2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

II separated by an 8-week interim maintenance (IM) phase
followed by maintenance therapy. 10
Subsequently, the BFM has refined therapy to include the
PRED prephase and replaced the 8-week IM phase with
protocol M that consists of four courses of high-dose methotrexate
(HD MTX; 5 g/m 2 over 24 hours followed by leucovorin
rescue) given at 2-week intervals, with outstanding
contemporary outcomes. 6 A fundamental difference between
BFM and COG regimens is that the BFM regimens do not
include steroid/vincristine pulses during maintenance. 11 Patients
identified to be at HR of relapse based on a poor
response to the PRED prephase (more than 1000 blasts/
microliter at day 8), adverse cytogenetics, or more recently
high levels of MRD at end induction/consolidation receive
KEY POINTS
Table 1. Comparison of Components of BFM and COG ALL Therapies
Treatment Phase BFM BFM HR COG SR ALL COG HR ALL (hABFM)
Induction (protocol Ia) 4 drugs/4 wks
PRED, Vcr, ASNase, Dauno
Consolidation (protocol Ib) 6 wks
CPM, Ara-C, 6-MP
4 drugs/4 wks
PRED, Vcr, ASNase, Dauno
6 wks
CPM, Ara-C
● Acute lymphoblastic leukemia (ALL) is the most
common pediatric cancer.
● Five-year survival rates for pediatric ALL now exceed
90%, as compared to less than 10% in the 1960s.
● Contemporary Children’s Oncology Group ALL treatment
regimens are derived from regimens developed
by the Berlin-Frankfurt-Muenster group in the 1970s
but have been refined through a series of randomized
clinical trials.
● Optimizing the use of standard cytotoxic chemotherapy
agents has led to significant outcome improvements
for some subsets of high-risk ALL patients,
whereas other subsets have benefitted little from this
approach.
● Novel and/or targeted therapies have benefitted children
and adolescents with Philadelphia chromosome–positive
ALL and will likely be tested in other
high-risk ALL subsets.
3 drugs/4 wks; DEX, Vcr,
ASNase
4 wks
6-MP, MTX
IM #1 HD MTX Three intensive 3-wk HR blocks 8 wks
Capizzi MTX, Dex, Vcr
DI #1 (protocol II) 8 wks
DEX, Vcr, ASNase, Doxo, CPM,
Ara-C, 6-TG
IM #2 Not given 4 wks
6-MP, MTX
8 wks
DEX, Vcr, ASNase, Doxo, CPM,
Ara-C, 6-TG
8 wks
DEX, Vcr, ASNase, Doxo, CPM,
Ara-C, 6-TG
8 wks
Capizzi MTX, DEX, Vcr
DI #2 (protocol II) Not given 8 wks
DEX, Vcr, ASNase, Doxo, CPM,
Ara-C, 6-TG
Maintenance 6-MP, MTX 6-MP, MTX 6-MP, MTX plus monthly
DEX/Vcr pulses
Not given Not given
4 drugs/4 wks; PRED (age 10�) or
DEX (age 1–9.99), Vcr, ASNase,
Dauno
8 wks (augmented)
CPM, Ara-C, 6-MP, Vcr, ASNase
8 wks
HD MTX, Vcr
8 wks (augmented)
DEX, Vcr, ASNase, Doxo, CPM,
Ara-C, 6-TG
8 wks
Capizzi MTX � ASNase, DEX, Vcr,
(some not all patients)
6-MP, MTX plus monthly PRED/Vcr
pulses
Treatment duration 30 mo 30 mo 27 mo, females; 39 mo, males 27 mo, females; 39 mo, males
Abbreviations: ALL, acute lymphoblastic leukemia; ASNase, asparaginase; BFM, Berlin-Frankfurt-Muenster; COG, Children’s Oncology Group; CPM, cyclophosphamide;
Dauno, daunorubicin; DEX, dexamethasone; DI, delayed intensification; Doxo, doxorubicin; hABFM, hemi-augmented BFM; HR, high risk; IM, interim
maintenance; mo, months; MTX, methotrexate; PRED, prednisone; SR, standard risk; Vcr, vincristine; wks, weeks; 6-MP, 6-mercaptopurine; 6-TG, 6-thioguanine.
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more intensive therapy in which protocol M is replaced by
three intensive multiagent chemotherapy blocks (HR blocks)
and protocol II is given twice. 12
CCG/COG Adoption of BFM-76-Based Therapy
STEPHEN P. HUNGER
The Children’s Cancer Group (CCG) recognized in the
1980s that outcomes reported by the BFM were superior to
those obtained in CCG trials with less intensive therapy.
This led to development of two pivotal trials that compared
the CCG regimens of that time to the BFM-76 regimen,
which did not include a PRED prephase or protocol M.
Because of this, CCG and COG ALL treatment regimens
resemble but do not recapitulate BFM therapies, although
they are now becoming more similar, with COG adoption of
HD MTX (see below).
The CCG 105 trial (1983 to 1989) was designed for
children with intermediate-risk ALL, which is similar but
not identical to NCI SR ALL. 13 Children enrolled in CCG
105 were randomly selected to receive the standard CCG
regimen of that time, which included a three-drug induction
(PRED, vincristine, and asparaginase but no daunorubicin)
followed by central nervous system (CNS) control and maintenance,
or the BFM regimen that included protocols I and
II. Two other randomly selected groups received protocol I
followed by CCG postinduction therapy or the CCG induction/consolidation
followed by protocol II. The results of this
study (updated in 2005 with 16-year follow-up) showed that
all three of the BFM-based regimens were superior to the
CCG regimen. 13,14 There was little outcome difference between
the three BFM-based regimens; thus, the CCG selected
the CCG induction/consolidation followed by protocol
II to bring forward in subsequent trials, as that regimen had
less short-term toxicity than the other two BFM-based
regimens. For this reason, all subsequent CCG and COG
regimens for SR ALL have included a three-drug induction
(without the intensive consolidation phase) and a DI phase.
Based on the results of the CCG 1922 study, children with
SR ALL enrolled in COG ALL trials now receive DEX rather