Skip to main navigation menu Skip to main content Skip to site footer

Original article

Vol. 149 No. 4546 (2019)

Toxicity associated with PD-1 blockade after allogeneic haematopoietic cell transplantation

DOI
https://doi.org/10.4414/smw.2019.20150
Cite this as:
Swiss Med Wkly. 2019;149:w20150
Published
10.11.2019

Abstract

Cancer immunotherapy with immune checkpoint inhibitors (ICIs) such as programmed death ligand-1 (PD-L1) blockers offers pronounced clinical benefit with durable responses and a manageable safety profile. Patients with a high risk of immune-related adverse events are generally excluded from clinical trials testing ICI therapy. Thus, only a little information on the safety and clinical outcome of patients treated with an ICI after allogeneic haematopoietic cell transplantation (HCT) is currently available. Here, we report the characteristics and outcomes of six patients with, respectively, clear cell renal carcinoma, diffuse large cell B-cell lymphoma, Hodgkin lymphoma, a microsatellite instable colorectal cancer and melanoma who were treated with PD-1 blocking antibodies. All patients had previously undergone allogeneic HCT. Severe grade 3–5 immune-related adverse events were observed in three of five patients who received full-dose ICI therapy. One patient received a lower dose of PD-1 blocking antibody. Only one patient had an objective response, whereas all the other patients had progressive disease. The high toxicity of a full- dose anti-PD-1 treatment regimen suggests that other treatment approaches for patients after allogeneic HCT are needed outside of the context of relapsed Hodgkin disease. In cases where ICI therapy is the only treatment option, reduced dosing should be explored.

References

  1. Haslam A, Prasad V. Estimation of the Percentage of US Patients With Cancer Who Are Eligible for and Respond to Checkpoint Inhibitor Immunotherapy Drugs. JAMA Netw Open. 2019;2(5):e192535. doi:.https://doi.org/10.1001/jamanetworkopen.2019.2535
  2. Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348(6230):56–61. doi:.https://doi.org/10.1126/science.aaa8172
  3. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27(4):450–61. doi:.https://doi.org/10.1016/j.ccell.2015.03.001
  4. Ramchandren R, Domingo-Domènech E, Rueda A, Trněný M, Feldman TA, Lee HJ, et al. Nivolumab for Newly Diagnosed Advanced-Stage Classic Hodgkin Lymphoma: Safety and Efficacy in the Phase II CheckMate 205 Study. J Clin Oncol. 2019;37(23):1997–2007. doi:.https://doi.org/10.1200/JCO.19.00315
  5. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–9. doi:.https://doi.org/10.1056/NEJMoa1411087
  6. Green MR, Rodig S, Juszczynski P, Ouyang J, Sinha P, O’Donnell E, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res. 2012;18(6):1611–8. doi:.https://doi.org/10.1158/1078-0432.CCR-11-1942
  7. Michonneau D, Sagoo P, Breart B, Garcia Z, Celli S, Bousso P. The PD-1 Axis Enforces an Anatomical Segregation of CTL Activity that Creates Tumor Niches after Allogeneic Hematopoietic Stem Cell Transplantation. Immunity. 2016;44(1):143–54. doi:.https://doi.org/10.1016/j.immuni.2015.12.008
  8. Haverkos BM, Abbott D, Hamadani M, Armand P, Flowers ME, Merryman R, et al. PD-1 blockade for relapsed lymphoma post-allogeneic hematopoietic cell transplant: high response rate but frequent GVHD. Blood. 2017;130(2):221–8. doi:.https://doi.org/10.1182/blood-2017-01-761346
  9. Herbaux C, Gauthier J, Brice P, Drumez E, Ysebaert L, Doyen H, et al. Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma. Blood. 2017;129(18):2471–8. doi:.https://doi.org/10.1182/blood-2016-11-749556
  10. Ijaz A, Khan AY, Malik SU, Faridi W, Fraz MA, Usman M, et al. Significant Risk of Graft-versus-Host Disease with Exposure to Checkpoint Inhibitors before and after Allogeneic Transplantation. Biol Blood Marrow Transplant. 2019;25(1):94–9. doi:.https://doi.org/10.1016/j.bbmt.2018.08.028
  11. Onizuka M, Kojima M, Matsui K, Machida S, Toyosaki M, Aoyama Y, et al. Successful treatment with low-dose nivolumab in refractory Hodgkin lymphoma after allogeneic stem cell transplantation. Int J Hematol. 2017;106(1):141–5. doi:.https://doi.org/10.1007/s12185-017-2181-9
  12. Yared JA, Hardy N, Singh Z, Hajj S, Badros AZ, Kocoglu M, et al. Major clinical response to nivolumab in relapsed/refractory Hodgkin lymphoma after allogeneic stem cell transplantation. Bone Marrow Transplant. 2016;51(6):850–2. doi:.https://doi.org/10.1038/bmt.2015.346
  13. Younes A, Santoro A, Shipp M, Zinzani PL, Timmerman JM, Ansell S, et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016;17(9):1283–94. doi:.https://doi.org/10.1016/S1470-2045(16)30167-X
  14. Armand P, Shipp MA, Ribrag V, Michot JM, Zinzani PL, Kuruvilla J, et al. Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure. J Clin Oncol. 2016;34(31):3733–9. doi:.https://doi.org/10.1200/JCO.2016.67.3467
  15. Armand P, Engert A, Younes A, Fanale M, Santoro A, Zinzani PL, et al. Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial. J Clin Oncol. 2018;36(14):1428–39. doi:.https://doi.org/10.1200/JCO.2017.76.0793
  16. Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A, et al.; ECHELON-1 Study Group. Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin’s Lymphoma. N Engl J Med. 2018;378(4):331–44. doi:.https://doi.org/10.1056/NEJMoa1708984
  17. Bashey A, Medina B, Corringham S, Pasek M, Carrier E, Vrooman L, et al. CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood. 2009;113(7):1581–8. doi:.https://doi.org/10.1182/blood-2008-07-168468
  18. Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, et al.; Leukemia and Lymphoma Society Blood Cancer Research Partnership. Ipilimumab for Patients with Relapse after Allogeneic Transplantation. N Engl J Med. 2016;375(2):143–53. doi:.https://doi.org/10.1056/NEJMoa1601202
  19. Blazar BR, Carreno BM, Panoskaltsis-Mortari A, Carter L, Iwai Y, Yagita H, et al. Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-gamma-dependent mechanism. J Immunol. 2003;171(3):1272–7. doi:.https://doi.org/10.4049/jimmunol.171.3.1272
  20. Saha A, Aoyama K, Taylor PA, Koehn BH, Veenstra RG, Panoskaltsis-Mortari A, et al. Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. Blood. 2013;122(17):3062–73. doi:.https://doi.org/10.1182/blood-2013-05-500801
  21. Saha A, O’Connor RS, Thangavelu G, Lovitch SB, Dandamudi DB, Wilson CB, et al. Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality. J Clin Invest. 2016;126(7):2642–60. doi:.https://doi.org/10.1172/JCI85796
  22. Juchem KW, Sacirbegovic F, Zhang C, Sharpe AH, Russell K, McNiff JM, et al. PD-L1 Prevents the Development of Autoimmune Heart Disease in Graft-versus-Host Disease. J Immunol. 2018;200(2):834–46. doi:.https://doi.org/10.4049/jimmunol.1701076
  23. Fujiwara H, Maeda Y, Kobayashi K, Nishimori H, Matsuoka K, Fujii N, et al. Programmed death-1 pathway in host tissues ameliorates Th17/Th1-mediated experimental chronic graft-versus-host disease. J Immunol. 2014;193(5):2565–73. doi:.https://doi.org/10.4049/jimmunol.1400954
  24. Danylesko I, Shimoni A. Second Malignancies after Hematopoietic Stem Cell Transplantation. Curr Treat Options Oncol. 2018;19(2):9. doi:.https://doi.org/10.1007/s11864-018-0528-y
  25. Roziakova L, Bojtarova E, Mistrik M, Mladosievicova B. Secondary malignancies after hematopoietic stem cell transplantation. Neoplasma. 2011;58(1):1–8. doi:.https://doi.org/10.4149/neo_2011_01_1

Most read articles by the same author(s)

1 2 > >>