Haematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: a descriptive observational study
Summary
Background Anti-programmed cell death 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) antibodies are novel immunotherapies for cancer that can induce immune-related adverse events (irAEs). These adverse events can involve all organs, including the haemopoietic system. Thus far, haematological irAEs (haem-irAEs) have not been extensively characterised. This study aims to provide a comprehensive report of the haem-irAEs induced by anti-PD-1 or anti-PD-L1.
Methods In this descriptive observational study, we included consecutive patients aged at least 18 years with grade 2 or worse haem-irAEs induced by anti-PD-1 or anti-PD-L1 immunotherapy registered in three French pharmacovigilance databases: the Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC; a prospective registry of patients treated with anti-PD-1 or anti-PD-L1 at a single centre), the ImmunoTOX committee of Gustave Roussy (a national referral database of suspected irAEs in patients treated with immunotherapy), and the registry of the Centre de Référence des Cytopénies Auto-Immunes de l’Adulte (CeReCAI; a national database of autoimmune cytopenias). Cases were reviewed by a central committee; adverse events had to be classed as certainly or probably related to anti-PD-1 or anti-PD-L1 therapy, and their severity was assessed according to the Common Terminology Criteria for Adverse Events (version 4.03). The primary endpoint was clinical description of haem-irAEs, as reported in all databases, and their frequency, as reported in the prospective REISAMIC registry.
Findings We screened 948 patients registered in the three databases from June 27, 2014, to June 29, 2018 (745 from REISAMIC, 190 from the ImmunoTOX committee, and 13 from CeReCAI). 35 patients (21 men and 14 women) with haem-irAEs related to anti-PD-1 or anti-PD-L1 were included in the study. Of 745 patients in the REISAMIC registry treated with anti-PD-1 or anti-PD-L1, four had haem-irAEs, giving a frequency of 0·5%. Median age in the 35 patients was 65 years (IQR 51–75), and the most common tumour types were melanoma (15 [43%] patients), non-small-cell lung cancer (12 [34%] patients), and lymphoma (four [11%] patients). 20 (57%) patients received nivolumab, 14 (40%) received pembrolizumab, and one (3%) received atezolizumab. Among the 35 patients, neutropenia, autoimmune haemolytic anaemia, and immune thrombocytopenia were the most common types of haem-irAE (each in nine patients [26%]), followed by pancytopenia or aplastic anaemia (five patients [14%]), bicytopenia (one patients with thrombocytopenia plus anaemia and one patient with neutropenia plus anaemia [6%]), and pure red cell aplasia (one patient [3%]). The maximum grade of severity was grade 2 in three (9%) patients, grade 3 in five (14%) patients, and grade 4 in 25 (71%) patients; two (6%) patients died from febrile neutropenia during haem-irAE related to anti-PD-1. Haem-irAEs resolved in 21 (60%) of the 35 patients.
Interpretation Haem-irAEs induced by PD-1 or PD-L1 inhibitors are rare but potentially life-threatening events. The most common clinical presentations are neutropenia, autoimmune haemolytic anaemia, immune thrombocytopenia, and aplastic anaemia. Investigations into earlier detection and better management are warranted.
Research in context Evidence before this study
Immune checkpoint blockade of programmed cell death 1 (PD-1) or its ligand, programmed cell death ligand 1 (PD-L1) increases antitumour immunity by blocking intrinsic downregulators of immunity. By increasing the activity of the immune system, it is now well known that immune checkpoint blockade can trigger inflammatory side-effects that can theoretically reach all organs. Many studies have described immune related adverse events (irAEs) affecting the skin, gastrointestinal tract, endocrine glands, liver, lungs, joints, nervous system, and muscles, but data about the haemopoietic system remain scarce. We searched PubMed for clinical studies on May 1, 2018, without date or language restrictions, using the terms “neutropenia”, “leucopenia”, “anemia, hemolytic, autoimmune”; “anemia, aplastic”, “pancytopenia”,
“immune thrombocytopenic purpura”, “red-cell aplasia, pure”. All these terms were crossed (“AND”) with the following research terms for checkpoint inhibitors: “anti-programmed cell death 1”, “anti-programmed cell death ligand 1”, “nivolumab”, “pembrolizumab”, “atezolizumab”, “avelumab”, and “durvalumab”. We identified 31 articles that were single case reports (n=28) or a short description of two to three cases (n=3). Otherwise, a large study by Weber and colleagues assessing the pooled safety data of nivolumab in 576 patients had 39 (7%) patients with any grade of blood and lymphatic system disorder and seven (1%) patients with grades 3–4.
The other large study by Zimmer and colleagues identified three cases of haematological toxicities among 496 patients treated with nivolumab or pembrolizumab. However, these two studies of irAEs did not provide a full description of haematological toxicities. These scarce data do not provide About 71% of patients treated have any-grade irAEs and 10% have grade 3–4 irAEs after anti-PD-1 immunotherapy.1,2 In most cases, they involve the skin, gastrointestinal tract, thyroid or endocrine glands, liver, lungs, or joints.3 However, all organs can potentially be affected, including the haemopoietic system.1,4
Haematological irAEs (haem-irAEs) induced by anti- PD-1 or anti-PD-L1 immunotherapy are much less frequent than those induced with classic cytotoxic chemotherapy. In patients treated for advanced lung cancer, neutropenia of all grades occurred in 31% of patients who received docetaxel chemotherapy versus 1% of patients who received nivolumab, an anti-PD-1 monoclonal antibody.5 However, haem-irAEs related to immunotherapy have not been extensively characterised. The only descriptions available are case reports of immune thrombocytopenia,6,7 neutropenia,8,9 pancytopenia or aplastic anaemia,10,11 autoimmune haemolytic anaemia,12,13 and pure red cell aplasia.14 In this study, we aimed to provide a comprehensive clinical description of the haem- irAEs induced by anti-PD-1 or anti-PD-L1 therapy and to assess their frequency.
Added value of this study
We report here, for the first time to the best of our knowledge, a case series of 35 patients with haematological immune cytopenia induced by anti-PD-1 or anti-PD-L1, enrolled via three nationwide registries of irAEs in France. Adverse events were dominated by neutropenia, haemolytic anaemia, thrombocytopenia, and aplastic anaemia. Although the frequency of haematological toxicities was low (0·5%),
the events recorded were often clinically serious and life threatening (27 [77%] of 35 patients’ haem-irAEs had a severity of grade 4 or higher). Three (9%) patients treated for a solid tumour had a concomitant past medical history of chronic lymphocytic leukaemia, raising the question of a potential increased risk of haematological immunotoxicity in patients with an underlying mature lymphoid B clone.
Implications of all the available evidence
Immunological cytopenia is a rare but potentially serious complication of anti-PD-1 or anti-PD-L1 immunotherapies. Given the increasing number of patients expected to be treated for cancer in the coming years, anti-PD-1 or anti-PD-L1 should be understood as a potential cause of immunological cytopenia. This study should allow oncologists to better recognise haematological toxicities of immune checkpoint inhibitors and therefore detect them earlier. Furthermore, our results could contribute to improvement of future management guidelines of haematological toxicities in the clinical practice of oncologists.
Methods
Study design and participants
This was a descriptive observational study focused on haem-irAEs induced by anti-PD-1 or anti-PD-L1. We included all consecutive patients aged at least 18 years with grade 2 or worse haem-irAEs induced by anti-PD-1 or anti-PD-L1 who were registered in three French pharmacovigilance databases. Anti-PD-1 or anti-PD-L1 drugs could have been given as anticancer therapy for any type of solid tumour or haematological malignancy. The databases we used were the French nationwide Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC), the ImmunoTOX committee of Gustave Roussy,15 and the French academic registry of the Centre de Référence des Cytopénies Auto-Immunes de l’Adulte (CeReCAI).
Patients gave oral informed consent for the study, and consent was not required for inclusion in the national registries. This study was approved by the institutional review board of Gustave Roussy and the REISAMIC registry was declared at the Commission Nationale de l’Informatique et des Libertés (2098694v0).
Procedures
The REISAMIC register is an academic initiative implemented at Gustave Roussy (Villejuif, France), to collate and investigate all immunotherapy-related grade 2 or worse adverse events in patients of any age receiving any immunomodulatory monoclonal antibody across France. Suspected irAEs reported nationally through the REISAMIC website are assessed by the ImmunoTOX committee, an academic board of physicians who can advise on the management of these adverse events in clinical practice. Separately, REISAMIC follows up all patients of any age treated at Gustave Roussy with anti- PD-1 or anti-PD-L1 as anticancer therapy to monitor for the development of irAEs in a prospective registry. Both the REISAMIC registry and ImmunoTOX committee began data collection from June 27, 2014. CeReCAI is the French national reference centre for immune cytopenia; since June 9, 2017, it has collected information about haematological toxicities of immunotherapies in patients aged 18 years or older in a national registry. J-MM verified the absence of overlap between data, using date of birth to ensure that the same patient was not included twice in two different registries.
We assessed frequency of haem-irAEs over the study period using the prospective REISAMIC registry only. For this analysis, we included all patients aged 18 years or older treated at Gustave Roussy with anti-PD-1 or anti- PD-L1 treatments, irrespective of their estimated survival, and calculated the number who developed grade 2 or worse haem-irAEs as a proportion of those who received anti-PD-1 or anti-PD-L1 therapy overall.
The severity of haem-irAEs was assessed according to the Common Terminology Criteria for Adverse Events (version 4.03) in all registries. For data to be included in this study, the causal relationship of the adverse event with anti-PD-1 or anti-PD-L1 had to be classed as certain or probable according to WHO’s Uppsala Monitoring Center scale.16 All cases of haem-irAEs were reviewed by a board of experts in haematology and autoimmune diseases (OL, SC, J-MM, and JL). Bone marrow analysis was done in patients with lymphoma (from all registries) to rule out disease infiltration as a potential cause of haem-irAE (appendix). The following data were assessed: characteristics of immune checkpoint inhibitors received and all concomitant treatments, clinical characteristics, pathological and cytological details of bone marrow aspiration or biopsy samples (if done), results of serological assay for autoimmune factors (if done), medications administered to treat the irAEs, and the outcomes of the adverse event.
Outcomes
The primary endpoints were the clinical description of the haem-irAEs induced by anti-PD-1 or anti-PD-L1 and their frequency. Secondary endpoints were the time to onset and duration of grade 2 or worse events. The time to onset was defined as the time between the initiation of anti-PD-1 or anti-PD-L1 (first infusion) and the first clinical or biological abnormalities of haem-irAEs of grade 2 or worse. The duration of haem-irAEs was defined as the duration of the adverse event at grade 2 or worse.
The follow-up period of patients with haem-irAEs was defined as the period from the beginning of the adverse event until final follow-up or death. Antitumoral responses after anti-PD-1 or anti-PD-L1 were recorded and assessed by investigator’s review using Response Evaluation Criteria in Solid Tumors (version 1.1) in all databases, immune-related response criteria for solid tumours,17 and by International Harmonization Project for Response Criteria in Lymphoma Clinical Trials criteria for lymphoma.18
Statistical analysis
The time to onset and duration at grade 2 or worse were compared for each type of haem-irAE using a non-parametric Kruskal-Wallis test, with a significance threshold of p<0·05. The proportion of patients with resolution of their adverse event were compared across each type of adverse event using a contingency table with a χ² test; the distributions were considered statistically different with an α risk of 5% if the p value was less than 0·05. All statistical analyses were done with R (version 3.3.3) and GraphPad Prism (version 5.03). Role of the funding source The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors have approved the final manuscript. ALV, SL, ND, AM, J-MM, and OL had access to raw data in the study. The corresponding author had full access to all the data and the final responsibility to submit the manuscript for publication. Results Between June 27, 2014, and June 29, 2018, 745 patients were prospectively included in the REISAMIC registry following anti-PD-1 (726 patients) or anti-PD-L1 treat- ment (19 patients). Four (0·5%) of these patients had haem-irAEs, which were confirmed as anti-PD-1 or anti-PD-L1 treatment related. Over the same period, the ImmunoTOX committee received 190 referrals for patients with irAEs who had been treated by immunotherapy, of whom 29 had a suspected haem- irAE. Over the same time, the CeReCAI registry recorded 13 patients with haem-irAEs induced by anti-PD-1 or anti-PD-L1 (figure 1). After review by the board of experts, seven patients’ haem-irAEs were assessed as unlikely to be caused by anti-PD-1 or anti-PD-L1, so these patients were excluded from the analysis. Four of these seven patients had another concomitant treatment implicated in the causality of the haem-irAE and three had other causes of cytopenia. 35 patients (18 certain and 17 probable in causality assessment) with grade 2 or worse haem-irAEs related to anti-PD-1 or anti-PD-L1 were analysed in the study (figure 1). The median age of the 35 patients was 65 years (IQR 51–75), and there were 1·5 times more men (n=21) than women (n=14; table 1). The tumour types in order of prevalence were melanoma, non-small-cell lung cancer, lymphoma, and other malignancies. Three (9%) patients treated by anti-PD-1 for a solid tumour had previously diagnosed chronic lymphocytic leukaemia (appendix). The immunotherapies associated with haem-irAEs were nivolumab (Opdivo, Bristol-Myers Squibb, Princeton, USA), given intravenously 240 mg, every 2 weeks in 20 (57%) of the 35 patients; pembrolizumab (Keytruda, Merck, Whitehouse Station, USA), given intravenously, 200 mg every 3 weeks, in 14 (40%) patients; and atezolizumab (Tecentriq, Genentech, San Francisco, USA), given intravenously, 1200 mg every 2 weeks, in one (3%) patient. 33 (94%) of the 35 patients received the anti-PD-1 or anti-PD-L1 treatment as a monotherapy. The two remaining patients received nivolumab in combination with oral chemotherapy: temozolomide in one patient treated for melanoma and procarbazine in one patient treated for Hodgkin lymphoma (appendix). In these patients, oral chemotherapy was discontinued during the first cycle because of haem-irAEs, and at resolution, nivolumab was resumed alone. The haem- irAEs then recurred when nivolumab was given alone and were considered related to nivolumab in both patients.
Seven (28%) of 24 evaluable patients had an overall antitumour response after anti-PD-1 or anti-PD-L1 treatment (table 1). 12 (34%) of the 35 patients died after occurrence of haem-irAEs and during the follow-up period. Two patients died from febrile neutropenia while the haem-irAE was ongoing: one patient with lung cancer developed aplastic anaemia related to nivolumab, and another with melanoma developed neutropenia related to nivolumab. These two deaths were recorded as fatal irAEs related to anti-PD-1 immunotherapy. In the ten other patients who died, causes of deaths were cancer progression (nine patients) and coronary syndrome (one patient) that were unrelated to anti-PD-1 therapy.
Among the 35 patients, neutropenia, autoimmune haemolytic anaemia, and immune thrombocytopenia were the most common types of haem-irAE (each in nine patients; 26%), followed by pancytopenia or aplastic anaemia (five patients; 14%), bicytopenia (two patients; 6%), and pure red cell aplasia (one patient; 3%; table 2). To treat the haem-irAEs, 22 (63%) of the 35 patients were given steroids orally, five (14%) were given steroids intravenously and orally, 11 (31%) had intravenous immunoglobulins, and seven (20%) had rituximab. Supportive care among the 35 patients were red blood cell or platelet transfusions for 15 (43%) patients, granulocyte colony-stimulating factors (G-CSF) for 12 (34%) patients, thrombopoietin agonists for three (9%) patients, and erythropoiesis-stimulating drugs for two (6%) patients (table 2).
The maximum grade of severity of haem-irAEs in the 35 patients was grade 2 in three (9%) patients, grade 3 in five (14%) patients, grade 4 in 25 (71%) patients, and grade 5 in two (6%) patients. The anti-PD-1 or anti-PD-L1 treatments were permanently discontinued in 28 (80%) of the 35 patients (table 3). Beyond the resolution of haem-irAEs, seven (20%) of the 35 patients were rechallenged by the same class of immune checkpoint inhibitor, and the same adverse event recurred in three (43%) of these seven patients (table 3).
Detailed characteristics of each adverse event are provided in the appendix, and adverse events are summarised by category in table 3. In the nine patients who had neutropenia, neutrophil count decrease was generally profound, with a median nadir neutrophil count of 0·18 × 10⁹ cells per L (IQR 0·11–0·40; normal range 2·0–7·0 × 10⁹ cells per L). Complications of immune neutropenia were mainly infectious: six (67%) patients with immune neutropenia developed febrile neutropenia and one (11%) patient died of septic shock during the episode of febrile neutropenia. The bone marrow aspiration showed blockage in granulocyte maturation in four (44%) patients, granulocytic lineage hypoplasia in two (22%) patients, and a near normal granulocytic lineage and bone marrow smear in the three (33%) remaining patients. To treat neutropenia, eight (89%) patients received G-CSF, and three (33%) received corticosteroids. Median duration of neutropenia at grade 2 or worse was 2·4 weeks (IQR 1·6–10·1; table 3). At final follow-up, neutropenia had resolved in six (67%) patients. Beyond resolution, three (33%) patients were subsequently rechallenged with anti-PD-1, of whom two (67%) had a second episode of immune neutropenia.
Of the nine patients who had autoimmune haemolytic anaemia, all had a direct antiglobulin test and were positive, of whom four (44%) had low positivity. The direct antiglobulin test was positive for complement 3d (six [67%] patients) or for IgG (three [33%] patients). Three (33%) patients had a cold antibody or cold agglutinin associated with haemolytic anaemia. Two patients with solid tumours had pre-existing B-cell chronic lymphocytic leukaemia, but the disease was not in progression at the time of the autoimmune haemolytic anaemia and thus, anti-PD-1 treatment was regarded as the triggering factor for the haem-irAE. The anaemia was generally severe and profound (grade 4 in eight [89%] patients; table 3). All patients required red blood cell transfusions. Four patients required treatment with corticosteroids alone (without rituximab), and autoimmune haemolytic anaemia resolved after corticosteroids. Conversely, the other five patients did not
respond sufficiently to corticosteroids and had additional treatment with rituximab. At final follow-up, anaemia was resolved in six (67%) patients. The anti-PD-1 or anti- PD-L1 had been permanently discontinued in eight (89%) patients. One (11%) patient was rechallenged with the same anti-PD-1 drug and did not have further autoimmune haemolytic anaemia events.
Nine patients had immune thrombocytopenia: seven (78%) detected only as a laboratory blood count abnormality, and two (22%) with haemorrhagic symptoms (appendix). Median nadir platelet count was 5 × 10⁹ cells per L (IQR 5–13 × 10⁹; normal range 150–400 × 10⁹ cells per L). One (11%) patient had a previous history of B-cell chronic lymphocytic leukaemia and developed immune thrombocytopenia after anti-PD-1 therapy. Bone marrow aspirate analysis in the seven patients with available data showed normal cellularity and presence of megakaryocytes, suggesting a peripheral mechanism of platelet destruction. Serum antinuclear antibody assay was positive in three (33%) patients. All patients received steroids, and six (67%) patients received additional intravenous immunoglobulins. Two (22%) patients did not response to steroids or intravenous immunoglobulins and were treated with thrombopoietin agonists or rituximab. The anti-PD-1 drug was permanently discontinued in six (67%) patients (table 3). Three (33%) patients were rechallenged with anti-PD-1 and one (33%) of these had a recurrence of immune thrombocytopenia after the rechallenge. At final follow-up, seven (78%) of the nine patients had resolution of immune thrombocytopenia.
Four (80%) of the five patients with pancytopenia had bone marrow biopsies done, which showed severe hypoplasia of the three haemopoietic lineages without malignant infiltration or blast proliferation, consistent with immune-related aplastic anaemia; the remaining patient had near-normal bone marrow aspirate. Four (80%) of the five patients required multiple transfusions of red blood cells or platelets. One (20%) patient with aplastic anaemia died because of febrile neutropenia. Three (60%) patients received steroids for aplastic anaemia without a response. Anti-PD-1 immunotherapy was permanently discontinued in all five patients (table 3). Symptoms associated with pancytopenia were generally long lasting (up to 232 days). At final follow-up, one (20%) patient’s pancytopenia was resolved.
Two patients had bicytopenia. One was a woman aged 49 years who developed bicytopenia (grade 4 thrombo- cytopenia and grade 4 anaemia) after 13 cycles of nivolumab. The bone marrow aspirate and biopsy showed a central mechanism for the bicytopenia, with hypoplasia of red cell progenitors and absence of megakaryocytes. The patient responded poorly to oral steroids, and the bicytopenia was not resolved at final follow-up. The other patient was a man aged 64 years who was treated for advanced melanoma and developed bicytopenia (grade 4 neutropenia and grade 2 anaemia) after three cycles of pembrolizumab. Bone marrow aspirate aspect was normal, suggesting a peripheral cause. Biological assays of autoimmunity were positive in the serum: serum monoclonal antibody immobilisation of granulocyte antigens was positive, antinuclear assay showed a titre of 1/5120 (normal titre <1/160). This patient received oral prednisone and G-CSF, after which bicytopenia resolved. Anti-PD-1 was permanently discontinued in these two patients with bicytopenia (table 3). One male patient aged 82 years developed pure red cell aplasia after three cycles of pembrolizumab. Bone marrow aspiration showed profound hypoplasia of red cell progenitors. Parvovirus B19 infection was ruled out by a negative PCR result in blood and bone marrow. The patient responded poorly to oral prednisone and intravenous immunoglobulins, and the pure red cell aplasia was not resolved at final follow-up (table 3). Pembrolizumab was permanently discontinued in this patient. The median time between initiation of anti-PD-1 or anti-PD-L1 and occurrence of haem-irAE was 10·1 weeks (IQR 3·6–24·1; range 0·9–198·0; figure 2A, table 3) and did not differ significantly between the types of haem- irAEs (p=0·427; figure 3A). Median duration of haem- irAEs at grade 2 or worse was 4·2 weeks (1·7–8·9) and did not significantly differ between the types of haem- irAEs (p=0·422; figure 3B). With a median follow-up after haem-irAEs of 19·4 weeks (IQR 9·4–55·4), haem- irAEs resolved in 21 (60%) of the 35 patients, with no significant difference between the types of haem-irAEs (p=0·136; figure 2B). Discussion To our knowledge this case series of 35 patients with haematological immune cytopenia induced by anti-PD-1 or anti-PD-L1, enrolled via three nationwide registries of immune-related adverse events in France, is the first study to describe the characteristics of these complications in detail. Haematological immune-related adverse events appeared mostly as neutropenia, haemolytic anaemia, thrombocytopenia, and aplastic anaemia. Although the frequency of haematological toxicities was low, occurring at grade 2 or worse in less than 1% of patients who had been treated with anti-PD-1 or anti-PD-L1, those that did occur were often clinically serious and life threatening (grade 4 or worse in 27 [77%] of 35 patients in our study). The main limitations of this study are its partially retrospective nature and the declarative method of reporting side-effects, which both have selection biases. Under-reporting of adverse events by the treating physician is possible, especially when these adverse events are not yet well known by the medical community. The number of cases reported in this series remains low. These limitations meant we could not draw any definitive conclusions about the exact frequency, description, or distribution of the different types of haem-irAEs induced by anti-PD-1 or anti-PD-L1. Many studies have assessed irAEs, but detailed data specifically on haem-irAEs is scarce. A large study of all types of irAEs reported by Zimmer and colleagues19 identified three haematological irAEs among 496 patients treated with nivolumab or pembrolizumab; however, the clinical descriptions were not detailed. In a large study by Weber and colleagues2 assessing the pooled data safety of nivolumab among 576 patients, 39 (7%) patients had any grade of blood and lymphatic system disorders and seven (1%) had grades 3–4; however, no further details were available.2 We believe that our findings give a clear estimate of the frequency and description of the clinical characteristics of haem-irAEs. When using novel drugs such as PD-1 or PD-L1 inhibitors, oncologists have to judge whether a clinical or laboratory effect is related or not related to the drug given. This causal relationship will depend on the results of the work-up and on the outcome after rechallenge, if done.20 In patients who have been rechallenged with the same drug and have a recurrence of the same toxicity, the causal relationship can be regarded as certain. When the adverse event is typical and expected, without other causes identified, the relationship could also be regarded as certain. In other cases, the link could be likely or possible according to the pharmacovigilance rules of the international drug monitoring system.20 According to these pharmacovigilance rules and to provide a clear figure of what is expected with anti-PD-1 or PD-L1, we only retained the cases of certain or probable haem-irAEs in this study. The median time to onset of haem-irAE in our study was 10·1 weeks, which is similar to times for other classical irAEs.2 The time to occurrence of haem-irAEs was varied in our study (0·9–198·0 weeks), and the regularity of the curve of occurrence suggests that haem- irAEs can potentially occur at any time. Furthermore, a wide variety of haem-irAEs occurred with anti-PD-1 or anti-PD-L1, mimicking virtually all types of immune cytopenias known in human diseases. Notably, autoimmune haemolytic anaemias were both warm (37°C) and cold (4°C) antibody types, demonstrating the diversity of immune toxicity encountered with anti-PD-1 or anti-PD-L1 immunotherapies. Guidelines on the management of immune toxicities have recently been published by the American Society of Clinical Oncology,3 which recommend the early suspension of immune-checkpoint inhibitors in the case of haematological toxicity—at the onset of a grade 1 event for aplastic anaemia and at grade 2 for immune thrombocytopenia and haemolytic anaemia. Except for the increase in eosinophil blood count that can be regarded as a non-clinically significant event,21 our study supports that any new blood count abnormality after anti-PD-1 or anti-PD-L1 must be considered as a potential clinically significant event. This study could contribute to improvement of future management guidelines of haematological toxicities in the clinical practice of oncologists. In our study, three (9%) of the 35 patients had a concomitant medical history of B-cell chronic lymphocytic leukaemia. Some reports of autoimmune haemolytic anaemia induced by anti-PD-1 in patients with chronic lymphocytic leukaemia have been published elsewhere.22,23 Our data, alongside the results of these previous studies, raise the question of a potential increased risk of haematological immunotoxicity in patients with an underlying mature lymphoid B clone. A screening for underlying chronic lymphocytic leukaemia could be done in patients with haem-irAEs. In terms of management in patients with underlying chronic lymphocytic leukaemia, anti-B-cell therapy such as rituximab24 should be rapidly considered in cases of insufficient responses to corticosteroids. Neutropenia was one of the most frequent haem-irAEs in our study. Several case reports of similar immune- related neutropenia have been described elsewhere,8,9,25,26 and further guidelines might address how to manage these events. We found that immune neutropenia was abrupt and profound in our study. In such cases of immune neutropenia, the risk of mortality is generally from bacterial or fungal infection.27 To mitigate infection risk, G-CSF could be used until the resolution of neutropenia, and we discourage systematic treatment with corticosteroids in this context, because it might increase the risk of infection. The thrombocytopenia induced by anti-PD-1 that was described in our study seems to mimic classic cases of immune thrombocytopenia.28 From these similarities, further guidelines about the management of immune thrombocytopenia induced by immune checkpoint inhibitors could be modelled on the management of classical immune thrombocytopenia.28 The management of immune thrombocytopenia is generally guided by clinical context with a careful screen for symptoms of bleeding, rather than the platelet count alone. In the context of immune thrombocytopenia, a simple and useful haemorrhagic clinical score29 could help to rapidly identify patients at risk of severe bleeding who require immediate treatment with intravenous immunoglobulins in addition to corticosteroids. Aplastic anaemia induced by anti-PD-1 is described in previous studies as one of the most serious haematological immune toxicities, mainly because of the profound and long-lasting nature of pancytopenia.11,30–32 Similarly, a small proportion of patients (one [20%] of five) achieved resolution of aplastic anaemia in our study. Few data are available to guide the treatment of such immune-related aplastic anaemia. In most patients with aplastic anaemia induced by anti-PD-1 or anti-PD-L1, corticosteroids plus adequate anti-infective prophylaxis seem a suitable option.3 Depending on the haematological lineages most affected, growth factors such as G-CSF or thrombopoietin agonists might be of use to mitigate cytopenias.33,34 In severe cases of aplastic anaemia, immunosuppressive therapies such as ciclosporin, antilymphocyte serum, or androgens could be considered.33,34 Furthermore, our study provides some preliminary data about the safety of rechallenge in patients who have had haematological toxicities after anti-PD-1 or anti- PD-L1. Seven (20%) of the 35 patients were rechallenged and three (43%) of them had a recurrence of the haem- irAE. These data are too scarce to draw any definitive conclusion, but our results indicate that the risk of recurrence of adverse event exists after rechallenge, and the rechallenge thus should be carefully considered and patients should be closely monitored. In conclusion, immunological cytopenia is a rare but potentially serious complication of anti-PD-1 or anti- PD-L1 immunotherapies. Although we note limitations due to the rarity of haem-irAEs and the retrospective nature of this study, our data provide a clinical picture dominated by neutropenia, autoimmune haemolytic anaemia, thrombocytopenia, and aplastic anaemia. This observational study encourages further, in-depth investi- gations of haematological immune toxicities, to search for biomarkers that can be helpful for earlier detection. Further clinical studies will enhance capacity for early detection and help to optimise management of these adverse events.