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An Episode of Pseudothrombocytopenia during Pembrolizumab Therapy in NSCLC Patient

An Episode of Pseudothrombocytopenia during Pembrolizumab Therapy in NSCLC Patient Hindawi Case Reports in Oncological Medicine Volume 2020, Article ID 4196178, 4 pages https://doi.org/10.1155/2020/4196178 Case Report An Episode of Pseudothrombocytopenia during Pembrolizumab Therapy in NSCLC Patient 1,2 1 1 1 Kinga Krukowska , Robert Kieszko, Katarzyna Kurek, Izabela Chmielewska, 1 1 Paweł Krawczyk, and Janusz Milanowski Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Poland Genetics and Immunology Laboratory, GENIM LLC, Lublin, Poland Correspondence should be addressed to Kinga Krukowska; kingakrukowska@gmail.com Received 28 August 2019; Accepted 23 April 2020; Published 9 May 2020 Academic Editor: Josep M. Ribera Copyright © 2020 Kinga Krukowska et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Immunotherapy with immune checkpoint inhibitors (ICI) is a new option of treatment in a growing range of neoplasms. In addition to an antitumor effect, ICI are associated with autoimmune reactions resulting in a wide spectrum of toxicities that have not been seen in patients receiving chemotherapy. In this article, we present a case of a patient with advanced lung adenocarcinoma who developed an EDTA-dependent pseudothrombocytopenia (PTCP) during pembrolizumab therapy. To the best of our knowledge, this is the first reported case of EDTA-dependent PTCP occurring during immunotherapy treatment of nonsmall lung cell cancer with ICI. The phenomenon of EDTA-dependent PTCP may prompt clinical decisions, as unnecessary transfusions or even exclusion from pembrolizumab therapy. Therefore, it is important to be aware of PTCP as a possible side effect of this therapy. 1. Introduction bladder cancer, renal cell carcinoma, and other types of cancer [1–4]. Immunotherapy with immune checkpoint inhibitors target- Although immune checkpoint inhibitors (ICI) therapy ing programmed cell death 1 receptor (PD-1), programmed have shown clinical benefits and general good tolerance, the death ligand 1 (PD-L1), or cytotoxic T lymphocyte- literature describes many cases of immune-related adverse associated antigen 4 (CTLA-4) is a profitable cancer treat- events (irAEs), particularly in the treatment of NSCLC or melanoma patients [5, 6]. Fatigue is the most frequently ment strategy. It has demonstrated advantageous outcomes in clinical practice including regression of advanced tumors mentioned irAE correlated to PD-1, PD-L1, or CTLA-4 and improvement of overall survival. The mechanism of blockade. ESMO (European Society of Medical Oncology) action of monoclonal anti-PD-1 antibodies, such as pembro- Clinical Practice Guidelines reports other clinically significant lizumab and nivolumab, involves a selective inhibition of immune-related toxicities: skin-affected toxicity (rash, PD-1 receptor on lymphocytes. The atezolizumab and dur- pruritus, and vitiligo), endocrinopathies (thyroid gland disor- valumab block PD-L1 activity on tumor cells and infiltrating ders, hypophysitis), hepatotoxicity, gastrointestinal toxicity immune cells. Ipilimumab efficiently binds to CTLA-4 (colitis, diarrhea, nausea, vomiting, abdominal pain), or pneu- receptor on activated T cells. In consequence, coinhibitory monitis. Apart from those mentioned above, neurological, signals are disturbed allowing the antitumor immune renal, cardiac, or haematological toxicities rarely occur [7, 8]. response to be restored. Immunotherapy might be used in Thrombocytopenia is a common entity in patients with monotherapy as well as in combination with chemotherapy malignant diseases, especially during systemic chemotherapy or radiotherapy in several malignancies including advanced treatment. It is defined as a platelet count of less than 150 000 stage nonsmall cell lung carcinoma (NSCLC), melanoma, cells/μL. When the platelet count falls to 10 000 cells/μL 2 Case Reports in Oncological Medicine Figure 1: The CT scan showed new target lesion situated paravertebrally in the left lung. Figure 2: Brain metastatic lesion in left occipital lobe with spontaneous bleeding may occur increasing the risk of sur- dimensions of 2:5cm × 2:1cm × 2:9cm. gical complications [9]. It may be caused by a central mechanism, as a consequence of bone marrow infiltration or as a result of treatment toxicity, a peripheral mecha- After third cycle of chemotherapy, the patient developed nism as it occurs, in microangiopathic disorders as dis- neutropenia (neutrophil count of 780 cells/μL) and anemia seminated intravascular coagulation (DIC), vasculitis or (erythrocytes count of 3.35 million cells/μL, haemoglobin hemolytic uremic syndrome (HUS) or both. [10–12]. Dur- concentration—10.5 mg/dL). The fourth cycle was tempo- ing chemotherapy, the presence of 3rd grade (platelets 25 rarily deferred. She was treated with G-CSF with the to 50 000 cells/μL) or 4th grade of thrombocytopenia improvement of neutrophils. After a few days, anemia also (platelets <25 000 cells/μL) induces delays or discontinua- improved. The fourth cycle of chemotherapy was adminis- tion of the treatment [11]. In this situation, a careful diag- tered, and the first-line treatment ended up successfully. nostic evaluation is required. After one year follow-up, cancer progression was Pseudothrombocytopenia (PTCP) is a falsely decrease of detected in a control CT scan showing a mass in the top of platelet count in EDTA blood samples. It is often due to the the left lung with a diameter of 21 mm. In MRI and occurrence of EDTA-dependent antiplatelet antibodies that PET-CT, we observed metastatic lesions—two with a bind to the platelet surface and cause platelet clumping diameter of 19.3 mm in the left occipital lobe of the brain. in vitro. As this entity can be mistaken for a false diagnosis In September 2018, the patient underwent stereotactic of thrombocytopenia, affecting therapeutic decisions, it has radiotherapy of brain metastasis with a positive response. to be kept in mind in the differential diagnosis of a decreased PD-L1 expression in 70% of tumor cells was detected by platelet count in cancer patients [13]. Nevertheless, there are immunohistochemistry, without expression of ALK pro- no reports of PTCP in association with cancer immunother- tein. The patient was qualified for second-line treatment apy thus far. In this article, we are presenting a case of lung with immunotherapy after meeting inclusion criteria, adenocarcinoma patients with EDTA-dependent pseudo- including the reference level of blood cell count and bio- thrombocytopenia which was detected during first-line chemical test results, the presence of target tumor situated pembrolizumab therapy. paravertebrally in the left lung (Figure 2) and no evidence of metastatic progression in the central nervous system. In October 2018, pembrolizumab at a dose of 200 mg 2. Case Presentation every three weeks was initiated. The patient tolerated four cycles of immunotherapy with no side effects. In the begin- Herein, we report a 58-years-old female patient with NSCLC. ning of 2019, before the administration of the 5th cycle of The patient was a former smoker with a ≥20 pack-year. The pembrolizumab, a routine blood cell count test was per- patient had not previously reported episodes of thrombocy- formed, showing a sudden decrease in platelet count to 53 topenia or bleeding episodes. The analysis of the whole blood 000 cells/μL in EDTA-K sample. Unfortunately, the blood test at the time of cancer diagnosis and also a previous blood smear was not performed. Currently, it is impossible to reper- test had not shown any alternations. In 2016, computed form it as the blood sample has not been archived. However, to tomography (CT) scans of the chest demonstrated a tumor explain this phenomenon, two additional blood samples were of the left lung (Figure 1). The bronchoscopic forceps biopsy drawn in sodium citrate anticoagulated probe and Thrombo- of the mass in the bronchus of the left lung revealed adeno- Exact (Sarstedt®) probe with magnesium salt. In both those samples, we found the platelet count at an acceptable level carcinoma. No EGFR mutations were detected. The patient underwent the upper lobectomy of the left lung in October (223 000 cells/μL). Testing two additional, differently anticoa- 2016, and she was qualified to an adjuvant chemotherapy gulated blood samples were highly likely to make a possible with cisplatin and vinorelbine in standard doses. diagnosis of PTCP in the EDTA-K sample. The initial 2 Case Reports in Oncological Medicine 3 during ICIs therapy in various cancer patients. In three suspicion of thrombocytopenia was excluded, and a 200 mg dose of immunotherapy was maintained. trials, pembrolizumab therapy for NSCLC patients was Platelet count was strictly monitored during the treat- administrated. The authors showed that anemia, thrombo- ment, but no further episode of thrombocytopenia occurred. cytopenia, leukopenia, and neutropenia as toxicities among After ninth pembrolizumab infusion, the CT scan demon- haem-irAE [20]. strated an enlarged metastatic lesion in the left occipital lobe. Several cases of haematological immune-related adverse She underwent whole-brain radiotherapy. Immunotherapy events during ICI therapy have been reported. [21, 22]. was discontinued, and the patient was qualified for chemo- Bangley et al. presented a case of thrombocytopenia induced by anti-PD-1 treatment in NSCLC patients. [23]. Cases therapy with cisplatin and pemetrexed. Currently, she is being treated with chemotherapy that is being well-tolerated. of immune thrombocytopenia have been observed and described previously in melanoma patients treated with nivo- lumab, ipilimumab, or pembrolizumab. However, there were 3. Discussion no cases of EDTA-dependent PTCP [24, 25]. To the best of our knowledge, this is the first reported Pseudothrombocytopenia is a false decrease of the number of platelets that occurs in EDTA blood samples. It is mostly case of EDTA-dependent PTCP in a patient with NSCLC associated with the presence of EDTA-dependent antiplatelet treated with immune checkpoint inhibitors. Our case high- antibodies that cause platelet agglutination in vitro. These lights the importance of an accurate and comprehensive antibodies are usually IgG, IgM, and IgA cold agglutinins. diagnostic approach that must be kept in mind in this situa- tion and it can occur during ICI treatment. They bind to IIb/IIIa glycoprotein (GP) receptor on the platelet surface, triggering agglutination in the probe. In EDTA-coagulated samples, the decrease of temperature Conflicts of Interest might activate a reaction since cold agglutinins react opti- mally at 4-20 C. To rule out this entity, the blood sample needs The authors declare that there is no conflict of interest to be warmed or the test should be carried out in a probe with regarding the publication of this article. sodium citrate or magnesium salt [13, 14]. In this case, the platelet count was reevaluated for both anticoagulants. References The phenomenon of PTCP is very rare (it appears in 0.1% of the population), and it has been identified in various [1] L. A. Emens, P. A. Ascierto, P. K. Darcy et al., “Cancer immu- diseases and in healthy people. PTCP has been reported in notherapy: opportunities and challenges in the rapidly evolv- infections, sepsis, autoimmune diseases, thrombotic or car- ing clinical landscape,” European Journal of Cancer, vol. 81, diovascular disorders and also in association with malignan- pp. 116–129, 2017. cies like bladder cancer or neuroendocrine cancers [15, 16]. [2] Q. Haifeng, W. Fang, H. Liu et al., “New advances in immuno- PTCP has been observed during insulin, valproic acid, or therapy for non-small cell lung cancer,” American Journal of antibiotic treatment [17, 18]. Balcik et al. studied 49 cases Translational Research, vol. 10, no. 8, pp. 2234–2245, 2018. of PTCP diagnosed patients. The authors made a platelet [3] R. S. Herbst, P. Baas, D.-W. Kim et al., “Pembrolizumab versus assessment in EDTA and citrate-coagulated samples, asses- docetaxel for previously treated, PD-L1-positive, advanced sing for the existence of cold agglutinins, concomitant dis- non-small-cell lung cancer (KEYNOTE-010): a randomised eases, medications, malignancy, pregnancy, and antinuclear controlled trial,” The Lancet, vol. 387, no. 10027, pp. 1540– (ANA) or anticardiolipin (ACA) autoantibodies. They found 1550, 2016. that hospitalization, infection, pregnancy, and the use of low [4] F. S. Hodi, V. Chiarion-Sileni, R. Gonzalez et al., “Nivolumab molecular weight heparins were significant risk factors for plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of PCTP. However, there was no significant relationship a multicentre, randomised, phase 3 trial,” The Lancet Oncol- between PTCP presence of autoantibodies [19]. ogy, vol. 19, no. 11, pp. 1480–1492, 2018. It is known that haematological immune-related events [5] J. M. Michot, C. Bigenwald, S. Champiat et al., “Immune- (haem-irARs) caused by immunotherapy with ICI may related adverse events with immune checkpoint blockade: a occur, even though it is not a common phenomenon. A com- comprehensive review,” European Journal of Cancer, vol. 54, prehensive study made by Delanoy et al. in a group of 745 can- pp. 139–148, 2016. cer patients receiving immunotherapy showed its frequency [6] N. Delanoy, J.-M. Michot, T. Comont et al., “Haematological of 0.5%. The authors, using data from three French registries immune-related adverse events induced by anti-PD-1 or anti- of irAEs, found 35 patients affected by haem-irARs including PD-L1 immunotherapy: a descriptive observational study,” 12 (34%) patients with NSCLC. Nevertheless, among all types The Lancet Haematology, vol. 6, no. 1, pp. e48–e57, 2019. of immune-related haematological toxicities, the most com- [7] J. B. A. G. Haanen, F. Carbonnel, C. Robert et al., “Manage- mon were neutropenia, thrombocytopenia, and autoimmune ment of toxicities from immunotherapy: ESMO Clinical Prac- hemolytic anemia (AHA). Only three patients had AHA asso- tice Guidelines for diagnosis, treatment and follow-up,” ciated with the presence of cold agglutinins. There were other Annals of Oncology, vol. 28, Supplement 4, pp. iv119–iv142, toxicities mentioned like pancytopenia or aplastic anemia, bicytopenia, and pure red cell aplasia [6]. [8] F. Kroschinsky, on behalf of the Intensive Care in Hematolog- In another study, Sui et al. analyzed and compared results ical and Oncological Patients (iCHOP) Collaborative Group, of 26 clinical trials describing haematological toxicities F. Stölzel et al., “New drugs, new toxicities: severe side effects 4 Case Reports in Oncological Medicine [24] C. Pföhler, H. Eichler, B. Burgard, N. Krecké, C. S. L. Müller, of modern targeted and immunotherapy of cancer and their management,” Critical Care, vol. 21, no. 1, p. 89, 2017. and T. Vogt, “A case of immune thrombocytopenia as a rare side effect of an immunotherapy with PD1-blocking agents [9] D. J. Kuter, “Managing thrombocytopenia associated with for metastatic melanoma,” Transfusion Medicine and chemotherapy,” Oncology, vol. 29, pp. 282–294, 2015. Hemotherapy, vol. 44, no. 6, pp. 426–428, 2017. [10] L. S. Elting, E. B. Rubenstein, C. G. Martin et al., “Incidence, [25] E. Shiuan, K. E. Beckermann, A. Ozgun et al., “Thrombocyto- cost, and outcomes of bleeding and chemotherapy dose mod- penia in patients with melanoma receiving immune check- ification among solid tumor patients with chemotherapy- point inhibitor therapy,” Journal for Immunotherapy of induced thrombocytopenia,” Journal of Clinical Oncology, Cancer, vol. 5, no. 1, p. 8, 2017. vol. 19, no. 4, pp. 1137–1146, 2001. [11] H. A. Liebman, “Thrombocytopenia in cancer patients,” Thrombosis Research, vol. 133, no. S2, pp. S63–S69, 2014. [12] C. Piatek and M. Akhtari, “Thrombocytopenia: optimizing approaches in cancer patients,” Oncology Journal, vol. 29, no. 4, 2015. [13] G. Lippi and M. Plebani, “EDTA-dependent pseudothrombo- cytopenia: further insights and recommendations for preven- tion of a clinically threatening artifact,” Clinical Chemistry and Laboratory Medicine, vol. 50, no. 8, pp. 1281–1285, 2012. [14] N. Bizzaro, “EDTA-dependent pseudothrombocytopenia: a clinical and epidemiological study of 112 cases, with 10-year follow-up,” American Journal of Hematology, vol. 50, no. 2, pp. 103–109, 1995. [15] C. Sahin, I. Kırlı, H. Sozen, and T. D. Canbek, “EDTA-Induced Pseudothrombocytopenia in Association with Bladder Can- cer,” Case Reports, vol. 2014, article bcr2014205130, 2014. [16] H. J. Kim, I. H. Moh, H. Yoo et al., “Ethylenediaminetetraace- tic acid-dependent pseudothrombocytopenia associated with neuroendocrine carcinoma: a case report,” Oncology Letters, vol. 4, no. 1, pp. 86–88, 2012. [17] C. Beyan, K. Kaptan, and A. Ifran, “Pseudothrombocytopenia after changing insulin therapy in a case with insulin- dependent diabetes mellitus: a first case report,” American Journal of Hematology, vol. 85, no. 11, pp. 909-910, 2010. [18] H. Yoshikawa, “EDTA-dependent pseudothrombocytopenia induced by valproic acid,” Neurology, vol. 61, no. 4, pp. 579- 580, 2003. [19] A. Isik, O. S. Balcik, D. Akdeniz, H. Cipil, S. Uysal, and A. Kosar, “Relationship between some clinical situations, auto- antibodies and pseudothrombocytopenia,” Clinical and Applied Thrombosis/Hemostasis, vol. 18, no. 6, pp. 645–649, [20] J. D. Sui, Y. Wang, Y. Wan, and Y. Z. Wu, “Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer patients: a meta-analysis of current studies,” Drug Design, Development and Therapy, vol. 12, pp. 1645–1657, 2018. [21] A. Le Roy, E. Kempf, F. Ackermann et al., “Two cases of immune thrombocytopenia associated with pembrolizumab,” European Journal of Cancer, vol. 54, pp. 172–174, 2016. [22] Y. Karakas, D. Yuce, and S. Kılıckap, “Immune thrombocyto- penia induced by nivolumab in a metastatic non-small cell lung cancer patient,” Oncology Research and Treatment, vol. 40, no. 10, pp. 621-622, 2017. [23] S. J. Bagley, J. A. Kosteva, T. L. Evans, and C. J. Langer, “Immune thrombocytopenia exacerbated by nivolumab in a patient with non-small- cell lung cancer,” Cancer Treatment Communications, vol. 6, pp. 20–23, 2016. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Oncological Medicine Hindawi Publishing Corporation

An Episode of Pseudothrombocytopenia during Pembrolizumab Therapy in NSCLC Patient

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Hindawi Case Reports in Oncological Medicine Volume 2020, Article ID 4196178, 4 pages https://doi.org/10.1155/2020/4196178 Case Report An Episode of Pseudothrombocytopenia during Pembrolizumab Therapy in NSCLC Patient 1,2 1 1 1 Kinga Krukowska , Robert Kieszko, Katarzyna Kurek, Izabela Chmielewska, 1 1 Paweł Krawczyk, and Janusz Milanowski Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Poland Genetics and Immunology Laboratory, GENIM LLC, Lublin, Poland Correspondence should be addressed to Kinga Krukowska; kingakrukowska@gmail.com Received 28 August 2019; Accepted 23 April 2020; Published 9 May 2020 Academic Editor: Josep M. Ribera Copyright © 2020 Kinga Krukowska et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Immunotherapy with immune checkpoint inhibitors (ICI) is a new option of treatment in a growing range of neoplasms. In addition to an antitumor effect, ICI are associated with autoimmune reactions resulting in a wide spectrum of toxicities that have not been seen in patients receiving chemotherapy. In this article, we present a case of a patient with advanced lung adenocarcinoma who developed an EDTA-dependent pseudothrombocytopenia (PTCP) during pembrolizumab therapy. To the best of our knowledge, this is the first reported case of EDTA-dependent PTCP occurring during immunotherapy treatment of nonsmall lung cell cancer with ICI. The phenomenon of EDTA-dependent PTCP may prompt clinical decisions, as unnecessary transfusions or even exclusion from pembrolizumab therapy. Therefore, it is important to be aware of PTCP as a possible side effect of this therapy. 1. Introduction bladder cancer, renal cell carcinoma, and other types of cancer [1–4]. Immunotherapy with immune checkpoint inhibitors target- Although immune checkpoint inhibitors (ICI) therapy ing programmed cell death 1 receptor (PD-1), programmed have shown clinical benefits and general good tolerance, the death ligand 1 (PD-L1), or cytotoxic T lymphocyte- literature describes many cases of immune-related adverse associated antigen 4 (CTLA-4) is a profitable cancer treat- events (irAEs), particularly in the treatment of NSCLC or melanoma patients [5, 6]. Fatigue is the most frequently ment strategy. It has demonstrated advantageous outcomes in clinical practice including regression of advanced tumors mentioned irAE correlated to PD-1, PD-L1, or CTLA-4 and improvement of overall survival. The mechanism of blockade. ESMO (European Society of Medical Oncology) action of monoclonal anti-PD-1 antibodies, such as pembro- Clinical Practice Guidelines reports other clinically significant lizumab and nivolumab, involves a selective inhibition of immune-related toxicities: skin-affected toxicity (rash, PD-1 receptor on lymphocytes. The atezolizumab and dur- pruritus, and vitiligo), endocrinopathies (thyroid gland disor- valumab block PD-L1 activity on tumor cells and infiltrating ders, hypophysitis), hepatotoxicity, gastrointestinal toxicity immune cells. Ipilimumab efficiently binds to CTLA-4 (colitis, diarrhea, nausea, vomiting, abdominal pain), or pneu- receptor on activated T cells. In consequence, coinhibitory monitis. Apart from those mentioned above, neurological, signals are disturbed allowing the antitumor immune renal, cardiac, or haematological toxicities rarely occur [7, 8]. response to be restored. Immunotherapy might be used in Thrombocytopenia is a common entity in patients with monotherapy as well as in combination with chemotherapy malignant diseases, especially during systemic chemotherapy or radiotherapy in several malignancies including advanced treatment. It is defined as a platelet count of less than 150 000 stage nonsmall cell lung carcinoma (NSCLC), melanoma, cells/μL. When the platelet count falls to 10 000 cells/μL 2 Case Reports in Oncological Medicine Figure 1: The CT scan showed new target lesion situated paravertebrally in the left lung. Figure 2: Brain metastatic lesion in left occipital lobe with spontaneous bleeding may occur increasing the risk of sur- dimensions of 2:5cm × 2:1cm × 2:9cm. gical complications [9]. It may be caused by a central mechanism, as a consequence of bone marrow infiltration or as a result of treatment toxicity, a peripheral mecha- After third cycle of chemotherapy, the patient developed nism as it occurs, in microangiopathic disorders as dis- neutropenia (neutrophil count of 780 cells/μL) and anemia seminated intravascular coagulation (DIC), vasculitis or (erythrocytes count of 3.35 million cells/μL, haemoglobin hemolytic uremic syndrome (HUS) or both. [10–12]. Dur- concentration—10.5 mg/dL). The fourth cycle was tempo- ing chemotherapy, the presence of 3rd grade (platelets 25 rarily deferred. She was treated with G-CSF with the to 50 000 cells/μL) or 4th grade of thrombocytopenia improvement of neutrophils. After a few days, anemia also (platelets <25 000 cells/μL) induces delays or discontinua- improved. The fourth cycle of chemotherapy was adminis- tion of the treatment [11]. In this situation, a careful diag- tered, and the first-line treatment ended up successfully. nostic evaluation is required. After one year follow-up, cancer progression was Pseudothrombocytopenia (PTCP) is a falsely decrease of detected in a control CT scan showing a mass in the top of platelet count in EDTA blood samples. It is often due to the the left lung with a diameter of 21 mm. In MRI and occurrence of EDTA-dependent antiplatelet antibodies that PET-CT, we observed metastatic lesions—two with a bind to the platelet surface and cause platelet clumping diameter of 19.3 mm in the left occipital lobe of the brain. in vitro. As this entity can be mistaken for a false diagnosis In September 2018, the patient underwent stereotactic of thrombocytopenia, affecting therapeutic decisions, it has radiotherapy of brain metastasis with a positive response. to be kept in mind in the differential diagnosis of a decreased PD-L1 expression in 70% of tumor cells was detected by platelet count in cancer patients [13]. Nevertheless, there are immunohistochemistry, without expression of ALK pro- no reports of PTCP in association with cancer immunother- tein. The patient was qualified for second-line treatment apy thus far. In this article, we are presenting a case of lung with immunotherapy after meeting inclusion criteria, adenocarcinoma patients with EDTA-dependent pseudo- including the reference level of blood cell count and bio- thrombocytopenia which was detected during first-line chemical test results, the presence of target tumor situated pembrolizumab therapy. paravertebrally in the left lung (Figure 2) and no evidence of metastatic progression in the central nervous system. In October 2018, pembrolizumab at a dose of 200 mg 2. Case Presentation every three weeks was initiated. The patient tolerated four cycles of immunotherapy with no side effects. In the begin- Herein, we report a 58-years-old female patient with NSCLC. ning of 2019, before the administration of the 5th cycle of The patient was a former smoker with a ≥20 pack-year. The pembrolizumab, a routine blood cell count test was per- patient had not previously reported episodes of thrombocy- formed, showing a sudden decrease in platelet count to 53 topenia or bleeding episodes. The analysis of the whole blood 000 cells/μL in EDTA-K sample. Unfortunately, the blood test at the time of cancer diagnosis and also a previous blood smear was not performed. Currently, it is impossible to reper- test had not shown any alternations. In 2016, computed form it as the blood sample has not been archived. However, to tomography (CT) scans of the chest demonstrated a tumor explain this phenomenon, two additional blood samples were of the left lung (Figure 1). The bronchoscopic forceps biopsy drawn in sodium citrate anticoagulated probe and Thrombo- of the mass in the bronchus of the left lung revealed adeno- Exact (Sarstedt®) probe with magnesium salt. In both those samples, we found the platelet count at an acceptable level carcinoma. No EGFR mutations were detected. The patient underwent the upper lobectomy of the left lung in October (223 000 cells/μL). Testing two additional, differently anticoa- 2016, and she was qualified to an adjuvant chemotherapy gulated blood samples were highly likely to make a possible with cisplatin and vinorelbine in standard doses. diagnosis of PTCP in the EDTA-K sample. The initial 2 Case Reports in Oncological Medicine 3 during ICIs therapy in various cancer patients. In three suspicion of thrombocytopenia was excluded, and a 200 mg dose of immunotherapy was maintained. trials, pembrolizumab therapy for NSCLC patients was Platelet count was strictly monitored during the treat- administrated. The authors showed that anemia, thrombo- ment, but no further episode of thrombocytopenia occurred. cytopenia, leukopenia, and neutropenia as toxicities among After ninth pembrolizumab infusion, the CT scan demon- haem-irAE [20]. strated an enlarged metastatic lesion in the left occipital lobe. Several cases of haematological immune-related adverse She underwent whole-brain radiotherapy. Immunotherapy events during ICI therapy have been reported. [21, 22]. was discontinued, and the patient was qualified for chemo- Bangley et al. presented a case of thrombocytopenia induced by anti-PD-1 treatment in NSCLC patients. [23]. Cases therapy with cisplatin and pemetrexed. Currently, she is being treated with chemotherapy that is being well-tolerated. of immune thrombocytopenia have been observed and described previously in melanoma patients treated with nivo- lumab, ipilimumab, or pembrolizumab. However, there were 3. Discussion no cases of EDTA-dependent PTCP [24, 25]. To the best of our knowledge, this is the first reported Pseudothrombocytopenia is a false decrease of the number of platelets that occurs in EDTA blood samples. It is mostly case of EDTA-dependent PTCP in a patient with NSCLC associated with the presence of EDTA-dependent antiplatelet treated with immune checkpoint inhibitors. Our case high- antibodies that cause platelet agglutination in vitro. These lights the importance of an accurate and comprehensive antibodies are usually IgG, IgM, and IgA cold agglutinins. diagnostic approach that must be kept in mind in this situa- tion and it can occur during ICI treatment. They bind to IIb/IIIa glycoprotein (GP) receptor on the platelet surface, triggering agglutination in the probe. In EDTA-coagulated samples, the decrease of temperature Conflicts of Interest might activate a reaction since cold agglutinins react opti- mally at 4-20 C. To rule out this entity, the blood sample needs The authors declare that there is no conflict of interest to be warmed or the test should be carried out in a probe with regarding the publication of this article. sodium citrate or magnesium salt [13, 14]. In this case, the platelet count was reevaluated for both anticoagulants. References The phenomenon of PTCP is very rare (it appears in 0.1% of the population), and it has been identified in various [1] L. A. Emens, P. A. Ascierto, P. K. Darcy et al., “Cancer immu- diseases and in healthy people. PTCP has been reported in notherapy: opportunities and challenges in the rapidly evolv- infections, sepsis, autoimmune diseases, thrombotic or car- ing clinical landscape,” European Journal of Cancer, vol. 81, diovascular disorders and also in association with malignan- pp. 116–129, 2017. cies like bladder cancer or neuroendocrine cancers [15, 16]. [2] Q. Haifeng, W. Fang, H. Liu et al., “New advances in immuno- PTCP has been observed during insulin, valproic acid, or therapy for non-small cell lung cancer,” American Journal of antibiotic treatment [17, 18]. Balcik et al. studied 49 cases Translational Research, vol. 10, no. 8, pp. 2234–2245, 2018. of PTCP diagnosed patients. The authors made a platelet [3] R. S. Herbst, P. Baas, D.-W. Kim et al., “Pembrolizumab versus assessment in EDTA and citrate-coagulated samples, asses- docetaxel for previously treated, PD-L1-positive, advanced sing for the existence of cold agglutinins, concomitant dis- non-small-cell lung cancer (KEYNOTE-010): a randomised eases, medications, malignancy, pregnancy, and antinuclear controlled trial,” The Lancet, vol. 387, no. 10027, pp. 1540– (ANA) or anticardiolipin (ACA) autoantibodies. They found 1550, 2016. that hospitalization, infection, pregnancy, and the use of low [4] F. S. Hodi, V. Chiarion-Sileni, R. Gonzalez et al., “Nivolumab molecular weight heparins were significant risk factors for plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of PCTP. However, there was no significant relationship a multicentre, randomised, phase 3 trial,” The Lancet Oncol- between PTCP presence of autoantibodies [19]. ogy, vol. 19, no. 11, pp. 1480–1492, 2018. It is known that haematological immune-related events [5] J. M. Michot, C. Bigenwald, S. Champiat et al., “Immune- (haem-irARs) caused by immunotherapy with ICI may related adverse events with immune checkpoint blockade: a occur, even though it is not a common phenomenon. A com- comprehensive review,” European Journal of Cancer, vol. 54, prehensive study made by Delanoy et al. in a group of 745 can- pp. 139–148, 2016. cer patients receiving immunotherapy showed its frequency [6] N. Delanoy, J.-M. Michot, T. Comont et al., “Haematological of 0.5%. 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Journal

Case Reports in Oncological MedicineHindawi Publishing Corporation

Published: May 9, 2020

References