2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Development and Refinement of Augmented
Treatment Regimens for Pediatric High-Risk
Acute Lymphoblastic Leukemia
Overview: The 5-year survival rate for children and adolescents
with acute lymphoblastic leukemia (ALL) is now at least
90%. However, clinical features (age and initial white blood
cell count [WBC]), early treatment response, and the presence/absence
of specific sentinel genomic lesions can identify
subsets of high-risk (HR) ALL patients with a much higher risk
of treatment failure. Chemotherapy regimens used to treat HR
ALL have been refined over the past 3 decades through
randomized clinical trials conducted by the Children’s Oncology
Group (COG) in North America and the Berlin-Frankfurt-
Muenster (BFM) group in Western Europe. Contemporary COG
HR ALL treatment regimens were developed from the BFM-76
regimen, with subsequent changes that led to development
and refinement of a so-called augmented BFM (ABFM) regimen
used today. Although contemporary COG and BFM treatment
ALL IS the most common cancer that occurs in children
and adolescents younger than age 20, comprising
approximately 25% of malignancies occurring before age 15
and 12% of those occurring in adolescents aged 15 to 20. 1
ALL was virtually incurable until the early- to mid-1960s,
with less than a 10% survival rate as recently as the late
1960s. A recent large review of results of COG clinical trials
showed 5-year survival rates of 90% for more than 7,000
children diagnosed with ALL between 2000 and 2005, and it
is anticipated that the long-term survival rate for those
diagnosed between 2006 and 2010 will approach or exceed
90%. 2 Despite these dramatic improvements in survival,
clinical features, early-treatment response characteristics,
and the presence/absence of specific favorable- or poor-risk
sentinel genetic lesions in the leukemia cells can be used to
identify patient subsets at higher risk of relapse. 3 Powerful
predictive characteristics include the combination of age and
WBC at initial diagnosis, which together are used to define
the so-called NCI/Rome standard risk (SR; age 1 to 9.99
years and WBC less than 50,000/microliter) and HR (age �
1or�10 years and/or WBC � 50,000 microliter) groups. 4
The second powerful predictor of outcome is initial treatment
response, measured either by response to a 1-week
prednisone (PRED) (plus a single dose of intrathecal methotrexate
[IT MTX]) prephase (also termed prophase), bone
marrow morphology after 1 to 2 weeks of multiagent chemotherapy,
or measurements of minimal residual disease
(MRD) at end of induction and/or consolidation therapy. The
MRD response is the most powerful single prognostic factor
and is now used by most groups in North America and
Western Europe to modulate the intensity of postinduction
therapy. 5,6 Leukemia genetics also provides critical prognostic
information, with ETV6-RUNX1 (TEL-AML1) fusion and
hyperdiploidy and/or favorable chromosome trisomies recognized
as favorable features, and BCR-ABL1 fusion (Phpositive
ALL) or MLL translocations generally considered to
be adverse features that merit specific therapies and/or
intensified treatment. 3
HR ALL is generally treated with more intensive therapies
than SR ALL. The COG uses an ABFM baseline
By Stephen P. Hunger, MD
regimens are not identical, there are many more similarities
than differences. With improvements in survival, it has become
clear that although the outcome of some patients with
HR ALL can be improved by optimizing use of standard
cytotoxic chemotherapy agents, this approach has had only
limited success for other patient subsets. In contrast, introduction
of the tyrosine kinase inhibitor imatinib has led to
dramatic outcome improvements for children and adolescents
with Philadelphia chromosome–positive ALL. Genomic studies
are identifying new sentinel genomic lesions that can serve as
potential therapeutic targets, which will likely lead to the
testing of novel and/or targeted therapies in more children
with HR ALL. Such studies will require increased collaboration
between Western European and North American cooperative
groups.
treatment regimen 7 that bears significant similarity to, but
has fundamental differences from, the BFM regimen developed
in the early 1970s by Riehm and colleagues in Berlin. 8
Table 1 provides a comparison of different contemporary
BFM and COG treatment regimens. Different therapies are
used for certain HR subtypes of ALL, most notably Phpositive
ALL that is treated with intensive chemotherapy
and tyrosine kinase inhibitors (TKI) such as imatinib or
dasatinib. 9
Development and Refinement of the BFM Treatment
Regimen for ALL
In 1977, Riehm and colleagues reported outstanding early
results of treatment outcome with an intensive 8-week,
eight-drug induction regimen, cranial irradiation, and maintenance
therapy. 8 The 8-week induction was later termed
protocol I and included two distinct phases. Protocol Ia is
what the COG calls a four-drug induction and included
PRED, asparaginase, vincristine, and daunorubicin. This
was immediately followed by protocol Ib (the COG consolidation),
which included cyclophosphamide, repeated low
doses of ara-C, 6-mercaptopurine (6-MP), four weekly doses
of IT MTX, and cranial irradiation (18 Gy).
Subsequently, the BFM 76/79 study showed that outcome,
particularly for patients with a high WBC, could be improved
when protocol I was repeated with some modifications
designed to minimize drug resistance (replacement of
PRED with dexamethasone [DEX], daunorubicin with doxorubicin,
and 6-MP with 6-thioguanine). This was termed
protocol II (delayed intensification [DI] in COG terminology).
The 10-year disease-free survival rate was 67% for
patients treated in the BFM 76/79 trial with protocols I and
From the Children’s Hospital Colorado, Aurora, CO; Department of Pediatrics, University
of Colorado School of Medicine, Aurora, CO.
Author’s disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Stephen P. Hunger, MD, Center for Cancer and Blood
Disorders, Children’s Hospital Colorado, 13123 East 16th Ave., Box B115, Aurora, CO
80045; email: stephen.hunger@childrenscolorado.org.
© 2012 by American Society of Clinical Oncology.
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