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 (alloHCT) 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) alloHCT 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 alloHCT. 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 alloHCT vs conventional chemotherapy alone are not yet available, RIC alloHCT 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 alloHCT is a safe and effective treatment modality in high-risk elderly AML patients and in younger AML patients with medical comorbidities.
AppelbaumF.R., GundackerH., HeadD.R.. Age and acute myeloid leukemia.Blood.2006; 107(9): 3481–3485.
3.
FormanS.J.. What is the role of reduced-intensity transplantation in the treatment of older patients with AML?Hematology Am Soc Hematol Educ Program.2009: 406–413.
4.
GrimwadeD., WalkerH., HarrisonG.. 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): 1312–1320.
5.
LeithC.P., KopeckyK.J., GodwinJ.. 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): 3323–3329.
6.
BaerM.R., GeorgeS.L., DodgeR.K.. Phase 3 study of the mul-tidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720.Blood.2002; 100(4): 1224–1232.
7.
NüsslerV., Pelka-FleischerR., ZwierzinaH.. P-glycoprotein expression in patients with acute leukemia-clinical relevance.Leukemia.1996; 10(suppl 3): S23–S31.
8.
LöwenbergB., OssenkoppeleG.J., van PuttenW.. High-dose daunorubicin in older patients with acute myeloid leukemia.N Engl J Med.2009; 361(13): 1235–1248.
9.
Cancer and Leukemia Group B 8461, FaragS.S., ArcherK.J.. 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 8461.Blood.2006; 108(1): 63–73.
10.
FröhlingS., SchlenkR.F., KayserS.. 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): 3280–3288.
11.
RoweJ.M., NeubergD., FriedenbergW.. 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): 479–485.
12.
BurnettA.K., WheatleyK., GoldstoneA.H.. 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(2): 385–400.
13.
CassilethP.A., HarringtonD.P., AppelbaumF.R.. 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(23): 1649–1656.
14.
CornelissenJ.J., van PuttenW.L., VerdonckL.F.. 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? results of a HOVON/SAKK donor versus no donor analysis.Blood.2007; 109(9): 3658–3666.
15.
SchlenkR.F., DöhnerK., KrauterJ.. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia.N Engl J Med.2008; 358(18): 1909–1918.
16.
HamadaniM., AwanF.T., CopelanE.A.. Hematopoietic stem cell transplantation in adults with acute myeloid leukemia.Biol Blood Marrow Transplant.2008; 14(5): 556–567.
17.
de LimaM., AnagnostopoulosA., MunsellM.. 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): 865–872.
18.
de LimaM., CourielD., ThallP.F.. Once-daily intravenous busul-fan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS.Blood.2004; 104(3): 857–864.
19.
BacigalupoA.. Third EBMT/AMGEN Workshop on reduced-intensity conditioning allogeneic haemopoietic stem cell transplants (RIC-HSCT), and panel consensus.Bone Marrow Transplant.2004; 33(7): 691–696.
20.
GiraltS., BallenK., RizzoD.. Reduced-intensity conditioning regimen workshop: defining 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): 367–369.
21.
BacigalupoA., BallenK., RizzoD.. Defining the intensity of conditioning regimens: working definitions.Biol Blood Marrow Transplant.2009; 15(12): 1628–1633.
22.
HamadaniM., CraigM., AwanF.T.. How we approach patient evaluation for hematopoietic stem cell transplantation.Bone Marrow Transplant.2010; 45(8): 1259–1268.
23.
RingdénO., HorowitzM.M., GaleR.P.. Outcome after allogeneic bone marrow transplant for leukemia in older adults.JAMA.1993; 270(1): 57–60.
24.
SorrorM.L., MarisM.B., StorbR.. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT.Blood.2005; 106(8): 2912–2919.
25.
SorrorM.L., GiraltS., SandmaierB.M.. 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; 110(13): 4606–4013.
26.
SorrorM., StorerB., SandmaierB.M.. 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): 1992–2001.
27.
EsteyE., de LimaM., TibesR.. 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): 1395–1400.
28.
AoudjhaneM., LabopinM., GorinN.C.. 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): 2304–2312.
29.
McCluneB.L., WeisdorfD.J., PedersenT.L.. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome.J Clin Oncol.2010; 28(11): 1878–1887.
30.
TauroS., CraddockC., PeggsK.. Allogeneic stemcell 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): 9387–9393.
31.
ValcarcelD., MartinoR., CaballeroD.. Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versushost disease is the strongest factor improving survival.J Clin Oncol.2008; 26(4): 577–584.
32.
HegenbartU., NiederwieserD., SandmaierB.M.. 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): 444–453.
33.
KohrtH.E., TurnbullB.B., HeydariK.. TLI and ATG conditioning with low risk of graft-versushost disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors.Blood.2009; 114(5): 1099–1109.
34.
GriggA.P., GibsonJ., BardyP.G.. A prospective multicenter trial of peripheral blood stem cell sibling allografts for acute myeloid leukemia in first complete remission using fludarabine-cyclophosphamide reduced intensity conditioning.Biol Blood Marrow Transplant.2007; 13(5): 560–567.
35.
BlaiseD.P., Michel BoironJ., FaucherC.. Reduced intensity conditioning prior to allogeneic stem cell transplantation for patients with acute myeloblastic leukemia as a first-line treatment.Cancer.2005; 104(9): 1931–1938.
36.
van BesienK., ArtzA., SmithS.. Fludarabine, melphalan, and alemtuzumab conditioning in adults with standard-risk advanced acute my-eloid leukemia and myelodysplastic syndrome.J Clin Oncol.2005; 23(24): 5728–5738.
37.
MohtyM., LabopinM., MilpiedN.. 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 first complete remission (CR1).Blood.2008; 112: 345.
38.
MohtyM., de LavalladeH., LadaiqueP.. 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): 916–920.
39.
MohtyM., de LavalladeH., El-CheikhJ.. 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): 194–196.
40.
AppelbaumF.R., PearceS.F.. Hematopoietic cell transplantation in first complete remission versus early relapse.Best Pract Res Clin Haematol.2006; 19(2): 333–339.
41.
BloomfieldC.D., LawrenceD., ByrdJ.C.. Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype.Cancer Res.1998; 58(18): 4173–4179.
42.
SayerH.G., KrögerM., BeyerJ.. 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): 1089–1095.
43.
MichalletM., ThomasX., VernantJ.P.. Long-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: a retrospective study of 379 patients reported to the Société Francaise de Greffe de Moelle (SFGM).Bone Marrow Transplant.2000; 26(11): 1157–1163.
44.
BiggsJ.C., HorowitzM.M., GaleR.P.. Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy.Blood.1992; 80(4): 1090–1093.
45.
WongR., ShahjahanM., WangX.. 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): 108–114.
46.
DuvalM., KleinJ.P., HeW.. Hematopoietic stemcell transplantation for acute leukemia in relapse or primary induction failure.J Clin Oncol.2010; 28(23): 3730–3738.
47.
BlaiseD., VeyN., FaucherC.. Current status of reduced-intensityconditioning allogeneic stem cell transplantation for acute myeloid leukemia.Haematologica.2007; 92(4): 533–541.
48.
SchmidC., SchleuningM., LedderoseG.. Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stemcell transplantation, and prophylactic donor lymphocyte transfusion in highrisk acute myeloid leukemia and myelodysplastic syndrome.J Clin Oncol.2005; 23(24): 5675–5687.
49.
BornhäuserM., IllmerT., OelschlaegelU.. 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): 5585–5593.
50.
PagelJ.M., GooleyT.A., RajendranJ.. Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome.Blood.2009; 114(27): 5444–5453.
51.
PlatzbeckerU., ThiedeC., FüsselM.. Reduced intensity conditioning allows for upfront allogeneic hematopoietic stem cell transplantation after cytoreductive induction therapy in newly-diagnosed high-risk acute my-eloid leukemia.Leukemia.2006; 20(4): 707–714.
52.
MartinM.G., UyG.L., ProcknowE.. Allo-SCT conditioning for myelodysplastic syndrome and acute myeloid leukemia with clofarabine, cytarabine and ATG.Bone Marrow Transplant.2009; 44(1): 13–17.
53.
JabbourE., GiraltS., KantarjianH.. Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia.Cancer.2009; 115(9): 1899–1905.
54.
AlyeaE.P., KimH.T., HoV.. 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(10): 1047–1055.
55.
AlyeaE.P., KimH.T., HoV.. Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age.Blood.2005; 105(4): 1810–1814.
56.
RingdénO., LabopinM., EhningerG.. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia.J Clin Oncol.2009; 27(27): 4570–4577.
57.
ShimoniA., HardanI., Shem-TovN.. Allogeneic hematopoietic stemcell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity.Leukemia.2006; 20(2): 322–328.
58.
PidalaJ., KimJ., AnasettiC.. Pharmacokinetic targeting of intravenous busulfan reduces conditioning regimen related toxicity following allogeneic hematopoietic cell transplantation for acute myelogenous leukemia.J Hematol Oncol.2010; 3: 36.
59.
ShimoniA., HardanI., Shem-TovN.. Comparison between two fludarabine-based reduced-intensity conditioning regimens before allogeneic hematopoietic stemcell transplantation: fludarabine/melphalan is associated with higher incidence of acute graft-versushost disease and nonrelapse mortality and lower incidence of relapse than fludarabine/busulfan.Leukemia.2007; 21(10): 2109–2116.
60.
RussellJ.A., DuanQ., ChaudhryM.A.. Transplantation from matched siblings using once-daily intravenous busulfan/fludarabine 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): 888–895.
61.
de LimaM., CourielD., ThallP.F.. Once-daily intravenous busul-fan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS.Blood.2004; 104(3): 857–864.
62.
AlatrashG., de LimaM., HamerschlakN.. Myeloablative reduced-toxicity i.v. busulfan-fludarabine 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.2011 Feb 18. Epub ahead of print.
63.
CopelanE.A., BiggsJ.C., ThompsonJ.M.. Treatment for acute myelocytic leukemia with allogeneic bone marrow transplantation following preparation with BuCy2.Blood.1991; 78(3): 838–843.
LitzowM.R., PerezW.S., KleinJ.P.. Comparison of outcome following allogeneic bone marrow transplantation with cyclophosphamide-total body irradiation versus busulphan-cyclophosphamide conditioning regimens for acute myelogenous leukaemia in first remission.Br J Haematol.2002; 119(4): 1115–1124.
69.
HosingC., MunsellM., YazjiS.. 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): 450–459.
70.
LimZ., BrandR., MartinoR.. Allogeneic hematopoietic stemcell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia.J Clin Oncol.2010; 28(3): 405–411.
71.
RochaV., LabopinM., SanzG.. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia.N Engl J Med.2004; 351(22): 2276–2285.
72.
LaughlinM.J., EapenM., RubinsteinP.. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia.N Engl J Med.2004; 351(22): 2265–2275.
73.
BarkerJ.N., WeisdorfD.J., DeForT.E.. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy.Blood.2005; 105(3): 1343–1347.
74.
BrunsteinC.G., BarkerJ.N., WeisdorfD.J.. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease.Blood.2007; 110(8): 3064–3070.
75.
BarkerJ.N., WeisdorfD.J., DeForT.E.. Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning.Blood.2003; 102(5): 1915–1919.
RioB., ChevretS., VigourouxS.. 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: 911.
78.
AversaF., TabilioA., TerenziA.. 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): 3948–3955.
79.
AversaF., TabilioA., VelardiA.. 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): 1186–1193.
80.
AversaF., TerenziA., TabilioA.. Full haplotype-mismatched hematopoietic stemcell transplantation: a phase II study in patients with acute leukemia at high risk of relapse.J Clin Oncol.2005; 23(15): 3447–3454.
81.
BethgeW.A., FaulC., BornhäuserM.. Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: an update.Blood Cells Mol Dis.2008; 40(1): 13–19.
82.
CiureaS.O., SalibaR., RondonG.. Reduced-intensity conditioning using fludarabine, melphalan and thiotepa for adult patients undergoing haploidentical SCT.Bone Marrow Transplant.2010; 45(3): 429–436.
