Current Opinion in Hematology:
MYELOID DISEASE: Edited by Martin S. Tallman
Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first complete remission: have the indications changed?
Paun, Oana; Lazarus, Hillard M.
Department of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio, USA
Correspondence to Hillard M. Lazarus, MD, FACP, University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA. Tel: +1 216 844 3629; fax: +1 216 844 5979; e-mail: Hillard.Lazarus@case.edu
Purpose of review: Many improvements in chemotherapy and supportive care, as well as greater understanding of immunology and procuring graft sources, have led to more acute myeloid leukemia patients proceeding to hematopoietic cell transplantation, now the most common indication for this procedure.
Recent findings: As treatment-related mortality rates have been reduced, more practitioners and patients are amenable to use of this modality if the risk : benefit ratio appears justified. Clinical factors initially were used to identify patients at highest risk for relapse using conventional approaches, a strategy supplanted by one based on the genetic alterations of the leukemia cells. More recently, molecular factors are used to identify such candidates; the issue of which first remission acute myeloid leukemia patients receive hematopoietic cell transplantation is referred to as risk stratification.
Summary: With significant improvements in donor : recipient matching and a more varied graft source, greater numbers of patients can proceed to alternative donor hematopoietic cell transplantation. Advancing age appears to be less of a barrier and outcomes are reasonable in patients with good performance status and few comorbidities. The most interesting aspect of the moving target of which patients to take to hematopoietic cell transplantation is to define those with favorable-risk disease and avoid the procedure, while using the armamentarium at hand to identify those at higher and highest risk for relapse as the group most likely to benefit. The field, however, still awaits the data that demonstrate improved outcome in these poor-risk patients using the hematopoietic cell transplantation approach.
Acute myeloid leukemia (AML) is the most common indication for allogeneic hematopoietic cell transplantation (HCT), a modality regularly employed as a curative treatment option for patients with various disorders. Dramatic improvements in the donor-to-recipient matching graft selection process  as well as improved supportive care have markedly reduced treatment-related mortality (TRM) [2▪,3▪]. The emergence of reduced-intensity conditioning (RIC) in deference to myeloablative conditioning (MAC) broadens the applicability of this modality to patients who formerly would have been excluded from HCT due to advanced age or comorbid conditions. The use of graft sources such as umbilical cord blood (UCB), matched-unrelated, and haploidentical donors ensures that almost every patient now can be transplanted [4,5]. These data encourage practitioners to default to HCT in poor-risk patients even though supporting studies demonstrating a superior outcome compared with nontransplant options are lacking.
HCT remains plagued, however, by relapse of malignancy, graft-versus-host disease (GVHD), infectious complications, and TRM; an appropriate patient selection strategy is imperative in this context. This review will address informed decision making to identify those AML patients in first complete remission (CR1) who should be offered HCT.
Several clinical features at presentation are associated with particularly poor outcome for AML patients. Age over 60 years, hyperleukocytosis, poor performance status, secondary AML (after antecedent myelodysplasia), or treatment-related myeloid neoplasm (t-MN) and, in some series, two induction cycles rather than one to attain CR1 are clinical factors that portend worse outcome . As a result, many investigators proceed to offer HCT to such individuals. Supporting data to show an improved outcome in this group, compared with conventional approaches, however, often are lacking. Better methods of identifying the risk : benefit ratio for HCT versus conventional therapy continually are being developed.
ACUTE MYELOID LEUKEMIA CLASSIFICATION
In 1976, the French American British (FAB) classification provided the first consistent morphologic and cytochemical framework in which the significance of the genetic lesions could be appreciated. During its decades of use, investigators realized that many AML cases are associated with recurring genetic abnormalities that affect cellular pathways of myeloid maturation and proliferation. The FAB classification was modified by the World Health Organization (WHO) in 2002 and again in 2008  to include biologic, clinical, immunophenotypic, and genetic features to define specific disease entities.
Cytogenetics, however, remains the most robust prognostic marker for risk stratification of AML at the time of diagnosis as well as in selection of postremission treatments [8,9▪▪,10]. On the basis of specific structural and numerical cytogenetic abnormalities, AML patients are divided into favorable-risk, intermediate-risk, and adverse-risk groups. This approach, in part, reflects the use of HCT in patients on the basis of ‘biologic assignment,’ that is, transplant using a matched-sibling donor. In a meta-analysis of prospective biologic assignment studies, 3638 AML patients in CR1 were shown to have a significant survival advantage after allogeneic HCT when compared with conventional postremission therapy. A notable exception is the favorable cytogenetic risk group, in whom HCT did not further improve outcome . This HCT strategy remains the cornerstone of approaching patients although assignment of risk based on cytogenetics remains extremely complex (see below).
FAVORABLE-RISK ACUTE MYELOID LEUKEMIA
Patients with core binding factor (CBF) leukemia, that is, t[8;21] or inv or t[16;16], or acute promyelocytic leukemia (APL) with t(15;17), are considered at relatively lower risk of relapse and thus are assigned to the favorable-risk cytogenetics group [8,9▪▪]. As noted above, the meta-analysis of prospective ‘genetic randomization’ studies  showed no benefit of HCT in patients with favorable-risk cytogenetics in CR1. With all-trans retinoic acid or arsenic trioxide-based treatments, the outcome of APL with t(15;17) has improved significantly. The expected relapse rate is usually 10–25% and these treatment strategies lead to cure in the majority of patients . In CBF-AML, however, only 50% of patients were alive at 5 years. Therefore, some of these patients may still have a high risk of relapse. The role of KIT mutations (mKIT) in CBF-AML has been investigated  to identify a high-risk subset in the otherwise favorable CBF group. Two commonly identified KIT mutations [exon 17 (mKIT 17) and exon 8 (mKIT 8)] in CBF-AML appear to have prognostic relevance although the data from these studies are not consistent. Discrepant results may be related to a smaller number of patients and differences in the treatments.
Repetitive cycles of high-dose cytarabine (HiDAC) as postremission therapy are associated with favorable outcomes in patients with CBF-AML . Patients with ‘CBF-AML with mKIT,’ however, are considered intermediate risk and thus candidates for HCT in CR1; no data yet are available to show benefit. The high risk of relapse in these patients merits the investigation of alternative treatment strategies including HCT or possibly molecular targeted therapies using tyrosine kinase inhibitors.
UNFAVORABLE-RISK OR ADVERSE-RISK ACUTE MYELOID LEUKEMIA – MONOSOMAL KARYOTYPE
Monosomal karyotype, one type of unfavorable AML with an extremely poor prognosis , is defined as 2 or more distinct autosomal monosomies or a single autosomal monosomy in the presence of other structural abnormalities. Less than 4% of monosomal karyotype-positive patients were projected to be alive 4 years after the initial diagnosis; the only monosomal karyotype-positive patients alive and disease-free more than 6 years from diagnosis received allogeneic HCT while in CR1. In a retrospective review of 432 HCT recipients from the Fred Hutchinson Cancer Research Center [16▪], 14% of whom were monosomal karyotype-positive, 4-year overall survival after HCT was 25% for monosomal karyotype-positive AML and 56% for monosomal karyotype-negative AML (P < 0.0001). Specific monosomies did not appear to differ in prognosis, except for monosomy 5; 14 of 15 monosomal karyotype-positive patients with this defect failed to survive to 18 months after HCT, a 0% estimated overall 4-year survival. HCT appears to improve monosomal karyotype-positive patient outcome, especially those without a complex karyotype. Allogeneic HCT should be offered to younger patients but given the extremely poor prognosis of monosomal karyotype in older patients, the authors recommend alternative treatment strategies.
INTERMEDIATE-RISK ACUTE MYELOID LEUKEMIA
AML patients without favorable or unfavorable cytogenetic aberrations are classified as the intermediate-risk cytogenetic subclass. Typically, this group includes cytogenetically normal disease and accounts for approximately 60% of all AML patients. In the past decade, great strides have been made to further define this heterogeneous group in which gene mutation and gene expression studies may discern favorable versus unfavorable subsets.
In recent years, a variety of novel molecular markers including mutations in the fms-related tyrosine kinase 3 (FLT3) gene , the nucleophosmin (NPM1) gene , and the CCAAT/enhancer-binding protein alpha (CEBPA) gene [19▪▪] have refined the risk stratification of intermediate-risk AML. FLT3-internal tandem duplication (ITD) is present in roughly one-quarter of AML cases and represents an often lethal subtype of AML. While FLT3-ITD AML patients may achieve complete remission at or near the same rate for patients lacking these mutations, relapse (within 5 months) is far more likely than the FLT3-ITD wild-type counterparts. Allogeneic HCT CR1 data from the group at Johns Hopkins [20▪] show that the survival for patients with FLT3-ITD AML is equivalent to non-FLT3-mutated AML. The optimal therapeutic approach for a patient with FLT3-ITD AML would be conventional induction therapy followed as rapidly as possible by allogeneic HCT, including the use of alternative donors, if necessary.
Mutations involving the NPM1 gene are among the most frequent molecular alterations in AML with normal karyotype, accounting for approximately 60% of cases (i.e. one-third of adult AML) . AML with mutated NPM1 generally is characterized by good response to induction chemotherapy and favorable prognosis (in the absence of a concomitant FLT3-ITD mutation). However, a significant number of cases with NPM1-mutated AML still show poor outcome, especially those associated with the FLT3-ITD mutation as well as elderly patients.
The presence of NPM1 mutation in cytogenetically normal AML often is associated with higher complete remission rates and better event-free survival (EFS) . Multiple studies  have shown that the genotype ‘mutated NPM1 without FLT3-ITD’ represents a favorable prognostic marker, with higher complete remission rates, and better overall survival reminiscent of that seen in patients with inv(16) or t(8;21). This favorable impact of mutated NPM1 (with or without FLT3-ITD) on survival end points also seems to hold up among older-age patients. Among the cytogenetically normal AML, HCT in CR1 could be deferred in the favorable genotype of ‘mutated NPM1 without FLT3-ITD.’
Other molecular markers such as CEBPA are beginning to penetrate clinical practice and influence decision making, but a full discussion is outside the scope of this review. Several investigators have used combinations of molecular markers to improve the patient's risk assessment in cytogenetically normal AML. In a series based on four prospective clinical trials conducted by the German–Austrian Acute Myeloid Leukemia Study Group, Schlenk and coworkers  analyzed the role of mutational status of NPM1, FLT3, CEBPA, and other markers to guide postremission therapy for cytogenetically normal AML in CR1. Those 150 patients with an HLA-matched-related donor were assigned to undergo HCT. The benefit of HCT was limited to the subgroup of patients with the prognostically adverse genotype FLT3-ITD or the genotype consisting of wild-type NPM1 and CEBPA without FLT3-ITD. This single study requires validation by other groups. The complexities of using multiple biomarkers for prognosis suggest the need for integration in a combined analysis, that is, integrative prognostic scores. The Erasmus group [23▪▪] and a research group from China  have begun to address this important approach for AML patients. Hence, these new mutations may be useful in helping to refine the definition of so-called favorable-risk AML.
ROLE OF ALTERNATIVE DONOR HEMATOPOIETIC CELL TRANSPLANTATION IN ACUTE MYELOID LEUKEMIA FIRST COMPLETE REMISSION
Most comparison studies for conventional chemotherapy versus allogeneic HCT [5,25] involve grafts from matched-related donor rather than alternative donors, that is, comparisons of alternative donor HCT to conventional therapies are scant. Gupta et al. for the US Center for International Blood and Marrow Transplant Research (CIBMTR) [26▪] reported similar outcomes for unfavorable cytogenetics AML CR1 patients receiving either matched-related (n = 226) or matched-unrelated (n = 358) donor grafts, similar to the studies cited above [5,24]. Although with fewer data, a study reported by Walter et al. in intermediate-risk AML CR1 patients demonstrated comparable outcomes on the matched-related compared with the alternative donor graft source group. Unfortunately, there do not appear to be published data yet on specific intermediate-risk cytogenetic AML CR1 patients who have adverse molecular markers such as FLT3-ITD mutations.
UCB grafts are used in HCT at a rapidly increasing rate, but the utility of this graft source in AML CR1 at present is uncertain. A retrospective analysis from the US CIBMTR by Eapen and coworkers  showed that despite using UCB grafts (n = 165) that were not as well HLA matched as those obtained from unrelated adult donors (n = 888 blood, 472 marrow), leukemia-free survival rates were comparable. TRM, however, was higher in the UCB group, a common finding due to slower engraftment rates, in part a reflection of the lesser numbers of hematopoietic progenitor cells infused. Many investigators  have begun to infuse double UCB grafts to address this limitation. Additional conclusions regarding the specific situation of UCB HCT in AML CR1 are not possible given the heterogeneity of the patient diagnoses and disease states. A recently reported Japanese study  noted inferior outcome due to higher TRM in the AML CR1 UCB recipients compared with unrelated marrow graft recipients. Finally, there are too few data to draw conclusions regarding the relative effectiveness of haploidentical grafts in AML CR1 patients. Use of matched-unrelated donor (MUD) grafts is hampered by a longer procurement time compared with UCB grafts. Institutional UCB HCT experience, however, is a major factor to consider in view of the nearly 20% incidence of engraftment failures and slower tempo to marrow reconstitution, even though for a given degree of HLA match, GVHD likelihood is reduced when compared with HCT using a MUD adult donor. HCT using volunteer adult MUD grafts and probably UCB grafts should be utilized in AML CR1 patients considered high risk for relapse.
TREATMENT-RELATED MYELOID NEOPLASM (ACUTE MYELOID LEUKEMIA)
As more patients survive therapy for cancer, t-MN is increasing and may account for 10–20% of cases of AML. Conventional chemotherapy is not curative and hence HCT is a potential option, although there are few prospective studies to guide practitioners. The results of HCT in this patient group are inferior to de-novo AML patients, a result not unexpected given the likelihood of unfavorable cytogenetics and usually active disease at time of transplant [31,32]. For example, in the CBF-AML patients, patient outcome for t(8;21) patients was inferior to de-novo AML . In a series in which the authors accounted for disease status and cytogenetics [34,35], however, patient outcome of de-novo AML and treatment-related AML, especially for those with inv(16), did not differ. For patients who were younger, in CR1, had a matched-sibling donor, or well/partially matched donor, HCT gave encouraging results. Litzow et al., for the US CIBMTR , proposed a prognostic scoring system that may be particularly useful in selection of patients for HCT as the 5-year survivals ranged from 50 to 4% in the five categories. These data suggest that given the poor prognosis of this patient group, HCT in CR1 should be considered for patients who have suitable donors and are not considered one of the extremely poor-risk categories.
MYELOABLATIVE CONDITIONING VERSUS REDUCED-INTENSITY CONDITIONING
The US CIBMTR developed definitions for the intensity of the conditioning therapy as this issue is confounded by a significant inherent selection bias, that is, which patients receive which regimens . Patients thought to be at highest risk for relapse often are offered MAC, as the preparative regimen intensity will provide a greater antileukemic effect. On the other hand, RIC usually is offered to the more elderly or those with comorbid conditions in order to lessen TRM; in this situation, leukemia eradication is more dependent on the allogeneic or graft-versus-leukemia effect. The comparison data for different regimen intensities are often retrospective in nature. At present, the US Blood and Marrow Transplant Clinical Trials Network has undertaken a prospective, randomized clinical trial (BMT CTN 0901) comparing MAC with RIC in patients who fulfill the criteria for either approach. Until completion of this study, we must rely on the plethora of these somewhat flawed studies. The conclusions of this large data set suggest that TRM is lower with RIC, whereas relapse rates are higher compared with MAC [37–39]. In one of the largest trials reported to date, Luger et al. for the US CIBMTR  compared outcomes of 3731 MAC with 1448 RIC and nonmyeloablative conditioning (NMA) procedures. NMA conditioning was inferior but disease-free survival and overall survival between RIC and MAC regimens did not differ. While these data suggest that higher regimen intensity may contribute to improved survival in patients with AML/myelodysplastic syndrome (MDS), prospective studies comparing regimens are needed to confirm this finding and determine the optimal approach to patients who are eligible for either MAC or RIC/NMA conditioning. As no study to date has shown superiority of RIC to MAC in AML, we recommend reserving the lesser intensity conditioning (RIC and not NMA) only to patients thought to be ineligible (due to advanced age or comorbidities) for the more intense regimen.
HEMATOPOIETIC CELL TRANSPLANTATION IN THE MORE ELDERLY ACUTE MYELOID LEUKEMIA PATIENT
Advanced patient age clearly impacts negatively on outcome in AML and conventional chemotherapy is not curative in most patients of 60 years of age or older. Further, the unacceptably high TRM in this patient population traditionally has been a barrier to HCT . The advent of RIC, shown to be feasible with reasonable outcomes in the more elderly patient, even with use of alternative donors, steadily has been increasing and overcoming many of the barriers including hesitancy of referring physicians and lack of insurance coverage. McClune et al. for the US CIBMTR  recently reported retrospective registry data showing similar 2-year leukemia-free survival and overall survivals in 545 AML CR1 patients aged at least 40 years (63 patients older than 65 years). Deschler and associates  and Koreth and coworkers  using RIC, while Gyurkocza and colleagues using NMA , published similar results in which there was no unfavorable impact of age on HCT. In fact, recipients of matched-related donors had survivals nearly equivalent to those who received well matched, unrelated donor grafts. Thus, one can recommend that suitably fit patients up to age 70 years should be offered HCT in CR1.
QUALITY OF LIFE-BASED DECISIONS
Using a database of 2029 adult AML CR1 patients, Kurosawa and colleagues [45▪▪] performed a Markov decision analysis (allogeneic HCT versus conventional chemotherapy) to compare survival outcomes with a quality of life (QOL) evaluation. Patients who had intermediate-risk and unfavorable-risk AML had a longer life expectancy after HCT than patients treated with chemotherapy alone. Likewise, patients who had received a related donor HCT in CR1 had a longer life expectancy. QOL-adjusted life expectancies in most of the subgroups were longer in the HCT group than in the chemotherapy group. The results showed that older patients with a matched-related donor and younger patients with unfavorable cytogenetics benefited the most from HCT in CR1.
Newer initiatives that may be useful for determining risk stratification include micro-RNA expression. These small (19–22 nucleotides), highly conserved RNA molecules play crucial functions in the regulation of essential cellular processes and several studies  have defined patterns of micro-RNA expression associated with cytogenetics, molecular subgroups, and clinical outcome in AML.
The trend of growth in number of HCTs performed in adult AML patients can be expected to continue, based on acceptance and availability of unrelated donors and UCB grafts. Few data are available for the reliable estimates of the number of transplants for AML and the total number of AML patients for whom transplantation is appropriate. Table 1 summarizes the current allogeneic HCT indications for younger (<60 years) AML patients. Finding the optimal individualized strategy for patients requires a better understanding of the disease itself and a true personalized approach based on a combination of cytologic and molecular markers, in conjunction with the clinical scenario and the patient's beliefs and expectations. In the particular case of intermediate-risk AML, the development of an integrative score with prognostic and predictive significance, based on the available gene expression profiling-derived data, certainly will help guide the management decisions. Further research is needed in the field, and the enrollment of patients in well designed prospective trials cannot be overemphasized.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 128).
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