Pembrolizumab-induced thrombotic thrombocytopenic purpura

2019 ◽  
Vol 26 (5) ◽  
pp. 1237-1240 ◽  
Author(s):  
Marcus SR Dickey ◽  
Anant J Raina ◽  
Peter J Gilbar ◽  
Brendan L Wisniowski ◽  
Joel T Collins ◽  
...  
Keyword(s):  
Adverse Events ◽  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Oral Prednisolone ◽  
Autoimmune Disorder ◽  
Community Acquired Pneumonia ◽  
Thrombocytopenic Purpura ◽  
Life Threatening

Introduction Pembrolizumab is a humanised monoclonal antibody targeting the receptor programmed cell death protein-1 (PD-1), with anti-tumour activity demonstrated for many malignancies. Such immune checkpoint inhibitors are associated with many immune-related adverse events including rash, colitis, hepatitis, pneumonitis, endocrinopathy and, rarely, haematological adverse events, including immune-related thrombocytopenia. Case report We report a 60-year-old female with metastatic non-small cell lung cancer treated with pembrolizumab every three weeks. Following her fifth cycle, she presented to our hospital with community-acquired pneumonia. Thrombocytopenia developed the next day and, after detailed investigations, thrombotic thrombocytopenic purpura was diagnosed. Management and outcome Pembrolizumab was immediately ceased and plasma exchange commenced along with IV methylprednisolone 250 mg daily for three days followed by oral prednisolone. After five days of plasma exchange, platelet counts normalised and haemolytic anaemia resolved. Discussion Acquired thrombotic thrombocytopenic purpura is an autoimmune disorder caused by an inhibitory autoantibody against ADAMTS-13. While most cases of acquired thrombotic thrombocytopenic purpura are idiopathic, certain conditions (e.g. bacterial infection, autoimmune disorders, malignancies) and medications are associated with thrombotic thrombocytopenic purpura. Other potential causes were eliminated in our patient. As acquired thrombotic thrombocytopenic purpura is an autoimmune disorder, pembrolizumab, given its unique mechanism of action and association with immune-related adverse events, is believed to be implicated in the development of thrombotic thrombocytopenic purpura. This case is one of only two linking anti-PD-1 therapy to thrombotic thrombocytopenic purpura development (the other occurring in a patient on nivolumab plus ipilimumab). Thrombotic thrombocytopenic purpura is life-threatening and clinicians are advised to be aware of its possible occurrence in immune checkpoint inhibitor-treated patients.

COVID-19 as a Potential Trigger for Immune Thrombotic Thrombocytopenic Purpura and Reason for an Unusual Treatment: A Case Report

2021 ◽  
Author(s):  
Marie-Kristin Schwaegermann ◽  
Lukas Hobohm ◽  
Johanna Rausch ◽  
Michael Reuter ◽  
Thomas-Friedrich Griemert ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Immunosuppressive Treatment ◽  
Autoimmune Disorder ◽  
Treatment Modalities ◽  
Therapeutic Drug ◽  
Thrombocytopenic Purpura ◽  
Tissue Ischemia ◽  
Platelet Receptor ◽  
Life Threatening ◽  
A Disintegrin And Metalloproteinase

AbstractImmune thrombotic thrombocytopenic purpura (iTTP) is a rare autoimmune disorder characterized by severely reduced activity of the von Willebrand factor (VWF)-cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) due to autoantibodies. This leads to the development of pathogenic multimers of VWF, causing a thrombotic microangiopathy with decreased number of platelets, hemolysis, and life-threatening tissue ischemia of mostly brain, heart, and kidneys. Standard treatment of iTTP involves daily plasma exchange to remove ultra large multimers of VWF, inhibitors, substituting ADAMTS13, and the accompaniment of an immunosuppressive treatment with steroids. Recently, caplacizumab was approved for iTTP. Caplacizumab is a nanobody binding the A1 domain of VWF, blocking its interaction with glycoprotein Ib–IX–V platelet receptor and therefore preventing platelet aggregation. VWF activities may serve as therapeutic drug monitoring of caplacizumab, whereas ADAMTS13 activities may be used for biomarkers to guide caplacizumab treatment modalities and overall treatment duration. Additional immunosuppressive treatment by inhibiting autoantibody formation (e.g., the use of Rituximab, a chimeric monoclonal antibody directed against the B-cell antigen CD20) is a further treatment option. Infections are well-known causes for an acute episode for patients with iTTP. The novel SARS-CoV-2 virus is mainly associated with acute respiratory distress as well as diffuse endothelial inflammation and increased coagulopathy. However, little is known about an infection with SARS-CoV-2 virus triggering iTTP relapses. We herein report the case of an acute iTTP episode accompanying a SARS-CoV-2 infection.

scholarly journals Management of pulmonary toxicity associated with immune checkpoint inhibitors

2019 ◽  
Vol 28 (154) ◽  
pp. 190012 ◽  
Author(s):  
Myriam Delaunay ◽  
Grégoire Prévot ◽  
Samia Collot ◽  
Laurent Guilleminault ◽  
Alain Didier ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Pulmonary Toxicity ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Serious Adverse Events ◽  
Programmed Cell Death 1 ◽  
Life Threatening

Immunotherapy has become a standard of care in oncology, following the recent approvals of cytotoxic T-lymphocyte-associated protein-4 and programmed cell death-1 inhibitors in lung cancer, melanoma, renal cell carcinoma, Hodgkin's lymphoma, bladder, head and neck cancers. Besides their efficacy, these agents also generate specific immune-related adverse events. Due to the increasing prescription of immune-checkpoint inhibitors, the incidence of immune toxicity will continue to rise. The awareness of immune-related adverse events is key to ensuring both diagnosis and management of the possible serious adverse events. Although severe immune-related adverse events remain rare, they can lead to discontinued treatment or to death if they are not forecasted and managed properly. Even if lung toxicity is not the most frequent adverse event, it remains critical as it can be life-threatening. Herein, the main aspects of pulmonary toxicity are reviewed and guidelines are also proposed in order to manage the possible side-effects.

scholarly journals Management of rheumatic complications of immune checkpoint inhibitor therapy – an oncological perspective

Rheumatology ◽  
2019 ◽  
Vol 58 (Supplement_7) ◽  
pp. vii29-vii39 ◽  
Author(s):  
Neil M Steven ◽  
Benjamin A Fisher
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Cancer Control ◽  
Myasthenic Crisis ◽  
Life Threatening ◽  
Checkpoint Inhibitor Therapy ◽  
The Common ◽  
Risk And Benefit

Abstract Immune checkpoint inhibitors (CPIs) are an effective treatment for many cancers but cause diverse immune-related adverse events (IrAEs). Rheumatological IrAEs include arthralgia, arthritis, tenosynovitis, myositis, polymyalgia rheumatica and sicca syndrome. CPI use can unmask RA as well as causing flares of prior autoimmune or connective tissue disease. Oncologists categorize and grade IrAEs using the Common Terminology Criteria for Adverse Events and manage them according to international guidelines. However, rheumatological events are unfamiliar territory: oncologists need to work with rheumatologists to elicit and assess symptoms, signs, results of imaging and autoantibody testing and to determine the use of steroids and DMARDs. Myositis may overlap with myasthenic crisis and myocarditis and can be life-threatening. Treatment should be offered on balance of risk and benefit, including whether to continue CPI treatment and recognizing the uncertainty over whether glucocorticoids and DMARDs might compromise cancer control.

scholarly journals Critical Care COVID-19 Patient with a Picture of Thrombotic Thrombocytopenic Purpura

2020 ◽  
Author(s):  
Rehab AL-Ansari ◽  
Mohanad Bakkar ◽  
Leena Abdalla ◽  
Khaled Sewify
Keyword(s):  
Mechanical Ventilation ◽  
Critical Care ◽  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Kidney Injury ◽  
Therapeutic Plasma Exchange ◽  
Thrombocytopenic Purpura ◽  
Threatening Condition ◽  
Life Threatening

Background: Thrombotic thrombocytopenic purpura (TTP) is an uncommon haematological disease which can occur at any age and may present with COVID-19. This case describes a COVID-19 complication associated with a presentation resembling TTP. Case description: A 51-year-old man who had received a kidney transplant and was on immunosuppressant medication, was admitted to a critical care unit with severe COVID-19 pneumonia/acute respiratory distress syndrome (ARDS) which required intubation, mechanical ventilation and inotropic support. The course was complicated by the classic pentad of thrombocytopenia, intravascular haemolysis, acute kidney injury, neurological symptoms and fever, which prompted the diagnosis of probable TTP. After five sessions of therapeutic plasma exchange, the patient’s general status improved, he was weaned off mechanical ventilation and his renal panel and haemolytic markers normalized. Conclusion: TTP is a life-threatening condition which requires urgent management with therapeutic plasma exchange. This case highlights some possible complications of COVID-19 generally and in immunocompromised patients specifically. The potential role of plasma exchange in COVID-19 patients without a positive diagnosis of TTP (the so-called ‘TTP resembling presentation’) is an area of further research.

scholarly journals Rapid Turnaround ADAMTS13 Testing Is Likely to Improve Diagnosis of Thrombotic Thrombocytopenic Purpura and Avoid Unnecessary Plasma Exchange

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Eric McGinnis ◽  
Spencer D. Martin ◽  
Tyler W. Smith
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Blood Product ◽  
Vancouver General Hospital ◽  
Adamts13 Activity ◽  
Clinical Tool ◽  
Thrombocytopenic Purpura ◽  
Hospital Patients ◽  
Life Threatening ◽  
Exposure Risks

Introduction: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy (TMA) resulting from severe ADAMTS13 deficiency, which is generally treated with therapeutic plasma exchange (PLEX). Although ADAMTS13 activity is often assayed to differentiate TTP from TMAs not requiring PLEX, technical and logistical constraints often limit rapid turnaround of results, with PLEX initiated based on clinical suspicion of TTP while awaiting ADAMTS13 activity results. We estimated the potential reduction in plasma product use if rapid turnaround ADAMTS13 activity testing were available in our centre. Methods: We reviewed medical records for all Vancouver General Hospital patients with ADAMTS13 activity testing since assay implementation. Patients receiving PLEX but ultimately diagnosed with a disease not requiring PLEX were identified as "potentially avoidable PLEX" (paPLEX), and their plasma product exposures and related blood product costs were estimated. Laboratory results, ADAMTS13 activity, and PLASMIC scores (a validated clinical tool for TTP diagnosis) of this group were compared to those of newly diagnosed TTP patients (N=35). Results: We identified 16 paPLEX patients, including TMAs secondary to malignant hypertension, infection, hemolytic uremic syndrome, illicit drug use, autoimmune renal disease, and malignancy (Table 1). These patients underwent 104 total PLEX cycles (3-12 per patient, median 6), involving 1,428 plasma units (28-199 per patient, median 71.5) and estimated product-associated costs of $187,759 CAD ($140,889 USD). Median platelet counts were significantly lower in TTP than the paPLEX group (7x109/L versus 38x109/L), as was serum creatinine (98µmol/L versus 224µmol/L). PLASMIC scores indicating low or intermediate likelihood of TTP were observed in 63% of patients receiving paPLEX and 17% of patients with TTP. All patients with TTP had ADAMTS13 activity < 10%, while all patients receiving paPLEX had ADAMTS13 activity ≥ 30%. Conclusions: Unnecessary PLEX carries significant patient blood product exposure risks and system costs that may be circumvented if TTP can be reliably distinguished from other TMAs at the time of initial presentation. In our cohort, ADAMTS13 activity results provided clear separation of these groups and improved upon TTP diagnosis by clinical judgement and PLASMIC scores. Rapid turnaround of ADAMTS13 activity testing results has the potential to reduce the unnecessary costs and blood product exposures resulting from PLEX administration to patients with non-TTP TMAs. Figure 1 Disclosures Smith: Alexion: Other: Participated in an advisory board without receiving financial compensation.

scholarly journals Endocrine toxicity of cancer immunotherapy: clinical challenges

2021 ◽  
Author(s):  
Bliss Anderson ◽  
Daniel L Morganstein
Keyword(s):  
Type 1 Diabetes ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Thyroid Disease ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Endocrine Dysfunction ◽  
Life Threatening ◽  
The Common

Immune checkpoint inhibitors are now widely used in the treatment of multiple cancers. The major toxicities of these treatments are termed immune related adverse events and endocrine dysfunction is common. Thyroid disease, hypopituitarism and a form of diabetes resembling type 1 diabetes are now all well described, with different patterns emerging with different checkpoint inhibitors. We review the presentation and management of the common endocrine immune related adverse events, and discuss a number of recent advances in the understanding of these important, potentially life threatening toxicities. We also discuss some remaining dilemmas in management.

Caplacizumab: an anti–von Willebrand factor antibody for the treatment of thrombotic thrombocytopenic purpura

2020 ◽  
Vol 77 (15) ◽  
pp. 1201-1207
Author(s):  
Alyssa L Hollifield ◽  
Justin R Arnall ◽  
Donald C Moore
Keyword(s):  
Adverse Events ◽  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Antibody Fragment ◽  
Self Administration ◽  
Phase 3 ◽  
Thrombocytopenic Purpura ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Purpose The pharmacology, pharmacokinetics, efficacy, safety, dosing and administration, and place in therapy of caplacizumab, a novel antibody fragment that inhibits von Willebrand factor, for the treatment of acquired thrombotic thrombocytopenic purpura (TTP) are summarized. Summary Caplacizumab is a humanized anti–von Willebrand factor monoclonal antibody fragment that inhibits the interaction between ultralarge von Willebrand factor multimers and platelets. Caplacizumab is indicated for use in combination with standard-of-care modalities such as plasma exchange and immunosuppressive therapy for the treatment of adults with acquired TTP. By inhibiting von Willebrand factor, caplacizumab offers a new approach to the management of TTP by preventing the development of potentially life-threatening microvascular thrombosis that can occur in the disease process. In a randomized, placebo-controlled phase 3 trial, patients with acquired TTP treated with caplacizumab had more rapid platelet level normalization than placebo users; caplacizumab use also resulted in lower rates of disease recurrence and TTP-related death. The most common adverse events associated with caplacizumab use are bleeding-related events. In a phase 3 trial, serious bleeding-related adverse events were reported in 8 patients (11%) in the caplacizumab group and 1 patient (1%) in the placebo group. Caplacizumab is administered as an 11-mg intravenous loading dose 15 minutes prior to plasma exchange, followed by administration of 11 mg subcutaneously daily after plasma exchange. Once-daily caplacizumab administration can be continued for 30 days after the last plasma exchange. The medication and supplies for administration are provided as a single-use kit; patients should be trained on proper reconstitution and self-administration technique prior to the use of caplacizumab in the ambulatory setting. Conclusion Caplacizumab is a first-in-class von Willebrand factor inhibitor approved for the treatment of adults with acquired TTP.

scholarly journals Immune Checkpoint Inhibitors: Common Questions About Uncommon Adverse Events

2021 ◽  
Vol 12 (3) ◽  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Life Threatening

At JADPRO Live Virtual 2020, Lisa Kottschade, APRN, MSN, CNP, highlighted considerations for advanced practitioners on the recognition and monitoring of rare and life-threatening immune-related adverse events (irAEs), as well as strategies for managing patients who have corticosteroid-refractory irAEs.

scholarly journals Cascade of immunologic adverse events related to pembrolizumab treatment

2019 ◽  
Vol 12 (6) ◽  
pp. e229149 ◽  
Author(s):  
Arnaud Dhenin ◽  
Vassiliki Samartzi ◽  
Sarah Lejeune ◽  
Emmanuel Seront
Keyword(s):  
Lung Cancer ◽  
Patient Outcome ◽  
Adverse Events ◽  
Cancer Patient ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Life Threatening

Immune checkpoint inhibitors, such as pembrolizumab, have significantly improved cancer patient outcome. Toxicities are usually moderate and manageable. However, some adverse events, if not early recognised, could be life-threatening. We report a patient with non-small cell lung cancer who received treatment with pembrolizumab and developed multiple immune-related adverse events both during and after completing treatment, including rash, pericarditis, colitis and myasthenia gravis.

The South East England Thrombotic Thrombocytopenic Purpura Registry.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1064-1064
Author(s):  
Marie Scully ◽  
Helen Yarranton ◽  
Ri Liesner ◽  
Jamie Cavenagh ◽  
Beverley Hunt ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Oral Prednisolone ◽  
Median Number ◽  
The South ◽  
Thrombocytopenic Purpura ◽  
Treatment Protocols ◽  
Abdominal Symptoms ◽  
Life Threatening ◽  
South East England ◽  
Prompt Diagnosis

Abstract Thrombotic thrombocytopenic purpura (TTP) is an acute, rare, life threatening disorder. We present data from the South East (SE) England registry for TTP, from April 2002–December 2005. Included are 156 patients and 179 acute episodes. Seventy four percent of cases were female and 26% males, median age at presentation, 41 and 47.5 years respectively. Mortality to December 2003 was 12%, and from January 2004 to December 2005 was 5%; 5/12 died before treatment was instigated. The main ethnic groups were Caucasian (63%), Afro Caribbean (22%) and Asian (12%). In 61%, this was their first TTP episode; 39% represented with acute relapse. Precipitating events (n=123); idiopathic (56%), a defined infection (11%), pregnancy (6%), HIV disease (7%), congenital (5%) and associated autoimmune disease (6%). Features at presentation include: neurological disease (39%), temperature (15%), abdominal symptoms (12%), renal impairment (10%), symptomatic cardiac disease (7%), symptoms related to low platelets (17%) and no symptoms (2%). From April 2002–December 2003, the median number of plasma exchanges until complete remission (CR) recorded in 36 patients was 20 (5–79). One patient received plasma infusion (PI) in conjunction with PEX. 33 patients received 3 doses of pulsed intravenous methylprednisolone (IV MP) and 9 orally. Other therapies used were Rituximab (1), defibrotide (5), cyclosporine (9) and vincristine (15). In the second cohort (January 2004–December 2005), the median number of PEX to CR in 88 episodes was 8 (3–80). PI was used in 5 cases, 48 patients received 3 doses of pulsed IV MP on admission and 6 patients oral prednisolone. Other therapies used were Rituximab (26), defibrotide (2), cyclosporine (3), vincristine (5) and BPL 8Y (9). The latter is an intermediate purity Factor VIII concentrate used in congenital TTP. The median Haemoglobin (Hb) was 9.9g/dL at presentation and platelet count 18 ×109/L. The 2002–2003 group had 48% cases with platelet counts <150 ×109/L at 7 days, but only 25% of cases in 2004–2005. ADAMTS 13 activity, measured by collagen binding assay (CBA) (normal range 66–126%), in 136 episodes was <5% in 60%, 5–40% in 21%, 40–66 in 12% and >66% in 7% at presentation. Antibody to ADAMTS 13 (determined by mixing studies using CBA and/or anti-ADAMTS 13 IgG antibodies) was present in 61% of all cases. In those patients with acute idiopathic TTP, 93% had associated antibody. In conclusion: Improved recognition and prompt diagnosis of TTP may be associated with reduction in mortality and changes in treatment protocols reduced the number of PEX to achieve CR. Acute idiopathic TTP is the most common presentation, but improved identification of subgroups such as HIV and congenital TTP have resulted in appropriate tailoring of therapy.

Sign in / Sign up

Export Citation Format

Share Document