A fatal allo- and immune-mediated thrombocytopenia with a PD-L1 inhibitor

A fatal allo- and immune-mediated thrombocytopenia with a PD-L1 inhibitor PD1/PD-L1 inhibitors can be prescribed as second-line treatment and have also emerged as a first-line treatment in non-small-cell lung cancer patients (in patients with high PD-L1 expression) [1]. While these inhibitors are generally well-tolerated, adverse uncommon immune-related events can still occur which need to be addressed to prevent negative effects on outcome. A 39-year-old-man with metastatic non-small-cell lung cancer (stage IV adenocarcinoma), without oncogenic addiction, was initially treated in a clinical trial with the PD-L1 inhibitor durvalumab (from April to September 2016). The PD-L1 inhibitor was discontinued because of disease progression and platinum-based chemotherapy (carboplatin with pemetrexed) was then initiated, rapidly followed by another chemotherapy (paclitaxel with bevacizumab) (Figure 1). Figure 1. View largeDownload slide Evolution of platelets under treatment. Figure 1. View largeDownload slide Evolution of platelets under treatment. In November, he received his first platelet transfusion because of grade 4 thrombocytopenia. He was then transfused daily from the 9th to the 22nd of December without improvement. To explore this severe thrombocytopenia, which appeared 2 months after cessation of treatment with the PD-L1 inhibitor, a bone marrow examination was carried out and the results confirmed immune-mediated peripheral thrombocytopenia. Blood tests revealed the presence of human platelet antigen (HPA) integrins GPIib/IIIa and GPIaIIa autoantibodies and anti-HLA alloantibodies. These antibodies were not detected in April before PD-L1 inhibitor treatment, nor in August and September during PD-L1 inhibitor treatment. Polyvalent immunoglobulins (25 g/day for 4 days) and steroid treatment (1 mg/kg) were administered unsuccessfully. The patient sadly passed away 36 days after the first transfusion due to intra-alveolar hemorrhage. Immune-mediated peripheral thrombocytopenia has already been described in metastatic melanoma treated with ipilimumab: 6 out of the 10 patients required therapy but were deemed steroid refractory. No fatal hemorrhage was reported [2–4]. In the case described above, it appears that two mechanisms may be involved. First, the production of anti-HPA auto-antibodies at the end of treatment with the PD-L1 inhibitor was aggravated by chemotherapy-induced thrombocytopenia. Secondly, the condition was exacerbated by transfusion via anti platelet allo-immunization. The PD-L1 inhibitor seems to be able to interfere with HPA tolerance, with production of anti-HPA auto-antibodies causing autoimmune thrombocytopenia. This event, concomitant with the production of anti HLA alloantibodies, can explain the refractory and deadly character of the thrombocytopenia experienced by the patient. We present the first case, to our knowledge, of immune-mediated thrombocytopenia after treatment with a PD-L1 inhibitor, associated with alloimmunization from platelet transfusion, which was refractory and fatal. This supports the view that checkpoint inhibitors can generate immune related hematologic events. Funding None declared. Disclosure The authors have declared no conflicts of interest. References 1 Reck M, Rodríguez-Abreu D, Robinson AG et al.   Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med  2016; 375( 19): 1823– 1833. Google Scholar CrossRef Search ADS PubMed  2 Sagjjad M, Georget T, Weber JS et al.   Thrombocytopenia associated with ipilimumab therapy of advanced melanoma at a single institution. J Clin Oncol  2013; 31(Suppl 15): 9072. 3 Kopecky J, TRojanova P., Kubecek O. and al. Treatment possibilities of ipilimumab-induced thrombocytopenia–case study and literature review. Jpn J Clin Oncol  2015; 45( 4): 381– 384. Google Scholar CrossRef Search ADS PubMed  4 Ahmad S, Lewis M, Corrie P et al.   Ipilimumab-induced thrombocytopenia in a patient with metastatic melanoma. J Oncol Pharm Pract  2012; 18( 2): 287– 292. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Oncology Oxford University Press

A fatal allo- and immune-mediated thrombocytopenia with a PD-L1 inhibitor

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Publisher
Oxford University Press
Copyright
© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
ISSN
0923-7534
eISSN
1569-8041
D.O.I.
10.1093/annonc/mdx693
Publisher site
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Abstract

PD1/PD-L1 inhibitors can be prescribed as second-line treatment and have also emerged as a first-line treatment in non-small-cell lung cancer patients (in patients with high PD-L1 expression) [1]. While these inhibitors are generally well-tolerated, adverse uncommon immune-related events can still occur which need to be addressed to prevent negative effects on outcome. A 39-year-old-man with metastatic non-small-cell lung cancer (stage IV adenocarcinoma), without oncogenic addiction, was initially treated in a clinical trial with the PD-L1 inhibitor durvalumab (from April to September 2016). The PD-L1 inhibitor was discontinued because of disease progression and platinum-based chemotherapy (carboplatin with pemetrexed) was then initiated, rapidly followed by another chemotherapy (paclitaxel with bevacizumab) (Figure 1). Figure 1. View largeDownload slide Evolution of platelets under treatment. Figure 1. View largeDownload slide Evolution of platelets under treatment. In November, he received his first platelet transfusion because of grade 4 thrombocytopenia. He was then transfused daily from the 9th to the 22nd of December without improvement. To explore this severe thrombocytopenia, which appeared 2 months after cessation of treatment with the PD-L1 inhibitor, a bone marrow examination was carried out and the results confirmed immune-mediated peripheral thrombocytopenia. Blood tests revealed the presence of human platelet antigen (HPA) integrins GPIib/IIIa and GPIaIIa autoantibodies and anti-HLA alloantibodies. These antibodies were not detected in April before PD-L1 inhibitor treatment, nor in August and September during PD-L1 inhibitor treatment. Polyvalent immunoglobulins (25 g/day for 4 days) and steroid treatment (1 mg/kg) were administered unsuccessfully. The patient sadly passed away 36 days after the first transfusion due to intra-alveolar hemorrhage. Immune-mediated peripheral thrombocytopenia has already been described in metastatic melanoma treated with ipilimumab: 6 out of the 10 patients required therapy but were deemed steroid refractory. No fatal hemorrhage was reported [2–4]. In the case described above, it appears that two mechanisms may be involved. First, the production of anti-HPA auto-antibodies at the end of treatment with the PD-L1 inhibitor was aggravated by chemotherapy-induced thrombocytopenia. Secondly, the condition was exacerbated by transfusion via anti platelet allo-immunization. The PD-L1 inhibitor seems to be able to interfere with HPA tolerance, with production of anti-HPA auto-antibodies causing autoimmune thrombocytopenia. This event, concomitant with the production of anti HLA alloantibodies, can explain the refractory and deadly character of the thrombocytopenia experienced by the patient. We present the first case, to our knowledge, of immune-mediated thrombocytopenia after treatment with a PD-L1 inhibitor, associated with alloimmunization from platelet transfusion, which was refractory and fatal. This supports the view that checkpoint inhibitors can generate immune related hematologic events. Funding None declared. Disclosure The authors have declared no conflicts of interest. References 1 Reck M, Rodríguez-Abreu D, Robinson AG et al.   Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med  2016; 375( 19): 1823– 1833. Google Scholar CrossRef Search ADS PubMed  2 Sagjjad M, Georget T, Weber JS et al.   Thrombocytopenia associated with ipilimumab therapy of advanced melanoma at a single institution. J Clin Oncol  2013; 31(Suppl 15): 9072. 3 Kopecky J, TRojanova P., Kubecek O. and al. Treatment possibilities of ipilimumab-induced thrombocytopenia–case study and literature review. Jpn J Clin Oncol  2015; 45( 4): 381– 384. Google Scholar CrossRef Search ADS PubMed  4 Ahmad S, Lewis M, Corrie P et al.   Ipilimumab-induced thrombocytopenia in a patient with metastatic melanoma. J Oncol Pharm Pract  2012; 18( 2): 287– 292. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Annals of OncologyOxford University Press

Published: Feb 1, 2018

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