Reduced Intensity transplantation vs chemotherapy. A prospective, pseudorandomized study in 50-70 year old AML patients

Reduced Intensity transplantation vs chemotherapy. A prospective, pseudorandomized study in 50-70 year old AML patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Reduced Intensity transplantation vs chemotherapy. A prospective, pseudorandomized study in 50-70 year old AML patients Per Ljungman, Mats Brune, Thomas Kiss, Harald Andersson, Malin Nicklasson, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4253193/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Sep, 2024 Read the published version in Bone Marrow Transplantation → Version 1 posted 9 You are reading this latest preprint version Abstract The aim of this prospective, international multicenter, pseudorandomized study using the donor versus no-donor concept to compare RICT HCT to standard-of-care chemotherapy in intermediate- or high risk AML patients 50 – 70 years in CR1. Part 1 included only patients with potential family donors (RD) at the date of HLA-typing of the first potential sibling or CR-date, if later. In Part 2), patients without a possible sibling donor could be included with the inclusion date at the start of an unrelated donor (URD) search. 360 patients were registered and 309 analyzed. The median follow-up was 47 months (1-168). There was no difference in overall survival (OS) between the RD (n=124) and the Control (n=77) groups (p=0.50, 3-year OS RD: 0.41(95% CI; 0.32-0.50); Controls: 0.49 (95% CI; 0.37-0.59)). The main cause of death was relapse (67% RD; 88% Controls). Comparing URD-HCT (n=86) and Controls (n=20), the 3-year survival was 0.60 (95% CI 0.50-0.70) for URD-HCT and 0.37 (95% CI 0.13-0.62) in the Controls, respectively (p=.10). When analyzing transplanted patients (Part 2), the OS at 3-years was higher for URD-HCT than RD-HCT (0.67 (0.55-0.76) vs. 0.42 (0.26-0.57; p=.005). The risks for severe acute and extensive chronic GVHD were lower in the URD-HCT group. Health sciences/Health care/Therapeutics/Stem-cell therapies Health sciences/Diseases/Haematological diseases/Haematological cancer/Leukaemia/Acute myeloid leukaemia Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION The curative potential of allo-HCT is due to the preparative chemotherapy, and the immunological graft-versus-leukemia (GvL) effect exerted by donor T-cells. The introduction of reduced intensity and thereby lower toxicity conditioning before allo-HCT (RICT) has expanded the transplant option to elderly patients and patients with co-morbidities 1,2 , with the aim of retaining GvL whilst reducing NRM. Different approaches were used to compare allo-HCT with chemotherapy. These were mainly retrospective studies utilizing registry data 3–5 . A well-recognized problem is the difficulty to compare in a controlled setting allo-HCT vs. standard-of-care since stringent randomized studies are very difficult to perform. Imitating randomization, HCT vs chemotherapy studies have been performed using biological allocation (presence or absence of an HLA-identical sibling donor) in patients undergoing myeloablative HCT 6 . Zittoun et al found in a prospective study, where treatment allocation was done in first CR, an improvement after both auto- and allo-HCT as compared to chemotherapy 7 . In a similarly designed prospective study, Cassileth et al found a slight advantage of chemotherapy compared to auto- or allo-HCT 8 . In contrast, Cornelissen et al found an improvement in disease free survival by donor availability with transplants performed with myeloablative conditioning in patients < 55 years having an intermediate or high-risk profile 9 . In this study, the aim was to use comparable starting points for the two treatments using the time for start of donor search for either a family or unrelated donor but also requiring that the patients had entered first complete remission. METHODS Study design The design of this study used the pseudorandomized donor versus no donor concept with the aim to compare RICT to standard-of-care chemotherapy in AML patients between 50–70 years. When the study was initiated (2003) only patients having a potential HLA-identical sibling (RD) were eligible for the study (Part 1). Due to an increased use of unrelated donors, the study design was changed to allow inclusion of patients without potential HLA-identical siblings (Part 2). Patients could be registered into the study at any time after diagnosis but were only eligible for study inclusion after having entered CR1. The date for study inclusion was the date the first sample was obtained for HLA-typing of a sibling (Parts 1 and 2) or start of unrelated donor (URD) search (Part 2). If either of these occurred before CR, the date of CR was set as the inclusion date. Patients never entering CR were excluded. Study Part 1 (2003–2012). The primary objective both for first part of the study and the whole study was to evaluate in an intention-to-treat setting the OS after RICT from HLA-identical sibling donors compared to standard-of-care chemotherapy. Additional objectives were to assess relapse-free survival (RFS), NRM, and relapse incidence (RI) between the two groups. After entering CR1, patients with at least one sibling were informed about the study and after signed consent included into the study. If the sibling(s) were willing and had no contraindication for stem cell donation, HLA-typing was performed, and patients were assigned to one of two groups; RD (donor identified) or Controls (no donor). Study Part 2 (2012–2016) . The protocol was updated due to slow accrual and the increasing use of URD allowing search for a suitable URD either after failed RD search or upfront in patients without an available sibling. Depending on possible donor types, the patients were grouped into three strata (Fig. 1 ). HLA typing of potential related donors and unrelated donor search was permitted after registration but before confirmation of CR to decrease the time between diagnosis and transplant. Patients without a donor were allocated to one of the Control groups. The additional objectives of this part of the study, besides the original objective of comparing RD vs. Controls, were to assess if patients receiving RICT from URD had superior OS compared with Controls (no RD, no URD) or to RICT from RD. Other objectives were to analyze RFS, NRM, and RI after URD RICT compared to Controls. Study procedures Patients ages 50–70 years with intermediate- or high-risk AML in CR1 and who were judged to be able to tolerate further therapy including RIC-HCT could be included. Important exclusion criteria were favorable risk AML as defined by cytogenetics and as of study part 2 by presence of mutation in NPM1 as sole molecular abnormality, abnormal renal (s-creatinine > 2 x ULN) or liver function (AST or ALT > 3 x ULN), or severe concurrent illness preventing additional post-remission therapy. Treatments Induction and consolidation therapy were given according to standard-of-care at participating centers, which varied between countries. The protocol recommended as conditioning regimens either the use of fludarabine 5–6 days (150–180 mg/sqm) combined with busulphan either given orally (total dose 8–11 mg/kg) or iv (Busulphex®; total dose 6.4 mg/kg) or a combination of fludarabine, carmustin, and melphalan. As graft-versus-host disease (GVHD) prophylaxis before URD HCT either anti-thymocyte globuline (ATG) or alemtuzumab was allowed. Recommended immunosuppression was ciclosporin (CyA) combined either with methotrexate (used in 63% of the patients) or mycophenolate mofetil (MMF). Cytogenetic and disease risk features Two independent reviewers categorized the patients as high or intermediate risk according to the European Leukemia Net 2017 genetic risk classification 10,11 . Interpretable reports from diagnostic bone marrow samples were available for 262 patients (85%). Patients with favorable risk cytogenetics were excluded including those with only NPM1 mutation. Clinical high-risk features were defined as more than two inductions to reach CR1, secondary AML, and blasts ≥ 15% after first induction. Patients with any high-risk feature were assigned to the high-risk group. Administrative information The study was registered at ClinicalTrial.gov (CTN #00342316). All patients signed informed consent. The study protocol and ensuing amendments were approved by the Ethical Committee at University of Gothenburg for Swedish patients ( S 240-04, S 288-03, S-266-03, S 272-03, S-231-12 ), and by the corresponding authorities in participating centers and countries. Statistics Additional information about statistical analysis is given in Supplementary information. The primary endpoint was OS in an intention to treat (ITT) setting. Baseline and treatment data were compared between ITT groups by Fisher´s exact tests and Wilcoxon´s rank-sum tests. Kaplan-Meier and Cumulative incidence plots were used for illustration of time-to event endpoints. All endpoints (OS, RFS, NRM and RI) were determined from date of inclusion. The patients were grouped into strata A-D according to Fig. 1 based on the partition of the study in Part 1 and Part 2 and possible type of donor. In the ITT analyses, it was assumed that treatment allocation within strata was random. OS and RFS were compared by stratified log-rank tests and NRM and RI by stratified Gray´s tests considering competing risks. Three-year values with 95% confidence intervals are also presented. Hazard ratios (HR) were determined by means of stratified Cox regression. Proportions of patients with acute and chronic GVHD were analyzed with Fisher´s Exact test. Stata version 14 and R version 4.1.0 were used in the statistical analyses. RESULTS Patient population and distribution The study population is described in Fig. 1 . 360 patients were registered into the study. Twenty patients never reached CR and were therefore not included. Thus, 340 patients were included in the study population. 31 were excluded due to donor search initiation before inclusion (n = 19), low-risk cytogenetics (n = 9), missing consent (n = 2), and missing data (n = 1). Moreover, three patients withdrew consent within the first three months after study inclusion. These are included in the analysis until date of consent withdrawal. Thus, the analyzed study cohort included 309 patients of which 135 were included in Part 1 (2003 - April 2012), and 174 in Part 2 (May 2012–2016) of the study. The age of patients (median 62 vs 64 years) was similar in the two parts. The median unrelated donor age was 25 (18–68) years (Part 2), whereas sibling donors were older; 60 (48–76) years; p < .001; Parts 1 and 2). The first patient was included December 18, 2003, and the last patient was included July 19, 2016. Data was analyzed as of August 1, 2018. RD versus Controls; study parts 1 and 2 combined The patient and donor distributions in the different study parts are shown in Fig. 1 . 71 patients were assigned to the RD/donor and 64 to the Control/no donor group in Part 1 of the study (Fig. 1 ; Stratum A). Some study sites continued during the 2nd part of the study including only patients fulfilling the criteria of study Part 1 (Stratum B: RD; n = 8, and Controls; n = 5). In study Part 2, 45 patients had RD and patients without either RD or URD (n = 8) were considered as controls for both the RD and URD comparisons (Stratum C). Thus, the total number of patients with RD was 124 (71 + 8 + 45) and the number of Controls was 77 (64 + 5 + 8). In the Control group, 8/77 (8%) patients were treated off-protocol by allografting from alternative donors. These patients were included in the intention to treat (ITT) analysis as Controls. URD versus Controls; study part 2 An URD was identified for 96 patients. Twenty patients without an identified donor were Controls to the URD group (Fig. 1 ; Strata C and D). Six patients underwent transplants from either cord blood or haploidentical donors. These patients were included as Controls in the ITT analysis. RD versus Control (Part 1 and 2) 201 patients were included in the RD versus Control ITT comparison, 138 (69%) of whom died during follow-up. Median (min-max) follow-up time for the surviving patients was 76 (1-168) months. Patient characteristics were similar between RD and Control groups (Table 1 ). Ninety-seven patients underwent RICT at a median of 10 (3–33) weeks post inclusion while 27/124 (22%) patients did not reach transplant due to early relapse (n = 18), medical infirmity (n = 4), withdrawn consent (n = 2) or death (n = 3). Table 1 Characteristics of patients in the RD vs Control primary endpoint analysis Controls (n = 77) RICT/RD (n = 124) p-value Gender F/M – n (%) 36 (47) / 41 (53) 55 (44) / 69 (56) NS Median age at Inclusion, years (min - max) 63 (51–70) 63 (51–71) NS Risk group IR/HR – n (%) 50 (65) / 27 (35) 68 (55) / 56 (45) NS Median time from diagnosis to inclusion, days (min – max) 64 (32–256) 64 (29–319) NS Given therapy Chemotherapy only 69 27 Transplanted 8* 97** Median time from inclusion to transplant, days (min – max) 73 (23–236) Causes of death – n (%) 0.003 GvHD or related infection – 9 (7) Infection 1 (1) 11 (9) Other 3 (4) 4 (3) Relapse 50 (65) 54 (44) Secondary malignancy 3 (4) 3 (2) * 6 URD, 1 cord blood, 1 haploidentical HCT ** All RICT/RD Overall Survival. 81/124 (65%) and 57/77 (74%) patients died in the RD and Control groups, respectively. Most deaths were due to relapse; 67% in the RD group and 88% in the Control group. Other causes are shown in Table 1 . OS is shown in Fig. 2 . At three years it was 0.41 (95% CI; 0.32–0.50) and 0.49 ((95% CI; 0.37–0.59); p = .50, logrank test) in the RD and control group, respectively. The data are not consistent with a constant hazard ratio over time: HR = 2.31 (95% CI: 1.34–4.01) before one year and HR = 0.57 (0.34–0.95) after one year (p = .0003 for difference) suggesting relatively higher mortality in the RD group the first year after inclusion and lower thereafter. In an analysis performed with RD transplant as a time-dependent covariate, the analysis reflects the given treatment: A patient always starts as a Control patient and shifts to an RD patient at transplantation. The HR was 0.81 (0.56–1.17, p = .25) between the hazard for patients who received a transplant to the those who did not. Follow-up was censored at transplantation for the six Controls transplanted with an URD. Other outcomes RFS 85/124 (69%) and 60/77 (78%) events occurred in the RD and Control groups, respectively (HR = 0.97 (0.69–1.37); p = 0.87). The RFS at 3 years was 0.38 (95% CI 0.29–0.46) in RD patients and 0.35 (95% CI 0.24–0.45) in Controls. NRM 27/124 (22%) and 7/77 (9%) non-relapse deaths occurred in the RD groups and Control groups, respectively. With relapse as a competing event, the cumulative NRM incidence at 3 years was 0.17 (0.11–0.25) in the RD group, and 0.039 (0.01–0.10) in Controls (p = .033, Gray’s test). RI 58/124 (47%) and 53/77 (69%) patients relapsed in the RD and Control groups, respectively; With NRM as a competing risk, the cumulative relapse incidence at 3 years was 0.45 (95% CI 0.36–0.54) in the RD group, and 0.61 (95% CI 0.50–0.71) in Controls (p = .097, Gray’s test). Unrelated Donor (URD) versus No donor (Part 2). Results . At study closure, 65/116 (56%) patients were alive after a follow-up of median 39 (3–70) months. 16/96 (17%) of the patients in the URD group did not undergo transplantation. 39/96 (41%) patients in the URD-group and 12/20 Controls (60%) died. Patient characteristics and causes of death are shown in Table 2 . Table 2 Characteristics of patients in the URD vs Control analysis Controls (n = 20) RICT/MUD (n = 96) p-value Gender F/M – n (%) 10 (50) /10 (50) 36 (38) / 60 (63) NS Median age at Inclusion, years (min - max) 63 (55–69) 64 (52–71) NS Risk group IR/HR – n (%) 10 (50) / 10 (50) 46 (48) / 50 (52) NS Median time from diagnosis to inclusion, days (min – max) 57 (32–160) 64 (28–244) NS Given therapy Chemotherapy only 14 16 Transplanted 6* 80** Median time from inclusion to transplant, days (min – max) 93 (23–302) Cause of death – n (%) NS GvHD or rel inf – 1 (1) Infection 1 (5) 5 (5) Other 0 3 (3) Relapse 10 (50) 30 (31) Secondary malignancy 1 (5) 0 * 1 cord blood, 5 haploidentical HCT ** All RICT/URD The three-year OS was 0.60 (95% CI 0.50–0.70) in the URD-HCT group and 0.37 (95% CI 0.13–0.62) in the Control group (p = .10; Fig. 3 ). The HR comparing URD-HCT and Controls was 0.59 (95% CI 0.31–1.12; p = .11). There was neither any significant difference in RFS between URD-HCT and Controls (three-year values with 95% CI 0.52 (0.41,0.61) and 0.39 (0.19–0.60) respectively, p = .21), nor in NRM (0.10 (0.05–0.17) and 0.10 (0.02–0.27), p = .85), or RI (0.39 (0.29–0.48) and 0.51 (0.27–0.70), p = .32. RD versus URD versus Controls, according to given treatment (Part 2) OS from study inclusion was analyzed with one time-varying covariates for each type of transplant. The HR´s were 0.70 (0.39–1.26) for RD-HCT versus Controls, and 0.27 (0.15–0.47) for URD-HCT versus Controls. A direct comparison yields that HR for URD-HCT was significantly lower than for RD-HCT (p = .0041) indicating that survival after URD was superior to RD. RD versus URD from transplantation (Part 2) Patient characteristics are shown in Table 3 . At study closure, 73 of 123 (59%) patients were alive after median 38 (1–66) months of follow-up from transplants. 24/43 (56%) patients died in the RD and 26/80 (33%) in the URD group. The OS was higher (p = .005) for patients undergoing URD (Fig. 4 ). Three year survival was 0.42 (0.26–0.57) in the RD-group and 0.67 (0.55–0.76) in the URD group. Furthermore, RFS was higher in the URD group (3-year RFS 0.61 [0.49,0.71] vs. 0.36 [0.21,0.51]; p = .01), NRM was lower (0.11 [0.05,0.19] vs. 0.30 [0.16,0.44]; p = .01), while there was no significant difference in RI ( 0.29 [0.19,0.39] vs 0.34 [0.20,0.49]; p = .46). Table 3 Characteristics of RD vs URD patients in study period 2 RICT/RD (n = 43) RICT/URD (n = 80) p-value Gender F/M – n (%) 18 (42) / 25 (58) 30 (38) / 50 (63) NS Median age at Inclusion, years (min-max) 63 (53–71) 65 (53–71) NS Time from CR to inclusion, days (min-max) 14 (0–173) 14 (0–138) NS Time from Inclusion to HCT days (min-max) 79 (23–236) 93 (23–302) Risk group IR/HR – n (%) 16 (37) /27 (63) 35 (44) / 45 (56) NS Flu/Bu p.o. / Not Flu/Bu p.o. – n (%) 16 (37) / 27 (63) 50 (63) / 30 (38) 0.008 No ATG / ATG – n (%) 33 (77) /10 (23) 5 (6) / 75 (94) < .0001 Immunosuppression treatment – n (%) 0.008 CyA + MTX 22 61 Other 21 19 Donor age, median, yr (range) 61 (49–73) 25 (18–68) < .0001 Female donor to male recipient – n (%) .052 Yes 10 (23) 7 (9) No 33 (77) 73 (92) Acute and chronic GVHD in RD (Parts 1 + 2) and URD (Part 2) There was a lower risk for acute GVHD grades III – IV in patients undergoing URD HCT (6% URD vs 19% RD; p = .01) and a lower risk for extensive chronic GVHD at 12 months (URD 12.7% vs. RD 40.3%; p < .001), 24 months (9.6% URD vs. 38.3% RD; p < .001), and 36 months (8.3% URD vs. 40% RD; p = .003) after transplantation compared to RD HCT patients (Suppl. Figure 1). DISCUSSION Whether RICT allogeneic HCT in elderly patients with AML results in improved long-term survival has been discussed for many years. It has been exceedingly difficult to perform proper randomized prospective studies in allogeneic HCT in general due to the donor selection process including the willingness of patients and donors to be randomized to non-HCT therapy. Studies using other approaches have reported that RICT-HCT can result in long-term leukemia-free survival 1,12–16 . However, a recent large prospective cohort study has challenged this concept in elderly patients and those with co-morbidities 17 . The aim of this study was to use pseudo-randomization based on the availability of at least one sibling willing to be typed and with the starting date either the day of a sample obtained for HLA-typing of a potential sibling donor or the day of CR if typing was performed before the patient entered CR. Our study, designed now several years ago, shows now with extended follow-up no advantage for a reduced intensity allogeneic-HCT with a sibling donor compared to Controls. As expected, the NRM was higher in the transplant group compared to Controls and although there was a slightly higher incidence of relapse in the Controls, this did not compensate for the higher risk for NRM. Similar results were seen when an URD was used, but the low number of Controls makes it difficult to draw any firm conclusion from this comparison. The main cause of death in all study groups was leukemia relapse and not NRM. Many relapses occurred in the “transplant groups” before the patient could get to transplant. Several important advances in supportive care especially the introduction of new drugs against infections have occurred since the study was initiated improving the outcome of allogeneic HCT. Furthermore, the selected conditioning regimen has been shown to be inferior to more intensive conditioning regimens 10,18 , and it is possible that a more intensive but still reduced intensity regimen could have yielded better results. Interestingly, a large prospective study including patients during the latter part of our study period (2013–2017) also failed to show a survival benefit in elderly patients and in these who were medically infirm 17 . Moreover, new alternatives for non-transplant therapy of AML in the elderly such as azacytidine +- venetoclax have been introduced also changing the therapeutic landscape 19 . The study included patients with a median age of 62–64 years in the different groups so not real elderly according to what is the clinical practice today. This, however, ought to have reduced rather than increased the risk for NRM if we translate the results to today’s situation. The results of URD transplants were better than the results of HLA-identical sibling transplants with higher OS and RFS. Moreover, the NRM and the risks for especially severe acute and chronic GVHD were lower in the URD group suggesting that the best donor for an elderly patient might not be an HLA-identical sibling. This might be due to the positive impact of younger donor age on outcome of allo-HCT as shown in other studies 20–22 . Indeed, the median unrelated donor age was 25 years compared to 61 years in the RD group. It is important, however, that 94% of URD patients received ATG compared to only 11% of the patients receiving HLA-identical sibling donor transplants, which may explain the lower frequency of severe GVHD in the URD-group. The strengths of this study are that it is large and multinational with analyses based on biological randomization enabling unbiased comparisons between HCT and Control.. There are, however, also several weaknesses most importantly that many developments have occurred since the design of the study. Furthermore, the controls for the URD group were few making it difficult to draw conclusions from this comparison. Moreover, molecular risk stratification has not been evenly applied to study patients and Hematopoietic cell transplant comorbidity score data was not collected. In summary, this study doesn’t support the use of elderly HLA-identical siblings as donors for older AML patients undergoing a RICT allogeneic HCT in first CR. It moreover indicates that a younger URD might be superior to an elderly RD. . Declarations Acknowledgements Inger Andersson and Joanne Blais for their work for the study. Economic support was granted by the Swedish Research Council (2012-38102-91941-45), the Swedish Cancer Foundation, CA 2017/364, 2017/369 , the Swedish State under the ALF agreement, Lion´s Cancer Research Fund of Western Sweden, and NordForsk Project No. 71306. The study was supported by Cell Therapy Transplant Canada (formerly named Canadian Blood and Marrow Transplant Group), and Otsuka pharmaceuticals (Canada). Authorship Contributions MB, PL, TK designed the study. MB, TK obtained funding. HA performed the statistical analyses, MN, EW worked on the data collection and data management. PL, MB, MN, HA wrote the paper. All other authors participated as investigators, collected data, and reviewed the manuscript. References Feinstein LC, Sandmaier BM, Hegenbart U, et al. Non-myeloablative allografting from human leucocyte antigen-identical sibling donors for treatment of acute myeloid leukaemia in first complete remission. Br J Haematol . 2003;120(2):281-288. 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(11):3390-3400. Ustun C, Le-Rademacher J, Wang HL, et al. Allogeneic hematopoietic cell transplantation compared to chemotherapy consolidation in older acute myeloid leukemia (AML) patients 60-75 years in first complete remission (CR1): an alliance (A151509), SWOG, ECOG-ACRIN, and CIBMTR study. Leukemia . 2019;33(11):2599-2609. Farag SS, Maharry K, Zhang MJ, et al. Comparison of reduced-intensity hematopoietic cell transplantation with chemotherapy in patients age 60-70 years with acute myelogenous leukemia in first remission. Biol Blood Marrow Transplant . 2011;17(12):1796-1803. Medeiros BC, Satram-Hoang S, Hurst D, Hoang KQ, Momin F, Reyes C. Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States. Ann Hematol . 2015;94(7):1127-1138. Ljungman P, de WT, Verdonck L, et al. Bone marrow transplantation for acute myeloblastic leukaemia: an EBMT Leukaemia Working Party prospective analysis from HLA-typing. Br J Haematol . 1993;84(1):61-66. 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 [see comments]. New England Journal of Medicine . 1995;332(4):217-223. 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 [see comments]. New England Journal of Medicine . 1998;339(23):1649-1656. 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(9):3658-3666. Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood . 2017;129(4):424-447. Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood . 2010;115(3):453-474. Gyurkocza B, Storb R, Storer BE, et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol . 2010;28(17):2859-2867. 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(3):865-872. Tauro S, Craddock C, Peggs K, et al. Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol . 2005;23(36):9387-9393. Blaise D, Farnault L, Faucher C, et al. Reduced-intensity conditioning with Fludarabin, oral Busulfan, and thymoglobulin allows long-term disease control and low transplant-related mortality in patients with hematological malignancies. Exp Hematol . 2010;38(12):1241-1250. Devillier R, Forcade E, Garnier A, et al. In-depth time-dependent analysis of the benefit of allo-HSCT for elderly patients with CR1 AML: a FILO study. Blood Adv . 2022;6(6):1804-1812. Sorror ML, Gooley TA, Storer BE, et al. An 8-year pragmatic observation evaluation of the benefits of allogeneic HCT in older and medically infirm patients with AML. Blood . 2023;141(3):295-308. Beelen DW, Trenschel R, Stelljes M, et al. Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial. Lancet Haematol . 2020;7(1):e28-e39. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med . 2020;383(7):617-629. Bastida JM, Cabrero M, Lopez-Godino O, et al. Influence of donor age in allogeneic stem cell transplant outcome in acute myeloid leukemia and myelodisplastic syndrome. Leuk Res . 2015;39(8):828-834. Ayuk F, Beelen DW, Bornhauser M, et al. Relative Impact of HLA Matching and Non-HLA Donor Characteristics on Outcomes of Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome. Biol Blood Marrow Transplant . 2018;24(12):2558-2567. Seo S, Usui Y, Matsuo K, et al. Impact of the combination of donor age and HLA disparity on the outcomes of unrelated bone marrow transplantation. Bone Marrow Transplant . 2021;56(10):2410-2422. Additional Declarations The authors have declared there is NO conflict of interest to disclose. Supplementary Files SupplementaryinformationRICTstudy.docx Cite Share Download PDF Status: Published Journal Publication published 02 Sep, 2024 Read the published version in Bone Marrow Transplantation → Version 1 posted Editorial decision: revise 10 Jun, 2024 Review # 2 received at journal 02 Jun, 2024 Reviewer # 2 agreed at journal 22 May, 2024 Review # 1 received at journal 06 May, 2024 Reviewer # 1 agreed at journal 22 Apr, 2024 Reviewers invited by journal 20 Apr, 2024 Submission checks completed at journal 12 Apr, 2024 First submitted to journal 11 Apr, 2024 Editor assigned by journal 11 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4253193","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":293563001,"identity":"6c56f85d-75b3-4c88-ac76-bd76ad164f0f","order_by":0,"name":"Per Ljungman","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYJACZgYeKOvDAQkStTDOIF4LjMFzgAjl5uy9D5gZZA7nyYcdfvbY5owFg3x7A34tlj3HDYAOO1xseDvN3DjnhgSDwRkCVhncSAP55XDixtkJZtI5H4BaJBIIaLn/DKYl/Zu0BVCL/PwHhGxhg2iZL51jJs0AdBjDDfw6gH5JYzjMwJOeuEE6p0yy54wEj8EZAg4zZz/G+Phnj3Xi/Nnp2yR+HKuTk28/QMBhQHyAsQfIgCrkwacaroWB4QcDg3wDQbWjYBSMglEwUgEAWOs/XdXDBXoAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-8281-3245","institution":"Karolinska University Hospital / Huddinge","correspondingAuthor":true,"prefix":"","firstName":"Per","middleName":"","lastName":"Ljungman","suffix":""},{"id":293563002,"identity":"05ec17d7-2a12-4639-965c-3a741a5e8544","order_by":1,"name":"Mats Brune","email":"","orcid":"","institution":"Sahlgrenska University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mats","middleName":"","lastName":"Brune","suffix":""},{"id":293563003,"identity":"9c99aa5f-b0f6-4a69-abbb-9fd80abba7a2","order_by":2,"name":"Thomas Kiss","email":"","orcid":"","institution":"Maisonneuve Rosemont Hospital","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Kiss","suffix":""},{"id":293563004,"identity":"a01242c0-419c-4f7b-a97a-465c90ec8578","order_by":3,"name":"Harald Andersson","email":"","orcid":"","institution":"University of Lund","correspondingAuthor":false,"prefix":"","firstName":"Harald","middleName":"","lastName":"Andersson","suffix":""},{"id":293563005,"identity":"b48ebf1c-11f6-40c3-8582-5796c422efb2","order_by":4,"name":"Malin Nicklasson","email":"","orcid":"","institution":"Sahlgrenska University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Malin","middleName":"","lastName":"Nicklasson","suffix":""},{"id":293563006,"identity":"cd51c063-535a-4501-83ff-c5f1fd528f01","order_by":5,"name":"Robert Delage","email":"","orcid":"","institution":"CHU de Québec-Université Laval","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"","lastName":"Delage","suffix":""},{"id":293563007,"identity":"0f324eb1-1731-4b15-a388-821be8adc0ed","order_by":6,"name":"Jürgen Finke","email":"","orcid":"https://orcid.org/0000-0002-1799-5927","institution":"Faculty of Medicine and Medical Center - University of Freiburg","correspondingAuthor":false,"prefix":"","firstName":"Jürgen","middleName":"","lastName":"Finke","suffix":""},{"id":293563008,"identity":"6b5422ea-6619-4816-af2c-63068e45655e","order_by":7,"name":"Tobias Gedde-Dahl","email":"","orcid":"","institution":"Oslo University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tobias","middleName":"","lastName":"Gedde-Dahl","suffix":""},{"id":293563009,"identity":"bb7b9973-7981-4923-8dd9-a14ee12e1d47","order_by":8,"name":"Josée Hébert","email":"","orcid":"","institution":"Maisonneuve Rosemont Hospital","correspondingAuthor":false,"prefix":"","firstName":"Josée","middleName":"","lastName":"Hébert","suffix":""},{"id":293563010,"identity":"61c63613-f32b-4ce9-a9e0-dfd579415d20","order_by":9,"name":"Martin Höglund","email":"","orcid":"","institution":"Uppsala University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Martin","middleName":"","lastName":"Höglund","suffix":""},{"id":293563011,"identity":"fea79831-fc2f-44a8-afaf-a2bf6cce5d9b","order_by":10,"name":"Ain Kaare","email":"","orcid":"https://orcid.org/0000-0002-3170-1016","institution":"Tartu University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ain","middleName":"","lastName":"Kaare","suffix":""},{"id":293563012,"identity":"c8dad6b5-970a-4646-b0dd-ba7ceee0cc74","order_by":11,"name":"Vladimir Lazarevic","email":"","orcid":"","institution":"Lund University","correspondingAuthor":false,"prefix":"","firstName":"Vladimir","middleName":"","lastName":"Lazarevic","suffix":""},{"id":293563013,"identity":"f1416752-5c51-4470-9a89-d9b74fed39ca","order_by":12,"name":"Lars Möllgård","email":"","orcid":"","institution":"Sahlgrenska University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lars","middleName":"","lastName":"Möllgård","suffix":""},{"id":293563014,"identity":"6026e76a-6de5-4547-9f67-e2139126224b","order_by":13,"name":"Kari Remes","email":"","orcid":"","institution":"Turku University Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kari","middleName":"","lastName":"Remes","suffix":""},{"id":293563015,"identity":"3d5d4cdb-c1a0-4f6c-a080-b091c1ecf218","order_by":14,"name":"David Ritchie","email":"","orcid":"","institution":"Peter MacCallum Cancer Centre and Royal Melbourne Hospital","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Ritchie","suffix":""},{"id":293563016,"identity":"9d591bdc-15dd-406d-a475-4e0efd8e6a88","order_by":15,"name":"Alexandros Spyridonidis","email":"","orcid":"https://orcid.org/0000-0003-3097-2532","institution":"University Medical School of Patras","correspondingAuthor":false,"prefix":"","firstName":"Alexandros","middleName":"","lastName":"Spyridonidis","suffix":""},{"id":293563017,"identity":"5c91ee64-a288-44a8-8715-942dabc3dcf3","order_by":16,"name":"Mitchell Sabloff","email":"","orcid":"https://orcid.org/0000-0002-0122-6138","institution":"The Ottawa Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mitchell","middleName":"","lastName":"Sabloff","suffix":""},{"id":293563018,"identity":"b22a5610-7f78-48e1-98ff-ae70d9b6590b","order_by":17,"name":"Ruth Spearing","email":"","orcid":"","institution":"Christchurch Hospital and University of Otago, New Zealand","correspondingAuthor":false,"prefix":"","firstName":"Ruth","middleName":"","lastName":"Spearing","suffix":""},{"id":293563019,"identity":"6d42c784-e90f-4678-94d6-d44a9ae51217","order_by":18,"name":"Elisabeth Wallhult","email":"","orcid":"","institution":"Sahlgrenska University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Elisabeth","middleName":"","lastName":"Wallhult","suffix":""}],"badges":[],"createdAt":"2024-04-11 15:00:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4253193/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4253193/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41409-024-02408-x","type":"published","date":"2024-09-02T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":55529557,"identity":"47cd1e8b-b580-406c-80e1-d6f6ec47b47d","added_by":"auto","created_at":"2024-04-29 15:26:44","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":334183,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flow chart describing patient inclusion in the two different study periods.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4253193/v1/fab0091dd0b3d3aeb8525b53.jpeg"},{"id":55528848,"identity":"aee5708f-3e06-4c8f-a704-fac033244fd7","added_by":"auto","created_at":"2024-04-29 15:18:44","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":284180,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival from study inclusion in RD vs Controls (study parts 1 and 2)\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4253193/v1/76d098a6e9d22ec7029474bc.jpeg"},{"id":55528842,"identity":"d0458913-bec4-4dbe-b38c-b52742bdcea3","added_by":"auto","created_at":"2024-04-29 15:18:44","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":266212,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival from study inclusion; no potential sibling donor (study part 2).\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4253193/v1/f9486ab4b6d5a8445ca0d5dc.jpeg"},{"id":55528843,"identity":"3144a55e-0f1a-46e7-ba63-35a53489b67e","added_by":"auto","created_at":"2024-04-29 15:18:44","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":286653,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival in patients transplanted from RD or URD (study period 2)\u003c/p\u003e","description":"","filename":"floatimage7.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4253193/v1/44c29717de5a144e65e2d728.jpeg"},{"id":63865007,"identity":"8e28ead3-c86a-4627-b6e5-99271fcf538b","added_by":"auto","created_at":"2024-09-03 07:10:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1785136,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4253193/v1/fc9ab312-100e-4459-9a4f-cb67f1d4beda.pdf"},{"id":55528847,"identity":"0069ca21-8164-43eb-9888-d3b99900099e","added_by":"auto","created_at":"2024-04-29 15:18:44","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":100032,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SupplementaryinformationRICTstudy.docx","url":"https://assets-eu.researchsquare.com/files/rs-4253193/v1/3e9e645d05686956c6cc59d2.docx"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Reduced Intensity transplantation vs chemotherapy. A prospective, pseudorandomized study in 50-70 year old AML patients","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eThe curative potential of allo-HCT is due to the preparative chemotherapy, and the immunological graft-versus-leukemia (GvL) effect exerted by donor T-cells. The introduction of reduced intensity and thereby lower toxicity conditioning before allo-HCT (RICT) has expanded the transplant option to elderly patients and patients with co-morbidities\u003csup\u003e1,2\u003c/sup\u003e, with the aim of retaining GvL whilst reducing NRM.\u003c/p\u003e \u003cp\u003eDifferent approaches were used to compare allo-HCT with chemotherapy. These were mainly retrospective studies utilizing registry data\u003csup\u003e3\u0026ndash;5\u003c/sup\u003e. A well-recognized problem is the difficulty to compare in a controlled setting allo-HCT vs. standard-of-care since stringent randomized studies are very difficult to perform. Imitating randomization, HCT vs chemotherapy studies have been performed using biological allocation (presence or absence of an HLA-identical sibling donor) in patients undergoing myeloablative HCT\u003csup\u003e6\u003c/sup\u003e. Zittoun et al found in a prospective study, where treatment allocation was done in first CR, an improvement after both auto- and allo-HCT as compared to chemotherapy\u003csup\u003e7\u003c/sup\u003e. In a similarly designed prospective study, Cassileth et al found a slight advantage of chemotherapy compared to auto- or allo-HCT\u003csup\u003e8\u003c/sup\u003e. In contrast, Cornelissen et al found an improvement in disease free survival by donor availability with transplants performed with myeloablative conditioning in patients\u0026thinsp;\u0026lt;\u0026thinsp;55 years having an intermediate or high-risk profile\u003csup\u003e9\u003c/sup\u003e. In this study, the aim was to use comparable starting points for the two treatments using the time for start of donor search for either a family or unrelated donor but also requiring that the patients had entered first complete remission.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThe design of this study used the pseudorandomized donor versus no donor concept with the aim to compare RICT to standard-of-care chemotherapy in AML patients between 50\u0026ndash;70 years. When the study was initiated (2003) only patients having a potential HLA-identical sibling (RD) were eligible for the study (Part 1). Due to an increased use of unrelated donors, the study design was changed to allow inclusion of patients without potential HLA-identical siblings (Part 2). Patients could be registered into the study at any time after diagnosis but were only eligible for study inclusion after having entered CR1. The date for study inclusion was the date the first sample was obtained for HLA-typing of a sibling (Parts 1 and 2) or start of unrelated donor (URD) search (Part 2). If either of these occurred before CR, the date of CR was set as the inclusion date. Patients never entering CR were excluded.\u003c/p\u003e \u003cp\u003e \u003cem\u003eStudy Part 1 (2003\u0026ndash;2012).\u003c/em\u003e The primary objective both for first part of the study and the whole study was to evaluate in an intention-to-treat setting the OS after RICT from HLA-identical sibling donors \u003cem\u003ecompared to\u003c/em\u003e standard-of-care chemotherapy. Additional objectives were to assess relapse-free survival (RFS), NRM, and relapse incidence (RI) between the two groups.\u003c/p\u003e \u003cp\u003e After entering CR1, patients with at least one sibling were informed about the study and after signed consent included into the study. If the sibling(s) were willing and had no contraindication for stem cell donation, HLA-typing was performed, and patients were assigned to one of two groups; RD (donor identified) or Controls (no donor).\u003c/p\u003e \u003cp\u003e \u003cem\u003eStudy Part 2 (2012\u0026ndash;2016)\u003c/em\u003e. The protocol was updated due to slow accrual and the increasing use of URD allowing search for a suitable URD \u003cem\u003eeither\u003c/em\u003e after failed RD search or upfront in patients without an available sibling. Depending on possible donor types, the patients were grouped into three strata (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). HLA typing of potential related donors and unrelated donor search was permitted after registration but before confirmation of CR to decrease the time between diagnosis and transplant. Patients without a donor were allocated to one of the Control groups. The additional objectives of this part of the study, besides the original objective of comparing RD vs. Controls, were to assess if patients receiving RICT from URD had superior OS compared with Controls (no RD, no URD) or to RICT from RD. Other objectives were to analyze RFS, NRM, and RI after URD RICT compared to Controls.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy procedures\u003c/h2\u003e \u003cp\u003ePatients ages 50\u0026ndash;70 years with intermediate- or high-risk AML in CR1 and who were judged to be able to tolerate further therapy including RIC-HCT could be included. Important exclusion criteria were favorable risk AML as defined by cytogenetics and as of study part 2 by presence of mutation in NPM1 as sole molecular abnormality, abnormal renal (s-creatinine\u0026thinsp;\u0026gt;\u0026thinsp;2 x ULN) or liver function (AST or ALT\u0026thinsp;\u0026gt;\u0026thinsp;3 x ULN), or severe concurrent illness preventing additional post-remission therapy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eTreatments\u003c/h2\u003e \u003cp\u003eInduction and consolidation therapy were given according to standard-of-care at participating centers, which varied between countries. The protocol recommended as conditioning regimens either the use of fludarabine 5\u0026ndash;6 days (150\u0026ndash;180 mg/sqm) combined with busulphan either given orally (total dose 8\u0026ndash;11 mg/kg) or iv (Busulphex\u0026reg;; total dose 6.4 mg/kg) or a combination of fludarabine, carmustin, and melphalan. As graft-versus-host disease (GVHD) prophylaxis before URD HCT either anti-thymocyte globuline (ATG) or alemtuzumab was allowed. Recommended immunosuppression was ciclosporin (CyA) combined either with methotrexate (used in 63% of the patients) or mycophenolate mofetil (MMF).\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eCytogenetic and disease risk features\u003c/h2\u003e \u003cp\u003eTwo independent reviewers categorized the patients as high or intermediate risk according to the European Leukemia Net 2017 genetic risk classification\u003csup\u003e10,11\u003c/sup\u003e. Interpretable reports from diagnostic bone marrow samples were available for 262 patients (85%). Patients with favorable risk cytogenetics were excluded including those with only NPM1 mutation.\u003c/p\u003e \u003cp\u003eClinical high-risk features were defined as more than two inductions to reach CR1, secondary AML, and blasts\u0026thinsp;\u0026ge;\u0026thinsp;15% after first induction. Patients with any high-risk feature were assigned to the high-risk group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003eAdministrative information\u003c/h2\u003e \u003cp\u003eThe study was registered at ClinicalTrial.gov (CTN #00342316). All patients signed informed consent. The study protocol and ensuing amendments were approved by the Ethical Committee at University of Gothenburg for Swedish patients (\u003cem\u003eS 240-04, S 288-03, S-266-03, S 272-03, S-231-12\u003c/em\u003e), and by the corresponding authorities in participating centers and countries.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistics\u003c/h2\u003e \u003cp\u003eAdditional information about statistical analysis is given in Supplementary information.\u003c/p\u003e \u003cp\u003eThe primary endpoint was OS in an intention to treat (ITT) setting. Baseline and treatment data were compared between ITT groups by Fisher\u0026acute;s exact tests and Wilcoxon\u0026acute;s rank-sum tests. Kaplan-Meier and Cumulative incidence plots were used for illustration of time-to event endpoints. All endpoints (OS, RFS, NRM and RI) were determined from date of inclusion. The patients were grouped into strata A-D according to Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e based on the partition of the study in Part 1 and Part 2 and possible type of donor. In the ITT analyses, it was assumed that treatment allocation within strata was random. OS and RFS were compared by stratified log-rank tests and NRM and RI by stratified Gray\u0026acute;s tests considering competing risks. Three-year values with 95% confidence intervals are also presented. Hazard ratios (HR) were determined by means of stratified Cox regression. Proportions of patients with acute and chronic GVHD were analyzed with Fisher\u0026acute;s Exact test. Stata version 14 and R version 4.1.0 were used in the statistical analyses.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003ePatient population and distribution\u003c/h2\u003e \u003cp\u003eThe study population is described in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. 360 patients were registered into the study. Twenty patients never reached CR and were therefore not included. Thus, 340 patients were included in the study population. 31 were excluded due to donor search initiation before inclusion (n\u0026thinsp;=\u0026thinsp;19), low-risk cytogenetics (n\u0026thinsp;=\u0026thinsp;9), missing consent (n\u0026thinsp;=\u0026thinsp;2), and missing data (n\u0026thinsp;=\u0026thinsp;1). Moreover, three patients withdrew consent within the first three months after study inclusion. These are included in the analysis until date of consent withdrawal.\u003c/p\u003e \u003cp\u003eThus, the analyzed study cohort included 309 patients of which 135 were included in Part 1 (2003 - April 2012), and 174 in Part 2 (May 2012\u0026ndash;2016) of the study. The age of patients (median 62 vs 64 years) was similar in the two parts. The median unrelated donor age was 25 (18\u0026ndash;68) years (Part 2), whereas sibling donors were older; 60 (48\u0026ndash;76) years; p\u0026thinsp;\u0026lt;\u0026thinsp;.001; Parts 1 and 2). The first patient was included December 18, 2003, and the last patient was included July 19, 2016. Data was analyzed as of August 1, 2018.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eRD versus Controls; study parts 1 and 2 combined\u003c/h2\u003e \u003cp\u003eThe patient and donor distributions in the different study parts are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. 71 patients were assigned to the RD/donor and 64 to the Control/no donor group in Part 1 of the study (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e; Stratum A). Some study sites continued during the 2nd part of the study including only patients fulfilling the criteria of study Part 1 (Stratum B: RD; n\u0026thinsp;=\u0026thinsp;8, and Controls; n\u0026thinsp;=\u0026thinsp;5).\u003c/p\u003e \u003cp\u003eIn study Part 2, 45 patients had RD and patients without either RD or URD (n\u0026thinsp;=\u0026thinsp;8) were considered as controls for both the RD and URD comparisons (Stratum C). Thus, the total number of patients with RD was 124 (71\u0026thinsp;+\u0026thinsp;8\u0026thinsp;+\u0026thinsp;45) and the number of Controls was 77 (64\u0026thinsp;+\u0026thinsp;5\u0026thinsp;+\u0026thinsp;8). In the Control group, 8/77 (8%) patients were treated off-protocol by allografting from alternative donors. These patients were included in the intention to treat (ITT) analysis as Controls.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eURD versus Controls; study part 2\u003c/h2\u003e \u003cp\u003eAn URD was identified for 96 patients. Twenty patients without an identified donor were Controls to the URD group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e; Strata C and D). Six patients underwent transplants from either cord blood or haploidentical donors. These patients were included as Controls in the ITT analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eRD versus Control (Part 1 and 2)\u003c/h2\u003e \u003cp\u003e201 patients were included in the RD versus Control ITT comparison, 138 (69%) of whom died during follow-up. Median (min-max) follow-up time for the surviving patients was 76 (1-168) months. Patient characteristics were similar between RD and Control groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Ninety-seven patients underwent RICT at a median of 10 (3\u0026ndash;33) weeks post inclusion while 27/124 (22%) patients did not reach transplant due to early relapse (n\u0026thinsp;=\u0026thinsp;18), medical infirmity (n\u0026thinsp;=\u0026thinsp;4), withdrawn consent (n\u0026thinsp;=\u0026thinsp;2) or death (n\u0026thinsp;=\u0026thinsp;3).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of patients in the RD vs Control primary endpoint analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;77)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRICT/RD (n\u0026thinsp;=\u0026thinsp;124)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender F/M \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (47) / 41 (53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55 (44) / 69 (56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian age at Inclusion, years (min - max)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63 (51\u0026ndash;70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63 (51\u0026ndash;71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRisk group IR/HR \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50 (65) / 27 (35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68 (55) / 56 (45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian time from diagnosis to inclusion, days (min \u0026ndash; max)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64 (32\u0026ndash;256)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64 (29\u0026ndash;319)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGiven therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemotherapy only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransplanted\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e97**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian time from inclusion to transplant, days (min \u0026ndash; max)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73 (23\u0026ndash;236)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCauses of death \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGvHD or related infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50 (65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecondary malignancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e* 6 URD, 1 cord blood, 1 haploidentical HCT\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e** All RICT/RD\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eOverall Survival.\u003c/em\u003e \u003c/p\u003e \u003cp\u003e81/124 (65%) and 57/77 (74%) patients died in the RD and Control groups, respectively. Most deaths were due to relapse; 67% in the RD group and 88% in the Control group. Other causes are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. OS is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. At three years it was 0.41 (95% CI; 0.32\u0026ndash;0.50) and 0.49 ((95% CI; 0.37\u0026ndash;0.59); p\u0026thinsp;=\u0026thinsp;.50, logrank test) in the RD and control group, respectively. The data are not consistent with a constant hazard ratio over time: HR\u0026thinsp;=\u0026thinsp;2.31 (95% CI: 1.34\u0026ndash;4.01) before one year and HR\u0026thinsp;=\u0026thinsp;0.57 (0.34\u0026ndash;0.95) after one year (p\u0026thinsp;=\u0026thinsp;.0003 for difference) suggesting relatively higher mortality in the RD group the first year after inclusion and lower thereafter.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn an analysis performed with RD transplant as a time-dependent covariate, the analysis reflects the given treatment: A patient always starts as a Control patient and shifts to an RD patient at transplantation. The HR was 0.81 (0.56\u0026ndash;1.17, p\u0026thinsp;=\u0026thinsp;.25) between the hazard for patients who received a transplant to the those who did not. Follow-up was censored at transplantation for the six Controls transplanted with an URD.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eOther outcomes\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eRFS\u003c/strong\u003e \u003cp\u003e85/124 (69%) and 60/77 (78%) events occurred in the RD and Control groups, respectively (HR\u0026thinsp;=\u0026thinsp;0.97 (0.69\u0026ndash;1.37); p\u0026thinsp;=\u0026thinsp;0.87). The RFS at 3 years was 0.38 (95% CI 0.29\u0026ndash;0.46) in RD patients and 0.35 (95% CI 0.24\u0026ndash;0.45) in Controls.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eNRM\u003c/strong\u003e \u003cp\u003e27/124 (22%) and 7/77 (9%) non-relapse deaths occurred in the RD groups and Control groups, respectively. With relapse as a competing event, the cumulative NRM incidence at 3 years was 0.17 (0.11\u0026ndash;0.25) in the RD group, and 0.039 (0.01\u0026ndash;0.10) in Controls (p\u0026thinsp;=\u0026thinsp;.033, Gray\u0026rsquo;s test).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eRI\u003c/strong\u003e \u003cp\u003e58/124 (47%) and 53/77 (69%) patients relapsed in the RD and Control groups, respectively; With NRM as a competing risk, the cumulative relapse incidence at 3 years was 0.45 (95% CI 0.36\u0026ndash;0.54) in the RD group, and 0.61 (95% CI 0.50\u0026ndash;0.71) in Controls (p\u0026thinsp;=\u0026thinsp;.097, Gray\u0026rsquo;s test).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eUnrelated Donor (URD)\u003c/b\u003e \u003cb\u003eversus\u003c/b\u003e \u003cb\u003eNo donor (Part 2).\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003cem\u003eResults\u003c/em\u003e. At study closure, 65/116 (56%) patients were alive after a follow-up of median 39 (3\u0026ndash;70) months. 16/96 (17%) of the patients in the URD group did not undergo transplantation.\u003c/p\u003e \u003cp\u003e39/96 (41%) patients in the URD-group and 12/20 Controls (60%) died. Patient characteristics and causes of death are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of patients in the URD vs Control analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRICT/MUD (n\u0026thinsp;=\u0026thinsp;96)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender F/M \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (50) /10 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (38) / 60 (63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian age at Inclusion, years (min - max)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63 (55\u0026ndash;69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64 (52\u0026ndash;71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRisk group IR/HR \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (50) / 10 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46 (48) / 50 (52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian time from diagnosis to inclusion, days (min \u0026ndash; max)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57 (32\u0026ndash;160)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64 (28\u0026ndash;244)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGiven therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemotherapy only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransplanted\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian time from inclusion to transplant, days (min \u0026ndash; max)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e93 (23\u0026ndash;302)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCause of death \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGvHD or rel inf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecondary malignancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e* 1 cord blood, 5 haploidentical HCT\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e** All RICT/URD\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe three-year OS was 0.60 (95% CI 0.50\u0026ndash;0.70) in the URD-HCT group and 0.37 (95% CI 0.13\u0026ndash;0.62) in the Control group (p\u0026thinsp;=\u0026thinsp;.10; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The HR comparing URD-HCT and Controls was 0.59 (95% CI 0.31\u0026ndash;1.12; p\u0026thinsp;=\u0026thinsp;.11). There was neither any significant difference in RFS between URD-HCT and Controls (three-year values with 95% CI 0.52 (0.41,0.61) and 0.39 (0.19\u0026ndash;0.60) respectively, p\u0026thinsp;=\u0026thinsp;.21), nor in NRM (0.10 (0.05\u0026ndash;0.17) and 0.10 (0.02\u0026ndash;0.27), p\u0026thinsp;=\u0026thinsp;.85), or RI (0.39 (0.29\u0026ndash;0.48) and 0.51 (0.27\u0026ndash;0.70), p\u0026thinsp;=\u0026thinsp;.32.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eRD versus URD versus Controls, according to given treatment (Part 2)\u003c/h2\u003e \u003cp\u003eOS from study inclusion was analyzed with one time-varying covariates for each type of transplant. The HR\u0026acute;s were 0.70 (0.39\u0026ndash;1.26) for RD-HCT versus Controls, and 0.27 (0.15\u0026ndash;0.47) for URD-HCT versus Controls. A direct comparison yields that HR for URD-HCT was significantly lower than for RD-HCT (p\u0026thinsp;=\u0026thinsp;.0041) indicating that survival after URD was superior to RD.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eRD versus URD from transplantation (Part 2)\u003c/h2\u003e \u003cp\u003ePatient characteristics are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. At study closure, 73 of 123 (59%) patients were alive after median 38 (1\u0026ndash;66) months of follow-up from transplants. 24/43 (56%) patients died in the RD and 26/80 (33%) in the URD group. The OS was higher (p\u0026thinsp;=\u0026thinsp;.005) for patients undergoing URD (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Three year survival was 0.42 (0.26\u0026ndash;0.57) in the RD-group and 0.67 (0.55\u0026ndash;0.76) in the URD group. Furthermore, RFS was higher in the URD group (3-year RFS 0.61 [0.49,0.71] vs. 0.36 [0.21,0.51]; p\u0026thinsp;=\u0026thinsp;.01), NRM was lower (0.11 [0.05,0.19] vs. 0.30 [0.16,0.44]; p\u0026thinsp;=\u0026thinsp;.01), while there was no significant difference in RI ( 0.29 [0.19,0.39] vs 0.34 [0.20,0.49]; p\u0026thinsp;=\u0026thinsp;.46).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of RD vs URD patients in study period 2\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRICT/RD\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRICT/URD (n\u0026thinsp;=\u0026thinsp;80)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender F/M \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (42) / 25 (58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (38) / 50 (63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian age at Inclusion, years (min-max)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63 (53\u0026ndash;71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65 (53\u0026ndash;71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from CR to inclusion, days (min-max)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (0\u0026ndash;173)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (0\u0026ndash;138)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from Inclusion to HCT days (min-max)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79 (23\u0026ndash;236)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e93 (23\u0026ndash;302)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRisk group IR/HR \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (37) /27 (63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (44) / 45 (56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFlu/Bu p.o. / Not Flu/Bu p.o. \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (37) / 27 (63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 (63) / 30 (38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo ATG / ATG \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (77) /10 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (6) / 75 (94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmunosuppression treatment \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCyA\u0026thinsp;+\u0026thinsp;MTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDonor age, median, yr (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61 (49\u0026ndash;73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (18\u0026ndash;68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale donor to male recipient \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.052\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73 (92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eAcute and chronic GVHD in RD (Parts 1\u0026thinsp;+\u0026thinsp;2) and URD (Part 2)\u003c/h2\u003e \u003cp\u003eThere was a lower risk for acute GVHD grades III \u0026ndash; IV in patients undergoing URD HCT (6% URD vs 19% RD; p\u0026thinsp;=\u0026thinsp;.01) and a lower risk for extensive chronic GVHD at 12 months (URD 12.7% vs. RD 40.3%; p\u0026thinsp;\u0026lt;\u0026thinsp;.001), 24 months (9.6% URD vs. 38.3% RD; p\u0026thinsp;\u0026lt;\u0026thinsp;.001), and 36 months (8.3% URD vs. 40% RD; p\u0026thinsp;=\u0026thinsp;.003) after transplantation compared to RD HCT patients (Suppl. Figure\u0026nbsp;1).\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eWhether RICT allogeneic HCT in elderly patients with AML results in improved long-term survival has been discussed for many years. It has been exceedingly difficult to perform proper randomized prospective studies in allogeneic HCT in general due to the donor selection process including the willingness of patients and donors to be randomized to non-HCT therapy. Studies using other approaches have reported that RICT-HCT can result in long-term leukemia-free survival\u003csup\u003e1,12\u0026ndash;16\u003c/sup\u003e. However, a recent large prospective cohort study has challenged this concept in elderly patients and those with co-morbidities\u003csup\u003e17\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe aim of this study was to use pseudo-randomization based on the availability of at least one sibling willing to be typed and with the starting date either the day of a sample obtained for HLA-typing of a potential sibling donor or the day of CR if typing was performed before the patient entered CR. Our study, designed now several years ago, shows now with extended follow-up no advantage for a reduced intensity allogeneic-HCT with a sibling donor compared to Controls. As expected, the NRM was higher in the transplant group compared to Controls and although there was a slightly higher incidence of relapse in the Controls, this did not compensate for the higher risk for NRM. Similar results were seen when an URD was used, but the low number of Controls makes it difficult to draw any firm conclusion from this comparison. The main cause of death in all study groups was leukemia relapse and not NRM. Many relapses occurred in the \u0026ldquo;transplant groups\u0026rdquo; before the patient could get to transplant.\u003c/p\u003e \u003cp\u003eSeveral important advances in supportive care especially the introduction of new drugs against infections have occurred since the study was initiated improving the outcome of allogeneic HCT. Furthermore, the selected conditioning regimen has been shown to be inferior to more intensive conditioning regimens\u003csup\u003e10,18\u003c/sup\u003e, and it is possible that a more intensive but still reduced intensity regimen could have yielded better results. Interestingly, a large prospective study including patients during the latter part of our study period (2013\u0026ndash;2017) also failed to show a survival benefit in elderly patients and in these who were medically infirm\u003csup\u003e17\u003c/sup\u003e. Moreover, new alternatives for non-transplant therapy of AML in the elderly such as azacytidine +- venetoclax have been introduced also changing the therapeutic landscape\u003csup\u003e19\u003c/sup\u003e. The study included patients with a median age of 62\u0026ndash;64 years in the different groups so not real elderly according to what is the clinical practice today. This, however, ought to have reduced rather than increased the risk for NRM if we translate the results to today\u0026rsquo;s situation.\u003c/p\u003e \u003cp\u003eThe results of URD transplants were better than the results of HLA-identical sibling transplants with higher OS and RFS. Moreover, the NRM and the risks for especially severe acute and chronic GVHD were lower in the URD group suggesting that the best donor for an elderly patient might not be an HLA-identical sibling. This might be due to the positive impact of younger donor age on outcome of allo-HCT as shown in other studies\u003csup\u003e20\u0026ndash;22\u003c/sup\u003e. Indeed, the median unrelated donor age was 25 years compared to 61 years in the RD group. It is important, however, that 94% of URD patients received ATG compared to only 11% of the patients receiving HLA-identical sibling donor transplants, which may explain the lower frequency of severe GVHD in the URD-group.\u003c/p\u003e \u003cp\u003eThe strengths of this study are that it is large and multinational with analyses based on biological randomization enabling unbiased comparisons between HCT and Control.. There are, however, also several weaknesses most importantly that many developments have occurred since the design of the study. Furthermore, the controls for the URD group were few making it difficult to draw conclusions from this comparison. Moreover, molecular risk stratification has not been evenly applied to study patients and Hematopoietic cell transplant comorbidity score data was not collected.\u003c/p\u003e \u003cp\u003eIn summary, this study doesn\u0026rsquo;t support the use of elderly HLA-identical siblings as donors for older AML patients undergoing a RICT allogeneic HCT in first CR. It moreover indicates that a younger URD might be superior to an elderly RD.\u003c/p\u003e \u003cp\u003e.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInger Andersson and Joanne Blais for their work for the study.\u003c/p\u003e\n\u003cp\u003eEconomic support was granted by the Swedish Research Council (2012-38102-91941-45), the Swedish Cancer Foundation, CA\u0026nbsp;2017/364, 2017/369\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003ethe Swedish State under the ALF agreement, Lion\u0026acute;s Cancer Research Fund of Western Sweden, and NordForsk Project No. 71306. The study was supported by Cell Therapy Transplant Canada (formerly named Canadian Blood and Marrow Transplant Group), and Otsuka pharmaceuticals (Canada).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMB, PL, TK designed the study. MB, TK obtained funding. HA performed the statistical analyses, MN, EW worked on the data collection and data management. PL, MB, MN, HA wrote the paper. All other authors participated as investigators, collected data, and reviewed the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFeinstein LC, Sandmaier BM, Hegenbart U, et al. Non-myeloablative allografting from human leucocyte antigen-identical sibling donors for treatment of acute myeloid leukaemia in first complete remission. \u003cem\u003eBr J Haematol\u003c/em\u003e. 2003;120(2):281-288.\u003c/li\u003e\n\u003cli\u003eMcSweeney 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. \u003cem\u003eBlood\u003c/em\u003e. 2001;97(11):3390-3400.\u003c/li\u003e\n\u003cli\u003eUstun C, Le-Rademacher J, Wang HL, et al. Allogeneic hematopoietic cell transplantation compared to chemotherapy consolidation in older acute myeloid leukemia (AML) patients 60-75 years in first complete remission (CR1): an alliance (A151509), SWOG, ECOG-ACRIN, and CIBMTR study. \u003cem\u003eLeukemia\u003c/em\u003e. 2019;33(11):2599-2609.\u003c/li\u003e\n\u003cli\u003eFarag SS, Maharry K, Zhang MJ, et al. Comparison of reduced-intensity hematopoietic cell transplantation with chemotherapy in patients age 60-70 years with acute myelogenous leukemia in first remission. \u003cem\u003eBiol Blood Marrow Transplant\u003c/em\u003e. 2011;17(12):1796-1803.\u003c/li\u003e\n\u003cli\u003eMedeiros BC, Satram-Hoang S, Hurst D, Hoang KQ, Momin F, Reyes C. Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States. \u003cem\u003eAnn Hematol\u003c/em\u003e. 2015;94(7):1127-1138.\u003c/li\u003e\n\u003cli\u003eLjungman P, de WT, Verdonck L, et al. Bone marrow transplantation for acute myeloblastic leukaemia: an EBMT Leukaemia Working Party prospective analysis from HLA-typing. \u003cem\u003eBr J Haematol\u003c/em\u003e. 1993;84(1):61-66.\u003c/li\u003e\n\u003cli\u003eZittoun 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\u0026apos;Adulto (GIMEMA) Leukemia Cooperative Groups [see comments]. \u003cem\u003eNew England Journal of Medicine\u003c/em\u003e. 1995;332(4):217-223.\u003c/li\u003e\n\u003cli\u003eCassileth 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 [see comments]. \u003cem\u003eNew England Journal of Medicine\u003c/em\u003e. 1998;339(23):1649-1656.\u003c/li\u003e\n\u003cli\u003eCornelissen 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? \u003cem\u003eBlood\u003c/em\u003e. 2007;109(9):3658-3666.\u003c/li\u003e\n\u003cli\u003eDohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. \u003cem\u003eBlood\u003c/em\u003e. 2017;129(4):424-447.\u003c/li\u003e\n\u003cli\u003eDohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. \u003cem\u003eBlood\u003c/em\u003e. 2010;115(3):453-474.\u003c/li\u003e\n\u003cli\u003eGyurkocza B, Storb R, Storer BE, et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. \u003cem\u003eJ Clin Oncol\u003c/em\u003e. 2010;28(17):2859-2867.\u003c/li\u003e\n\u003cli\u003ede 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. \u003cem\u003eBlood\u003c/em\u003e. 2004;104(3):865-872.\u003c/li\u003e\n\u003cli\u003eTauro 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. \u003cem\u003eJ Clin Oncol\u003c/em\u003e. 2005;23(36):9387-9393.\u003c/li\u003e\n\u003cli\u003eBlaise D, Farnault L, Faucher C, et al. Reduced-intensity conditioning with Fludarabin, oral Busulfan, and thymoglobulin allows long-term disease control and low transplant-related mortality in patients with hematological malignancies. \u003cem\u003eExp Hematol\u003c/em\u003e. 2010;38(12):1241-1250.\u003c/li\u003e\n\u003cli\u003eDevillier R, Forcade E, Garnier A, et al. In-depth time-dependent analysis of the benefit of allo-HSCT for elderly patients with CR1 AML: a FILO study. \u003cem\u003eBlood Adv\u003c/em\u003e. 2022;6(6):1804-1812.\u003c/li\u003e\n\u003cli\u003eSorror ML, Gooley TA, Storer BE, et al. An 8-year pragmatic observation evaluation of the benefits of allogeneic HCT in older and medically infirm patients with AML. \u003cem\u003eBlood\u003c/em\u003e. 2023;141(3):295-308.\u003c/li\u003e\n\u003cli\u003eBeelen DW, Trenschel R, Stelljes M, et al. Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial. \u003cem\u003eLancet Haematol\u003c/em\u003e. 2020;7(1):e28-e39.\u003c/li\u003e\n\u003cli\u003eDiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. \u003cem\u003eN Engl J Med\u003c/em\u003e. 2020;383(7):617-629.\u003c/li\u003e\n\u003cli\u003eBastida JM, Cabrero M, Lopez-Godino O, et al. Influence of donor age in allogeneic stem cell transplant outcome in acute myeloid leukemia and myelodisplastic syndrome. \u003cem\u003eLeuk Res\u003c/em\u003e. 2015;39(8):828-834.\u003c/li\u003e\n\u003cli\u003eAyuk F, Beelen DW, Bornhauser M, et al. Relative Impact of HLA Matching and Non-HLA Donor Characteristics on Outcomes of Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome. \u003cem\u003eBiol Blood Marrow Transplant\u003c/em\u003e. 2018;24(12):2558-2567.\u003c/li\u003e\n\u003cli\u003eSeo S, Usui Y, Matsuo K, et al. Impact of the combination of donor age and HLA disparity on the outcomes of unrelated bone marrow transplantation. \u003cem\u003eBone Marrow Transplant\u003c/em\u003e. 2021;56(10):2410-2422.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4253193/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4253193/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe aim of this prospective, international multicenter, pseudorandomized study using the \u003cem\u003edonor versus no-donor \u003c/em\u003econcept to compare RICT HCT to standard-of-care chemotherapy in intermediate- or high risk AML patients 50 – 70 years in CR1. Part 1 included only patients with potential family donors (RD) at the date of HLA-typing of the first potential sibling or CR-date, if later. In Part 2), patients without a possible sibling donor could be included with the inclusion date at the start of an unrelated donor (URD) search.\u003c/p\u003e\n\u003cp\u003e360 patients were registered and 309 analyzed. The median follow-up was 47 months (1-168). There was no difference in overall survival (OS) between the RD (n=124) and the Control (n=77) groups (p=0.50, 3-year OS RD: 0.41(95% CI; 0.32-0.50); Controls: 0.49 (95% CI; 0.37-0.59)). The main cause of death was relapse (67% RD; 88% Controls). Comparing URD-HCT (n=86) and Controls (n=20), the 3-year survival was 0.60 (95% CI 0.50-0.70) for URD-HCT and 0.37 (95% CI 0.13-0.62) in the Controls, respectively (p=.10). When analyzing transplanted patients (Part 2), the OS at 3-years was higher for URD-HCT than RD-HCT (0.67 (0.55-0.76) vs. 0.42 (0.26-0.57; p=.005). The risks for severe acute and extensive chronic GVHD were lower in the URD-HCT group.\u003c/p\u003e","manuscriptTitle":"Reduced Intensity transplantation vs chemotherapy. A prospective, pseudorandomized study in 50-70 year old AML patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-29 15:18:39","doi":"10.21203/rs.3.rs-4253193/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-06-10T11:36:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-06-02T18:38:08+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-05-22T07:23:46+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-05-06T06:48:02+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-04-22T05:41:22+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-04-20T20:18:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-12T09:55:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"Bone Marrow Transplantation","date":"2024-04-11T14:56:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-11T14:56:29+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"911f1b1f-8981-4605-aab8-34d406d248d6","owner":[],"postedDate":"April 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":30940324,"name":"Health sciences/Health care/Therapeutics/Stem-cell therapies"},{"id":30940325,"name":"Health sciences/Diseases/Haematological diseases/Haematological cancer/Leukaemia/Acute myeloid leukaemia"}],"tags":[],"updatedAt":"2024-09-03T07:10:42+00:00","versionOfRecord":{"articleIdentity":"rs-4253193","link":"https://doi.org/10.1038/s41409-024-02408-x","journal":{"identity":"bone-marrow-transplantation","isVorOnly":false,"title":"Bone Marrow Transplantation"},"publishedOn":"2024-09-02 04:00:00","publishedOnDateReadable":"September 2nd, 2024"},"versionCreatedAt":"2024-04-29 15:18:39","video":"","vorDoi":"10.1038/s41409-024-02408-x","vorDoiUrl":"https://doi.org/10.1038/s41409-024-02408-x","workflowStages":[]},"version":"v1","identity":"rs-4253193","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4253193","identity":"rs-4253193","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}