2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

ABFM THERAPY FOR PEDIATRIC ALL
than PRED during induction and in the steroid/vincristine
pulses given every 4 weeks during maintenance therapy. 15
The CCG 1991 trial showed that Capizzi escalating intravenous
(IV) MTX without rescue (no asparaginase) was superior
to oral 6-MP and MTX during the IM phase(s), 16 and
this approach is now standard in contemporary COG SR
ALL trials.
In parallel to CCG 105, the CCG 106 trial (1983 to 1987)
compared BFM therapy to the contemporary CCG HR regimen
and to the more intensive “New York” regimen. 17
Better outcomes were seen with both the BFM and New
York regimens as compared to the CCG regimen, but the
BFM regimen was associated with less toxicity and lower
cumulative doses of chemotherapy than the New York regimen.
Based on the results of CCG 106, the BFM-76-based
regimen became the baseline CCG/COG regimen used for
HR ALL, and subsequent trials included a four-drug induction,
the intensive consolidation (protocol Ib), and one or
more protocol II (DI) phases.
Development of Refinement of ABFM Therapy
by the CCG/COG
The CCG recognized that a poor early response to chemotherapy
was a strong adverse prognostic factor. 18 In CCG
1882 (1991 to 1995), children with HR ALL and a slow early
response to therapy (SER; more than 25% marrow blasts at
day 8 of induction) were randomly selected to received the
CCG-modified BFM regimen or an ABFM regimen that
contained a number of changes to baseline treatment. 7
These changes included intensifying consolidation (Ib) therapy
by extending it to 8 weeks and including doses of
vincristine and asparaginase during the neutropenic phases
that followed cyclophosphamide and ara-C, using Capizzi I
escalating IV MTX without leucovorin rescue plus asparaginase
during the 8-week IM #1 phase, giving second IM and
DI phases, and giving prophylactic cranial irradiation to all
patients. The ABFM regimen produced results that were
significantly better than the standard CCG regimen, with
5-year event-free survival (EFS) rates of 75% versus 55%
(p � 0.001) and overall survival (OS) rates of 78% versus
67% (p � 0.02). 7
Based on the results of CCG 1882, the subsequent CCG
1961 HR-ALL trial tested the ABFM regimen in patients
with a rapid early response to therapy (day 8 marrow blasts
less than or equal to 25%) and attempted to determine the
most important components of ABFM therapy by randomly
selecting patients in a2x2manner to receive the baseline
regimen, the full ABFM regimen, the baseline regimen with
2 IM and DI phases, or the ABFM regimen with only single
IM and DI phases (termed hemi-ABFM, or hABFM). 19 The
results of CCG 1961 showed that the augmented parts of
ABFM therapy were critical and improved 5-year EFS (81%
vs. 72%; p � 0.001) and OS (89% vs. 83%; p � 0.003)
significantly. Equally important, repeating the IM and DI
phases did not improve outcome (5-year EFS: 76% vs. 76.8%
for single compared with double IM/DI; p � 0.94). Based on
these results, the hABFM regimen with single IM/DI phases
became the standard regimen for children with HR ALL and
a good response to induction therapy in COG trials, although
a second IM and/or DI phase has been retained in some
trials for those with a poor early response.
COG AALL0232 Shows Superiority of HD MTX
The COG AALL0232 (2003 to 2011) trial for children and
adolescents with HR B-cell precursor (BCP) ALL used the
hABFM regimen and had a2x2randomization to 28 days
of PRED 60 mg/m 2 /day versus 14 days of DEX 10 mg/m 2 /day
during induction and to HD MTX versus Capizzi MTX plus
asparaginase during IM #1. Accrual to this trial was stopped
in early 2011 when results for the MTX randomization
crossed predefined monitoring boundaries. Eric Larsen, the
COG AALL0232 study chair, presented results of the MTX
randomization at the plenary session of the 2011 ASCO
annual meeting. 20 Planned interim monitoring showed that
the 5-year EFS for patients randomly selected to receive
HD-MTX (1,209 patients) was 82% � 3.4% vs. 75.4% � 3.6%
for the Capizzi MTX plus asparaginase (1,217 patients)
regimen, p � 0.006. Based on these practice-changing results,
the COG now considers HD MTX to be the standard of
care for BCP HR ALL, further increasing the symmetry
between COG and BFM regimens.
The results of the induction steroid randomization were
more complex. In 2008, the COG stopped the steroid randomization
in children age 10 or older because of an increased
incidence of osteonecrosis (ON) among patients of
this age treated with DEX. Because the rate of ON was quite
low in children younger than age 10 and there was no
difference in ON rates between the two steroid arms, the
randomization continued for younger patients. There was an
interaction between the steroid and MTX regimens among
patients younger than age 10, so when the outcome for
children randomly selected to receive DEX versus PRED
was compared, the analysis was limited to those randomly
selected to receive HD MTX. 21 The younger children who
received DEX/HD MTX had a superior outcome to those who
received PRED/HD MTX (5-year EFS: 93.7% � 5.4% vs.
81.2% � 7.7%; p � 0.03). Retrospective review of the
patients age 10 or older who were randomly selected to
receive DEX versus PRED during the initial 4 years of the
study showed no differences in outcome (5-year EFS: 74.7%
� 4.6% and 76.5% � 4.6%, respectively; p � 0.80) and
confirmed the higher rate of ON seen in the patients age 10
or older who were treated with DEX (24.3% vs. 15.1%; p �
0.0007). Based on these results, 14 days of DEX 10 mg/m 2 /
day on days 1 through 14 is now considered the standard
regimen for children younger than age 10 enrolled in COG
HR BCP ALL trials, whereas PRED 60 mg/m 2 /day on days 1
through 28 is considered the standard for those age 10 or
older.
COG T-ALL Trials
Because of differences between T-cell ALL (T-ALL) and
BCP ALL in biology, treatment response, prognostic factors,
and outcome, the COG is conducting separate trials for BCP
and T-ALL, whereas the BFM group has a single trial that
includes both T-ALL and BCP ALL. The backbone therapy
for the COG AALL0434 T-ALL study (opened to patient
accrual in 2007 and currently projected to complete accrual
in 2014) is the PRED/Capizzi MTX plus asparaginase arm of
AALL0232 (see above). The study isa2x2randomized trial.
The first comparison is the identical HD MTX versus Capizzi
MTX plus asparaginase randomization conducted in
AALL0232. Careful consideration was given to the results of
AALL0232 when they became available, with a decision to
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