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Impact of type of reduced-intensity conditioning regimen on the outcomes of allogeneic haematopoietic cell transplantation in classical Hodgkin lymphoma
Ahmed, S., Ghosh, N., Ahn, K. W., Khanal, M., Litovich, C., Mussetti, A., Chhabra, S., Cairo, M., Mei, M., William, B., et al
British journal of haematology. 2020
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Editor's Choice
Abstract
Reduced-intensity conditioning (RIC) allogeneic haematopoietic cell transplantation (allo-HCT) is a curative option for select relapsed/refractory Hodgkin lymphoma (HL) patients; however, there are sparse data to support superiority of any particular conditioning regimen. We analyzed 492 adult patients undergoing human leucocyte antigen (HLA)-matched sibling or unrelated donor allo-HCT for HL between 2008 and 2016, utilizing RIC with either fludarabine/busulfan (Flu/Bu), fludarabine/melphalan (Flu/Mel140) or fludarabine/cyclophosphamide (Flu/Cy). Multivariable regression analysis was performed using a significance level of <0.01. There were no significant differences between regimens in risk for non-relapse mortality (NRM) (P = 0.54), relapse/progression (P = 0.02) or progression-free survival (PFS) (P = 0.14). Flu/Cy conditioning was associated with decreased risk of mortality in the first 11 months after allo-HCT (HR = 0.28; 95% CI = 0.10-0.73; P = 0.009), but beyond 11 months post allo-HCT it was associated with a significantly higher risk of mortality, (HR = 2.46; 95% CI = 0.1.32-4.61; P = 0.005). Four-year adjusted overall survival (OS) was similar across regimens at 62% for Flu/Bu, 59% for Flu/Mel140 and 55% for Flu/Cy (P = 0.64), respectively. These data confirm the choice of RIC for allo-HCT in HL does not influence risk of relapse, NRM or PFS. Although no OS benefit was seen between Flu/Bu and Flu/Mel 140; Flu/Cy was associated with a significantly higher risk of mortality beyond 11 months from allo-HCT (possibly due to late NRM events).
PICO Summary
Population
Adult patients undergoing human leucocyte antigen (HLA)-matched sibling or unrelated donor allo-HCT for Hodgkin lymphoma (n=492)
Intervention
Reduced intensity conditioning with fludarabine/busulfan (Flu/Bu, n=102) or fludarabine/melphalan (Flu/Mel140, n=318)
Comparison
Reduced intensity conditioning with fludarabine/cyclophosphamide (Flu/Cy, n=72).
Outcome
There were no significant differences between regimens in risk for non-relapse mortality (NRM), relapse/progression or progression-free survival (PFS). Flu/Cy conditioning was associated with decreased risk of mortality in the first 11 months after allo-HCT (HR = 0.28), but beyond 11 months post allo-HCT it was associated with a significantly higher risk of mortality, (HR = 2.46). Four-year adjusted overall survival (OS) was similar across regimens at 62% for Flu/Bu, 59% for Flu/Mel140 and 55% for Flu/Cy, respectively. These data confirm the choice of RIC for allo-HCT in HL does not influence risk of relapse, NRM or PFS. Although no OS benefit was seen between Flu/Bu and Flu/Mel 140; Flu/Cy was associated with a significantly higher risk of mortality beyond 11 months from allo-HCT (possibly due to late NRM events).
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Trends in postrelapse survival in classic Hodgkin lymphoma patients after experiencing therapy failure following auto-HCT
Badar, T., Epperla, N., Szabo, A., Borson, S., Vaughn, J., George, G., Saini, N., Shah, A. R., Patel, R. D., Ahmed, S., et al
Blood advances. 2020;4(1):47-54
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Abstract
Patients with classic Hodgkin lymphoma (cHL) who relapse after autologous hematopoietic cell transplantation (auto-HCT) historically have had poor outcomes. We hypothesized that, post-auto-HCT relapse, overall survival (PR-OS) has improved in recent years as a result of more widespread use of novel therapies and allogeneic HCT (allo-HCT). We conducted a retrospective study in 4 US academic centers, evaluating 215 patients who underwent auto-HCT from 2005 to 2016 and relapsed thereafter. Patients were divided into 2 cohorts based on timing of auto-HCT, 2005 through 2010 (cohort 1; n = 118) and 2011 to 2016 (cohort 2; n = 97), to compare differences in clinical outcomes. The median age and disease status at auto-HCT were similar in cohorts 1 and 2. The proportions of patients who received brentuximab vedotin (Bv; 55% vs 69%; P = .07), checkpoint inhibitors (CPIs; 3% vs 36%; P ≤ .001), and allogeneic-HCT (22% vs 35%, P = .03) were significantly different between cohorts 1 and 2, respectively. At the 5-year follow-up after auto relapse, 32% and 50% of patients were alive in cohorts 1 and 2, respectively (P = .01). In multivariate analysis for PR-OS, cohort 1 vs 2 (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.14-4.60; P = .01), age at auto-HCT (HR, 1.48; 95% CI, 1.18-1.87; P ≤ .001), and time to relapse from auto-HCT (HR, 0.59; 95% CI, 0.47-74; P ≤ .0001), retained independent prognostic significance for PR-OS. Our study supports the hypothesis that survival of cHL patients after auto-HCT failure has significantly improved in recent years, most likely because of incorporation of novel therapies and more widespread use of allo-HCT.
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Lower GVHD and relapse risk in PTCy-based Haploidentical vs Matched Sibling Donor RIC Transplant for Hodgkin Lymphoma
Ahmed, S., Kanakry, J. A., Ahn, K. W., Litovich, C., Abdel-Azim, H., Aljurf, M., Bacher, V. U., Bejanyan, N., Cohen, J. B., Farooq, U., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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Editor's Choice
Abstract
Classical Hodgkin lymphoma (cHL) patients with relapsed or refractory disease may benefit from allogeneic hematopoietic cell transplantation (allo-HCT), but many lack a matched sibling donor (MSD). Herein, we compare outcomes of two reduced-intensity conditioning (RIC) HCT platforms in cHL: T cell-replete related donor haploidentical (haplo) HCT with post-transplantation cyclophosphamide (PTCy)-based approach versus MSD/calcineurin inhibitor (CNI)-based approach. The study included 596 adult patients who underwent a first RIC allo-HCT for cHL between 2008-2016, using either haplo-PTCy (n=139) or MSD/CNI-based (n=457) approach. Overall survival (OS) was the primary endpoint. Secondary endpoints included acute (a) and (c) graft-versus-host disease (GVHD), non-relapse mortality (NRM), relapse/progression, and progression-free survival (PFS). On multivariate analysis, there was no significant difference between haplo/PTCy and MDS/CNI-based approaches in terms of OS (hazard ratio [HR]=1.07; 95%CI=0.79-1.45; p=0.66) or PFS (HR=0.86; 95%CI=0.68-1.10; p=0.22). Haplo/PTCy was associated with a significantly higher risk of grade 2-4 aGVHD (odds ratio [OR]=1.73, 95%CI=1.16-2.59, p=0.007), but the risk of grade 3-4 aGVHD was not significantly different between the two cohorts (OR=0.61, 95%CI=0.29-1.27, p=0.19). The haplo/PTCy platform provided a significant reduction in cGVHD risk (HR=0.45, 95%CI=0.32-0.64, p<0.001), and a significant reduction in relapse risk (HR=0.74, 95%CI=0.56-0.97, p=0.03). There was a statistically non-significant trend towards higher NRM with haplo/PTCy approach (HR=1.65, 95%CI=0.99-2.77, p=0.06). Haplo/PTCy-based approaches are associated with lower incidence of cGVHD and relapse, with PFS and OS outcomes comparable to MSD/CNI-based approaches. There was a leaning towards higher NRM with haplo/PTCy-based platform. These data show that haplo/PTCy allo-HCT in cHL results in survival comparable to MSD/CNI-based allo-HCT.
PICO Summary
Population
Adult patients who underwent a first RIC allo-HCT for classical Hodgkin lymphoma between 2008-2016 (n=596)
Intervention
T cell-replete related donor haploidentical HCT with post-transplantation cyclophosphamide (Haplo/PTCy) (n=139)
Comparison
Matched Sibling Donor with calcineurin inhibitor (MSD/CNI) (n=457)
Outcome
On multivariate analysis, there was no significant difference between Haplo/PTCy and MSD/CNI-based approaches in terms of overall survival or progression-free survival. Haplo/PTCy was associated with a significantly higher risk of grade 2-4 aGVHD, but the risk of grade 3-4 aGVHD was not significantly different between the two cohorts. The haplo/PTCy platform provided a significant reduction in cGVHD risk, and a significant reduction in relapse. There was a statistically non-significant trend towards higher NRM with haplo/PTCy approach.
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Survival of Lymphoma Patients Experiencing Relapse or Progression after an Allogeneic Hematopoietic Cell Transplantation
Epperla, N., Hamadani, M., Ahn, K. W., He, F., Kodali, D., Kleman, A., Hari, P. N., Pasquini, M., Fenske, T. S., Craig, M. D., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
BACKGROUND Outcome and management of patients who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) has evolved in a recent decade. Using a multi-institutional retrospective database, we report the predictive factors and survival of lymphoma patients who relapse following allo-HCT. METHODS We evaluated 495 allo-HCT recipients transplanted between 2000-2015 at three academic US medical centers. Landmark analysis evaluating predictive factors was performed at 1-month post allo-HCT relapse with primary end-point of post-relapse overall survival (PR-OS). RESULTS A total of 175 lymphoma patients (35%) experienced relapse post allo-HCT. Of these, 126 patients at the median age of 46 years (range 19-71 years) were evaluable. Most patients (86%) received subsequent therapy; 80 patients received targeted agents and 19 donor lymphocyte infusion. On univariate analysis, median PR-OS for patients with Hodgkin lymphoma was 47.9 months compared to 11.3 months in patients with indolent and 10.1 months in aggressive non-Hodgkin lymphoma (p=0.04). On multivariate analysis, post-relapse therapy administration (no therapy vs targeted therapy: HR=0.21, 95%CI=0.10-0.45; no therapy vs non-targeted therapy: HR=0.26, 95%CI=0.11-0.57), late relapse after 130 days post allo-HCT (relative to early relapse, HR 0.25; p<0.001) and ECOG performance status of 0-1 (vs ECOG ≥ 2, HR 0.49; p=0.003) were associated with a significantly reduced risk of mortality. Patients relapsing ≥130 days from the time of allo-HCT yield PR-OS of 48.8 months compared to 6.5 months in patients with early relapse (p<0.001). CONCLUSIONS Our data suggest that in the contemporaneous era, therapies used for patients experiencing post allo-HCT lymphoma relapse can extend survival.
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Effect of Routine Surveillance Imaging on the Outcomes of Patients With Classical Hodgkin Lymphoma After Autologous Hematopoietic Cell Transplantation
Kapke, J. T., Epperla, N., Shah, N., Richardson, K., Carrum, G., Hari, P. N., Pingali, S. R., Hamadani, M., Karmali, R., Fenske, T. S.
Clinical lymphoma, myeloma & leukemia. 2017;17(7):408-414
Abstract
BACKGROUND Patients with relapsed and refractory classical Hodgkin lymphoma (cHL) are often treated with autologous hematopoietic cell transplantation (auto-HCT). After auto-HCT, most transplant centers implement routine surveillance imaging to monitor for disease relapse; however, there is limited evidence to support this practice. PATIENTS AND METHODS In this multicenter, retrospective study, we identified cHL patients (n = 128) who received auto-HCT, achieved complete remission (CR) after transplantation, and then were followed with routine surveillance imaging. Of these, 29 (23%) relapsed after day 100 after auto-HCT. Relapse was detected clinically in 14 patients and with routine surveillance imaging in 15 patients. RESULTS When clinically detected relapse was compared with to radiographically detected relapse respectively, the median overall survival (2084 days [range, 225-4161] vs. 2737 days [range, 172-2750]; P = .51), the median time to relapse (247 days [range, 141-3974] vs. 814 days [range, 96-1682]; P = .30) and the median postrelapse survival (674 days [range, 13-1883] vs. 1146 days [range, 4-2548]; P = .52) were not statistically different. In patients who never relapsed after auto-HCT, a median of 4 (range, 1-25) surveillance imaging studies were performed over a median follow-up period of 3.5 years. CONCLUSION A minority of patients with cHL who achieve CR after auto-HCT will ultimately relapse. Surveillance imaging detected approximately half of relapses; however, outcomes were similar for those whose relapse was detected using routine surveillance imaging versus detected clinically in between surveillance imaging studies. There appears to be limited utility for routine surveillance imaging in cHL patients who achieve CR after auto-HCT.