ACUTE LYMPHOID LEUKEMIA

Adolescents and Young Adults with Acute Lymphoblastic

Leukemia
Wendy Stock1
1University

of Chicago, Chicago, IL

During the last decade, increasing attention has been paid to a unique group of patients with acute lymphoblastic
leukemia (ALL) who lie at the crossroad of therapeutic care by pediatric and adult hematologists/oncologists. ALL is a
disease that affects infants, children, adolescents, and adult patients. With current therapies, the vast majority of
children with ALL are now long-term survivors; unfortunately, the same good results have not yet been obtained for
adults with ALL. This review will describe current controversies surrounding the treatment of adolescents and young
adults with ALLa group who finds themselves in the transition from pediatric to adult treatment approaches. The
review focuses on recent insights into disease biology, prognostic factors, and treatment outcomes that have led to a
series of prospective clinical trials specifically designed for adolescents and younger adults (AYAs) with ALL. These
trials have been designed to provide important new clinical, psychosocial, and biological insights, and to further
improve the survival of this challenging and unique group of patients.

Introduction
Acute lymphocytic leukemia (ALL) is a heterogeneous disease,
both in terms of its pathology and the populations that it affects.
Disease pathogenesis involves a number of deregulated pathways
controlling cell proliferation, differentiation, and survival that are
important determinants of treatment response.1 Approximately 5200
new cases of ALL are estimated to have occurred in the United
States in 2007,2 and survival varies with age and disease biology.
Recent data extracted from the Surveillance, Epidemiology and End
Results (SEER) registry have demonstrated a statistically significant
improvement in survival for older adolescent and adults with ALL
(ages 1559 years) during the past two decades from 1980 to
2004.3,4 The greatest survival improvements occurred in the 15- to
19-year-old age bracket, for whom 5-year relative survival improved from 41.0% to 62.1%, with lower rates of improvement
achieved for patients 20 to 59 years of age.3,4 Nevertheless, survival
for even the most favorable young adult group (the older
adolescents) falls short of the outstanding results now achieved in
children between the ages of 2 and 10 years, in which nearly 90%
are long-term survivors.5 Below, a brief review of the known
biological and clinical prognostic features followed by a description
of the highly successful treatment of children with ALL lays the
groundwork for discussion of the challenge to further improvements
in survival for adolescents and young adults (AYAs) with ALL.
Definition of the age range that encompasses the AYA patient is
itself controversial, because the age range described in the literature
for this population varies depending on the study. This review will
largely focus on the group of patients who are 16 to 21 years old at
the time of diagnosis, the group of patients most commonly treated
by both the pediatric and adult oncologists. Most of the retrospective studies described below have focused on this age group,
although the definition of the AYA patient varies, and may include
patients up to the age of 30 and, in recent studies, even up to 40
years of age. Prospective studies discussed below that utilize
high-risk pediatric ALL regimens are testing this approach in adults
up to 60 years of age. These prospective studies will undoubtedly
help to define specific biological and therapeutic tolerance and may

Hematology 2010

help us to further refine the optimal treatment for the young adult
with ALL.

Biological and Clinical Prognostic Factors in ALL:

Setting the Stage for Risk-Adapted Therapy
Of the many variables that influence prognosis, genetic subsets,
initial white blood cell count (WBC), age at diagnosis, and early
treatment response are the most important.6 Although improved
treatment and access to treatment has abolished the prognostic
strength of some of the previously described adverse prognostic
indicators in pediatric ALL, including male sex, African-American
race, and the presence of the t(1;19) E2A-PBX fusion gene, it should
be stressed that even so-called low-risk children need a certain
degree of treatment intensification to avoid unacceptable rates of
relapse.1,7 Table 1 lists the prognostic factors in children and adults
that may be used for risk stratification in current clinical trials. In
contrast to pediatric ALL, due to the poorer outcomes in adult trials,
no group is considered favorable risk; rather, the prognostic groups
in adult ALL are distinguished by standard or adverse features.
The prognostic impact of age, and to a lesser extent, leukocyte count
can be explained by their association with specific genetic abnormalities. For example, there is a preponderance of cases with favorable
genetic abnormalities of hyperdiploidy 50 chromosomes or ETV6RUNX1 in patients 1 to 9 years of age.8 ETV6-RUNX1 mutations are
not found in ALL in adults. Adverse genetic abnormalities such as
MLL rearrangements occur in 70% to 80% of infant cases, and the
Philadelphia chromosome (Ph) occurs in 25% to 30% percent of
adult patients. In a population-based study from the northern United
Kingdom of 349 adults diagnosed with ALL over a period of 19
years, Ph ALL accounted for 39% of the cases in adults over the
age of 60 years.9
Although many genetic abnormalities are associated with clinical
outcome, only a few are routinely used for treatment stratification.
The Childrens Oncology Group also uses trisomy of chromosomes
4, 10, and 17 (triple trisomy) as a favorable prognostic factor in its
clinical trials.10 There is clinical heterogeneity within each specific

21

Table 1. Prognostic factors used in pediatric and adult clinical trials

PROGNOSTIC FACTORS
ADULT
Age (years)
Leukocyte count (x109/L)
Immunophenotype
Genotype

STANDARD

ADVERSE

<35
<30
Mid T-cell (cortical)
-------

>60
>100
Early T-cell, Mature T-cell
BCR-ABL1
MLL-AF4/ other MLL
Hypodiploidy < 44
Complex ( > 5 abnormalities)
>0.01%

Minimal residual disease <0.01%

after induction
FAVORABLE
PEDIATRICS
Age (years)
Leukocyte count (x109/L)
Immunophenotype
Genotype

Minimal residual disease

after induction

1 to 9
<50
Precursor B-cell
Hyperdiploidy >50
ETV6-RUNX1
<0.01%

ADVERSE
<1 or 10
>50
Early thymic precursor
Hypodiploidy <44
BCR-ABL1
MLL-AF4/ other MLL
1%

genetic subtype. For example, among patients with Ph ALL,

patients ages 1 to 9 years fared significantly better than the older
patients.11 In adults, Ph ALL is associated not only with a high
initial leukocyte count, but also with a dismal prognosis with
standard chemotherapeutic regimens.12 Allogeneic stem cell transplantation (allo-SCT) in the first complete remission (CR1) has
remained a standard curative approach for these adults. In patients
with MLL-AF4 fusion, infants and adults have a worse prognosis
than children. Approximately 6% of adults with ALL have rearrangements involving the MLL gene.13 The basis of these differences may
be related to some combination of secondary genetic events, the
developmental stage of the target cell undergoing malignant transformation, and the pharmacogenetics or pharmacokinetic features of
the patient. In addition to the t(4;11), the MLL gene is involved in a
number of other translocations in ALL, for example, t(11;19) and
t(9;11).8 Due to their poor prognosis, allogeneic transplant in CR1 is
recommended for adult cases with translocation involving the MLL
gene. In one of the largest published series, the outcome of 34
patients with t(4;11) from the LALA-94 study were evaluated.13
Patients with t(4;11) were assigned to allo-SCT in CR1 if a donor
was available, with the remaining patients assigned to either
autologous stem-cell transplantation (auto-SCT) or intensive postremission chemotherapy. The outcome for the t(4;11) patients was
significantly better for those receiving an allo-SCT in CR1, with a 5
year disease-free survival (DFS) of 66% (13%) compared with
11% for those receiving an auto-SCT and 20% for those receiving
chemotherapy (p 0.02).
As mentioned above, the significance of many prognostic factors
changes with improvements in treatment. For example, the outcome
for both children and adults with Ph ALL has improved substantially with the addition of tyrosine kinase inhibitors to the treatment.14 Recently, children with this genotype treated with chemotherapy and imatinib (without allo-SCT) had a 3-year event-free
survival (EFS) of over 80%.15 If the favorable outcome is confirmed
with longer follow-up, the Ph chromosome may join a long list of
other factors such as male sex and African-American ethnicity that
have lost adverse prognostic impact with improved treatment in
childhood ALL.16 18 The recent finding of adverse prognosis of
CD20 expression in adult19 but not in childhood ALL20 may have

22

therapeutic implications with the availability of targeted monoclonal antibodies that can be added to front-line therapies.
More recently, the application of microarray-based, genome-wide
analysis of gene expression and DNA copy number, complemented
by transcriptional profiling, re-sequencing and epigenetic approaches, has identified specific genetic alterations with biologic
and therapeutic implications. For example, genetic expression
profiling studies have classified T-ALL cases into several distinct
genetic subgroups that correspond to specific T-cell development
stages: HOX11L2, LYL1 LMO2; TAL1 LMO1; or LMO2,
HOX11, MLL-ENL. While HOX11L2 generally confers a poor
outcome, HOX11 and MLL-ENL are associated with a favorable
outcome.21,22 Among many other mutations in T-cell ALL, NOTCH1
or FBXW7 mutations are associated with a favorable prognosis, and
NUP214-ABL1 fusion is responsive to tyrosine kinase inhibition.2325 Recent genome-wide studies in precursor B-cell ALL
identified two high-risk subgroups, one with a genetic profile similar
to that of cases with BCR-ABL1 fusion, characterized by IKZF1
deletion, and the other with a JAK2 mutation.26 28 These data
suggest potential new therapeutic targets, including gamma secretase inhibitors, to target NOTCH1 mutations and JAK and ABL
kinase inhibitors.

Treatment Strategies for ALL

Treatment of ALL involves some of the most complex chemotherapy combinations and treatment schedules used in oncology.
Induction chemotherapy is used first to reduce the burden of
lymphoblasts in the bone marrow and to restore normal hematopoietic function. Consolidation therapy (also termed intensification) is
used with the intention of clearing any drug-resistant leukemia cells
that have survived induction therapy and to eliminate minimal
residual disease (MRD). Maintenance chemotherapy consists of 2 to
3 years of low-dose antineoplastic drugs designed to prevent
leukemia relapse during the crucial few years after remission
induction and consolidation. Finally, central nervous system (CNS)
prophylaxis is necessary to treat sanctuary sites that are shielded
from systemic therapy by the blood-brain barrier. A number of drug
combinations and schedules have been empirically developed over
the years to bring this multi-step treatment theory into practice.

American Society of Hematology

Importantly, the methods by which children and adults are treated

have evolved in very different ways.

Cure of ALL in Children: How Did We Get There?

The significant improvements in survival for children with ALL
during the past two decades can be attributed to both favorable
disease biology and to the success of carefully designed, riskadapted treatment. Risk stratification evolved during these decades
to incorporate response to initial treatment, cytogenetics, and other
biological characteristics of the disease. Measurement of MRD, as
discussed above, is now used to improve risk stratification and to
allocate patients to allo-SCT in many pediatric and in at least one
adult clinical trial.29 31
The initial successful strategy was pioneered in the 1980s by the
Berlin-Frankfurt-Muenster (BFM) group, who demonstrated that an
intensive multi-drug induction and consolidation followed by a
delayed intensification phase resulted in improvements in survival
to about 70% for children enrolled in these studies.32 The BFM
framework consists of: 1) an induction regimen including oral
corticosteroids, intravenous vincristine and daunorubicin, intramuscular L-asparaginase, and intrathecal cytarabine and methotrexate;
2) a consolidation regimen of 6-mercaptopurine and intravenous
and intrathecal methotrexate; 3) a re-intensification regimen of
dexamethasone, vincristine, doxorubicin, and L-asparaginase alternating with cyclophosphamide, cytarabine, 6-thioguanine, and
intrathecal methotrexate; and 4) maintenance therapy including oral
methotrexate and 6-mercaptopurine for an optimal time of 24 to 36
months.32 Subsequently, as discussed by Smith et al.,5 treatment
refinements tested in cooperative group trials identified several key
improvements: the addition of an interim maintenance phase,
augmentation of the BFM-type delayed intensification, and a
reduction in the percentage of children receiving cranial irradiation
for CNS prophylaxis.3335 These strategies, which are focused on
extended and intensive use of the core drugs glucocorticoids,
vincristine, l-asparaginase (and more recently, the use of an
extended release PEG-asparaginase,36 methotrexate, and antimetabolites, have resulted in cure in the vast majority of children
with ALL.
Two recent reports from pediatric oncology group trials demonstrate the efficacy of this approach for the AYA patient. In a subset
analysis, the Dana Farber Cancer Institute ALL consortium evaluated the treatment outcome for 51 AYA patients ages 15 to 18 years
treated on two consecutive trials from 1991 to 2000.37 With a
median follow-up of 6.5 years, they reported a 5-year EFS of 78%,
which was not statistically significantly different than the outcome
of the younger children aged 110 years where EFS was 85%
(p.09). The Childrens Oncology Group also performed a subset
analysis of 262 AYA patients aged 16 21 years enrolled on the
CCG 1961 trial from 1996 2002.38 This trial randomly assigned
therapies to evaluate the impact of post-induction treatment intensification on outcome. The five-year EFS and OS survival for the
AYA patients was 71.5% and 77.5%, respectively. Thus, the
outcome for even the highest risk group of patients, the AYAs, is
beginning to approach the remarkable cure rates for children with
ALL.

trials that have been conducted during the past two decades, adult
cooperative group trials have generally tested dose intensification of
active, myelosuppressive agents such as daunorubicin, cytarabine,
and cyclophosphamide and the use of allo-SCT in first remission.
The hyper-CVAD regimen designed by the MD Anderson group
uses four alternating courses each of cyclophosphamide, vincristine,
doxorubicin, and dexamethasone in conjunction with methotrexate/
leucovorin and cytarabine for a total of eight cycles of therapy.39
CNS prophylaxis is provided with intrathecal methotrexate and
cytarabine. Maintenance therapy with 6-mercaptopurine, methotrexate, vincristine, and prednisone continues for a total of two years.39
The regimen by Larson et al. (CALGB 8811) added cyclophosphamide to the induction regimen of prednisone, vincristine, daunorubicin, and L-asparaginase. In addition, the Cancer and Leukemia
Group B (CALGB) investigators added more intensive postremission therapy that was modeled on pioneering pediatric trials.
Their strategy included the use of 6-mercaptopurine, L-asparaginase, and 6-thioguanine along with cyclophosphamide, vincristine,
cytarabine, corticosteroids, and methotrexate during early and late
intensification after remission. CNS-directed therapy was provided
with cranial radiation and intrathecal methotrexate. Maintenance
therapy consisted of vincristine, prednisone, oral methotrexate, and
6-mercaptopurine for a total of 24 months after diagnosis.40 In
general, the cumulative dose of L-asparaginase and vincristine is
lower in adult protocols. All of these adult trials have similar
outcomes with overall survival of only 35 40%. These outcomes
reflect adults of all ages ranging from 16 years to older than 80
years.
The role of auto-SCT and allo-SCT in first remission was also been
explored in a number of trials during this period. A meta-analysis of
seven trials that included 1274 patients revealed that there was no
beneficial effect of auto-SCT.41 Allogeneic transplant, based on a
donor vs no donor comparison, conferred a survival advantage,
particularly for high-risk patients. An evidence-based review panel
subsequently recommended allogeneic SCT for ALL in first remission for adults with high risk, but not standard risk disease.42
However, a recently published trial carried out by the Medical
Research Council in Great Britain and the Eastern Cooperative
Oncology Group (MRC UKALL XII/ECOG 2993 tested the benefit
of allogeneic transplant in first remission for adults under the age of
50 years and reported a different outcome than previously published
trials.43 In a donor-versus-no donor comparison for the Philadelphia
chromosome-negative patients, an overall 5-year survival advantage
was noted for patients with a donor of 55% in contrast to 45% for the
no-donor group. This survival advantage was noted particularly for
the standard risk patients (all under age 35 years with no adverse
biologic features) where survival was 62% for those with a donor. In
contrast, the high-risk patients (defined as 35 years old and/or
with high risk biologic features), there was no survival advantage
for the donor group where treatment related mortality was unacceptable at nearly 36% and overall survival for the donor group was 41%
vs 35% for the no donor group. Importantly, this study also
demonstrated that auto-SCT in CR1 is not recommended as
frontline therapy. Patients receiving auto-SCT in CR1 had an
inferior outcome compared to those who received standard consolidation and long-term maintenance chemotherapy.

The AYA Patient: At the Therapeutic Intersection

Treatment of Adults with ALL During the Past Two

Decades
Clinical trials for adults with ALL have been modeled after the trials
pioneered by childhood ALL. However, in contrast to the pediatric

Hematology 2010

The trials in both pediatric and adult ALL described above included,
but did not specifically focus on the AYA patient. Evaluation of the
outcomes of the AYA patient, here defined as patients between the
ages of 1521 years old, presents specific challenges. Because of

23

Table 2. Retrospective comparison of trials involving AYA ALL patients

Trial Comparison

AYA Patients/
Median age, y

CR Rate

Survival Rate

United States44
CALGB (Adult)
CCG (Pediatric)

124 / 19
197 / 16

90%
90%

(7 year OS)
46%
67%

France56
LALA-94 (Adult)
FRALLE-93 (Pediatric)

100 / 18
77 / 16

83%
94%

( 5 year EFS)
41%
67%

The Netherlands57
HOVON (Adult)
DCOG (Pediatric)

73 / 20
47 / 12

91%
98%

(5 year EFS)
38%
71%

Italy58
GIMEMA (Adult)
AIEOP (Pediatric)

95 / 16
150 / 15

89%
94%

(2 year OS)
71%
80%

67 / 15-17
61 / NA

94%
98%

(5 year OS)
56%
71%

Sweden60
Adult ALL Grp (Adult)
NOPHO-92 (Pediatric)

99 / 18
36 / 16

90%
99%

(5 year OS)
39%
74%

Finland45
Finnish Leukemia (Adult)
NOPHO (Pediatric)

97 / 19
128 / 13

97%
96%

( 5 year OS)
60%
67%

United Kingdom59
UKALLXII/E2993 (Adult)
ALL97 (Pediatric)

Y years; NA not available

community referral patterns, these patients may be treated by either

pediatric or adult oncologists. As such, the treating physician may
view the 15 -21 year old either as an older child or as a younger
adult. The oncologist will choose a regimen most appropriate for the
population usually seen by that particular physician. A number of
comparisons of the clinical outcome of adolescents enrolled on
adult and pediatric clinical trials (Table 2) have resulted in
interesting observations about what that appropriate treatment
regimen should be and have guided the design of a number of
prospective clinical trials designed specifically for AYAs with ALL.

Retrospective Comparison of Pediatric and Adult

Cooperative Group Trials in AYAs
The retrospective comparisons summarized in Table 2 were performed by large cooperative groups throughout the world and
examined the outcome of the AYA patient treated on pediatric or
adult cooperative group trials in ALL that were conducted contemporaneously. The majority of these retrospective comparison studies
demonstrated a significant survival advantage for the AYA patient
treated by the pediatric vs the adult cooperative group. The first of
these trials to have been reported highlights many of the interesting
questions posed by these comparisons and will be reviewed briefly
below.44 The Cancer and Leukemia Group B (CALGB) and the
Childrens Cancer Group (CCG) examined the outcome of 321
AYA patients between 16 20 years treated on consecutive trials
from 1988 2001. The two patient groups were well matched for
biological features including immunophenotype and cytogenetics;
although the age range was the same in both groups examined, the
median age of the patients in the CALGB studies was 19 years
compared to 16 years for the CCG patients. CR rates were identical,
90% for both CALGB and CCG AYAs. However, CCG AYAs had
a 63% EFS and a 67% overall survival (OS) at 7 years, in contrast to
the CALGB AYAs, in which 7-year EFS was only 34% (p 0.001;
relative hazard ratio [RHR] 2.2]) and the OS was 46% (p
0.001; RHR 1.9). Interestingly, the CALGB AYAs 16 to 17 years
of age achieved similar outcomes to all CCG AYAs, with 7-year
EFS of 55%. In contrast, EFS for 18- to 20-year-old CALGB
patients was only 29% (p 0.01). A difference in pattern of relapse
was also noted. The incidence of CNS relapses was significantly
higher in CALGB AYAs (11%) compared with the CCG AYAs
(1.4%; p 0.001). While the studies performed by the two groups

24

during this period had similarities in terms of overall treatment plan

and schedule, comparison of the planned cumulative doses of drugs
administered identified some potentially important differences.
CCG patients received considerably more treatment with nonmyelosuppressive drugs, including glucocorticoids (both dexamethasone and prednisone), vincristine, and L-asparaginase. CNS prophylaxis was administered earlier, with greater frequency, and for a
more prolonged period during CCG treatment. Long-term maintenance therapy was also continued for a longer period in CCG
patients.
Since the initial report of these findings in 2000, multiple national
European cooperative groups have reported similar results with
improvement in the outcome of AYAs treated on pediatric compared with adult protocols; these are summarized in Table 2. Given
the retrospective nature of these comparison trials and the significant differences in treatment approach applied by the pediatric and
adult treatment groups, it is harder to critically interpret several of
these trials. Significant variation in the ages of the patients studied,
small numbers of patients in several of these trials, and variations in
the regimens utilized, with SCT often applied as a post-remission
strategy in the adult European cooperative group trials, make firm
conclusions difficult and will require prospective comparisons for
validation of these conclusions. Nevertheless, a basic theme emerges
from all of these trials: survival was generally significantly better for
the young adults treated on pediatric cooperative group trials.
Similar to the CALGB and CCG comparison, the major treatment
differences included significantly greater cumulative dosing of the
glucocorticoids, vincristine, and l-asparaginase, and more intensive
CNS prophylaxis.
The results of a retrospective comparison of patients treated in
Finland differ from those from the studies described above. In this
study,45 a group of 128 patients from 10 to 16 years of age (median
age, 12.9 years) treated on pediatric protocols were compared with
97 patients 17 to 25 years of age (median age, 18.9 years). Despite
the significant difference in median age and some differences in
drug schedule and dosing between the two groups, there was no
significant difference in the 5-year EFS (67% for the pediatric group
and 60% for the adult group) or OS (77% in the pediatric group and
70% for the adult group). Interestingly, in this comparison, there
were no significant differences in the doses of corticosteroids,
vincristine, or asparaginase between the pediatric and adult trials,
although the pediatric trials contained higher cumulative doses of
methotrexate and, in the adult protocols, more anthracycline.
Similarly, retrospective data from the MD Anderson Cancer Center
using the HYPER-CVAD regimen have also reported favorable
results in their AYA patients. With a median age of 19 years, the CR
rate was 97% for 102 AYAs with newly diagnosed ALL and OS was
65%.46 In both the Finnish study and the MD Anderson study, all
patients were treated in large referral centers for treatment of
leukemia. One possible interpretation of these retrospective analyses is that treatment outcomes may be better regardless of nuances
in chemotherapy dose and schedule when patients are treated at
larger centers with greater experience and expertise in the administration of these complex regimens.

Hints to Differences in Outcome for AYAs:

Treatment/Pharmacodynamics/Compliance?
As alluded to above, several potential explanations exist for the
striking differences seen in the majority, but not all, of the
retrospective comparisons. In addition to clear differences in

American Society of Hematology

protocol design and dose intensity, highlighted above, other explanations include interesting new pharmacodynamic insights, clinical
and demographic differences in AYAs receiving treatment at
pediatric compared with adult centers, and potential variations in the
degree of adherence to protocol drug administration by adult
compared with pediatric oncologists.
As highlighted in the CALGB versus CCG comparison, while the
adult trials often focused on dose intensification of the myelosuppressive agents, including cyclophosphamide and anthracyclines, the
pediatric regimens employed significantly higher cumulative doses
of the drugs that have made up the backbone of the BFM model:
glucocorticoids, vincristine, and l-asparaginase. CNS prophylaxis in
the pediatric regimens always begins during induction therapy and
continues during maintenance therapy, achieving a higher cumulative dose than the majority of the adult trials. Overall, the pediatric
regimens also continue long-term maintenance for a longer period,
particularly for male patients.

central referral hospitals in Finland, possibly ensuring a higher

degree of familiarity and compliance to treatment. Finally, due to
differences in referral patterns to pediatric or adult centers, most of
the comparison trials show a significant skewing of age, with a
significantly lower median age in the pediatric AYA patient
compared with the adult AYA patient. From the CALGB versus
CCG comparison, in which the youngest CALGB AYAs (16 17
years of age) fared as well as the CCG AYAs compared with the 18to 20-year-old CALGB AYAs, it is intriguing to postulate that the
significantly worse outcomes in only the older CALGB AYAs could
result from the that that the 18- to 20-year-olds are living independently and removed from family members who might ensure greater
compliance with protocol medications and outpatient follow-up.
Others have suggested that the older AYAs may face significantly
more challenges in access to health care due to insurance issues and
prescription drug coverage for the crucial outpatient medications
that are the mainstays of therapy.50

Prospective Trials: Moving Forward

Recent studies are beginning to shed new light on potential
biological differences in AYA patients. Metabolism of some of the
key drugs may begin to change during late adolescence, resulting in
potential increases in drug-related toxicities and/or decreased exposure to critical drugs such a l-asparaginase and dexamethasone.47
There are few studies quantifying the tolerability of l-asparaginase
in young adults. In a preliminary review of the serious toxicities
reported in the first 112 patients enrolled in the new NorthAmerican intergroup study C-10403, which includes patients 16 to
39 years of age, there were serious adverse events attributed to
PEG-asparaginase, including hypersensitivity (11%), coagulopathy
(20%), and pancreatitis (3%) (W. Stock and K Donohue, personal
communication). Data from children treated on the Dana Farber
91 01 trial showed that older children (9 18 years) had a significantly higher incidence of thrombosis compared with younger
children (15% vs. 2%; p 0.01).7 Thus, the ability to actually
deliver the dose intensity of the agents that contribute to successful
outcomes may be more challenging as patients enter their young
adult years.
The degree of myelosuppression achieved during long-term maintenance has also been demonstrated to be of particular importance to
EFS for adolescents with B-lineage intermediate risk ALL.48 While
nearly all collaborative group pediatric ALL protocols recommend
adjustment of the doses of methotrexate and 6 mercaptopurine
during maintenance therapy to be adjusted to a target WBC level,
few adult cooperative group trials have recommended this dose
adjustment.
One of the more intriguing issues posed by these retrospective
comparisons is the potential contribution of disparity in the practice
patterns of the pediatric and adult hematologists/oncologists and
patient compliance to the outcome of AYA patients. This topic has
been discussed heatedly at recent hematology meetings and in the
literature,49 yet the question remains largely unanswered. Virtually
all children with ALL are referred to pediatric centers and treated in
clinical trials by pediatric oncologists who are focused on the
treatment of ALL and have highly skilled support staff who
carefully monitor protocol compliance. In contrast, ALL is a rare
disease for adult hematologists/oncologists, for whom familiarity
and compliance with the complex ALL treatment regimens are
likely to pose a significant challenge. Of note, in the Finnish trial
where no significant differences in outcome were noted between
pediatric and adult trials, all patients were treated at one of five

Hematology 2010

To begin to address the many unanswered questions that have been

raised by the retrospective comparison trials and to determine
whether AYA patients treated by adult hematologists/oncologists
can achieve similarly improved outcomes to the pediatricians for
this age group, prospective cooperative group trials in North
America and in Europe have begun, and early results from several of
these trials have recently been reported. The Program Espanol de
Tratamiento en Hematologa (PETHEMA) Protocol ALL-96 addressed the toxicity and results of a pediatric-based protocol in 35
adolescent (age 1518 years) and 46 young adults (age 19 30 years)
with standard-risk ALL.51 In this trial, patients received a standard
five-drug, five-week induction course, followed by two cycles of
early consolidation, maintenance with monthly reinforcement cycles
for one year following remission, and standard maintenance chemotherapy for up to two years following CR. The adolescents and
young adults were well-matched for pre-treatment characteristics.
The CR rate was 98% and with median follow-up of 4.2 years, the
6-year EFS and OS were 61% and 69%, respectively. The only
significant predictor of poor EFS for the entire group was a slow
response to initial induction therapy (10% blasts remaining in
bone marrow aspirate done on day 14 of induction therapy). Thus,
the investigators concluded that a pediatric regimen was tolerable
and efficacious in AYAs with ALL up to the age of 30 years.
Two pilot studies from French adult cooperative groups have also
demonstrated the feasibility of employing modified pediatricinspired regimens in adults with ALL, although the age range of
these studies extended well into the middle years of adult life. In the
FRALLE study, 28 Philadelphia chromosome-negative adult ALL
patients 16 to 57 years of age were treated on the FRALLE 2000
protocol, which consisted of a prednisone prophase and a four-drug
induction including L-asparaginase, consolidation, delayed intensification, and maintenance chemotherapy. The 4-year DFS was 90%
versus 47% seen in matched historical controls.52 In the GRAALL2003 study, 225 patients with Philadelphia chromosome-negative
ALL 15 to 60 years old (median, 31 years) were treated between
2003 and 2005 with five drug-induction, dose-intense consolidation,
delayed intensification, and two-year maintenance therapy.53 Notably, allo-SCT for patients 55 years was recommended in this trial
and makes interpretation of this trial more problematic. The CR rate
was 93.5%. Among the 139 CR patients, 71 actually underwent
transplantation in CR1 and were censored at the time of transplant.
At 42 months, EFS was 55% versus 41% when comparing patients
from an earlier French trial, the LALA-94, and OS was 61%,

25

significantly better than 41% OS in the LALA-94 (p0.001). The

benefit of the GRAALL approach was not statistically significant in
patients older than 45 years due to a significant increase in
treatment-related mortality of 23% in comparison to 5% TRM for
patients 45 years old. The investigators concluded that the use of
a pediatric inspired regimen in adults up to 45 years old was
tolerable and markedly improved outcome for younger adults
with ALL. As mentioned above, several factors must be considered
when interpreting these results this regimen included older adults
up to the age of 60 years and utilized only a modified pediatric
regimen that did not employ the dose intensity of corticosteroids,
asparaginase and vincristine that are routinely used in current
pediatric regimens. Another difference from the pediatric regimens
is that all patients on these trials still received prophylactic cranial
irradiation. Also, the majority of CR1 patients actually underwent
allo-SCT, which is not the approach employed by pediatric groups.
Thus, any interpretation of the contribution of the chemotherapy
intensification component of these trials to DFS is very difficult.

children with ALL have been well described and include neurocognitive and neurologic dysfunction, endocrine and metabolic abnormalities (including obesity), bone toxicity (osteonecrosis), cardiac
toxicity and secondary malignancies.55 To guide the frequency and
focus of medical visits, and the ordering of appropriate surveillance
tests, comprehensive guidelines have been published in many
countries, including North America, where guidelines created by the
Childrens Oncology Group, entitled Long-Term Follow-up Guidelines for Survivors of Childhood, Adolescent and Young Adult
Cancers are available at www.survivorshipguidelines.org and
should be adopted by the adult oncology community. The next
generation of studies, linked to important biological, psychosocial
and pharmacological correlates, will result in further insights into
optimizing the comprehensive approach to treatment and follow-up
for this significant group of patients with ALL and may be the next
step to achieving the high cure rate and successful transition back to
normal life now routinely achieved in children with ALL.

How I Treat
In contrast, the Dana-Farber Cancer Institute consortium has also
extended their successful pediatric regimen37 to older patients
18 50 years old. The trial design here was a true pediatric approach
with intensification of E coli l-asparaginase, glucocorticoids and
vincristine for patients up to 50 years old allo-SCT was not
routinely recommended. Early results from this completed phase II
trial were presented at the 2007 ASH meeting and long-term
follow-up is now available (Dr. Dan DeAngelo, maunuscript in
preparation 2010, and personal communication).54 Ninety-four
patients were evaluable, with a median age of 28 years (range
18 50). Seventy-nine patients (84%) achieved a CR after one
month of intensive induction therapy. With a median follow-up time
of 45 months, their group reports an estimated DFS rate for all
patients of 66% and OS rate of 65%. For the 74 patients with
Philadelphia chromosome-negative ALL, DFS was 70% and OS
was 68%.
The largest prospective trial to evaluate the feasibility of utilizing a
pediatric regimen in AYA patients treated by adult medical
hematologists/oncologists is ongoing in North America (C-10403).
The US adult and pediatric cooperative groups have enrolled over
125 of a planned 300 patients on a prospective phase II trial for
AYAs from 16 39 years old (C-10403) that utilizes one treatment
arm of the current COG study (AALL0232) for adolescents (and
high-risk children with ALL).35,38 This study will examine prospectively molecular genetics, MRD, psychosocial disparities and
treatment adherence on the part of physicians and patients referred
to and treated on an intensive pediatric regimen by adult oncologists. Importantly, the ability to administer in a safe and timely
manner the same treatment that is being used by the US pediatric
cooperative group will be examined. Treatment toxicities in addition to schedule and dose compliance are being collected prospectively. Each patient participates in a baseline and follow-up
questionnaire to explore psycho-social and socio-economic conditions to begin to gather critical information about the other critical
issues that likely influence treatment outcomes.
These prospective trials are demonstrating that it is possible to
achieve significant improvements in outcome for AYAs with ALL
although many challenges remain to ensure access to care, to
minimize treatment toxicity and to develop and follow specific
survivorship monitoring plans. While fewer specific data are
available on long term complications of survivors of young adults
with ALL, the long term complications of successful treatment of

26

A 20 year old college student is admitted to the adult oncology ward

for treatment of newly diagnosed ALL. Initial CBC showed a WBC
of 2.3 K/l, hemoglobin of 9.4 gm/dL, and platelet count of 19K/l.
A bone marrow examination demonstrates precursor B-lymphoblastic leukemia extensively involving a hypercellular marrow. Flow
cytometry had demonstrated that the blasts were CD19, CD20,
CD10, CD79a, CD51. CD34 and Tdt. Cytogenetics
revealed a normal male karyotype. LDH is 850 u/L.
This young adult with ALL has presented with standard risk
features. Based on the preponderance of data presented in the
review, the best therapeutic approach for this patient would be an
intensive pediatric regimen with intensive glucocorticoids, vincristine, and PEG-asparaginase with early and frequent CNS prophylaxis. Prolonged maintenance therapy with adequate myelosuppression is also a key feature of a pediatric regimen. While the
ECOG/MRC data have suggested that a young adult patient has
improved survival with allo-SCT compared to their standard
chemotherapy regimen (which was not a pediatric-like regimen),
there are no data that have unequivocally shown the benefit of an
allogeneic transplant for this patient. Thus, I would ask this patient
to participate in the current intergroup phase II trial, C-10403
(www.clinicaltrials.gov) that is a phase II trial for adolescents and
young adults with ALL that is being conducted in collaboration with
the Childrens Oncology Group Study AAALL0232 and which
utilizes a regimen that has resulted in an EFS of 72% in 262 patients
16 21 years old.
The patient consents for the trial. I would give induction therapy as
an in-patient since sudden sepsis and early treatment toxicities from
the multi-drug induction therapy are common. This patient should
be treated with allopurinol for 10 days to prevent hyperuricemia and
complications of tumor lysis. Rasburicase administered prior to
initiation of chemotherapy should also be considered. Routine
anti-viral and PCP prophylaxis are administered throughout the
treatment. It is important to remember that no sulfa drug (or
non-steroidals, etc) should be given on days that he receives
methotrexate since there many commonly used drugs that can
interfere with renal excretion of methotrexate. It is mandated in the
protocol that all patients are pre-medicated with hydrocortisone and
tylenol prior to each dose of PEG-asparaginase to try to lessen the
risk of hypersensitivity reactions. No routine anti-thrombotic prophylaxis is recommended; there are some data from pediatric groups
suggesting that the use of anti-thrombin III treatment may be useful

American Society of Hematology

but this has not been routinely employed by the adult oncology
community and there are no prospective studies. Cryoprecipitate
should be administered for fibrinogen levels 50 to avoid
hemorrhagic complications. The patient has an uncomplicated
induction course and has a rapid early response to treatment
documented by the day 15 of induction therapy bone marrow
examination. Other than some mild agitation and hyperglycemia
which are medically managed, his course is uncomplicated and he
achieves a CR on d 28 of induction therapy which is documented by
bone marrow examination and flow cytometry for MRD.
Following recovery from the induction therapy, the remainder of
therapy is administered as an outpatient. We routinely create a
detailed calendar for the patient. Together, nursing staff and
physicians routinely review supportive care meds, encourage patients to keep a treatment diary, and always try to have the same
caregivers in our IV therapy suite to establish and maintain
continuity and close rapport. As all patients and caregivers know,
the successful treatment of ALL depends heavily on commitment to
medication compliance and protocol adherence and these are often
tall orders to fill, particularly for young adults who are seeking
independence and freedom from constant supervision. Thus, it truly
takes a village to achieve successful completion of these arduous,
but highly successful protocols. Frequent laboratory and physical
examinations are important to assess for the toxicities of the
treatment particularly the hyperglycemia, liver dysfunction, and
peripheral neuropathy that can be cumulative during these prolonged therapies. Our social worker and staff psychologist are key
caregivers for these young adults and meet with the patient routinely
during his follow-up visits. Routine yearly bone density tests are
monitored. As this patient continues during long-term remission, we
would advise following survivorship monitoring guidelines as
recommended by the pediatricians and referenced above in the text.

Disclosures
Conflict-of-interest disclosure: The author declares no competing
financial interest.
Off-label drug use: Alemtuzumab and rituxan may be discussed in
clinical trials of ALL.

Correspondence
Wendy Stock, MD, University of Chicago Medical Center, 5841 S.
Maryland Ave., MC 2115, Chicago, IL 60637; Phone: (773)
834-8982; Fax: (773) 702-0963; e-mail: wstock@medicine.bsd.
uchicago.edu

References
1. Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet. 2008;371:1030 1043.
2. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA
Cancer J Clin. 2009;59:225249.
3. Pulte D, Gondos A, Brenner H. Trends in survival after
diagnosis with hematologic malignancy in adolescence or
young adulthood in the United States, 19812005. Cancer.
2009;115:4973 4979.
4. Pulte D, Gondos A, Brenner H. Improvement in survival in
younger patients with acute lymphoblastic leukemia from the
1980s to the early 21st century. Blood. 2009;113:1408 1411.
5. Smith MA, Seibel NL, Altekruse SF, et al. Outcomes for
children and adolescents with cancer: challenges for the twentyfirst century. J Clin Oncol. 2010;28:26252634.

Hematology 2010

6. Pui CH, Campana D, Pei D, et al. Treating childhood acute

lymphoblastic leukemia without cranial irradiation. N Engl
J Med. 2009;360:2730 2741.
7. Silverman LB, Gelber RD, Dalton VK, et al. Improved outcome
for children with acute lymphoblastic leukemia: results of
Dana-Farber Consortium Protocol 91 01. Blood. 2001;97:1211
1218.
8. Moorman AV, Ensor HM, Richards SM, et al. Prognostic effect
of chromosomal abnormalities in childhood B-cell precursor
acute lymphoblastic leukaemia: results from the UK Medical
Research Council ALL97/99 randomised trial. Lancet Oncol.
2010;11:429 438.
9. Moorman AV, Chilton L, Wilkinson J, et al. A populationbased cytogenetic study of adults with acute lymphoblastic
leukemia. Blood. 2010;115:206 214.
10. Schultz KR, Pullen DJ, Sather HN, et al. Risk- and responsebased classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from
the Pediatric Oncology Group (POG) and Childrens Cancer
Group (CCG). Blood. 109:926 35, 2007
11. Arico M, Valsecchi MG, Camitta B, et al. Outcome of
treatment in children with Philadelphia chromosome-positive
acute lymphoblastic leukemia. N Engl J Med. 2000;342:998
1006.
12. Gokbuget N, Hoelzer D. Treatment of adult acute lymphoblastic leukemia. Semin Hematol. 2009;46:64 75.
13. Vey N, Thomas X, Picard C, et al. Allogeneic stem cell
transplantation improves the outcome of adults with t(1;19)/E2APBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94
study. Leukemia. 2006;20:21552161.
14. Ravandi F, Kebriaei P. Philadelphia chromosome-positive
acute lymphoblastic leukemia. Hematol Oncol Clin North Am.
2009;23:10431063.
15. Schultz KR, Bowman WP, Aledo A, et al. Improved early
event-free survival with imatinib in Philadelphia chromosomepositive acute lymphoblastic leukemia: a childrens oncology
group study. J Clin Oncol. 2009;27:51755181.
16. Moricke A, Reiter A, Zimmermann M, et al. Risk-adjusted
therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169
unselected pediatric and adolescent patients enrolled in the trial
ALL-BFM 95. Blood. 2008;111:4477 4489.
17. Pui CH, Sandlund JT, Pei D, et al. Results of therapy for acute
lymphoblastic leukemia in black and white children. JAMA.
2003;290:20012007.
18. Silverman LB, Sallan SE. Newly diagnosed childhood acute
lymphoblastic leukemia: update on prognostic factors and
treatment. Curr Opin Hematol. 2003;10:290 296.
19. Thomas DA, OBrien S, Jorgensen JL, et al. Prognostic
significance of CD20 expression in adults with de novo
precursor B-lineage acute lymphoblastic leukemia. Blood.
2009;113:6330 6337.
20. Jeha S, Behm F, Pei D, et al. Prognostic significance of CD20
expression in childhood B-cell precursor acute lymphoblastic
leukemia. Blood. 2006;108:33023304.
21. Baak U, Gokbuget N, Orawa H, et al. Thymic adult T-cell acute
lymphoblastic leukemia stratified in standard- and high-risk
group by aberrant HOX11L2 expression: experience of the
German multicenter ALL study group. Leukemia. 2008;22:
1154 1160.
22. Ballerini P, Landman-Parker J, Cayuela JM, et al. Impact of

27

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

28

genotype on survival of children with T-cell acute lymphoblastic leukemia treated according to the French protocol FRALLE93: the effect of TLX3/HOX11L2 gene expression on outcome.
Haematologica. 2008;93:1658 1665.
Asnafi V, Buzyn A, Le Noir S, et al. NOTCH1/FBXW7
mutation identifies a large subgroup with favorable outcome in
adult T-cell acute lymphoblastic leukemia (T-ALL): a Group
for Research on Adult Acute Lymphoblastic Leukemia
(GRAALL) study. Blood. 2009;113:3918 3924.
Breit S, Stanulla M, Flohr T, et al. Activating NOTCH1
mutations predict favorable early treatment response and longterm outcome in childhood precursor T-cell lymphoblastic
leukemia. Blood. 2006;108:11511157.
Mansour MR, Sulis ML, Duke V, et al. Prognostic implications
of NOTCH1 and FBXW7 mutations in adults with T-cell acute
lymphoblastic leukemia treated on the MRC UKALLXII/
ECOG E2993 protocol. J Clin Oncol. 2009;27:4352 4356.
Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A
subtype of childhood acute lymphoblastic leukaemia with poor
treatment outcome: a genome-wide classification study. Lancet
Oncol. 2009;10:125134.
Harvey RC, Mullighan CG, Chen IM, et al. Rearrangement of
CRLF2 is associated with mutation of JAK kinases, alteration
of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in
pediatric B-progenitor acute lymphoblastic leukemia. Blood.
2010 Jul 1;115(26):53125321.
Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and
prognosis in acute lymphoblastic leukemia. N Engl J Med.
2009;360:470 480.
Bassan R, Spinelli O, Oldani E, et al. Improved risk classification for risk-specific therapy based on the molecular study of
minimal residual disease (MRD) in adult acute lymphoblastic
leukemia (ALL). Blood. 2009;113:4153 4162.
Campana D. Progress of minimal residual disease studies in
childhood acute leukemia. Curr Hematol Malig Rep. 2010
Jul;5(3):169 176.
Conter V, Bartram CR, Valsecchi MG, et al. Molecular
response to treatment redefines all prognostic factors in children
and adolescents with B-cell precursor acute lymphoblastic
leukemia: results in 3184 patients of the AIEOP-BFM ALL
2000 study. Blood. 2010;115:3206 3214.
Schrappe M, Reiter A, Zimmermann M, et al. Long-term results
of four consecutive trials in childhood ALL performed by the
ALL-BFM study group from 1981 to 1995. Berlin-FrankfurtMunster. Leukemia. 2000;14:22052222.
Bostrom BC, Sensel MR, Sather HN, et al. Dexamethasone
versus prednisone and daily oral versus weekly intravenous
mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Childrens Cancer Group. Blood.
2003;101:3809 3817.
Nachman JB, Sather HN, Sensel MG, et al. Augmented
post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl
J Med. 1998;338:16631671.
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 Childrens Oncology Group. Blood. 2008;111:
2548 2555.
Silverman LB, Supko JG, Stevenson KE, et al. Intravenous
PEG-asparaginase during remission induction in children and
adolescents with newly diagnosed acute lymphoblastic leukemia. Blood. 2010;115:13511353.

37. Barry E, DeAngelo DJ, Neuberg D, et al. Favorable outcome

for adolescents with acute lymphoblastic leukemia treated on
Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia
Consortium Protocols. J Clin Oncol. 2007;25:813 819.
38. Nachman JB, La MK, Hunger SP, et al. Young adults with
acute lymphoblastic leukemia have an excellent outcome with
chemotherapy alone and benefit from intensive postinduction
treatment: a report from the childrens oncology group. J Clin
Oncol. 2009;27:5189 5194.
39. Kantarjian HM, OBrien S, Smith TL, et al. Results of
treatment with hyper-CVAD, a dose-intensive regimen, in adult
acute lymphocytic leukemia. J Clin Oncol. 2000;18:547561.
40. Larson RA, Dodge RK, Burns CP, et al. A five-drug remission
induction regimen with intensive consolidation for adults with
acute lymphoblastic leukemia: cancer and leukemia group B
study 8811. Blood. 1995;85:20252037.
41. Yanada M, Matsuo K, Suzuki T, et al. Allogeneic hematopoietic stem cell transplantation as part of postremission therapy
improves survival for adult patients with high-risk acute
lymphoblastic leukemia: a metaanalysis. Cancer. 2006;106:
26572663.
42. Hahn T, Wall D, Camitta B, et al. The role of cytotoxic therapy
with hematopoietic stem cell transplantation in the therapy of
acute lymphoblastic leukemia in adults: an evidence-based
review. Biol Blood Marrow Transplant. 2006;12:130.
43. Goldstone AH, Richards SM, Lazarus HM, et al. In adults with
standard-risk acute lymphoblastic leukemia, the greatest benefit
is achieved from a matched sibling allogeneic transplantation in
first complete remission, and an autologous transplantation is
less effective than conventional consolidation/maintenance
chemotherapy in all patients: final results of the International
ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008;111:
18271833.
44. Stock W, La M, Sanford B, et al. What determines the outcomes
for adolescents and young adults with acute lymphoblastic
leukemia treated on cooperative group protocols? A comparison of Childrens Cancer Group and Cancer and Leukemia
Group B studies. Blood. 2008;112:1646 1654.
45. Usvasalo A, Raty R, Knuutila S, et al. Acute lymphoblastic
leukemia in adolescents and young adults in Finland. Haematologica. 2008;93:11611168.
46. Thomas DA, OBrien S, Rytting M, et al. Acute lymphoblastic
leukemia (ALL) or lymphoblastic lymphoma (LL) after frontline therapy with hyper-CVAD regimens. [Abstract]. Blood.
2008;112:674.
47. Yang L, Panetta JC, Cai X, et al. Asparaginase may influence
dexamethasone pharmacokinetics in acute lymphoblastic leukemia. J Clin Oncol. 2008;26:19321939.
48. Schmiegelow K, Heyman M, Gustafsson G, et al. The degree of
myelosuppression during maintenance therapy of adolescents
with B-lineage intermediate risk acute lymphoblastic leukemia
predicts risk of relapse. Leukemia. 2010 Apr;24(4):715720.
49. Schiffer CA. Differences in outcome in adolescents with acute
lymphoblastic leukemia: a consequence of better regimens?
Better doctors? Both? J Clin Oncol. 2003;21:760 761.
50. Kantarjian HM, OBrien S. Insurance policies in the United
States may explain part of the outcome differences of adolescents and young adults with acute lymphoblastic leukemia
treated on adult versus pediatric regimens. Blood. 2009;113:
1861; author reply 1862.
51. Ribera JM, Oriol A, Sanz MA, et al. Comparison of the results
of the treatment of adolescents and young adults with standardrisk acute lymphoblastic leukemia with the Programa Espanol

American Society of Hematology

52.

53.

54.

55.

56.

de Tratamiento en Hematologia pediatric-based protocol ALL96. J Clin Oncol. 2008;26:18431849.

Haiat S, Marjanovic Z, Lapusan S, et al. Outcome of 40 adults
aged from 18 to 55 years with acute lymphoblastic leukemia
treated with double-delayed intensification pediatric protocol.
Leuk Res. 2010 Apr 29. [Epub ahead of print]
Huguet F, Leguay T, Raffoux E, et al. Pediatric-inspired
therapy in adults with Philadelphia chromosome-negative acute
lymphoblastic leukemia: the GRAALL-2003 study. J Clin
Oncol. 2009;27:911918.
DeAngelo DJ, Dahlberg S, Silverman LB, et al. A multicenter
phase ii study using a dose intensified pediatric regimen in
adults with untreated acute lymphoblastic leukemia [Abstract].
Blood. 2007;110:587.
Nathan PC, Wasilewski-Masker K, Janzen LA. Long-term
outcomes in survivors of childhood acute lymphoblastic
leukemia. Hematol Oncol Clin North Am. 2009;23:1065
1082.
Boissel N, Auclerc MF, Lheritier V, et al. Should adolescents
with acute lymphoblastic leukemia be treated as old children or

Hematology 2010

57.

58.

59.

60.

young adults? Comparison of the French FRALLE-93 and

LALA-94 trials. J Clin Oncol. 2003;21:774 780.
de Bont JM, van der Holt B, Dekker AW, et al. Adolescents
with acute lymphatic leukaemia achieve significantly better
results when treated following Dutch paediatric oncology
protocols than with adult protocols [Article in Dutch]. Ned
Tijdschr Geneeskd. 2005;149:400 406.
Testi AM, Valsecchi MG, Conter V, et al. Difference in
outcome of adolescents with acute lymphoblastic leukemia
renrolled in pediatric (AE10P) and adult (GIMEMA) protocols.
Blood. 2004;104:539.
Ramanujachar R, Richards S, Hann I, et al. Adolescents with
acute lymphoblastic leukaemia: outcome on UK national
paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer. 2007;48:254 261.
Hallbook H, Gustafsson G, Smedmyr B, et al. Treatment
outcome in young adults and children 10 years of age with
acute lymphoblastic leukemia in Sweden: a comparison between a pediatric protocol and an adult protocol. Cancer.
2006;107:15511561.

29