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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).
2.
Improved GRFS after posttransplant cyclophosphamide-based vs ATG-based HLA-mismatched unrelated donor transplant
Jimenez Jimenez, A. M., Komanduri, K., Brown, S., Wang, T. P., Pereira, D. L., Goodman, M., Beitinjaneh, A., Lekakis, L. J., Chinapen, S., Devlin, S. M., et al
Blood advances. 2022
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Editor's Choice
Abstract
A common method to prevent graft versus host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) from an HLA-mismatched unrelated donor (MMUD) is tacrolimus, methotrexate and anti-thymocyte globulin (ATG). The use of post-transplant cyclophosphamide (PTCy) demonstrated promise in a prospective trial for MMUD HCT. We compared one-year GVHD-free, relapse-free survival (GRFS) in 128 recipients of tacrolimus/methotrexate/ATG (ATG group, N = 46) with PTCy, mycophenolate mofetil, and tacrolimus or sirolimus (PTCy group, N = 82) based prophylaxis after MMUD HCT. Patients receiving HCT from a MMUD mismatched at ≥ 1 locus among HLA-A, -B, -C, and -DRB1 were included. The two groups were well matched for HCT indication, high-risk disease, and HCT comorbidity index, whereas more patients on PTCy received bone marrow (50% versus 26%, P = 0.01) and >1 locus HLA-mismatched grafts (30.5% vs. 2.2%, P = 0.001). The one-year GRFS was 16% (95% confidence interval: 8% - 31%) versus 54% (44% - 66%, P < 0.001) in the ATG and PTCy groups, respectively. The multivariable-adjusted hazard ratio (HR) for GRFS was 0.34 (0.21 - 0.55, P < 0.001) with the use of PTCy. The one-year overall survival (OS) in the ATG group was 45% (32% - 62%) versus 75% (66% - 85%) in the PTCy group (P < 0.001). Relapse incidence was similar. One-year non-relapse mortality was greater after ATG-based prophylaxis: (38%, 23% - 52%; versus 16%, 9% - 25%; P < 0.001). In summary, PTCy based prophylaxis resulted in superior GRFS and OS in recipients of MMUD.
PICO Summary
Population
Adults from 11 centres in USA, transplanted from a mismatched unrelated donor, mismatched at ≥ 1 locus among HLA-A, -B, -C, and -DRB1.
Intervention
Methotrexate 5 to 15 mg/m2 IV, on days 1, 3, 6, and 11 post-HCT, peritransplant dose-adjusted tacrolimus, and 5 to 7.5 mg/kg rabbit ATG, before allograft infusion. (ATG group, n= 46)
Comparison
50 mg/kg IV cyclophosphamide on days 3 and 4, post-allograft infusion (PTCy group, n= 82)
Outcome
The one-year GRFS was 16% (95% confidence interval: 8% - 31%) versus 54% (44% - 66%,) in the ATG and PTCy groups, respectively. The multivariable-adjusted hazard ratio (HR) for GRFS was 0.34 (0.21 - 0.55) with the use of PTCy. The one-year overall survival (OS) in the ATG group was 45% (32% - 62%) versus 75% (66% - 85%) in the PTCy group. Relapse incidence was similar. One-year non-relapse mortality was greater after ATG-based prophylaxis: (38%, 23% - 52%; versus 16%, 9% - 25%).
3.
Comparison of outcomes following transplantation with T-replete HLA-haploidentical donors using post-transplant cyclophosphamide to matched related and unrelated donors for patients with AML and MDS aged 60 years or older
Bashey, Z. A., Zhang, X., Brown, S., Jackson, K., Morris, L. E., Holland, H. K., Bashey, A., Solomon, S. R., Solh, M.
Bone marrow transplantation. 2018
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Editor's Choice
Abstract
Allografting from HLA-haploidentical donors (HID) is being increasingly utilized worldwide for patients lacking a conventional matched donor. However, its efficacy in older patients with AML and MDS is unclear. We analyzed 127 consecutive allografts for AML/MDS patients aged ≥ 60 years at our center to compare outcomes using HID to those of contemporaneous transplants using matched sibling (MRD) or matched unrelated (MUD) donors. Patient characteristics were similar except HID transplants were more likely in non-white patients and were more commonly performed with reduced intensity conditioning and a marrow graft. For MRD, MUD and HID transplants respectively, 2-year estimates of non-relapse mortality (17, 23, and 9%), relapse (32, 34, and 33%), overall survival (OS) (62, 55, and 67%) and disease-free survival (DFS) (51, 43, and 58%) were not significantly different. Maximum cumulative incidences of grade 2-4 acute GVHD were not different (27, 37, 39%), but incidences of NIH grade moderate to severe (39, 35, 15%, p = 0.028 MUD vs. HID, p = 0.026 MRD vs. HID) and severe chronic GVHD (9, 12, 0%, p = 0.030 MUD vs. HID, p = 0.009 MRD vs. HID) were significantly higher in MRD and MUD than in HID transplants. On multivariable analysis, donor type was not a significant determinant of OS, DFS, TRM, or relapse. However, male gender and high/very high Disease Risk Index (DRI) were associated with significantly higher rates of relapse (HR 1.94, p = 0.047 for male gender, HR 2.48, p = 0.004 for high/very high DRI) and lower OS (HR 1.94, p = 0.018 for male gender, HR 1.80, p = 0.025 for high/very high DRI). HIDs are an acceptable alternative to matched donors in older patients with AML and MDS.