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Chapter 66 Acute Lymphoblastic Leukemia in Adults 1041

regimens routinely incorporate CNS prophylaxis during the mainte-
nance phase. Pediatric studies have also reported favorable impact on Alternative Stem Cell Sources; Alternative Preparative
DFS of achieving adequate myelosuppression with the chemotherapy Regimens for Allogeneic Stem Cell Transplantation
drugs during the maintenance phase. Thus, it appears that careful
adjustment of the doses of the oral agents used during maintenance Matched sibling donors (MSDs) remain the preferred modality for
therapy to achieve optimal yet safe myelosuppression improves treat- the stem cell source (Table 66.7). For patients lacking an MSD, a
ment outcomes. matched unrelated donor (MUD) or an alternative donor source
(e.g., umbilical cord blood [UCB]) should be pursued. In a Center
ALLOGENEIC STEM CELL TRANSPLANT IN FIRST for International Blood and Marrow Transplant Research (CIBMTR)
registry study, outcomes of 169 patients with ALL in CR1 who
COMPLETE REMISSION underwent unrelated donor (URD) transplants between 1995 and
2004 were analyzed. A total of 41% were HLA well matched, 41%
Despite attempts to improve DFS in adult ALL, OS with the standard partially HLA matched, and 18% HLA mismatched. The major-
chemotherapy regimens described earlier has been “fixed” at about ity (93%) of the patients had at least one HR feature. One-year
35% to 45% for the past decade. Thus, several groups have evaluated transplant-related mortality (TRM) was high at 36%, and TRM
the role of treatment intensification with transplant (both aSCT and at 5 years was 42%. The relapse rate at 5 years was 20%, with
ASCT) as postremission therapy and compared the outcomes with 5-year DFS and OS of 38% and 39%, respectively. Factors associated
9
the traditional chemotherapy approaches described previously. Con- with worse survival included WBC greater than 100 × 10 /L, time
ventionally, an aSCT has been reserved as the standard recommenda- to CR1 longer than 8 weeks, cytomegalovirus seropositivity, HLA
tion for only HR patients in CR1. In one of the earliest randomized mismatching, and T-cell depletion. The Minnesota group recently
trials to investigate the role of allogeneic transplant, the French reported outcomes of myeloablative aSCT for ALL patients trans-
LALA-87 study, patients in CR1 were assigned to a donor group (if planted at their center and compared retrospectively the outcomes
they had an HLA-matched related donor); the remaining patients with respect to different donor sources. In an analysis restricted to
(no-donor group) were randomized to ASCT versus chemotherapy. 91 adult patients who received aSCT in CR1 or CR2 from 1990
In this study, patients with HR ALL (defined as the presence of to 2005, there was no difference between the allogeneic donor
Philadelphia chromosome, or null leukemia [defined by a CD10, sources (matched related donor versus matched URD versus UCB
CD20-immunophenotype], undifferentiated leukemia, or common donor) for OS, DFS, or TRM. Similarly, in the ALL-SCT-BFM
leukemia with at least one adverse prognosis factor such as age older 2003 study of children and adolescents, no difference was observed
than 35 years, WBC count greater than 30,000/µL, or time to CR between matched related donor sources and at least 9 out of 10
longer than 4 weeks) benefitted from aSCT. For the HR group, 5-year MUD sources.
OS was 44% in the donor arm (n = 41), which was significantly Because the majority of older adults are not candidates for a
better than the 20% in the no-donor arm (n = 55; p = .03). The myeloablative aSCT, reduced-intensity conditioning (RIC) approaches
outcome of the SR group was not improved with aSCT (5-year OS have been explored in this patient population (Table 66.8). The
of 51% in the donor arm versus 45% in the no-donor arm). Similar Seattle group recently reported outcomes of aSCT using nonmyeloab-
results were seen in a follow-up of LALA-94 trials with benefit of lative conditioning in 51 patients with ALL (median age: 56 years),
aSCT in the HR group. In contrast, the Program Espaňol de Trata- half of whom were Ph positive. For the Ph-negative group, the 3-year
miento en (PETHEMA) ALL-93 trial failed to show benefit of aSCT OS for those transplanted in CR1 was 52%. The incidence of chronic
in HR ALL patients. graft-versus-host disease, however, was high at 44%. A recent registry
In the MRC UKALLXII/ECOG E2993 trial, all patients (age <50 study examined the efficacy of RIC in 93 ALL patients and compared
years or <55 years after 2003) in CR1, irrespective of risk status, were it with 1428 ALL patients receiving myeloablative conditioning for
assigned to aSCT if they had an HLA-compatible sibling donor. All aSCT using either a sibling or unrelated donor in CR1/CR2. Interest-
other patients were randomized to consolidation or maintenance ingly, the TRM at 3 years was similar between the RIC and myeloab-
therapy, or to an ASCT. In this largest adult ALL trial to date, 1646 lative regimens (32% versus 33%, respectively). The relapse rate at 3
Ph-negative patients were enrolled; 1484 (90%) achieved CR1. After years was slightly higher in the RIC arm, although this was not sta-
excluding patients who were older than 55 years of age and those tistically significant (35% versus 26%; p = .08). The OS at 3 years
without available HLA-typed siblings, 1031 CR1 patients (55% SR; was similar between the two groups (38% for RIC arm versus 43%
45% HR) were HLA typed. In a “genetic randomization” approach for myeloablative arm, p = .39). This was a retrospective registry
using donor (n = 443) versus no-donor (n = 588) analysis, OS benefit study; however, it provides evidence that RIC regimens can lead to
was seen for the donor arm when all patients were considered (5-year similar survival in adults with ALL as aSCT with a more intensive,
OS, 53% versus 45%; p = .01). In a subgroup analysis, the survival myeloablative conditioning regimen. This is particularly compelling
benefit of transplant was restricted to patients who were younger than because the median age was significantly older for those receiving
35 years of age. For patients older than 35 years of age or with adverse RIC (median age in RIC arm: 45 years versus 28 years for myeloabla-
cytogenetics, OS was not better than with standard chemotherapy tive arm). The group from Minnesota has also reported encouraging
because of transplant-related toxicities, which resulted in early deaths. results with UCB donor transplantation using a RIC regimen.
In a report by the Dutch–Belgian HOVON group, patients Eighteen adults (median age: 49 years; range: 24–68 years) with
+
younger than 50–55 years in CR1 were offered an aSCT. In a donor high-risk ALL (majority Ph ALL) received a cord blood transplant
(n = 96) versus no-donor (n = 161) analysis for all patients, 5-year using a RIC conditioning regimen and reported 3-year OS, TRM,
OS was 61% for the donor arm compared with 47% in the no-donor and relapse rates of 49%, 28%, and 33%, respectively. Notably,
arm (p = .08). In subset analysis, the survival benefit of transplant patients in CR1 had a TRM of only 8% with no events after 6
was restricted to SR patients, which were those without any of the months. These results with UCB donor transplantation are promising
following HR features: presence of a high WBC count at diagnosis and compare favorably to conventional aSCT with relatively low
(>30,000/µL in B-ALL or >100,000/µL in T-ALL), cytogenetic TRM in this high-risk population. Thus RIC-based aSCT regimens
abnormalities (t[4;11], t[1;19], t[9;22]), pro–B-cell immunopheno- with alternative donor sources should be considered for older adults
type, and CR achievement longer than 4 weeks from start of in prospective clinical trials.
induction. In summary, aSCT is a curative option for patients with ALL and
A meta-analysis of seven studies (with 1274 patients) that pro- can be considered the standard recommendation for patients with a
spectively assessed OS using genetic randomization based on donor good performance status but with adverse disease risk factors in CR1.
availability reported significantly better OS in the donor group versus There have been significant improvements in transplantation tech-
the no-donor groups (hazard ratio: 1.29; p = .037), which was more niques (better supportive care, refinement of preparative regimens,
pronounced in patients with HR features. and uses of alternative donors as a source of stem cells) that are