Treatment of Acute Lymphoblastic Leukemia in Nita L. Seibel

ACUTE LYMPHOBLASTIC LEUKEMIA _______________________________________________________________
Treatment of Acute Lymphoblastic Leukemia in
Children and Adolescents: Peaks and Pitfalls
Nita L. Seibel1
1
Senior Investigator, Clinical Investigations Branch, Cancer Treatment Evaluation Program, National
Cancer Institute, Bethesda, MD
Survival of children with acute lymphoblastic leukemia
(ALL) is often described as the success story for
oncology. The improvements in the treatment of ALL
represent the work of cooperative groups at their best.
Fifty years ago a pediatric oncologist would have
never considered using the term “cure” in a discussion with a family whose child was diagnosed with
ALL. Today the term is not only used in the initial
discussion but referred to frequently thereafter.
However, as we all know, cure is not assured and is
not obtained without sequelae. This review will focus
on the improvements in treatment for newly diagnosed
ALL in children and adolescents according to risk
group and some of the challenges that remain despite
the improved outcome.
Survival
Improvements in the 5-year survival rate for ALL in children continue to be seen. In the l996-2004 SEER data the
5-year survival for patients with ALL was 84% for children
and young adults less than 19 years of age and 88% for
children and teens less than 15 years of age. This is in
comparison to 3% reported in the 1960’s.1 Multiple factors
have contributed to this improvement, including a better
understanding of the immunobiology of ALL and disease
burden, recognition of sanctuary sites and integration of
presymptomatic central nervous system (CNS) prophylaxis,
use of effective drugs and intensification of treatment, delineation of prognostic factors with risk-adapted treatment
and improvements in supportive care. Large randomized
clinical trials have been responsible for the majority of
these advances. Despite the reporting of subgroup results
in children with ALL, the overall outcomes are fairly similar, and more than 95% will attain remission and close to
85% will survive free of leukemia recurrence at least 5 years
from diagnosis.2
Figure 1. Improvement in survival for children with acute
lymphoblastic leukemia (ALL).1 Five-year survival rates for
children less than 15 years old with ALL: 1960–2004. SEER
Cancer Statistics Review 1975-2005.
374
Risk Classification Systems and
Risk-Adapted Therapy
Since intensification of treatment has contributed to the
improvement in event-free survival (EFS) in children with
ALL, this approach results in some patients being exposed
to more aggressive therapy than necessary for cure. Nevertheless, patients identified at diagnosis as having better
risk features still account for most treatment failures. This
has formed the basis for “risk-adapted therapy.” Children
who have historically had a very good outcome are treated
with modest therapy and spared toxicity, while allowing
children with a historically lower probability of long-term
survival to receive more-intensive therapy to maximize
cure. The Pediatric Oncology Group (POG) and Children’s
Cancer Group (CCG) adopted a common set of risk criteria
in 1993 at an international conference supported by the
National Cancer Institute (NCI).3 The NCI criteria were based
on factors that had international acceptance and reproducibility, including age, initial white blood count (WBC) and
the presence of extramedullary disease at diagnosis. Both
POG and CCG refined therapy based on additional risk
factors such as ploidy, blast karyotype, and early morphologic response. As a result of the merger between CCG and
POG, the Children’s Oncology Group (COG) developed a
consensus classification strategy for treatment assignment
based on the retrospective analysis of over 6000 children
and adolescents with ALL from CCG and POG data. Based
on this analysis, patients with precursor B-cell ALL are
initially assigned to a standard-risk or high-risk group based
American Society of Hematology
on age and initial WBC (ages 1 to 9.99 years, and WBC <
50,000 cells/μL is considered standard risk). All children
with T-cell disease phenotype are considered high risk regardless of age and initial WBC. Early treatment response
and cytogenetics are subsequently used to modify initial
risk-group classification. Patients are classified as very high
risk if they have any of the following features (regardless of
initial risk group): t(9;22) and/or BCR/ABL, hypodiploidy
less than 44 chromosomes, and induction failure.4
Different approaches to risk classification are being
used by other cooperative groups. The Berlin-FrankfurtMunster Group (BFM) categorizes risk almost solely on
treatment response criteria. Minimal residual disease
(MRD) measurements at two timepoints are used in addition to prednisone prophase response. All patients with
either t(9;22) or t(4;11) are considered high risk, regardless
of marrow response.5 The Dana-Farber Cancer Institute
(DFCI) ALL Consortium is testing a new risk classification
system for patients with precursor B-cell ALL. Patients are
initially classified according to age and WBC and presence of CNS disease as standard or high risk and then, based
on the level of MRD at the end of induction, postinduction
treatment may be intensified. At St. Jude Children’s Research Hospital (SJCRH), risk classification is based mainly
on MRD level (assessed by flow cytometry) after 6 weeks
of remission induction therapy.
Age
Age has remained an independent predictor of outcome.
Children (ages 1 to 9 years) have a better disease-free survival than older children, adolescents or infants. This is
partly explained by the more frequent occurrence of favorable cytogenetics in the leukemic blasts including hyperdiploidy (> 51 chromosomes) or the t(12;21)(TEL-AML1
translocation). Children and adolescents aged 10 to 20 years
have a slightly worse outcome that has been associated
with a higher incidence of precursor T-cell disease and lower
incidence of favorable cytogenetics. ALL cells from children less than 10 years of age when compared to ALL cells
from older children and adults tend to be more sensitive to
multiple antileukemic drugs.6 Infants with ALL have a very
high risk of treatment failure. This is partly related to the
high incidence of unfavorable very immature proB-ALL
phenotype and the presence of mixed lineage leukemia
gene (MLL) gene rearrangements.7 Infants whose leukemia
has a germline MLL gene frequently present with CD10/
cALLa-positive precursor B-cell immunophenotype and
have a much better outcome than infants with the ALL and
MLL gene rearrangements.8,9
Treatment
Treatment of ALL with multiagent chemotherapy is divided
into four stages: remission induction, CNS-directed treatment and consolidation, reinduction, and maintenance.
Hematology 2008
Remission-induction
The goal of induction treatment is to induce a morphologic remission and restore normal bone marrow hematopoiesis. A three-drug induction consisting of vincristine,
prednisone/dexamethasone plus L-asparaginase with intrathecal therapy results in complete remission rates of
greater than 95%.10 Patients with a higher risk of treatment
failure may be treated with a more intense induction regimen consisting of the addition of an anthracycline (daunomycin) in addition to the vincristine, glucocorticoid and
L-asparaginase. The majority of children with newly diagnosed ALL will be in a morphologic complete remission
(CR) by the first 4 weeks of treatment. Of those who fail to
achieve a CR within the first 4 weeks, about half of them
will experience a death due to toxicity and the other half
will have resistant disease. Patients whose disease requires
more that 4 weeks to go into remission have a poorer prognosis.5 Outcome is also less favorable for patients who demonstrate more than 25% blasts in the bone marrow or persistent blasts in the peripheral blood after 1 week of intensive multiagent chemotherapy.11,12
CNS-directed therapy
Only 3% of patients have detectable (CNS) involvement at
the time of diagnosis (≥ 5 WBC/μL with lymphoblasts
present). Patients with CNS involvement at diagnosis are
treated with intrathecal therapy and subsequent radiation.
Other groups of patients such as patients with the precursor
T-cell phenotype and high WBC are treated with intrathecal therapy and cranial irradiation (12-18 Gy) in the absence of obvious CNS involvement. Unless specific therapy
is directed toward the CNS, 50% to 70% or more of children will develop overt CNS leukemia.13 Therefore, early
CNS therapy is critical for eliminating clinically evident
CNS disease at diagnosis and preventing CNS relapse in
patients without overt CNS disease. Generally this is started
at the beginning of induction, intensified during consolidation and continued throughout maintenance. The goal
is to achieve effective CNS therapy while minimizing neurotoxicity. This is usually accomplished by weekly or biweekly intrathecal therapy along with systemic drugs such
as high-dose methotrexate, 6-mercaptopurine, dexamethasone, L-asparaginase, cyclophosphamide or cytarabine.
Reinduction therapy
The intensity of the postinduction period varies, but all
patients receive some form of intensification following
achievement of remission and before beginning continuous maintenance therapy. Reinduction therapy or delayed
intensification most often use drugs similar to those used
during induction and consolidation, but may also use intermediate- or high-dose methotrexate, or different drug
combinations with little known crossresistance to the induction therapy drug combination, the extended use of
high-dose L-asparaginase, or combinations of all of these.
375
Maintenance therapy
Maintenance for ALL generally uses daily oral mercaptopurine and weekly oral methotrexate. Maintenance
therapy is the longest therapy phase for ALL and generally
continues until 2 to 3 years of continuous complete remission. In some protocols additional pulses of vincristine and
corticosteroids may be added.
Controversies and Challenges in Therapy
Despite this basic framework for treatment for ALL, there
remain numerous areas of controversy and challenge. Several of those areas will be discussed.
Asparaginase
Several forms of L-asparaginase are available for the treatment of children with ALL. Escherichia coli L-asparaginase is the most commonly used. PEG–L-asparaginase is an
alternative form of L-asparaginase that has a much longer
half-life than native E coli L-asparaginase. A single intramuscular dose of PEG–L-asparaginase given in conjunction with vincristine and prednisone during induction
therapy appears to have similar activity and toxicity as 9
doses of intramuscular E coli L-asparaginase (3 times a week
for 3 weeks). In a comparison between PEG L-asparaginase
versus native E coli asparaginase in which each agent was
given over 30-week period following remission, similar
outcome and similar rates of asparaginase-related toxicities were observed for both groups.14 In a randomized trial
in which patients with standard risk ALL were randomized
at diagnosis to receive PEG–L-asparaginase or native E coli
asparaginase during induction and two delayed intensification phases, the use of PEG–L-asparaginase was associated with more rapid blast clearance and a lower incidence
of neutralizing antibodies.15 Currently COG protocols use
PEG–L-asparaginase for all patients with ALL. Patients who
develop an allergic reaction to PEG–L-asparaginase should
be switched to Erwinia L-asparaginase. Erwinia has a much
shorter half life and therefore requires more frequent administration and a higher dose. There have been two studies in which patients were randomly assigned to receive
Erwinia L-asparaginase on the same schedule and dosage
as E coli–L-asparaginase and they demonstrated a significantly worse EFS.16,17 Questions regarding the optimal doses,
intensity, forms and route of administration of asparaginase are being addressed in current and planned studies.
Patients who develop antibodies to asparaginase preparations remain a challenge in how they should be handled to
avoid compromising their antileukemic therapy. Issues with
availability of asparaginase preparations persist. Newer
preparations of asparaginase are undergoing clinical testing as well as intravenous administration.
Presymptomatic CNS involvement
The approach to presymptomatic CNS involvement centers around the findings that long-term intrathecal (IT)
376
therapy is as effective as radiotherapy with comparable EFS
and survival rates. High-dose methotrexate, which has been
used in protocols to prevent CNS relapse, is not as effective
as radiotherapy in preventing CNS relapse. However, intravenous methotrexate reduces systemic relapses.18 In addition, CNS-directed therapy is influenced by systemic
therapy. Patients with standard-risk ALL treated on CCG
1922 who were randomized to receive oral dexamethasone
had a 50% decrease in the CNS relapse rate as compared
with patients receiving oral prednisone (both groups received IT methotrexate alone for CNS prophylaxis).19 The
optimal IT chemotherapy is not clear. Standard-risk patients
were randomized in CCG 1952 between triple IT chemotherapy (methotrexate, hydrocortisone, cytarabine) or single
IT (methotrexate). The results showed an isolated CNS relapse rate of 3.4% for triple IT therapy and 5.9% for single
IT therapy (P = .004). There were more bone marrow relapses in the group that received triple IT therapy leading
to a worse overall survival in this group (90.3%) compared
with the single IT therapy group of 94.4% (P = .01). When
the analysis was restricted patients with precursor B cells
with a M1 day 14 bone, there was no difference in the CNS
relapse rate, EFS or OS.20 Certain groups of patients may
require more intensive IT therapy such as patients with
blasts in the cerebrospinal fluid but less than 5 WBC and
patients with a traumatic lumbar puncture with blasts at the
time of diagnosis who are at an increased risk of CNS relapse.21,22 In summary, radiotherapy has been replaced by
long-term IT therapy to prevent CNS relapses. It is not clear
whether triple IT therapy has an advantage over IT methotrexate alone. Systemic therapy can be a factor in CNSdirected therapy. Certain high-risk groups of patients continue to undergo presymptomatic cranial irradiation. Current studies are ongoing in the pediatric cooperative groups
to look at presymptomatic CNS therapy. St Jude Children’s
Research Hospital is testing whether patients with clinically evident CNS disease at diagnosis can be treated with
intensive IT and systemic chemotherapy without radiation.
Intensification of therapy
Improvement in the outcome of patients with standard-risk
disease have been achieved with a limited exposure to
chemotherapeutic agents such as anthracyclines and alkylating agents which are associated with late toxic effects.
This has been accomplished through the use of regimens
utilizing a limited number of courses of intermediate-dose
or high-dose methotrexate, extended use of high-dose asparaginase or by using limited amounts of anthracyclines
and alkylating agents in the form of delayed intensification. In higher-risk patients, a number of different approaches have been used, including blocks of intensified
therapy such as delayed intensification blocks.5 Augmented
postinduction therapy (consisting of 2 blocks of delayed
intensification and interim maintenance phases) has been
American Society of Hematology
shown to improve the outcome for high-risk patients who
show a slow response to 4-drug induction (based on the
day-7 marrow) and in patients showing a rapid response to
4-drug induction.23-25 However, for patients showing a rapid
bone marrow response to 7 days of induction there was no
benefit to an increased duration of intensive therapy—a
single delayed intensification/interim maintenance phase
was as effective as 225 (Figure 2). This regimen, which consists of a single delayed intensification/interim maintenance
phase, is the backbone of therapy in higher-risk and precursor T-cell COG studies.
Glucocorticoids
The question of which steroid (dexamethasone vs prednisone) to use in treatment is controversial. Dexamethasone when compared with prednisone has been shown to
significantly lower the risk of CNS relapse and bone marrow relapses.19,26 Osteonecrosis (ON),a disorder characterized by segmental death of one or more osseous sites, has
only recently arisen as a significant toxicity as increasing
numbers of patients with ALL have received dexamethasone-based delayed-intensification therapies with improved
disease survival. In CCG 1882, females between 10 and 15
years old and males between 16 and 20 years of age who
received multiple courses of steroids had the highest risk
of developing ON.27 In CCG 1961 the incidence of ON was
decreased in patients who were receiving double delayed
intensification phases by alternating the weeks of dexamethasone instead of 3 consecutive weeks.28 Dexamethasone
clearance can be influenced by a variety of host- and treat-
Figure 2. Five-year event-free survival (EFS) according to
the type of postinduction intensification (PII)
chemotherapy for higher risk acute lymphoblastic
leukemia (ALL) patients.23
Reprinted with permission from Seibel NL, Steinherz PG, Sather
HN, et al. Early postinduction intensification therapy improves
survival for children and adolescents with high-risk acute
lymphoblastic leukemia: a report from the Children’s Oncology
Group. Blood. 2008;111:2548-2555. © the American Society of
Hematology
Hematology 2008
ment-related factors that can ultimately lead to increased
toxicity. These include the patient’s age, asparaginase allergy and serum albumin level. In standard- and high-risk
patients with low albumin as a reflection of asparaginase
activity, dexamethasone exposure was prolonged.29
Precursor T-cell ALL
Different approaches have been taken for patients with Tcell ALL. Historically, these patients have had a worse outcome than B-cell precursor patients. With current treatment
approaches, outcomes for children with precursor T-cell
ALL are similar to those achieved for children with precursor B-cell ALL. The addition of high-dose methotrexate to
the DFCI-based chemotherapy regimen resulted in fewer
CNS relapses and a significantly improved EFS for patients
with precursor T-cell ALL treated on POG-9404.30 Asparaginase (high dose) and doxorubicin were also important
components of this protocol. In contrast, CCG-treated patients with precursor T-cell ALL on the same protocols as
precursor B cell patients. Treatment assignment was based
on age and WBC at presentation and then on the disease
response to initial therapy. Most patients with precursor Tcell disease were treated on the Higher Risk protocol, CCG
1961, which showed that a single delayed intensification
course produced the best results for patients who were rapid
responders to initial induction therapy. CNS relapses were
the most common events in this group. When comparing
the outcomes for these two studies, the results were similar;
however, all patients on POG 9404 underwent cranial irradiation, whereas only patients showing a slow morphologic remission on 1961 underwent cranial irradiation.31
Patients with standard-risk precursor T-cell ALL treated on
CCG-l952 and CCG-1991 had an inferior EFS compared to
children treated on POG 9404.32 In COG, patients with precursor T-cell ALL are currently being treated on a separate
protocol from the patients with precursor B cells that utilizes a post-induction intensification backbone. Standardand high-risk patients will be treated with nelarabine (a
nucleoside analogue that is intracellularly converted to
arabinoside furanosylguanine with demonstrated activity
in patients with relapsed and refractory T-cell lymphoblastic disease) and randomized between high dose methotrexate and escalating increasing doses of intravenous methotrexate.33 Low risk precursor T cell patients will not undergo cranial irradiation whereas all standard and high risk
precursor T cell patients will.
Adolescents and young adults
Treatment protocols for adolescents and young adults
(AYA) with newly diagnosed ALL have been revised based
on retrospective analyses that showed improved outcomes
for AYAs when treated on protocols for pediatric patients as
compared to protocols to treat adult patients. These results
have been confirmed in the U.S. and Europe2,34-38 (Table
377
1).There are several potential explanations for these observed differences in outcomes. They include clinical and
demographic differences in adolescents receiving treatment
at pediatric compared to adult centers, clear differences in
protocol design and dose intensity, and potential variations in the degree of adherence to protocol drug administration by adult compared to pediatric oncologists and by
the patients treated. Ribera et al showed that for patients
treated on a “pediatric type” treatment regimen, there was
no difference in outcome for patients 15 to 18 years of age
and those 19 to 30 years of age.39 U.S. adult and pediatric
cooperative groups are embarking on a prospective trial to
address some of the questions related to this group of patients and outcome. Newly diagnosed patients 16 to 30
years of age will be enrolled on an intergroup study that
parallels the current COG study for adolescents and highrisk children. This study will examine disease biology,
psycho-social disparities between adolescents referred to
and undergoing treatment by pediatric oncologists or medical oncologists to assess the ability to administer safely
and in a timely manner the same therapy used by the U.S.
pediatric cooperative group.34
New Agents
Targeted therapy in ALL holds potential for contributing
to improvement in outcome for children and adolescents
in ALL. Imatinib mesylate (a selective inhibitor of the BCRABL protein kinase) has been combined with conventional
chemotherapy in children with Philadelphia chromosome–
positive ALL and improves early EFS and reduces minimal
residual disease.40 Dasatinib and nilotinib are newer agents
in clinical trials that show dual inhibition against BCRABL (including mutations) . Overexpression of wild-type
FLT3 particularly in MLL-rearranged ALL is a target that
is being investigated in infant ALL. FLT3 inhibitors such
as lestaurtinib (CEP-701), a highly selective small molecule FLT3 tyrosine kinase inhibitor, are being combined
with chemotherapy in newly diagnosed infants with ALL
and MLL rearrangements.41 Other groups of agents that have
shown promising activity in the pediatric preclinical testing
program for ALL include a BCL-2 protein inhibitor (ABT263) and an aurora A kinase inhibitor (MLN8237).42,43 Monoclonal antibodies directed against a variety of targets such
as cells expressing CD 19 (SAR3419, XMAb5574), CD 20
(rituximab), CD22 (epratuzumab), CD33 (gemtuzumab) and
CD52 (alemtuzumab) are being developed or already in
clinical trials.44,45
Summary
The outlook for children and adolescents diagnosed with
ALL today is much better than ever before as result of welldesigned clinical trials, identification of higher risk features with appropriate treatment changes, and tailoring of
therapy according to response and risk groups. This progress
378
Table 1. Adolescent acute lymphoblastic leukemia (ALL)
outcome according to treatment protocol.2
Age
Range, yr
Number
5-year
EFS
USA
CCG
CALGB
16-21
16-21
197
124
63*
34*
France
FRALLE 93
LALA 94
15-20
15-20
77
100
67
41
The Netherlands
DCOG
HOVON
15-18
15-18
47
44
69
34
United Kingdom
MRC ALL
UKALLXII
15-17
15-17
61
67
65
49
Sweden
NOPHO 92
Adult
15-18
15-20
36
21
74
39
Site
Ref.
34
35
36
37
38
*7-year EFS
Abbreviations: CCG, Children’s Cancer Group; CALGB, Cancer
and Leukemia Group B; FRALLE, French Acute Lymphoblastic
Leukemia Pediatric group; LALA, Leucémie Aiguë Lymphoblastique de l’Adulte; DCOG, Dutch Childhood Oncology Group;
HOVON, Dutch-Belgian Hemato-Oncology Cooperative Group;
UKALLXII-United Kingdom Acute Lymphoblastic Leukemia;
NOPHO 92, Nordic Society of Pediatric Haematology and
Oncology
should continue with the measurement of MRD, additional
understanding about how patients metabolize chemotherapy, genomic profiling and identification of new targets for treatment. Together these should provide further
guidance into optimizing treatment and minimizing the
toxicity for the future.
Disclosures
Conflict-of-interest disclosure: The author declares no competing financial interests.
Off-label drug use: Vincristine, daunomycin, dexamethasone, prednisone, cyclophosphamide, cytarabine, antimetabolites, methotrexate-most of the chemotherapy that we
use to treat children with ALL.
Correspondence
Nita L. Seibel, MD, Cancer Therapy Evaluation Program,
National Cancer Institute, National Institutes of Health,
6130 Executive Boulevard, Room 7025, Bethesda, MD
20892; Phone: 301-496-2522; Fax: 301-402-0557; e-mail:
seibelnl@mail.nih.gov.
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