Low immunosuppressive burden after HLA-matched related or unrelated BMT using posttransplantation cyclophosphamide

Kanakry, Christopher G.; Bolaños-Meade, Javier; Kasamon, Yvette L.; Zahurak, Marianna; Duraković, Nadira; Furlong, Terry; Mielcarek, Marco; Medeot, Marta; Gojo, Ivana; Smith, B. Douglas; Kanakry, Jennifer A.; Borrello, Ivan; Brodsky, Robert A.; Gladstone, Douglas E.; Huff, Carol Ann; Matsui, William; Swinnen, Lode J.; Cooke, Kenneth R.; Ambinder, Richard F.; Fuchs, Ephraim J.; Lima, Marcos J.G. de; Andersson, Börje S.; Varadhan, Ravi; O’Donnell, Paul V.; Jones, Richard J.; Luznik, Leo

doi:10.1182/blood-2016-09-737825

Cited by 77 publications

(60 citation statements)

References 25 publications

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“…Most importantly, and by definition, GVHD prophylaxis was inherently different among groups. As results of allo-HCT using the PTCy bone marrow platform in HLA-compatible settings emerge, 33 heterogeneity in the groups, as the number of patients identified in the 2 registries who were transplanted using a myeloablative conditioning regimen was ,20 in the haplo group. NMC/RIC allotransplants represent a significant proportion of this activity in patients with DLBCL; allo-HCT is most frequently used when patients fail auto-HCT, and information coming from some registry analyses indicates that the intensity of the conditioning regimen does not significantly modify the outcome of the procedure.…”

Section: Discussionmentioning

confidence: 99%

PTCy-based haploidentical vs matched related or unrelated donor reduced-intensity conditioning transplant for DLBCL

et al. 2019

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This study retrospectively compared long-term outcomes of nonmyeloablative/reduced intensity conditioning (NMC/RIC) allogeneic hematopoietic cell transplantation (allo-HCT) from a haploidentical family donor (haplo-HCT) using posttransplant cyclophosphamide (PTCy) with those of matched sibling donor (MSD) and matched unrelated donor (MUD) with or without T-cell depletion (TCD+/TCD−) in patients with relapsed diffuse large B-cell lymphoma (DLBCL). Adult patients with DLBCL who had undergone their first NMC/RIC allo-HCT between 2008 and 2015 were included. Recipients of haplo-HCT were limited to those receiving graft-versus-host disease (GVHD) prophylaxis with PTCy. GVHD prophylaxis in MSD was limited to calcineurin inhibitor (CNI)–based approaches without in vivo TCD, while MUD recipients received CNI-based prophylaxis with or without TCD. Outcome analyses for overall survival (OS) and progression-free survival (PFS), nonrelapse mortality (NRM), and disease relapse/progression were calculated. A total of 1438 patients (haplo, 132; MSD, 525; MUD TCD+, 403; and MUD TCD−, 378) were included. Patients with haplo donors were significantly older, had a better performance status and had more frequently received total body irradiation-based conditioning regimens and bone marrow grafts than MSD and MUD TCD+ or TCD−. 3-year OS, PFS, NRM and relapse/progression incidence after haplo-HCT was 46%, 38%, 22%, and 41%, respectively, and not significantly different from outcomes of matched donor transplants on multivariate analyses. Haplo-HCT was associated with a lower cumulative incidence of chronic GVHD compared with MSD, MUD TCD+/TCD−. NMC/RIC haplo-HCT with PTCy seems to be a valuable alternative for patients with DLBCL considered for allo-HCT but lacking a matched donor.

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Section: Discussionmentioning

confidence: 99%

PTCy-based haploidentical vs matched related or unrelated donor reduced-intensity conditioning transplant for DLBCL

et al. 2019

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“…This supports the avoidance of systemic immunosuppression to treat skin-only grade II aGVHD, when possible, because most cases can be watched expectantly without necessitating the reinitiation of immunosuppression; such an approach could limit side effects, infectious risk, and maintain the graft-versus-tumor effects of GVHD. We have previously shown that PTCy minimizes the global immunosuppressive burden experienced by patients undergoing HLA-matched BMT [15], and this work emphasizes the importance of exploring the further minimization of pharmacologic agents post-transplant in other platforms such as reported recently by our group in haplo BMT with PTCy [39]. Although this and other recent studies [9,15,39,40] suggest that potent anti-tumor immune responses are maintained with PTCy, fully deciphering these interactions requires further mechanistic studies.…”

Section: Discussionmentioning

confidence: 99%

“…with mesna on days +3 and +4. No additional immunosuppression was given unless patients developed extracutaneous aGVHD, grade IV cutaneous aGVHD, moderate/severe cGVHD, or required it for other reasons such as engraftment syndrome [15]. …”

Section: Methodsmentioning

confidence: 99%

Development of Grade II Acute Graft-versus-Host Disease Is Associated with Improved Survival after Myeloablative HLA-Matched Bone Marrow Transplantation using Single-Agent Post-Transplant Cyclophosphamide

McCurdy

Kanakry

Tsai

et al. 2019

Biology of Blood and Marrow Transplantation

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Post-transplant cyclophosphamide (PTCy) can be used as the sole immunosuppression after myeloablative conditioning (MAC) for HLA-matched bone marrow transplantation (BMT). However, the effects of graft-versus-host disease (GVHD) with this platform are undefined. We retrospectively analyzed 298 consecutive adult patients with hematologic malignancies who engrafted after MAC HLA-matched sibling donor (MSD; n = 187) or HLA-matched unrelated donor (MUD; n = 111) T-cell-replete BMT with PTCy 50 mg/kg on days +3 and +4. After MSD and MUD BMT, 35% and 57% of patients, respectively, developed grade II acute GVHD (aGVHD) by 100 days, 11% and 14% grade III to IV aGVHD by 100 days, and 9% and 16% chronic GVHD (cGVHD) by 1 year. In landmark analyses at 100 days after HLA-matched BMT, 4-year overall survival (OS) and progression-free survival (PFS) were 57% (95% confidence interval [CI], .49 to .67) and 40% (95% CI, .31 to .51) in patients without grades II to IV aGVHD, and 68% (95% CI, .59 to .78) and 54% (95% CI, .44 to .65) in patients with grade II aGVHD. In adjusted time-dependent multivariable analyses, grade II aGVHD was associated with improved OS (hazard ratio, .58; 95% CI, .37 to .89; P = .01) and PFS (hazard ratio, .50; 95% CI, .34 to .74; P < .001) after HLA-matched BMT with PTCy. The ability of PTCy to limit grades III to IV aGVHD and cGVHD while maintaining grade II aGVHD may contribute to its effectiveness, and further attempts to reduce aGVHD may be detrimental.

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“…This cytotoxic effect is observed in actively replicating as well as resting, non-replicating cells. Therefore, CYP has gained attraction as an immunosuppressive treatment in a number of autoimmune disorders, such as rheumatoid arthritis, vasculitis, and systemic lupus erythematosus, and also for chronic graft-versus-host disease in recipients of allogeneic stem cell transplants [17].…”

Section: Neutrophilic Rebound Response To Cypmentioning

confidence: 99%

The potential use of physical resilience to predict healthy aging

Schorr

Carter

Ladiges

2017

Pathobiology of Aging & Age-related Diseases

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Physical resilience is the ability of an organism to respond to stressors that acutely disrupt normal physiological homeostasis. By definition, resilience decreases with increasing age, while frailty, defined as a decline in tissue function, increases with increasing age. Assessment of resilience could therefore be an informative early paradigm to predict healthy aging compared to frailty, which measures late life dysfunction. Parameters for resilience in the laboratory mouse are not yet well defined, and no single standardized stress test exists. Since aging involves multiple genetic pathways, integrative responses involving multiple tissues, organs, and activities need to be measured to reveal the overall resilience status, suggesting a battery of stress tests, rather than a single all-encompassing one, would be most informative. Three simple, reliable, and inexpensive stressors are described in this review that could be used as a panel to determine levels of resilience. Brief cold water immersion allows a recovery time to normothermia as an indicator of resilience to hypothermia, i.e. the quicker the return to normal body temperature, the more robust the resilience. Sleep deprivation (SD) impairs remote memory in aged mice, and has detrimental effects on glucose metabolism. Cyclophosphamide (CYP) targets white blood cells, especially myeloid cells resulting in neutropenia with a rebound neutrophilia in an age-dependent manner. Thus a strong neutrophilic response indicates resilience. In conclusion, resilience promises to be an especially useful measurement of biological age, i.e. how fast a particular organ or tissue ages. The three stressors, cold, SD, and CYP, are applicable to human medicine and aging because they represent clinically relevant stress conditions that have effects in an age-dependent manner. They are thus an attractive perturbation for resilience testing in mice to measure the effectiveness of interventions that target basic aging processes.

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Low immunosuppressive burden after HLA-matched related or unrelated BMT using posttransplantation cyclophosphamide

Cited by 77 publications

References 25 publications

PTCy-based haploidentical vs matched related or unrelated donor reduced-intensity conditioning transplant for DLBCL

PTCy-based haploidentical vs matched related or unrelated donor reduced-intensity conditioning transplant for DLBCL

Development of Grade II Acute Graft-versus-Host Disease Is Associated with Improved Survival after Myeloablative HLA-Matched Bone Marrow Transplantation using Single-Agent Post-Transplant Cyclophosphamide

The potential use of physical resilience to predict healthy aging

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