Once a complete remission has been achieved, including negative MRD status, additional therapy is required to avoid disease relapse. Various combinations and numbers of courses of therapy have been tested.
Dose and Duration
Although agreement exists on the role of cytarabine-based intensification therapy, especially for core-binding factor myeloid leukemias in which additional courses of cytarabine appear to decrease relapse risk significantly, the optimal number of cycles of intensification chemotherapy is not known
.146,
166,
167 The published pediatric AML trials have used either 2 or 3 courses of consolidation therapy, for a total of 4 or 5 courses of therapy.
168, 169 and 170 The MRC AML-10 trial randomized patients to either auto-HSCT transplant or no further therapy and demonstrated a decreased relapse risk in patients receiving auto-HSCT. However, the addition of auto-HSCT was associated with significant morbidity and mortality, thus abrogating any OS advantage.
169 The CCG-2961 trial gave patients a total of 3 courses of chemotherapy with a resulting overall survival of 57% following changes in supportive care recommendations.
171 The MRC AML-12 trial randomized patients to a total of 4 versus 5 courses of chemotherapy with an OS of 81% versus 78%, respectively, at 5 years (
P = 0.5). However, the survival for patients with very high risk AML was significantly less than for patients with intermediate and favorable risk AML; thus, any attempts to test 4 versus 3 courses of therapy should likely be done in the latter groups.
162
With the exception of patients with APL, the use of maintenance therapy with relatively low dose chemotherapy has been currently abandoned with the exception of BFM studies, which in part base this choice on the results of BFM-87, in which a maintenance phase was beneficial to a low-risk group of patients who did not receive HSCT. However, when only randomized patients were analyzed, no significant difference in outcome was observed, and no significant difference was observed.
172 Other cooperative groups, however, have shown that maintenance therapy is associated with a decrease in both EFS and OS when compared to shorter, more intensive regimens, with relapsed disease being more resistant to subsequent therapies.
173,
174,
175
Hematopoietic Stem Cell Transplantation
Sustained improvements in chemotherapeutic regimens and supportive care have continued to reduce the need for patients to receive allogeneic HSCT. Furthermore, several studies have shown equivalent overall survival when compared to chemotherapy; most co-operative groups have thus omitted autologous HSCT from consideration in order potentially to avoid greater short- and long-term toxicities.
145,
168,176,
177 However, with equivalency of overall outcome between autologous HSCT and chemotherapy, one might also conclude that either approach would be a reasonable, evidenced-based recommendation.
178 In addition, alternative approaches to transplantation, such as the use of nonablative or intensity-reduced allogeneic or haplo-identical HSCT, remain experimental and need prospective testing in comparison to more conventional approaches.
Pediatric cooperative groups generally agree that intensive cytarabine-based post-remission induction therapy is required to minimize relapse risk. The role of allogeneic HSCT has continued to evolve. This has in large part been due to the advances in chemotherapy-based treatments for patients who might have previously been considered candidates for allogeneic HSCT. Key questions are whether allogeneic HSCT provides an overall improvement in survival and quality of life compared to chemotherapy-only treatment approaches. In order to answer these questions, it has been necessary to define risk groups more carefully in terms of outcome and potential for benefit from HSCT. In addition, whereas most trials have analyzed outcomes on whether patients did or did not have an HLA-matched donor, the improving success being obtained using matched unrelated donor HSCT has led to outcome analysis based on availability of the best HLA-matched donor.
162
Many trials have shown that allogeneic HSCT results in an improved disease-free survival compared to chemotherapy or autologous HSCT.
162,
168,
177,179,
180,181 However, HSCT has not usually resulted in an improved event-free or overall survival, reflecting the associated increased treatment-related mortality. Such results suggest that HSCT may benefit some groups more than others. Several studies have attempted to define such subgroups more precisely.
The availability of an HLA-matched donor was used to analyze outcome in the MRC AML 10 trial.
182 There was no statistically significant difference in overall survival between those children with (68%) or without (59%) a donor at 10 years, even those there was a significant difference in relapse rate (30% with donors vs. 45% without donors). Based on the MRC cytogenetic and response-based risk stratification, overall survival at 5 years from the time of relapse was 57%, 14%, and 8% for good, standard, and poor risk groups, respectively; this led to the conclusion that allogeneic HSCT should be done in good risk AML in CR2. Although outcomes from MRC AML 10 also suggested that allo-HSCT in first remission as improved for patients with intermediate- and high-risk AML, combined data from the MRC AML 10 and 12 trials showed no statistically significant benefit for these groups of patients compared to chemotherapy alone.
182 BFM trials and POG 8,821 and 9,421 studies showed comparable results although in the POG trials did not do a detailed subgroup stratification.
155,183,184
In contrast, analysis of post-remission treatment of 1,464 children less than age 21 years on 5 consecutive CCG trials from 1979 to 1996 has shown an advantage to those patients assigned a HSCT in terms of overall survival (
P = 0.026), disease-free survival (
P = 0.005), and relapse rate (
P < 0.001).
185 Subgroup analysis demonstrated that HSCT was associated with improved survival for patients with WBC greater than 50,000/µL and for those with normal karyotype, but was not beneficial for patients with AML characterized by good -risk cryogenics, such as inv(16) or t(8;21). In support of such data, a report from the CCG 2961 trial showed no statistically significant advantage of having a HSCT donor in terms of OS or DFS in the subgroup of patients with inv(16) or t(8;21) chromosomal translocations.
171 A detailed analysis of the effect of donor availability on patients with standard and poor risk features was not reported although no advantage of having a HSCT matched family member donor was observed compared to chemotherapy for the entire study population. Overall, these results appear to be consistent with those reported from pediatric MRC AML trials.
A more detailed analysis of the MRC AML 12 outcomes has reported no advantage of HSCT for patients in the good and intermediate groups, but a statistically significant advantage for relapse-free survival and overall survival for a subset of patients with high-risk AML; for example, in the 12% of patients defined as having poor-risk AML, HSCT was associated with an overall survival of 41% compared to 10% for those who received only chemotherapy (
P = 0.001).
162
Whether patients with other subtypes of AML might also benefit from receiving an allogeneic HSCT remains controversial. A high FLT3-ITD mutant to normal allele frequency has been uniformly associated with a poor prognosis when patients are treated with standard chemotherapeutic regimens alone.
186,
187,188 A significant question is whether more allogeneic HSCT is able to improve outcomes in patients with a high allelic ratio FLT3-ITD AML.
Some studies have strongly suggested an advantage of HSCT for patients with a high mutant allele frequency of
FLT3-ITD
mutations.
188, 189, 190 and 191 Data from the CCG 2941 and 2961 trials showed a borderline significant difference in relapse for patients with FLT3-ITD positive AML who received a allogeneic matched sibling donor HSCT (27% ± 27%) compared to those treated with only chemotherapy (65% ± 15%,
p = 0.05). However, overall survival at 4 years from the end of the second course of treatment was not significantly different (64% ± 29% for those with FLT3-ITD AML who received an allogeneic HSCT and 48% ± 17% for those treated with chemotherapy [
p = 0.4]).
188,192 The MRC AML 10 and 12 trials concluded that there was no strong evidence that FLT3 status should be considered as to whether to perform a HSCT based on their analysis of 1,135 young adult patients.
193 Because OS was not significantly improved by having a donor in patients with FLT3-ITD positive or negative AML, it was concluded that allogeneic HSCT is not able to overcome the intrinsic chemoresistance or radiation resistance of FLT3-ITD positive AML. Thus, whether allogeneic HSCT can improve outcomes for patients with FLT3-ITD remains an open question. Nevertheless, most ongoing clinical trials for children and young adults assign allogeneic HSCT for patients with AML characterized by a high mutant FLT3-ITD to normal allelic ratio, often in the context of additional targeted therapy directed toward inhibition of the mutant receptor.
Current strategies for determining which patients should receive matched or single mismatched family donor or alternative donor HSCT are thus based on risk assessment and stratification. Patients with AML characterized by alternations in core binding or transcription factors (e.g., t(8;21), inv(16), biallelic
CEBPA mutations) have an approximately 80% overall survival with chemotherapy alone and, thus, HSCT is recommended only in CR2. Similarly, children and young adults with APL have an overall survival of 75% to 90%, depending on risk group, with chemotherapy plus all-
trans-retinoic acid (ATRA) and, more recently, arsenic.
194,
195 Thus, HSCT is not usually recommended in CR1 for these patients, but instead following CR2, in which case allogeneic, and in some instances autologous, HSCT result in an approximately 70% overall survival.
195, 196 and 197
MLL-rearranged AML represents an extremely heterogeneous group of leukemias associated with variable outcomes. For example, an international trial has reported that survival is 100%, 63%, 27%, and 22% for patients with the t(1;11), the t(9;11), the t(4;11), and the t(6;11), respectively.
198 Because of the wide variability of outcomes along with small numbers of patients with MLL subtypes as well as no prospective definitive data that demonstrate HSCG improves outcome in this group of patients, most cooperative group clinical trials have not used allogeneic HSCT in CR1.
178 An intention-to-treat analysis of the AML-BFM 98 study has suggested an improved OS with allogeneic MSD HSCT for patients with 11q23 (MLL) rearrangements.
199
AML characterized by a normal karyotype represents a large percentage of cases, however, it is also proving to be a molecularly heterogeneous group. For example, nucleophosmin member 1 (
NPM1) mutations are associated with an improved outcome, although not necessarily in the presence of high mutant FLT3-ITD to normal allelic ratio is somewhat controversial.
200,201 AML with
CEBPA mutations is usually associated with normal karyotype AML and improved overall survival, thus making HSCT undesirable in CR1.
50 Point mutations involving
KIT, RAS, or
WT1 (Wilms tumor 1) have not yet been definitively shown to improve outcome although some data exist linking them to a poorer prognosis.
202,203 Furthermore, patients with AML having high-risk cytogenetics, such as monosomy 7 or del(5q)- and -5, are recommended to have HSCT in CR1 (
Table 77.2).
The Children’s Oncology Group (COG) frontline AML clinical trial AAML1031 uses allogeneic HSCT in first remission only for patients with predicted high risk of treatment failure based on unfavorable cytogenetic, molecular characteristics and elevated end-of-induction MRD levels.
204 In contrast, the AML-BFM 2004 clinical trial restricted allogeneic HSCT to patients in second CR and to refractory AML, based on results from their AML-BFM 98 study showing no improvement in DFS or OS for high-risk patients receiving allogeneic HSCT.
205 Although the optimal timing for allogeneic HSCT has not been determined, most cooperative groups recommend doing HSCT following the second or third course of chemotherapy, based in part due to the time involved in obtaining HLA typing. The use of matched unrelated donors (MUD), haploidentical donors, single- or double-cord blood donor, or nonablative approaches for HSCT in CR1 are not as clearly established as MSD HSCT, but are increasingly used to provide potential curative treatment for patients with recurrent AML (
Table 77.3).
206,207
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