VC 2007 Wiley-Liss, Inc.

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1 Reduced intensity compared with high dose conditioning for allotransplantation in acute myeloid leukemia and myelodysplastic syndrome: A comparative clinical analysis Catherine M. Flynn, 1,3 Betsy Hirsch, 4 Todd DeFor, 3 Juliet N. Barker, 1,3 Jeffrey S. Miller, 1,3 John E. Wagner, 2,3 Bruce R. Blazar, 2,3 Linda J. Burns, 1,3 Margaret L. MacMillan, 2,3 Mukta Arora, 1,3 and Daniel Weisdorf 1,3 * 1 Departments of Medicine and 2 Pediatrics and the 3 Blood and Marrow Transplant Program, University of Minnesota Medical School, Minneapolis, Minnesota 4 Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota We evaluated the efficacy of hematopoietic stem cell transplantation (HSCT) using reduced intensity (RI) vs. myeloablative (MA) conditioning for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome. Thirty two patients (median age 54) who underwent a RI HSCT ( ) were compared with 187 patients (median age 39) who received a MA transplant ( ). Neutrophil engraftment was more rapid in the RI group (median 11.5 vs. 21 days). Platelet recovery was similar and graft failure was infrequent. The incidence of graft-versus-host disease (GVHD) and treatment-related mortality was similar though relapse was more frequent after RI conditioning (RR 2.2 [95% CI ] P ). At 2 years, disease-free survival (DFS) (31% vs. 30%, P > 0.1) and overall survival (33% vs. 35%, P > 0.1) were comparable between RI and MA groups, respectively. We suggest that RI allografts can yield satisfactory DFS both for older as well as younger patients with pre-existing comorbidities, who are ineligible for MA allografts. Advances in GVHD management and new approaches for relapsed or refractory disease are necessary to improve these outcomes. Am. J. Hematol. 82: , VC 2007 Wiley-Liss, Inc. Introduction Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are clonal hematopoietic disorders that occur with increasing frequency in older individuals who often have coexistent morbidities that may compromise their tolerance of intensive therapy. Older individuals with myeloid diseases also have high risk cytogenetic phenotypes and increased multidrug resistance gene expression [1 3]; hence they are less likely cured with chemotherapy alone. Allogeneic hematopoietic stem cell transplantation (HSCT) is potentially curative with a reported disease-free survival (DFS) of 30 50% [4 9]. In MDS, HSCT is the only therapy known to improve survival [10]. For nearly a decade nonmyeloablative (MA) or reduced intensity (RI) HSCT has been explored as a means to ameliorate the intensity of the conditioning and decrease the transplant-related toxicity while retaining the graft versus leukemia effect. We report the comparative safety, efficacy, and outcomes of allogeneic HSCT using RI versus MA conditioning for patients with AML and MDS. Results Patients Patient and transplant characteristics are shown in Tables I and II. In the RI transplant recipients with MDS (n 5 9), 5 (55%) had advanced disease using the International Prognostic Scoring System (IPSS) score including three with Int- 2 and two with high risk MDS with >10% bone marrow (BM) blasts at the time of transplant [11]. Among the AML RI patients, 13 were in CR1, 7 were in CR2, and 3 were in relapse. Ninety percent of RI patients had received previous chemotherapy prior to transplant. Three (10%) patients with MDS were not previously treated. Eighteen patients had received three or more cycles of chemotherapy prior to transplant. Five (16%) patients had therapy-related AML/ MDS. Among the MA transplant recipients with MDS (n 5 VC 2007 Wiley-Liss, Inc. 50), 42 (84%) had advanced disease; 21 with Int-2 and 21 with high risk IPSS scores. In the MA patients with AML, 72 were in CR1, 28 were in CR2, and 37 were in relapse. Disease free survival and overall survival Two-year DFS (31% ± 16% vs. 30% ± 7%, P ) and overall survival (OS) (33% ± 17% vs. 35% ± 7%, P ) were comparable between recipients of RI and MA conditioning, respectively (Table IV, Figs. 1 and 2). Multivariate analysis confirmed similar outcomes in RI and MA HSCT, but demonstrated significantly poorer DFS and OS in recipients with AML beyond CR2 or in relapse and AML with poor risk cytogenetics. This was observed in both RI and MA groups with survival (at 1 year) following RI conditioning [AML CR1 46%(19 73, 95% confidence interval) vs. CR2 1 10% [(0 29)]; MA conditioning CR1 54% [(42 65)] vs. CR2 1 33% [(22 44)]; and RI conditioning [intermediate/good risk cytogenetics 43% [(23 64)] vs. poor risk 22% [lsqb(0 49)]; MA conditioning intermediate/good risk 53% [(43 62)] vs. poor risk 29% [(16 42)]. Significantly poorer survival was also observed in cytomegalovirus (CMV) seropositive recipients. DFS and OS among MA recipients were not different when analyzed by year of transplant. Contract grant sponsors: National Cancer Institute; Contract grant number: PO1-CA21737; Contract grant sponsor: National Heart, Lung and Blood Institute; Contract grant numbers: NO1-HB-47095, N01-HB-67139; Contract grant sponsor: Children s Cancer Research Fund. *Correspondence to: Daniel Weisdorf MD, Division of Hematology, Oncology and Transplantation, University of Minnesota, Mayo Mail Code 480, 420 Delaware Street SE, Minneapolis, MN weisd001@umn.edu Received for publication 19 January 2007; Accepted 11 April 2007 Am. J. Hematol. 82: , Published online 6 July 2007 in Wiley InterScience ( wiley.com). DOI: /ajh American Journal of Hematology 867

2 TABLE I. Patient Characteristics RI (N 5 32) MA (N 5 187) P Median age, 54 (19 69) 39 (18 60) <0.01 years (range) Male, n (%) 18 (56) 93 (50) NS Median weight, 70 (51 138) 75.9 ( ) 0.1 kg (range) Performance score 22 (69) 110 (59) 0.07 (Karnofsky 90%), n (%) CMV seropositive 16 (50) 100 (53) NS recipient, n (%) Diagnosis, n (%) AML CR1 13 (41) 72 (38) NS AML CR21, advanced 10 (31) 65 (35) MDS 9 (28) 50 (27) Median time from Dx 8.8 ( ) 5.1 ( ) <0.01 to Tx, months (range) Cytogenetics Good/intermediate 23 (72) 110 (59) NS Poor 9 (28) 48 (26) Unknown 0 29 (16) P values represent v 2 or Wilcoxon rank sum tests for significance. CMV, cytomegalovirus; AML, acute myeloid leukemia; CR1, first complete remission; MDS, myelodysplastic syndrome; Dx, diagnosis; Tx, transplant. NS, not significant (P > 0.05). Hematological recovery and donor chimerism Neutrophil recovery was quicker and more complete with RI HSCT (Table III). The median time to neutrophil recovery was 11.5 versus 21 days in recipients of RI and MA therapies, respectively (P < 0.01). Platelet recovery appeared similar between the groups in univariate analysis, but in multivariate analysis adjusted for donor type and cytogenetic risk group, platelet recovery was significantly superior in patients treated with RI conditioning (RR 1.9 ( , P ). More patients receiving MA conditioning had related donors (94% vs. 53%, Table II), and independent of the conditioning used a related donor [BM or peripheral blood stem cells (PBSC)] graft was associated with more rapid hematological recovery. Graft failure was unlikely regardless of conditioning (0% after RI and 4% after MA [P ]). Mixed donor chimerism was uncommon; the median donor marrow chimerism was 100% in both groups at 1 year. TABLE II. Transplant Characteristics RI (N 5 32) MA (N 5 187) P Donor type n (%) <0.01 Unrelated 15 (47) 11 (6) Sibling 17 (53) 176 (94) Graft source n (%) <0.01 Umbilical cord blood 14 (44) 11 (6) Bone marrow 3 (9) 107 (57) PBSC 15 (47) 69 (36) Median graft nucleated cell dose (310 8 /kg) (range) UCB 0.3 ( ) 0.2 ( ) 0.07 Median CD34 (310 6 /kg) (range) UCB 0.4 ( ) 0.2 ( ) 0.02 PBSC/marrow 5.9 ( ) 6.0 ( ) 0.37 HLA matching n (%) <0.01 4/6 UCB 8 (25) 10 (5) 5/6 UCB 4 (13) 1 (1) PBSC/marrow 2 (6) 7 (4) 6/6 UCB 2 (6) 0 PBSC/marrow 16 (50) 169 (90) Conditioning n (%) <0.01 Bu/Flu/TBI or Clad/Flu/TBI 20 (63) Cy/Flu/TBI ± ATG/MP 12 (37) Cy/TBI 177 (95) Bu/Cy 10 (5) GVHD prophylaxis n (%) <0.01 CSA/MMF 32 (100) CSA 1 methotrexate 121 (65) CSA ± other 64 (34) Methotrexate alone 2 (1) Follow-Up For survivors Median years, (range) 1.7 ( ) 4.2 (1 12.9) P values represent v 2 or Wilcoxon rank sum tests for significance between RI and MA cohorts for the characteristics shown. PBSC, peripheral blood stem cells; TNC, total nucleated cells; Bu, busulfan; TBI, total body irradiation; Clad, cladribine; Flu, fludarabine; ATG, anti-thymocyte globulin; GVHD, graft versus host disease; CSA, cyclosporine; MMF, mycophenolate mofetil; MP, methylprednisone. Graft-versus-host disease The cumulative incidence of moderate/severe (Grade III-IV) acute graft-versus-host disease (GVHD) by day 1100 was similar after RI (22% [95% CI 8% 36%]) and MA conditioning (17% [95% CI 12% 22%]) P (Table III, Fig. 3). At 1 year the incidence of chronic GVHD was also similar after RI (6% [95% CI 0 14]) and MA conditioning (13% [95% CI 8% 18%]) P (Table III, Fig. 4). In multivariate analysis, poor risk cytogenetics was independently associated with a higher incidence of both acute and chronic GVHD; gender mismatch was associated with less chronic GVHD. The incidence of acute or chronic GVHD was not affected by conditioning regimen (Table III) or by age or donor graft source (not shown). Treatment related mortality Despite more rapid hematological recovery with RI HSCT and comparable rates of acute grade III IV and chronic GVHD, treatment related mortality (TRM) at 6 months was similar following RI (34% [95% CI 29% 65%]) and MA (33% [95% CI 39% 55%]) conditioning, P (Table Figure 1. Disease-free survival after HSCT using RI or MA conditioning. IV). In multivariate analysis, female recipients had a 1.9- fold greater risk of TRM at 6 months while age, conditioning intensity, and donor source had no independent impact. 868 American Journal of Hematology DOI /ajh

3 Relapse The cumulative incidence of relapse is shown in Table IV. Multivariate analysis adjusted for age, diagnosis, and cytogenetic risk group showed a significantly higher relapse risk following RI conditioning (RR 2.2; [95% CI ], P ). Additionally, patients with advanced AML (RR [95% CI ], P ), older patients (RR by decade [95% CI ], P ), and those with poor risk cytogenetics (RR 3.3 [95% CI 2 10], P < 0.01) had a higher risk of relapse. Causes of death There were 154 deaths; 22 (69%) in the RI group and 132 (71%) in the MA group. In both the RI and MA groups respectively, disease relapse (45% and 39%) and GVHD (36% and 30%) accounted for the majority of deaths. Among both cohorts, 37% of patients died from other nonrelapse causes including infection, hemorrhage, respiratory failure, new malignancies, and others. Figure 2. Survival after HSCT using RI or MA conditioning. Discussion RI HSCT has been practiced for over a decade, expanding the accessibility of transplantation for previously ineligible older or sicker patients [12,13]. Earlier studies examined how to effectively and safely administer RI regimens to patients with a range of hematological diseases [14]; recently there is a shift towards addressing disease specific approaches. This comparative analysis was undertaken to determine whether RI or MA HSCT is a comparable therapeutic approach for patients with myeloid malignancies. We wanted to analyze the efficiency of RI HSCT compared with MA HSCT in these diseases to maximize the graft versus leukemia effect while minimizing toxicity and relapse risk. The population studied was heterogeneous with limited patient numbers, and while multivariate analyses were TABLE III. Outcomes of HSCT in RI and MA Patients (I) Univariate Multivariate regression Incidence (95% CI) Median days (range) P RR (95%CI) P Neutrophil recovery (ANC > 500/ll atday1 42 ) RI 100% 11.5 (6 42) < ( ) <0.01 MA 96% (93 99%) 21 (12 42) 1.0 Donor type Unrelated 96% (88 100%) 21 (6 42) < Related marrow 96% (92 100%) 24 (14 42) 2.5 ( ) <0.01 Related PBSC 97% (94 100%) 16 (6 38) 6.9 ( ) <0.01 Platelet recovery (> /ll atday1180) RI 63% (45 81%) 35 (0 77) ( ) 0.03 MA 71% (58 84%) 36 (13 161) 1.0 Donor type Unrelated 56% (34 78%) 88 (1 161) < ( ) <0.01 Related 73% (60 85%) 31 (0 111) 1.0 Poor 55% (37 73%) 88 (0 161) Int/good 75% (61 89%) 35 (0 161) 1.8 ( ) 0.04 Acute GVHD (grade III IV at day 1100) RI 22% (8 36%) ( ) 0.48 MA 17% (12 22%) 1.0 Int/good 13% (8 18%) < Poor 30% (18 42%) 2.5 (1.25 5) <0.01 Unknown 29% (92 26%) 2.0 (0.7 5) 0.16 Chronic GVHD (at 1 year) RI 6% (0 14%) ( ) 0.74 MA 13% (8 18%) 1.0 Int/good 9% (4 14%) Poor 16% (7 25%) 3.3 ( ) 0.02 Unknown 21% (6 36%) 1.1 ( ) 0.94 Gender match Match 16% (9 23%) Mismatch 9% (4 14%) 0.4 ( ) 0.04 American Journal of Hematology DOI /ajh 869

4 TABLE IV. Outcomes of HSCT in RI and MA Patients (II) Univariate Multivariate regression Incidence (95% CI) P RR (95%CI) P Figure 3. Cumulative incidence of grade III-IV acute GVHD. Figure 4. Cumulative incidence of chronic GVHD. used to adjust for differences, these data must be interpreted cautiously. While MA HSCT currently represents the standard of care for adults with AML/MDS, we have observed satisfactory and comparable disease-free and OS with RI allografts for AML and MDS in older patients with high risk myeloid diseases and a group of somewhat younger patients with similarly high risk disease treated with MA HSCT. These outcomes are similar to other reported series, with comparable patient populations [15 17]. Unrelated umbilical cord blood (UCB) HSCT had similarly successful outcomes as volunteer unrelated donors (URD) transplants using RI conditioning [18]. These data add to an increasing body of evidence [19 22] that RI HSCT can be clinically potent with an antileukemia effect capable of inducing and maintaining a long term remission in these aggressive myeloid malignancies. The preferred intensity within the spectrum of RI or non-ma conditioning regimens for myeloid leukemia continues to be a subject of study [16,23]. Regimens sufficiently nontoxic, but with antileukemic potency to effectively cyto-reduce the tumor mass while still permissive of donor engraftment and the ensuing immunological graft versus leukemia effect await evaluation in prospective clinical trials. The optimal RI regimen with sufficient antileukemic effect may need to be tailored to the patient s age, comorbidity score [24], and disease characteristics to minimize the toxicity and also limit the relapse risk. RI regimens have been reported to reduce the cytokine release and damage to mucosal tissues and result in less agvhd compared with MA, Treatment related mortality (at 6 months) RI 34% (29 65%) (0.5 2) 0.54 MA 33% (39 55%) 1.0 Gender Male 25% (17 33%) < Female 42% (32 52%) 1.9 ( ) <0.01 Relapse (at 2 years) RI 34% (17 51%) ( ) 0.03 MA 30% (23 37%) 1.0 Int/good 26% (18 34%) < Poor 42% (28 56%) 3.3 (2 10) <0.01 Unknown 28% (11 45%) 3.3 (1.1 10) 0.04 Disease CR1 22% (13 31%) < MDS 35% (22 48%) 0.7 ( ) 0.41 CR21/relapse 37% (25 49%) 2.5 ( ) 0.01 Age (by decade) Continuous 1.3 ( ) 0.04 Disease free survival (at 2 years) RI 31% (15 47%) ( ) 0.11 MA 30% (23 37%) 1.0 Int/good 36% (27 44%) Poor 19% (9 29%) 2.0 ( ) <0.01 Unknown 28% (11 44%) 1.4 ( ) 0.16 Disease CR1 39% (28 49%) MDS 29% (17 41%) 1.2 ( ) 0.40 CR21/relapse 21% (12 30%) 1.9 ( ) <0.01 Overall survival at 2 years RI 33% (16 50%) ( ) 0.18 MA 35% (28 42%) 1.0 Int/good 40% (32 48%) Poor 22% (11 33%) 1.7 ( ) <0.01 Unknown 31% (14 48%) 1.25 (0.7 2) 0.53 Disease CR1 41% (31 51%) MDS 35% (22 48%) 1.0 ( ) 0.84 CR21/Relapse 25% (15 35%) 1.8 ( ) <0.01 CMV serostatus Negative 44% (34 54%) Positive 26% (18 34%) 1.4 ( ) 0.05 RI, Reduced intensity; MA, myeloablative; CR1, acute myeloid leukemia first complete remission; MDS, myelodysplastic syndrome; CR2, acute myeloid leukemia second complete remission. which can contribute to a lower TRM. The TRM using RI regimens has been reported from 5% [25] to nearly 20% [20,22,26]. TRM varies with the patient population, the time point at which it is assessed following HSCT, and the intensity of the RI regimen. This study and others show similar risks of moderate/severe acute and chronic GVHD using RI compared with MA conditioning [15,26,27]. In the current study, almost one third of our patients had poor risk cytogenetics and extensive pretreatment, possibly contributing to the slightly higher TRM we observed. Patients conventionally considered ineligible for transplantation received therapy with tolerable toxicity and a comparable TRM. Patients with AML beyond CR2 or in relapse treated with chemotherapy alone rarely survive [28]. In this analysis, these individuals also had poorer survival following either RI or 870 American Journal of Hematology DOI /ajh

5 MA HSCT. There is an ongoing need for new and better treatments for patients with advanced disease and poor risk cytogenetics who have an unsatisfactory outcome with any treatment regimen. These risks are often compounded by the cumulative morbidity of multiple reinduction therapies [29] and pre-hsct infections. Nonetheless we observed continuing freedom from relapse in 66% of such patients, supporting the promise of leukemia control using RI allografts. While a prospective comparison of RI versus MA conditioning may be scientifically desirable, MA HSCT may be unsuitable for an older population and will thereby confound the trial design. It remains unanswered whether RI HSCT is suitable for treatment of high risk myeloid leukemia in younger patients. In this study nearly all of the unrelated grafts were UCB in both the RI and MA groups. The use of UCB as the unrelated graft source with RI HSCT for leukemia is a novel approach. Several studies [30 32] with other hematological malignancies are encouraging, but disease specific outcomes are inconclusive. Previous UCB studies [33] have shown slower hematopoietic recovery and increased chronic GVHD associated with cord blood transplantation for leukemia. In our study, hematopoietic recovery was rapid using both sibling and UCB grafts. The incidence of chronic GVHD was low in all patients. These results compare favorably with other reports of RI HSCTs using either related or URD, BM, or PBSC grafts with reported 2-year DFS of 16% 45% [17,19]. The most effective treatment strategy might incorporate HSCT along with small molecule antileukemia inhibitors and will undoubtedly be the subject of future studies. Ongoing clinical study is still needed to identify patients with myeloid leukemia who are most likely to benefit from the less toxic approach of RI HSCT. Patients and Methods Patients and eligibility All consecutive adult transplant patients with AML and MDS who underwent an allogeneic HSCT at the University of Minnesota between January 1990 and October 2003 were included in this analysis. Thirtytwo patients (18 males; median age 54 years [range 19 69] transplanted between January 2000 and October 2003) received a RI preparative therapy; 187 patients (93 males; median age 39 years [range 18 60] transplanted between January 1990 and September 2003) received a MA preparative therapy. All patients gave written informed consent prior to HSCT using forms approved by the University IRB. Baseline demographic data including disease characteristics, dates of diagnosis and treatment, complications, survival times, causes of death and relapse were prospectively recorded in the University of Minnesota Blood and Marrow Transplant Database. This was supplemented by individual medical record reviews for hematologic recovery post transplant, complications and toxicity, and verification of response, relapse, and progression. Patients were eligible for a RI preparative therapy if they met one or more of the following criteria: older age (55 years of age for a related donor transplant or 45 years of age for an URD transplant, n 5 12), history of prior transplant (4 autografts and 2 allografts, n 5 6), history of recent fungal infection, compromised organ function, or poor performance status (n 5 14). Seven patients met more than one of these eligibility criteria. Cytogenetics Cytogenetic data prior to transplant was reviewed for all patients. Cytogenetics were classified as good, intermediate, or poor using a combined CALGB/MRC schema [34,35]. Good risk cytogenetics were inv 16, t(8;21), and t(15;17). Intermediate risk cytogenetics were normal cytogenetics and all numerical and/or structural abnormalities not included in the good or poor groups or 7q2 as a sole abnormality. Deletion or loss of 7q was considered intermediate unless part of a complex clone. Poor risk cytogenetics were monosomy 7 or a complex clone (three or more abnormalities). Cytogenetic data were available for all RI and 84% of MA HSCT recipients. Preparative regimens RI conditioning included fludarabine (Flu) 40 mg/m 2 daily intravenously for 5 days, busulfan (Bu) 2 mg/kg orally every 12 hr for four doses, and total body irradiation (TBI) 200 cgy as a single fraction (n 5 19). One patient received cladribine (C) 10 mg/m 2 instead of fludarabine [36]. Twelve patients received a Cy/Flu/TBI regimen, where cyclophosphamide (Cy) 50 mg/kg intravenously replaced Bu. In recipients of UCB grafts who had not received intensive therapy prior to HSCT, an increased risk of graft failure had been observed previously [37]. Three UCB recipients received intravenous equine anti-thymocyte globulin (ATG, ATGAM) 15 mg/m 2 twice daily for 3 days and intravenous methylprednisone 1 mg/kg prior to ATG in addition to Cy/Flu/TBI. MA conditioning included Cy 60 mg/kg on 2 consecutive days with either fractionated TBI 13.2 Gy (n 5 177) or Bu 1 mg/kg orally every 6 hr for 16 doses (n 5 10). Donor cell source Among the 32 RI patients, 15 received URD HSCT transplants (14 UCB and one adult volunteer BM). Seventeen received related donor transplants with filgrastim-mobilized PBSC. Among the 187 MA transplant recipients, 11 received unrelated UCB and 176 received related donor grafts (BM (n 5 107), PBSC (n 5 67) and PBSC plus BM (n 5 2). (Table II). Graft versus host disease prophylaxis RI recipients received cyclosporin-a (CSA) (day 23 until day 1180) and mycophenolate mofetil 15 mg/kg orally twice daily (day 23 until day 130). MA recipients received CSA with short course methotrexate (n 5 121), CSA alone (n 5 11), CD341 selection (n 5 5), tacrolimus (n 5 5), methylprednisone (n 5 22), or T cell depletion by elutriation (n 5 21). Two MA patients received methotrexate alone as GVHD prophylaxis. (Table II) Supportive care All patients received transfusions, infection prophylaxis and therapy, nutrition supplementation, and other supportive care according to University of Minnesota Blood and Marrow Transplant Program supportive protocol guidelines. Statistical Analysis Time to neutrophil engraftment was defined as the first of 3 consecutive days with an absolute neutrophil count /L. Donor engraftment was defined as sustained, donor-derived neutrophil recovery after HSCT. Donor chimerism at 1 year was defined as BM reconstitution of 90% donor. Platelet recovery was defined as a sustained untransfused platelet count /L by day GVHD was diagnosed using established criteria [38,39]. Acute GVHD most often developed within 100 days of HSCT (with cumulative incidence reported at day 100), and chronic GVHD was diagnosed when patients developed distinct clinical manifestations unique to chronic GVHD [40]. The cumulative incidence was reported at 1 year. Post-transplant event times were measured from the date of transplantation to the date of death or last contact. Graft failure, GVHD, transplant-related mortality (TRM), and relapse were calculated using the cumulative incidence method with death (or relapse for TRM) as a competing event. DFS and OS were estimated using the Kaplan Meier method [41]. The population studied was heterogeneous with respect to stem cell sources included sibling, unrelated and UCB donors. Multivariate analysis was performed using forward stepwise Cox regression for clinically relevant covariates along with conditioning intensity (RI and MA) to adjust for demographic, disease and donor differences. Covariates considered in the regression analyses included recipient age, sex, weight, CMV serological status, time from diagnosis to transplant, Karnofsky score 80%, disease status (AML CR1, AML CR21, MDS), cytogenetic risk group, donor gender, HLA disparity, donor source (related or unrelated), donor cell type (peripheral blood stem cells (PBSC), American Journal of Hematology DOI /ajh 871

6 bone marrow (BM) or umbilical cord blood (UCB) and graft cell dose (within graft type cohorts). Factors entered regression models if suggested as significant (P < 0.01) as adjusted for the primary comparison of RI versus MA conditioning. Testing for proportional hazards assumptions identified no violations in any regression models and no significant statistical interactions between conditioning intensity and other significant variables were identified. Acknowledgment We thank Carol Taubert for assistance with editing and formatting of this manuscript. References 1. Lowenberg B. Managing therapy in older adult patients with acute myeloid leukemia. Semin Hematol 2001;38: Leith CP, Kopecky KJ, Chen I-M, et al. Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-Glycoprotein, MRP1, and LRP in acute myeloid leukemia. A Southwest Oncology Group Study. Blood 1999;94: Farag SS, Archer KJ, Mrozek K, 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: Frassoni F, Labopin M, Gluckman E, et al. Results of allogeneic bone marrow transplantation for acute leukemia have improved in Europe with time A report of the acute leukemia working party of the European group for blood and marrow transplantation (EBMT). Bone Marrow Transplant 1996;17: 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: Cornelissen JJ, Lowenberg B. Role of allogeneic stem cell transplantation in current treatment of acute myeloid leukemia. Hematology (Am Soc Hematol Edu Program) 2005; 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: 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: 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: Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: Delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 2004;104: Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89: Slavin S, Nagler A, Naparstek E, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998;91: McSweeney PA, Niederwieser D, Shizuru JA, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: Replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001;97: Djulbegovic B, Seidenfeld J, Bonnell C, Kumar A. Nonmyeloablative allogeneic stem-cell transplantation for hematologic malignancies: A systematic review. Cancer Control 2003;10: 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: 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: 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: Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, Miller JS, Wagner JE. Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning. Blood 2003; 102: 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: 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 highrisk acute myeloid leukemia and myelodysplasia. J Clin Oncol 2005;23: Martino R, Caballero MD, Simon JA, et al. Evidence for a graft-versus-leukemia effect after allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes. Blood 2002;100: 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: Perez-Simon JA, Diez-Campelo M, Martino R, et al. Influence of the intensity of the conditioning regimen on the characteristics of acute and chronic graftversus-host disease after allogeneic transplantation. Br J Haematol 2005;130: 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: Ho AYL, 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: 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: 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: Leopold LH, Willemze R. The treatment of acute myeloid leukemia in first relapse: A comprehensive review of the literature. Leuk Lymphoma 2002;43: Craddock C, Tauro S, Moss P, Grimwade D. Biology and management of relapsed acute myeloid leukaemia. Br J Haematol 2005;129: Misawa M, Kai S, Okada M, et al. Reduced-intensity conditioning followed by unrelated umbilical cord blood transplantation for advanced hematologic malignancies: Rapid engraftment in bone marrow. Int J Hematol 2006;83: Majhail NS, Weisdorf DJ, Wagner JE, et al. Comparable results of umbilical cord blood and HLA-matched sibling donor hematopoietic stem cell transplantation after reduced-intensity preparative regimen for advanced Hodgkin lymphoma. Blood 2006;107: Ballen KK, Spitzer TR, Yeap BY, et al. Double Unrelated reduced-intensity umbilical cord blood transplantation in adults. Biol Blood Marrow Transplant 2007;13: 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: 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: Grimwade D, Walker H, Oliver F, et al. The Importance of Diagnostic Cytogenetics on Outcome in AML: Analysis of 1,612 Patients Entered Into the MRC AML 10 Trial. Blood 1998;92: Markova M, Barker JN, Miller JS, et al. Fludarabine vs cladribine plus busulfan and low-dose TBI as reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation: A prospective randomized trial. Bone Marrow Transplant 2007;39: Barker JN, Weisdorf DJ, Defor TE, Wagner JE. Non-myeloablative umbilical cord blood transplantation (UCBT): Low transplant-related mortality in 59 high-risk adults [abstract]. Blood 2004;104: Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versushost disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974;18: Przepiorka D, Weisdorf D, Martin P, et al Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995;15: Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease. I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005;11: Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53: American Journal of Hematology DOI /ajh