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”… tive. Although well-recognized age-related dissimilarities
William Wordsworth in the biology of ALL and event-free survival exist (Tables
2 and 3), the more favorable outcomes for older adoles-
Background cents treated on pediatric regimens in Table 1 cannot be
Within childhood acute lymphoblastic leukemia (ALL) explained by differences in patient characteristics. Nor
populations, older children have had inferior outcomes1 would one expect other potential “adult vs. pediatric”
and within adult ALL populations, younger adults have
had superior outcomes.2,3 In recent reports, “overlapping”
Table 1. Older child/young adult acute lymphoblastic
populations of older children and young adults have been
leukemia (ALL) outcomes.
compared for the likelihood of inducing a complete remis-
sion and long-term event-free survival (Table 1).4-8 Age in # CR 5-Yr EFS
None of the clinical trials listed in Table 1 was de- Country Nat’l Trial Years Pts (%) (%) Ref.
signed to be compared to its age-overlapping pediatric or US: CCG (P) 16-21 196 96 64* 4
adult counterpart; thus, the comparisons were all retrospec- CALGB (A) 103 93 38*
France: FRALLE 93 (P) 15-20 77 94 67 5
LALA94 (A) 100 83 41

Division of Hematology/Oncology, Children’s Hospital and Holland: DCOG (P) 15-18 47 98 69 6

HVON (A) 44 91 34
Department of Pediatrics, Harvard Medical School, Boston,
Massachusetts UK: ALL97 (P) 15-17 61 98 65 7
UKALLXII (A) 67 94 49
Supported in part by grant CA 68484 from the National Cancer Italy: AIEOP (P) 14-18 150 94 80** 8
Institute, National Institutes of Health, Bethesda, Maryland Gimema (A) 95 89 71**

Correspondence: Stephen Sallan, MD, Dana Farber Cancer Abbreviations: CR, complete remission; EFS, event-free
Institute, 44 Binney St, Rm 1642, Boston MA 02115-6084; survival; P, pediatric protocol; A, adult protocol
Phone 617-632-3316; Fax 617-632-5511; Email * 6-yr EFS
stephen_sallan@dfci.harvard.edu ** 2-year overall survival

128 American Society of Hematology

differences (for example, co-morbidities associated with smok- Table 2. Acute lymphoblastic leukemia (ALL): incidence &
ing, or host pharmacokinetic differences based on age) to biological differences.
play a substantial role in the findings summarized in Table 1.
Children Adults
There are clear differences between current adult and
Peak incidence 5 years 50 years
pediatric therapeutic approaches. For example, bone mar-
row transplantation in first remission is more common for % of Leukemias 80-85% 15%
adults (in part, because of the higher incidence of Philadel- Chromosomes
Ph+ 3% 30%
phia chromosome–positive ALL), and pediatric regimens MLL 1-2% 7%
generally include greater dose density of many chemothera- TEL/AML1 20% 2%
peutic agents (such as asparaginase, vincristine, cortico- Hyperdiploid 25% 5%
steroids and methotrexate). T-cell 10-15% 20-25%
What are some plausible explanations for these differ- Mature B 1-2% 3-5%
ences between pediatric and adult outcomes? In a thought-
ful, provocative and prescient editorial, Dr. Charles Schiffer
reflected on biological differences among the hosts and Table 3. Five-year event-free survival.
diseases, and also raised issues pertaining to clinical prac-
tice, such as the frequency of and familiarity with ALL Children Adults
protocols and care of such patients.9 In addition to recog- Pre-B > 80% 30-40%
nizing that ALL is the most common malignancy in chil- T-cell 75-80% 45-55%
dren and relatively rare in adult oncology populations, he Ph+ 20-25% < 10%
also noted that most children, but not most adults, with MLL 40-50% 20%
ALL were treated in the context of clinical trials, by expe- TEL/AML1 90% N/A
rienced support teams, and that many adults were not treated
at academic medical centers. The cultural differences be-
tween care of pediatric and adult ALL patients, described Frequency of and familiarity with ALL
as “disparities in treating attitudes” by Boissel and co-work- Although there might be as many adults with ALL as there
ers,5 was highlighted by Schiffer’s colorful and accurate are children with the disease11 (Figure 1), the relative fre-
description of pediatricians’ tight adherence to complex quency of the disease is markedly higher in young chil-
treatment protocols “…with a military precision on the basis dren. ALL represents about 15% of all malignancies in 1-
of near-religious conviction about the necessity of main- 15 year olds, 5% in 15-19 year olds, and < 10% of malig-
taining prescribed dose and schedule come hell, high wa- nancy in > 20 year olds.
ter, birthdays, Bastille Day, or Christmas.” Although the
necessity of such vigor has not been formally tested, the Adherence to protocol and
proof of the pudding is in the tasting. mitigating psychosocial factors
Although most of the drugs used for ALL today have ex-
Obstacles to Age-Unrestricted, isted for over four decades, little is known about their ideal
Biology-based Treatment antileukemia dose or the role of individual patient differ-
Why have adults with ALL not received the same chemo-
therapeutic regimens as children?
There are two principal hurdles: 1) systems of care,
and 2) regulatory impediments.

“Systems of care” and related differences

Referral patterns
Commonly held views suggest that pediatricians refer 15-
to 20-year-old patients to pediatric academic medical cen-
ters 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 cen-
ters, 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, as-
sures 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 neces-
sary, 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 psy-
chological problem? Have the older patients fully recov-
ered physiologically, or are there other mitigating features
(e.g., “I need some time with my family”) resulting in de-
lays 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 remis-
sion. All pediatric trials report complete remission at the
end of approximately 1 month of multiagent chemotherapy.
However, many adult trials report on the complete remis-
sion rates after 2 months of treatment (Table 4). Although
the time to attain a complete remission was not of prognos-
tic 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 com-
plete 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 re-
view 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 % CR after Two
Study Cycle of Chemo 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
130
pharmaceutical company-sponsored trials) frequently es-
tablish “biologically arbitrary” age limits for protocol eli-
gibility 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. How-
ever, this approach, based on the single differentiating mea-
sure—patient age—has until recently hampered clinical re-
search across a broader spectrum of the disease. Although
likely a meaningful host variable, age, per se, is highly un-
likely to trump leukemia biology or the impact of an indi-
vidual treatment regimen. Overcoming such well-institution-
alized barriers to research remains a formidable challenge.
Recently, the Dana-Farber Pediatric ALL Consortium,
a group of nine collaborating pediatric centers with a suc-
cessful record of ALL research and treatment,16 joined to-
gether with nine adult institutions to form a Dana-Farber
Combined Adult/Pediatric ALL Consortium.
In anticipation of a common approach to the over 18-
year-old patients, we evaluated our oldest pediatric ALL
population—those aged 15-18 years old.17 Among 844 pa-
tients 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 sig-
nificant 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 translo-
cation 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 statis-
tically significant differences with regard to 5-year event-
free 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 pancre-
atitis 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 Ameri-
can 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 Con-
sortium, 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 chil-
dren 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 Con-
sortium, as well as similar efforts by others who are striving
toward the same goals—improved outcome for all, dimin-
ished toxicity and a better understanding of leukemia biol-
ogy—will be rewarding and result in lives saved and qual-
ity 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 regi-
mens, is often cited as a prime example.
Lesson #2. Our initial adult protocol, a feasibility trial us-
ing one arm of our pediatric ALL regimen, includes 30
weeks of high-dose asparaginase therapy. Adults ages 18-
50 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/pedi-
atric clinical trials because the remission mortality in chil-
dren (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 chro-
mosome–positive ALL that accounts for the increased in-
cidence 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 chil-
dren and 5% of adults have lymphoblasts in their CSF dis-
ease at time of diagnosis. Routine lumbar puncture at the
time of diagnosis and prior to initiating systemic chemo-
therapy, 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 diagnos-
tic lumbar puncture.
Myth #5. Who needs a parent or caregiver?
The patient and his or her physician are sufficient for opti-
mal care and outcomes.
Lesson #5. Never underestimate the value of a caregiver! The
best motivated patient and physician can have their well-
intended treatments and outcomes enhanced by surrounding
themselves with “a mother figure”; in fact, parental surro-
gates, 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 fu-
ture clinical trials will focus on “the ages of uncertainty”:
the 21- to 50-year-old population. Age-unrestricted, biol-
ogy-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.
References
1. Irken G, Oren H, Gulen M, et al. Treatment outcome of
adolescents with acute lymphoblastic leukemia. Ann
Hematol. 2002;81:641-645.
2. Kantarjian H, Thomas D, O’Brien S, et al. Long-term follow-
up results of hyperfractionated cyclophosphamide,
vincristine, doxorubicin, and dexamethasone (Hyper-
CVAD), a dose-intensive regimen, in adult acute lymphocytic
leukemia. Cancer. 2004;101:2788-2801.
3. Larson RA, Dodge RK, Burns CP, et al. A five-drug remis-
sion induction regimen with intensive consolidation for adults
with acute lymphoblastic leukemia: Cancer and Leukemia
Group B Study 8811. Blood. 1995;85:2025-2037.
4. Stock W, Sather H, Dodge RK, Bloomfield CD, Larson RA,
Nachman J. Outcome of adolescents and young adults with
ALL: A comparison of Children’s Cancer Group (CCG) and
Cancer and Leukemia Group B (CALGB) regimens. Blood.
2000;96:467a.
5. Boissel N, Auclerc M-F, Lheritier V, et al. Should adolescents
with acute lymphoblastic leukemia be treated as old children
or young adults? Comparison of the French FRALLE-93 and
LALA-94 trials. J Clin Oncol. 2003;21:774-780.
6. deBont JM, van der Holt B, Dekker AW, van der Does-van
den Berg A, Sonneveld P, Pieters R. Significant difference in
outcome for adolescents with acute lymphoblastic leukemia
treated on pediatric vs adult protocols in the Netherlands.
Leukemia. 2004;18:2032-2035.
7. Ramanujachar R, Richards S, Hann I, Webb D. Adolescents
with acute lymphoblastic leukaemia: Emerging from the
shadow of paediatric and adult treatment protocols. Pediatr
Blood Cancer. 2006; [Epub ahead of print]
8. Testi AM, Valsecchi MG, Conter V, et al. Difference in
outcome of adolescents with acute lymphoblastic leukemia
131
 (ALL) enrolled in pediatric (AIEOP) and adult (GIMEMA)
protocols. Blood. 2004;104:1954a.
9. Schiffer CA. Differences in outcome in adolescents with acute
lymphoblastic leukemia: a consequence of better regimens?
Better doctors? Both? J Clin Oncol. 2003;21:760-7611.
10. Bleyer A. The adolescent and young adult gap in cancer
care and outcome. Curr Probl Pediatr Adolesc Health Care.
2005;35:182-217.
11. Bleyer A, O’Leary M, Barr R, Ries LAG (eds). Cancer
Epidemiology in Older Adolescents and Young Adults 15 to
29 years of Age, including SEER Incidence and Survival:
1975-2000. National Cancer Institute, NIH Pub. No. 06-5767.
Bethesda, MD 2006.
12. Rowe JM, Buck G, Burnett AK, et al. Induction therapy for
adults with acute lymphoblastic leukemia: Results of more
than 1500 patients from the international ALL trial: MRC
UKALL XII/ECOG E 2993. Blood. 2005;106:3760-3767.
132
13. Thomas X, Boiron J-M, Huguet F, et al. Outcome of
treatment in adults with acute lymphoblastic leukemia:
analysis of the LALA-94 trial. J Clin Oncol. 2004;22:4075-
4086.
14. Daniel D’Angelo, M.D. Personal Communication May 2006.
15. Silverman LB, Gelber RD, Young ML, Dalton VK, Barr RD,
Sallan SE. Induction failure in acute lymphoblastic leukemia
of childhood. Cancer. 1999;85:1395-1404.
16. Silverman LB, Declerck L, Gelber RD, et al. Results of
Dana-Farber Cancer Institute Consortium protocols for
children with newly diagnosed acute lymphoblastic leukemia
(1981-1995). Leukemia. 2000;14:2247-2256.
17. Barry E, DeAngelo DJ, Neuberg D, et al. Favorable outcome
for adolescents with acute lymphoblastic leukemia treated
on Dana Farber Cancer Institute ALL Consortium protocols.
J Clin Oncol. In press.
American Society of Hematology