Page 1200 - Hematology_ Basic Principles and Practice ( PDFDrive )

1048 Part VII Hematologic Malignancies

Retrospective Comparison of Pediatric and extends well into the middle years of adult life. In the French Acute
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Adult Cooperative Group Trials in Adolescents Lymphoblastic Leukemia Pediatric group (FRALLE) study, 28 Ph
adult ALL patients 16–57 years old were treated on the FRALLE
and Young Adults 2000 protocol consisting of a prednisone prophase, four-drug induc-
tion including L-asparaginase, consolidation, delayed intensification,
The retrospective comparisons summarized in Table 66.10 were and maintenance chemotherapy. Four-year DFS was 90% versus 47%
performed by large cooperative groups throughout the world and seen in matched historical control participants. In the GRAALL 2003
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examined the outcome of the AYA patients aged 15–21 years treated study, 225 Ph ALL patients 15–60 years old (median: 31 years) were
on pediatric or adult cooperative group trials for newly diagnosed treated between 2003 and 2005 with five-drug induction, dose-
ALL that were conducted contemporaneously. The majority of these intense consolidation, delayed intensification, and 2-year maintenance
retrospective comparison studies demonstrated a significant survival therapy. Notably, aSCT for patients younger than 55 years was rec-
advantage for AYA patients treated by the pediatric versus the adult ommended in this trial and makes interpretation of this trial more
cooperative group. The first of these trials to have been reported problematic. The CR rate was 93.5%. Among the 139 CR patients,
highlights many of the interesting questions posed by these compari- 71 actually underwent transplantation in CR1 and were censored at
sons and is reviewed briefly here. The CALGB and the Children’s the time of transplant. At 42 months, EFS was 55% versus 41% when
Cancer Group (CCG) examined the outcome of 321 AYA patients comparing patients from an earlier French trial, the LALA-94, and
between 16 and 20 years of age treated on consecutive trials from the OS was 61%, significantly better than the 41% OS observed in
1988 to 2001. The two patient groups were well matched for biologic the LALA-94 trial (p < .001). The benefit of the GRAALL approach
features, including immunophenotype and cytogenetics. Although was not statistically significant in patients older than 45 years of age
the age range was the same in both groups examined, the median age because of a significant increase in treatment-related mortality of
of the patients in the CALGB studies was 19 years compared with 23% compared with 5% treatment-related mortality for patients
16 years for the CCG patients. CR rates were identical—90% for younger than 45 years old. The investigators concluded that the use
both CALGB and CCG AYAs. However, CCG AYAs had a 63% EFS of a pediatric-inspired regimen in adults up to 45 years of age was
at 7 years and 67% OS at 7 years in contrast to the CALGB AYAs, tolerable and markedly improved outcome for “younger” adults with
in which the 7-year EFS was only 34%. A difference in pattern of ALL. This regimen included older adults up to the age of 60 years
relapse was also noted. The incidence of CNS relapses was signifi- and used only a modified pediatric regimen that did not use the dose
cantly higher in CALGB AYAs (11%) compared with the CCG AYAs intensity of corticosteroids, asparaginase, and vincristine that are
(1.4%; p < .001). routinely used in current pediatric regimens. Another difference from
Since the initial report of these findings in 2000, multiple national the pediatric regimens is that all patients in these trials still received
European cooperative groups have reported similar results with prophylactic cranial irradiation. Also, the majority of CR1 patients
improvement in the outcome of AYAs treated on pediatric compared actually underwent aSCT, which is not the approach used by pediatric
with adult protocols, and these are summarized in Table 66.10. groups. Thus any interpretation of the contribution of the “chemo-
Although the treatment approaches differ among countries, several therapy” intensification component of these trials to DFS is very
treatment themes have emerged as being potentially important. Pedi- difficult to assess.
atric studies throughout the world use considerably more treatment The Dana-Farber Cancer Institute (DFCI) consortium has also
with nonmyelosuppressive drugs, including glucocorticoids (both extended its successful pediatric regimen to older patients 18–50
dexamethasone and prednisone), vincristine, and L-asparaginase. years old. The trial design here was a true pediatric approach with
CNS prophylaxis is typically administered earlier, with a greater intensification of Escherichia coli L-asparaginase, glucocorticoids, and
frequency, and for a more prolonged period during pediatric group vincristine for patients up to 50 years old; aSCT was not routinely
trials. Finally, long-term maintenance therapy was also continued recommended. A total of 92 patients, with a median age of 28 years
for a longer period in pediatric cooperative group trials. Based on (range: 18–50 years) were evaluable. Seventy nine patients (85%)
additional retrospective data from Finland and the MD Anderson achieved a CR after 1 month of intensive induction therapy. With a
Cancer Center, it appears that treating patients in a uniform fashion median follow-up time of 4.5 years, the 4-year DFS rate for all
by an experienced group of physicians and nurses is also a very patients was 69% and the OS rate 67%. For the 74 patients with
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important component in the successful treatment of young adults Ph ALL, DFS was 71%, and OS was 70%.
with ALL. The largest prospective trial to evaluate the feasibility of using a
To begin to address the many unanswered questions that have pediatric regimen in AYA patients treated by adult medical hematolo-
been raised by the retrospective comparison trials and to determine gists and oncologists is ongoing in North America (CALGB-10403).
whether AYA patients treated by adult hematologists and oncologists The United States adult and pediatric cooperative groups are cur-
can achieve similarly improved outcomes to the pediatricians for this rently enrolling a total of 300 young adults aged between16 and 39
age group, prospective cooperative group trials are being conducted years on a prospective phase II trial (CALGB-10403) that uses one
in North America and in Europe. Early results from several of these treatment arm of a successful Children’s Oncology Group (COG)
trials have recently been reported. The PETHEMA Protocol ALL-96 protocol for adolescents (and HR children with ALL). Early results
addressed the toxicity and results of a pediatric-based protocol in 35 from this trial also suggest both the feasibility of use of an intensive
adolescent (age: 15–18 years) and 46 young adults (age: 19–30 years) pediatric regimen in young adults and significant improvement in
with SR ALL. In this trial, patients received a standard five-drug, EFS of 66% and OS of 79% compared with historical controls.
5-week induction course followed by two cycles of early consolida- Longer follow-up is required to substantiate these promising early
tion, maintenance with monthly reinforcement cycles for 1 year after results.
remission, and standard maintenance chemotherapy for up to 2 years These prospective trials are demonstrating that it is possible to
after CR. The AYAs were well matched for pretreatment characteris- achieve significant improvements in outcome for AYAs with ALL,
tics. The CR rate was 98%, and with a median follow-up of 4.2 years, although many challenges remain to ensure access to care, to mini-
the 6-year EFS and OS were 61% and 69%, respectively. The only mize treatment toxicity, and to develop and follow specific survivor-
significant predictor of poor EFS for the entire group was a slow ship monitoring plans. As stated previously, the successful outcome
response to initial induction therapy (>10% blasts remaining in BM of a patient with ALL is, largely, based on the ability of both the
aspirate done on day 14 of induction therapy). Thus the investigators medical team and the patient to adhere to the rigorous and lengthy
concluded that a pediatric regimen was tolerable and efficacious in regimens that currently remain the gold standard of care. The next
AYAs with ALL up to the age of 30 years. generation of studies, linked to important biologic, psychosocial, and
Two pilot studies from French adult cooperative groups have also pharmacologic correlates, will result in further insights into optimiz-
demonstrated the feasibility of using modified pediatric-inspired ing the comprehensive approach to treatment and follow-up for this
regimens in adults with ALL, but the age range of these studies significant group of patients with ALL, and may be the next step to