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Signatures of GVHD and relapse after posttransplant cyclophosphamide revealed by immune profiling and machine learning
McCurdy, S. R., Radojcic, V., Tsai, H. L., Vulic, A., Thompson, E., Ivcevic, S., Kanakry, C. G., Powell, J. D., Lohman, B., Adom, D., et al
Blood. 2022;139(4):608-623
Abstract
The key immunologic signatures associated with clinical outcomes after posttransplant cyclophosphamide (PTCy)-based HLA-haploidentical (haplo) and HLA-matched bone marrow transplantation (BMT) are largely unknown. To address this gap in knowledge, we used machine learning to decipher clinically relevant signatures from immunophenotypic, proteomic, and clinical data and then examined transcriptome changes in the lymphocyte subsets that predicted major posttransplant outcomes. Kinetics of immune subset reconstitution after day 28 were similar for 70 patients undergoing haplo and 75 patients undergoing HLA-matched BMT. Machine learning based on 35 candidate factors (10 clinical, 18 cellular, and 7 proteomic) revealed that combined elevations in effector CD4+ conventional T cells (Tconv) and CXCL9 at day 28 predicted acute graft-versus-host disease (aGVHD). Furthermore, higher NK cell counts predicted improved overall survival (OS) due to a reduction in both nonrelapse mortality and relapse. Transcriptional and flow-cytometric analyses of recovering lymphocytes in patients with aGVHD identified preserved hallmarks of functional CD4+ regulatory T cells (Tregs) while highlighting a Tconv-driven inflammatory and metabolic axis distinct from that seen with conventional GVHD prophylaxis. Patients developing early relapse displayed a loss of inflammatory gene signatures in NK cells and a transcriptional exhaustion phenotype in CD8+ T cells. Using a multimodality approach, we highlight the utility of systems biology in BMT biomarker discovery and offer a novel understanding of how PTCy influences alloimmune responses. Our work charts future directions for novel therapeutic interventions after these increasingly used GVHD prophylaxis platforms. Specimens collected on NCT0079656226 and NCT0080927627 https://clinicaltrials.gov/.
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National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2020 Etiology and Prevention Working Group Report
Williams, K. M., Inamoto, Y., Im, A., Hamilton, B., Koreth, J., Arora, M., Pusic, I., Mays, J. W., Carpenter, P. A., Luznik, L., et al
Transplantation and cellular therapy. 2021
Abstract
Preventing chronic graft-versus-host disease (GVHD) remains challenging because the unique cellular and molecular pathways that incite chronic GVHD are poorly understood. One major point of intervention for potential prevention of chronic GVHD occurs at the time of transplantation when acute donor anti-recipient immune responses first set the events in motion that result in chronic GVHD. After transplantation, additional insults causing tissue injury can incite aberrant immune responses and loss of tolerance, further contributing to chronic GVHD. Points of intervention are actively being identified so that chronic GVHD initiation pathways can be targeted without affecting immune function. The major objective in the field is to continue basic studies and to translate what is learned about etiopathology to develop targeted prevention strategies that decrease the risk of morbid chronic GVHD without increasing the risks of cancer relapse or infection. Development of strategies to predict the risk of developing debilitating or deadly chronic GVHD is a high research priority. This working group recommends further interrogation into the mechanisms underpinning chronic GVHD development, and we highlight considerations for future trial design in prevention trials.
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Shortened-Duration Tacrolimus after Nonmyeloablative, HLA-Haploidentical Bone Marrow Transplantation
Kasamon, Y. L., Fuchs, E. J., Zahurak, M., Rosner, G. L., Symons, H. J., Gladstone, D. E., Huff, C. A., Swinnen, L. J., Brodsky, R. A., Matsui, W. H., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018;24(5):1022-1028
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Abstract
With post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, nonmyeloablative HLA-haploidentical (NMA haplo) and HLA-matched blood or marrow transplantation (BMT) have comparable outcomes. Early discontinuation of immunosuppression may reduce the risk of relapse and improve immune reconstitution, but may increase the risk of GVHD. We conducted a prospective trial of NMA haplo BMT for patients with hematologic malignancies (median age, 61 years), evaluating the safety of early discontinuation of tacrolimus. All patients received T cell-replete bone marrow followed by high-dose PTCy, mycophenolate mofetil, and tacrolimus. Tacrolimus was prespecified to stop without taper at day +90, +60, or +120, contingent on having ≥5% donor T cells, no relapse, and no grade II-IV acute or significant chronic GVHD. Safety stopping rules were based on ≥5% graft failure, ≥10% nonrelapse mortality (NRM), or a ≥20% combined incidence of severe acute and chronic GVHD from the tacrolimus stop date through day +180. Of the 47 patients in the day +90 arm, 23 (49%) stopped tacrolimus as planned. Of the 55 patients in the day +60 arm, 38 (69%) stopped as planned. Safety stopping criteria were not met. In both arms, at day +180, the probability of grade II-IV acute GVHD was <40%, that of grade III-IV acute GVHD was <8%, and that of NRM was <5%. The 1-year probabilities of chronic GVHD and NRM were <15% and <10%, respectively, in both arms. The 1-year GVHD-free relapse-free survival was higher in the day 60 arm. Thus, stopping tacrolimus as early as day +60 is feasible and carries acceptable risks after NMA haplo BMT with PTCy. This approach may facilitate post-transplantation strategies for relapse reduction.
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What is known?
NIHMS969487
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What did they show?
What are the implications for practice and for future work?
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Blood and Marrow Transplant Clinical Trials Network Report on the Development of Novel Endpoints and Selection of Promising Approaches for Graft-versus-Host Disease Prevention Trials
Pasquini, M. C., Logan, B., Jones, R. J., Alousi, A. M., Appelbaum, F. R., Bolaños-Meade, J., Flowers, M. E. D., Giralt, S., Horowitz, M. M., Jacobsohn, D., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018;24(6):1274-1280
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Abstract
Graft-versus-host disease (GVHD) is a common complication after hematopoietic cell transplantation (HCT) and associated with significant morbidity and mortality. Preventing GVHD without chronic therapy or increasing relapse is a desired goal. Here we report a benchmark analysis to evaluate the performance of 6 GVHD prevention strategies tested at single institutions compared with a large multicenter outcomes database as a control. Each intervention was compared with the control for the incidence of acute and chronic GVHD and overall survival and against novel composite endpoints: acute and chronic GVHD, relapse-free survival (GRFS), and chronic GVHD, relapse-free survival (CRFS). Modeling GRFS and CRFS using the benchmark analysis further informed the design of 2 clinical trials testing GVHD prophylaxis interventions. This study demonstrates the potential benefit of using an outcomes database to select promising interventions for multicenter clinical trials and proposes novel composite endpoints for use in GVHD prevention trials.
Clinical Commentary
What is known?
NIHMS933037
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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Grade II Acute Graft-versus-Host Disease and Higher Nucleated Cell Graft Dose Improve Progression-Free Survival after HLA Haploidentical Transplant with Post-Transplant Cyclophosphamide
McCurdy, S. R., Kanakry, C. G., Tsai, H. L., Kasamon, Y. L., Showel, M. M., Bolanos-Meade, J., Huff, C. A., Borrello, I., Matsui, W. H., Brodsky, R. A., et al
Biology of Blood & Marrow Transplantation. 2017
Abstract
Compared with standard graft-versus-host disease (GVHD) prophylaxis platforms, post-transplantation cyclophosphamide (PTCy) after T cell-replete HLA-haploidentical (haplo) bone marrow transplantation (BMT) reduces the risk of grades III to IV acute (a) and chronic (c) GVHD but maintains similar rates of grade II aGVHD. Given that mild GVHD has been associated with reduced treatment failure in HLA-matched BMT, we evaluated the risk factors for and effects of GVHD on survival in 340 adults with hematologic malignancies who engrafted after nonmyeloablative haplo-BMT with PTCy, mycophenolate mofetil, and tacrolimus. The cumulative incidence at 100 days of grade II and grades III to IV aGVHD were 30% (95% confidence interval [CI], 25% to 35%) and 2% (95% CI, 1% to 4%), respectively. The 1-year cumulative incidence of cGVHD was 10% (95% CI, 7% to 13%). In landmark analyses at 100 days, the 4-year probabilities of overall survival (OS) and progression-free survival (PFS) were significantly different, at 48% (95% CI, 41% to 56%) and 39% (95% CI, 32% to 47%) for patients without grades II to IV aGVHD, compared with 63% (95% CI, 53% to 73%) and 59% (95% CI, 50% to 71%) for patients with grade II aGVHD (P=.05 and P=.009). In multivariable modeling, when compared with patients who never experienced GVHD, the hazard ratio (HR) for OS and PFS in patients with grade II aGVHD was .78 (95% CI, .54 to 1.13; P=.19) and .69 (95% CI, .48 to .98; P=.04). Higher nucleated cell graft dose was also associated with improved OS and PFS (HR, .88 [95% CI, .78 to 1.00; P=.05] and HR, .89 [95% CI, .79 to 1.0; P=.05], respectively) and decreased risk of grades III to IV aGVHD (subdistribution HR, .66; 95% CI, .46 to .96; P=.03). PTCy reduces grades III to IV aGVHD and cGVHD but retains similar incidence of grade II aGVHD, the development of which improves PFS. Higher nucleated cell graft dose goals may also improve survival after nonmyeloablative haplo-BMT with PTCy. Copyright © 2017. Published by Elsevier Inc.
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Post-Transplantation Cyclophosphamide after Bone Marrow Transplantation Is Not Associated with an Increased Risk of Donor-Derived Malignancy
Majzner, R. G., Mogri, H., Varadhan, R., Brown, P., Cooke, K. R., Bolanos-Meade, J., Swinnen, L., Kanakry, J., Luznik, L., Jones, R. J., et al
Biology of Blood & Marrow Transplantation. 2017;23(4):612-617
Abstract
Post-transplantation cyclophosphamide (PTCy) can be used for graft-versus-host disease (GVHD) prophylaxis alone or in combination with other agents and is associated with excellent rates of engraftment and acute and chronic GVHD, as well as absence of post-transplantation lymphoproliferative disease. No study has previously evaluated the risk for developing donor-derived malignancy (DDM) in patients who receive PTCy. Giving chemotherapy in the immediate post-transplantation period carries with it a theoretic risk of disturbing the graft at a time of increased hematopoietic stress and causing or accelerating the development of malignancy. From 2000 to 2011, 789 patients underwent allogeneic transplantation and received PTCy at the Johns Hopkins Hospital. There were 4 cases of DDM identified among this large population, which is similar to or below the rate of DDM published in the literature. We found that the estimated cumulative incidence by competing risk analysis of DDM is 1.4% (SE,1.02%). The use of PTCy does not appear to increase the risk of DDM.Copyright © 2017 The American Society for Blood and Marrow Transplantation. All rights reserved.