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Current Opinion in Hematology:
doi: 10.1097/MOH.0b013e32834ff54b
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.

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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:

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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.

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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 [1] 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.

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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 [6]. 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.

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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 [7] 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 [11]. This HCT strategy remains the cornerstone of approaching patients although assignment of risk based on cytogenetics remains extremely complex (see below).

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Patients with core binding factor (CBF) leukemia, that is, t[8;21] or inv[16] 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 [11] 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 [12]. 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 [13] 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 [14]. 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.

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Monosomal karyotype, one type of unfavorable AML with an extremely poor prognosis [15], 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.

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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 [17], the nucleophosmin (NPM1) gene [18], 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) [21]. 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) [18]. Multiple studies [22] 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 [22] 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 [24] 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.

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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.[27] 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 [28] 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 [29] 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 [30] 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.

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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 [33]. 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 [31], 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.

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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 [36]. 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 [37] 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.

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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 [40]. 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 [41] 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 [42] and Koreth and coworkers [43] using RIC, while Gyurkocza and colleagues using NMA [44], 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.

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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.

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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 [46] have defined patterns of micro-RNA expression associated with cytogenetics, molecular subgroups, and clinical outcome in AML.

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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.

Table 1
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Conflicts of interest

There are no conflicts of interest.

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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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1. Lee SJ, Klein J, Haagenson M, et al. High-resolution donor–recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 2007; 110:4576–4583.

Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010; 363:2091–2101.

The authors found a substantial reduction in the hazard of death related to allogeneic HCT, as well as increased long-term survival over the past decade, with improvement in rates of organ damage, infection, and severe acute GVHD.

Horan JT, Logan BR, Agovi-Johnson MA, et al. Reducing the risk for transplantation-related mortality after allogeneic hematopoietic cell transplantation: how much progress has been made? J Clin Oncol 2011; 29:805–813.

The study showed that innovations in transplantation care have reduced the risk of TRM in patients undergoing allogeneic HCT for AML, with corresponding improved overall survival.

4. Barker JN, Byam CE, Kernan NA, et al. Availability of cord blood extends allogeneic hematopoietic stem cell transplant access to racial and ethnic minorities. Biol Blood Marrow Transplant 2010; 16:1541–1548.

5. Schlenk RF, Döhner K, Mack S, et al. Prospective evaluation of allogeneic hematopoietic stem-cell transplantation from matched related and matched unrelated donors in younger adults with high-risk acute myeloid leukemia: German–Austrian trial AMLHD98A. J Clin Oncol 2010; 28:4642–4648.

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Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010; 116:354–365.

Very large study examining the prognostic significance of rare, recurring cytogenetic abnormalities.

10. Byrd JC, Mrózek K, Dodge RK, et al. Cancer and Leukemia Group B (CALGB 8461)Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB8461). Blood 2002; 100:4325–4336.

11. Koreth J, Schlenk R, Kopecky KJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 2009; 301:2349–2361.

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13. Paschka P, Marcucci G, Ruppert AS, et al. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol 2006; 24:3904–3911.

14. Byrd JC, Ruppert AS, Mrozek K, et al. Repetitive cycles of high-dose cytarabine benefit patients with acute myeloid leukemia and inv(16)(p13q22) or t(16;16)(p13;q22): results from CALGB 8461. J Clin Oncol 2004; 22:1087–1094.

15. Medeiros BC, Othus M, Fang M, et al. Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group (SWOG) experience. Blood 2010; 116:2224–2228.

Fang M, Storer B, Estey E, et al. Outcome of patients with acute myeloid leukemia with monosomal karyotype who undergo hematopoietic cell transplantation. Blood 2011; 118:1490–1494.

HCT appears to improve the overall outcome of monosomal karyotype-positive patients, especially patients without a complex karyotype.

17. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood 2002; 100:1532–1542.

18. Thiede C, Koch S, Creutzig E, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood 2006; 107:4011–4020.

Green CL, Koo KK, Hills RK, et al. Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations. J Clin Oncol 2010; 28:2739–2747.

Screening for CEBPA mutations can be restricted to patients with intermediate-risk cytogenetics lacking an FLT3-ITD or NPM1 mutation; only the presence of a CEBPA double mutation should be used for therapy risk stratification.

DeZern AE, Sung A, Kim S, et al. Role of allogeneic transplantation for FLT3/ITD acute myeloid leukemia: outcomes from 133 consecutive newly diagnosed patients from a single institution. Biol Blood Marrow Transplant 2011; 17:1404–1409.

Single-institution study of consecutively treated AML patients shows that allogeneic HCT in early CR1 improves the long-term outcomes for FLT3-ITD AML.

21. Falini B, Martelli MP, Bolli N, et al. Acute myeloid leukemia with mutated nucleophosmin (NPM1): is it a distinct entity? Blood 2011; 117:1109–1120.

22. Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358:1909–1918.

Rockova V, Abbas S, Wouters BJ, et al. Risk stratification of intermediate-risk acute myeloid leukemia: integrative analysis of a multitude of gene mutation and gene expression markers. Blood 2011; 118:1069–1076.

Large study looking at the interrelationships and relative prognostic importance of gene expression levels in risk-stratification of cytogenetically normal AML.

24. Shen Y, Zhu YM, Fan X, et al. Gene mutation patterns and their prognostic impact in a cohort of 1,185 patients with acute myeloid leukemia. Blood 2011; 118:5593–5603.

25. Basara N, Schulze A, Wedding U, et al. East German Study Group Hematology and Oncology (OSHO)Early related or unrelated haematopoietic cell transplantation results in higher overall survival and leukaemia-free survival compared with conventional chemotherapy in high-risk acute myeloid leukaemia patients in first complete remission. Leukemia 2009; 23:635–640.

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The study showed that HCT using HLA-well-matched-unrelated donors and matched-sibling donors resulted in similar leukemia-free survival and overall survival in AML patients in CR1 with unfavorable cytogenetics; outcomes from HLA-partially-matched-unrelated donors were inferior.

27. Walter RB, Pagel JM, Gooley TA, et al. Comparison of matched unrelated and matched related donor myeloablative hematopoietic cell transplantation for adults with acute myeloid leukemia in first remission. Leukemia 2010; 24:1276–1282.

28. Eapen M, Rocha V, Sanz G, et al. Center for International Blood and Marrow Transplant Research; Acute Leukemia Working Party Eurocord (the European Group for Blood Marrow Transplantation); National Cord Blood Program of the New York Blood CenterEffect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol 2010; 11:653–660.

29. Brunstein CG, Gutman JA, Weisdorf DJ, et al. Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood. Blood 2010; 116:4693–4699.

30. Atsuta Y, Suzuki R, Nagamura-Inoue T, et al. Japan Cord Blood Bank NetworkDisease-specific analyses of unrelated cord blood transplantation compared with unrelated bone marrow transplantation in adult patients with acute leukemia. Blood 2009; 113:1631–1638.

31. Litzow MR, Tarima S, Pérez WS, et al. Allogeneic transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia. Blood 2010; 115:1850–1857.

32. Kröger N, Brand R, van Biezen A, et al. Myelodysplastic Syndromes Subcommittee of The Chronic Leukaemia Working Party of European Group for Blood and Marrow Transplantation (EBMT)Risk factors for therapy-related myelodysplastic syndrome and acute myeloid leukemia treated with allogeneic stem cell transplantation. Haematologica 2009; 94:542–549.

33. Gustafson SA, Lin P, Chen SS, et al. Therapy-related acute myeloid leukemia with t(8;21) (q22;q22) shares many features with de novo acute myeloid leukemia with t(8;21)(q22;q22) but does not have a favorable outcome. Am J Clin Pathol 2009; 131:647–655.

34. Chang C, Storer BE, Scott BL, et al. Hematopoietic cell transplantation in patients with myelodysplastic syndrome or acute myeloid leukemia arising from myelodysplastic syndrome: similar outcomes in patients with de novo disease and disease following prior therapy or antecedent hematologic disorders. Blood 2007; 110:1379–1387.

35. Armand P, Kim HT, DeAngelo DJ, et al. Impact of cytogenetics on outcome of de novo and therapy-related AML and MDS after allogeneic transplantation. Biol Blood Marrow Transplant 2007; 13:655–664.

36. Bacigalupo A, Ballen K, Rizzo D, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 2009; 15:1628–1633.

37. Luger SM, Ringdén O, Zhang MJ, et al. Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS. Bone Marrow Transplant 2011. [Epub ahead of print]

38. Khabori MA, El-Emary M, Xu W, et al. Impact of intensity of conditioning therapy in patients aged 40–60 years with AML/myelodysplastic syndrome undergoing allogeneic transplantation. Bone Marrow Transplant 2011; 46:516–522.

39. Ringdén O, Labopin M, Ehninger G, et al. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol 2009; 27:4570–4577.

40. Wallen H, Gooley TA, Deeg HJ, et al. Ablative allogeneic hematopoietic cell transplantation in adults 60 years of age and older. J Clin Oncol 2005; 23:3439–3446.

41. McClune BL, Weisdorf DJ, Pedersen TL, et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol 2010; 28:1878–1887.

42. Deschler B, Binek K, Ihorst G, et al. Prognostic factor and quality of life analysis in 160 patients aged > or =60years with hematologic neoplasias treated with allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2010; 16:967–975.

43. Koreth J, Aldridge J, Kim HT, et al. Reduced-intensity conditioning hematopoietic stem cell transplantation in patients over 60 years: hematologic malignancy outcomes are not impaired in advanced age. Biol Blood Marrow Transplant 2010; 16:792–800.

44. Gyurkocza B, Storb R, Storer BE, et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol 2010; 28:2859–2867.

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Quality of life analyses showed that older patients with a related donor and younger patients with unfavorable cytogenetics benefited the most from allogeneic HCT in CR1.

46. Marcucci G, Radmacher MD, Maharry K, et al. MicroRNA expression in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358:1919–1928.

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Blood Reviews, 27(1): 13-22.
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acute leukemia; allogeneic hematopoietic cell transplantation; graft-versus-host disease; molecular markers; relapse; treatment-related mortality

© 2012 Lippincott Williams & Wilkins, Inc.


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