ALLOGENEIC STEM CELL TRANSPLANTATION IN FIRST COMPLETE REMISSION

Abstract

Purpose of review

The optimal post-remission therapy of acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. This review summarizes the recent developments in the clinical research and therapeutic applications defining the role of allogeneic hematopoietic stem cell transplantation (allo-HCT) in CR1.

Recent findings

Molecular markers in combinations with cytogenetics have improved the risk stratification and informed decision-making in patients with AML in CR1. In parallel, several important advances in the transplant field, such as better supportive care, improved transplant technology, increased availability of alternative donors, and reduced-intensity conditioning have improved the safety as well as access of allo-HCT for a larger number of patients.

Summary

The progress in risk stratification and transplant technology dictate that early donor identification search should be initiated for all eligible AML patients in CR1.

Introduction

Achieving cure in acute myeloid leukemia (AML) has been a challenge and depends on successful induction therapy to achieve a complete remission (CR) and subsequent post-remission therapy to prevent relapse. While more than 70% of adult AML patients will enter a first CR (CR1) after induction chemotherapy, most later experience disease relapse [1]. The overall survival (OS) of adults with AML is poor, even in the most favorable cytogenetic groups, such as those with core binding factor (CBF) translocations [2]. The options for post-remission treatment are broad and the choice of therapy is determined by the prognostic factors at diagnosis and beyond. Physician and patient biases also impact the choices of therapy offered and chosen. Among the alternatives, allogeneic hematopoietic stem cell transplantation (allo-HCT) after myeloablative conditioning (MAC) may be a preferred curative option for younger patients with AML in CR1. However, concerns regarding allo-HCT related toxicity and questions regarding its benefit, limit its use for patients in CR1. The current recommendations for allo-HCT for patients in CR1 are limited to those whose risk of relapse significantly exceeds the mortality from allo-HCT and is based on cytogenetic stratification into good-, intermediate-, and poor-risk AML. These are summarized in treatment guidelines of the National Comprehensive Cancer Network (V2.2011: available at http://www.nccn.org). However, with progress in understanding the disease biology of AML and identification of new molecular markers, current practice may of course, still evolve. Additionally, with advances in transplant field including better supportive care, the use of high-resolution allele-level human leukocyte antigen-(HLA) typing leading to better donor selection and the introduction of reduced intensity conditioning (RIC), the risk-benefit ratio of allo- HCT has improved.

Is there benefit with allo-HCT in AML CR1?

Multiple prospective trials investigated the role of allo-HCT for AML in CR1. Treatment assignment has been based on donor availability: patients with HLA-matched related donors (MRD), usually siblings, are recommended to undergo allo-HCT (donor group), and those without matched siblings are assigned to nonallogeneic HCT therapy (no-donor group). These donor: no donor comparisons may be confounded by limited application of the assigned therapy and the results have not always been consistent leaving the role of allo-HCT in AML patients in CR1 unclear [3–7]. A large meta-analysis analyzed 24 prospective studies including over 6000 patients with AML in CR1 compared the role of HCT to non-HCT treatments [8]. In the studies, 3,638 patients were analyzed by cytogenetic risk category, including 547 good-risk, 2,499 intermediate-risk, and 592 poor-risk patients. Compared with nonallogeneic therapy, the hazard ratio (HR) of relapse or death with an allo-HCT for patients in CR1 was 0.80 (95% CI 0.74 to 0.86). But when the analysis was broken down by risk category and outcome, there was a significant survival advantage for allo-HCT during CR1 in intermediate- and high-risk AML patients, but not in good-risk patients. Although these results were encouraging to define allo-HCT as a better treatment, most studies addressed patients younger than 60 leaving unclear whether older patients could benefit similarly. There are also concerns about various late effects such as graft-versus-host disease (GVHD) that might lower the quality of life (QOL) after cure of AML with allo-HCT. Recently, a Markov decision analysis compared survival outcomes after allo-HCT (related and unrelated donors) and chemotherapy using a QOL evaluation from a database of 2029 adult AML patients (up to age 70, median age 50) who achieved CR1 [9]. In this study, patients with favorable-risk AML in the chemotherapy group had a longer life expectancy (LE) than patients in the allo-HCT group. In contrast, patients with intermediate, unfavorable, and unknown-risk AML in the allo-HCT group had a longer median LE than patients in the chemotherapy group (intermediate risk, 73.6 vs 66.4 months; unfavorable, 61.6 vs 53.4 months). Although quality-adjusted life expectancy (QALE) was less favorable in the allo-HCT group, the median QALE remained longer in the allo-HCT group with intermediate- and high-risk risk cytogenetics (intermediate, 59.4 vs 55.6 months; unfavorable, 47.6 vs 44.4 months). Both younger and older patients with intermediate- and high- risk disease had improvements in LE and QALE, but the older patients with a suitable related donor benefited the most from allo-HCT in CR1. This study was conducted with patients treated between 1999 and 2006. One might expect even better results after unrelated donor allo-HCT using allele level matching, a practice of recent years.

Identification of gene mutations, deregulated expression of genes and noncoding RNAs (ie, microRNAs) is unraveling the enormous molecular genetic heterogeneity within cytogenetically defined subsets of AML, in particular the large group with cytogenetically normal (CN) AML [10–14]. It has become clear that specific chromosome abnormalities and molecular genetic changes are among the most important prognostic markers and may therefore be used for stratification to apply risk-adapted therapeutic strategies. Recently European LeukemiaNet proposed a standardized reporting system for genetic abnormalities using data correlating genetic findings with clinical outcome (Table 1) [15].

Table 1.

Standardized reporting for correlation of cytogenetic and molecular genetic data in AML by European LeukemiaNet [15]

Genetic Group	Subsets
Favorable	t(8;21)(q22;q22); RUNX1-RUNX1T1 inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 Mutated NPM1 without FLT3-ITD (normal karyotype) Mutated CEBPA (normal karyotype)
Intermediate-I	Mutated NPM1 and FLT3-ITD (normal karyotype) Wild-type NPM1 and FLT3-ITD (normal karyotype) Wild-type NPM1 without FLT3-ITD (normal karyotype)
Intermediate-II	t(9;11)(p22;q23); MLLT3-MLL Cytogenetic abnormalities not classified as favorable or adverse
Adverse	inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 t(6;9)(p23;q34); DEK-NUP214 t(v;11)(v;q23); MLL rearranged −5 or del(5q); −7; abnl(17p); complex karyotype‡

^‡Three or more chromosome abnormalities in the absence of one of the WHO designated recurring translocations or inversions, that is, t(15;17), t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23), t(6;9), inv(3) or t(3;3).

Source: Reproduced with permission from: Dohner, H., et al., Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood, 2010. 115(3): p. 453–74.

Role of allo-HCT in CN-AML

Several authors have shown the prognostic significance for mutations in the NPM1, CEBPA, and FLT3 genes, alone or in combination for both younger and older adults with CN-AML, which constitutes 40%–50% of all AML (Table 2)[16–18]. CN-AML patients harboring internal tandem duplication (ITD) of the FLT3 gene have an inferior outcome compared with cases without FLT3-ITD [19–21]. There is also evidence that outcome may be more related to the level of the mutated allele [21, 22] and to the insertion site of the ITD [23, 24]. The prognostic significance of FLT3-TKD mutations remains controversial in view of conflicting data [25, 26]. NPM1 mutation in CN-AML has been associated with higher CR rates and better relapse free survival (RFS) and event-free survival (EFS) [27, 28]. However, 40% of patients with NPM1 mutations also carry FLT3-ITD. Multiple studies have shown that the genotype “mutated NPM1 without FLT3-ITD” represents a favorable prognostic marker, with higher CR rates, and better RFS and OS; similar to patients with inv(16) or t(8;21) [19, 27, 28]. The favorable impact of mutated NPM1 (without FLT3-ITD) on survival endpoints also seems to hold up among patients of older age [29]. CN-AML with mutations in CEBPA has also been associated with a favorable prognosis [30, 31]. Though the groups are small, the survival data are similar to those of AML patients with mutated NPM1 without FLT3-ITD. Recently, it was shown that only cases with double CEBPA mutations, usually biallelic, have a favorable outcome [32].

Table 2.

Genetic alterations in CN-AML

Mutation	Frequency in CN-AML (%)
NPM1	45–55
FLT3-ITD	35–45
IDH1*	8–9
MLL-PTD	5–10
CEBPA	~10
NRAS	5–10
WT1*	8
RUNX*	14–34
FLT3-TKD	5–8

^*Requires confirmation by additional studies.

Abbreviation: CN, normal cytogenetic.

Source: Original

In a study from Germany, researchers analyzed the role of mutational status of NPM1, FLT3, CEBPA, along with MLL and NRAS in guiding post-remission therapy for CN-AML in CR1 younger than age 60 [19]. For post-remission therapy, patients with an HLA- MRD were assigned to undergo allo-HCT in CR1; those without a donor were randomly assigned to receive high-dose cytarabine consolidation or autologous transplant. Importantly, the assigned allo-HCT was performed in 82% of patients. Autologous transplant or consolidation therapy resulted in similar outcomes. An intention-to-treat analysis on the basis of donor availability demonstrated significantly longer RFS in the donor group (P = .009). Data were further analyzed on the basis of mutation status, and patients were subdivided into 2 groups: patients with “mutated (m)NPM1 without FLT3-ITD,” and patients with all other genotypes. Because of small numbers, patients with mCEBPA were excluded. RFS was similar either with or without a donor in the favorable genotype patients having mNPM1 without FLT3-ITD (P = .71). Among the patients with CN-AML and other genotypes, superior RFS was observed in those with a donor. Therefore again, other than the most favorable genotype group, outcomes were better with a donor for allo-HCT.

There is a growing list of genetic abnormalities potentially influencing the outcome of AML. These include mutation analyses of the WT1 [33], RUNX1 [34], TET2 [35] and IDH1 genes [36] and the analyses of gene expression signatures [37, 38] or of deregulated expression of single genes, such as EVI1[39], ERG [40], MN1 [41], and BAALC [42] genes.

Despite abundant information about the prognostic impact of single markers, little is known about their cumulative effect on disease outcomes. A recent study by HOVON/SAKK analyzed clinical and molecular markers to develop an integrative prognostic risk score (IPRS) in CN-AML patients younger than 60 to determine treatment strategies in CR1 [43]. In the dataset of 275 adult patients, 2 clinical (age, white blood cell count) and 7 molecular markers (mutation/polymorphism status of FLT3/NPM1, CEBPA, WT1 SNP rs16754, expression levels of MN1, BAALC, ERG, and WT1) fulfilled the significance criteria and 3 risk groups were defined having different OS and RFS. These results were confirmed in 2 independent validation cohorts. The prognostic benefit of a MRD allo-HCT in CR1 in defined risk groups was outlined. In the low risk group, there was no difference in OS and RFS between donor and no-donor group. In the high risk group, donor availability was independently associated with improved OS and RFS. On the other hand, in the intermediate risk group, donor availability was an independent predictor for shorter OS and RFS. One particular finding of this study was the high prevalence of NPM1/FLT3-ITD high-risk mutation status in all IPRS groups (30%, 61%, and 92% in the low-, intermediate-, and high-risk IPRS groups, respectively). Although most patients in the IPRS high-risk group were identified by NPM1/FLT3-ITD mutation status, there was a significant proportion of patients appeared not to benefit from allo-HCT that could be identified by IPRS apart from the NPM1/FLT3-ITD mutation status.

Allo-HCT in Favorable Cytogenetic Risk AML

No advantage has been shown for allo-HSCT in CR1 for CBF AML [8, 44]; if intensive consolidation chemotherapy is administered. However, in one subgroup with worse prognosis; CBF AML with KIT mutations, allo-HCT may be considered. KIT mutations are found in 25% to 30% of cases of CBF-AML while rare in other AML subsets [45]. In most studies, KIT mutations have been associated with inferior outcome [37]. Although there is no clear data supporting the use of KIT mutational status to guide therapy, allo-HCT can be considered in CR1 for patients with KIT mutation as their 5-year relapse risk is similar to that reported with adverse cytogenetics.

Logistics of allo-HCT in CR1: The role of alternative donors and age

Meta-analysis of prospective biologic assignment studies comparing the role of HCT to non-HCT treatments have shown a strong survival advantage of allo-HCT using a MRD for intermediate- and high risk AML patients in CR1. Yet only 30% of patients have a suitable MRD. Thus, it is important to expand the acceptable donor pool for patients with AML. Registry data from the Center for International Blood and Marrow Transplant Research (CIBMTR) [46] and two prospective studies [7, 47] comparing MRD with unrelated donor (URD) with adverse risk AML patients in CR1 have shown comparable outcomes. These suggest that when a MRD is not available, an HLA-well matched URD is appropriate. There is lesser consensus whether such a strategy should be routinely adopted for patients with intermediate cytogenetics lacking a MRD due to insufficient prospective studies and inherent selection bias in patients chosen for such procedure. Unrelated umbilical cord blood (UCB) has emerged as an alternative source for allo-HCT and may be particularly valuable for patients who have a narrow time window of opportunity to proceed to transplantation. Recent studies have demonstrated similar leukemia free survival (LFS) after UCB and URD transplantation after MAC in patients with acute leukemia [48, 49]. Although various hematological malignancies at different disease stages were included in those studies, it can be suggested that those results would also apply to AML patients in CR1.

Haploidentical transplants (haplo-HCT) present another alternative for patients with a poor prognosis for whom no sibling donor is available. Although there are less cumulative data on using this procedure than on using URD transplants, a recent European Bone Marrow Transplant Registy (EBMTR) study indicated that the haplo-HCT results for high-risk AML in CR are similar to what has been reported for URD transplants [50]. Conventional chemotherapy options are not curative in a large majority of AML patients ≥ 60 years of age [51, 52]. Short leukemia free survival is due mainly to inability to maintain CR. There has been no consolidation chemotherapy that has been shown to improve LFS with acceptable toxicity although this has been the mostly applied post-remission therapy in older AML patients. The introduction of RIC has extended the availability of allo-HCT to this population. A recent CIBMTR analyses demonstrated that transplantation toxicity, relapse, and survival for older adults are similar to those for younger adults undergoing RIC allo-HCT in AML CR1 (2 year OS was ~ 30%) [53]. A recent study compared the outcome of 100 AML patients aged 60–70 years who received RIC allo-HCT in CR1 and were reported to the CIBMTR to that of 96 AML patients treated with only standard induction and post-remission chemotherapy on Cancer and Leukemia Group B protocols (47). In the chemotherapy-treated group, only patients who remained in CR1 for at least 4 months were included in order to reduce selection bias. Allo-HCT was associated with longer LFS compared to chemotherapy. The 3-year LFS from CR1 for HCT patients was 34% compared to 17% for chemotherapy-treated patients.

Despite these encouraging results, in a small prospective study, less than 15% older AML patients received allo-HCT in CR1 [54]. Reluctance to use allo-HCT may be due to concerns that selection bias leads to selection of only the "fittest” older patients for RIC HCT and that results of the procedure may not generalize to majority of older patients in CR1. Data from prospective clinical trials are required to overcome skepticism for observational data that might overestimate the efficacy of allo-HCT.

Real World Data

The only population based study for AML patients undergoing allo-HCT was presented by Swedish Acute Leukemia Registry where all high risk AML patients were recommended for allo-HCT [55]. Intermediate risk patients were also transplanted if the balance between disease-related and transplant-related risk favored allo-HCT, but patients with favorable cytogenetics were not transplanted. Among 797 AML patients younger than 60 diagnosed between 1996 and 2007, 29% of patients underwent allo-HCT in CR1. Approximately half of the donors were unrelated. The median time to HCT from diagnosis was 136 and 176 days for MRD and URD, respectively. Superior 5-year survival from CR1 was observed in patients who were transplanted in CR1 compared with non-transplant approaches (61% vs. 48%, p=0.005). This study was unique since it included not only medically fit patients, but also those with poor performance status who might not be included in clinical trials.

Conclusion

Decision-making about allo-HCT in AML CR1 is complex requiring consideration of patient and disease characteristics, but also available donor type, conditioning regimen chosen and anticipated TRM. However, available data suggests the initiation of an early donor search for all AML patients and directed efforts to ensure that eligible patients receive transplants in a timely manner. Since survival of relapsed patients is poor, all suitable patients with other than the most favorable disease features should proceed with allo-HCT during CR1.

Key points.

• Current recommendations for allo-HCT for patients in CR1 are limited to those whose risk of relapse significantly exceeds the mortality from allo-HCT and is based on cytogenetic stratification into good-, intermediate-, and poor-risk AML

• Recent studies have shown significant survival advantage for allo-HCT during CR1 in intermediate- and high-risk AML patients.

• Based on risk stratification and patient characteristics, allo-HCT should be considered and donor search be initiated early in the disease course.