Graft Versus Host Disease Associated with Immune Checkpoint Inhibitors: A Pharmacovigilance Study and Systematic Literature Review

Lee S Nguyen, Lisa Raia, Bénédicte Lebrun-Vignes, Joe-Elie Salem, Lee S Nguyen, Lisa Raia, Bénédicte Lebrun-Vignes, Joe-Elie Salem

Abstract

Background: In patients with allogenic hematopoietic stem cell transplantation (allo-HSCT), immune-checkpoint inhibitors (ICI) are used to treat malignancy recurrence. However, ICI are also associated with graft vs. host disease (GVHD). In this pharmacovigilance analysis, we aimed to characterize cases of GVHD associated with ICI, drawn from the World Health Organization pharmacovigilance database, VigiBase®, and from literature. Methods: We performed VigiBase® query of cases of GVHD associated with ICI. These cases were combined with those of literature, not reported in VigiBase®. The Bayesian estimate of disproportionality analysis, the information component, was considered significant if its 95% credibility interval lower bound was positive; denoting a significant association between GVHD and the suspected ICI. Time to onset between ICI and GVHD onset and subsequent mortality were assessed. Results: Disproportionality analysis yielded 93 cases of GVHD associated with ICI (61.8% men, median age 38 [interquartile range = 27; 50] years). Cases were mostly associated with nivolumab (53/93, 57.0%), pembrolizumab (23/93, 24.7%) and ipilimumab (12/93, 12.9%) monotherapies. GVHD events occurred after 1 [1; 5.5] injection of ICI, with a time to onset of 35 [IQR = 14; 176] days. Immediate subsequent mortality after GVHD was 24/93, 25.8%. There was no significant difference in mortality depending on the molecule (p = 0.41) or the combination regimen (combined vs. monotherapy, p = 0.60). Previous history of GVHD was present in 11/18, 61.1% in cases reported in literature. Conclusion: In this worldwide pharmacovigilance study, disproportionality yielded significant association between GVHD and ICI, with subsequent mortality of 25.8%. Previous history of GVHD was reported in more than half of cases. Clinicaltrials.gov identifier: NCT03492242.

Keywords: adverse (side) effects; graft-versus-host disease; immunotherapy; pharmacovigilance; vigibase®.

Conflict of interest statement

J-ES has participated to BMS advisory boards. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Nguyen, Raia, Lebrun-Vignes and Salem.

Figures

FIGURE 1
FIGURE 1
Evolution of information component (IC) over time of ICI associated GVHD (thru December 2019). Whiskers represent the 95% credibility interval lower and upper bounds (respectively IC025 and IC975). IC is considered significant when IC025 is >0.Statistics: IC = log2 [(Nobserved + 0.5)/(Nexpected + 0.5)], where Nexpected = (Ndrug × Neffect)/Ntotal, with Nexpected being the number of ICSRs expected for the drug-ADR combination; Nobserved being the actual number of ICSRs observed for the drug-ADR combination; Ndrug being the number of ICSRs for the drug, regardless of ADR; Neffect being the number of ICSRs for the ADR, regardless of the drug; and Ntotal being the total number of ICSRs in the database. ADR = adverse drug reaction; ICSR = individual case safety report.
FIGURE 2
FIGURE 2
Overlap between concurrent immune-related adverse events (IrAE) with graft vs. host disease events associated with immune-checkpoint inhibitors (n = 23).

References

    1. Barrett A. J., Battiwalla M. (2010). Relapse after allogeneic stem cell transplantation. Expet. Rev. Hematol. 3 (4), 429–441. 10.1586/ehm.10.32
    1. Bate A., Lindquist M., Edwards I. R., Olsson S., Orre R., Lansner A., et al. (1998). A Bayesian neural network method for adverse drug reaction signal generation. Eur. J. Clin. Pharmacol. 54 (4), 315–321. 10.1007/s002280050466
    1. Boekstegers A. M., Blaeschke F., Schmid I., Wiebking V., Immler S., Hoffmann F., et al. (2017). MRD response in a refractory paediatric T-ALL patient through anti-programmed cell death 1 (PD-1) Ab treatment associated with induction of fatal GvHD. Bone Marrow Transplant. 52 (8), 1221–1224. 10.1038/bmt.2017.107
    1. Braun M., Dunavin N., Pike M., Dias A. L., Lin T. L., Shune L., et al. (2017). Successful management of treatment-emergent chronic graft-versus-host disease of the liver following nivolumab for relapsed hodgkin's lymphoma after allogeneic stem cell transplant. Blood 130 (Suppl. 1), 5492
    1. Charles J., Giovannini D., Terzi N., Schwebel C., Sturm N., Masson D., et al. (2019). Multi-organ failure induced by Nivolumab in the context of allo-stem cell transplantation. Exp. Hematol. Oncol. 8 (1), 8 10.1186/s40164-019-0132-2
    1. Esfahani K., Al-Aubodah T.-A., Thebault P., Lapointe R., Hudson M., Johnson N. A., et al. (2019). Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation. Nat. Commun. 10 (1), 4712 10.1038/s41467-019-12628-1
    1. Geraud A., Gougis P., Vozy A., Anquetil C., Allenbach Y., Romano E., et al. (2021). Clinical Pharmacology and interplay of immune checkpoint Agents: a yin-yang balance. Annu. Rev. Pharmacol. Toxicol. 61, 85 10.1146/annurev-pharmtox-022820-093805
    1. Godfrey J., Bishop M. R., Syed S., Hyjek E., Kline J. (2017). PD-1 blockade induces remissions in relapsed classical Hodgkin lymphoma following allogeneic hematopoietic stem cell transplantation. J. Immunother. Cancer 5 (1), 11 10.1186/s40425-017-0211-z
    1. Haverkos B. M., Abbott D., Hamadani M., Armand P., Flowers M. E., Merryman R., et al. (2017). PD-1 blockade for relapsed lymphoma post–allogeneic hematopoietic cell transplant: high response rate but frequent GVHD. Blood 130 (2), 221–228. 10.1182/blood-2017-01-761346
    1. Herbaux C., Merryman R., Devine S., Armand P., Houot R., Morschhauser F., et al. (2018). Recommendations for managing PD-1 blockade in the context of allogeneic HCT in Hodgkin lymphoma: taming a necessary evil. Blood 132 (1), 9–16. 10.1182/blood-2018-02-811174
    1. Ijaz A., Khan A. Y., Malik S. U., Faridi W., Fraz M. A., Usman M., et al. (2019). Significant risk of graft-versus-host disease with exposure to checkpoint inhibitors before and after allogeneic transplantation. Biol. Blood Marrow Transplant. 25 (1), 94–99. 10.1016/j.bbmt.2018.08.028
    1. Kim S.-J., Hyeon J., Cho I., Ko Y. H., Kim W. S. (2019). Comparison of efficacy of pembrolizumab between epstein-barr virus‒positive and‒negative relapsed or refractory non-hodgkin lymphomas. Cancer Res. Treat. 51 (2), 611–622. 10.4143/crt.2018.191
    1. Klobuch S., Weber D., Holler B., Herr W., Holler E., Wolff D. (2017). Potential role of the PD-1/PD-L1 Axis in the immune regulation of chronic GVHD. Oncol. Res. Treat. 40 (7-8), 447–450. 10.1159/000471768
    1. Lindquist M. (2008). VigiBase, the WHO global ICSR database system: basic facts. Drug Inf. J. 42 (5), 409–419. 10.1177/009286150804200501
    1. Merryman R. W., Kim H. T., Zinzani P. L., Carlo-Stella C., Ansell S. M., Perales M.-A., et al. (2017). Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma. Blood 129 (10), 1380–1388. 10.1182/blood-2016-09-738385
    1. Minson A., Douglas G., Bilmon I., Grigg A. (2019). Low dose PD-1 inhibition in relapsed refractory Hodgkin lymphoma after allogeneic stem cell transplant with concomitant active GVHD. Br. J. Haematol. 184 (5), 840–844. 10.1111/bjh.15186
    1. Nahas M. R., Soiffer R. J., Kim H. T., Alyea E. P., 3rd, Arnason J., Joyce R., et al. (2018). Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease. Blood 131 (25), 2836–2845. 10.1182/blood-2017-05-780239
    1. Nguyen L. S., Dolladille C., Drici M.-D., Fenioux C., Alexandre J., Mira J.-P., et al. (2020). Cardiovascular toxicities associated with hydroxychloroquine and azithromycin: an analysis of the World Health organization pharmacovigilance database. Circulation 120, 048238 10.1161/circulationaha.120.048238
    1. Norén G. N., Hopstadius J., Bate A. (2013). Shrinkage observed-to-expected ratios for robust and transparent large-scale pattern discovery. Stat. Methods Med. Res. 22 (1), 57–69. 10.1177/0962280211403604
    1. Onizuka M., Kojima M., Matsui K., Machida S., Toyosaki M., Aoyama Y., et al. (2017). Successful treatment with low-dose nivolumab in refractory Hodgkin lymphoma after allogeneic stem cell transplantation. Int. J. Hematol. 106 (1), 141–145. 10.1007/s12185-017-2181-9
    1. Ramachandran V., Kolli S. S., Strowd L. C. (2019). Review of graft-versus-host disease. Dermatol. Clin. 37 (4), 569–582. 10.1016/j.det.2019.05.014
    1. Salem J. E., Allenbach Y., Vozy A., Brechot N., Johnson D. B., Moslehi J. J., et al. (2019a). Abatacept for severe immune checkpoint inhibitor-associated myocarditis. N. Engl. J. Med. 380 (24), 2377–2379. 10.1056/NEJMc1901677
    1. Salem J. E., Manouchehri A., Bretagne M., Lebrun-Vignes B., Groarke J. D., Johnson D. B., et al. (2019b). Cardiovascular toxicities associated with ibrutinib. J. Am. Coll. Cardiol. 74 (13), 1667–1678. 10.1016/j.jacc.2019.07.056
    1. Salem J. E., Manouchehri A., Moey M., Lebrun-Vignes B., Bastarache L., Pariente A., et al. (2018). Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 19 (12), 1579–1589. 10.1016/s1470-2045(18)30608-9
    1. Salem J. E., Yang T., Moslehi J. J., Waintraub X., Gandjbakhch E., Bachelot A., et al. (2019c). Androgenic effects on ventricular repolarization: a translational study from the international pharmacovigilance database to iPSC-cardiomyocytes. Circulation 140 (13), 1070–1080. 10.1161/CIRCULATIONAHA.119.040162
    1. Schade H., Sen S., Neff C. P., Freed B. M., Gao D., Gutman J. A., et al. (2016). Programmed death 1 expression on CD4+ T cells predicts mortality after allogeneic stem cell transplantation. Biol. Blood Marrow Transplant. 22 (12), 2172–2179. 10.1016/j.bbmt.2016.08.007
    1. Shankar B., Zhang J., Naqash A. R., Forde P. M., Feliciano J. L., Marrone K. A., et al. (2020). Multisystem immune-related adverse events associated with immune checkpoint inhibitors for treatment of non–small cell lung cancer. JAMA Oncol. 6 (12), 1952–1956. 10.1001/jamaoncol.2020.5012
    1. Singh A. K., Porrata L. F., Aljitawi O., Lin T., Shune L., Ganguly S., et al. (2016). Fatal GvHD induced by PD-1 inhibitor pembrolizumab in a patient with Hodgkin’s lymphoma. Bone Marrow Transplant. 51 (9), 1268–1270. 10.1038/bmt.2016.111

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