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Chapter 66 Acute Lymphoblastic Leukemia in Adults 1049

achieving the high cure rate and successful transition back to “normal” and cyclophosphamide were then omitted from the induction cycle,
life now routinely achieved in children with ALL. In particular, due and 23 additional patients were treated with a CR rate of 70%; the
to significant pharmacogenomic variability and age-related changes induction death rate was reduced to 22%. The 2-year DFS and OS
in drug metabolism, further evaluation and potential dose modifica- for the entire series were 46% and 39%, respectively.
tions of some of the agents including glucocorticoids, vincristine, and Because most patients in this age group may not be eligible for
asparaginase, crucial to the successful outcomes of children, will need conventional myeloablative aSCT, consideration should be given for
to be addressed in future studies of AYA and older adults with ALL RIC-based aSCT. Initial results with the use of RIC conditioning
in order to optimize these regimens for these populations Enrollment have been favorable, and long-term data are awaited (see earlier
in clinical trials, which has led to the survival rates now approaching section on allogeneic stem cell transplant).
more than 90% in pediatric ALL, will be the key to making progress Many novel agents are being evaluated for this group of patients
in survival rates for both younger and older adults with ALL. given the poor prognosis with the currently available therapies. To
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date, with the exception of TKI-based therapy for Ph ALL in older
Comparison of Pediatric-Inspired Regimens adults, none have resulted in improved outcomes. The GRAALL-SA1
With Allogeneic Transplant for Adolescents randomized phase II trial compared the efficacy and toxicity of
pegylated liposomal doxorubicin (Peg-Dox) versus continuous-
and Young Adults infusion doxorubicin (CI-Dox) in patients 55 years of age and older
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with Ph ALL. Use of Peg-Dox led to significant lower toxicities;
Given these very encouraging improvements in outcome for AYAs however, there was a trend toward a lower CR rate, more refractory
with ALL using intensified pediatric regimens, the role of aSCT in disease, and higher relapse rate in the Peg-Dox arm compared with
CR1 has been reexamined in a recently presented retrospective CI-Dox arm. Other newer agents approved for relapsed disease,
comparison study. The International Bone Marrow Transplant Reg- including liposomal vincristine and the bispecific antibody blinatu-
istry (IBMTR) examined outcomes of patients 18–50 years old who momab, are being tested in frontline therapy for older adults with
were treated during 2002–2011 on the DFCI intensive pediatric ALL; these trials are currently ongoing. Single-agent activity of these
regimen described above (n = 108) compared with registry patients agents in the relapsed setting is described later in more detail in the
who received aSCT in CR1 using HLA matched related or unrelated novel therapies section. Consideration should be given to enrollment
donors (n = 422). These investigators reported significantly better of older adults into these new frontline therapies given the lack of
outcomes for patients receiving the intensive pediatric approach progress with dose intensification of traditional agents. Management
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compared to transplant (HR: 3.12; p < .0001). Overall, treatment of older adult patients with Ph ALL is discussed in the Ph ALL
using a pediatric-inspired regimen for young adults with ALL appears section; the incorporation of TKIs into frontline therapy has already
to result in significantly improved survival compared to aSCT in made significant improvements in DFS for these high-risk patients.
CR1. Similarly, data from the GRAALL pediatric-inspired protocols
GRAALL 2003 and 2005 showed that there was no difference in
relapse, nonrelapse mortality, or relapse-free survival (RFS) overall in RELAPSED ACUTE LYMPHOBLASTIC LEUKEMIA
patients that went onto aSCT compared to those that did not undergo
transplant. However, aSCT did result in a longer RFS in patients that As described earlier, with standard therapies for ALL, long-term DFS
were MRD positive after induction chemotherapy, suggesting there is only around 30% to 40%. Thus the majority of patients with ALL
is a select HR group of patients that still benefit from transplant. relapse despite the administration of postremission treatment. Postre-
lapse therapies will lead to a second CR (CR2) in 30% to 40% of
OLDER ADULTS WITH ACUTE patients with a 5-year OS of only around 10%. An aSCT is the only
chance for long-term cure in these patients and must be considered
LYMPHOBLASTIC LEUKEMIA for all patients.
In the largest report of relapsed adult ALL patients to date, Field-
Older adults (generally defined as >60 years old) constitute a chal- ing and colleagues analyzed the outcomes of relapsed adult ALL
lenging subset of ALL patients with worse prognosis reported in patients who were treated in the MRC UKALLXII/ECOG E2993
many studies compared with their younger counterparts. Most trial. Of the 1508 evaluable patients, 1372 (91%) achieved CR1, of
studies demonstrate that adults older than 60 years old have survival whom 609 (44% of the CR1 patients) relapsed at a median of 11
rates below 15%. Various factors contribute to the poor outcome of months. The 5-year OS was only 7% for the relapsed patients, which
these patients, both patient related (e.g., the presence of comorbidi- was significantly worse compared with 38% for the newly diagnosed
ties, less likely to be eligible for aSCT, poor tolerance of intensive ALL patients in this study. The median OS for the relapsed patients
chemotherapies) and disease related (more likely to have unfavorable was 5.5 months. The sites of the relapses were BM alone (86%), CNS
disease characteristics such as the presence of Philadelphia chromo- alone (4%), BM plus CNS (5%), and other extramedullary sites
some). It is important to note that many large clinical trials have (4%). The majority of the relapses (81%) occurred within 2 years of
excluded patients older than 60 years of age; therefore clinical diagnosis. In this series, none of the 55 patients who had CNS
outcome data for this group are sparse. Annino and colleagues involvement at relapse were alive at 5 years. Receiving aSCT after
reviewed the results of 679 older adult patients (variably defined as relapse led to significant improved outcomes compared with chemo-
older than 50 to older than 65 years of age, depending on the study) therapy alone (5-year OS, 23% for matched sibling SCT versus 4%
from 19 studies and reported a CR rate of 59% (range: 31% to 85%) for the chemotherapy-alone arm).
with an early mortality rate of 23% (range: 7.5% to 50%) and 2-year Tavernier and colleagues reported outcomes of 421 ALL patients
OS of 15% to 19%, all of which are inferior to younger ALL patients. who experienced first relapse after treatment on the French LALA-94
With hyper-CVAD regimens, the CR rate and 3-year survival for trial. A CR2 was achieved in 44% patients with a median DFS of
patients 60 years of age or older (n = 58) were 88% and 29%, 5.2 months and median OS of 6.3 months. Factors associated with
respectively. In a pooled analysis of six consecutive CALGB clinical favorable outcome after relapse included transplant performed in
trials, the CR rate and 3-year survival for patients 60 years of age or CR2, CR1 of longer than 1 year, and platelet count greater than
older (n = 197) were 61% and 15%, respectively. 100,000/µL at relapse. The outcomes after relapse were not influ-
Sancho and colleagues reported results of the Spanish PETHEMA- enced by risk stratification at diagnosis or the treatment received
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ALL 96 trial looking specifically at the outcomes of Ph ALL during first CR. An aSCT was performed in 24% (n = 99) of the
patients who were 55 years of age or older. They initially treated relapsing patients (in CR2 [n = 61] or with active disease at the time
10 patients with an induction regimen consisting of vincristine, of SCT [n = 38], directly as a salvage therapy after relapse [n = 14],
daunorubicin, prednisone, asparaginase, and cyclophosphamide. or after failure of salvage regimen [n = 24]). Median OS from an
However, 7 of the 10 patients died during induction. Asparaginase aSCT was 6.7 months with 5-year OS of 25% with a significantly