Jacques J. M. van Dongen, Andrea Biondi and Martin Wolf-Dieter Ludwig, Oskar A. Haas, Giovanni Cazzaniga, Rolf Koehler, Daniela Silvestri, Jutta Martin Stanulla, Franco Locatelli, Giuseppe Basso, Felix Niggli, Elena Barisone, Günter Henze, Panzer-Grümayer, Anja Möricke, Maurizio Aricò, Martin Zimmermann, Georg Mann, Giulio De Rossi, Valentino Conter, Claus R. Bartram, Maria Grazia Valsecchi, André Schrauder, Renate leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study children and adolescents with B-cell precursor acute lymphoblas tic Molecular response to treatment redefines all prognostic factors in http://bloodjournal.hematologylibrary.org/content/115/16/3206.full.html Updated information and services can be found at: (945 articles) Lymphoid Neoplasia (1293 articles) Free Research Articles (41 articles) CME article (3368 articles) Clinical Trials and Observation s Articles on similar topics can be found in the following Blood collections http://bloodjo urnal.hemato logylibrary.or g/site/misc/righ ts.xhtml#re pub_reque sts Information about repro ducing this article in parts or in its entirety may be found online at: http://bloodjo urnal.hemato logylibrary.or g/site/misc/righ ts.xhtml#re prints Information about ordering reprints may be found online at: http://bloodjo urnal.hemato logylibrary.or g/site/subsc riptions/index .xhtml Information about subscriptions and ASH membership may be found online at: Copyright 2011 by The American Society of Hematology; all rights reserved. Washington DC 20036. by the American Society of Hematology, 2021 L St, NW, Suite 900, Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly For personal use only. by guest on December 19, 2011. bloodjournal.hematologylibrary.org From
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doi:10.1182/blood-2009-10-248146Prepublished online February 12, 2010;2010 115: 3206-3214
SchrappeBradtke, Rosanna Parasole, Rita Beier, Jacques J. M. van Dongen, Andrea Biondi and MartinWolf-Dieter Ludwig, Oskar A. Haas, Giovanni Cazzaniga, Rolf Koehler, Daniela Silvestri, JuttaMartin Stanulla, Franco Locatelli, Giuseppe Basso, Felix Niggli, Elena Barisone, Günter Henze,Panzer-Grümayer, Anja Möricke, Maurizio Aricò, Martin Zimmermann, Georg Mann, Giulio De Rossi,Valentino Conter, Claus R. Bartram, Maria Grazia Valsecchi, André Schrauder, Renateleukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 studychildren and adolescents with B-cell precursor acute lymphoblasticMolecular response to treatment redefines all prognostic factors in
http://bloodjournal.hematologylibrary.org/content/115/16/3206.full.htmlUpdated information and services can be found at:
(945 articles)Lymphoid Neoplasia (1293 articles)Free Research Articles
(41 articles)CME article (3368 articles)Clinical Trials and Observations
Articles on similar topics can be found in the following Blood collections
http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub_requestsInformation about reproducing this article in parts or in its entirety may be found online at:
http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#reprintsInformation about ordering reprints may be found online at:
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Copyright 2011 by The American Society of Hematology; all rights reserved.Washington DC 20036.by the American Society of Hematology, 2021 L St, NW, Suite 900,Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly
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Molecular response to treatment redefines all prognostic factors in childrenand adolescents with B-cell precursor acute lymphoblastic leukemia:results in 3184 patients of the AIEOP-BFM ALL 2000 study
*Valentino Conter,1,2
*Claus R. Bartram,3
Maria Grazia Valsecchi,4
Andre Schrauder,5
Renate Panzer-Grumayer,6
Anja Moricke,5 Maurizio Arico,7 Martin Zimmermann,8 Georg Mann,6 Giulio De Rossi,9 Martin Stanulla,5 Franco Locatelli,10
Giuseppe Basso,11 Felix Niggli,12 Elena Barisone,13 Gunter Henze,14 Wolf-Dieter Ludwig,15 Oskar A. Haas,6
Jacques J. M. van Dongen,19 Andrea Biondi,1,16 and Martin Schrappe5
1Department of Pediatrics, University of Milano-Bicocca, Ospedale S Gerardo, Monza, Italy; 2Department of Pediatrics, Ospedali Riuniti, Bergamo, Italy;3Institute of Human Genetics, Ruprecht-Karls University, Heidelberg, Germany; 4Medical Statistics Unit, Department of Clinical Medicine and Prevention,
University of Milano-Bicocca, Milan, Italy; 5Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; 6Children’s
Cancer Research Institute and St Anna Kinderspital, Vienna, Austria; 7Department of Pediatric Hemato-Oncology, Ospedale Meyer, Firenze, Italy; 8Department
of Pediatric Hematology and Oncology, Medical School Hannover, Hannover, Germany; 9Department of Pediatric Hemato-Oncology, Ospedale Bambin Gesu,
Rome, Italy; 10Pediatric Hematology-Oncology, Fondazione, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Universita di
Pavia, Italy; 11Pediatric Hemato-Oncology, University of Padua, Ospedale Policlicnico, Padova, Italy; 12Pediatri c Oncology, University Child ren’s Hospital Zurich,
Zurich, Switzerl and; 13Department of Pediatric Hemato-Oncology, Ospedale Infantile Regina Margherita, Turin, Italy; 14Pediatric Hematology and Oncology,
Virchow Hospi tal, Charit e, Berlin, Germany; 15Hematol ogy/Oncol ogy, Robert-Rossle-Klin ik at the HELIOS Klinikum, Chari te, Berlin, Germany; 16Centro Ricerca
M Tettamant i, Clinica Pediatr ica Universit a Mi lano-Bicoc ca, Monza, Italy; 17Oncogenetic Laboratory, Pediatric Hematology and Oncology,
Justus-Liebig-University, Giessen, Germany; 18Department of Pediatrics Hemato-Oncology, Ospedale Pausillipon, Napoli, Italy; and 19Department of
Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
The Associazione Italiana di Ematologia On-
cologia Pediatrica and the Berlin-Frankfurt-
Munster Acute Lymphoblastic Leukemia
(AIEOP-BFM ALL 2000) study has for the
first time introduced standardized quantita-
tive assessmentof minimal residual disease
(MRD) based on immunoglobulin and T-cell
receptor gene rearrangements as polymer-
ase chain reaction targets (PCR-MRD), at
2 time points (TPs), to stratify patients in a
large prospective study. Patients with pre-
cursor B (pB) ALL (n 3184) were consid-
ered MRD standard risk (MRD-SR) if MRD
was already negative at day 33 (analyzed by
2 markers, with a sensitivity of at least 104);
MRD high risk (MRD-HR) if 103 or more at
day 78 and MRD intermediate risk (MRD-IR):
others. MRD-SR patients were 42% (1348):
5-year event-free survival (EFS, standard
error) is 92.3% (0.9). Fifty-two percent (1647)
were MRD-IR: EFS 77.6% (1.3). Six percent
of patients (189) were MRD-HR: EFS 50.1%
(4.1; P < .001). PCR-MRD discriminated
prognosis even on top of white blood cell
count, age, early response to prednisone,
and genotype. MRD response detected by
sensitive quantitative PCR at 2 predefined
TPs is highly predictive for relapse in child-
hood pB-ALL. The study is registered at
http://clinicaltrials.gov: NCT00430118 for
BFM and NCT00613457 forAIEOP. (Blood .
2010;115(16):3206-3214)
Continuing Medical Education online
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for
Continuing Medical Education (ACCME) through the joint sponsorship of Medscape, LLC and the American Society of
Hematology. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC
designates this educational activity for a maximum of 1.0 AMA PRA Category 1 credits™. Physicians should only claim credit
commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a
certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures;
(2) study the education content; (3) take the post-test and/or complete the evaluation at http://cme.medscape.com/journal/blood;
and (4) view/print certificate. For CME questions, see page 3418.
Disclosures
The authors and Associate Editor Martin S. Tallman declare no competing financial interests. The CME questions author Desiree Lie,
University of California, Irvine, CA, served as a nonproduct speaker for “Topics in Health” for Merck Speaker Services.
Submitted October 23, 2009; accepted December 10, 2009. Prepublished
online as Blood First Edition paper, February 12, 2010; DOI 10.1182/blood-
2009-10-248146.
*V.C. and C.R.B. share the first author position.
The online version of this article contains a data supplement.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
Patients were defined as MRD standard risk (MRD-SR) if MRD was found to be
negative at both days 33 (time point 1 [TP1]) and 78 (TP2), using at least
2 molecular markers with sensitivity of 104 or less.17 If MRD levels differed
between the 2 markers, the highest MRD level was chosen for the final MRD
assessment. Patients were considered to be MRD intermediate risk (MRD-IR)
when MRD was positive at 1 or both TPs but at a level of less than 103 at TP2
with at least 2 markers. Patients with MRD 10
3
or more at TP2 were definedMRD high risk (MRD-HR), independent of the sensitivity and the number of
markers. Patients with prednisone poor response (PPR; 1000 leukemic blasts
per microliter in the peripheral blood on day 8) or failure to achieve remission (ie,
with 5% leukemic blasts in the bone marrow on day33, or persistent extramed-
ullary disease) after induction phase IA (induction failure) or positivity for
MLL/AF4 fusion transcript were treated in the HR arm irrespective of their MRD
results. If MRD evaluation was not available, patients were assigned to the IR
group or, based on clinical parameters, to the HR group; these patients are not part
of this report.
Treatment protocol
All enrolled patients were treatedaccording to theAIEOP-BFMALL 2000 study
protocol: treatment outlines, details, and differences between AIEOP and BFM
are shown in supplemental Figure 1 and supplemental Table 1. The ethics
committee of each participating organization approved the studyprotocol.
Induction and consolidation phase. All patients underwent 7 days of
prephase with steroid therapy (prednisone) and 1 intrathecal dose of
methotrexate (intrathecal MTX), followed by induction phase IA and
induction consolidation phase IB; from day 8, patients were randomized to
continue steroid treatment with either prednisone (60 mg/m2 per day) or
dexamethasone (10 mg/m2 per day) until day 28 with subsequent tapering
of dose in 1 more week.
Protocol M and reinduction phases. SR andIR patients received 4 cycles
of high-dose MTX (HD-MTX, 5 g/m2); AIEOP patients with non–T ALL and
without central nervous system (CNS) or testicular involvement at diagnosis
received 2 g/m2. At the beginning of the reinduction phase, patients were
randomized to receive either protocol II or reduced-intensity protocol III in SR
group, or protocol II versus reduced-intensity protocol III given twice in the IR
group. HR patients were randomized to receive 3 blocks of non–cross-resistant
drugs followed by protocol IIIgiven3 times versus3 blocksfollowedby protocol
II given twice in the AIEOP group, or 6 blocks followed by protocol II in the
BFM group.
Maintenance therapy. Maintenance therapy consisted of daily 6-mer-
captopurine together with weekly MTX until 24 months from diagnosis.
CNS-directed therapy. CNS-directed therapy consisted of repeated
intrathecal MTX administration during each treatment phase. Only patients
who were treated in AIEOP centers and who did not undergo irradiation
received MTX treatment also during the continuation phase. Cranial
radiotherapy was given (dosage by age; supplemental Table 1) to patients at
HR or with CNS involvement at diagnosis.
Statistical analysis
Event-free survival (EFS) and survival times were calculated from date of
diagnosis to date of event, which, for EFS, was resistance, relapse, death, orsecond neoplasm, whichever occurred first, and, for survival, death from any
cause. Of note, stratification by MRD is possible, by definition, only on the
subpopulation of patients who are failure-free by TP2. EFS and survival curves
were estimated according to Kaplan-Meier with Greenwood standard error,
always indicated in parentheses, and compared according to log-rank test.
Cumulative incidence curves for relapse were estimated adjusting for competing
risks of other events and were compared with the Gray test. TheCox model, after
stratification by group (AIEOP and BFM), was used to analyze the prognostic
role of PCR-MRD in terms of cause-specific hazard of relapse.33 A 1-step
multivariate model that included the most frequently used conventional prognos-
tic features was applied. The proportional hazard assumption was tested by
graphic checks. Tests were 2-sided, with .05 significance level. Analyses were
carried out using SAS 9.1.
The study is registered at the US National Institutes of Health website
http://clinicaltrials.gov as “Combination Chemotherapy Based on Risk of
Relapse in Treating Young Patients With Acute Lymphoblastic Leukemia”
with the protocol identification number NCT00430118 for BFM and
NCT00613457 for AIEOP.
Results
The cohort of 4016 children between 1 and 18 years of age with
newly diagnosed Ph pB-ALL, enrolled in the AIEOP-BFM ALL
2000 study, had a 7-year EFS (standard error [SE]) and survival
(SE) of 80.4% (0.9) and 91.8% (0.5), respectively.
The 3184 children stratified by MRD had, by definition, completed
induction phase IA (TP1) and induction consolidation phase IB (TP2).
This report focuses only on these patients, alive at TP2 (day78).
Their overall 7-year estimates for EFS (SE) and survival (SE)
were 80.7% (1.0) and 92.8% (0.6), respectively, with a median
follow-up of 4.0 years (supplemental Figure 2). The 7-year EFS
and survival were 77.4% (1.6) and 92.0% (0.9) for 1329 AIEOP
patients vs 83.0% (1.3) and 93.4% (0.7) for 1855 BFM patients,
respectively. The difference in EFS was consistent in all subgroups
of patients stratified by MRD, and the impact of PCR-MRD was
found to be the same in AIEOP and BFM centers. The presentedanalyses will therefore concern the whole cohort of patients
recruited by the 2 groups and stratified by MRD.
Among the 3184 patients, 42% were MRD-SR, 52% MRD-IR,
and 6% MRD-HR; they had a significantly different outcome, with
5-year EFS estimates of 92.3% (0.9), 77.6% (1.3), and 50.1 (4.1),
respectively (Figure 1A). The 5-year survival estimates were
Only patients alive by TP2 are included in this cohort and consequently induction deaths in protocols IA and IB are not included.
ALL indicates acute lymphoblastic leukemia; MRD, minimal residual disease; SR, standard risk; IR, intermediate risk; HR, high risk; and CCR, continuous complete
remission.
*Resistant patients are those who did not achieve CR by the end of the third HR block of chemotherapy.
MRD affected outcome significantly (at the .001 level) in every subgroup.
ALL indicates acute lymphoblastic leukemia; MRD, minimal residual disease; SR, standard risk; IR, intermediate risk; HR, high risk; SE, standard error; WBC white blood
cell; NCI, National Cancer Institute; BFM, Berlin-Frankfurt-Munster; and AIEOP, Associazione Italiana di Ematologia Oncologia Pediatrica.
*Standard: age 1-9 years and WBC 50 000; high: age 10 years or WBC 50 000.
†High: PPR or no remission on day 33 or t(4;11); medium: no high-risk criteria, WBC 20 000 or age 6 years or T-ALL; standard: no high-risk criteria, WBC 20 000
and age between 1 and 6 years and no T-ALL.
‡These patients were at high risk for no CR day33 (n 1) or PPR (n 36).
§These patients were at high risk for no CR day33 (n 8) or MLL/AF4 fusion transcript (n 8) or PPR (n 114).
3210 CONTER et al BLOOD, 22 APRIL 2010 VOLUME 115, NUMBER 16
For personal use only.by guest on December 19, 2011.bloodjournal.hematologylibrary.orgFrom
Cox model stratified by group (AIEOP and BFM) on hazard of relapse in 2927 pB-ALL (Ph) patients (with 354 relapses) for whom information on most covariates was
available.
CI indicates confidence interval; WBC, whtie blood cell; PCR-MRD, polymerase chain reaction minimal residual disease; SR, standard risk; IR, intermediate risk; and HR,