scholarly journals The Sequential Flamsa-Bu Conditioning Regimen Does Not Improve Outcome in Patients Allografted for High Risk Acute Myeloid and Myelodysplasia Irrespective of Pre-Transplant MRD Status: Results of the UK NCRI Figaro Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2031-2031 ◽  
Author(s):  
Charles Craddock ◽  
Aimee E Jackson ◽  
Ram K Malladi ◽  
Maria H Gilleece ◽  
Andy Peniket ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Randomized Trial ◽  
Myeloid Leukemia ◽  
Conditioning Regimen ◽  
Disease Relapse ◽  
Transplant Outcome ◽  
Risk Of Disease ◽  
Acute Myeloid

INTRODUCTION: Allogeneic stem cell transplantation (allo-SCT) is an important curative strategy in adults with high risk acute myeloid leukemia (AML) and myelodysplasia (MDS). Disease relapse represents the major cause of treatment failure and whilst retrospective analyses have identified that pre-transplant measurable residual disease (MRD) is an important predictor of transplant outcome this has never been examined prospectively. The advent of reduced intensity conditioning (RIC) regimens has substantially increased the number of older adults eligible for allo-SCT but the optimal RIC regimen in high risk AML remains unknown. Registry data have demonstrated improved outcomes using a sequential transplant regimen utilizing cytosine arabinoside (araC)/amsacrine (AMSA) cytoreduction followed by a fludarabine (Flu)/busulfan (Bu) based RIC regimen (FLAMSA-Bu). However, although the FLAMSA-Bu regimen is now widely used in adults with high risk AML and MDS its benefit has not been evaluated in a randomized trial. We report the results of a randomized trial evaluating the FLAMSA-Bu regimen compared with standard RIC regimens which also represents the first prospective evaluation of the impact of pre-transplant MRD levels on transplant outcome. PATIENTS AND METHODS: 244 patients (median age 59 yrs) with high risk AML (n=164) or high risk myelodysplasia (n=80) were randomized 1:1 to a control arm determined by investigator's choice of either Flu/B2/ATG (Flu, Bu 3.2 mg/kg x 2 days, ATG 2.5 mg/kg x 2 days); Flu/Mel/Alemtuzumab (A) (Flu, Mel 140 mg/m2, A 50 mg) or Flu/Bu2/A (Flu, Bu 3.2 mg/kg x 2 days, A 50 mg) versus an experimental arm of FLAMSA-Bu (Flu, araC 2g/m2 x 4 days, AMSA 100mg/m2 x 4 days, Bu -total dose 11.2 mg/kg). Patients over the age of 60 received an adjusted FLAMSA-Bu regimen utilising a reduced dose of araC (1mg/m2 x 4 days) and a total Bu dose of 6.4 mg/kg. Patients were transplanted using either an HLA identical sibling (n=49) or matched (10/10 or 9/10) unrelated donor (n=195). All patients received cyclosporine GVHD prophylaxis. 155 patients with AML were in CR1 or CR2 at the time of transplant and 9 had primary refractory disease. MRD was monitored by flow cytometry (applying different-from-normal analysis when no diagnostic/relapse leukemic aberrant immunophenotype was available). Pre-transplant MRD levels were measured up to four weeks prior to transplantation in 201 patients (MRD positive = 80 (40%), MRD negative = 94 (47%), inadequate sample = 27 (13%)). MRD results were not reported to clinicians. The primary outcome was overall survival. RESULTS: Baseline characteristics including CR1/CR2 status, adverse cytogenetics and MRD levels were similar between regimens. Median follow up was 35 months. Transplant outcomes were comparable between patients allografted in the control and FLAMSA-Bu arms. 2 yr overall survival (OS) and cumulative incidence of relapse (CIR) were 61% and 30% respectively in the control arm vs 62% and 26% for the FLAMSA-Bu arm. Transplant related mortality at 100 days was 3.0% in patients allografted using the control regimen vs 14% in patients allografted using the FLAMSA-Bu regimen and 17% vs 21% at 1 year. In the study cohort pre-transplant MRD positivity was associated with both an increased CIR compared to patients testing MRD negative (2 yr CIR 42% vs 19%, p=0.009) and decreased OS (2 yr OS 52% vs 71%, p=0.048). The FLAMSA-Bu regimen failed to improve OS or reduce CIR in either MRD positive or MRD negative patients. CONCLUSIONS: This trial, the largest randomized trial of RIC regimens in AML to date, did not detect any benefit of intensification of the conditioning regimen in adults with high risk AML or MDS. Specifically, the FLAMSA-Bu regimen was not associated with improved transplant outcome in patients who were MRD positive pre-transplant. These data include the first demonstration in a prospective analysis that the presence of pre-transplant MRD measured in real time is associated with reduced OS consequent upon an increased risk of disease relapse. Further randomized studies of novel conditioning regimens in adult AML, crucially with integrated MRD studies, are now required but these results support exploration of alternative strategies, such as pre or post-transplant pharmacological intervention, as the most promising strategy to reduce the risk of disease relapse post allograft. Disclosures Russell: Jazz: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau. Freeman:Jazz Pharmaceuticals: Speakers Bureau. OffLabel Disclosure: We report data using the combination of fludarabine, busulphan, amsacrine and cytosine arabinsoide as a conditioning regimen in patients allografted for high risk acute myeloid leukemia

scholarly journals Augmented Reduced-Intensity Regimen Does Not Improve Postallogeneic Transplant Outcomes in Acute Myeloid Leukemia

2020 ◽  
pp. JCO.20.02308
Author(s):  
Charles Craddock ◽  
Aimee Jackson ◽  
Justin Loke ◽  
Shamyla Siddique ◽  
Andrea Hodgkinson ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Conditioning Regimen ◽  
Hazard Ratio ◽  
Prognostic Impact ◽  
Reduced Intensity ◽  
Acute Myeloid

PURPOSE Reduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials. PATIENTS AND METHODS Two hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome. RESULTS There was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival. CONCLUSION The intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.

scholarly journals Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse

Blood ◽  
2011 ◽  
Vol 117 (12) ◽  
pp. 3294-3301 ◽  
Author(s):  
Mark Levis ◽  
Farhad Ravandi ◽  
Eunice S. Wang ◽  
Maria R. Baer ◽  
Alexander Perl ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Randomized Trial ◽  
Myeloid Leukemia ◽  
Remission Rate ◽  
Platelet Recovery ◽  
First Relapse ◽  
Acute Myeloid

AbstractIn a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20μM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.

A Risk Score Combined Clinical and Molecular Profiles Identifies a High-Risk Subgroup within AML1-ETO-Positive Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-19
Author(s):  
Min Yang ◽  
Yi Zhang ◽  
Jinghan Wang ◽  
Lixia Liu ◽  
Chengcheng Wang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Risk Score ◽  
Myeloid Leukemia ◽  
Validation Cohort ◽  
Concordance Index ◽  
Scoring Model ◽  
Mutation Burden ◽  
Acute Myeloid

Background: AML1-ETO-positive acute myeloid leukemia, is classified as a favorable leukemia subtype according to the European Leukemia Net (ELN) risk stratification. Nevertheless, studies show the biology and prognosis within the AML1-ETO-positive AML are highly different, which suggests that more prognostic factors are needed to be identified. Aims: This study mainly revealed the genomic mutation characteristics and explored more factors which affect the prognosis of Chinese AML1-ETO-positive AML patients. Methods: A total of 167 AML1-ETO-positive patients who diagnosed and treated in Zhejiang Institute of Hematology had cryopreserved DNA for deep target 185-gene regional sequencing. Variants were detected with a variant allele frequency (VAF) cutoff of 0.5%. We used a LASSO Cox regression model to build risk score for predicting overall survival. A nomogram was constructed to display the risk of death in individuals. The discrimination of the risk score was measured by the concordance index (C-index) and areas under time-dependent receiver-operating characteristics (ROC) curves (AUCs), and the calibration of the risk score was explored graphically by calibration plots. Patients (n=75) from other hospital were used as a validation cohort. Results: The median age in analyzed patients was 42(6-78) years. The most common recurrent mutations occurred in KIT(n=84,50%), ASXL2(n=46,28%), NRAS(n=37,22%), FLT3-ITD(n=35,21%) and TET2(n=30,18%). We observed that high KIT mutant allele burden predicts for poor outcome in t(8:21) AML. High KIT VAF(≥15%) correlated with shortened overall survival compared to the other KIT mutated cases including low VAF and wild-type KIT (3-year OS 26.6% vs 59.0% vs 69.6%, HR 1.50, 95%CI 0.78-2.89, P=0.0005). In addition, we also identified some other mutated genes influence the prognosis of patients with t (8;21), such as FLT3-ITD high mutation burden(VAF≥44% vs other cases, 3-year OS 30.0% vs 56.2%, HR 2.94, 95%CI 0.43-20.18, P=0.056), TET2 high mutation burden (VAF≥43% vs other cases, 3-year OS 33.3% vs 56.5%, HR 2.87, 95%CI 0.66-12.46, P=0.018) and DHX15 high mutation burden (VAF≥22% vs other cases, 3-year OS 15.0% vs 58.3%, HR 2.65, 95%CI 0.81-8.73, P=0.011). In univariate analyses for OS, age>42 (3-year OS 46.3% vs 64.4%, HR 1.91, 95%CI 1.14-3.14, P=0.012), WBC>27.1×109/L(3-year OS 34.3% vs 60.0%, HR 2.59, 95%CI 1.13-5.9, P=0.001), BM blast>20% (3-year OS 52.2% vs 92.8%, HR 6.36, 95%CI 2.7-14.97, P =0.035), LDH > 504U/L (3-year OS 44.1% vs 67.1%, HR 2.62, 95%CI 1.50-4.59, P=0.0007), PLT≤28×109/L (3-year OS 47.1% vs 66.9%, HR 1.89, 95%CI 1.13-3.17, P=0.019), HB≤87g/L (3-year OS 49.4% vs 73.8%, HR 2.20, 95%CI 1.27-3.84, P=0.019) were significantly associated with poor OS. Six variables were incorporated in our scoring model by LASSO, including age, WBC, PLT, KIT mutation, FLT3-ITD mutation and TET2 mutation. A risk scoring model was developed incorporating the weighted coefficients of these variables. The risk score grouped AML1-ETO AML patients into two subgroup: low risk (LR, n=68) and high risk (HR, n=86) groups. The 3-year OS for LR and HR groups were 72.7% and 43.0% (P<0.0001, Figure A). The similar results were also observed in validation cohort (3-year OS 79.1% vs 49.5%, P= 0.01; Figure B). Concordance index [train: 0.708, 95% CI (0.680, 0.736), validation: 0.722, 95% CI (0.666, 0.778)] demonstrated well discrimination power and calibration plots showed that the nomograms did well compared with an ideal model. Conclusion: In this study, our findings indicate that the prognostic effect of gene mutation in de novo t(8:21) AML may be influenced by the relative abundance of the mutated allele. A novel scoring model was developed and validated that incorporated molecular and clinical profiles. According to our score model, AML1-ETO AML patients could be further stratified into two subgroups with distinct clinical outcomes. Our data can serve as a basis for guided and risk-adapted treatment strategies for CBF-AML patients. The results are needed to be validated in other independent cohorts and prospective studies before implementation into clinics. Disclosures No relevant conflicts of interest to declare.

Twice Daily Fludarabine and Cytarabine Combination Is Effective in Patients with Relapsed/Refractory Acute Myeloid Leukemia, High-Risk Myelodysplastic Syndromes, and Blast Phase Chronic Myeloid Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3629-3629
Author(s):  
Naval Daver ◽  
Hagop M. Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Jorge E. Cortes ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Chronic Myeloid Leukemia ◽  
Complete Remission ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Abnormal Karyotype ◽  
Blast Phase ◽  
Acute Myeloid

Abstract Abstract 3629 Background: High dose cytarabine containing regimens are still considered standard options for patients (pts) with AML relapsing after a first CR lasting more than 12 months. In a phase I study, 65 patients received fludarabine 15 mg/m2 every 12 hours and cytarabine 0.5 g/m2. Five days of administration were found to be safe and effective with a CR rate of 28%. Aim: This phase II study was conducted to evaluate the efficacy and safety of the combination of twice daily fludarabine and cytarabine (BIDFA) in patients with refractory/relapsed (R/R) acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), and chronic myeloid leukemia in myeloid blast phase (CML-BP). Methods: Pts with R/R AML, intermediate-2 and high-risk MDS, and CML-BP, whose disease relapsed or was refractory to frontline and/or salvage therapy were eligible. Pts with performance status 0–3 and adequate organ function, received fludarabine 15 mg/m2 intravenously (IV) q12 hours on Days 1 to 5 and cytarabine 0.5 g/m2 IV over 2 hours q12 hours on Days 1 to 5. Gentuzumab ozogamycin (GO) was administered at 3 mg/m2 IV on day 1 in the first 59 pts. Pts with CML-BP were allowed to receive concomitant tyrosine kinase inhibitors. Results: 107 pts were enrolled. The median age was 62 years (range, 19 to 85). 93 pts had AML, 5 had high-risk MDS, and 9 had CML-BP. All pts had received prior therapy. 65 (61%) pts had failed previous intensive chemotherapy, while 42 (39%) had failed targeted and hypomethylating agents. Cytogenetics analysis showed diploid karyotype in 36 (33%) and unfavorable chromosomal abnormalities involving chromosome 5 and 7 in 22 (21%). Of the 107 pts, 52 were in first salvage: first CR duration of less than 12 months in 43 (40%) pts, and more than 12 months in 9 (9%). Overall, 22 pts (21%) achieved complete remission (CR) and 5 (5%) achieved a complete remission without platelet recovery (CRp), for an overall response rate (ORR) of 26% (Table 1). The CR rates for patients with relapsed AML with first CR duration (CRD1) ≥12 months, relapsed AML with CRD1< 12 months, and R/R AML beyond first salvage were 56%, 26%, and 11%, respectively. These compare favorably with the expected response rates in matched cohorts treated at our institution where the ORR were 50%, 11%, and 7%, respectively. A multivariate analysis identified the following 3 factors to be independent adverse prognostic factors for response: abnormal karyotype (versus diploid), second salvage (versus first salvage regardless of the duration of the first CR), and older age (Table 2). With a median follow-up of 7 months, the 6-month event-free survival, overall survival, and complete remission duration (CRD) rates were 18%, 35%, and 70%, respectively. Abnormal karyotype, older age, an increasing in the peripheral blood blasts percentage, and low platelets count (<30 × 109/L) were independently associated with a significant worse overall survival. The most common side effects observed were gastro-intestinal toxicities, including nausea, vomiting, diarrhea, and mucositis. The overall 4-week mortality rate was 9%. Conclusion: BIDFA is active with an ORR of 26% in a heavily pre- treated population. This combination is safe with a low rate of 4-week-mortality of 9%. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Comparison of FLU-BU12 Conditioning with the Standard BU-CY Myeloablative Regimen in High-Risk Pediatric ACUTE Myeloid Leukemia Patients Undergoing Allogeneic STEM Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 30-31
Author(s):  
Olesia V Paina ◽  
Zhemal Zarifovna Rakhmanova ◽  
Polina Valerievna Kozhokar ◽  
Anastasia S Frolova ◽  
Liubov A. Tsvetkova ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Conditioning Regimens ◽  
Acute Myeloid

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for high-risk acute myeloid leukemia (AML).The preparative regimen consisting of busulfan and cyclophosphamide (BuCy) is considered as one of the classical myeloablative conditioning regimens (MAC); however, it is associated with significant early and long-term toxicities, leading to a high rate of transplant-related mortality (TRM). P urpose: To compare toxicities and outcomes of BuCy and FluBu12 conditioning in the pediatric population. Methods: We retrospectively analyzed 71 pediatric high-risk AML patients in CR1/2 (n=51, 71,8%) and R/R disease (n=20, 28,2%) received allo-HSCT from MSD (n=16, 22,5%), MUD (n=43, 60,6%) and Haplo donor (n=12, 16,9%). BuCy and FluBu conditioning regimens were used in 47 (66,2%) and 24 (33,8%) patients respectively. Median age was 6 years (0-17). GVHD prophylaxis was PTCy±CNI±m-TOR inhibitor in 32 (45%) or ATG±CNI in 39 (55%) patients. The primary end points were TRM, relapse-free survival (RFS), graft-versus-host disease (GVHD) free, relapse free survival (GRFS) and overall survival (OS). Secondary end points included neutrophil engraftment, sinusoidal obstruction syndrome (SOS), acute and chronic GVHD. Patient were censored at the time of death or last follow-up. Probabilities of OS, RFS and GRFS were estimated using Kaplan-Meier curves. TRM was defined as any death that occurred in the absence of disease relapse; relapse was a competing risk for this event. Results: Engraftment rate was 91% and 87,5% in patients received BuCy and FluBu, respectively (p=0,4). There was a trend to lower day 100 TRM after FluBu (4,1% vs 14,9% after BuCy, p=0,07). Overall survival at 2 years did not differ as well (BuCy 48,9%, FluBu 56%, p=0,5). BuCy showed borderline higher RFS at 2 years (70,2% vs 52%, p=0,06). The composite endpoint GRFS did not differ between two study cohorts being 31,8% and 29,2% at 2 years for BuCy and FluBu (p=0,7). We observed a tendency towards a higher incidence of III0-IV0 aGVHD and cGVHD following BuCy when compared with FluBu: 57,1% vs 41% (p=0,06) and 46,5% vs 28,5% respectively (p=0,2). No significant differences were found between the BuCy and FluBu groups in risk of SOS (6% and 8%, respectively). Conclusions: The optimal conditioning regimen for children with AML is still a matter of debate. Our results suggest that FluBu represents a valid myeloablative regimen, able to provide lower TRM, aGVHD and cGVHD. This conditioning might become an alternative approach in patients with a high risk of severe post-transplant complications. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of Adding Melphalan to Fludarabine and a Myeloablative Dose of Intravenous Busulfan for Patients Who Received Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 254-254
Author(s):  
Yoshimitsu Shimomura ◽  
Masahiko Hara ◽  
Hisashi Yamamoto ◽  
Tatsuo Ichinohe ◽  
Takahiro Fukuda ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Propensity Score ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Allogeneic Hsct ◽  
High Risk Disease ◽  
Standard Risk ◽  
Acute Myeloid

Introduction Fludarabine and a myeloablative dose of intravenous busulfan with or without total body irradiation (Flu/Bu4) is a widely accepted myeloablative conditioning regimen with reduced toxicity for allogeneic hematopoietic stem cell transplantation (HSCT) that has been able to expand the indications for allogeneic HSCT while maintaining the intensity. However, relapse is a major concern especially in patients with high-risk hematological malignancies. Accordingly, a novel conditioning regimen that included Flu/Bu4 plus melphalan (Flu/Bu4/Mel) was used, with excellent outcomes, i.e., the 2-year overall survival (OS) was 54.9% in patients with non-remission acute myeloid leukemia. However, no study has compared Flu/Bu4/Mel and other conditioning regimens. Therefore, this multicenter retrospective observational study aimed to investigate the impact of adding melphalan to Flu/Bu4 by comparing patients who received Flu/Bu4/Mel and those who received Flu/Bu4. Methods The present study included 2394 adult patients who received Flu/Bu4/Mel (n=581) or Flu/Bu4 (n=1813) between January 2010 and December 2016 at the Japan Society of Hematopoietic Cell Transplantation. High-risk disease was defined as incomplete remission in patients with acute myeloid leukemia and acute lymphoblastic leukemia as well as refractory anemia with excess blast transformation in patients with myelodysplastic syndrome; standard risk disease was defined as stable disease or disease progression in patients with malignant lymphoma before HSCT. We set the primary endpoint as the 5-year OS, evaluated by using the log-rank test. To compare the impact of the conditioning regimen on the primary endpoint, we used a multivariable Cox proportional hazards model. The following adjusted covariates were selected clinically based on previous studies: age, sex, disease, disease status at HSCT, hematopoietic cell transplant comorbidity index (HCT-CI), donor source, acute graft versus host disease prophylaxis, and years of HSCT. In addition, we performed propensity score matched analysis to minimize the potential treatment selection bias because the baseline characteristics of patients and disease could have influenced the selection of the conditioning regimen. Propensity score matching with a 1:1 ratio was performed by using the nearest neighbor-matching method with a caliper width fixed at 0.01. In addition, detailed analysis was performed by dividing patients into the high-risk and standard risk groups because the initial single-center retrospective studies mainly enrolled patients with high-risk disease. Results A total of 2394 patients were enrolled and analyzed: 581 patients received Flu/Bu4/Mel and 1813 patients received Flu/Bu4. The median age was 60 years (interquartile range, 53-63 years) and 1489 patients (62.2%) were men. The clinical characteristics of patients treated with Flu/Bu4/Mel and those treated with Flu/Bu4 were different. The Flu/Bu4/Mel group included more patients who were young, had acute myeloid leukemia and malignant lymphoma, had high-risk disease, had higher HCT-CI, received cord blood transplantation, received tacrolimus-based acute graft versus host disease prophylaxis, and had undergone transplantation recently. Regarding the primary endpoint, the 5-year OS after allogeneic HSCT was 33.7% (95% confidence interval [CI]: 27.5-40.1%) in the Flu/Bu4/Mel group vs 35.4% (95% CI: 32.7-38.1%) in the Flu/Bu4 group (p=0.794). The adjusted hazard ratio was 0.73 (95% CI: 0.62-0.85) for the Flu/Bu4/Mel group compared to the Flu/Bu4 group (p&lt;0.001). After propensity score matching, the 5-year OS after allogeneic HSCT was 35.1% (95% CI: 28.0-42.2%) in the Flu/Bu4/Mel group vs 28.1% (95% CI: 22.4-34.0%) in the Flu/Bu4 group (p=0.008; Figure). On detailed subgroup analysis, among patients with high-risk disease, the 5-year OS was 29.5% (95% CI: 23.0-36.4%) in the Flu/Bu4/Mel group vs 20.8% (95% CI: 17.3-24.6%) in the Flu/Bu4 group (p&lt;0.001), while among standard-risk patients, it was 46.3% (95% CI: 35.6-56.2%) in the Flu/Bu4/Mel group vs 43.8% (95% CI: 40.3-47.4%) in the Flu/Bu4 group (p=0.745; P for interaction: 0.010). Conclusion The results showed that Flu/Bu4/Mel resulted in superior 5-year OS compared to Flu/Bu4, with an adjusted hazard ratio of 0.73. In addition, patients with high-risk disease showed better survival benefit with Flu/Bu4/Mel treatment. Figure Disclosures Ichinohe: Astellas Pharma: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria.

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