Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation in Adults With Acute Myeloid Leukemia

Transcription

1 Reduced-intensity conditioning regimens decrease treatment-related toxicity and can be used in older AML patients and in younger AML patients with medical comorbidities. Gene Elling. St. Barts. Photograph. Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation in Adults With Acute Myeloid Leukemia Mehdi Hamadani, MD, Mohamad Mohty, MD, and Mohamed A. Kharfan-Dabaja, MD Background: Acute myeloid leukemia (AML), whether de novo or arising from antecedent hematologic disorders in elderly patients, is less likely to be curable with standard chemotherapy regimens used for younger patients. Allogeneic hematopoietic cell transplantation (allo-hct) is currently the most efficient anti-leukemia treatment for AML and has shown a survival advantage in younger patients with intermediate- or poor-risk cytogenetics. Methods: The authors review their experience as well as the published data regarding the role of reduced-intensity conditioning (RIC) allo-hct in adults with AML. MEDLINE/PubMed and EMBASE/Ovid were searched, as well as reference lists of relevant articles, conference proceedings, and ongoing trial databases. Results: Elderly patients with AML have a poor survival for all cytogenetics subgroups (except for acute promyelocytic leukemia) and higher rates of transplant-related mortality with myeloablative allo-hct. RIC regimens have been shown to decrease procedure-related toxicity and have emerged as an attractive treatment modality in AML patients not suitable for myeloablative conditioning regimens. While prospective data comparing outcomes of AML patients undergoing RIC allo-hct vs conventional chemotherapy alone are not yet available, RIC allo-hct is a reasonable option for high-risk older patients and for younger AML patients with medical comorbidities who achieve a first or subsequent remission. The application of RIC for patients with refractory disease or untreated relapse as well as the use of alternative donors should be considered within the context of clinical trials. Conclusions: RIC allo-hct is a safe and effective treatment modality in high-risk elderly AML patients and in younger AML patients with medical comorbidities. From the Osborn Hematopoietic Malignancy and Transplantation Program, Division of Hematology/Oncology at West Virginia University, Morgantown (MH), the Service d Hématologie Clinique, CHU Hôtel Dieu, Université de Nantes, Centre d Investigation Clinique en Cancerologie [CI2C] and INSERM U892, Nantes, France (MM), and the Division of Hematology/Oncology and Bone Marrow Transplantation, Department of Internal Medicine and the Naef K. Basile Cancer Institute, American University of Beirut, Beirut, Lebanon (MAK-D). Submitted January 6, 2011; accepted May 17, Address correspondence to Mehdi Hamadani, MD, Division of Hematology and Oncology, West Virginia University, PO Box 9162, 1 Medical Center Drive, Morgantown, WV shamadani@hsc. wvu.edu No significant relationship exists between the authors and the companies/organizations whose products or services may be referenced in this article. Introduction Acute myeloid leukemia (AML) is a disease of the elderly. According to the Surveillance, Epidemiology and End Results Program, the incidence of AML in the United States is 3.6 per 100,000, with approximately 13,000 new cases diagnosed annually and a median patient age of 67 years. 1 Compared to younger patients, AML in older adults (arbitrarily defined as age > 55 to 60 years) is frequently associated with a variety of adverse prognostic factors including history of antecedent hematologic disorders, higher incidence of poor-risk cytogenetics, increased expression of P-glycoprotein in myeloid blasts, and compromised performance status. 2-7 Following standard induction chemotherapy regimens, less than 50% of October 2011, Vol. 18, No. 4 Cancer Control 237

2 elderly AML patients achieve complete remission (CR), and long-term survival is rare. 8 According to a study from the Cancer and Leukemia Group B (CALGB 8461), the 5-year overall survival (OS) rate of older AML patients with good-, intermediate-, and poor-risk cytogenetics receiving conventional chemotherapies was 19%, 7%, and 0%, respectively. 9 Other cooperative groups studies have reported similar dismal outcomes in this particular population. 10,11 While myeloablative allogeneic hematopoietic cell transplantation (allo-hct) has improved survival outcomes of at least certain subgroups of younger AML patients, this has not been the case for elderly patients, mainly due to higher rates of nonrelapse mortality (NRM). Improvement in NRM rates using the so-called nonmyeloablative (NMA) or reduced-intensity conditioning (RIC) regimens has broadened applicability of allo-hct in elderly patients or in younger patients with comorbidities in whom the use of standard myeloablative conditioning regimens is contraindicated. To critically review the role of RIC allo-hct in AML, it is important to recognize that the myeloablative intensity of different conditioning regimens vary significantly and that the distinction between truly myeloablative regimens and RIC regimens is not precisely defined. The latter is further complicated by the recent advent of the so-called myeloablative reduced-toxicity conditioning (RTC) regimens that are associated with improved NRM rates. 17,18 The European Blood and Marrow Transplantation (EBMT) group 19 and the Center for International Blood and Marrow Transplant Research (CIBMTR) 20 recently attempted to clarify the differences in NMA, RIC, and myeloablative regimens. Henceforth, we refer to NMA, RIC, and myeloablative regimens strictly as defined recently, 21 which in a few instances may be different from the description used in the original reports. In this paper, we review the role of NMA or RIC allo-hct in older (or unfit) adults with AML, and we discuss the issues related to the timing of allografting, the significance of conditioning regimen intensity, and the alternative donor allo-hct in this particular population. Patient Selection for RIC Transplantation The decision to use NMA or RIC regimens for AML patients undergoing allo-hct is not always clearly delineated, and significant variations exist in the selection criteria used by transplant centers around the world. 22 Poor outcomes of elderly patients following myeloablative allo-hct are well established. 23 Sorror et al 24,25 evaluated the impact of a priori medical comorbidities on transplant outcomes by using the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) and reported significantly higher NRM rates and inferior OS in patients with an HCT-CI score of 3. While not validated in prospective clinical trials, it is becoming increasingly common practice to offer RIC allo-hct to AML patients of advanced age (generally > 50 to 55 years) and/or an HCT-CI > 2 (regardless of age), or to those with a prior history of autologous transplantation or poorer performance status. 26 Elderly AML patients undergoing allo-hct represent a highly selected cohort, with the procedure not being offered to a vast majority of this high-risk population. Estey et al 27 prospectively assessed the feasibility of RIC allo-hct in 259 older AML patients. In this series, 46 of 99 patients who achieved a CR were not referred for evaluation for allo-hct because of perceived advanced age of the patient, medical comorbidities, physician bias, or patient preference. Of the 53 patients in CR who were referred for a transplant consultation, a compatible HLA-matched donor, whether sibling or unrelated donor, was not found in 27 cases (51%). Ultimately, only 14 of 26 patients who had a suitable HLA-matched donor available underwent RIC allo-hct, representing only 14% of patients achieving a CR and 5% of patients originally included in the study. This finding underscores the importance of caution in interpreting results of RIC transplantation because it represents a selected cohort of better fitted AML patients with chemosensitive disease. 3 Following is a review of the published literature addressing the role of RIC allo-hct for AML patients in first CR (CR1), those beyond CR1, and those with refractory disease or untreated relapse. Where possible, these data are interpreted relative to expected outcomes in older patients with chemotherapy alone or with outcomes following myeloablative conditioning (in younger patients). The Role of RIC Transplantation for AML in CR1 The optimal management of older AML patients achieving CR1 remains controversial, with the majority of patients expected to relapse when treated with consolidation chemotherapy alone. 9,10 Registry data from EBMT 28 and CIBMTR 29 and from large multicenter retrospective studies 30,31 have shown 2-year leukemia-free survival (LFS) and OS rates of approximately 40% and 50%, respectively, for AML patients in CR1 undergoing RIC allo-hct. Table 1 summarizes selected prospective clinical trials that included AML patients in CR1 undergoing either NMA or RIC allo-hct. The largest prospective (phase II) clinical trial published to date by the Seattle consortium evaluated the role of NMA conditioning with 2 Gy total body irradiation (TBI) with or without fludarabine (90 mg/m 2 total dose) in 122 patients with AML. 32 Durable engraftment was achieved in 95% of cases, with relatively acceptable rates of acute and chronic graft-vs-host disease (GVHD). Analysis of 51 AML patients in CR1 included in this study demonstrated a 2-year OS rate of 51%. This finding, together with the lower risk of relapse noted in patients receiving allografts from unrelated donors, highlighted the importance of the immune-mediated graft-vs-leukemia effects in AML patients receiving a truly NMA conditioning regi- 238 Cancer Control October 2011, Vol. 18, No. 4

3 men. Kohrt et al 33 recently reported 3-year LFS and OS rates of 48% and 50%, respectively, in CR1 AML patients undergoing allo-hct following NMA conditioning with total lymphoid irradiation and antithymocyte globulin. To our knowledge, only two prospective clinical trials (have specifically addressed the role of RIC allo- HCT for AML patients in CR1. Grigg et al 34 reported a 2-year LFS rate of 68% and an OS rate of 56% in 34 CR1 AML patients. The NRM was 15%, with 37% cumulative incidence of disease relapse at 2 years. The second study, which specifically addressed the role of RIC transplantation for AML in CR1, included 31 patients and reported an impressive 2-year LFS rate of 76%, with low rates of relapse (18%) and NRM (9%). 35 It is plausible that these encouraging outcomes are due in part to intensive consolidation chemotherapy (± high-dose therapy and autologous transplantation) given to all patients before RIC allo-hct, which might not be feasible in most AML patients > 60 years of age. More importantly, these results highlight the significance of adequate disease control with intensive consolidation therapy before RIC allo-hct. Ongoing clinical trials such as CALGB and EBMT will provide additional data regarding the role of RIC in AML patients in CR1. While these prospective studies have helped to establish the feasibility of RIC transplantation for AML patients in CR1, 17,31-36 it is important to recognize their limitations, such as (1) inclusion of a heterogeneous group of AML patients with respect to remission status at time of allografting, (2) lack of homogeneous criteria to select patients for NMA or RIC regimens among the studies, (3) lack of uniformity regarding the intensities of preparative regimens, and (4) use of various GVHD prophylactic strategies in the studies. These limitations make direct comparison between these trials difficult. The median age of patients included in these trials (50 to 55 years) is still lower than the median age at diagnosis for AML patients, suggesting that this approach continues to be offered to a selective cohort of relatively younger AML patients. Moreover, unlike young AML patients in whom cytogenetics and genomic risk stratification have helped established the role of myeloablative allo-hct in CR1, no such prospective data are available for patients undergoing RIC allografting. Recent data from EBMT showed 2-year LFS rates of 64%, 57%, and 38% in CR1 AML patients with good-, intermediate-, and poor-risk cytogenetics, 37 which compares favorably to survival rates in respective cytogenetic groups with standard chemotherapy alone. 9 With the understanding of aforementioned limitations, it appears that a subset (approximately 35% to 45%) of CR1 AML patients who receive an NMA or RIC allo-hct do achieve long-term LFS. Table 1. Prospective Clinical Trials Evaluating the Role of Reduced-Intensity Conditioning Allogeneic Transplantation in Acute Myeloid Leukemia (AML) in First Complete Remission (CR1) Study Patient Age (Range) No. of CR1 AML Patients Unrelated Donors Conditioning Relapse Leukemia-Free Overall Transplant-Related Mortality de Lima et al (22 75) a 11 None Flu-Mel Flu-AraC-Id 40% a 33% a 40% a 30% a Blaise et al (26 60) 31 None Flu-Bu-ATG 18% 76% 79% (18 mos) 9% van Besien et al (17 71) a 9 54% a Flu-Mel-C 32% a 38% a 48% a 11.1% c Grigg et al (19 60) 34 None Flu-Cy 37% 56% 68% 15% c Valcarcel et al (21 70) a 59 a None Flu-Bu 44% (4 yrs) a 39% (4 yrs) a 42% (4 yrs) a 20% (4 yrs) a Kohrt et al (21 67) a 38 a 45% a TLI-ATG NR 48% 50% 3% to 4% a (1 Yr) Gyurkocza et al 84b 60 (5 74) a % a TBI ± Flu 39% (5 yrs) NR 37% (5 yrs) 18% = Sib 29% = MUD (5 yrs) C = alemtuzumab, AraC = cytarabine, ATG = antithymocyte globulin, Bu = busulfan, Cy = cyclophosphamide, Flu = fl udarabine, Id = idarubicin, Mel = melphalan, MUD = matched unrelated donor, NR = not reported, Sib = matched sibling donor, TBI = total body irradiation, TLI = total lymphoid irradiation. a Data for AML patients in CR1 not reported separately. b This retrospective study included patients enrolled on prospective trials at Fred Hutchinson Cancer Center, Seattle, Washington. c Transplant-related mortality not reported in the manuscript. October 2011, Vol. 18, No. 4 Cancer Control 239

4 Is RIC Allo-HCT for AML in CR1 Superior to Chemotherapy Alone? Studies using a genetic randomization (ie, a donor vs no donor comparison) in their design have provided additional knowledge of the role of myeloablative allo-hct for AML in CR However, such prospective data are not yet available in the context of RIC allo-hct. When comparing the outcomes of studies evaluating the role of RIC allo-hct in older adults to clinical trials where chemotherapy alone was used for such patients, there are obvious limitations because transplant studies have an inherent selection bias for relatively younger, healthier patients who not only achieve but also maintain disease remission until allo-hct. Interestingly, when the results of the MD Anderson study (described previously) 27 assessing the prospective feasibility of RIC in elderly AML patients were analyzed, using a donor-vs-no-donor comparison, the donor group had a better relapse-free survival. Mohty et al 38 retrospectively performed a genetic randomization through a donor-vs-no-donor comparison in 95 adult AML patients in CR1. The HLA-matched sibling donor group included 35 patients, and the no-donor group comprised 60 patients. In an intention-to-treat analysis, LFS was significantly higher in the donor group (54 vs 30% at 4 years). The LFS advantage in the donor group was even stronger when analysis was restricted to the 25 patients who actually received RIC allo-hct with fludarabine, busulfan, and antithymocyte globulin. A significant benefit regarding OS was also seen in the donor group, both by intention-to-treat analysis and by limiting analysis to patients who actually underwent allo-hct. An update of this study showed that the LFS advantage persisted in the donor group (72% vs 24%) at 7 years. 39 While these data provide useful clinical information, a prospective randomized study is needed to address this issue. Prospective clinical trials randomizing elderly AML patients to chemotherapy alone vs induction chemotherapy followed by NMA or RIC allo-hct will clarify the role of RIC transplantation in elderly AML patients in CR1. Ongoing trials, accessible at include the Trans Atlantic Leukemia Group 1/02 (NCT ), the EBMT-ALWP01/2008 (NCT ), and the SU (NCT ). The Role of RIC Transplantation for AML Beyond CR1 Chemotherapy alone offers little chance of cure for AML patients with relapsed disease. 40,41 Information addressing the role of RIC transplantation in AML beyond CR1 is limited. A multicenter retrospective analysis from the Cooperative German Transplant Study reported 2-year LFS rates of 52%, 40%, and < 20% for AML patients in CR1, in CR2, and with advance disease, respectively, 42 emphasizing that RIC allo-hct should be considered earlier in the course of the disease. Registry data from EBMT demonstrated a 2-year LFS rate of 55% for CR2 AML patients with RIC transplantation. 28 AML patients who are beyond CR1 represent only a minority of patients accrued in published prospective clinical trials (Table 2). 17,32,33,36 Acknowledging the limitations of available data, it appears that approximately 30% to 35% of AML patients beyond CR1 can be expected to be leukemiafree 2 to 3 years following RIC allo-hct. Interestingly, the outcomes of AML in CR2 patients who receive NMA allo-hct preparative regimens are encouraging (2- to 3-year LFS rates of approximately 40% to 50%), 32,33 with acceptable rates of NRM. In the absence of randomized prospective outcome data of AML patients beyond CR1, an NMA or RIC allo-hct should be strongly considered for these patients whenever possible as it provides the best prospect of cure. Table 2. Prospective Clinical Trials Evaluating the Role of Reduced-Intensity Conditioning Allogeneic Transplantation in Acute Myeloid Leukemia (AML) in Second Complete Remission (CR) or Beyond Study Patient Age (Range) No. of CR 2 AML Patients Unrelated Donors Conditioning Relapse Leukemia- Free Overall Transplant-Related Mortality de Lima et al (22 75) a 13 None Flu-Mel Flu-AraC-Id 40% a 33% a 40% a 30% a van Besien et al (17 71) 4 54% a Flu-Mel-C 32% a 38% a 48% a 33% a 39 52% a TBI ± Flu 34% = Sib Hegenbart et al (17 74) a 38% = MUD 44% 61% a 13% = Sib 21% = MUD Kohrt et al (21 67) a 38 a 45% a TLI-ATG NR 50% 37% 3% to 4% a C = alemtuzumab, AraC = cytarabine, ATG = antithymocyte globulin, Bu = busulfan, Flu = fl udarabine, Id = idarubicin, Mel = melphalan, MUD = matched unrelated donor, Sib = matched sibling donor, TBI = total body irradiation, TLI = total lymphoid irradiation, NR = not reported. a Data for AML patients in CR 2 not reported separately. 240 Cancer Control October 2011, Vol. 18, No. 4

5 The Role of RIC Transplantation in Refractory AML Patients with refractory AML are particularly challenging. Few retrospective studies or case series limited to a small subset of highly selected patients receiving a myeloablative allo-hct have been reported in the literature A large CIBMTR study has recently reported a remarkable 3-year OS rate of 42% with matched-sibling myeloablative allo-hct in a subset of refractory AML patients who had a good performance status, no circulating blasts, a prior CR duration of > 6 months, and no poor-risk cytogenetics. 46 The role of RIC in refractory AML, however, is more controversial. The retrospective Cooperative German Transplant Study reported an LFS rate of 49% for AML patients with < 5% blasts in the bone marrow at the time of allografting, compared to only 14% for those with > 20% myeloblasts. 42 It is likely that these poor outcomes are caused in part by the fact that most NMA or RIC regimens cannot provide adequate disease control to allow sufficient time for immune-reconstitution and development of graft-vs-leukemia effects. 47 Unlike myeloablative transplantation in young adults, surprisingly a number of prospective studies for NMA or RIC allo-hct included AML patients with refractory (active) disease or those in untreated relapse (Table 3). In the MD Anderson experience, treatment-related mortality of AML patients not in remission at the time of allografting was unacceptably high, with an LFS rate of 20% at 3 years. 17 No benefit of RIC over NMA conditioning was seen for this cohort. Similarly, van Besien et al 36 reported a 1-year LFS rate of only 25% in patients with refractory disease. Four of 7 patients in remission at 1 year relapsed during the second year. One might speculate that poor outcomes noted in these studies underscore the fact that in cases of progressive leukemia, NMA or RIC regimens are not sufficiently effective to control the disease long enough to allow a graft-vs-leukemia effect to develop. To address the issue of disease control, Schmid et al 48 used a strategy of sequential cytoreduction (with fludarabine, high-dose cytarabine, and amsacrine) followed immediately by RIC transplantation and planned prophylactic donor lymphocytic infusions in a cohort of 75 patients with high-risk AML or myelodysplastic syndrome (MDS). Using this intensive strategy, 44 AML patients with active disease had encouraging 2-year LFS and OS rates of 48% and 51%, respectively. These data support the concept of pretransplant disease debulking therapy with augmentation of graft-vs-leukemia effects with donor lymphocytic infusions. Further study of this strategy is warranted. Recognizing the importance of cytoreduction before NMA or RIC allo-hct in patients with refractory AML, different investigators have evaluated the feasibility of immunoconjugates (eg, gemtuzumab ozogamicin) 49 or radiolabeled monoclonal antibodies ( 131 I-labeled CD45 antibody) 50 to specifically target disease in the marrow and other sites of leukemia. Encouraging preliminary results have been reported (Table 3). Others have attempted to improve transplantation outcomes by early RIC allo- HCT during induction chemotherapy-induced aplasia, 51 by incorporating novel agents as part of conditioning regimens, 52 or by adding lower doses of hypomethylating agents to reduce the risk of leukemia relapse following transplantation. 3,53 Follow-up in most reported studies remains short, and the long-term efficacy and safety of these approaches remain unknown. While some of the Table 3. Prospective Clinical Trials Evaluating the Role of Reduced-Intensity Conditioning Allogeneic Transplantation in Acute Myeloid Leukemia (AML) Patients With Refractory/Active Disease Study No. of AML Patients Not in Complete Remission Conditioning Relapse Leukemia-Free Overall Transplant-Related Mortality de Lima et al Flu-Mel Flu-AraC-Id NR 20% 23% 34% e van Besien et al Flu-Mel-C 39% a 25% a 37% e 33% a Schmid et al b TBI-Cy-ATG NR 48% 51% 26% Bornhauser et al Flu-Mel Flu-TBI c 38% 35% 39% 30% Pagel et al TBI-Flu 40% NR 38% to 46% d,e 22% e C = alemtuzumab, Cy = cyclophosphamide, AraC = cytarabine, ATG = antithymocyte globulin, Flu = fl udarabine, Id = idarubicin, Mel = melphalan, NR = data for patients with active disease not reported, TBI = total body irradiation. a Data includes 4 patients with refractory myelodysplastic syndrome. b Data includes 22 patients with refractory AML and 18 with untreated relapse. c Five patients received myeloablative TBI doses. d 38% for patients with AML refractory to chemotherapy, and 46% for AML in untreated relapse. e Data for refractory AML patients not reported separately. October 2011, Vol. 18, No. 4 Cancer Control 241

6 reported studies do identify a small subset of AML patients with refractory disease who might benefit from RIC allo-hct (with or without some form of additional peritransplant therapy), such an intervention should be performed within the context of a clinical trial. The Role of Dose Intensity in the Context of RIC The inverse correlation between the intensity of the conditioning regimen and the risk of disease relapse, particularly in AML, is well known. However, higher conditioning regimen intensity is also directly proportional to poorer NRM. As a result, the optimal conditioning regimen in AML with the best therapeutic index remains undefined. A number of retrospective studies have compared outcomes of patients > 50 years of age undergoing either NMA or RIC transplantation against myeloablative allo-hct, and these studies have mostly shown improvement in NRM and possibly OS with the former. However, these less intense regimens also result in significantly higher risk of relapse in most studies 28,54,55 but not all. 56 Comparisons of RIC or RTC transplants against myeloablative allo-hct have shown similar results, with NRM rates favoring less intense regimens at the cost of higher relapse rates, 57 while limited comparisons of RTC regimens vs myeloablative conditioning suggest improved regimen-related toxicity with RTC without differences in relapse rates or cumulative incidence of NRM. 58 In the context of NMA and RIC allo-hct, the regimen with the best risk-to-benefit ratio is more controversial. A study by de Lima et al 17 retrospectively compared outcomes of MDS and AML patients undergoing NMA conditioning (fludarabine, cytarabine and idarubicin) to those receiving RIC (fludarabine and melphalan) transplants. More favorable outcomes regarding relapse rates and LFS were observed following the RIC regimen but at the expense of a higher NRM. No difference in survival was seen between the groups. Interestingly, for refractory AML, neither regimen provided a benefit in terms of reduced risk of relapse. Shimoni et al 59 retrospectively compared fludarabine-busulfan based RIC against transplantation with fludarabine-melphalan based RIC. 59 The melphalan-containing RIC was associated with more intense myelosuppression and higher NRM; however, OS was not better in the busulfan-containing group because of higher rates of disease relapse. This study highlights the fact that seemingly similar and dose-equivalent RIC regimens may have markedly different outcomes and should not be assumed to have an equal therapeutic index. At this time, the optimal conditioning regimen for older AML patients remains to be determined. Until then, the choice of preparative regimen for these patients will continue to depend on transplant center preference and physician bias. Ongoing studies such as the Bone Marrow Transplant Clinical Trials Network (BMT-CTN) study 0901 will help address this issue. Myeloablative Conditioning Regimens With Reduced Toxicity In the last 2 decades, the use of RIC regimens has increased steadily, mainly due to the associated lower rates of NRM. However, concerns regarding increased risk of disease relapse with such regimens have led others to develop myeloablative conditioning regimens (the socalled RTC regimens), with regimen-related toxicity significantly lower than that expected with traditional myeloablative regimens. 63,64 In a cohort of 96 patients with advanced AML or MDS, de Lima et al 61 reported that combining fludarabine with myeloablative doses of once-daily busulfan as transplant conditioning produced encouraging disease control, with impressive rates of NRM (3% at 1 year). In CR1 AML patients undergoing unrelated donor allo-hct, RTC with fludarabine and busulfan appears to provide an encouraging 3-year LFS rate of 70%, with an acceptable NRM rate of 15% at 3 years. 65 While myeloablative RTC regimens have been successfully employed, even in elderly patients with advanced myeloid malignancies, 62 prospective randomized studies showing their superiority over RIC regimens are not available, and limited retrospective data suggest comparable outcomes following allo-hct with fludarabine and busulfan-based RIC and RTC. 66 RIC for Therapy-Related or Transformed AML AML with a history of antecedent hematologic disorders and therapy-related AML (t-aml) are increasing in prevalence with the aging of the population and with improved survival of patients treated with chemotherapy or radiotherapy for other malignancies. 67 Outcomes of patients with t-aml, when treated with standard chemotherapy regimens alone, are disappointing. While a small subset of patients with t-aml (approximately 25% to 30%) can become long-term survivors following myeloablative allo-hct, 68 such intensive conditioning regimens are frequently not feasible in this high-risk patient cohort due to advanced age, medical comorbidities, and prior high-dose therapy. 69 Registry data from EBMT suggest that compared to myeloablative conditioning, RIC allo-hct in patients with t-aml or MDS is associated with higher relapse rates, lower NRM, and no significant difference in OS. 70 Considering the uniformly poor outcomes of patients with t-aml with standard therapies, performing RIC allo-hct (at least in patients achieving CR) is reasonable. Umbilical Cord Blood Transplantation The easy, rapid availability of a prescreened, HLA-typed product makes umbilical cord blood transplantation (UCBT) an attractive option for patients without a suitable HLA matched-sibling or unrelated donor. UCBT is associated with lower GVHD rates for the degree of HLA disparity, making it a reasonable alternative when 242 Cancer Control October 2011, Vol. 18, No. 4

7 a suitable donor is not available. 71,72 The low cell dose available from individual cord blood units has been the major limitation against the widespread use of UCBT in adults with AML or other hematologic malignancies. Preliminary data suggest that transplantation of multiple cord blood units from different donors double cord transplants (DCTs) is safe and feasible. 73 A number of mostly retrospective studies of DCTs following a variety of NMA or RIC regimens (eg, fludarabine-tbi-cyclophosphamide; fludarabine-tbi-busulfan; fludarabine-melphalan- antithymocyte globulin) have included AML patients at various stages of remission and report 3-year OS and disease-free survival rates of approximately 30% to 35%, with acceptable rates of acute GVHD (for the degree of HLA mismatch), NRM, and graft rejection Preliminary results from the Société Française de Greffe de Moelle Osseuse et de Thérapie Cellulaire and Eurocord s multicenter phase II trial for RIC UCBT in patients with AML were presented in the 2010 meeting of American Society of Hematology. 77 At 1 year, the rates of OS, LFS, relapse, and NRM for the 65 AML patients initially accrued on the study were 60%, 52%, 30%, and 18%, respectively. Ongoing large multicenter trials (eg, BMT-CTN 0604) will help confirm the feasibility of this approach and determine its clinical efficacy. This could potentially result in increased use of UCBT in the future. Expansion of the current pool of cord blood units could markedly broaden applicability of this transplant modality, particularly in minority populations who are underrepresented in current volunteer hematopoietic cell donor databases. RIC Haploidentical Transplantation Virtually all AML patients (without an HLA-identical sibling donor) have at least one haploidentical related donor available. The theoretical risks of increased GVHD, NRM, graft rejection, and opportunistic infections associated with haploidentical transplantation have prevented routine use of this modality. However, with rigorous ex vivo T-cell depletion and an intense conditioning regimen (which is not suitable for older AML patients), Aversa et al reported encouraging LFS rates of 30% to 45% of AML patients depending on remission status at the time of allografting. A number of small single-institution studies that included patients with various hematologic malignancies have assessed the feasibility of a variety of NMA or RIC regimens for haploidentical transplantation. These seminal studies have provided important preliminary evidence about the feasibility of NMA/RIC haploidentical transplantation for hematologic malignancies. Continued research is needed to better define preferred conditioning regimens, methods and degree of T-cell depletion, and optimal CD34+ cell dose in the allograft. Although RIC haploidentical transplantation is a potentially curative option for AML patients lacking a suitable sibling or unrelated donor, we believe that at this time it should be performed only in experienced centers, within the context of clinical trials, especially in patients with poor-risk AML in CR1. Conclusions The number of NMA or RIC allo-hcts performed in patients with AML has steadily increased over the last decade. The efficacy and feasibility data reviewed here support performing HLA typing and sibling and/or unrelated donor searches in newly diagnosed older AML patients who are able to tolerate this procedure. Offering NMA or RIC transplantation is a reasonable option for these older patients and for younger AML patients with medical comorbidities who achieve a first or subsequent remission. The application of NMA or RIC for patients with refractory disease or untreated relapse and the use of alternative donors should be considered within the context of clinical trials. Continued rigorous research efforts focusing on (1) the development of safer and more effective conditioning regimens, (2) novel methods to reduce the incidence and severity of GVHD without compromising the beneficial graft-vs-leukemia effects, (3) strategies to improve immune reconstitution following transplantation, and (4) increased availability of alternative-donor approaches are being pursued with the goal of ultimately achieving durable long-term remissions in older patients with AML. References 1. SEER Stat Fact Sheets - Acute Myeloid Leukemia. gov/statfacts/html/amyl.html. Accessed June 15, Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood. 2006;107(9): Forman SJ. What is the role of reduced-intensity transplantation in the treatment of older patients with AML? Hematology Am Soc Hematol Educ Program. 2009: Grimwade D, Walker H, Harrison G, et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood. 2001;98(5): Leith CP, Kopecky KJ, Godwin J, et al. Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood. 1997;89(9): Baer MR, George SL, Dodge RK, et al. Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study Blood. 2002;100(4): Nüssler V, Pelka-Fleischer R, Zwierzina H, et al. P-glycoprotein expression in patients with acute leukemia-clinical relevance. Leukemia. 1996;10(suppl 3):S23-S Löwenberg B, Ossenkoppele GJ, van Putten W, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009;361(13): Cancer and Leukemia Group B 8461, Farag SS, Archer KJ, et al. Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B Blood. 2006;108(1): Fröhling S, Schlenk RF, Kayser S, et al. Cytogenetics and age are major determinants of outcome in intensively treated acute myeloid leukemia patients older than 60 years: results from AMLSG trial AML HD98-B. Blood. 2006;108(10): Rowe JM, Neuberg D, Friedenberg W, et al. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004;103(2): Burnett AK, Wheatley K, Goldstone AH, et al. The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing October 2011, Vol. 18, No. 4 Cancer Control 243

8 risk of relapse: results of the UK MRC AML 10 trial. Br J Haematol. 2002; 118(2): Cassileth PA, Harrington DP, Appelbaum FR, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in fi rst remission. N Engl J Med. 1998;339(23): Cornelissen JJ, van Putten WL, Verdonck LF, et al. Results of a HO- VON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in fi rst remission acute myeloid leukemia in young and middle aged adults: benefi ts for whom? results of a HOVON/ SAKK donor versus no donor analysis. Blood. 2007;109(9): Schlenk RF, Döhner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18): Hamadani M, Awan FT, Copelan EA. Hematopoietic stem cell transplantation in adults with acute myeloid leukemia. Biol Blood Marrow Transplant. 2008;14(5): de Lima M, Anagnostopoulos A, Munsell M, et al. Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: dose is relevant for longterm disease control after allogeneic hematopoietic stem cell transplantation. Blood. 2004;104(3): de Lima M, Couriel D, Thall PF, et al. Once-daily intravenous busulfan and fl udarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood. 2004;104(3): Bacigalupo A. Third EBMT/AMGEN Workshop on reduced-intensity conditioning allogeneic haemopoietic stem cell transplants (RIC-HSCT), and panel consensus. Bone Marrow Transplant. 2004;33(7): Giralt S, Ballen K, Rizzo D, et al. Reduced-intensity conditioning regimen workshop: defi ning the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant. 2009;15(3): Bacigalupo A, Ballen K, Rizzo D, et al. Defi ning the intensity of conditioning regimens: working defi nitions. Biol Blood Marrow Transplant. 2009;15(12): Hamadani M, Craig M, Awan FT, et al. How we approach patient evaluation for hematopoietic stem cell transplantation. Bone Marrow Transplant. 2010;45(8): Ringdén O, Horowitz MM, Gale RP, et al. Outcome after allogeneic bone marrow transplant for leukemia in older adults. JAMA. 1993;270(1): Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specifi c comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106(8): Sorror ML, Giralt S, Sandmaier BM, et al. Hematopoietic cell transplantation-specifi c comorbidity index as an outcome predictor for patients with acute myeloid leukemia in fi rst remission: combined FHCRC and MDACC experiences. Blood. 2007;110(13): Sorror M, Storer B, Sandmaier BM, et al. Hematopoietic cell transplantation-comorbidity index and Karnofsky performance status are independent predictors of morbidity and mortality after allogeneic nonmyeloablative hematopoietic cell transplantation. Cancer. 2008;112(9): Estey E, de Lima M, Tibes R, et al. Prospective feasibility analysis of reduced-intensity conditioning (RIC) regimens for hematopoietic stem cell transplantation (HSCT) in elderly patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Blood. 2007;109(4): Aoudjhane M, Labopin M, Gorin NC, et al. Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT). Leukemia. 2005;19(12): 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 fi rst complete remission or with myelodysplastic syndrome. J Clin Oncol. 2010;28(11): Tauro S, Craddock C, Peggs K, et al. Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol. 2005;23(36): Valcarcel D, Martino R, Caballero D, et al. Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. J Clin Oncol. 2008;26(4): Hegenbart U, Niederwieser D, Sandmaier BM, et al. Treatment for acute myelogenous leukemia by low-dose, total-body, irradiation-based conditioning and hematopoietic cell transplantation from related and unrelated donors. J Clin Oncol. 2006;24(3): Kohrt HE, Turnbull BB, Heydari K, et al. TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors. Blood. 2009;114(5): Grigg AP, Gibson J, Bardy PG, et al. A prospective multicenter trial of peripheral blood stem cell sibling allografts for acute myeloid leukemia in fi rst complete remission using fl udarabine-cyclophosphamide reduced intensity conditioning. Biol Blood Marrow Transplant. 2007;13(5): Blaise DP, Michel Boiron J, Faucher C, et al. Reduced intensity conditioning prior to allogeneic stem cell transplantation for patients with acute myeloblastic leukemia as a first-line treatment. Cancer. 2005;104(9): van Besien K, Artz A, Smith S, et al. Fludarabine, melphalan, and alemtuzumab conditioning in adults with standard-risk advanced acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol. 2005;23(24): Mohty M, Labopin M, Milpied N, et al. Impact of cytogenetics risk on outcome after reduced intensity conditioning (RIC) allogeneic stem cell transplantation (allo-sct) from an HLA identical sibling for patients with acute myeloid leukemia (AML) in fi rst complete remission (CR1). Blood. 2008;112: Mohty M, de Lavallade H, Ladaique P, et al. The role of reduced intensity conditioning allogeneic stem cell transplantation in patients with acute myeloid leukemia: a donor vs no donor comparison. Leukemia. 2005; 19(6): Mohty M, de Lavallade H, El-Cheikh J, et al. Reduced intensity conditioning allogeneic stem cell transplantation for patients with acute myeloid leukemia: long term results of a donor versus no donor comparison. Leukemia. 2009;23(1): Appelbaum FR, Pearce SF. Hematopoietic cell transplantation in fi rst complete remission versus early relapse. Best Pract Res Clin Haematol. 2006; 19(2): Bloomfield CD, Lawrence D, Byrd JC, et al. Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res. 1998;58(18): Sayer HG, Kröger M, Beyer J, et al. Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia: disease status by marrow blasts is the strongest prognostic factor. Bone Marrow Transplant. 2003;31(12): Michallet M, Thomas X, Vernant JP, et al. Long-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: a retrospective study of 379 patients reported to the Societe Francaise de Greffe de Moelle (SFGM). Bone Marrow Transplant. 2000;26(11): Biggs JC, Horowitz MM, Gale RP, et al. Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy. Blood. 1992;80(4): Wong R, Shahjahan M, Wang X, et al. Prognostic factors for outcomes of patients with refractory or relapsed acute myelogenous leukemia or myelodysplastic syndromes undergoing allogeneic progenitor cell transplantation. Biol Blood Marrow Transplant. 2005;11(2): Duval M, Klein JP, He W, et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol. 2010;28(23): Blaise D, Vey N, Faucher C, et al. Current status of reduced-intensityconditioning allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica. 2007;92(4): Schmid C, Schleuning M, Ledderose G, et al. Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in highrisk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol. 2005;23(24): Bornhäuser M, Illmer T, Oelschlaegel U, et al. Gemtuzumab ozogamicin as part of reduced-intensity conditioning for allogeneic hematopoietic cell transplantation in patients with relapsed acute myeloid leukemia. Clin Cancer Res. 2008;14(17): Pagel JM, Gooley TA, Rajendran J, et al. Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibody plus fl udarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood. 2009;114(27): Platzbecker U, Thiede C, Füssel M, et al. Reduced intensity conditioning allows for up-front allogeneic hematopoietic stem cell transplantation after cytoreductive induction therapy in newly-diagnosed high-risk acute myeloid leukemia. Leukemia. 2006;20(4): Martin MG, Uy GL, Procknow E, et al. Allo-SCT conditioning for myelodysplastic syndrome and acute myeloid leukemia with clofarabine, cytarabine and ATG. Bone Marrow Transplant. 2009;44(1): Jabbour E, Giralt S, Kantarjian H, et al. Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia. Cancer. 2009;115(9): Alyea EP, Kim HT, Ho V, et al. Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood 244 Cancer Control October 2011, Vol. 18, No. 4

9 Marrow Transplant. 2006;12(10): Alyea EP, Kim HT, Ho V, et al. Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age. Blood. 2005;105(4): 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(27): Shimoni A, Hardan I, Shem-Tov N, et al. Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity. Leukemia. 2006;20(2): Pidala J, Kim J, Anasetti C, et al. Pharmacokinetic targeting of intravenous busulfan reduces conditioning regimen related toxicity following allogeneic hematopoietic cell transplantation for acute myelogenous leukemia. J Hematol Oncol. 2010;3: Shimoni A, Hardan I, Shem-Tov N, et al. Comparison between two fl udarabine-based reduced-intensity conditioning regimens before allogeneic hematopoietic stem-cell transplantation: fl udarabine/melphalan is associated with higher incidence of acute graft-versus-host disease and nonrelapse mortality and lower incidence of relapse than fl udarabine/busulfan. Leukemia. 2007;21(10): Russell JA, Duan Q, Chaudhry MA, et al. Transplantation from matched siblings using once-daily intravenous busulfan/fl udarabine with thymoglobulin: a myeloablative regimen with low nonrelapse mortality in all but older patients with high-risk disease. Biol Blood Marrow Transplant. 2008;14(8): de Lima M, Couriel D, Thall PF, et al. Once-daily intravenous busulfan and fl udarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood. 2004;104(3): Alatrash G, de Lima M, Hamerschlak N, et al. Myeloablative reduced-toxicity i.v. busulfan-fl udarabine and allogeneic hematopoietic stem cell transplant for patients with acute myeloid leukemia or myelodysplastic syndrome in the sixth through eighth decades of life. Biol Blood Marrow Transplant Feb 18. Epub ahead of print. 63. Copelan EA, Biggs JC, Thompson JM, et al. Treatment for acute myelocytic leukemia with allogeneic bone marrow transplantation following preparation with BuCy2. Blood. 1991;78(3): Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006;354(17): Bashir Q, Andersson BS, Fernandez-Vina M, et al. Unrelated donor transplantation for acute myelogenous leukemia in fi rst remission. Biol Blood Marrow Transplant. 2011;17(7): Hamadani M, Craig M, Phillips GS, et al. Higher busulfan dose intensity does not improve outcomes of patients undergoing allogeneic haematopoietic cell transplantation following fl udarabine, busulfan-based reduced toxicity conditioning. Hematol Oncol Feb 28. Epub ahead of print. 67. Borthakur G, Estey AE. Therapy-related acute myelogenous leukemia and myelodysplastic syndrome. Curr Oncol Rep. 2007;9(5): Litzow MR, Perez WS, Klein JP, et al. Comparison of outcome following allogeneic bone marrow transplantation with cyclophosphamide-total body irradiation versus busulphan-cyclophosphamide conditioning regimens for acute myelogenous leukaemia in fi rst remission. Br J Haematol. 2002;119(4): Hosing C, Munsell M, Yazji S, et al. Risk of therapy-related myelodysplastic syndrome/acute leukemia following high-dose therapy and autologous bone marrow transplantation for non-hodgkin s lymphoma. Ann Oncol. 2002;13(3): Lim Z, Brand R, Martino R, et al. Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia. J Clin Oncol. 2010;28(3): Rocha V, Labopin M, Sanz G, et al. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med. 2004;351(22): Laughlin MJ, Eapen M, Rubinstein P, et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med. 2004;351(22): Barker JN, Weisdorf DJ, DeFor TE, et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood. 2005;105(3): Brunstein CG, Barker JN, Weisdorf DJ, et al. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood. 2007;110(8): Barker JN, Weisdorf DJ, DeFor TE, et al. Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning. Blood. 2003;102(5): Ballen KK, Spitzer TR, Yeap BY, et al. Double unrelated reducedintensity umbilical cord blood transplantation in adults. Biol Blood Marrow Transplant. 2007;13(1): Rio B, Chevret S, Vigouroux S, et al. Reduced intensity conditioning regimen prior to unrelated cord blood transplantation in patients with acute myeloid leukemia : preliminary analysis of a prospective phase II multicentric trial on behalf of Société Française de Greffe de Moelle Osseuse de Thérapie Cellulaire (SFGM-TC) and Eurocord. Blood. 2010;116: Aversa F, Tabilio A, Terenzi A, et al. Successful engraftment of T- cell-depleted haploidentical three-loci incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum. Blood. 1994;84(11): Aversa F, Tabilio A, Velardi A, et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med. 1998;339(17): Aversa F, Terenzi A, Tabilio A, et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol. 2005;23(15): Bethge WA, Faul C, Bornhäuser M, et al. Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: an update. Blood Cells Mol Dis. 2008;40(1): Ciurea SO, Saliba R, Rondon G, et al. Reduced-intensity conditioning using fl udarabine, melphalan and thiotepa for adult patients undergoing haploidentical SCT. Bone Marrow Transplant. 2010;45(3): Rizzieri DA, Koh LP, Long GD, et al. Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution. J Clin Oncol. 2007;25(6): Gyurkocza B, Storb R, Storer BE, et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol. 2010;28(17): October 2011, Vol. 18, No. 4 Cancer Control 245