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Impact of reduced-intensity conditioning regimens on outcomes in diffuse large B-cell lymphoma undergoing allogeneic transplantation
Epperla, N., Ahn, K. W., Khanal, M., Litovich, C., Ahmed, S., Ghosh, N., Fenske, T. S., Kharfan-Dabaja, M. A., Sureda, A., Hamadani, M.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
BACKGROUND Reduced-intensity conditioning (RIC) regimens are frequently used for allogeneic hematopoietic cell transplantation (allo-HCT) in diffuse large B-cell lymphoma (DLBCL). However, the RIC regimen with the best risk/benefit profile for allo-HCT in DLBCL is not known. This is particularly important, as patients with DLBCL undergoing allo-HCT in the future would be enriched for those whose lymphoma has failed chimeric antigen receptor T-cell (CAR-T) therapy or other novel immunotherapies, with potentially more advanced disease and suboptimal performance scores. Using the CIBMTR database, we report the outcomes of the three most commonly used allo-HCT RIC regimens in DLBCL. METHODS 562 adult DLBCL patients in the CIBMTR registry undergoing allo-HCT using matched related or unrelated donors, between 2008-2016 were included in the analysis. Patients received one of the three RIC regimens: fludarabine/i.v. busulfan (~6•4mg/kg) (Flu/Bu), fludarabine/melphalan (140mg/m(2)) (Flu/Mel140) or BCNU/etoposide/cytarabine/melphalan (BEAM). FINDINGS The study cohort was divided into three groups: Flu/Bu (n=151), Flu/Mel140 (n=296) and BEAM (n=115). Relative to Flu/Bu, the Flu/Mel140 (HR=2.33, 95%CI=1.42-3.82; p=0.001) and BEAM (HR=2.54, 95%CI=1.34-4.80; p=0.004) regimens were associated with a higher non-relapse mortality (NRM) risk. Although the risk of relapse with Flu/Mel140 was lower compared to Flu/Bu (HR=0.70, 95%CI=0.52-0.95; p=0.02), this did not translate in an improvement in progression-free (HR=1.04) or overall survival (HR=1.30). There was a significantly higher risk of grade 3-4 acute graft-versus-host disease with BEAM (HR=2.19, 95%CI=1.10-4.35; p=0.03) compared to Flu/Bu. In the chemosensitive subset, multivariate analysis showed a significantly higher mortality risk with Flu/Mel140 (HR=1.48, 95%CI=1.07-2.04, p=0.02) relative to Flu/Bu conditioning. CONCLUSIONS In the largest analysis comparing the impact of various RIC conditioning regimens on the survival of DLBCL patients undergoing allo-HCT, our results suggest that Flu/Bu is a better RIC choice in less fit or heavily pretreated patients due to lowest NRM risk.
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Outcomes of Rituximab-BEAM Versus BEAM Conditioning Regimen in Patients With Diffuse Large B Cell Lymphoma Undergoing Autologous Transplantation
Jagadeesh, D., Majhail, N. S., He, Y., Ahn, K. W., Litovich, C., Ahmed, S., Aljurf, M., Bacher, U., Badawy, S. M., Bejanyan, N., et al
Cancer. 2020
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Editor's Choice
Abstract
BACKGROUND Although rituximab-based high-dose therapy is frequently used in diffuse large B cell lymphoma (DLBCL) patients undergoing autologous hematopoietic cell transplantation (auto-HCT), data supporting the benefits are not available. Herein, we report the impact of rituximab-based conditioning on auto-HCT outcomes in patients who have DLBCL. METHODS Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, 862 adult DLBCL patients undergoing auto-HCT between 2003 and 2017 using BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning regimen were included. All patients received frontline rituximab-containing chemoimmunotherapy and had chemosensitive disease pre-HCT. Early chemoimmunotherapy failure was defined as not achieving complete remission (CR) after frontline chemoimmunotherapy or relapse within 1 year of initial diagnosis. The primary outcome was overall survival (OS). RESULTS The study cohort was divided into 2 groups: BEAM (n = 667) and R-BEAM (n = 195). On multivariate analysis, no significant difference was seen in OS (P = .83) or progression-free survival (PFS) (P = .61) across the 2 cohorts. No significant association between the use of rituximab and risk of relapse (P = .15) or nonrelapse mortality (P = .12) was observed. Variables independently associated with lower OS included older age at auto-HCT (P < .001), absence of CR at auto-HCT (P < .001) and early chemoimmunotherapy failure (P < .001). Older age (P < .0002) and non-CR pre-HCT (P < .0001) were also associated with inferior PFS. There was no significant difference in early infectious complications between the 2 cohorts. CONCLUSION In this large registry analysis of DLBCL patients undergoing auto-HCT, the addition of rituximab to the BEAM conditioning regimen had no impact on transplantation outcomes. Older age, absence of CR pre auto-HCT, and early chemoimmunotherapy failure were associated with inferior survival.
PICO Summary
Population
Adult DLBCL patients undergoing auto-HCT between 2003 and 2017 (n=862)
Intervention
BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning with Rituximab (R-BEAM, n=195)
Comparison
BEAM conditioning without Rituximab (BEAM, n=667)
Outcome
On multivariate analysis, no significant difference was seen in OS or progression-free survival (PFS) across the 2 cohorts. No significant association between the use of rituximab and risk of relapse or nonrelapse mortality was observed. There was no significant difference in early infectious complications between the 2 cohorts.
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Higher total body irradiation dose-intensity in fludarabine/TBI-based reduced-intensity conditioning regimen is associated with inferior survival in non-Hodgkin lymphoma patients undergoing allogeneic transplantation: Flu/2Gy TBI vs Flu/4Gy TBI in NHL
Hamadani, M., Khanal, M., Ahn, K. W., Litovich, C., Chow, V. A., Eghtedar, A., Karmali, R., Winter, A., Fenske, T. S., Sauter, C., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
INTRODUCTION Disease relapse is the most common cause of therapy failure in non-Hodgkin lymphoma (NHL) patients undergoing reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT). It is not known whether or not increasing total body irradiation (TBI) dose from 2Gy to 4Gy in RIC-platform can provide improved disease control without increasing non-relapse mortality (NRM). Using the CIBMTR database we evaluated the outcomes of NHL patients receiving RIC alloHCT with either fludarabine (Flu)/2Gy TBI vs. Flu/4Gy TBI. METHODS In the CIBMTR registry, 413 adult NHL patients underwent a first alloHCT using either a matched related or unrelated donor between 2008-2017, utilizing a RIC regimen with either Flu/2Gy TBI (n=349) or Flu/4Gy TBI (n=64). The primary endpoint was overall survival (OS). Secondary endpoints included acute (a) and chronic (c) graft-versus-host disease (GVHD), NRM, relapse/progression and progression-free survival (PFS). RESULTS At baseline the Flu/2Gy TBI cohort had significantly fewer patients with KPS ≥90 and significantly more patients had a higher HCT-CI. On multivariate analysis the two conditioning cohorts were not significantly different in terms of risk of grade 3-4 aGVHD or cGVHD. Compared to Flu/2Gy TBI, the Flu/4Gy TBI conditioning was associated with a significantly higher risk of NRM (HR 1.79, 95%CI=1.11-2.89, p=0.02), and inferior OS (HR 1.51, 95%CI=1.03-2.23, p=0.03). No significant differences were seen in the risk of relapse/progression (HR 0.78, 95%CI=0.47-1.29, p=0.33) or PFS (HR 1.09, 95%CI=0.78-1.54, p=0.61) between the two regimens. Comparing Flu/2Gy TBI vs. Flu/4Gy TBI cohorts the 5-year adjusted outcomes were; NRM (28% vs. 47%; p=0.005), relapse/progression (35% vs. 29%; p=0.28), PFS (37% vs. 24%; p=0.03) and OS (51% vs. 31%; p=0.001), respectively. Relapse was the most common cause of death in both cohorts. CONCLUSIONS In NHL patients undergoing Flu/TBI-based conditioning, augmenting TBI dose from 2Gy to 4Gy is associated with higher NRM and inferior OS, without any significant benefit in terms of disease control. 2Gy is optimal dose in the RIC Flu/TBI platform for lymphomas.
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Is Autologous Transplant in Relapsed DLBCL Patients Achieving Only a PET+ PR Appropriate in the CAR-T cell Era?
Shah, N. N., Ahn, K. W., Litovich, C. A., He, Y., Sauter, C. S., Fenske, T. S., Hamadani, M.
Blood. 2020
Abstract
For relapsed, chemosensitive diffuse large B-cell lymphoma (DLBCL) consolidation with autologous hematopoietic cell transplantation (auto-HCT) is a standard option. Since the approval of anti-CD19 CAR T-cells in 2017, the Center for International Blood and Marrow Transplant Research (CIBMTR) reported a 45% decrease in the number of auto-HCT for DLBCL in the U.S. in 2018. Using the CIBMTR database, we report outcomes for auto-HCT in relapsed chemosensitive DLBCL in a partial response (PR). 249 relapsed DLBCL patients undergoing auto-HCT from 2003-13 with a PET/CT+ PR prior to transplant were identified. The study cohort was divided into two groups: (a) early chemo-immunotherapy failure (ECF) defined as patients with primary refractory disease (PRefD) or relapse within 12 months of diagnosis, (b) late chemoimmunotherapy failure defined as patients relapsing ≥12 months. Primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS) and relapse. 182 patients had ECF and 67 were no ECF. ECF patients were younger (57 versus (vs) 63 years, p<0.01) and 79% of had PRefD. The adjusted 5-year probabilities for PFS and OS (ECF vs no ECF) was not different: 41% vs 41% (p=0.93) and 51% vs 63% (p=0.09), respectively. On multivariate analysis, ECF patients had increased risk of death (HR=1.61, 95%CI 1.05-2.46, p=0.03) but no increased risk in PFS or relapse. In conclusion, for relapsed, chemosensitive DLBCL patients with residual PET/CT+ disease prior to auto-HCT, the adjusted 5-year PFS (41%) was comparable irrespective of time to relapse. These data support ongoing application of auto-HCT in chemosensitive DLBCL.
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Factors Associated With Unplanned 30-Day Readmissions After Hematopoietic Cell Transplantation Among US Hospitals
Dhakal, B., Giri, S., Levin, A., Rein, L., Fenske, T. S., Chhabra, S., Shah, N. N., Szabo, A., D'Souza, A., Pasquini, M., et al
JAMA network open. 2019;2(7):e196476
Abstract
Importance: Hematopoietic cell transplantation (HCT) is a therapeutic strategy in the management of several hematological cancers. Limited data exist on the incidence and predictors of 30-day readmission after HCT. Objective: To measure the incidence of and risk factors associated with 30-day readmission following HCT in the United States. Design, Setting, and Participants: This cohort study examined patient data from the US population-based Nationwide Readmissions Database. All adults (age ≥18 years) who underwent autologous (auto-) or allogenic (allo-) HCT in US hospitals between January 1, 2012, and November 30, 2014, were included. The analysis was performed from June 2018 to February 2019. Main Outcomes and Measures: The main outcome was 30-day readmission rates for auto-HCT and allo-HCT. Factors associated with readmission, including baseline demographic characteristics and disease- and hospital-related characteristics (including annual case volume), were measured. Results: A total of 28356 index admissions for auto-HCT in 244 centers (191 low-volume, 38 medium-volume, and 15 high-volume centers) and 17217 index admissions for allo-HCT in 211 centers (161 low-volume, 37 medium-volume, and 13 high-volume centers) were identified during the study period. The overall 30-day readmission rates were 11.6% for auto-HCT and 24.4% for allo-HCT. The odds of readmission were significantly higher in low-volume hospitals compared with high-volume hospitals (adjusted odds ratio [aOR], 1.69; 95% CI, 1.08-2.64 for auto-HCT and aOR, 1.41; 95% CI, 1.09-1.82 for allo-HCT) but comparable to medium-volume hospitals (aOR, 1.06; 95% CI, 0.62-1.83 for auto-HCT and aOR, 1.19; 95% CI, 0.90-1.57 for allo-HCT). Other factors associated with readmission for auto-HCT included younger age (aOR for age ≥50 vs <49 years, 0.82; 95% CI, 0.68-0.98), female sex (aOR, 1.21; 95% CI, 1.06-1.36), disease type (aOR for other vs myeloma, 1.37; 95% CI, 1.06-1.77), and Elixhauser comorbidity index score (aOR for ≥20 vs 0, 1.5; 95% CI, 1.17-1.93). For allo-HCT, factors associated with readmission included disease type (aOR for acute lymphoblastic leukemia vs acute myelogenous leukemia, 1.30; 95% CI, 1.04-1.62), insurance (aOR for Medicare vs private, 1.18; 95% CI, 1.02-1.36), and Elixhauser comorbidity index score (aOR for 1-9 vs 0, 1.2; 95% CI, 1.04-1.39). Infections, neutropenic fever, and gastrointestinal symptoms were the most common reasons for readmission for both types of HCT. Conclusions and Relevance: This study found substantial rates of readmission for both types of HCT and an inverse association between hospital HCT volume and 30-day readmission. These results may provide guidance when developing quality indicators and policies penalizing hospitals for HCT readmission.
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Outcomes of Medicare-age eligible NHL patients receiving RIC allogeneic transplantation: a CIBMTR analysis
Shah, N. N., Ahn, K. W., Litovich, C., Fenske, T. S., Ahmed, S., Battiwalla, M., Bejanyan, N., Dahi, P. B., Bolanos-Meade, J., Chen, A. I., et al
Blood advances. 2018;2(8):933-940
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Abstract
The application of allogeneic hematopoietic cell transplantation (allo-HCT) in non-Hodgkin lymphoma (NHL) patients ≥65 years in the United States is limited by lack of Medicare coverage for this indication. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we report allo-HCT outcomes of NHL patients aged ≥65 years (older cohort; n = 446) compared with a cohort of younger NHL patients aged 55-64 years (n = 1183). We identified 1629 NHL patients undergoing a first reduced-intensity conditioning (RIC) or nonmyeloablative conditioning allo-HCT from 2008 to 2015 in the United States. Cord blood or haploidentical transplants were excluded. The median age was 68 years (range 65-77) for the older cohort vs 60 years (range 55-64) in the younger cohort. The 4-year adjusted probabilities of nonrelapse mortality (NRM), relapse/progression (R/P), progression-free survival (PFS), and overall survival (OS) of the younger and older groups were 24% vs 30% (P = .03), 41% vs 42% (P = .82), 37% vs 31% (P = .03), and 51% vs 46% (P = .07), respectively. Using multivariate analysis, compared with the younger group, the older cohort was associated with increased NRM, but there was no difference between the 2 cohorts in terms of R/P, PFS, or OS. The most common cause of death was disease relapse in both groups. In NHL patients eligible for allo-HCT, there was no difference in OS between the 2 cohorts. Age alone should not determine allo-HCT eligibility in NHL, and Medicare should expand allo-HCT coverage to older adults.
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Fludarabine and Busulfan versus Fludarabine, Cyclophosphamide, and Rituximab as Reduced-Intensity Conditioning for Allogeneic Transplantation in Follicular Lymphoma
Epperla, N., Ahn, K. W., Armand, P., Jaglowski, S., Ahmed, S., Kenkre, V. P., Savani, B., Jagasia, M., Shah, N. N., Fenske, T. S., et al
Biology of Blood & Marrow Transplantation. 2017
Abstract
Large, multicenter studies comparing commonly used reduced-intensity conditioning (RIC) approaches in follicular lymphoma (FL) have not been performed. Using the Center for International Blood and Marrow Transplant Research database, we report the outcomes of the 2 most commonly used RIC approaches, fludarabine and busulfan (Flu/Bu) versus fludarabine, cyclophosphamide, and rituximab (FCR) in FL patients. We evaluated 200 FL patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) who received RIC with either Flu/Bu (n=98) or FCR (n=102) during 2008 to 2014. All patients received peripheral blood grafts, and graft-versus-host disease (GVHD) prophylaxis was limited to calcineurin inhibitor-based approaches. Median follow-up of survivors in the Flu/Bu and FCR groups was 48 months and 46 months, respectively. On univariate analysis in the Flu/Bu and FCR groups, the 3-year rates of nonrelapse mortality (11% versus 11%, P=.94), relapse/progression (18% versus 15%, P=.54), progression-free survival (PFS) (71% versus 74%, P=.65), and overall survival (OS) (73% versus 81%, P=.18) were not significantly different. On multivariate analysis no difference was seen between the FCR and Flu/Bu cohorts in terms of grades II to IV (relative risk [RR],1.06; 95% confidence interval [CI],.59 to 1.93; P=.84) or grades III to IV (RR,1.18; 95% CI, .47 to 2.99; P=.72) acute GVHD, nonrelapse mortality (RR,.83; 95% CI, .38 to 1.82; P=.64), relapse/progression (RR,.99; 95% CI, .49 to 1.98; P=.97), PFS (RR,.92; 95% CI, .55 to 1.54; P=.76), or OS (RR,.70; 95% CI, .40 to 1.23; P=.21) risk. However, RIC with FCR was associated with a significantly reduced chronic GVHD risk (RR,.52; 95% CI, .36 to .77; P=.001). RIC with either Flu/Bu or FCR in patients with FL undergoing allo-HCT provides excellent 3-year OS, with acceptable rates of nonrelapse mortality. FCR-based conditioning was associated with a lower risk of chronic GVHD. Copyright © 2017. Published by Elsevier Inc.
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Autologous Transplantation in Follicular Lymphoma with Early Therapy Failure: a NLCS and CIBMTR Analysis
Casulo, C., Friedberg, J. W., Ahn, K. W., Flowers, C., DiGilio, A., Smith, S. M., Ahmed, S., Inwards, D., Aljurf, M., Chen, A. I., et al
Biology of Blood & Marrow Transplantation. 2017
Abstract
Patients with follicular lymphoma (FL) experiencing early therapy failure (ETF) within two years of frontline chemoimmunotherapy have poor overall survival (OS). We analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) and the National LymphoCare Study (NLCS) to determine whether autologous hematopoietic cell transplant (autoHCT) can improve outcomes in this high-risk FL subgroup.ETF was defined as failure to achieve at least partial response after frontline chemoimmunotherapy or lymphoma progression within two years of frontline chemoimmunotherapy. We identified two groups: the non-autoHCT cohort (patients from the NLCS with ETF not undergoing autoHCT); and the autoHCT cohort (CIBMTR patients with ETF undergoing autoHCT). All patients received rituximab-based chemotherapy as frontline treatment. 174 non-autoHCT patients and 175 autoHCT patients were identified and analyzed. There was no difference in five year OS between the two groups (60% vs 67% respectively; p=0.16). A planned subgroup analysis showed that patients with ETF receiving autoHCT soon after treatment failure (<=1year of ETF; n=123) had higher five year OS than those without autoHCT (73% vs 60%, p=0.05). On multivariate analysis, early use of autoHCT was associated with significantly reduced mortality (HR=0.63, 95%CI:0.42-0.94, p=0.02). Patients with FL experiencing ETF after frontline chemoimmunotherapy lack optimal therapy. We demonstrate improved OS when receiving autoHCT within one year of treatment failure. Results from this unique collaboration between the NLCS and CIBMTR support consideration of early consolidation with autoHCT in select FL patients experiencing ETF.
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Reduced-Intensity Transplantation for Lymphomas Using Haploidentical Related Donors Versus HLA-Matched Sibling Donors: A Center for International Blood and Marrow Transplant Research Analysis
Ghosh, N., Karmali, R., Rocha, V., Ahn, K. W., DiGilio, A., Hari, P. N., Bachanova, V., Bacher, U., Dahi, P., de Lima, M., et al
Journal of Clinical Oncology. 2016;34(26):3141-9
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Abstract
PURPOSE Related donor haploidentical hematopoietic cell transplantation (Haplo-HCT) using post-transplantation cyclophosphamide (PT-Cy) is increasingly used in patients lacking HLA-matched sibling donors (MSD). We compared outcomes after Haplo-HCT using PT-Cy with MSD-HCT in patients with lymphoma, using the Center for International Blood and Marrow Transplant Research registry. MATERIALS AND METHODS We evaluated 987 adult patients undergoing either Haplo-HCT (n = 180) or MSD-HCT (n = 807) following reduced-intensity conditioning regimens. The haploidentical group received graft-versus-host disease (GVHD) prophylaxis with PT-Cy with or without a calcineurin inhibitor and mycophenolate. The MSD group received calcineurin inhibitor-based GVHD prophylaxis. RESULTS Median follow-up of survivors was 3 years. The 28-day neutrophil recovery was similar in the two groups (95% v 97%; P = .31). The 28-day platelet recovery was delayed in the haploidentical group compared with the MSD group (63% v 91%; P = .001). Cumulative incidence of grade II to IV acute GVHD at day 100 was similar between the two groups (27% v 25%; P = .84). Cumulative incidence of chronic GVHD at 1 year was significantly lower after Haplo-HCT (12% v 45%; P < .001), and this benefit was confirmed on multivariate analysis (relative risk, 0.21; 95% CI, 0.14 to 0.31; P < .001). For Haplo-HCT v MSD-HCT, 3-year rates of nonrelapse mortality (15% v 13%; P = .41), relapse/progression (37% v 40%; P = .51), progression-free survival (48% v 48%; P = .96), and overall survival (61% v 62%; P = .82) were similar. Multivariate analysis showed no significant difference between Haplo-HCT and MSD-HCT in terms of nonrelapse mortality (P = .06), progression/relapse (P = .10), progression-free survival (P = .83), and overall survival (P = .34). CONCLUSION Haplo-HCT with PT-Cy provides survival outcomes comparable to MSD-HCT, with a significantly lower risk of chronic GVHD. Copyright © 2016 by American Society of Clinical Oncology.
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Allogeneic transplantation provides durable remission in a subset of DLBCL patients relapsing after autologous transplantation
Fenske, T. S., Ahn, K. W., Graff, T. M., DiGilio, A., Bashir, Q., Kamble, R. T., Ayala, E., Bacher, U., Brammer, J. E., Cairo, M., et al
British Journal of Haematology. 2016;174(2):235-48
Abstract
For diffuse large B-cell lymphoma (DLBCL) patients progressing after autologous haematopoietic cell transplantation (autoHCT), allogeneic HCT (alloHCT) is often considered, although limited information is available to guide patient selection. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 503 patients who underwent alloHCT after disease progression/relapse following a prior autoHCT. The 3-year probabilities of non-relapse mortality, progression/relapse, progression-free survival (PFS) and overall survival (OS) were 30, 38, 31 and 37% respectively. Factors associated with inferior PFS on multivariate analysis included Karnofsky performance status (KPS) <80, chemoresistance, autoHCT to alloHCT interval <1-year and myeloablative conditioning. Factors associated with worse OS on multivariate analysis included KPS<80, chemoresistance and myeloablative conditioning. Three adverse prognostic factors were used to construct a prognostic model for PFS, including KPS<80 (4 points), autoHCT to alloHCT interval <1-year (2 points) and chemoresistant disease at alloHCT (5 points). This CIBMTR prognostic model classified patients into four groups: low-risk (0 points), intermediate-risk (2-5 points), high-risk (6-9 points) or very high-risk (11 points), predicting 3-year PFS of 40, 32, 11 and 6%, respectively, with 3-year OS probabilities of 43, 39, 19 and 11% respectively. In conclusion, the CIBMTR prognostic model identifies a subgroup of DLBCL patients experiencing long-term survival with alloHCT after a failed prior autoHCT. Copyright © 2016 John Wiley & Sons Ltd.