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Impact of pre-transplant induction and consolidation cycles on AML allogeneic transplant outcomes: a CIBMTR analysis in 3113 AML patients
Boyiadzis, M., Zhang, M. J., Chen, K., Abdel-Azim, H., Abid, M. B., Aljurf, M., Bacher, U., Badar, T., Badawy, S. M., Battiwalla, M., et al
Leukemia. 2022
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Editor's Choice
Abstract
We investigated the impact of the number of induction/consolidation cycles on outcomes of 3113 adult AML patients who received allogeneic hematopoietic cell transplantation (allo-HCT) between 2008 and 2019. Patients received allo-HCT using myeloablative (MAC) or reduced-intensity (RIC) conditioning in first complete remission (CR) or with primary induction failure (PIF). Patients who received MAC allo-HCT in CR after 1 induction cycle had 1.3-fold better overall survival (OS) than 2 cycles to CR and 1.47-fold better than ≥3 cycles. OS after CR in 2 or ≥3 cycles was similar. Relapse risk was 1.65-fold greater in patients receiving ≥3 cycles to achieve CR. After RIC allo-HCT, the number of induction cycles to CR did not affect OS. Compared to CR in 1 cycle, relapse risk was 1.24-1.41-fold greater in patients receiving 2 or ≥3 cycles. For patients receiving only 1 cycle to CR, consolidation therapy prior to MAC allo-HCT was associated with improved OS vs. no consolidation therapy. Detectable MRD at the time of MAC allo-HCT did not impact outcomes while detectable MRD preceding RIC allo-HCT was associated with an increased risk of relapse. For allo-HCT in PIF, OS was significantly worse than allo-HCT in CR after 1-3 cycles.
PICO Summary
Population
Adults with acute lymphoblastic leukaemia who received allogeneic hematopoietic cell transplantation (allo-HCT) in 450 centres worldwide (n=3113)
Intervention
Patients achieving complete remission (CR) after 1 induction cycle (n=862)
Comparison
Patients requiring 2 cycles to CR (n=454) or 3 or more cycles to CR (n=157).
Outcome
Patients who received myeloablative (MAC) allo-HCT in CR after 1 induction cycle had 1.3-fold better overall survival (OS) than 2 cycles to CR and 1.47-fold better than ≥3 cycles. OS after CR in 2 or ≥3 cycles was similar. Relapse risk was 1.65-fold greater in patients receiving ≥3 cycles to achieve CR. After reduced-intensity conditioning (RIC) allo-HCT, the number of induction cycles to CR did not affect OS. Compared to CR in 1 cycle, relapse risk was 1.24-1.41-fold greater in patients receiving 2 or ≥3 cycles. For patients receiving only 1 cycle to CR, consolidation therapy prior to MAC allo-HCT was associated with improved OS vs. no consolidation therapy. Detectable MRD at the time of MAC allo-HCT did not impact outcomes while detectable MRD preceding RIC allo-HCT was associated with an increased risk of relapse. For allo-HCT in PIF, OS was significantly worse than allo-HCT in CR after 1-3 cycles.
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Impact of conditioning regimen intensity on the outcomes of peripheral T-cell lymphoma, anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma patients undergoing allogeneic transplant
Savani, M., Ahn, K. W., Chen, Y., Ahmed, S., Cashen, A. F., Shadman, M., Modi, D., Khimani, F., Cutler, C. S., Zain, J., et al
British journal of haematology. 2022
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Abstract
There have been no large studies comparing reduced-intensity/non-myeloablative conditioning (RIC/NMA) to myeloablative conditioning (MAC) regimens in T-cell non-Hodgkin lymphoma (T-NHL) patients undergoing allogeneic transplant (allo-HCT). A total of 803 adults with peripheral T-cell lymphoma, anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma (age 18-65 years), undergoing allo-HCT between 2008-2019 and reported to the Center for International Blood and Marrow Transplant Research with either MAC (n = 258) or RIC/NMA regimens (n = 545) were evaluated. There were no significant differences between the two cohorts in terms of patient sex, race and performance scores. Significantly more patients in the RIC/NMA cohort had peripheral blood grafts, haematopoietic cell transplantation-specific comorbidity index (HCT-CI) of ≥3 and chemosensitive disease compared to the MAC cohort. On multivariate analysis, overall survival (OS) was not significantly different in the RIC/NMA cohort compared to the MAC cohort (hazard ratio (HR) = 1.01, 95% confidence interval (CI) = 0.79-1.29; p = 0.95). Similarly, non-relapse mortality (NRM) (HR = 0.85, 95% CI = 0.61-1.19; p = 0.34), risk of progression/relapse (HR = 1.29; 95% CI = 0.98-1.70; p = 0.07) and therapy failure (HR = 1.14; 95% CI = 0.92-1.41, p = 0.23) were not significantly different between the two cohorts. Relative to MAC, RIC/NMA was associated with a significantly lower risk of grade 3-4 acute graft-versus-host disease (HR = 0.67; 95% CI = 0.46-0.99, p = 0.04). Among chemorefractory patients, there was no difference in OS, therapy failure, relapse, or NRM between RIC/NMA and MAC regimens. In conclusion, we found no association between conditioning intensity and outcomes after allo-HCT for T-cell NHL.
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Outcomes Associated With Thiotepa-Based Conditioning in Patients With Primary Central Nervous System Lymphoma After Autologous Hematopoietic Cell Transplant
Scordo, M., Wang, T. P., Ahn, K. W., Chen, Y., Ahmed, S., Awan, F. T., Beitinjaneh, A., Chen, A., Chow, V. A., Dholaria, B., et al
JAMA oncology. 2021
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Editor's Choice
Abstract
IMPORTANCE Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens. OBJECTIVE To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM). DESIGN, SETTING, AND PARTICIPANTS This observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021. INTERVENTIONS Patients received 1 of 3 conditioning regimens: TBC (n?=?263), TT-BCNU (n?=?275), and BEAM (n?=?65). MAIN OUTCOMES AND MEASURES The primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival. RESULTS Of 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P?=?.03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P?.001). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79; 95% CI, 1.07-2.98; P?=?.03), lower risk of nonrelapse mortality (NRM) (HR, 0.50; 95% CI, 0.29-0.87; P?=?.01), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54; 95% CI, 0.93-2.55; P?=?.10). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC. CONCLUSIONS AND RELEVANCE In this cohort study, thiotepa-based conditioning regimen was associated with higher rates of survival compared with BEAM, despite higher rates of early toxic effects and NRM; these findings may assist clinicians in choosing between TBC or TT-BCNU based on patient and disease characteristics.
PICO Summary
Population
Adults with primary central nervous system lymphoma (PCNSL) who underwent autologous transplantation as initial, or subsequent, consolidation and were reported to the CIBMTR registry (n=603)
Intervention
Thiotepa/busulfan/cyclophosphamide conditioning (TBC, n=263), thiotepa/carmustine conditioning (TT-BCNU, n=275)
Comparison
Carmustine/etoposide/cytarabine/melphalan conditioning (BEAM, n=65).
Outcome
The mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%), owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79), lower risk of nonrelapse mortality (NRM) (HR, 0.50), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC.
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Fludarabine and Melphalan Compared with Reduced Doses of Busulfan and Fludarabine Improves Transplant Outcomes in Older MDS Patients
Oran, B., Ahn, K. W., Fretham, C., Beitinjaneh, A., Bashey, A., Pawarode, A., Wirk, B., Scott, B. L., Savani, B. N., Bredeson, C., et al
Transplantation and cellular therapy. 2021
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Editor's Choice
Abstract
Reduced-intensity conditioning (RIC) regimens developed to extend allogeneic stem cell transplantation (HSCT) to older patients have resulted in encouraging outcomes. We aimed to compare the two most commonly used RIC regimens, intravenous use of fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel), in myelodysplastic syndrome (MDS). Through CIBMTR, we identified 1045 MDS patients aged = 60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor using RIC. CIBMTR's definition of RIC was used: a regimen that incorporated an intravenous busulfan total dose = 7.2 mg/kg, or a low-dose melphalan total dose of = 150 mg/m(2). The two groups, FluBu (n=697) and FluMel (n=448), were comparable for disease and transplant-related characteristics except for the more frequent use of anti-thymocyte globulin or alemtuzumab in the FluBu group (39% vs. 31%). The median age was 67 in both groups. FluMel was associated with a reduced relapse incidence (RI) compared with FluBu, with a 1-year adjusted incidence of 26% vs. 44% (p=0.0001). Transplant-related mortality (TRM) was higher with FluMel compared with FluBu (26% vs. 16%, p=0.0001). Since the magnitude of improvement with FluMel in RI was greater than the improvement in TRM with FluBu, disease-free survival (DFS) was improved at 1-year and beyond with FluMel compared with FluBu (48% vs. 40% at 1 year, p=0.02, and 35% vs. 27% at 3 years, p=0.01). Overall survival (OS) was comparable at 1 year (63% vs. 61%, p=0.4) but significantly improved with FluMel compared with FluBu at 3 years (46% vs. 39%, p=0.03). Our results suggest that FluMel is associated with superior DFS compared with FluBu due to reduced RI in older MDS patients.
PICO Summary
Population
Patients with myelodysplastic syndrome aged >/=60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor, and were reported to the CIBMTR registry (n=1045)
Intervention
Reduced intensity regimen incorporating an intravenous busulfan total dose = 7.2 mg/kg (FluBu, n=697)
Comparison
Reduced intensity regimen incorporating a low-dose melphalan total dose of = 150 mg/m(2) (FluMel, n=448)
Outcome
The two groups were comparable for disease and transplant-related characteristics except for the more frequent use of anti-thymocyte globulin or alemtuzumab in the FluBu group (39% vs. 31%). The median age was 67 in both groups. FluMel was associated with a reduced relapse incidence (RI) compared with FluBu, with a 1-year adjusted incidence of 26% vs. 44%. Transplant-related mortality (TRM) was higher with FluMel compared with FluBu (26% vs. 16%). Since the magnitude of improvement with FluMel in RI was greater than the improvement in TRM with FluBu, disease-free survival (DFS) was improved at 1-year and beyond with FluMel compared with FluBu (48% vs. 40% at 1 year, and 35% vs. 27% at 3 years). Overall survival (OS) was comparable at 1 year (63% vs. 61%) but significantly improved with FluMel compared with FluBu at 3 years (46% vs. 39%). Our results suggest that FluMel is associated with superior DFS compared with FluBu due to reduced RI in older MDS patients.
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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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Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens: a CIBMTR report
Zhou, Z., Nath, R., Cerny, J., Wang, H. L., Zhang, M. J., Abdel-Azim, H., Agrawal, V., Ahmed, G., Al-Homsi, A. S., Aljurf, M., et al
Blood advances. 2020;4(13):3180-3190
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Editor's Choice
Abstract
There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.
PICO Summary
Population
Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 (n=1413)
Intervention
Fludarabine/busulfan reduced intensity conditioning regimen (FB, n=791)
Comparison
Fludarabine/melphalan reduced intensity conditioning regimen (FM, n=622)
Outcome
Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82), but was marginally superior beyond 3 months (HR = 0.87). LFS was better with FM compared with FB (HR = 0.89). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85). Long-term relapse was lower with FM (HR = 0.65). Analysis restricted to patients with CR showed comparable results.
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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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Myeloablative Conditioning for Allogeneic Transplantation Results in Superior Disease-Free Survival for Acute Myeloid Leukemia and Myelodysplastic Syndromes with Low/Intermediate, but not High Disease Risk Index: A CIBMTR Study: Superior DFS with MAC compared to RIC HCT in AML/MDS with low/intermediate risk DRI
Bejanyan, N., Zhang, M., Bo-Subait, K., Brunstein, C., Wang, H., Warlick, E. D., Giralt, S., Nishihori, T., Martino, R., Passweg, J., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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Editor's Choice
Abstract
Myeloablative (MAC) as compared to reduced-intensity conditioning (RIC) is generally associated with lower relapse risk after allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). However, disease specific risk factors in AML/MDS can further inform when MAC vs. RIC may yield differential outcomes. We analyzed HCT outcomes stratified by the disease risk index (DRI) in 4387 adults (age 40-65 years) to identify the impact of conditioning intensity. In the low/intermediate risk DRI cohort, RIC was associated with lower non-relapse mortality (NRM) (HR=0.74, 95% CI 0.62-0.88; p<0.001), but significantly higher relapse risk (HR=1.54, 95% CI 1.35-1.76; p<0.001) and thus inferior disease-free survival (DFS) (HR=1.19, 95% CI 1.07-1.33; p=0.001). In the high/very high risk DRI cohort, RIC resulted in marginally lower NRM (HR=0.83, 95% CI 0.68-1.00; p=0.051), and significantly higher relapse risk (HR=1.23, 95% CI 1.08-1.41; p=0.002) leading to similar DFS using either RIC or MAC. These data support MAC over RIC as the preferred conditioning intensity for AML/MDS with low/intermediate risk DRI, but similar benefit to RIC in high/very high risk DRI. Novel MAC regimens with less toxicity could benefit all, but more potent anti-neoplastic approaches are needed for the high/very high risk DRI group.
PICO Summary
Population
Adult patients aged 40-65 years with acute myeloid leukaemia or myelodysplastic syndrome (AML/MDS) (n=4387)
Intervention
Reduced intensity conditioning (RIC) and low/intermediate risk (n=999), RIC and high/very high risk (n=728)
Comparison
Myeloablative conditioning (MAC) and low/intermediate risk (n=1539), MAC and high/very high risk (n=1121)
Outcome
In the low/intermediate risk disease risk index (DRI) cohort, RIC was associated with lower non-relapse mortality (NRM) , but significantly higher relapse risk and thus inferior disease-free survival (DFS). In the high/very high risk DRI cohort, RIC resulted in marginally lower NRM, and significantly higher relapse risk leading to similar DFS using either RIC or MAC.
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Association of Reduced-Intensity Conditioning Regimens With Overall Survival Among Patients With Non-Hodgkin Lymphoma Undergoing Allogeneic Transplant
Ghosh, N., Ahmed, S., Ahn, K. W., Khanal, M., Litovich, C., Aljurf, M., Bacher, V. U., Bredeson, C., Epperla, N., Farhadfar, N., et al
JAMA oncology. 2020
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Abstract
Importance: Reduced-intensity conditioning and nonmyeloablative conditioning (RIC-NMAC) regimens are frequently used in allogeneic hematopoietic cell transplant (HCT) for non-Hodgkin lymphoma. However, the optimal RIC-NMAC regimen in allogeneic HCT for non-Hodgkin lymphoma is not known. Objective: To investigate whether RIC-NMAC regimens at a higher end of the intensity spectrum are associated with increased nonrelapse mortality and lower overall survival compared with RIC-NMAC regimens at the lower end of the intensity spectrum in patients with non-Hodgkin lymphoma undergoing allogeneic HCT. Design, Setting, and Participants: This cohort study used data from 1823 adult patients with non-Hodgkin lymphoma in the Center for International Blood and Marrow Transplant Research registry. Included patients underwent allogeneic HCT using matched related or unrelated donors between January 2008 and December 2016. Statistical analysis was performed from June 1, 2019, to February 10, 2020. Interventions: Patients received 1 of 4 RIC-NMAC regimens: fludarabine-intravenous busulfan (Flu-Bu), approximately 6.4 mg/kg (n = 458); fludarabine-melphalan (Flu-Mel140), 140 mg/m2 (n = 885); fludarabine-cyclophosphamide (Flu-Cy) (n = 391); or Flu-Cy with 2 Gy total body irradiation (Flu-Cy-2GyTBI) (n = 89). Main Outcomes and Measures: The primary outcome was overall survival. Secondary outcomes were nonrelapse mortality, incidence of relapse, progression-free survival, and the incidence of acute and chronic graft-vs-host disease (GVHD). Results: Of 1823 patients, 1186 (65%) were male, with a mean (SD) age of 54.8 (9.9) years. The 4-year adjusted OS was 58% in the Flu-Bu cohort, 67% in the Flu-Cy-2GyTBI cohort, 49% in the Flu-Mel140 cohort, and 63% in the Flu-Cy cohort (P < .001). After adjustment for age, Karnofsky performance score, HCT comorbidity index, NHL subtype, remission status at HCT, and the use of antithymocyte globulin or alemtuzumab, the regression analysis showed a significantly higher mortality risk associated with Flu-Mel140 compared with Flu-Bu (hazard ratio [HR], 1.34; 95% CI, 1.13-1.59; P < .001). Compared with the Flu-Cy cohort, the Flu-Mel140 cohort had a higher risk of chronic GVHD (HR, 1.38; 95% CI, 1.15-1.65; P < .001). The Flu-Mel140 regimen was associated with a higher nonrelapse mortality risk (HR, 1.78; 95% CI, 1.37-2.31; P < .001) compared with the Flu-Bu regimen. Conclusions and Relevance: The findings suggest that use of the more intense RIC-NMAC regimen, Flu-Mel140, may have a negative association with overall survival and may be associated with higher nonrelapse mortality. The Flu-Bu and Flu-Cy regimens with or without 2GyTBI regimens appeared to provide comparable overall survival.