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1.
The Simplified Comorbidity Index predicts non-relapse mortality in reduced-intensity conditioning allogeneic haematopoietic cell transplantation
Elias, S., Brown, S., Devlin, S. M., Barker, J. N., Cho, C., Chung, D. J., Dahi, P. B., Giralt, S., Gyurkocza, B., Jakubowski, A. A., et al
British journal of haematology. 2023
Abstract
Comorbidity assessment before allogeneic haematopoietic cell transplantation (allo-HCT) is essential for estimating non-relapse mortality (NRM) risk. We previously developed the Simplified Comorbidity Index (SCI), which captures a small number of 'high-yield' comorbidities and older age. The SCI was predictive of NRM in myeloablative CD34-selected allo-HCT. Here, we evaluated the SCI in a single-centre cohort of 327 patients receiving reduced-intensity conditioning followed by unmanipulated allografts from HLA-matched donors. Among the SCI factors, age above 60, mild renal impairment, moderate pulmonary disease and cardiac disease were most frequent. SCI scores ranged from 0 to 8, with 39%, 20%, 20% and 21% having scores of 0-1, 2, 3 and ≥4 respectively. Corresponding cumulative incidences of 3-year NRM were 11%, 16%, 22% and 27%; p = 0.03. In multivariable models, higher SCI scores were associated with incremental risks of all-cause mortality and NRM. The SCI had an area under the receiver operating characteristic curve of 65.9%, 64.1% and 62.9% for predicting 1-, 2- and 3-year NRM versus 58.4%, 60.4% and 59.3% with the haematopoietic cell transplantation comorbidity index. These results demonstrate for the first time that the SCI is predictive of NRM in patients receiving allo-HCT from HLA-matched donors after reduced-intensity conditioning.
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2.
Reduced Intensity Compared to Non-myeloablative Conditioning in Patients with Non-Hodgkin Lymphoma undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Nath, K., Peterson, K., Brown, S., Devlin, S., Rodriguez, N., Barker, J., Giralt, S., Gyurkocza, B., Jakubowski, A., Papadopoulos, E., et al
Transplantation and cellular therapy. 2023
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Editor's Choice
Abstract
BACKGROUND . Reduced intensity (RIC) and non-myeloablative (NMA) conditioning are preferred for patients with non-Hodgkin lymphoma (NHL) receiving allogeneic hematopoietic stem cell transplantation (allo-HCT). Although prior studies have suggested that higher-intensity regimens within RIC-NMA conditioning are associated with inferior outcomes in patients with NHL, the optimal conditioning regimen remains unknown. OBJECTIVES AND STUDY DESIGN . We performed a retrospective single-center analysis to determine outcomes of adult patients with B- and T-cell NHL who underwent allo-HCT and received either RIC or NMA conditioning between March 2008 - December 2019. RIC regimens included fludarabine-cyclophosphamide-thiotepa-4Gy-total body irradiation (Flu-Cy-TT-4Gy-TBI), fludarabine-melphalan (Flu-Mel), fludarabine-cyclophosphamide-4Gy-total body irradiation (Flu-Cy-4Gy-TBI) and fludarabine-busulfan-4 (Flu-Bu-4). The NMA regimen included fludarabine-cyclophosphamide-2Gy-total body irradiation (Flu-Cy-2Gy-TBI). The primary outcome was overall survival. Secondary outcomes included progression-free survival, non-relapse mortality and the incidence of acute and chronic graft-vs-host-disease (GvHD). RESULTS . Of 279 transplanted patients (median age, 58 years), 110 received RIC (55% Flu-Mel, 38% Flu-Cy-TT-4Gy-TBI, 6% Flu-Bu-4, 1% Flu-Cy-4Gy-TBI) and 169 received NMA conditioning with Flu-Cy-2Gy-TBI. With a median of 64 months of follow-up from allo-HCT, there was no significant difference in overall survival between the NMA and RIC groups (median not reached [NR] vs 103 months, respectively. P = 0.1), and this was maintained on multivariable analysis. Similarly, after adjustment for all independently significant covariates (age, Karnofsky performance status, HCT-CI, disease histology), the regression analysis showed no significant difference in progression-free survival with RIC compared to NMA conditioning (hazard ratio [HR] 1.38; 95% CI 0.92 - 2.09, P = 0.24). On univariable analysis, there was no significant difference in non-relapse mortality between RIC and NMA conditioning (100-day estimates: 10.0% vs. 1.8%, respectively, P = 0.5). After adjustment for age, ethnicity, Karnofsky performance score, HCT-CI, GvHD prophylaxis and donor source, RIC conditioning was associated with a significantly higher incidence of non-relapse mortality compared to NMA conditioning (HR 2.61, 95% CI 1.04 - 6.52, P = 0.039). On multivariable analysis, compared with the Flu-Cy-2Gy-TBI regimen, the RIC cohort had higher rates of grade II-IV (HR, 2.25; 95% CI, 1.31 - 3.86; P = 0.002) and grade III-IV acute GvHD (HR, 5.62; 95% CI, 2.03 - 15.6; P < 0.001). CONCLUSION . The findings of this study suggest that NMA conditioning with Flu-Cy-TBI-2Gy may be considered over more intensive RIC regimens for patients with NHL undergoing allo-HCT.
PICO Summary
Population
Adults with B- or T-cell non-Hodgkin lymphoma who underwent allogeneic stem cell transplant (allo-HSCT) at a single centre in USA (n=279)
Intervention
Reduced intensity conditioning (RIC) with or without total body irradiation (n=110)
Comparison
Non-myeloablative (NMA) conditioning (n=169)
Outcome
With a median of 64 months of follow-up from allo-HCT, there was no significant difference in overall survival between the NMA and RIC groups (median not reached [NR] vs 103 months, respectively), and this was maintained on multivariable analysis. Similarly, after adjustment for all independently significant covariates (age, Karnofsky performance status, HCT-CI, disease histology), the regression analysis showed no significant difference in progression-free survival with RIC compared to NMA conditioning (hazard ratio [HR] 1.38; 95% CI 0.92 - 2.09). On univariable analysis, there was no significant difference in non-relapse mortality between RIC and NMA conditioning (100-day estimates: 10.0% vs. 1.8%, respectively). After adjustment for age, ethnicity, Karnofsky performance score, HCT-CI, GvHD prophylaxis and donor source, RIC conditioning was associated with a significantly higher incidence of non-relapse mortality compared to NMA conditioning (HR 2.61, 95% CI 1.04 - 6.52). On multivariable analysis, compared with the Flu-Cy-2Gy-TBI regimen, the RIC cohort had higher rates of grade II-IV (HR, 2.25; 95% CI, 1.31 - 3.86) and grade III-IV acute GvHD (HR, 5.62; 95% CI, 2.03 - 15.6).
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3.
Reduced-intensity conditioning hematopoietic stem cell transplantation for chronic lymphocytic leukemia and Richter's transformation
Lahoud, O. B., Devlin, S. M., Maloy, M. A., Roeker, L. E., Dahi, P. B., Ponce, D. M., Gyurkocza, B., Koehne, G., Young, J. W., Castro-Malaspina, H. R., et al
Blood advances. 2021;5(14):2879-2889
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Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) may potentially cure patients with chronic lymphocytic leukemia (CLL) and Richter's transformation (CLL-RT) or CLL without RT, but the impact of novel agents on HSCT is unclear. CLL-RT patients have a grave prognosis, and their outcomes after HSCT are uncertain. We conducted a retrospective analysis of all 58 CLL patients, including 23 CLL-RT patients, who underwent reduced intensity conditioning (RIC) HSCT at Memorial Sloan Kettering Cancer Center (New York, NY) between September 2006 and April 2017. With a median follow-up of 68 months (range, 24-147 months), 5-year progression-free survival (PFS) was 40% (95% confidence interval [CI], 28%-56%), and overall survival (OS) was 58% (95% CI, 48%-74%). The 1-year graft-versus-host disease/relapse-free survival (GRFS) was 38% (95% CI, 25%-50%). Patients with CLL-RT and CLL patients without RT had comparable outcomes. In both cohorts, treatment-sensitive response and ≤3 previous lines of therapy produced superior PFS and OS. Outcomes were agnostic to adverse cytogenetic and molecular features. Novel agents did not have a negative impact on HSCT outcomes. Total body irradiation (TBI)-containing RIC yielded inferior PFS, OS, and GRFS. CLL-RT patients older than age 55 years who had an HSCT Comorbidity Index score of ≥2 demonstrated inferior OS. This study, which is the largest series of RIC-HSCT for patients with CLL-RT, provides evidence supporting RIC-HSCT in early remission courses for patients with CLL-RT and poor-risk CLL patients. TBI-containing RIC should be considered with caution.
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4.
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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5.
CD34(+) Cell Selection versus Reduced-Intensity Conditioning and Unmodified Grafts for Allogeneic Hematopoietic Cell Transplantation in Patients Age >50 Years with Acute Myelogenous Leukemia and Myelodysplastic Syndrome
Barba, P., Martino, R., Zhou, Q., Cho, C., Castro-Malaspina, H., Devlin, S., Esquirol, A., Giralt, S., Jakubowski, A. A., Caballero, D., et al
Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. 2018;24(5):964-972
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Abstract
Reduced-intensity conditioning (RIC) and T cell depletion (TCD) through CD34(+) cell selection without the use of post-transplantation immunosuppression are 2 strategies used to reduce nonrelapse mortality (NRM) in older patients after allogeneic hematopoietic cell transplantation (allo-HCT). To compare the efficacy of the RIC and TCD approaches, we evaluated the outcomes of patients age >50 years with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) who underwent allo-HCT from an HLA-matched donor with one of these strategies. Baseline characteristics were comparable in the patients receiving TCD (n = 204) and those receiving RIC (n = 151), except for a higher proportion of unrelated donors (68% versus 40%; P < .001) and a higher comorbidity burden (Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI] ≥3: 51% versus 38%; P < .001) in the TCD cohort. Analysis of outcomes at 3 years showed a higher chronic graft-versus-host disease (GVHD)/relapse-free survival (CRFS) (51% versus 7%; P < .001), lower incidences of grade II-IV acute GVHD (18% versus 46% at day +180) and chronic GVHD (6% versus 55% at 3 years; P < .001), and a lower incidence of relapse (19% versus 33% at 3 years; P = .001) in the TCD group compared with the RIC group. Relapse-free survival (RFS), overall survival (OS), and NRM were similar in the 2 groups. Combining transplantation approach (RIC versus TCD) and comorbidity burden (HCT-CI 0-2 versus ≥3), patients with an HCT-CI score of 0-2 seemed to benefit from the TCD approach. In conclusion, in this retrospective study, the use of a CD34(+) cell-selected graft and a myeloablative conditioning regimen was associated with higher CRFS and similar RFS and OS compared with unmodified allo-RIC in patients age >50 years with AML and MDS.
Clinical Commentary
What is known?
NIHMS931517
What did this paper set out to examine?
What did they show?
What are the implications for practice and for future work?
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6.
Reduced-intensity transplantation for lymphomas using haploidentical related donors vs HLA-matched unrelated donors
Kanate, A. S., Mussetti, A., Kharfan-Dabaja, M. A., Ahn, K. W., DiGilio, A., Beitinjaneh, A., Chhabra, S., Fenske, T. S., Freytes, C., Gale, R. P., et al
Blood. 2016;127(7):938-47
Abstract
We evaluated 917 adult lymphoma patients who received haploidentical (n = 185) or HLA-matched unrelated donor (URD) transplantation either with (n = 241) or without antithymocyte globulin (ATG; n = 491) following reduced-intensity conditioning regimens. Haploidentical recipients received posttransplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, whereas URD recipients received calcineurin inhibitor-based prophylaxis. Median follow-up of survivors was 3 years. The 100-day cumulative incidence of grade III-IV acute GVHD on univariate analysis was 8%, 12%, and 17% in the haploidentical, URD without ATG, and URD with ATG groups, respectively (P = .44). Corresponding 1-year rates of chronic GVHD on univariate analysis were 13%, 51%, and 33%, respectively (P < .001). On multivariate analysis, grade III-IV acute GVHD was higher in URD without ATG (P = .001), as well as URD with ATG (P = .01), relative to haploidentical transplants. Similarly, relative to haploidentical transplants, risk of chronic GVHD was higher in URD without ATG and URD with ATG (P < .0001). Cumulative incidence of relapse/progression at 3 years was 36%, 28%, and 36% in the haploidentical, URD without ATG, and URD with ATG groups, respectively (P = .07). Corresponding 3-year overall survival (OS) was 60%, 62%, and 50% in the 3 groups, respectively, with multivariate analysis showing no survival difference between URD without ATG (P = .21) or URD with ATG (P = .16), relative to haploidentical transplants. Multivariate analysis showed no difference between the 3 groups in terms of nonrelapse mortality (NRM), relapse/progression, and progression-free survival (PFS). These data suggest that reduced-intensity conditioning haploidentical transplantation with posttransplant cyclophosphamide does not compromise early survival outcomes compared with matched URD transplantation, and is associated with significantly reduced risk of chronic GVHD. Copyright © 2016 by The American Society of Hematology.