Acute Lymphoblastic Leukemia in Adults and Children

Acute Lymphoblastic Leukemia
in Adults and Children
Session Chair: Charles Linker, MD
Speakers: Stephen E. Sallan, MD; Nicola Gökbuget, MD; and Ching-Hon Pui, MD
Myths and Lessons from the Adult/Pediatric
Interface in Acute Lymphoblastic Leukemia
Stephen E. Sallan
The development of effective therapy for children with
acute lymphoblastic leukemia (ALL) is one of the great
successes of clinical oncology, with long-term survival
achieved in over 80% of patients. However, cure rates
for adults with ALL remain relatively low, with only
40% of patients cured. With an age-unrestricted,
biology-based approach, we anticipate a better
understanding about why these outcome differences
exist, and think that by extending successful pediatric
clinical programs to include adult patients with ALL, we
can directly compare uniformly treated adults and
children in terms of response to therapy, toxicity and
underlying biology.
“The child is the father of the man”…
William Wordsworth
tive. Although well-recognized age-related dissimilarities
in the biology of ALL and event-free survival exist (Tables
2 and 3), the more favorable outcomes for older adolescents treated on pediatric regimens in Table 1 cannot be
explained by differences in patient characteristics. Nor
would one expect other potential “adult vs. pediatric”
Background
Within childhood acute lymphoblastic leukemia (ALL)
populations, older children have had inferior outcomes1
and within adult ALL populations, younger adults have
had superior outcomes.2,3 In recent reports, “overlapping”
populations of older children and young adults have been
compared for the likelihood of inducing a complete remission and long-term event-free survival (Table 1).4-8
None of the clinical trials listed in Table 1 was designed to be compared to its age-overlapping pediatric or
adult counterpart; thus, the comparisons were all retrospec-
Table 1. Older child/young adult acute lymphoblastic
leukemia (ALL) outcomes.
Country Nat’l Trial
Age in
Years
#
Pts
CR 5-Yr EFS
(%)
(%)
Ref.
US:
CCG (P)
CALGB (A)
16-21
196
103
96
93
64*
38*
4
France:
FRALLE 93 (P) 15-20
LALA94 (A)
77
100
94
83
67
41
5
Division of Hematology/Oncology, Children’s Hospital and
Department of Pediatrics, Harvard Medical School, Boston,
Massachusetts
Holland: DCOG (P)
HVON (A)
15-18
47
44
98
91
69
34
6
UK:
ALL97 (P)
UKALLXII (A)
15-17
61
67
98
94
65
49
7
Supported in part by grant CA 68484 from the National Cancer
Institute, National Institutes of Health, Bethesda, Maryland
Italy:
AIEOP (P)
Gimema (A)
14-18
150
95
94
89
80**
71**
8
Correspondence: Stephen Sallan, MD, Dana Farber Cancer
Institute, 44 Binney St, Rm 1642, Boston MA 02115-6084;
Phone 617-632-3316; Fax 617-632-5511; Email
stephen_sallan@dfci.harvard.edu
Abbreviations: CR, complete remission; EFS, event-free
survival; P, pediatric protocol; A, adult protocol
* 6-yr EFS
** 2-year overall survival
128
American Society of Hematology
differences (for example, co-morbidities associated with smoking, or host pharmacokinetic differences based on age) to
play a substantial role in the findings summarized in Table 1.
There are clear differences between current adult and
pediatric therapeutic approaches. For example, bone marrow transplantation in first remission is more common for
adults (in part, because of the higher incidence of Philadelphia chromosome–positive ALL), and pediatric regimens
generally include greater dose density of many chemotherapeutic agents (such as asparaginase, vincristine, corticosteroids and methotrexate).
What are some plausible explanations for these differences between pediatric and adult outcomes? In a thoughtful, provocative and prescient editorial, Dr. Charles Schiffer
reflected on biological differences among the hosts and
diseases, and also raised issues pertaining to clinical practice, such as the frequency of and familiarity with ALL
protocols and care of such patients.9 In addition to recognizing that ALL is the most common malignancy in children and relatively rare in adult oncology populations, he
also noted that most children, but not most adults, with
ALL were treated in the context of clinical trials, by experienced support teams, and that many adults were not treated
at academic medical centers. The cultural differences between care of pediatric and adult ALL patients, described
as “disparities in treating attitudes” by Boissel and co-workers,5 was highlighted by Schiffer’s colorful and accurate
description of pediatricians’ tight adherence to complex
treatment protocols “…with a military precision on the basis
of near-religious conviction about the necessity of maintaining prescribed dose and schedule come hell, high water, birthdays, Bastille Day, or Christmas.” Although the
necessity of such vigor has not been formally tested, the
proof of the pudding is in the tasting.
Obstacles to Age-Unrestricted,
Biology-based Treatment
Why have adults with ALL not received the same chemotherapeutic regimens as children?
There are two principal hurdles: 1) systems of care,
and 2) regulatory impediments.
Table 2. Acute lymphoblastic leukemia (ALL): incidence &
biological differences.
Children
Adults
Peak incidence
5 years
50 years
% of Leukemias
80-85%
15%
Chromosomes
Ph+
MLL
TEL/AML1
Hyperdiploid
3%
1-2%
20%
25%
30%
7%
2%
5%
T-cell
10-15%
20-25%
Mature B
1-2%
3-5%
Table 3. Five-year event-free survival.
Children
Adults
Pre-B
> 80%
30-40%
T-cell
75-80%
45-55%
Ph+
20-25%
< 10%
MLL
40-50%
20%
TEL/AML1
90%
N/A
Frequency of and familiarity with ALL
Although there might be as many adults with ALL as there
are children with the disease11 (Figure 1), the relative frequency of the disease is markedly higher in young children. ALL represents about 15% of all malignancies in 115 year olds, 5% in 15-19 year olds, and < 10% of malignancy in > 20 year olds.
Adherence to protocol and
mitigating psychosocial factors
Although most of the drugs used for ALL today have existed for over four decades, little is known about their ideal
antileukemia dose or the role of individual patient differ-
“Systems of care” and related differences
Referral patterns
Commonly held views suggest that pediatricians refer 15to 20-year-old patients to pediatric academic medical centers where (a) > 90% of patients are < 15 years old, and b) >
90% of patients with ALL are enrolled on clinical trials.
Similarly, internists frequently refer 15- to 20-year-old
patients to adult hospitals, mostly not academic medical centers, where a) > 90% of the patients are > 40 years old and b)
most patients with ALL are not entered on clinical trials.10
Figure 1. Incidence of acute lymphoblastic leukemia (ALL)
by age, SEER 1992-1999.
Hematology 2006
129
ences in drug metabolism. In pediatric practice, “pushing
the dose” by using myelosuppression as the endpoint, assures delivery of the maximum dose for each child with
each course of chemotherapy. Although it is difficult to
assess whether such rigid adherence to protocols is necessary, Boissel and co-workers reported on one “therapeutic
practice” measure. They determined the median number of
days from the time of initial complete remission until the
time of the first postremission chemotherapy: 2 days in the
pediatric study and 7 days in the adult study; P = 0.002.5
Is this time-to-next-treatment measure a medical or psychological problem? Have the older patients fully recovered physiologically, or are there other mitigating features
(e.g., “I need some time with my family”) resulting in delays in therapy?
In the pediatric setting, in addition to the meticulous
attention to detail by the pediatricians, a primary driver of
subsequent therapy is the caretaker, usually the mother.
(“What are we waiting for? The leukemia is growing back.
Let’s get going!”)
Difficulties in comparisons
“Simple” apples-to-apples comparisons in a heterogenous
disease such as ALL can be difficult, and occult differences
in practices among internists and pediatricians might not
be appreciated.
For example, Table 1 demonstrates comparisons in the
percentage of complete remissions between older children
and adults. Not shown is the time to enter complete remission. All pediatric trials report complete remission at the
end of approximately 1 month of multiagent chemotherapy.
However, many adult trials report on the complete remission rates after 2 months of treatment (Table 4). Although
the time to attain a complete remission was not of prognostic importance in at least one adult trial,12 we found that in
childhood ALL, the time to enter a complete remission had
significant implications, and the difference between a complete remission in 1 month or 2 months was a matter of life
or death for the majority of slow responders.15
Regulatory obstacles
No diseases begin or end at age 18 years. But current review systems of clinical trials (e.g., Institutional Review
Boards) and funding sources (e.g., cooperative groups and
Table 4. Time to complete remission in adult acute
lymphoblastic leukemia (ALL) trials.
% CR after One
Cycle of Chemo
% CR after Two
Cycles of Chemo
UKALLXII/ECOG12
51%
91%
CALGB 88113
62%
86%
LALA-9413
72%
84%
Hyper-CVAD 2
81%
92%
DFCI pilot14
82%
N/A
Study
130
pharmaceutical company-sponsored trials) frequently establish “biologically arbitrary” age limits for protocol eligibility and evaluation. Thus, diseases such as ALL, whose
biology extends across a broad age spectrum, are usually
approached as two diseases: childhood ALL (patients < 18
years old), and adult ALL (patients ≥ 18 years old). Such
“age-restricted” criteria have played an integral role in our
current understanding of the disease and its treatment. However, this approach, based on the single differentiating measure—patient age—has until recently hampered clinical research across a broader spectrum of the disease. Although
likely a meaningful host variable, age, per se, is highly unlikely to trump leukemia biology or the impact of an individual treatment regimen. Overcoming such well-institutionalized barriers to research remains a formidable challenge.
Recently, the Dana-Farber Pediatric ALL Consortium,
a group of nine collaborating pediatric centers with a successful record of ALL research and treatment,16 joined together with nine adult institutions to form a Dana-Farber
Combined Adult/Pediatric ALL Consortium.
In anticipation of a common approach to the over 18year-old patients, we evaluated our oldest pediatric ALL
population—those aged 15-18 years old.17 Among 844 patients treated on two consecutive protocols (Dana-Farber
91-01 and 95-01) between 1991-2000, we found 51 (6%)
were in the 15- to 18-year-old population. Statistically significant biological characteristics at the time of diagnosis
included a higher proportion with T-cell ALL and a lower
proportion with hyperdiploidy or the TEL/AML1 translocation compared to younger patients. Except for a lower
incidence of complete remissions (1-14 year olds, 98% vs.
15-18 year olds, 94%; P = 0.01), there were no other statistically significant differences with regard to 5-year eventfree survival (> 1-10 years old, 85%; > 10-15 years old,
77%; and >15-18 years old, 78%; P = 0.10). Patients 10
years old and older had more asparaginase-related pancreatitis and thrombosis, but there were no differences between
the 10- to 14-year-old and 15- to 18-year-old populations.
An updated analysis of the efficacy of our pediatric regimen
for adult patients, 18-50 years old, appears as a 2006 American Society of Hematology abstract (DeAngelo et al).
We are now poised to investigate the biology of ALL
and its treatment across a broad age spectrum, and to have
common treatment regimens for common disease among
patients ages 1-50 years old.
From our DFCI Combined Adult/Pediatric ALL Consortium, many myths have surfaced, and many lessons have
been (and are being) learned.
Myths and Lessons
Myth #1. It cannot be done!
You cannot have a common approach to therapy for children and adults. The disease biology, medical practices,
regulations and cultures are incompatible with a uniform
approach to clinical research.
American Society of Hematology
Lesson #1. It can be done!
(But it isn’t easy.) Finding common ground requires time,
communication and compromise. We are confident that our
work within the DFCI Combined Adult/Pediatric ALL Consortium, as well as similar efforts by others who are striving
toward the same goals—improved outcome for all, diminished toxicity and a better understanding of leukemia biology—will be rewarding and result in lives saved and quality years of life added.
Myth #2. Adults do not tolerate asparaginase.
It is generally assumed that adults are less tolerant to the
acute and cumulative side effects of antileukemia drugs,
and asparaginase, a drug used in all pediatric ALL regimens, is often cited as a prime example.
Lesson #2. Our initial adult protocol, a feasibility trial using one arm of our pediatric ALL regimen, includes 30
weeks of high-dose asparaginase therapy. Adults ages 1850 years old and children ages 10-18 years old tolerate
multiple weekly asparaginase doses (≥ 12,500 IU/m2) with
similar incidences of allergic reactions, pancreatitis and
thrombosis.
Myth #3. Adults have a high rate of therapy-related deaths.
Some would argue against initiating combined adult/pediatric clinical trials because the remission mortality in children (now in the 1-2% range) is far less than in adults.
Lesson #3. In fact, the experience of Dutch6 and British7
investigators suggests that it is the practice of bone marrow
transplantation in first remission for non-Philadelphia chromosome–positive ALL that accounts for the increased incidence of therapy-related deaths. Given the paucity of data
supporting the superiority of bone marrow transplantation
in first remission, many now agree that use of chemotherapy
alone would result in both improved outcomes and in a
lower incidence of therapy-related deaths. Our DFCI adult
pilot protocol and mature pediatric protocols have ~1%
incidence of therapy-related deaths.
Myth #4. Adults don’t have asymptomatic central nervous
system (CNS) leukemia at diagnosis.
And because they don’t, the practice of routine sampling
of CSF at the time of diagnosis in asymptomatic patients is
variable among adult treatment regimens.
Lesson #4. ALL is always a systemic disease. About 2-3%
of children and adults have symptomatic CNS disease at
diagnosis and an additional 5-10% of asymptomatic children and 5% of adults have lymphoblasts in their CSF disease at time of diagnosis. Routine lumbar puncture at the
time of diagnosis and prior to initiating systemic chemotherapy, as well as routine CNS treatment, should be part of
ALL management for all patients. An argument against this
practice, that one might inadvertently introduce blasts into
Hematology 2006
the CSF, can be readily mitigated by the routine use of
intrathecal chemotherapy at the time of the initial diagnostic lumbar puncture.
Myth #5. Who needs a parent or caregiver?
The patient and his or her physician are sufficient for optimal care and outcomes.
Lesson #5. Never underestimate the value of a caregiver! The
best motivated patient and physician can have their wellintended treatments and outcomes enhanced by surrounding
themselves with “a mother figure”; in fact, parental surrogates, committed family members and loved ones, as well as
an extended supportive team of professionals (especially
nurses), are likely to assure optimal adherence to protocol,
emotional support, and (hopefully) better outcomes.
Conclusion
Retrospective analyses clearly demonstrate that current
pediatric therapeutic regimens are more effective than adult
regimens for 16- to 21-year-old patients. Current and future clinical trials will focus on “the ages of uncertainty”:
the 21- to 50-year-old population. Age-unrestricted, biology-based therapy should be the standard of all patients
with ALL. Pediatricians and internists treating patients with
ALL have much to learn from one another. Such efforts are
likely to result in more cures and a higher quality of life
among the survivors.
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American Society of Hematology