Biology of Blood and Marrow Transplantation
Volume 14, Issue 5 , Pages 556-567, May 2008

Hematopoietic Stem Cell Transplantation in Adults with Acute Myeloid Leukemia

  • Mehdi Hamadani

      Affiliations

    • Division of Hematology & Oncology, Arthur G. James Cancer Hospital, Ohio State University, Columbus, Ohio
    • ,
  • Farrukh T. Awan

      Affiliations

    • Division of Hematology & Oncology, Arthur G. James Cancer Hospital, Ohio State University, Columbus, Ohio
    • ,
  • Edward A. Copelan

      Affiliations

    • Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio
    • Corresponding Author InformationCorrespondence and reprint requests: Edward A. Copelan, MD, Cleveland Clinic Foundation, Taussig Cancer Center, 9500 Euclid Avenue, R35, Cleveland, OH 44195

Received 16 January 2008; accepted 27 February 2008.

Article Outline

Abstract 

Hematopoietic stem cell transplantation (HSCT) is an integral part of the treatment of many patients with acute myeloid leukemia (AML). Despite extensive study, the appropriate role and timing of allogeneic and autologous transplantation in AML are poorly defined. This review critically analyzes the extensive literature, focusing on the recent advances, and provides practical recommendations for the use of HSCT in AML.

Key Words: Acute myeloid leukemia, Hematopoietic stem cell transplantation, Bone marrow transplantation, Reduced intensity, Acute leukemia, Graft-versus-leukemia effect

 

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Introduction 

Acute myeloid leukemia (AML) is currently the most common indication for allogeneic hematopoietic stem cell transplantation (HSCT), and also accounts for a large proportion of autologous HSCT [1]. Despite numerous studies, the use and timing of allogeneic and autologous transplantation in AML vary widely, and many important questions remain unresolved. At the same time, modifications of supportive care and preparative regimens continue to improve results and extend the application of HSCT in AML. We review here the theory of HSCT in AML, critically analyze the vast literature on its use, and make recommendations for clinical practice.

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Theoretic Basis for Allogeneic Transplantation in AML 

The observation that animals given lethal doses of total-body irradiation (TBI) were protected from death by infusion of autologous [2], syngeneic [3], or allogeneic marrow [4] led to human studies in acute leukemia. Thomas and colleagues [5] hypothesized that lethal doses of TBI and cyclophosphamide could destroy leukemic cells, normal marrow, and the immune system of patients with leukemia, and that infusion of normal marrow from allogeneic histocompatible donors would rescue them. Thomas's early studies in end-stage leukemias confirmed their hypothesis and established a new therapy. Although many advances have occurred, Thomas's 5, 6 original clinical work more than 30 years ago achieved results remarkably similar to those achieved today.

It is now understood that AML consists of a hierarchy of cells derived from rare leukemia stem cells, which retain the unique capacity for self-renewal [7]. Leukemic stem cells replenish the bulk population of leukemic cells that possess only limited potential for proliferation. Leukemic stem cells sustain and propagate human leukemia. They are exceedingly rare: as few as 1 in 1 million leukemia cells may be capable of initiating and sustaining leukemia in immunologically susceptible mice [8].

Like normal hematopoietic stem cells, leukemic stem cells are quiescent and resistant to chemotherapeutic agents, which are most effective in proliferating cells. They excrete toxic drugs by ATP-binding transporters and repair DNA injury efficiently. Leukemic stem cells, therefore, are generally not affected by conventional chemotherapy [9]. Virtually all patients who achieve apparent eradication of malignant blasts and complete remission following induction chemotherapy will relapse as a result of undetectable residual leukemic stem cells if additional treatment is not given.

“Lethal” doses of TBI or drugs, for example, busulfan, destroy blast cells and may eliminate leukemic stem cells in a minority of cases, but the high relapse rate following syngeneic transplantation suggests that a graft-versus-leukemia (GVL) effect is required for eradication of leukemia in most patients [10]. The development of complete donor hematopoietic chimerism following nonmyeloablative preparative regimens demonstrates the capacity of donor immune cells to eradicate normal hematopoietic stem cells. Immunologically active donor T cells can also eliminate human acute myeloid leukemia stem cells, preventing the experimental development of human AML in mice [11] and curing AML in humans [12].

If the immunologic effect is of primary importance in eradication of leukemic stem cells, nonablative regimens designed to permit engraftment of donor immune cells with minimal toxicity would seem a wise strategy. Although patients with large blast burdens may not be susceptible to this approach because of rapid progression of disease, its apparent effectiveness in some patients lends credence to this theory.

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Theoretic Basis for (and Against) Autologous Transplantation 

Autologous transplantation is limited by contamination of the stem cell product by malignant cells and the absence of an immunologic effect of allogeneic cells. Clinical results reveal less curative potential for autotransplantation than for syngeneic transplantation and less for syngeneic than for allogeneic transplantation, suggesting that both of these limitations are operative. Still, autologous transplantation cures some patients. Thus, in some instances, high-dose preparative therapy must eradicate leukemic stem cells, and the stem cell graft must not contain leukemic stem cells capable of engrafting [13] and giving rise to AML.

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Clinical Results 

Allogeneic Transplantation in First Complete Remission (CR) 

Treatment with an anthracycline and cytarabine achieves CR in 60%-80% of adults <60 years of age with newly diagnosed AML [14], but virtually all patients relapse without further treatment 15, 16. Options for postremission therapy include allogeneic HSCT, autologous HSCT, and consolidation chemotherapy. Thomas and coworkers [6] pioneered the use of HLA (human leukocyte antigen)-identical sibling donor marrow transplantation for patients with AML in first CR, achieving sustained leukemia-free survival (LFS) in more than half. Prospective studies comparing allogeneic HSCT with consolidation chemotherapy in the 1980s and early 1990s (Table 1) showed lower relapse rates in patients who underwent allogeneic HSCT, but higher treatment-related mortality (TRM) and no survival advantage 17, 18, 19.

Table 1. Prospective Trials Evaluating Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia in First Complete Remission
No. of PatientsRelapse Rate (%)Leukemia-Free Survival (%)Overall Survival (%)
Author (Reference) Year (Cooperative Group)DesignAlloAutoCAlloAutoCAlloAutoCAlloAutoC
Appelbaum [18] 1984Allo versus C33—46NR—NR49—20NR—NR
Champlin [17] 1985Allo versus C23—4440—71NR—NR40—27
Archimbaud [19] 1994Allo versus C27—3143—6741—2741—46
Zittoun [20] 1995 (EORTC/GIMEMA AML-8)Allo versus C versus Auto168128126244157554830595646
Harousseau [23] 1997 (GOELAM)Allo versus C verus Auto737571374555494843555258
Cassileth [22] 1998 (ECOG/CALGB/SWOG)Allo versus C versus Auto113116117294861433434464352
Burnett [21] 1998 (MRC AML-10)Auto versus no further treatment—190191—3758—5340—5745
Suciu [24] 2003 (EORTC/GIMEMA AML-10)Allo versus Auto293441—3052—5242—5850—
Cornelissen [25] 2007 (HOVON-SAKK)Donor versus no donor326165398†32†59†48†37†54†46

Allo indicates allogeneic; auto, autologous; C, chemotherapy; NR, not reported.

Relapse rates, disease-free survival and overall survival shown above are at 4 years with the following exceptions. 1.Leukemia free survival reported by Appelbaum et al. is at 5years. 2. Relapse rate and leukemia-free survival reported by Archimbaud is at 7years. 3. Leukemia free and overall survival reported by Burnett et al. is at 7years.

†In HOVON-SAKK study relapse rate, disease-free survival and overall survival of patients getting chemotherapy or autologous-HSCT is (not provided separately, rather it is) reported together as “no donor” group.

Since 1995, 6 cooperative group trials have examined the role of HSCT in AML in first remission (Table 1) 20, 21, 22, 23, 24, 25. Patients with HLA-identical sibling donors were offered allogeneic transplantation (“genetic randomization”), whereas others were generally randomized between autologous transplantation and intensive consolidation chemotherapy (ICC). Lower relapse rates in patients undergoing allogeneic HSCT conferred improved or equivalent LFS and similar survival compared to ICC.

Autologous Transplantation in First Remission 

Although favorable results for autologous transplantation in patients with AML in first CR have been reported, there is no definitive data indicating that this approach is superior to ICC. In the Groupe Ouest Est Leuemieres Aigues Myeloblastiques (GOELAM) trial, in which the ICC group received high doses of cytarabine (HiDAC), which provides more effective consolidation than standard doses of cytarabine [26], there was no benefit in LFS for autotransplant compared to ICC [23], similar to the US intergroup trial [22]. Two separate meta-analyses of 6 randomized studies demonstrated that autologous bone marrow transplantation modestly prolonged event-free survival (EFS) but not overall survival (OS) compared to consolidation chemotherapy or no further treatment in adults with AML in first CR 27, 28. Because autotransplantation in first CR provides no clear advantage over chemotherapy, its routine use is unwarranted and shortsighted because it jeopardizes the safety and effectiveness of subsequent allogeneic transplantation in those who relapse and are candidates for this procedure.

Cytogenetics and Other Risk Factors 

An assortment of factors that influence outcome following treatment with chemotherapy alone or with transplantation have been identified. The factors that are critical to determining the best treatment in an individual are those that differentially affect the results of transplantation and consolidation chemotherapy. Analysis of several Southwest Oncology Group (SWOG) studies showed that older age adversely affected transplant outcome more than chemotherapy outcome, and that higher white blood cell count at diagnosis and a requirement for more than 1 induction cycle to achieve remission adversely affected chemotherapy outcome but not transplant outcome 29, 30. AML related to prior therapy, after accounting for cytogenetics, is not associated with an adverse prognosis following allogeneic transplantation 31, 32 as it is with chemotherapy alone [33].

Genetics largely determines the biologic behavior of AML and is the most powerful prognostic factor 34, 35. Specific genetic abnormalities affect results achieved with ICC and transplantation differentially. Patients with favorable cytogenetics producing aberrant core binding factor, including inversion (16), and translocation(8;21) fare better with HiDAC consolidation. The North American Intergroup trial [22], stratified according to cytogenetic risk [36], showed superior 5-year survival for patients with unfavorable cytogenetics who underwent allogeneic transplantation (44%) compared to autologous transplantation (13%) or ICC (15%). Meta-analysis of randomized studies confirmed the OS benefit of allogeneic HSCT for patients with poor-risk cytogenetics (coefficient of +0.24 on metaregression analysis) and suggested improved OS in the intermediate-risk group (coefficient of +0.09) [37].

The recent Dutch-Belgian Hemato-Oncology Co-operative Group (HOVON) and Swiss Group for Clinical Cancer Research (SAKK) trial demonstrated superior LFS with allogeneic HSCT for both intermediate and poor-risk groups [25]. Risk stratification included induction cycles needed to achieve CR, and white cell count, in addition to cytogenetics. Meta-analysis of 4 cooperative group (including the HOVON-SAKK study) trials of 4000 AML patients in CR1 demonstrated a 12% OS benefit at 4 years for patients with poor or intermediate risk cytogenetics who had an HLA-identical donor. Allogeneic HSCT was superior for patients whose apparent risk of relapse with ICC exceeded 35% [25].

Patients with intermediate-risk cytogenetics fare better with high-dose cytarabine consolidation than with standard doses [34]. The role of HLA-identical sibling transplantation in patients in first remission with intermediate-risk cytogenetics remains controversial. Genetic abnormalities undetectable with standard cytogenetic analyses can be used to segregate the nearly 50% of patients with normal cytogenetics into less favorable (partial tandem duplications of MLL gene, FLT3 internal tandem duplications [FLT3-ITD], high expression of BAALC) 38, 39, 40 or more favorable risk (nucleophosmin [NPM1] or CEBP-alpha transcription factor gene point mutation) 41, 42 groups. Analysis of 4 trials assigning patients with normal cytogenetics and an HLA-matched sibling donor to allogeneic transplantation in first CR showed that patients whose leukemia was NPM1 + /FLT3-ITD had no improvement in OS or LFS with transplantation, whereas patients with other combinations more than doubled their 4-year LFS with allogeneic-HSCT (47% versus 23%) [43]. Although further study is needed, these genetic aberrations are detectable by commercially available tests, and their apparent prognostic impact justifies their use in combination with other factors to help determine treatment in selected patients.

It is critical to recognize the limitations of the comparative trials. They employ “genetic randomization” and are not truly randomized. Many use consolidation regimens that are inferior to HiDAC in favorable and intermediate-risk groups. The studies use intent-to-treat analyses, but have high “dropout” rates (except in the HOVON-SAKK trial where compliance was 82%) of patients randomized to receive an allograft [44], underestimating the effect of HSCT. Analysis by cytogenetic risk categories is confounded by small numbers of patients: individuals with poor-risk cytogenetics assigned to allogeneic-HSCT in MRC AML-10, SWOG/ECOG, EORTC/GIMEMA AML-10, and HOVON-SAKK were 13, 18, 64, and 36, respectively. Last, induction and consolidation chemotherapy, transplantation preparative regimens, graft-versus-host disease (GVHD) prophylaxis, supportive care measures, and even cytogenetic risk categories (Table 2) are not uniform, complicating comparisons and summarizations.

Table 2. Comparison of Cytogenetic Risk Group Definitions
Cytogenetic Risk Groups
StudyGoodIntermediatePoor
ECOG/SWOG
•inv16, t(16;16), 16q-

•t(8;21) without -9q and CK

•t(15;17)


•NN

•+8

•+6

•-Y

•del(12p)


•-5/5q-

•-7/7q-

•t(6;9)

•t(9;22)

•abnormal 3q, 9q, 11q, 20q, 21q, and 17p

•CK

MRC AML-10 [95]
•inv16, t(16;16), 16q-

•t(8;21)

•t(15;17)


•All other cytogenetic abnormalities


•-5/5q-

•-7

•abnormal 3q

•t(6;9)

•t(9;22)

•CK

EORTC/GIMEMA AML-10
•t(8:21)

•inv16, t(16;16), 16q-


•NN

•-Y


•All other cytogenetic abnormalities

HOVON-SAKK
•t(8:21)

•inv16, t(16;16), 16q-


•All other cytogenetic abnormalities


•-5/5q-

•-7/7q-

•abnormal 3q

•t(6;9)

•t(9;22)

•abn(11q23)

•CK

CK indicates complex karyotype; NN, normal karyotype.

Unrelated Donor Transplantation in First CR 

Less than 30% of patients have an HLA-identical sibling donor [45]. Adult matched unrelated donor (URD) or cord blood transplantation are options in patients lacking sibling donors. Approximately 11 million HLA-typed volunteer donors are currently registered in the Bone Marrow Donors Worldwide file (www.bmdw.org). The probability of finding an HLA-A, -B, -C, -DR, and –DQ match by high-resolution DNA typing is 35%-40% for a Caucasian [46] and less for some minorities. Recent reports show similar rates of acute GVHD (aGVHD), TRM, relapse rate, and OS in patients with standard-risk hematologic malignancies undergoing HLA-identical sibling transplantation compared to HLA-allelic-matched URD (10 of 10) transplantation 47, 48. The risk of GVHD, graft failure, and mortality increases with an increasing number of HLA disparities between the recipient and donor [49], and disparities are tolerated more poorly by older patients. In a series of 161 patients in first CR treated with variably matched unrelated transplants, the 5-year LFS was 50% [50]. High graft cell doses and CMV seronegativity were favorable prognostic factors.

The 5-year OS for patients with unfavorable cytogenetics undergoing URD transplantation in CR1 was 30% in a CIBMTR/NMDP (National Marrow Donor Program) study [51], which compares favorably with survival rates below 15% reported for such patients with autologous-HSCT or ICC [36]. The German AML 01/99 trial prospectively studied patients with AML in first CR at high risk for relapse based on unfavorable cytogenetic abnormalities or more than 5% blasts on day 15 marrow. Four-year survival was 68%, 56%, and 23%, respectively, for those who underwent sibling, unrelated, and autologous transplantation (P < .01) [52]. URD transplantation is appropriate for younger patients with AML in CR1 with high-risk cytogenetics. Transplantation using well-matched URD might also be considered for selected patients with normal cytogenetics and unfavorable genetic abnormalities or otherwise at high risk for relapse who lack significant comorbidities.

Umbilical Cord Blood Transplantation (UCBT) 

The easy and rapid availability of a prescreened, HLA-typed product makes UCBT an attractive option for patients without a HLA-matched sibling or adult unrelated donor. Transplantation using cord blood is associated with lower GVHD rates for the degree of HLA-mismatching. UCBT is an appropriate alternative when a well-matched URD is not available within a reasonable time 53, 54, 55, 56, 57, 58. Limited experience with UCBT and the low stem cell dose available from individual cord units has limited the use of UCBT in adults with AML, but the use of multiple units from different donors may improve engraftment [58]. Expansion of the current pool of cord blood units could markedly extend the application of transplantation, particularly to minority populations underrepresented in adult registries.

Comorbidities 

Although the role of genetics and other factors in predicting the behavior of AML have received considerable attention, factors that determine the risk of TRM have received less emphasis, but are of at least equal importance. Older age and poor performance status are appropriately used in patients in first CR to select consolidation chemotherapy over allogeneic transplantation where the adverse risk of these factors is magnified. But systematic assessment of comorbidities is rare [59]. The hematopoietic cell transplantation comorbidity index, developed by Sorror and colleagues 60, 61, is the most influential risk factor for nonrelapse mortality and survival in patients with AML in first CR who undergo allogeneic transplantation. Evaluation and scoring take <10 minutes. The same index has predictive value for chemotherapy-treatment of AML [62] and for reduced intensity transplantation [63]. It should be used to estimate treatment-related risk and to guide decisions on treatment. The judgment to perform allogeneic transplantation in first remission must balance the increased risk of TRM with transplantation against the extent to which transplantation decreases the risk of relapse in an individual patient. The potential for delayed complications, particularly chronic GVHD (cGVHD), following transplantation is also an important consideration. Most transplantation survivors, however, are healthy and active.

Allogeneic Transplantation for Primary Refractory AML 

For the approximately 30% of patients with AML who fail to achieve CR with standard induction chemotherapy, allogeneic HSCT is the lone curative option [64]. Table 3 illustrates the outcome of transplantation in studies containing at least 50 patients with primary induction failure 65, 66, 67, 68, 69. Patient characteristics and inclusion criteria are heterogenous, and the number of failed induction chemotherapies varies. The 3-year LFS is approximately 20% to 30%. Favorable prognostic factors include availability of an HLA-identical sibling 66, 67, good performance status [66], young age [66], fewer cycles of induction chemotherapy 65, 69, good-or intermediate-risk cytogenetics [67], and low tumor burden 65, 69. It is essential to consider allogeneic transplantation early in the course of patients who do not achieve remission with initial therapy.

Table 3. Retrospective Studies Looking at Allogeneic Stem Cell Transplantation for Primary Refractory AML
Author (Reference)No. of PatientsDisease Burden (% Blasts in Marrow)No. of Prior RegimensDonor TypeLeukemia-Free SurvivalOverall SurvivalRelapse RateTreatment-Related Mortality
Biggs [65]8825%≥2∗100% mSib21% at 3 yearsNR62% at 3 years44%
Michallet [66]69NRNR
mSib

mmSib

MUD

mMUD

9% at 5 years13% at 5 yearsNR51%
Fung [67]6836%
≤2 (82%)

>2 (18%)


79% mSib

10% MUD

7% mMUD

31% at 3 years30% at 3 years51%NR†
Esteve [68]346NRNR100% mSib18% at 2 years25% at 2 years57% at 2 years25%
Wong [69]5323%NR
mSib

mmSib

MUD

26% at 2 years29% at 2 yearsNR62%

mSib indicates HLA-identical sibling donor; mmSib, 1 antigen mismatched related donor; MUD, matched unrelated donor; mMUD, mismatched unrelated donor; NR, not reported; TRM, treatment-related mortality; CR, complete remission.

∗Data available for 55 patients only.

†Study claimed TRM comparable to figures with allogeneic transplant in first CR, but no figures were provided.

Transplantation for AML beyond First Remission 

Chemotherapy offers little chance of cure for AML patients who relapse. Despite higher rates of TRM and relapse and substantially lower LFS [46] than transplantation in first CR, allogeneic HSCT still provides the best prospect for cure 70, 71. For patients who previously underwent autologous or allogeneic HSCT in first remission, however, the likelihood of successful allografting is markedly reduced [70].

Patients in first relapse nearly always receive chemotherapy in an attempt to achieve second CR. The 3-year LFS, however, was nearly 30% in 2 studies of transplantation in untreated first relapse 72, 73. Because less than half of those who undergo reinduction therapy will obtain second CR, where allotransplantation is curative in only about 30%, more patients might be cured with allotransplantation in early relapse. Candidates for allotransplantation who are not transplanted in first CR should have early identification of potential donors to permit timely transplantation at relapse. They should have their blood counts monitored closely and undergo marrow examination for abnormal counts, permitting some to undergo allotransplantation in untreated early relapse. For those with sibling donors, rapid transplantation can often be accomplished. Matched URD usually require months for identification and procurement, but initial survey of URD can speed this process in patients who do not undergo allogeneic transplantation in first CR. Patients lacking potential donors can have autologous stem cells procured while in first remission.

The 5 year LFS of patients undergoing URD HSCT in CR1 and CR2, at Fred Hutchinson Cancer Center were 50% and 28%, respectively [50]. Results of URD transplantation in patients not in remission are significantly affected by disease burden (bone marrow blasts >20%, blasts in peripheral blood >5000/μL, or both) and number of prior treatments 50, 74. Patients with advanced disease who do not achieve remission with salvage chemotherapy experience TRM rates approaching 50% and only 10%-15% achieve sustained LFS with allotransplantation [75].

Autologous Transplantation in Second CR 

Autologous HSCT results in sustained LFS in selected patients in second or subsequent CR 76, 77, 78. EBMT registry data demonstrate sustained LFS in 35% of patients undergoing autologous HSCT in second CR [78]. Longer duration of CR1, M3 subtype, grafts harvested in CR1, and younger patient age are associated with improved survival 76, 77, 78. Patient selection appears to be largely responsible for the favorable results obtained in many trials of autologous transplantation. Among 741 patients (enrolled in MRC AML 10 and 12 trials) who achieved a second CR, 480 underwent HSCT (116 = sibling allogeneic transplants, 192 = autograft, and 154 = matched URD). The 5-year OS of patients undergoing HSCT was superior to those receiving further chemotherapy (39% versus 22%). The 5-year survival rates for patients undergoing sibling, URD, and autologous transplantations were 54%, 40%, and 33%, respectively [79].

Reduced-Intensity Conditioning (RIC) 

RIC limits the toxicity and lowers the transplant-related mortality of allogeneic transplantation. Most RIC studies in AML are retrospective or nonrandomized prospective series, and include heterogeneous patients (often including some with myelodysplastic syndromes). Information on cytogenetics is unfortunately limited. Table 4 lists the studies utilizing RIC regimens in AML (and MDS) patients that included at least 50 patients.

Table 4. Studies Utilizing Reduced-Intensity Conditioning (RIC) Regimens in AML and MDS
Author (Year) (Reference)DesignDisease CategoryPatients in CR (%)Donor Type (%)RegimenNo. of PatientsRelapse Rate (%)Leukemia-Free Survival (%)Overall Survival (%)TRM (%)
Sayer (2003) [96]RetrospectiveAML22.1
44-MRD

44-MUD

11-MMUD

1-MMRD

FB/TBI11325.7 (2 years)29 (2 years)32 (2 years)53 (2 years)
de Lima (2004) [97]RetrospectiveAML+ MDS14
47-MUD

40-MRD

13-MMRD

FM623032 (3 years)35 (3 years)30 (1 year)
Ho (2004) [98]Prospective seriesAML+ MDS58-MRD55.3-MUD
38.7-MRD

61.3-MUD

FBC62≥24-MRD≥10.5-MUD61-MRD59-MUD (1 year)73-MRD71-MUD (1 year)
5-MRD

21-MUD (1yr)

Van Besien (2005) [99]Prospective seriesAML+ MDS37
44-MUD

43-MRD

8-MMRD

6-MMUD

FMC5240 (2 years)38 (2 years)39 (2 years)33 (2 years)
Aoudjhane (2005) [81]Retrospective registryAML71MRDFB/TBI31541 (2 years)40 (2 years)47 (2 years)18 (2 years)
Tauro (2005) [100]Prospective seriesAML+ MDS55.3
46-MRD

54-MUD

FMC7634.2 (3 years)37 (3 years)41 (3 years)
19-MRD

24-MUD

(1 year)

Martino (2006) [101]Retrospective registryAML+ MDS≥30.7MRDFB/M/C/TBI21545 (3yrs)33 (3yrs)41 (3 years)22 (3 years)
Hegenbart (2006) [82]Prospective seriesAML74
48-MRD

34-MUD

18-MMUD

F/TBI12239 (2 years)44 (2 years)48 (2 years)16 (2 years)

MRD indicates matched related donor; MUD, matched unrelated donor; MMUD, mismatched inrelated donor; MMRD, mismatched related donor; NR, not reported; TRM, tansplant-related mortalityl; CR, complete remission; F, fludarabine; M, melphalan; B, Busulphan, A, Cytarabine (Ara-C); I, Idarubicin; C, Alemtuzumab (Campath); TBI, total-body irradiation.

No prospective, randomized trials comparing myeloablative (MA) with RIC regimens in AML have been performed; however, retrospective comparisons have been reported 80, 81. The Acute Leukemia Working Party of EBMT [81] used registry data to compare 315 recipients of RIC with 407 patients who received MA conditioning prior to HLA-matched sibling allografts. Over 70% of patients were in CR1 or CR2. At 2 years, TRM was significantly lower (18% versus 36%), but relapse rates significantly higher (41% versus 24%) in the RIC group. LFS and OS were not significantly different. For patients, mostly in first or second CR, who received a matched related or URD allograft following RIC, Hegenbart reported a relapse rate of 39%, LFS of 44%, and OS of 48% at 2 years. TRM was significantly higher in the URD group (22% versus 10%) [82].

Seventy percent of patients with AML are over the age of 55 years [83] and are at high risk of TRM with ablative allogeneic transplantation. Although RIC studies have included many elderly patients, they have also included younger patients with and without compromised organ function. Table 5 lists those studies where the median age was >60 years. Alyea et al. [80] detected no significant difference in LFS and OS at 2 years in a RIC group (20% and 28%) compared to a myeloablative group (31% and 34%) in a retrospective comparison of 152 patients older than 50 years. Hegenbart et al. [82] demonstrated that 2-year OS and LFS, in patients over the age of 60 years (45% and 42%) was similar to that of the whole cohort of patients aged 17 to 74 years.

Table 5. Studies Utilizing Reduced-Intensity Conditioning (RIC) Regimens in Elderly Patients with AML and MDS
Author (Year) (Reference)DesignDisease CategoryPatients in CR (%)Median Age (Years)Donor Type (%)RegimenNo. of PatientsRelapse Rate (%)Leukemia-Free Survival (%)Overall Survival (%)TRM (%)
Bertz (2003) [102]Phase II
AML+

MDS+

OMF

(1 patient)

1064
63-MUD

37-MRD

FM1921 (3 years)61 (1 year)68 (1 year)22 (1 year)
Ringhoffer (2005) [103]Phase I-II
AML+

MDS+

ALL

(2 patients)

6063
55-MRD

45-MUD

FM/BCNU/Anti-CD 66 mAb2045 (3 years)30 (2 years)52 (2 years)30 (2 years)
Gupta (2005) [104]ProspectiveAML+MDS5864MRDFTBI2427 (2 years)44 (2 years)52 (2 years)25 (2 years)

BCNU indicates carmustine; OMF, osteomyelofibrosis; MUD, matched unrelated donor; MRD, matched related donor.

In general, patients older than 60 years show lower TRM and similar OS and LFS compared to those undergoing MA conditioning 63, 84, 85, 86. Follow-up, however, is too short to fully evaluate late TRM and relapse. RIC regimens seem a reasonable option in older patients in remission who have significant comorbidities. These older patients have poor prognoses with ICC. They should be enrolled on well-designed clinical trials. Specific criteria to identify patients likely to fare better with RIC regimens must be established.

The Future 

No simple algorithm is sufficient to determine treatment in individual patients. Attention to the cumulative risk of multiple comorbidities can improve patient selection for transplantation. Better identification and characterization of the entirety of genetic abnormalities will improve risk stratification. For example, the impact of FLT3-ITD on survival in patients with a normal karyotype depends not merely on its presence but on the ratio of mutant to wild-type FLT3 [87]. The KIT-D816 mutation does not appear to influence survival in patients with a normal karyotype, but has a negative impact on survival in patients with t(8;21) where it occurs more commonly [88].

Methods such as high resolution single nucleotide polymorphisms arrays identifies previously unrecognized genetic lesions that will almost certainly be clinically relevant [89]. More meaningful characterization of the biologic behavior of an individual's leukemic cells might require more sophisticated methods such as gene expression profiling [90] or techniques designed to identify differences in signaling biology [91]. Advances in immunophenotyping and cell separation [92] may permit the characterization of signaling pathways in leukemic stem cells [91], providing targets in the only cells capable of maintaining the leukemia hierarchy.

The ultimate goal of such work is to systemically administer agents that selectively eradicate leukemic stem cells and spare normal hematopoietic stem cells. More immediately, the use of agents that can be used in vitro to selectively eradicate leukemic stem cells, while sparing normal hematopoietic stem cells [93], could improve autotransplantation. Agents that can be administered systemically to effectively kill both normal and leukemic stem cells [94] would require allogeneic or autologous (purged) rescue. These and other applications of basic work would make HSCT more effective in a broader range of patients.

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References 

  1. Gratwohl A, Baldomero H, Frauendorfer K, et al. Results of the EBMT activity survey 2005 on haematopoietic stem cell transplantation: focus on increasing use of unrelated donors. Bone Marrow Transplant. 2007;39:71–87
  2. Mannick JA, Lochete HL, Ashley CA, et al. Autografts of bone marrow in dogs after lethal total-body radiation. Blood. 1960;15:255–266
  3. Lorenz E, Uphoff D, Reid TR, et al. Modification of irradiation injury in mice and guinea pigs by bone marrow injections. J Natl Cancer Inst. 1951;12:197–201
  4. Storb R, Epstein RB, Graham TC, et al. Methotrexate regimens for control of graft-versus-host disease in dogs with allogeneic marrow grafts. Transplantation. 1970;9:240–246
  5. Thomas ED, Buckner CD, Banaji M, et al. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood. 1977;49:511–533
  6. Thomas ED, Buckner CD, Clift RA, et al. Marrow transplantation for acute nonlymphoblastic leukemia in first remission. N Engl J Med. 1979;301:597–599
  7. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–737
  8. Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645–658
  9. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5:275–284
  10. Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990;75:555–562
  11. Bonnet D, Warren EH, Greenberg PD, et al. CD8(+) minor histocompatibility antigen-specific cytotoxic T lymphocyte clones eliminate human acute myeloid leukemia stem cells. Proc Natl Acad Sci USA. 1999;96:8639–8644
  12. Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006;354:1813–1826
  13. Pearce DJ, Taussig D, Zibara K, et al. AML engraftment in the NOD/SCID assay reflects the outcome of AML: implications for our understanding of the heterogeneity of AML. Blood. 2006;107:1166–1173
  14. Creutzig U, Ritter J, Zimmermann M, et al. A systematic collaborative overview of randomized trials comparing idarubicin with daunorubicin (or other anthracyclines) as induction therapy for acute myeloid leukaemia. AML Collaborative Group. Br J Haematol. 1998;103:100–109
  15. Buchner T, Urbanitz D, Hiddemann W, et al. Intensified induction and consolidation with or without maintenance chemotherapy for acute myeloid leukemia (AML): two multicenter studies of the German AML Cooperative Group. J Clin Oncol. 1985;3:1583–1589
  16. Geller RB. Post-remission therapy of acute myelocytic leukemia in adults: curability breeds controversy. Leukemia. 1992;6:915–925
  17. Champlin RE, Ho WG, Gale RP, et al. Treatment of acute myelogenous leukemia. A prospective controlled trial of bone marrow transplantation versus consolidation chemotherapy. Ann Intern Med. 1985;102:285–291
  18. Appelbaum FR, Dahlberg S, Thomas ED, et al. Bone marrow transplantation or chemotherapy after remission induction for adults with acute nonlymphoblastic leukemia. A prospective comparison. Ann Intern Med. 1984;101:581–588
  19. Archimbaud E, Thomas X, Michallet M, et al. Prospective genetically randomized comparison between intensive postinduction chemotherapy and bone marrow transplantation in adults with newly diagnosed acute myeloid leukemia. J Clin Oncol. 1994;12:262–267
  20. Zittoun RA, Mandelli F, Willemze R, et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J Med. 1995;332:217–223
  21. Burnett AK, Goldstone AH, Stevens RM, et al. Randomized comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. UK Medical Research Council Adult and Children's Leukaemia Working Parties. Lancet. 1998;351:700–708
  22. 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 first remission. N Engl J Med. 1998;339:1649–1656
  23. Harousseau JL, Cahn JY, Pignon B, et al. Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. The Groupe Ouest Est Leucemies Aigues Myeloblastiques (GOELAM). Blood. 1997;90:2978–2986
  24. Suciu S, Mandelli F, de Witte T, et al. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial. Blood. 2003;102:1232–1240
  25. Cornelissen JJ, van Putten WL, Verdonck LF, et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom?. Blood. 2007;109:3658–3666
  26. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med. 1994;331:896–903
  27. Levi I, Grotto I, Yerushalmi R, et al. Meta-analysis of autologous bone marrow transplantation versus chemotherapy in adult patients with acute myeloid leukemia in first remission. Leukemia Res. 2004;28:605–612
  28. Nathan P, Sung L, Crump M, Beyene J. Consolidation therapy with autologous bone marrow transplantation in adults with acute myeloid leukemia: a meta-analysis. J Natl Cancer Inst. 2004;96:38–45
  29. Tallman MS, Kopecky KJ, Amos D, et al. Analysis of prognostic factors for the outcome of marrow transplantation or further chemotherapy for patients with acute nonlymphocytic leukemia in first remission. J Clin Oncol. 1989;7:326–337
  30. Appelbaum FR, Pearce SF. Hematopoietic cell transplantation in first complete remission versus early relapse. Best Pract Res Clin Haematol. 2006;19:333–339
  31. 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
  32. 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
  33. Smith SM, Le Beau MM, Huo D, et al. Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood. 2003;102:43–52
  34. 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;58:4173–4179
  35. Byrd JC, Mrozek K, Dodge RK, et al. 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 (CALGB 8461). Blood. 2002;100:4325–4336
  36. Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96:4075–4083
  37. Yanada M, Matsuo K, Emi N, et al. Efficacy of allogeneic hematopoietic stem cell transplantation depends on cytogenetic risk for acute myeloid leukemia in first disease remission: a metaanalysis. Cancer. 2005;103:1652–1658
  38. Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98:1752–1759
  39. Dohner K, Tobis K, Ulrich R, et al. Prognostic significance of partial tandem duplications of the MLL gene in adult patients 16 to 60 years old with acute myeloid leukemia and normal cytogenetics: a study of the Acute Myeloid Leukemia Study Group Ulm. J Clin Oncol. 2002;20:3254–3261
  40. Baldus CD, Tanner SM, Kusewitt DF, et al. BAALC, a novel marker of human hematopoietic progenitor cells. Exp Hematol. 2003;31:1051–1056
  41. Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352:254–266
  42. Preudhomme C, Sagot C, Boissel N, et al. Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). Blood. 2002;100:2717–2723
  43. Schlenk R, Corbacioglu A, Krauter J, et al. Gene mutations as predicitive markers for postremission therapy in younger adults with normal karyotype AML. Blood. 2006;108:4
  44. Drobyski WR. The role of allogeneic transplantation in high-risk acute myelogenous leukemia. Leukemia. 2004;18:1565–1568
  45. Anasetti C, Perkins J, Nieder ML, et al. Are matched unrelated donor transplants justified for AML in CR1?. Best Pract Res Clin Haematol. 2006;19:321–328
  46. Cornelissen JJ, Lowenberg B. Role of allogeneic stem cell transplantation in current treatment of acute myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2005;151–155
  47. Yakoub-Agha I, Mesnil F, Kuentz M, et al. Allogeneic marrow stem-cell transplantation from human leukocyte antigen-identical siblings versus human leukocyte antigen-allelic-matched unrelated donors (10/10) in patients with standard-risk hematologic malignancy: a prospective study from the French Society of Bone Marrow Transplantation and Cell Therapy. J Clin Oncol. 2006;24:5695–5702
  48. Cutler C, Li S, Ho VT, et al. Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation. Blood. 2007;109:3108–3114
  49. Flomenberg N, Baxter-Lowe LA, Confer D, et al. Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome. Blood. 2004;104:1923–1930
  50. Sierra J, Storer B, Hansen JA, et al. Unrelated donor marrow transplantation for acute myeloid leukemia: an update of the Seattle experience. Bone Marrow Transplant. 2000;26:397–404
  51. Tallman M, Dewald G, Gandham S, et al. Impact of cytogenetics on outcome of matched unrelated donor hematopoietic stem cell transplantation for acute myeloid leukemia in first of second complete remission. Blood. 2007;110:409–417
  52. Krauter J, Heil G, Hoelzer D, et al. Role of consolidation therapy in the treatment of patients up to 60 years with high risk AML. Blood. 2005;106:Abstract 172
  53. Rubinstein P, Carrier C, Scaradavou A, et al. Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med. 1998;339:1565–1577
  54. 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;351:2265–2275
  55. 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;351:2276–2285
  56. Hwang WY, Samuel M, Tan D, et al. A meta-analysis of unrelated donor umbilical cord blood transplantation versus unrelated donor bone marrow transplantation in adult and pediatric patients. Biol Blood Marrow Transplant. 2007;13:444–453
  57. Takahashi S, Ooi J, Tomonari A, et al. Comparative single-institute analysis of cord blood transplantation from unrelated donors with bone marrow or peripheral blood stem-cell transplants from related donors in adult patients with hematologic malignancies after myeloablative conditioning regimen. Blood. 2007;109:1322–1330
  58. Brunstein CG, Barker JN, McGlave PB, et al. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood. 2007;110:3064–3070
  59. Sekeres MA, Stone RM, Zahrieh D, et al. Decision-making and quality of life in older adults with acute myeloid leukemia or advanced myelodysplastic syndrome. Leukemia. 2004;18:809–816
  60. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912–2919
  61. Sorror ML, Giralt S, Sandmaier BM, et al. Hematopoietic cell transplantation-specific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: combined FHCRC and MDACC experiences. Blood. 2007;
  62. Giles FJ, Borthakur G, Ravandi F, et al. The haematopoietic cell transplantation comorbidity index score is predictive of early death and survival in patients over 60 years of age receiving induction therapy for acute myeloid leukaemia. Br J Haematol. 2007;136:624–627
  63. Scott BL, Sandmaier BM, Storer B, et al. Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a retrospective analysis. Leukemia. 2006;20:128–135
  64. Song KW, Lipton J. Is it appropriate to offer allogeneic hematopoietic stem cell transplantation to patients with primary refractory acute myeloid leukemia?. Bone Marrow Transplant. 2005;36:183–191
  65. Biggs JC, Horowitz MM, Gale RP, et al. Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy. Blood. 1992;80:1090–1093
  66. 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;26:1157–1163
  67. Fung HC, Stein A, Slovak M, et al. A long-term follow-up report on allogeneic stem cell transplantation for patients with primary refractory acute myelogenous leukemia: impact of cytogenetic characteristics on transplantation outcome. Biol Blood Marrow Transplant. 2003;9:766–771
  68. Esteve J, Labopin M, Finke J, et al. Allogeneic stem-cell transplantation for patients with de novo acute myeloid leukemia not in complete response: results of a survey from the European Group for Blood and Bone Marrow Transplantation (EBMT). Blood. 2004;104:633a
  69. 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;11:108–114
  70. Breems DA, Van Putten WL, Huijgens PC, et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol. 2005;23:1969–1978
  71. Gale RP, Horowitz MM, Rees JK, et al. Chemotherapy versus transplants for acute myelogenous leukemia in second remission. Leukemia. 1996;10:13–19
  72. Clift RA, Buckner CD, Appelbaum FR, et al. Allogeneic marrow transplantation during untreated first relapse of acute myeloid leukemia. J Clin Oncol. 1992;10:1723–1729
  73. Brown RA, Wolff SN, Fay JW, et al. High-dose etoposide, cyclophosphamide, and total body irradiation with allogeneic bone marrow transplantation for patients with acute myeloid leukemia in untreated first relapse: a study by the North American Marrow Transplant Group. Blood. 1995;85:1391–1395
  74. Blum W, Bolwell BJ, Phillips G, et al. High disease burden is associated with poor outcomes for patients with acute myeloid leukemia not in remission who undergo unrelated donor cell transplantation. Biol Blood Marrow Transplant. 2006;12:61–67
  75. Basara N, Baurmann H, Kolbe K, et al. Antithymocyte globulin for the prevention of graft-versus-host disease after unrelated hematopoietic stem cell transplantation for acute myeloid leukemia: results from the multicenter German cooperative study group. Bone Marrow Transplant. 2005;35:1011–1018
  76. Linker CA, Damon LE, Ries CA, et al. Autologous stem cell transplantation for advanced acute myeloid leukemia. Bone Marrow Transplant. 2002;29:297–301
  77. Chantry AD, Snowden JA, Craddock C, et al. Long-term outcomes of myeloablation and autologous transplantation of relapsed acute myeloid leukemia in second remission: a British Society of Blood and Marrow Transplantation registry study. Biol Blood Marrow Transplant. 2006;12:1310–1317
  78. Gorin NC, Labopin M, Meloni G, et al. Autologous bone marrow transplantation for acute myeloblastic leukemia in Europe: further evidence of the role of marrow purging by mafosfamide. European Co-operative Group for Bone Marrow Transplantation (EBMT). Leukemia. 1991;5:896–904
  79. Burnett AK, Hills RK, Goldstone AH, et al. The impact of transplant in AML in 2nd CR: A prospective study of 741 in the MRC AML 10 and 12 Trials. Blood. 2004;104:Abstract 620
  80. 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;105:1810–1814
  81. 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;19:2304–2312
  82. 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;24:444–453
  83. Rieg LAG, Melbert D, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2004. Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/csr/1975_2004/, based on November 2006 SEER data submission, posted to the SEER website 2007.
  84. Niederwieser D, Lange T, Cross M, et al. Reduced intensity conditioning (RIC) haematopoietic cell transplants in elderly patients with AML. Best Pract Res Clin Haematol. 2006;19:825–838
  85. Kojima R, Kami M, Kanda Y, et al. Comparison between reduced intensity and conventional myeloablative allogeneic stem-cell transplantation in patients with hematologic malignancies aged between 50 and 59 years. Bone Marrow Transplant. 2005;36:667–674
  86. 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 Marrow Transplant. 2006;12:1047–1055
  87. Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activing mutation in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99:4326–4335
  88. Schnittger S, Kohl TM, Haferlach T, et al. KIT-D816 mutations in AML 1-ETO-positive AML are associated with impaired event-free and overall survival. Blood. 2006;107:1791–1799
  89. Gondek L, Tiu R, O'Keefe C, et al. Chromosomal lesion and uniparental disomy detected by SNP arrays in MDS, MDS/MPD and MDS-derived AML. Blood. 2007 Oct 22;[Epub ahead of print]
  90. Gal H, Amariglio N, Trakhtenbrt L, et al. Gene expression profiles of AML derived stem cells; similarity to hematopoietic stem cells. Leukemia. 2006;20:2147–2154
  91. Irish JM, Hovland R, Krutzik PO, et al. Single cell profiling of potentiated phospho-protein networks in cancer cells. Cell. 2004;118:217–218
  92. Blair A, Hogge DE, Ailles LE, et al. Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in-vitro and in-vivo. Blood. 1997;89:3104–3112
  93. Guzman ML, Rossi RM, Karnischky L, et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood. 2005;105:4163–4169
  94. Jin L, Hope KJ, Zhai Q, et al. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med. 2006;12:1167–1174
  95. Burnett AK, Wheatley K, Goldstone AH, et al. The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial. Br J Haematol. 2002;118:385–400
  96. Sayer HG, Kroger 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;31:1089–1095
  97. 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 long-term disease control after allogeneic hematopoietic stem cell transplantation. Blood. 2004;104:865–872
  98. Ho AY, Pagliuca A, Kenyon M, et al. Reduced-intensity allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, busulphan, and alemtuzumab (FBC) conditioning. Blood. 2004;104:1616–1623
  99. 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;23:5728–5738
  100. 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;23:9387–9393
  101. Martino R, Iacobelli S, Brand R, et al. Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood. 2006;108:836–846
  102. Bertz H, Potthoff K, Finke J. Allogeneic stem-cell transplantation from related and unrelated donors in older patients with myeloid leukemia. J Clin Oncol. 2003;21:1480–1484
  103. Ringhoffer M, Blumstein N, Neumaier B, et al. 188Re or 90Y-labelled anti-CD66 antibody as part of a dose-reduced conditioning regimen for patients with acute leukaemia or myelodysplastic syndrome over the age of 55: results of a phase I-II study. Br J Haematol. 2005;130:604–613
  104. Gupta V, Daly A, Lipton JH, et al. Nonmyeloablative stem cell transplantation for myelodysplastic syndrome or acute myeloid leukemia in patients 60 years or older. Biol Blood Marrow Transplant. 2005;11:764–772

PII: S1083-8791(08)00108-0

doi:10.1016/j.bbmt.2008.02.019

Biology of Blood and Marrow Transplantation
Volume 14, Issue 5 , Pages 556-567, May 2008

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