2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

continue this randomization based on the different biology of
BCP and T-ALL (the reason that the question was asked
separately in two parallel trials in the first place). Interestingly,
the best reported contemporary results in pediatric
T-ALL come from the UKALL 2003 trial, which used essentially
a COG ABFM backbone regimen with Capizzi MTX
plus asparaginase during IM. 22
The second randomization in AALL0434 is to receive
versus not receive six 5-day courses of nelarabine during the
first �16 months of therapy. Nelarabine, a prodrug of ara-G,
showed substantial clinical activity in phase I/II T-ALL
trials, but was associated with significant, often severe, and
sometimes fatal CNS toxicity. 23,24 The COG then conducted
a pilot study of nelarabine plus BFM-86 type chemotherapy
in children with newly diagnosed T-ALL and found encouraging
activity but much lower rates of overall and severe
toxicity than had been seen in relapsed patients treated in
the phase I/II trials. 25 AALL0434 included a pilot safety
phase during which only an HR subset of T-ALL patients
with a poor response was randomly selected to be treated
with/without nelarabine. This safety phase was concluded
with no significant differences in toxicity among the patients
treated with/without nelarabine, and AALL0434 is now in
the efficacy phase in which �90% of patients are randomly
selected to be treated with/without nelarabine (all except for
a tightly defined low-risk patient subset). 26
VHR ALL
A small subset of pediatric ALL patients can be defined as
being at very high risk (VHR) of relapse. The definition of
this subgroup is constantly evolving, but there is a general
consensus that alternative treatment strategies may be
indicated for these patients in comparison with treatment
given to other patients with HR ALL. As discussed above,
the BFM group has termed this group HR and uses intensive
multiagent chemotherapy HR blocks, an additional protocol
II for these patients, with hematopoietic stem cell transplant
(HSCT) in CR1 for the subset with a poor treatment
response at end of protocol Ib. The COG AALL0031 pilot
study (2002 to 2006) tested an intensive multiagent chemotherapy
regimen in children with VHR ALL, which included
Ph-positive ALL, hypodiploidy (chromosome number less
than 44), poor response to induction therapy (more than 25%
marrow blasts at day 29 or 5% to 25% marrow blasts/more
than 1% MRD at day 43 after 2 weeks of extended induction
therapy), or MLL translocation and an SER (more than 5%
blasts at day 15 of induction). 9,27 The results were encouraging
for patients with Ph-negative VHR ALL, with a
nonsignificant trend toward improved outcome for those
treated with HSCT. 27 The study design with all patients
receiving identical chemotherapy and those with Ph-positive
ALL also receiving imatinib facilitated assessment of imatinib
toxicity. Notably, the addition of imatinib was quite
safe and did not lead to increased toxicity. 9 More importantly,
adding imatinib led to major improvements in early
614
outcome for patients with Ph-positive ALL, with a 3-year
EFS rate of 80% � 11% (95% CI, 64% to 90%), which was
more than twice that of historic controls treated in the
preimatinib era (35% � 4%; p � 0.0001). There was no
apparent advantage to HSCT as compared with intensive
chemotherapy plus imatinib. These results have been stable
with longer follow-up 28 and have led to changes in clinical
practice in treatment of children with Ph-positive ALL.
The COG has now completed enrollment (2008 to 2012) on
a successor Ph-positive ALL trial (AALL0622) that utilized
the AALL0031 chemotherapy backbone with imatinib replaced
with dasatinib, a more potent second-generation Abl
TKI. The study showed that it was safe to add continuous
dasatinib treatment (60 mg/m 2 /day) to this intensive chemotherapy
regimen; it is still much too early to assess treatment
efficacy. In 2012, the COG and European EsPhALL
groups will commence enrollment on a joint pilot study (developed
in conjunction with Bristol Myers Squibb) that will test
the safety and efficacy of dasatinib added to the BFM HR
treatment backbone, which has lower cumulative doses of
many chemotherapy agents than the AALL0031 regimen.
Future Perspectives
STEPHEN P. HUNGER
The substantial improvements that have occurred in outcome
for pediatric HR ALL over the past few decades have
been accompanied by recognition that there are a number of
different ALL subsets that come under the umbrella term
HR ALL. For some subsets, outcomes have been improved
by optimizing delivery of chemotherapy agents that have
been in widespread clinical use for the past 25 years, as
exemplified by the results of COG AALL0232. For other
subsets, such as Ph-positive ALL, optimizing traditional
cytotoxic chemotherapy agents led to limited improvements
in outcome, 29 but introduction of new and/or targeted therapies
had a major effect on outcome. 9 It is expected that
ongoing genomic studies will lead to recognition of additional
VHR ALL subsets defined by the presence of specific
sentinel genomic lesions that can potentially be targeted by
novel therapies. 30 The rarity of these and other VHR ALL
subsets will require increased collaborations between North
American and Western European investigators in order to
test the efficacy of novel/targeted therapies in these patient
subsets.
Acknowledgments
The author dedicates this manuscript to the memory of Jim
Nachman, who passed away unexpectedly, and far too early, in
2011. Jim developed the ABFM regimen; played a major role in
developing productive, fruitful interactions between the CCG/
COG and BFM groups; and shaped the design of most COG ALL
trials of the past 25 years. He was widely recognized as an
international leader in pediatric oncology clinical research and
as a mentor to many investigators. The author and the rest of
the pediatric oncology community miss his advice, his infectious
enthusiasm, his laugh and politically incorrect sense of humor,
and most of all his friendship.