IMPACT OF CONDITIONING INTENSITY AND GENOMICS ON RELAPSE AFTER ALLOGENEIC TRANSPLANTATION FOR PATIENTS WITH MYELODYSPLASTIC SYNDROME

Myelodysplastic Syndrome (MDS) patients are at risk of relapse after allogeneic hematopoietic cell transplantation (alloHCT). The utility of ultra-deep genomic testing to predict, and the impact of conditioning intensity to prevent, MDS relapse are unknown. Targeted error-corrected DNA sequencing was performed on pre-conditioning blood samples from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0901 phase III randomized clinical trial which compared outcomes by alloHCT conditioning intensity in adult patients with less than 5% marrow myeloblasts and no leukemic myeloblasts in blood on morphological analysis at the time of pre-transplant assessment. Using a previously described set of 10 gene regions, 42% of patients had mutations detectable prior to randomization to reduced intensity or myeloablative conditioning. Testing positive was associated with increased rates of relapse and decreased overall survival. In those testing positive, relapse rates were higher and relapse-free survival was lower in reduced intensity versus myeloablative conditioning arms. Testing additional genes, including those associated with MDS, did not improve prognostication. This study provides evidence that post-transplant relapse rates in MDS patients are highest in those with pre-transplant genomic evidence of high-risk disease. In those testing positive, randomization to myeloablative conditioning lowered but did not eliminate relapse risk.

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Impact of Conditioning Intensity and Genomics on Relapse After Allogeneic Transplantation for Patients With Myelodysplastic Syndrome

JCO Precision Oncology ◽

10.1200/po.20.00355 ◽

2021 ◽

pp. 265-274

Author(s):

Laura W. Dillon ◽

Gege Gui ◽

Brent R. Logan ◽

Mingwei Fei ◽

Jack Ghannam ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Dna Sequencing ◽

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Phase Iii ◽

Random Assignment ◽

Conditioning Intensity ◽

Relapse Rates

PURPOSE Patients with myelodysplastic syndrome (MDS) are at risk of relapse after allogeneic hematopoietic cell transplantation. The utility of ultra-deep genomic testing to predict and the impact of conditioning intensity to prevent MDS relapse are unknown. METHODS Targeted error-corrected DNA sequencing was performed on preconditioning blood samples from patients with MDS (n = 48) from the Blood and Marrow Transplant Clinical Trials Network 0901 phase III randomized clinical trial, which compared outcomes by allogeneic hematopoietic cell transplantation conditioning intensity in adult patients with < 5% marrow myeloblasts and no leukemic myeloblasts in blood on morphological analysis at the time of pretransplant assessment. Clinical end points (53-month median follow-up) included transplant-related mortality (TRM), relapse, relapse-free survival (RFS), and overall survival (OS). Of the 48 patients examined, 14 experienced TRM, 23 are relapse-free, and 11 relapsed, of which 7 died. RESULTS Using a previously described set of 10 gene regions, 42% of patients (n = 20) had mutations detectable before random assignment to reduced intensity conditioning (RIC) or myeloablative conditioning (MAC). Testing positive was associated with increased rates of relapse (3-year relapse, 40% v 11%; P = .022) and decreased OS (3-year OS, 55% v 79%, P = .045). In those testing positive, relapse rates were higher (3-year relapse, 75% v 17%; P = .003) and RFS was lower (3-year RFS, 13% v 49%; P = .003) in RIC versus MAC arms. Testing additional genes, including those associated with MDS, did not improve prognostication. CONCLUSION This study provides evidence that targeted DNA sequencing in patients with MDS before transplant can identify those with highest post-transplant relapse rates. In those testing positive, random assignment to MAC lowered but did not eliminate relapse risk.

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CMV Reactivation is Associated with Reduced Relapse Risk, Better Disease-Free Survival and Expansion of Adaptive NK Cells after Reduced Intensity Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood.v124.21.668.668 ◽

2014 ◽

Vol 124 (21) ◽

pp. 668-668 ◽

Cited By ~ 2

Author(s):

Frank Cichocki ◽

Zachary B. Davis ◽

Todd E. DeFor ◽

Sarah A. Cooley ◽

Yenan T. Bryceson ◽

...

Keyword(s):

Nk Cells ◽

Board Of Directors ◽

Hematopoietic Cell Transplantation ◽

Nk Cell ◽

Myeloablative Conditioning ◽

Advisory Committees ◽

Relapse Risk ◽

Cmv Reactivation ◽

Relapse Rates ◽

Reduced Intensity

Abstract We have previously shown that while NK cells are the first lymphocyte reconstituting after allogeneic transplantation, these NK cells are immature and functionally hyporesponsive when exposed to tumor targets. Remarkably, this can be reversed by reactivation of human cytomegalovirus (CMV). A distinct population of natural killer (NK) cells with attributes of immunological memory arises specifically in response to acute CMV infection in healthy individuals or reactivation of latent CMV in hematopoietic cell transplantation (HCT) recipients. These adaptive NK cells are defined by expression of the activating receptor NKG2C and maturation marker CD57 and display a heightened capacity for inflammatory cytokine production and cytolysis in response to target cell recognition. Since the differentiation and maturation of NK cells is dependent upon interactions with cells of the myeloid lineage, including antigen-presenting cells, we hypothesized that the expansion of adaptive NK cells could influence relapse risk, particularly after a reduced intensity conditioning (RIC) regimen where residual host myeloid cells may intensify donor adaptive NK cell expansion in response to CMV reactivation after HCT. Thus, we analyzed 1-year relapse rates in 674 allogeneic HCT recipients at the University of Minnesota (470 umbilical cord blood (UCB) and 204 matched sibling donor (MSD)) between 2001-2013 with AML (n=313), ALL (n=187), MDS (n=85), CML (n=28), NHL (n=42), Hodgkins (n=14) and Multiple Myeloma (n=5) segregated by recipient CMV serostatus (270 seronegative and 404 seropositive). Within the CMV seropositive group, 190 individuals experienced CMV reactivation. We observed no association between CMV reactivation and 1-year relapse rates in recipients of myeloablative conditioning (n=366; 16% [10%-22%] for CMV seronegative vs. 18% [12-24%] for CMV seropositive without CMV reactivation vs. 15% [8%-22%] for CMV seropositive recipients with CMV reactivation). In marked contrast, CMV reactivation was associated with lower 1-year relapse rates following RIC (n=308; 35% [27%-43%] for CMV seronegative vs. 30% [20-40%] for CMV seropositive without CMV reactivation vs. 26% [17%-35%] for CMV seropositive with CMV reactivation [p for trend=0.05, Figure 1A]). In multivariate analyses adjusting for recipient CMV status, conditioning regimen, donor type (MSD vs. UCB), diagnosis (AML [shown to be sensitive to NK cell effects] vs. other), gender, disease risk (standard vs. high) and prior autologous transplant, CMV reactivation was independently associated with lower relapse risk (RR=0.6 [0.4-1.0], p=0.06) and increased DFS (RR=0.7 [0.5-1.0], p=0.05) following RIC, but not myeloablative HCT. Although CMV reactivation led to superior DFS within the entire cohort (RR=0.7 [0.6-1.0], p=0.04), CMV reactivation was not independently associated with lower relapse risk (RR=1.0 [0.5-1.8], p=0.88) with myeloablative conditioning. To determine whether the preparative regimen also influenced adaptive NK cell differentiation post-transplant, we analyzed the percentage of CD56dimCD57+NKG2C+ NK cells. Compared to myeloablative recipients, after RIC, the percentage of circulating CD56dimCD57+NKG2C+ NK cells was significantly higher at 4 weeks post-CMV reactivation (8.58% vs. 4.64%, p=0.02), 8 weeks post-CMV reactivation (7.77% vs. 3.84%, p=0.02), and 6 months post-transplant (14.80% vs. 6.29%, p=0.01) (Figure 1B). Our results demonstrate a relationship between CMV reactivation and enhanced graft-versus-leukemia (GVL) in patients treated with RIC. The association between lower relapse risk and in vivo expansion and survival of adaptive NK cells suggests that these cells may be critical to reducing the risk of relapse. Strategies to isolate and expand adaptive NK cells in order to enhance the GVL effect without clinical CMV reactivation are being actively explored. Figure 1 Figure 1. Disclosures Miller: Coronado: Speakers Bureau; BioSciences: Membership on an entity's Board of Directors or advisory committees; SAB: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Reduced-Intensity Conditioning Regimens for Hematologic Malignancies: What Have We Learned over the Last 10 Years?

Hematology ◽

10.1182/asheducation-2005.1.384 ◽

2005 ◽

Vol 2005 (1) ◽

pp. 384-389 ◽

Cited By ~ 21

Author(s):

Sergio Giralt

Keyword(s):

Older Patients ◽

Successful Outcome ◽

Low Grade ◽

Severe Toxicity ◽

Reduced Intensity Conditioning ◽

Myeloablative Conditioning ◽

Conditioning Regimens ◽

The Impact ◽

Relapse Rates ◽

Reduced Intensity

Abstract Reduced-intensity conditioning (RIC) regimens have been investigated for more than 10 years as an alternative to traditional myeloablative conditioning regimens. RIC regimens are being commonly used in older patients as well as in disorders in which traditional myeloablative conditioning regimens are associated with high rates of non-relapse mortality. Hodgkin disease, myeloma, and low-grade lymphoid malignancies have been the diseases most impacted by RIC regimens. RIC regimens have also been shown to be safe and effective in older patients as well as patients with co-morbidities, although patients with chemorefractory disease still have high relapse rates and poor outcomes. Patients with chemosensitive disease have outcomes similar to those obtained with conventional ablative therapies, and thus comparative trials are warranted. RIC regimens are associated with lower rates of severe toxicity and non-relapse mortality; however, infections, graft-versus-host disease, and relapse of primary disease remain the most common obstacles to a successful outcome. The impact on survival and the relative benefits of RIC allografting compared with traditional conditioning regimens or alternative therapy remain to be defined. Incorporating targeted therapies as part of the conditioning regimens or as maintenance therapies is currently being explored to reduce relapse rates without increasing toxicity.

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Effect of Age on Outcome of Reduced-Intensity Hematopoietic Cell Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission or With Myelodysplastic Syndrome

Journal of Clinical Oncology ◽

10.1200/jco.2009.25.4821 ◽

2010 ◽

Vol 28 (11) ◽

pp. 1878-1887 ◽

Cited By ~ 324

Author(s):

Brian L. McClune ◽

Daniel J. Weisdorf ◽

Tanya L. Pedersen ◽

Gisela Tunes da Silva ◽

Martin S. Tallman ◽

...

Keyword(s):

Complete Remission ◽

Myelodysplastic Syndrome ◽

Cell Transplantation ◽

Older Patients ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Myelogenous Leukemia ◽

The Impact ◽

First Complete Remission ◽

Reduced Intensity

PurposeAcute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) primarily afflict older individuals. Hematopoietic cell transplantation (HCT) is generally not offered because of concerns of excess morbidity and mortality. Reduced-intensity conditioning (RIC) regimens allow increased use of allogeneic HCT for older patients. To define prognostic factors impacting long-term outcomes of RIC regimens in patients older than age 40 years with AML in first complete remission or MDS and to determine the impact of age, we analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR).Patients and MethodsWe reviewed data reported to the CIBMTR (1995 to 2005) on 1,080 patients undergoing RIC HCT. Outcomes analyzed included neutrophil recovery, incidence of acute or chronic graft-versus-host disease (GVHD), nonrelapse mortality (NRM), relapse, disease-free survival (DFS), and overall survival (OS).ResultsUnivariate analyses demonstrated no age group differences in NRM, grade 2 to 4 acute GVHD, chronic GVHD, or relapse. Patients age 40 to 54, 55 to 59, 60 to 64, and ≥ 65 years had 2-year survival rates as follows: 44% (95% CI, 37% to 52%), 50% (95% CI, 41% to 59%), 34% (95% CI, 25% to 43%), and 36% (95% CI, 24% to 49%), respectively, for patients with AML (P = .06); and 42% (95% CI, 35% to 49%), 35% (95% CI, 27% to 43%), 45% (95% CI, 36% to 54%), and 38% (95% CI, 25% to 51%), respectively, for patients with MDS (P = .37). Multivariate analysis revealed no significant impact of age on NRM, relapse, DFS, or OS (all P > .3). Greater HLA disparity adversely affected 2-year NRM, DFS, and OS. Unfavorable cytogenetics adversely impacted relapse, DFS, and OS. Better pre-HCT performance status predicted improved 2-year OS.ConclusionWith these similar outcomes observed in older patients, we conclude that older age alone should not be considered a contraindication to HCT.

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Reduced Intensity Allogeneic Stem Cell Transplantation in Patients with Myelodysplastic Syndrome: Does the Conditioning Matter?.

Blood ◽

10.1182/blood.v110.11.4924.4924 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4924-4924

Author(s):

Louis Terriou ◽

Zina Chir ◽

Helene Esperou ◽

Jean-Michel Boiron ◽

Jean-Paul Vernant ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Chronic Gvhd ◽

Immunosuppressive Treatment ◽

Conditioning Regimen ◽

Progression Free Survival ◽

Allogeneic Transplantation ◽

Peripheral Blood Stem Cells ◽

Blood Stem Cells ◽

The Impact ◽

Reduced Intensity

Abstract Allogeneic transplantation following a reduced-intensity conditioning (RIC) has emerged as an alternative to myeloablative transplantation in pts with myelodysplastic syndrome (MDS). Given the uncertainty regarding the most appropriate conditioning regimen, SFGM-TC conducted a retrospective multicenter study in the attempt to evaluate the impact of conditioning on pts’ outcome. The record of 61 pts (37 males) with MDS who received a RIC were reviewed. The median age was 55 years (range: 18–70). According to the FAB classification, 11 pts had RA at diagnosis, of whom one had progressed to REAB and one to AML before transplantation. Thirty two pts had REAB at diagnosis, of whom 2 had progressed to REAB-T and 7 to AML before transplantation. Twelve pts had REAB-T at diagnosis and 6 CMML, of whom 8 progressed to AML before transplantation. The median time from diagnosis to RIC was 12 months (6–129). Conditioning consisted of Fludarabin (Flu) plus busulfan (FB; n=29), Flu plus 2-Gy TBI (F-TBI; n=20) and idarubicin plus aracytine and Flu (FlagIda; n=12). Donors were HLA-identical siblings (n=52) and HLA-matched unrelated (n=9). All pts received peripheral blood stem cells. The median of CD34+ infused cell dose was 5 x 106/kg (0.5–17.3). The median follow-up was 44.7 months (21–85). Estimated 3-year overall survival (OS), progression free survival (PFS), relapse and transplant-relapse mortality (TRM) were 35%, 27%, 66% and 30%, respectively. Neither of the 3 conditioning regimens used (FB, F-TBI and FlagIda) had impact on patients’ outcome. In multivariable analyses, while acute III/IV grade GVHD development was the only factor found to adversely influencing OS (HR=3.6; 95% CI: 1.1–12.2), chronic GVHD development was the only favourably influencing PFS and relapse ratios (HR=0.3; 95% CI: 0.1–0.7 and HR=0.2; 95% CI: 0.1–0.6, respectively). TRM was adversely influenced by male sex of recipient (HR=9.2; 95% CI: 1.5–66.6). RIC is an effective treatment in MDS patients irrespective of conditioning type. While acute III/IV grade GVHD appeared to be detrimental, the benefit effect of chronic GVHD was to be bound to GVL effect as demonstrated by the improvement of PFS and relapse rates in patients who developed chronic GVHD. This study shows no impact of conditioning in pts’ outcomes. New approaches with focus on immunosuppressive treatment are needed to enhance the GVL effect with an acceptable risk of GVHD.

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Risk factors for acute GVHD and survival after hematopoietic cell transplantation

Blood ◽

10.1182/blood-2011-06-364265 ◽

2012 ◽

Vol 119 (1) ◽

pp. 296-307 ◽

Cited By ~ 317

Author(s):

Madan Jagasia ◽

Mukta Arora ◽

Mary E. D. Flowers ◽

Nelson J. Chao ◽

Philip L. McCarthy ◽

...

Keyword(s):

Risk Factors ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Marrow Transplant ◽

Hematopoietic Cell ◽

Blood And Marrow Transplant ◽

Cell Transplants ◽

Total Body ◽

Conditioning Intensity ◽

The Impact

Abstract Risk factors for acute GVHD (AGVHD), overall survival, and transplant-related mortality were evaluated in adults receiving allogeneic hematopoietic cell transplants (1999-2005) from HLA-identical sibling donors (SDs; n = 3191) or unrelated donors (URDs; n = 2370) and reported to the Center for International Blood and Marrow Transplant Research, Minneapolis, MN. To understand the impact of transplant regimen on AGVHD risk, 6 treatment categories were evaluated: (1) myeloablative conditioning (MA) with total body irradiation (TBI) + PBSCs, (2) MA + TBI + BM, (3) MA + nonTBI + PBSCs, (4) MA + nonTBI + BM, (5) reduced intensity conditioning (RIC) + PBSCs, and (6) RIC + BM. The cumulative incidences of grades B-D AGVHD were 39% (95% confidence interval [CI], 37%-41%) in the SD cohort and 59% (95% CI, 57%-61%) in the URD cohort. Patients receiving SD transplants with MA + nonTBI + BM and RIC + PBSCs had significantly lower risks of grades B-D AGVHD than patients in other treatment categories. Those receiving URD transplants with MA + TBI + BM, MA + nonTBI + BM, RIC + BM, or RIC + PBSCs had lower risks of grades B-D AGVHD than those in other treatment categories. The 5-year probabilities of survival were 46% (95% CI, 44%-49%) with SD transplants and 33% (95% CI, 31%-35%) with URD transplants. Conditioning intensity, TBI and graft source have a combined effect on risk of AGVHD that must be considered in deciding on a treatment strategy for individual patients.

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Reduced-Intensity Conditioning Versus Myeloablative Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients with Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis of Randomized Trials

Blood ◽

10.1182/blood-2018-99-114452 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5770-5770

Author(s):

Ahmad Kamal ◽

Muhammad Abu Zar ◽

Hafiz Muhammad Fazeel ◽

Seren Durer ◽

Ceren Durer ◽

...

Keyword(s):

Systematic Review ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Meta Analysis ◽

P Value ◽

Reduced Intensity Conditioning ◽

Myeloablative Conditioning ◽

Conditioning Intensity ◽

Reduced Intensity ◽

Risk Of Relapse

Abstract Background: Allogenic hematopoietic cell transplantation (alloHCT) is a curative option for patients with high-risk myelodysplastic syndrome (MDS). The benefit of higher conditioning intensity in MDS is controversial. While myeloablative conditioning (MAC) regimens can mitigate the risk of relapse, they are associated with higher non-relapse mortality (NRM). In contrast, the reduced intensity conditioning (RIC) regimens are associated with higher risk of relapse. And owing to the lower NRM, they are feasible in patients with advanced age or comorbidities. Methods: We report here a systematic review and meta-analysis of randomized controlled trials (RCTs) that directly compared the safety and efficacy of MAC vs RIC regimens in MDS. The efficacy was evaluated in terms of overall survival (OS), relapse-free survival (RFS) and relapse incidence (RI). The safety was evaluated in terms of non-related mortality (NRM) and incidence of acute (a) and chronic (c) graft-versus-host disease (GVHD). A systematic search of databases using PubMed, Embase, Web of science, Cochrane database and Clinicaltrials.gov was performed on May 6th, 2018 with no restrictions of language or time period. RCTs comparing MAC with RIC regimens that include MDS patients were considered eligible for inclusion. After duplicates removal, a total of 683 articles were scrutinized for relevance by screening the abstracts and/or full length articles. Based on the eligibility criteria, only two randomized studies (BMT CTN 0901 Trial Scott, B. et al. 2017 & EBMT RICMAC Trial Kroger, N. et al. 2017) qualified for inclusion and quantitative synthesis. The quality assessment was done using the Cochrane tool regarding the bias in study selection, performance, detection, attrition and reporting of the clinical trials. Results: Out of total 392 MDS and acute myeloid leukemia (AML) patients enrolled in these two trial, 169 patients had MDS (N=115 in Kroger et al and N=54 cases in Scott et al). Eighty one patients received MAC and 88 patients received RIC followed by either a related or unrelated alloHCT. The median age range at the time of transplant was 50-54 years and these patients were followed for a period of 18-24 months. There were no statistically significant differences in the baseline patient characteristics between two regimen groups in the both trials. The use of RIC regimen was associated with a statistically non-significant trend towards improved OS (OR 1.52: 95% CI: 0.93-2.5, p-value= 0.097), along with a significantly reduced risk of NRM (OR 0.39: 95% CI: 0.16-0.94, p-value= 0.04). The RIC alloHCT was not associated with a higher risk of disease relapse (OR: 4.24, 95% CI: 0.34-52.22, p-value= 0.26) or inferior RFS (OR: 0.64, 95% CI: 0.196-2.06, p-value= 0.45). There was no difference between the two conditioning intensities in terms of risk of developing aGVHD (OR: 0.51, 95% CI: 0.11-2.27, p-value= 0.37) or cGVHD (OR: 0.50, 95% CI: 0.18-1.40, p-value= 0.19). The meta-analysis results are shown in figure-1. The Infectious complications were comparable for both groups in Scott, et al. But Kroger et al reported significantly lower overall infections rate at day 100 (4.3 vs. 6.9, p=0.002) and at total follow up (1.4 vs. 2.0, p= 0.002) for RIC. Conclusion: In adult patients with MDS undergoing alloHCT, RIC regimens were associated with a significantly lower risk of NRM, without increased risk of relapse, mortality or GVHD. It is unknown if any specific poor risk groups regarding clinical indicators (e.g. IPSS score) or genomic predictors (e.g. p53 mutations or RAS pathway mutations) may benefit from higher conditioning intensity and warrants further investigation. Disclosures Hamadani: Sanofi Genzyme: Research Funding, Speakers Bureau; ADC Therapeutics: Research Funding; Ostuka: Research Funding; Janssen: Consultancy; Merck: Research Funding; MedImmune: Consultancy, Research Funding; Cellerant: Consultancy; Celgene Corporation: Consultancy; Takeda: Research Funding.

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Results of a Phase III Randomized, Multi-Center Study of Allogeneic Stem Cell Transplantation after High Versus Reduced Intensity Conditioning in Patients with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML): Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0901

Blood ◽

10.1182/blood.v126.23.lba-8.lba-8 ◽

2015 ◽

Vol 126 (23) ◽

pp. LBA-8-LBA-8 ◽

Cited By ~ 44

Author(s):

Bart L Scott ◽

Marcelo C. Pasquini ◽

Brent Logan ◽

Juan Wu ◽

Steve Devine ◽

...

Keyword(s):

Overall Survival ◽

Cause Of Death ◽

Conflicts Of Interest ◽

Phase Iii ◽

Reduced Intensity Conditioning ◽

Significant Difference ◽

The Difference ◽

Conditioning Intensity ◽

Relapse Rates ◽

Reduced Intensity

Abstract Although reduced intensity conditioning (RIC) has a lower toxicity profile and lower treatment related mortality (TRM), retrospective analyses have shown higher relapse rates and similar overall survival (OS) when compared to myeloablative (MAC) regimens in patients with myeloid malignancies. The BMT CTN performed a phase III randomized trial to compare outcomes by conditioning intensity in patients with MDS (N=54) or AML (N=218) (18-65 years, HCT-specific comorbidity index score ≤ 4) who had < 5% marrow myeloblasts by morphology at time of pre-transplant assessment. The primary endpoint of the study was 18 month post-randomization overall survival (OS). Secondary endpoints included: relapse free survival (RFS), relapse rates, TRM, graft-versus-host disease (GVHD), and quality of life (QOL). The RIC regimens were fludarabine (120-180 mg/m2) with busulfan (≤ 8 mg/kg oral or IV equivalent) (Flu/Bu, N=110) or melphalan (< 150 mg/m2) (FM, N=27). The MAC regimens were busulfan (16 mg/kg oral or 12.8 mg/kg IV) with cyclophosphamide (120 mg/kg) (Bu/Cy, N=40); or fludarabine (120-180 mg/m2) (Bu/Flu, N=87); or, cyclophosphamide (120 mg/kg) and total body irradiation (1200-1420cGy) (CyTBI, N=8). The planned enrollment was 356 patients; however, accrual was stopped early due to a presumed benefit of MAC as assessed by an independent DSMB safety review. Among 272 patients enrolled, 135 received MAC and 137 received RIC regimens. Seven enrolled patients did not receive a transplant (RIC N=4, MAC N=3) mainly due to relapse. Most (80.3%) patients randomized to RIC received a busulfan-based regimen. At 18 months, OS for patients on the RIC arm was 67.7% (95%CI 59.1-74.8%) versus 77.4% (95%CI 69.3-83.6%) on the MAC arm, based on intention-to-treat analysis. Although survival was higher with MAC, the difference was not statistically significant (difference of 9.7%, 95% CI -0.9-20.3%, p=0.07). Grade II-IV acute GVHD through 100 days was 31.6% on the RIC arm versus 44.7% on the MAC arm, p=0.024. TRM on the RIC arm was 4.4% (95%CI 1.8-8.9%) versus 15.8% (95%CI 10.2-22.6%) on the MAC arm, p=0.02. Relapse on the RIC arm was 48.3% (95%CI 39.6-56.4%) versus 13.5% (95%CI 8.3-19.9%) on the MAC arm, p<0.01. RFS for patients on the RIC arm was 47.3% (95%CI 38.7-55.4%) versus 67.7% (95%CI 59.0-74.9%) on the MAC arm and the difference was statistically significant (difference of 20.4%, 95%CI 8.8-31.9%, p<0.01). Among patients randomized to RIC, 44 died; relapse was the primary cause of death (86.4%). Among patients randomized to MAC, 31 died; GVHD was the primary cause of death (51.6%) followed by relapse (32.2%). QOL was assessed as a secondary endpoint in this trial using FACT and SF36 tools. Better QOL was observed at day 100 and one year with RIC, particularly regarding physical components with fewer differences in mental and social components. This trial confirms that RIC results in higher relapse rates and lower TRM compared to MAC, with a statistically significant advantage in RFS for patients receiving MAC. The appropriate choice of conditioning intensity remains challenging with a necessity to balance the risk of relapse with TRM in individual patients; however the data from this trial support MAC as the standard of care for patients able to receive it. For patients who are not candidates for MAC, novel regimens, which incorporate enhanced anti-leukemia activity without increasing toxicity, are needed.Figure.OS and Relapse by Treatment ArmFigure. OS and Relapse by Treatment Arm Disclosures: No relevant conflicts of interest to declare.

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