Common Guidelines For Diagnostic Approaches To Leukemias PDF
Common Guidelines For Diagnostic Approaches To Leukemias PDF
Common Guidelines For Diagnostic Approaches To Leukemias PDF
ENCCA
EUROPEAN NETWORK for CANCER research in CHILDREN and
ADOLESCENTS
Network of Excellence
Duration: 48 months
Project co-funded by the European Commission within the Seventh Framework Programme
(2011-2014)
Dissemination Level
Public
PU
ENCCA DELIVERABLES
Summary
In this deliverable we describe consensus recommendations on the diagnosis of childhood
acute leukemia from a European viewpoint based on surveys of the groups participating to
the AIEOP-BFM ALL 2009 study, a 7-country-based international frontline treatment trial on
acute lymphoblastic leukemia (ALL) in children and adolescents, a survey of the work group
DCOG Molecular Research of the Dutch Childhood Oncology Group, and the Biology &
Diagnosis Committee of the International BFM Study Group, the largest initiative on
childhood leukemias worldwide which unifies cooperative national study groups on
childhood leukemia from more than 30 different, mostly European countries. Topics covered
relate to cytomorphology, immunophenotyping, cyto- and molecular genetics, and the
evaluation of measures of treatment response.
The recommendations provide a common ground for systematic implementation of
molecularly-based diagnostic strategies in acute leukemias to be developed within ENCCA
and, therefore, can be seen as a prerequisite for the implementation of rational molecular
information-based treatment approaches in pediatric hematology and oncology.
The diagnostic guidelines will be published on the website of the international BFM study
group (http://www.bfm-international.org).
ENCCA DELIVERABLES
Description
Common guidelines for diagnostic approaches to leukemias
Correspondence to:
Susanne Kilian, PhD, MLaw
University Medical Center Schleswig-Holstein
Department of General Pediatrics Campus Kiel
Schwanenweg 20 24105 Kiel, Germany
Tel.: +49 (0)431 597-3947 Fax: -3966
Email: kilian-ibfm@pediatrics.uni-kiel.de
Disclaimer:
While the advice and information in these guidelines is believed to be true and accurate,
neither the authors, the International BFM Study Group nor the European Network for
Cancer Research in Children and Adolescents accept any legal responsibility for the
content of this document.
Writing group:
ENCCA WP9 and I-BFM Biology & Diagnosis Committee members
Declarations of Interest:
None of the authors are considered to have a conflict of interest with regards to the
recommendations made in this document.
ENCCA DELIVERABLES
Contents
Deliverable in context of WP9
12
19
22
References
24
ENCCA DELIVERABLES
ENCCA DELIVERABLES
ENCCA DELIVERABLES
DNA content of leukemic cells. In addition, a combined approach using cytogenetic and
molecular genetic techniques is used for the detection of genetic aberrations, such as nonrandom recurrent chromosomal translocations or their molecular equivalents (e.g., the
t(9;22) or the BCR/ABL1 fusion transcript). Molecular-genetic techniques and/or flow
cytometry are also used to monitor disease burden during therapy by measuring minimal
residual disease (MRD). A last important issue addresses the definition of what is called
complete remission and relapse: complete remission is defined as the absence of leukemic
blasts in blood and CSF, fewer than 5% lymphoblasts in bone marrow aspiration smears,
and no evidence of localized disease. Relapse is defined as the recurrence of lymphoblasts
or localized leukemic infiltrates at any site.
Prognostic factors and risk-adapted treatment
Continuing research on the clinical and biological aspects of ALL has identified numerous
features with prognostic potential some of which are displayed in Table 1. On modern
protocols, risk-adapted therapy reflecting the probability of treatment failure has become a
common feature in the clinical management of childhood ALL. For this purpose, the initially
assessed prognostic factors are used to estimate an individual patients risk of relapse and
to adjust the required treatment intensity by therapy stratification into different risk groups
(e.g., standard/low, intermediate, high). The prognostic significance of an inadequate early
reduction of leukemic blasts in the peripheral blood was first described by the BFM study
group and confirmed by several other study groups. Of importance, the specificity of
response evaluation might vary with the composition of the induction regimen and the time
point of response evaluation. However, although a poor early response to induction therapy
as described above is highly predictive of treatment failure, the majority of recurrences
occur in the large group of patients with an adequate morphological response to treatment.
Of advantage in this context, the sub-microscopic assessment of MRD is approximately
1000 to 10000-fold more sensitive compared to methods based on morphological detection
and provides excellent prognostic information. Although most of the experience on MRD in
clinical settings was gained through DNA-PCR-based detection of leukemic clone-specific
immunoglobulin and/or T-cell receptor gene rearrangements, it was shown that flowcytometry-based analyses by detection of specific antigen patterns of the leukemic clone
yield sensitive and reliable results comparable to PCR-based methods.
Remission induction treatment
Contemporary treatment approaches for childhood ALL aim at an initial remission induction
and restoration of normal hematopoiesis within approximately 4 to 6 weeks. In most study
groups this goal is achieved in approximately 98% of patients through the systemic
application of three drugs (glucocorticoid, vincristine, L-asparaginase) to which an
anthracycline may be added as a fourth drug. On ALL-BFM protocols, remission induction is
initiated by a 7-day monotherapy with orally administered prednisone (and one intrathecal
dose of intrathecal methotrexate on day 1), which isparticularly useful in avoiding
complications related to extensive tumor cell lysis. Undoubtedly, the dose intensity of the
induction phase can have a major impact on the overall treatment outcome. Nevertheless,
in specific subgroups of childhood ALL, the necessity of a four-drug induction regimen is
ENCCA DELIVERABLES
subject to debate and it is, for example, unclear if addition of an anthracycline to a threedrug induction regimen is of real benefit to certain low- or intermediate-risk patients.
Another frequently discussed issue addresses the choice of the glucocorticoid for optimal
induction. Despite some debate on a truly equivalent dose, compared to prednisolone,
dexamethasone appears to have a stronger antileukemic effect in vitro and has been shown
to provide better leukemic CNS control and lower relapse rates. However, dexamethasone
was also associated with increased side effects including severe infectious complications.
The 2% of patients not in remission after induction therapy will either have died of
treatment- or disease-related complications or display nonresponsive disease. The latter
group includes patients that will achieve only delayed remission or show resistant disease.
Because of the poor prognosis of this minor non-responsive patient population, alternative
therapeutic approaches should be considered early during the disease process.
Consolidation/intensification and reinduction treatment
Eradication of residual leukemic blasts in patients who are in remission by morphologic
criteria
is
the
primary
aim
of
consolidation/intensification
treatment.
Consolidation/intensification treatment is necessary as patients successfully induced into
remission, but not given additional treatment, usually relapse within months. A so-called
reinduction or delayed intensification treatment can further enhance the effect of previous
consolidation/intensification therapy. As consolidation/intensification phases administered in
protocols of the large study groups on treatment of childhood ALL are variable and may
differ, for example, with regard to amounts, timing, and number of drug doses, drug
composition and overall treatment context, the direct contributions of most of these
consolidation/intensification strategies and/or their individual components are difficult to
assess and associated with limited generalizability. Today, most protocols use high-dose
methotrexate (combined with folinic acid rescue) together with 6-mercaptopurine (6-MP)
and/or prolonged administrations of asparaginase in consolidation/intensification.
Reinduction treatment mainly consists of a late repetition of the initial remission induction
and early intensification phases. A randomized trial by the Childrens Cancer Group
applying an augmented BFM protocol showed that intensified consolidation and doubledelayed intensification can further improve the outcome of high-risk patients with a slow
initial treatment response. Of interest in this context, in a recent subsequent trial on higherrisk patients with a rapid marrow response to induction therapy by the same group, the
investigators demonstrated an improved event-free survival for more intensive but not for
longer postinduction intensification treatment. Unfortunately, further intensification of
treatment and the related higher doses of glucocorticoids have been associated with a high
incidence of osteonecrosis, especially in older children. Consequently, some investigators
suggest glucocorticoid administration in intensification/consolidation on alternate weeks for
children older than 10 years to improve complication rates.
Central nervous system-directed therapy
CNS-directed therapy has become a prerequisite for successful treatment of childhood ALL.
Before its introduction in the 1960s, more than 50% of children with ALL suffered from
disease recurrence originating from the CNS. This high rate could be reduced to less than
ENCCA DELIVERABLES
ENCCA DELIVERABLES
lity and increased incorporation of phosphorylated thiopurines in DNA and RNA. During
maintenance treatment, 6-MP and methotrexate doses are adjusted according to absolute
leukocyte or neutrophil and platelet counts. Important to note and a potential source of
heterogeneity with regard to outcome analyses, the starting dose as well as dose
adjustment guidelines while on therapy may differ between the different study groups. As
several reports suggested an improved outcome with bedtime administration, 6-MP is
commonly administered in the evening hours. Also, 6-MP should not be given in
combination with milk since the xanthine oxidase activity contained in milk decreases the
bioavailability of 6-MP. Of utmost clinical importance, at St. Jude Childrens Research
Hospital researchers have demonstrated that maintaining the highest tolerable dose of daily
6-MP in maintenance therapy is an important prognostic factor in childhood ALL.
Intensification of maintenance treatment by the administration of vincristine/dexamethasone
pulses was recently shown to provide no extra benefit. The reduction of maintenance below
two years (from the time point of initial diagnosis) was associated with an increased
frequency of leukemic relapses. Although it was proven disadvantageous to shorten
maintenance treatment, whether or not extended maintenance of up to three years is
offering any beneficial effect for particular subgroups in the context of different treatment
strategies is not completely evaluated. With regard to the debate on the better thiopurine,
three randomized studies compared the toxicity and efficacy of 6-thioguanine (6-TG) with 6MP in interim maintenance and maintenance therapy of childhood ALL. However, due to the
observation of dose-dependent high rates of severe hepatotoxic side effects associated
with the application of 6-thioguanine, the current thiopurine drug of choice for maintenance
treatment remains 6-MP.
10
ENCCA DELIVERABLES
Table 1. Important prognostic factorsa and their approximate incidences in childhood ALL
Factor
Favorable prognostic factors and their
Unfavorable or less favorable prognostic factors
approximate incidence (%)
and their approximate incidence (%)
Age at diagnosis
1 and < 10 years (77%)
< 1 year (3%) or 10 years (20%)
Gender
female (45%)
male (55%)
CNS diseaseb
CNS 1 (80%)
Genetic featuresc
hyperdiploidy (20%),
TEL/AML1 positivity (20%)
50.000/l (20%)
CD10-negative precursor B-cell ALL (4%),
T-ALL (13%)
CNS 3 (3%),
TLP+ (7%)
hypodiploidy (1%),
t(9;22) or BCR/ABL1 positivity (2%),
t(4;11) or MLL/AF4 positivity (2%)
Prednisone responsed
prognostic factors are treatment dependent and, therefore, the selection presented in the table above cannot be entirely comprehensive; it reflects the current recommendations of AIEOP-BFM
ALL study group and the Biology & Diagnosis Committee of the I-BFM Study Group .
CNS1 (puncture nontraumatic, no leukemic blasts in the cerebrospinal fluid (CSF) after cytocentrifugation); CNS3 (puncture nontraumatic, >5 leukocytes/L CSF with identifiable blasts); TLP+
(traumatic lumbar puncture with identifiable leukemic blasts); a TLP with no identifiable blasts is not an adverse factor; the prognostic impact of CNS2 status (puncture nontraumatic, 5
leukocytes/L CSF with identifiable blasts) is debated. For cytomorphological examination, CSF samples should be analyzed after cytospin preparation, a method through which cellular components
within the CSF are concentrated by centrifugation.
c
hyperdiploidy defined as the presence of more than 50 chromosomes or a DNA index (the ratio of DNA content in leukemic G0/G1 cells to that of normal diploid lymphocytes) 1.16; hypodiploidy
defined by <45 chromosomes; the prognostic value of MLL gene rearrangements other than MLL/AF4 and presence of the E2A/PBX1 fusion transcript are debated.
d
after 7 days induction with daily prednisone and a single intrathecal dose of methotrexate on treatment day 1.
e
-4
assessed by molecular genetic techniques or flow cytometry; markers required to have a sensitivity of at least 10 .
b
11
ENCCA DELIVERABLES
ENCCA DELIVERABLES
13
ENCCA DELIVERABLES
14
ENCCA DELIVERABLES
15
ENCCA DELIVERABLES
BCR-ABL1 fusion
Routine cytogenetic analysis and RT-PCR readily detects the t(9;22)(q34;q11)/BCR-ABL1
fusion in the majority of patients. Those with a normal or ill-defined karyotype, a failed
cytogenetic result or a discrepancy between the cytogenetic and molecular result should be
tested by FISH. The use of a dual colour, dual fusion probe is recommended. The detection
of two fusion signals indicates a positive result with both fusion products present, for which
the false positive rate is extremely low. At the same time these probes will show the
presence of a second copy of the Philadelphia (Ph) chromosome, which is a characteristic
feature of Ph-positive ALL and indicate deletions from the derivative chromosome 9
involving the reciprocal ABL1-BCR fusion. These probes will also detect the NUP214-ABL1
fusion, found as a secondary change in T-ALL and other rarely occurring ABL1
translocations, which may be responsive to imatinib treatment. It could be argued that the
presence of the BCR-ABL1 fusion is the significant event; therefore FISH or RT-PCR could
replace cytogenetic analysis for the detection of this abnormality. However, for the purpose
of monitoring patients following treatment with imatinib, it is important to be aware of
secondary or chromosomal changes acquired during therapy.
MLL fusion
For risk stratification in current childhood ALL treatment trials, the translocation
t(4;11)(q21;q23)/MLL-AFF1 fusion is classified as high-risk, although the prognosis of the
other MLL partners may become significant in the future. As for BCR-ABL1, the
t(4;11)(q21;q23)/MLL-AFF1 fusion is readily detectable by cytogenetics and RT-PCR.
Multiplex molecular approaches may be applied for the detection of this fusion in
conjunction with other common MLL translocations. A dual colour breakapart probe
provides a highly effective approach for the detection of all chromosomal rearrangements
involving MLL by FISH, including variant t(4;11) translocations and cryptic insertions. This
FISH probe also detects 3 deletions associated with MLL translocations. This confirms, that
as for BCR-ABL1, those samples with a normal or ill-defined karyotype, a failed
cytogenetic result or a discrepancy between the cytogenetic and molecular result should be
tested by FISH.
ETV6-RUNX1 fusion
This fusion arises from the translocation t(12;21)(p13;q22). Although the fusion transcript
can be detected by RT-PCR, the translocation is kryptic at the cytogenetic level. An extra
signal or dual colour fusion probe is usually used for detection by FISH. The advantage of
the FISH approach is that fusions arising from rare variant breakpoints are also identified,
which may not be detected by RT-PCR. In ETV6-RUNX1 positive cases, FISH provides
information on the status of the second ETV6 homologue: whether it is retained or deleted,
as well as indicating the number of RUNX1 and fusion signals. Deletion of the second ETV6
allele and additional fusion signals are important secondary events in this ALL subtype,
which may be linkable to outcome in future stuies and, therefore, are recommended to be
assessed.
16
ENCCA DELIVERABLES
ENCCA DELIVERABLES
sis or their presence is inferred by the finding of the doubled population. This mixture of
near-haploid and doubled populations makes FISH detection of hidden populations difficult.
Probes specific for chromosomes which would be expected to be present as a single copy
in the near-haploid clone need to be applied in parallel with probes specific for
chromosomes which would be expected to have four copies within the doubled population.
As chromosomes 3, 7, 9, 11 and 22 are rarely gained in near-haploidy, centromeric probes
to chromosomes 3 and 7, in addition to the BCR-ABL1 and MLL probes should identify the
near-haploid clone. In these cases flow cytometry to measure the DNA index of the two
populations may provide a more appropriate and accurate detection method.
IGH@ translocations
Translocations involving IGH@ at 14q32 are emerging as a significant subgroup in
childhood ALL. Dual colour breakapart probes can identify these translocations and in
metaphase will identify their partners allowing studies to inform of their biological and
prognostic significance. This probe will also indicate gains of chromosome 14 in hidden high
hyperdiploid cases.
t(17;19)(q22;p13)
The translocation, t(1;19)(q23;p13)/TCF3-PBX1, fusion is now regarded as a standard risk
abnormality in childhood BCP-ALL. It has been shown that not all translocations involving
t(1;19)(q23;p13) at the cytogenetic level involve this fusion. This has been demonstrated by
FISH using a breakapart probe to TCF3. In addition this probe is able to detect the
presence of variant translocations involving TCF3. Of note is the t(17;19)(q22;p13) with the
TCF3-HLF fusion, which even on current therapies has a very dismal outcome. Although
this translocation is rare, it is usually visible by cytogenetic analysis and primers exist for its
detection by RT-PCR. However, in cases with failed and normal cytogenetic results FISH
with the TCF3 probe would be valuable to ensure that all cases are identified in view of the
high risk associated with this abnormality.
CDKN2A deletions
FISH with a commercially available probe to CDKN2A provides a reliable method for the
detection of deletions around this gene. Although this is known to be an important
secondary abnormality in both BCP- and T-ALL, its relative incidence among the different
cytogenetic subgroups and its relative prognostic significance remain unclear. Routine FISH
screening within different treatment protocols will be of value to inform the design of future
treatment protocols.
IKZF1 and CRLF2
As further evidence is accumulating regarding their potential inclusion in future riskstratification algorithms, deletions of IKZF1 and the PAR region on chromosome X including
CRLF2 is recommended to be assessed by MLPA. In addition, other techniques for the
assessment of aberrant IKZF1 and/or CRLF2 (e.g., real-time quantitative PCR, fusion gene
expression bei RT-PCR, and cell surface expression by flow cytometry are strongly encou-
18
ENCCA DELIVERABLES
raged to be evaluated in clinical trials on ALL as their exact prognostic value is yet to be
defined.
TPMT
To prevent prolonged hematopoietic toxicity for TPMT deficient individuals upon exposure
towards thiopurine drugs (6-MP, 6-TG), all patients with ALL should be genotyped for the
most common variant TPMT alleles before introduction of thiopurine medications (TPMT*2,
and *3A, *3C).
Treatment response evaluation
Response to treatment is the most important indicator of outcome in childhood ALL. Most
study groups evaluate treatment response by cytomorphology in the bone marrow after
treatment days 8, 14, or 15, and after the end of induction therapy (e.g., days 28 or 33).
Measures of cytomorphological treatment response are relevant for stratification on many
protocols. The difficulties of assessing hypoplastic bone marrow are well acknowledged
here. Besides cytomorphological response assessment, MRD analyses by mainly two
technical approaches, DNA-based PCR of clone-specific Ig or TCR gene rearrangements or
assessment of an aberrant immunophenotype by flow cytometry (see also section on
immunophenotyping), have become the main stratification elements in childhood ALL. It has
to be stressed that MRD analyses should be incorporated in the context of clinical trials
and, if appropriate, for treatment stratification. However, the latter can only be
recommended in association with the existing international study groups on MRD to assure
comparable and quality-controlled procedures.
Biobanking
Biobanking of spare diagnostic material in the context of clinical trials according to
standardized operating procedures is recommended. Consent issues should be addressed
already in the trial protocols.
19
ENCCA DELIVERABLES
ENCCA DELIVERABLES
21
ENCCA DELIVERABLES
22
ENCCA DELIVERABLES
23
ENCCA DELIVERABLES
24
ENCCA DELIVERABLES
References
Abrahamsson J, Forestier E, Heldrup J, et al. Response-guided induction therapy in pediatric acute myeloid
leukemia with excellent remission rate. J Clin Oncol 29:310-315, 2011
Alford KA, Reinhardt K, Garnett C, et al. Analysis of GATA1 mutations in Down syndrome transient
myeloproliferative disorder and myeloid leukemia. Blood 18:2222-2238, 2011
Alonzo TA, Wells RJ, Woods WG, et al. Postremission therapy for children with acute myeloid leukemia: the
Childrens Cancer Group experience in the transplant era. Leukemia 19:965-970, 2005
Arico M, Basso G, Mandelli F, Rizzari C, Colella R, Barisone E, et al. Good steroid response in vivo predicts a
favorable outcome in children with T-cell acute lymphoblastic leukemia. Cancer 75:1684-1693, 1995
Aric M, Valsecchi MG, Camitta B, Schrappe M, Chessells J, Baruchel A, et al. Outcome of treatment in
children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med 342:998-1006,
2000
Aric M, Valsecchi MG, Rizzari C, Barisone E, Biondi A, Casale F, et al. Long-term results of the AIEOP-ALL95 Trial for Childhood Acute Lymphoblastic Leukemia: insight on the prognostic value of DNA index in the
framework of Berlin-Frankfurt-Mnster based chemotherapy. J Clin Oncol 26:283-289, 2008
Balduzzi A, Valsecchi MG, Uderzo C, De Lorenzo P, Klingebiel T, Peters C, et al. Chemotherapy versus
allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete
remission: comparison by genetic randomisation in an international prospective study. Lancet 366:635-642,
2005
Balgobind BV, Hollink IH, Arentsen-Peters ST, et al. Integrative analysis of type-I and type-II aberrations
underscores the genetic heterogeneity of pediatric acute myeloid leukemia. Haematologica 96:1478-1487,
2011
Balgobind BV, Hollink IH, Reinhardt D, et al. Low frequency of MLL-partial tandem duplications in paediatric
acute myeloid leukaemia using MLPA as a novel DNA screenings technique. Eur J Cancer 46:1892-1899,
2010
Balgobind BV, Lugthart S, Hollink IH, et al. EVI1overexpression in distinct subtypes of pediatric acute myeloid
leukemia. Leukemia 24:942-949, 2010
Balgobind BV, Raimondi SC, Harbott J, et al. Novel prognostic subgroups in childhood 11q23/MLL-rearranged
acute myeloid leukemia: results of an international retrospective study. Blood 114:2489-2496, 2009
Balgobind BV, Van den Heuvel-Eibrink MM, De Menezes RX, et al. Evaluation of gene expression signatures
predictive of cytogenetic and molecular subtypes of pediatric acute myeloid leukemia. Haematologica 96:221230, 2011
Behm FG, Raimondi SC, Frestedt JL, Liu Q, Crist WM, Downing JR, et al. Rearrangement of the MLL gene
confers a poor prognosis in childhood acute lymphoblastic leukemia, regardless of presenting age. Blood
87:2870-2877, 1996
Bene MC, Castoldi G, Knapp W, Ludwig WD, Matutes E, Orfao A, et al. Proposals for the immunological
classification of acute leukaemias. European group for the immunological characterisation of leukaemias
(EGIL). Leukemia 9:1783-1786, 1995
25
ENCCA DELIVERABLES
Bene MC, Nebe T, Bettelheim P, et al. Immunophenotyping of acute leukemia and lymphoproliferative
disorders: a consensus proposal of the European LeukemiaNet Work Package 10. Leukemia 25:567-574,
2011
Bennett JM, Catovski D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposals for the classification
of the acute leukaemias. French-American-British (FAB) cooperative group. Br J Haematol 33:451-458, 1976
Berman JN, Gerbing RB, Alonzo TA, et al. Prevalence and clinical implications of NRAS mutations in
childhood AML: a report from the Childrens Oncology Group. Leukemia 25:1039-1042, 2011
Betts DR, Ammann RA, Hirt A, et al. The prognostic significance of cytogenetic aberrations in childhood acute
myeloid leukaemia: a study of the Swiss Paediatric Oncology Group (SPOG). Eur J Haematol 78:468-476,
2007
Borkhardt A, Cazzaniga G, Viehmann S, Valsecchi MG, Ludwig WD, Burci L, Mangioni S, et al. Incidence and
clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in the
German and Italian multicenter therapy trials. Associazione Italiana Ematologia Oncologia Pediatrica and the
Berlin-Frankfurt-Munster Study Group. Blood 90:571-577, 1997
Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, et al. Clinical significance of
minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic
factors: a Children's Oncology Group study. Blood 111:5477-5485, 2008
Bostrom BC, Sensel MR, Sather HN, Gaynon PS, La MK, Johnston K, et al. Dexamethasone versus
prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute
lymphoblastic leukemia: a report from the Childrens Cancer Group. Blood 101:3809-3817, 2003
Brisco MJ, Condon J, Hughes E, Neoh SH, Sykes PJ, Seshadri R, et al. Outcome prediction in childhood
acute lymphoblastic leukaemia by molecular quantification of residual disease at the end of induction. Lancet
343:196-200, 1994
Brown P, McIntyre E, Rau R, et al. The incidence and clinical significance of nucleophosmin mutations in
childhood AML. Blood 110:979-985, 2007
Brger B, Zimmermann M, Mann G, Khl J, Lning L, Riehm H, et al. Diagnostic cerebrospinal fluid (CSF)
examination in children with acute lymphoblastic leukemia (ALL): Significance of low leukocyte counts with
blasts or traumatic lumbar puncture. J Clin Oncol 21:184-188, 2003
Cario G, Izraeli S, Teichert A, Rhein P, Skokowa J, Mricke A, et al. High interleukin-15 expression
characterizes childhood acute lymphoblastic leukemia with involvement of the CNS. J Clin Oncol 25:48134820, 2007
Cave H, van der Werff ten Bosch J, Suciu S, Guidal C, Waterkeyn C, Otten J, et al. European Organization for
Research and Treatment of CancerChildhood Leukemia Cooperative Group. Clinical significance of minimal
residual disease in childhood acute lymphoblastic leukemia. N Engl J Med 339:591-598, 1998
Cazzaniga G, DellOro MG, Mecucci C, et al. Nucleophosmin mutations in childhood acute myelogenous
leukemia with normal karyotype. Blood 106:1419-1422, 2005
Childhood ALL Collaborative Group. Duration and intensity of maintenance chemotherapy in acute
lymphoblastic leukaemia: overview of 42 trials involving 12 000 randomised children. Lancet 347:1783-1788,
1996
26
ENCCA DELIVERABLES
Ciudad J, San Miguel JF, Lpez-Berges MC, Vidriales B, Valverde B, Ocqueteau M, et al. Prognostic value of
immunophenotypic detection of minimal residual disease in acute lymphoblastic leukemia. J Clin Oncol
16:3774-3781, 1998
Clarke M, Gaynon P, Hann I, Harrison G, Masera G, Peto R, et al. CNS-directed therapy for childhood acute
lymphoblastic leukemia: Childhood ALL Collaborative Group overview of 43 randomized trials. J Clin Oncol
21:1798-1809, 2003
Conter V, Valsecchi MG, Silvestri D, Campbell M, Dibar E, Magyarosy E, et al. Pulses of vincristine and
dexamethasone in addition to intensive chemotherapy for children with intermediate-risk acute lymphoblastic
leukaemia: a multicentre randomised trial. Lancet 369:123-131, 2007
Coustan-Smith E, Sancho J, Hancock ML, Boyett JM, Behm FG, Raimondi SC, et al. Clinical importance of
minimal residual disease in childhood acute lymphoblastic leukemia. Blood 96:2691-2696, 2000
Creutzig U, Kaspers GJ. Revised recommendations of the International Working Group for diagnosis,
standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in
acute myeloid leukemia. J Clin Oncol 22:3432-3433, 2004
Creutzig U, Ritter J, Zimmermann M, Schellong G. Does cranial irradiation reduce the risk for bone marrow
relapse in acute myelogenous leukemia? Unexpected results of the Childhood Acute Myelogenous Leukemia
Study BFM-87. J Clin Oncol 11:279-286, 1993
Creutzig U, van den Heuvel-Eibrink MM, Gibson B, Dworzak MN, Adachi S, de Bont E et al. Diagnosis and
management of acute myeloid leukemia in children and adolescents: recommendations from an international
expert panel. Blood 120:3187-3205, 2012
Creutzig U, Zimmermann M, Bourquin JP, et al. CNS irradiation in pediatric acute myleoid leukemia: equal
results by 12 or 18 Gy in studies AMLBFM98 and 2004. Pediatr Blood Cancer 57:986-992, 2011
Creutzig U, Zimmermann M, Bourquin JP, et al. Second induction with high-dose cytarabine and
mitoxantrone: different impact on pediatric AML patients with t(8;21) and with inv(16). Blood 118:5409-5415,
2011
Creutzig U, Zimmermann M, Ritter J, et al. Definition of a standard-risk group in children with AML. Br J
Haematol 104:630-639, 1999
Dahl GV, Simone JV, Hustu HO, Mason C. Preventive central nervous system irradiation in children with acute
nonlymphocytic leukemia. Cancer 42:2187-2192, 1978
Damm F, Thol F, Hollink I, et al. Prevalence and prognostic value of IDH1 and IDH2 mutations in childhood
AML: a study of the AML-BFM and DCOG study groups. Leukemia 25:1704-1710, 2011
Dervieux T, Hancock ML, Evans WE, Pui CH, Relling MV. Effect of methotrexate polyglutamates on
thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with
mercaptopurine. Leukemia 16:209-212, 2002
Dworzak MN, Froschl G, Printz D, Mann G, Ptschger U, Mhlegger N, et al. Prognostic significance and
modalities of flow cytometric minimal residual disease detection in childhood acute lymphoblastic leukemia.
Blood 99:1952-1958, 2002
Evans AE, Gilbert ES, Zandstra R. The increasing incidence of central nervous system leukemia in children.
Cancer 26:404-409, 1970
27
ENCCA DELIVERABLES
Fletcher JA, Lynch EA, Kimball VM, Donnelly M, Tantravahi R, Sallan SE. Translocation t(9;22) is associated
with extremely poor prognosis in intensively treated children with acute lymphoblastic leukemia. Blood 77:435439, 1991
Flohr T, Schrauder A, Cazzaniga G, Panzer-Grmayer R, van der Velden V, Fischer S, et al. Minimal residual
disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell
receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute
lymphoblastic leukemia. Leukemia 22:771-782, 2008
Foroni L, Harrison JC, Hoffbrand AV, Potter MN. Investigation of minimal residual disease in childhood and
adult acute lymphoblastic leukemia by molecular analysis. Br J Haematol 105:7-24, 1999
Gajjar A, Harrison PL, Sandlund JT, Rivera GK, Ribeiro RC, Rubnitz JE, et al. Traumatic lumbar puncture at
diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia. Blood 96:3381-3384, 2000
Gajjar A, Ribeiro R, Hancock ML, Rivera GK, Mahmoud H, Sandlund JT, et al. Persistence of circulating blasts
after 1 week of multiagent chemotherapy confers a poor prognosis in childhood acute lymphoblastic leukemia.
Blood 86:1292-1295, 1995
Gamis AS, Alonzo TA, Gerbing RB, et al. Natural history of transient myeloproliferative disorder clinically
diagnosed in Down syndrome neonates: a report from the Childrens Oncology Group Study A2971. Blood
118:6752-6759, 2011
Gaynon PS, Bleyer WA, Steinherz PG, Finklestein JZ, Littman P, Miller DR, et al. Day 7 marrow response and
outcome for children with acute lymphoblastic leukemia and unfavorable presenting features. Med Pediatr
Oncol 18:273-279, 1990
Gaynon PS, Trigg ME, Heerema NA, Sensel MG, Sather HN, Hammond GD. Children's Cancer Group trials in
childhood acute lymphoblastic leukemia: 1983-1995. Leukemia 14:2223-2233, 2000
Gerr H, Zimmermann M, Schrappe M, et al. Acute leukaemias of ambiguous lineage in children:
characterization, prognosis and therapy recommendations. Br J Haematol 149:84-92, 2010
Gibson BE, Wheatley K, Hann IM, et al. Treatment strategy and long-term results in paediatric patients treated
in consecutive UK AML trials. Leukemia 19:2130-2138, 2005
Giverhaug T, Loennechen T, Aarbakke J. Increased concentrations of methylated 6-mercaptopurine
metabolites and 6-thioguanine nucleotides in human leukemic cells in vitro by methotrexate. Biochem
Pharmacol 55:1641-1646, 1998
Goemans BF, Zwaan CM, Miller M, et al. Mutations in KIT and RAS are frequent events in pediatric corebinding factor acute myeloid leukemia. Leukemia 19:1536-1542, 2005
Grenier MA, Lipshultz SE. Epidemiology of anthracycline cardiotoxicity in children and adults. Semin Oncol
25:72-85, 1998
Gustafsson G, Schmiegelow K, Forestier E, Clausen N, Glomstein A, Jonmundsson G, et al. Improving
outcome through two decades in childhood ALL in the Nordic countries: the impact of high-dose methotrexate
in the reduction of CNS irradiation. Nordic Society of Pediatric Haematology and Oncology (NOPHO).
Leukemia 14:2267-2275, 2000
28
ENCCA DELIVERABLES
Harbott J, Ritterbach J, Ludwig W-D, Bartram CR, Reiter A, Lampert F. Clinical significance of cytogenetic
studies in childhood acute lymphoblastic leukemia: experience of the BFM trials. Recent Results in Cancer
Research 131:123-132, 1993
Harrison CJ, Haas O, Harbott J, Biondi A, Stanulla M, Trka J, Izraeli S et al. Detection of prognostically
relevant genetic abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: recommendations
from the Biology and Diagnosis Committee of the International Berlin-Frankfurt-M+nster study group. Br J
Haematol. 151:132-42, 2010
Harms DO, Gbel U, Spaar HJ, Graubner UB, Jorch N, Gutjahr P, et al. Thioguanine offers no advantage over
mercaptopurine in maintenance treatment of childhood ALL: results of the randomized trial COALL-92. Blood
102:2736-2740, 2003
Harms DO, Janka-Schaub GE. Co-operative study group for childhood acute lymphoblastic leukemia
(COALL): long-term follow-up of trials 82, 85, 89 and 92. Leukemia 14:2234-2239, 2000
Harris MB, Shuster JJ, Carroll A, Look AT, Borowitz MJ, Crist WM, et al. Trisomy of leukemic cells
chromosomes 4 and 10 identifies children with B-progenitor cell acute lymphoblastic leukemia with a very low
risk of treatment failure: a Pediatric Oncology Group study. Blood 79:3316-3324, 1992
Harrison CJ, Hills RK, Moorman AV, et al. Cytogenetics of childhood acute myeloid leukemia: United Kingdom
Medical Research Council Treatment trials AML 10 and 12. J Clin Oncol 28:2674-2681, 2010
Hasle H, Alonzo TA, Auvrignon A, et al. Monosomy 7 and deletion 7q in children and adolescents with acute
myeloid leukemia: an international retrospective study. Blood 109:4641-4647, 2007
Hasle H, Niemeyer CM, Chessells JM, et al. A pediatric approach to the WHO classification of myelodysplastic
and myeloproliferative diseases. Leukemia 17:277-282, 2003
Heerema NA, Nachman JB, Sather HN, Sensel MG, Lee MK, Hutchinson R, et al. Hypodiploidy with less than
45 chromosomes confers adverse risk in childhood acute lymphoblastic leukemia: a report from the Childrens
Cancer Group. Blood 94:4036-4045, 1999
Hiddemann W, Wormann B, Ritter J, Thiel E, Gohde W, Lahme B, et al. Frequency and clinical significance of
DNA aneuploidy in acute leukemia. Ann N Y Acad Sci 468:227-240, 1986
Ho PA, Alonzo TA, Gerbing RB, et al. Prevalence and prognostic implications of CEBPA mutations in pediatric
acute myeloid leukemia (AML): a report from the Childrens Oncology Group. Blood 113:6558-6566, 2009
Ho PA, Kutny MA, Alonzo TA, et al. Leukemic mutations in the methylation-associated genes DNMT3A and
IDH2 are rare events in pediatric AML: a report from the Childrens Oncology Group. Pediatr Blood Cancer
57:204-209, 2011
Hollink IH, Van den Heuvel-Eibrink MM, Arentsen-Peters ST, et al. NUP98/NSD1 characterizes a novel poor
prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern. Blood 118:36453656, 2011
Hollink IH, Van den Heuvel-Eibrink MM, Zimmermann M, et al. Clinical relevance of Wilms tumor 1 gene
mutations in childhood acute myeloid leukemia. Blood 113:5951-5960, 2009
Hollink IH, Zwaan CM, Zimmermann M, et al. Favorable prognostic impact of NPM1 gene mutations in
childhood acute myeloid leukemia, with emphasis on cytogenetically normal AML. Leukemia 23:262-270, 2009
Howard SC, Metzger ML, Wilimas JA, Quintana Y, Pui CH, Robison LL, et al. Childhood cancer epidemiology
in low-income countries. Cancer 112:461-472, 2008
29
ENCCA DELIVERABLES
Hurwitz CA, Silverman LB, Schorin MA, Clavell LA, Dalton VK, Glick KM, et al. Substituting dexamethasone
for prednisone complicates remission induction in children with acute lymphoblastic leukemia. Cancer
88:1964-1969, 2000
Igarashi S, Manabe A, Ohara A, Kumagai M, Saito T, Okimoto Y, et al. No advantage of dexamethasone over
prednisolone for the outcome of standard- and intermediate-risk childhood acute lymphoblastic leukemia in the
Tokyo Childrens Cancer Study Group L95-14 protocol. J Clin Oncol 23:6489-6498, 2005
Janka-Schaub GE, Sthrk H, Kortm B, Graubner U, Jrgens H, Spaar HJ, et al. Bone marrow blast count at
day 28 as the single most important prognostic factor in childhood acute lymphoblastic leukemia. Haematol
Blood Transfus 34:233-237, 1992
Jones B, Freeman AI, Shuster JJ, Jacquillat C, Weil M, Pochedly C, et al. Lower incidence of meningeal
leukemia when prednisone is replaced by dexamethasone in the treatment of acute lymphocytic leukemia.
Med Pediatr Oncol 19:269-275, 1991
Jones LK, Saha V. Philadelphia positive acute lymphoblastic leukaemia of childhood. Br J Haematol 130:489500, 2005
Kamps WA, Bkkerink JP, Hakvoort-Cammel FG, Veerman AJ, Weening RS, van Wering ER, et al. BFMoriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment
reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991-1996). Leukemia 16:1099-1111,
2002
Kaspers GJ, Veerman AJ, Popp-Snijders C, Lomecky M, Van Zantwijk CH, Swinkels LM, et al. Comparison of
the antileukemic activity in vitro of dexamethasone and prednisolone in childhood acute lymphoblastic
leukemia. Med Pediatr Oncol 27:114-121, 1996
Klusmann JH, Creutzig U, Zimmermann M, et al. Treatment and prognostic impact of transient leukemia in
neonates with Downs syndrome. Blood 111:2991-2998, 2008
Langebrake C, Creutzig U, Dworzak M, et al. Residual disease monitoring in childhood acute myeloid
leukemia by multiparameter flow cytometry: the MRD-AML-BFM Study Group. J Clin Oncol 24:3686-3692,
2006
Lie SO, Abrahamsson J, Clausen N, et al. Treatment stratification based on initial in vivo response in acute
myeloid leukaemia in children without Downs syndrome: results of NOPHOAML trials. Br J Haematol
122:217-225, 2003
Linabery AM, Ross JA. Trends in childhood cancer incidence in the U.S. (1992-2004). Cancer 112:416-432,
2008
Loh ML, Reynolds MG, Vattikuti S, et al. PTPN11mutations in pediatric patients with acute myeloid leukemia:
results from the Childrens Cancer Group. Leukemia 18:1831-1834, 2004
Loh ML, Silverman LB, Young ML, Neuberg D, Golub TR, Sallan SE, et al. Incidence of TEL/AML1 fusion in
children with relapsed acute lymphoblastic leukemia. Blood 15:4792-4797, 1998
Ludwig W-D, Harbott J, Bartram CR, Riehm H. Incidence and prognostic significance of immunophenotypic
subgroups in childhood acute lymphoblastic leukemia: experience of the BFM study 86. In: Recent advances
in cell biology of acute leukemia: impact on clinical diagnosis and therapy (Ludwig W-D, Thiel E, eds.), Berlin:
Springer Verlag, 269-282, 1993
Mahmoud HH, Rivera GK, Hancock ML, Krance RA, Kun LE, Behm FG, et al. Low leukocyte counts with blast
cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med
329:314-319, 1993
30
ENCCA DELIVERABLES
Manabe A, Ohara A, Hasegawa D, Koh K, Saito T, Kiyokawa N, et al. Significance of the complete clearance
of peripheral blasts after 7 days of prednisolone treatment in children with acute lymphoblastic leukemia: the
Tokyo Children's Cancer Study Group Study L99-15. Haematologica 93:1155-1160, 2008
Mann G, Reinhardt D, Ritter J, et al. Treatment with all-trans retinoic acid in acute promyelocytic leukemia
reduces early deaths in children. Ann Hematol 80:417-422, 2001
Mastrangelo R, Poplack D, Bleyer A, Riccardi R, Sather HN, DAngio G. Report and recommendations of the
Rome workshop concerning poor-prognosis acute lymphoblastic leukemia in children: Biologic bases for
staging, stratification, and treatment. Med Pediatr Oncol 14:191-194, 1986
Mattano LA, Sather HN, Trigg ME, Nachman JB. Osteonecrosis as a complication of treating acute
lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol 18:3262-3272,
2000
Matutes E, Pickl WF, Vant Veer M, et al. Mixed phenotype acute leukemia: clinical and laboratory features
and outcome in 100 patients defined according to the WHO 2008 classification. Blood 117:3163-3171, 2011
Mejstrikova E, Volejnikova J, Fronkova E, et al. Prognosis of children with mixed phenotype acute leukemia
treated on the basis of consistent immunophenotypic criteria. Haematologica 95:928-935, 2010
Mercher T, Busson-Le Coniat M, Nguyen KF, et al. Recurrence of OTT-MAL fusion in t(1;22) of infant AMLM7. Genes Chromosomes Cancer 33:22-28, 2002
Meshinchi S, Alonzo TA, Stirewalt DL, et al. Clinical implications of FLT3 mutations in pediatric AML. Blood
108:3654-3661, 2006
Meshinchi S, Appelbaum FR. Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin
Cancer Res 15:4263-4269, 2009
Mitchell CD, Richards SM, Kinsey SE, Lilleyman J, Vora A, Eden TO, et al. Benefit of dexamethasone
compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research
Council ALL 97 randomized trial. Br J Haematol 129:734-745, 2005
Moghrabi A, Levy DE, Asselin B, Barr R, Clavell L, Hurwitz C, et al. Results of the Dana-Farber Cancer
Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood 109:896-904,
2007
Mricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Drdelmann M, et al. Risk-adjusted therapy of
acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169
unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 111:4477-4489, 2008
Nachman JB, Heerema NA, Sather H, Camitta B, Forestier E, Harrison CJ, et al. Outcome of treatment in
children with hypodiploid acute lymphoblastic leukemia. Blood 110:1112-1125, 2007
Nachman JB, Sather HN, Sensel MG, Trigg ME, Cherlow JM, Lukens JN, et al. Augmented post-induction
therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl
J Med 338:1663-1671, 1998
Niewerth D, Creutzig U, Bierings MB, Kaspers GJ. A review on allogeneic stem cell transplantation for newly
diagnosed pediatric acute myeloid leukemia. Blood 116:2205-2214, 2010
31
ENCCA DELIVERABLES
Nyvold C, Madsen HO, Ryder LP, Seyfarth J, Svejgaard A, Clausen N, et al. Precise quantification of minimal
residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent
outcome. Blood 99:1253-1258, 2002
Perel Y, Auvrignon A, Leblanc T, et al. Impact of addition of maintenance therapy to intensive induction and
consolidation chemotherapy for childhood acute myeloblastic leukemia: results of a prospective randomized
trial, LAME 89/91. Leucamie Aique Myeloide Enfant. J Clin Oncol 20:2774-2782, 2002
Pession A, Valsecchi MG, Masera G, Kamps WA, Magyarosy E, Rizzari C, et al. Long-term results of a
randomized trial on extended use of high dose L-asparaginase for standard risk childhood acute lymphoblastic
leukemia. J Clin Oncol 23:7161-7167, 2005
Pession A. The open issue of central nervous system disease in pediatric acute myeloid leukemia. Pediatr
Blood Cancer 55:399-400, 2010
Pieters R, Schrappe M, De Lorenzo P, Hann I, De Rossi G, Felice M, et al. A treatment protocol for infants
younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a
multicentre randomised trial. Lancet 370:240-250, 2007
Pinkel, D. Five year follow-up of Total Therapy of childhood lymphocytic leukemia. JAMA 216:648-652, 1971
Pui CH, Boyett JM, Relling MV, Harrison PL, Rivera GK, Behm FG, et al. Sex differences in prognosis for
children with acute lymphoblastic leukemia. J Clin Oncol 17:818-824, 1999
Pui CH, Carroll WL, Meshinchi S, Arceci RJ. Biology, risk stratification, and therapy of pediatric acute
leukemias: an update. J Clin Oncol 29:551-565, 2011
Pui CH, Evans WE. Treatment of childhood acute lymphoblastic leukemia. N Engl J Med 354:166-178, 2006
Pui CH, Howard SC. Current management and challenges of malignant disease in the CNS in paediatric
leukaemia. Lancet Oncol 9:257-268, 2008
Pui CH, Rivera GK, Hancock ML, Raimondi SC, Sandlund JT, Mahmoud HH, et al. Clinical significance of
CD10 expression in childhood acute lymphoblastic leukemia. Leukemia 7:35-40, 1993
Pui CH, Sandlund JT, Pei D, Campana D, Rivera GK, Ribeiro RC, et al. Improved outcome for children with
acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital.
Blood 104:2690-2696, 2004
Pui CH, Williams DL, Raimondi SC, Rivera GK, Look AT, Dodge RK, George SL, Behm FG, et al.
Hypodiploidy is associated with a poor prognosis in childhood acute lymphoblastic leukemia. Blood 70:247253, 1987
Redaelli A, Laskin BL, Stephens JM, Botteman MF, Pashos CL. A systematic literature review of the clinical
and epidemiological burden of acute lymphoblastic leukaemia (ALL). Eur J Cancer Care (Engl) 14:53-62, 2005
Relling MV, Hancock ML, Boyett JM, Pui CH, Evans WE. Prognostic importance of 6-mercaptopurine dose
intensity in acute lymphoblastic leukemia. Blood 93:2817-2823, 1999
Riehm H, Gadner H, Henze G, Langermann H-J, Odenwald E. The Berlin childhood acute lymphoblastic
leukemia therapy study, 1970-1976. Am J Pediatr Hematol Oncol 2:299-306, 1980
32
ENCCA DELIVERABLES
Riehm H, Reiter A, Schrappe M, Berthold F, Dopfer R, Gerein V, et al. The in vivo response on corticosteroid
therapy as an additional prognostic factor in childhood acute lymphoblastic leukemia (therapy study ALL-BFM
83). Klin Pdiatr 199:151-160, 1987
Rivard GE, Infante-Rivard C, Dresse MF, Leclerc JM, Champagne J. Circadian time-dependent response of
childhood lymphoblastic leukemia to chemotherapy: a longterm follow-up study of survival. Chronobiol Int
10:201-204, 1993
Rizzari C, Valsecchi MG, Aric M, Conter V, Testi A, Barisone E, et al. Associazione Italiano Ematologia
Oncologia Pediatrica. Effect of protracted high-dose L-asparaginase given as a second exposure in a BerlinFrankfurt-Mnster-based treatment: results of the randomized 9102 intermediate-risk childhood acute
lymphoblastic leukemia studya report from the Associazione Italiana Ematologia Oncologia Pediatrica. J Clin
Oncol 19:1297-1303, 2001
Rubnitz JE, Inaba H, Dahl G, et al. Minimal residual disease-directed therapy for childhood acute myeloid
leukaemia: results of theAML02 multicentre trial. Lancet Oncol 11:543-552, 2010
Rubnitz JE, Link MP, Shuster JJ, Carroll AJ, Hakami N, Frankel LS, et al. Frequency and prognostic
significance of HRX rearrangements in infant acute lymphoblastic leukemia: a Pediatric Oncology Group
study. Blood 84:570-573, 1994
Schlieben S, Borkhardt A, Reinisch I, Ritterbach J, Janssen JW, Ratei R, et al. Incidence and clinical outcome
of children with BCR/ABL-positive acute lymphoblastic leukemia (ALL). A prospective RT-PCR study based on
673 patients enrolled in the German pediatric multicenter therapy trials ALL-BFM 90 and CoALL-05-92.
Leukemia 10:957-963, 1996
Schmiegelow K, Glomstein A, Kristinsson J, Salmi T, Schroder H, Bjork O. Impact of morning versus evening
schedule for oral methotrexate and 6-mercaptopurine on relapse risk for children with acute lymphoblastic
leukemia. Nordic Society for Pediatric Hematology and Oncology (NOPHO). J Pediatr Hematol Oncol 19:102109, 1997
Schrappe M, Reiter A, Zimmermann M, Harbott J, Ludwig WD, Henze G, et al. Longterm results of four
consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Leukemia
14:2205-2222, 2000
Schrauder A, von Stackelberg A, Schrappe M, Cornish J, Peters C. Allogeneic hematopoietic SCT in children
with ALL: current concepts of ongoing prospective SCT trials. Bone Marrow Transplant 41:Suppl 2, 2008
Seibel NL, Steinherz PG, Sather HN, Nachman JB, DeLaat C, Ettinger LJ, et al. Early postinduction
intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic
leukemia: a report from the Children's Oncology Group. Blood 111:2548-2555, 2008
Shih LY, Liang DC, Huang CF, et al. Cooperating mutations of receptor tyrosine kinases and Ras genes in
childhood core-binding factor acute myeloid leukemia and a comparative analysis on paired diagnosis and
relapse samples. Leukemia 22:303-307, 2008
Silverman LB, Gelber RD, Dalton VK, Asselin BL, Barr RD, Clavell LA, et al. Improved outcome for children
with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 97:1211-1218,
2001
Smith LA, Cornelius VR, Plummer CJ, et al. Cardiotoxicity of anthracycline agents for the treatment of cancer:
systematic review and metaanalysis of randomised controlled trials. BMC Cancer 10:337, 2010
33
ENCCA DELIVERABLES
34
ENCCA DELIVERABLES
Veerman AJ, Hhlen K, Kamps WA, Van Leeuwen EF, De Vaan GA, Solbu G, et al. High cure rate with a
moderately intensive treatment regimen in non-high-risk childhood acute lymphoblastic leukemia. Results of
protocol ALL VI from the Dutch Childhood Leukemia Study Group. J Clin Oncol 14:911-918, 1996
Viehmann S, Teigler-Schlegel A, Bruch J, Langebrake C, Reinhardt D, Harbott J. Monitoring of minimal
residual disease (MRD) by real-time quantitative reverse transcription PCR (RQ-RTPCR) in childhood acute
myeloid leukemia with AML1/ETO rearrangement. Leukemia 17:1130-1136, 2003
Vilmer E, Suciu S, Ferster A, Bertrand Y, Cav H, Thyss A, et al. Long-term results of three randomized trials
(58831, 58832, 58881) in childhood acute lymphoblastic leukemia: a CLCG-EORTC report. Children
Leukemia Cooperative Group. Leukemia 14:2257-2266, 2000
von Neuhoff C, Reinhardt D, Sander A, et al. Prognostic impact of specific chromosomal aberrations in a large
group of pediatric patients with acute myeloid leukemia treated uniformly according to trial AML-BFM 98. J
Clin Oncol 28:2682-2689, 2010
Vora A, Mitchell CD, Lennard L, Eden TO, Kinsey SB, Lilleyman J, et al. Toxicity and efficacy of 6-thioguanine
versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. Lancet 368:1339-1348,
2006
Waber DP, Carpentieri SC, Klar N, Silverman LB, Schwenn M, Hurwitz CA, et al. Cognitive sequelae in
children treated for acute lymphoblastic leukemia with dexamethasone or prednisone. J Pediatr Hematol
Oncol 22:206-213, 2000
Wechsler J, Greene M, McDevitt MA, et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of
Down syndrome. Nat Genet 32:148-152, 2002
Wells RJ, Woods WG, Lampkin BC, et al. Impact of high-dose cytarabine and asparaginase intensification on
childhood acute myeloid leukemia: a report from the Childrens Cancer Group. J Clin Oncol 11:538-545, 1993
Wheatley K, Burnett AK, Goldstone AH, et al. A simple, robust, validated and highly predictive index for the
determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial: United
Kingdom Medical Research Councils Adult and Childhood Leukaemia Working Parties. Br J Haematol
107:69-79, 1999
Wood BL, Arroz M, Barnett D, et al. Bethesda International Consensus recommendations on the
immunophenotypic analysis of hematolymphoid neoplasia by flow cytometry: optimal reagents and reporting
for the flow cytometric diagnosis of hematopoietic neoplasia. Cytometry B Clin Cytom 72(Suppl 1):S14-S22,
2007
Woods WG, Neudorf S, Gold S, et al. A comparison of allogeneic bone marrow transplantation, autologous
bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in
remission. Blood 97:56-62, 2001
Zwaan CM, Reinhardt D, Zimmerman M, et al. Salvage treatment for children with refractory first or second
relapse of acute myeloid leukaemia with gemtuzumab ozogamicin: results of a phase II study. Br J Haematol
148:768-776, 2010
35