Supplementary Material
Appendix 1a.
Cytogenetic Analysis:
Since findings presented in this paper represent a retrospective study, there are historically based
differences between the CCG and the POG with respect to the different criteria for defining whether
particular karyotypic findings were included or excluded from their final data analyses for their different
protocols.
For the CCG, data were collated from more than 100 Institutional cytogenetic laboratories.
Whereas the POG used data contributed by only 12 Reference cytogenetic laboratories. Irrespective of
these differences, cytogenetic diagnostic criteria followed standard protocols, procedures and guidelines
for clinical genetics laboratories. Members of the CCG and POG Cytogenetics Committees
independently reviewed and approved all cytogenetics analyses from their respective laboratories for
each case. No fluorescence in-situ hybridization (FISH) results are included in this study since these
techniques were unavailable for earlier protocols. It is recognized that in a number of patients classified
as having a “normal” karyotype, abnormalities detectable by other techniques such as fluorescence in-situ
hybridization (FISH) or by Polymerase Chain Reaction (PCR), for example t(12;21), or the abnormal
clone, may have been missed. Also, since no upper limit was set on chromosome number, very rare
triploid or tetraploid cases have not been specifically excluded. Informative cytogenetics was defined as:
CCG: An abnormal clone with structural or numerical abnormalities identified from either bone marrow or
unstimulated leukemic blood, or a minimum of 20 normal cells analyzed from bone marrow only.
Translocations (4;11) and (9;22), hypodiploidy fewer than 45 chromosomes, unsatisfactory cytogenetics,
and infants <1 year old were excluded.
POG: An abnormal clone with either structural or numerical abnormalities identified from bone marrow or
unstimulated leukemic blood. Hypodiploidy <45 chromosomes was not excluded. Although data were
collected for normal karyotypes (minimum 10 metaphase spreads) these were excluded from final data
analyses and reported separately. Translocations (4;11) and t(9;22), unsatisfactory cytogenetic results
and infants <1 year old were also excluded.
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Appendix 1b.
Diagnosis:
CCG: ALL diagnosis was determined by cell morphology, cytochemical stains and cell-surface
expression in two or more differentiation antigens. Immunophenotyping was centralized in the CCG ALL
Biology Reference Laboratory and patients identified with T-lineage leukemia excluded, but no
immunophenotyping was available for a proportion of early protocol patients. It is recognized that some
patients without immunophenotyping may have had T-cell leukemia. However, in the NCI Standard Risk
ALL subset, such patients are estimated to be very few (<4%, data not shown). Patients with B-lineage or
no immunophenotype and informative cytogenetics, met the criteria for inclusion in these data sets.
POG: Diagnostic criteria included cytochemical stains and morphology consistent with ALL and reference
laboratory immunophenotyping consistent with B-precursor ALL. Only patients with informative
immunophenotyping and informative cytogenetic results were eligible and used in these analyses.
Appendix 1c.
Patients: Patients were ages 12 months to 21.99 years inclusive, with newly diagnosed B-precursor ALL
consecutively enrolled on CCG and POG protocols. Protocols were approved by the NCI and
participating institution’s Institutional Review Boards (IRBs) with informed consent, in compliance with the
Declaration of Helsinki, obtained from patients or legal guardians before enrollment.
CCG: A total number of 5121 patients were initially enrolled between December 1988 to August 1995 on
the 1881, 1882, 1891, 1901, and 1902 CCG protocols. Of these, 1946 patients were evaluable according
to CCG criteria and, after exclusions, final data for 1582 patients were included in the current studies.
POG: The number of patients initially enrolled between January 1986 to November 1999 on ALinC 14,
15, and 16 (8602, 9005, 9006, 9201, 9405, 9406, and 9605) POG protocols was 6608. Of these, 5255
patients were entered on the POG Phase III B-Precursor treatment protocol. After exclusions, data for
3902 patients with B-precursor ALL were included.
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Appendix 1d.
CCG Treatment Protocols:
Age(yrs)
WBC
Risk
Protocol
Reference
2-9
<10,000
Low
-1881
Hutchinson et al Proc Am Soc Clin Oncol 13:319. 1994
2-9
10,000-49,999
Intermediate
-1891
Lange B et al Blood 90:5599. 1997.
1 -<2
<50,000
1-9
<50,000
Low + Interm
-1922
Bostrom B et al Proc Am Soc Clin Oncol 17:5279.1998.
1-9
>50,000
Poor
-1882
Nachman et al New Eng J Med 338:663-1671. 1998.
>10
Any
Nachman et al J Clin Oncol 16:920-930. 1998.
Poor, Mult unfav
-1901
Steinherz P et al Cancer 83:600-612.1998.
POG Treatment Protocols:
Age(yrs)
WBC
Risk
Protocol
Reference
1 -21
Any
Any
8602 C vs. D
Land VJ et al J Clin Oncol 12:1939. 1994.
1 -10
3- 5
<10,000 or
<100,000
Standard
8602 A,B,C
Harris MB et al J Clin Oncol 16:2840. 1998.
1 -21
Any
Any
8602 B vs. C
Harris MB et al Leukemia 14:1570. 2000.
Any
Any
Standard
9005 A vs. B
Mahoney DH et al J Clin Oncol 16:246. 1998.
Any
Any
Standard
9005 A vs. C
Mahoney DH et al J Clin Oncol 18:1285. 2000.
1-2
6 - 21
Any
10-99,999 or
10-99,999 or
>100,000
High
9006 A vs B
Lauer SJ et al Leukemia 15:1038. 2001.
1-9
<50,000
Standard
9201
unpublished
Any
Any
Standard
9405 A,B,C,D
unpublished
1-9
<50,000
Standard
9605 A,B,C,D
unpublished
High
9406 A,B,C,D
unpublished
>10 OR >50,000
Note:
1.
2.
For studies 9005 and 9006, patients were down-risked on the basis of a DNA index (DI) > 1.16. For studies 9201, 9405,
9406, and 9605, patients were down-risked on the basis of simultaneous trisomies of chromosomes 4 and 10 or if
cytogenetics were uninformative, on the basis of DI > 1.16.
Age is rounded down to whole number.
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