Immune-mediated complications of monoclonal antibodies used in onco-hematology

I. Introduction

Monoclonal antibodies are well-established targeted therapies that revolutionized the treatment of different types of cancer as well as other disorders such as autoimmune and infectious diseases. The first monoclonal antibody, rituximab, was created in 1975. It is the first monoclonal antibody approved for oncology patients. Approximately 100 monoclonal antibodies have been approved for human use since then⁽¹⁾. Technological advances enabled the development of numerous monoclonal antibodies directed against distinct antigens, as well as bispecific monoclonal antibodies capable of binding two different antigens simultaneously⁽²⁾.

Monoclonal antibodies have become one of the main treatment options in many hematological diseases, used either alone or in combinations⁽³⁾. Besides being the first described monoclonal antibody, rituximab was the first monoclonal antibody used in hematology. Rituximab targets CD20, an antigen located on the B cell surface. Rituximab was proven effective in several B-cell lymphomas, such as diffuse large B-cell lymphoma, Burkitt lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia and chronic lymphocytic leukemia^(1,4,5), but also in non-malignant hematological diseases, namely autoimmune anemia and immune thrombocytopenia^(6,7).

Almost every malignant hematological disease has at least one monoclonal antibody incorporated in its treatment protocol. Besides rituximab, there are other monoclonal antibodies efficient in chronic lymphoproliferative diseases such as obinutuzumab, ibritumomab, polatuzumab vedotin, brentuximab vedotin, alemtuzumab, mogamulizumab, nivolumab and pembrolizumab^(5,8,9). Multiple myeloma has a potential good response to three monoclonal antibodies, daratumumab, elotuzumab and isatuximab⁽¹⁰⁾. Acute leukemias have a lower benefit from monoclonal antibodies. In acute lymphoblastic leukemia, blinatumomab and inotuzumab ozogamicin are indicated in relapse and refractory settings⁽¹¹⁾; acute myeloblastic leukemia benefits from one monoclonal antibody, gemtuzumab ozogamicin, recommended only in selected cases⁽¹²⁾.

Non-malignant hematological diseases can also benefit from monoclonal antibodies – as previously mentioned, autoimmune anemia and immune thrombocytopenia could respond to rituximab, paroxysmal nocturnal hemoglobinuria to eculizumab and ravulizumab, and thrombotic thrombocytopenic purpura to caplacizumab^(6,7,13,14).

Monoclonal antibodies are generally better tolerated than standard chemotherapy. However, they are not free of adverse reactions. The possible side effects of monoclonal antibodies include immune-mediated adverse reactions, infections, platelet and thrombotic disorders, autoimmune diseases, cancer, dermatitis, cardiotoxicity and cytokine storm⁽¹⁵⁾.

In the current review, we will focus on immune-mediated adverse reactions to the most commonly used monoclonal antibodies in hematology.

II. Immune-mediated adverse reactions – general considerations

1. Hypersensitivity reactions have increased in number since the use of monoclonal antibodies. Hypersensitivity reactions to monoclonal antibodies include infusion-related reactions, cytokine-release syndrome, and types I, III and IV reactions^(16,17). Infusion-related reactions can occur at the time of the first infusion. They are characterized mainly by fever with chills, flushing, hypertension, tachycardia, dyspnea, vomiting and syncope⁽¹⁶⁾. The cytokine release reaction results in an exaggerated systemic immune response involving the release of cytokines from the targeted cells. It manifests similarly to infusion-related reactions, can also occur at the first infusion, and has similar manifestations^(16,18). Type I hypersensitivity reaction is caused by the release of various mediators from mast cells and basophils. Clinical manifestations range from flushing, pruritus and urticaria to life-threatening anaphylaxis⁽¹⁶⁾. Type III hypersensitivity reaction is caused by deposits of immune complexes⁽¹⁶⁾. A delayed type IV hypersensitivity reaction occurs in a time span between 12 hours to weeks after the infusion. The clinical manifestations range from a non-severe maculopapular rash to severe reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis⁽¹⁶⁾.

Patients who suffer from severe hypersensitivity reactions could switch to an alternative treatment or undergo a desensitization protocol. Desensitization methods consist in the administration of the same drug, at a progressive rate of infusion, starting with a very low dose; the protocol differs depending on the drug^(16,17). However, the possibility that the patient still develops a hypersensitivity reaction at the next infusions needs to be taken into account during the subsequent cycles⁽¹⁶⁾. The risks and benefits should be weighed when considering a patient for desensitization. In severe forms of hypersensitivity reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis (TEN), desensitization is absolutely contraindicated⁽¹⁷⁾. In serum sickness and hemolytic anemia, it is recommended that desensitization be avoided⁽¹⁷⁾.

2. Immune-mediated disorders can occur as a result of monoclonal antibody therapy, as a consequence of their immunomodulatory actions. Some of the immune disorders reported as secondary to monoclonal antibo­dies are described below.

2.1. Immune-mediated hematological disorders

Drug-induced autoimmune hemolytic anemia (AIHA) is a rare disorder, associated mainly with the administration of antimicrobial, anti-inflammatory and anti-neoplastic drugs⁽¹⁹⁾. In 2009, 125 drugs were linked to drug-induced AIHA⁽¹⁹⁾. The mechanisms of drug-induced AIHA are incompletely understood. Some drugs cause the production of antibodies against red blood cells (RBCs), while other drugs bind to proteins of the RBCs membrane and trigger antibody production against this new antigen^(19,20). The suspicion of drug-induced AIHA is raised based on the signs, symptoms and the laboratory findings of anemia and hemolysis, occurring days to weeks after the exposure to a drug known to cause AIHA⁽²¹⁾. Drug-dependent antibody testing can be useful in establishing the diagnosis and avoiding further use of the sensitizing drug⁽²¹⁾. However, in the current clinical practice, drug-dependent antibody testing is not widely available. The management of drug-induced AIHA depends on the severity, but always includes the discontinuation of the presumed drug. Transfusions, treatment of complications, AIHA (corticotherapy, intravenous immunoglobulins) and presumptive treatment for other possible etiologies may be required⁽²¹⁾.

More recently, drug-induced AIHA was reported after the treatment with monoclonal antibodies^(20,22-24). Tanios et al. searched the U.S. Food and Drug Administration database for autoimmune hemolytic anemia in patients who received immune checkpoint inhibitors, namely nivolumab, pembrolizumab, ipilimumab and atezolizumab, and found 68 cases out of 12,631 total cases⁽²⁰⁾. The mechanisms are different from those of the other drugs, probably by increasing or redirecting immune surveillance⁽²⁰⁾. AIHA following immune checkpoint inhibitors is often severe and requires treatment’s discontinuation, high-dose corticosteroids and intensive supportive treatment, including RBCs transfusions and volume replacement. Rituximab is also a feasible option in selected cases, refractory to standard steroid therapy⁽²⁰⁾. The decision regarding the continuation of treatment with checkpoint inhibitors after the resolution of AIHA should be made by weighing the risks and benefits.

Besides checkpoint inhibitors, drug-induced AIHA was reported after alemtuzumab^(22,24). It is a life-threatening complication that can occur several months after alemtuzumab infusions^(22,24). The presumed mechanism is the increase in the regeneration of self-reactive T-cells in the recovery period of lymphocytes⁽²⁴⁾. In these cases, corticosteroids are often inefficient, the hemolysis being intravascular⁽²⁴⁾. Second-line therapies, such as intravenous immunoglobulins, plasmapheresis and rituximab, should be considered⁽²⁴⁾. The clinician should closely monitor the patient for AIHA for months after the discontinuation of the treatment.

Drug-induced immune thrombocytopenia (ITP) is a type of secondary ITP, caused by drug-induced antibody-mediated platelet destruction⁽²⁵⁾. A variety of drugs, vaccines, herbal remedies, supplements and foods are linked to immune thrombocytopenia⁽²⁵⁾. The diagnosis of drug-induced ITP is difficult. All patients with acute manifestations and an unknown etiology should be suspected of drug-induced ITP⁽²⁵⁾. However, many possible factors can coexist, making it difficult to pinpoint the responsible factor. Recurrent acute thrombocytopenia after repeated exposure to the presumptive drug and the documentation of drug-dependent anti-platelet antibodies establish the diagnosis of drug-induced immune thrombocytopenia⁽²⁶⁾. The management is similar to that of primary ITP, specifically corticosteroids or other immunosuppressive agents, intravenous immunoglobulins, plasma exchange, rituximab, thrombopoietin agonists and platelet transfusions; in addition, it is also suggested to discontinue the sensitizing drug^(25,27,28).

Among the monoclonal antibodies, cases of immune thrombocytopenia have been reported secondary to alemtuzumab⁽²⁷⁾, nivolumab^(28-30), pembrolizumab⁽³¹⁾, abciximab, infliximab, efalizumab, bevacizumab and rituximab^(15,25).

Alemtuzumab-induced immune thrombocytopenia is distinguished by delayed onset, its responsiveness to conventional treatment and a persistent response⁽²⁷⁾. The mechanisms are different from those seen in drug-induced ITP; alemtuzumab causes abnormalities in central tolerance checkpoints during lymphocyte reconstruction⁽²⁷⁾.

Immune thrombocytopenia is one of the most frequent immune-related adverse reactions to checkpoint inhibitors⁽²⁸⁾. The risk is higher in the first four weeks after administration. It can occur as early as one or two cycles or after years of treatment⁽²⁸⁾. The mechanisms remain unknown; it is considered that the activation of the immune system contributes to immune thrombocytopenia⁽²⁸⁾. The management is similar to that of primary immune thrombocytopenia; however, compared to alemtuzumab-induced thrombocytopenia, the response to corticosteroids is lower^(27,28).

Drug-induced immune neutropenia occurs when neutrophils are destroyed by drug-dependent or drug-induced antibodies against membrane glycoproteins^(32-34). Many drugs can cause immune neutropenia, such as non-steroidal anti-inflammatory drugs, antibiotics and psychoactive medicines⁽³²⁾. The diagnosis of drug-induced immune neutropenia should be considered when a decrease in neutrophils is observed within a week after repeated exposure to a drug^(32,34). Without treatment, the patients can develop life-threatening infections^(32,33). The management in these cases includes the discontinuation of the sensitizing drug, granulocyte colony-stimulating factors as supportive measures, treatment of any infection, and other supportive care means^(32,33). Upon reintroducing the presumed drug, the neutropenia reappears, even though low doses are used⁽³⁴⁾. Immune-related neutropenia was reported as a rare adverse reaction of checkpoint inhibitors, such as nivolumab^(29,30), pembrolizumab⁽³⁵⁾, ipilimumab⁽³⁶⁾ and rituximab⁽³⁷⁾.

The management of immune-mediated adverse reactions to monoclonal antibodies is a difficult task. There are no guidelines regarding the diagnosis and treatment of these complications. Detecting the drug-dependent antibodies involved in immune hematological adverse reactions is rarely performed in day-to-day practice. The diagnosis is based on clinical signs and symptoms, a complete blood count and on the exposure to a drug known to cause immune cytopenia. However, the clinician should always consider other factors for cytopenia, such as chemotherapy-induced cytopenia, cancer evolution, metastases and sepsis.

2.2. Non-hematological immune-mediated complications of immune checkpoint inhibitors

Dermatological immune-related adverse reactions are the most common immune-related adverse reactions of immune checkpoint inhibitors⁽³⁸⁾. The manifestations vary from eczematous rash, vitiligo, lichen planus, lichen sclerosus or psoriasis to life-threatening conditions, such as Sweet syndrome, Steven-Johnson syndrome and toxic epidermal necrosis^(38-40). The severe reactions are rare, but require further investigations, such as skin biopsy, for differential diagnosis^(38,39). The American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology (ESMO) guidelines recommend that the immune checkpoint inhibitors should be continued with caution in grade 1 toxicities and stopped in grade ≥3 toxicities; systemic and topical corticotherapy, intravenous immunoglobulins or cyclosporine can be required in selected cases^(41,42).

Gastrointestinal and hepatic immune-related adverse reactions are also common complications of immune checkpoint inhibitors. The most frequent ones are gastritis, enterocolitis, colitis and hepatitis⁽⁴¹⁾. The majority of these adverse event are mild; however, life-threatening complications may occur.

In severe cases of gastrointestinal immune-related adverse reactions, an endoscopy and mucosal biopsies are indicated in order to establish the diagnosis^(41,42). Noninvasive procedures should be considered, if available, in order to avoid intestinal perforation, such as confocal laser microscopy^(39,43). The management of immune colitis include, according to the ASCO and ESMO guidelines, the discontinuation of the checkpoint inhibitor, supportive therapy (loperamide and hydration), corticotherapy, and infliximab or vedolizumab in refractory cases^(41,42).

Hepatitis is often asymptomatic, increases in aspartate and alanine transaminase and bilirubin being found at routine testings⁽³⁹⁾. Patients with hepatitis during immune checkpoint inhibitors treatment should be screened for other etiological factors, such as viral infections, autoimmune diseases and metastases. In severe cases, a liver biopsy should be considered⁽⁴²⁾. The treatment, according to the ASCO and ESMO guidelines, consists in the discontinuation of immune checkpoint inhibitor in grade ≥2 events, discontinuation of unnecessary medication, especially hepatotoxic one, and corticotherapy. Cases refractory to corticotherapy could benefit from mycophenolate mofetil^(41,42). In immune hepatitis, infliximab is contraindicated⁽⁴¹⁾.

Immune-related endocrinopathies associated with immune checkpoint inhibitors involve mainly the thyroid, pituitary, adrenal glands and pancreatic endocrinologic function. The symptomatology is often unspecific, making the diagnosis difficult.

Regarding thyroid immune-related adverse reactions, both hypothyroidism and hyperthyroidism have been reported^(39,41,42). Hyperthyroidism is rare and usually precedes hypothyroidism⁽⁴²⁾; symptomatic patients should discontinue immune checkpoint inhibitor treatment and receive beta-blocker therapy⁽⁴²⁾. Patients who develop hypothyroidism should discontinue the treatment when symptomatic; hormonal replacement therapy and corticosteroids in case of inflammation are recommended by current guidelines^(41,42).

Hypophysitis occurs more commonly after ipilimumab therapy⁽³⁹⁾. In the case of hypothyroidism or adrenal insufficiency, a distinction should be made between pituitary gland abnormalities and peripheral thyroid or adrenal gland disorders⁽⁴¹⁾. A low level of adrenocorticotropic hormone is suggestive of a central cause; in these cases, it is most likely hypophysitis⁽⁴¹⁾. The immune checkpoint inhibitor should be discontinued even in asymptomatic patients until the values stabilize under hormonal replacement therapy. The hormonal replacement therapy should begin with corticosteroid replacement to prevent adrenal crisis, followed by thyroid hormone replacement, testosterone or estrogen therapy⁽⁴¹⁾.

Diabetes mellitus is a rare complication of immune checkpoint inhibitors, caused by autoimmune beta-cell destruction. The ASCO and ESMO guidelines recommend the discontinuation of the immune checkpoint inhibitor in case of severe symptoms or complications, oral antidiabetic medication or insulin therapy^(41,42).

Pancreatitis is rare; most cases report elevated amy­lase and lipase, but do not meet the criteria for pancreatitis⁽³⁸⁾. An ultrasonography should be performed to differentiate immune pancreatitis from an obstructive cause⁽³⁸⁾. The management should include corticotherapy and drug immune checkpoint inhibitors discontinuation⁽³⁹⁾.

Less frequent immune-mediated adverse reactions of immune checkpoint inhibitors include pneumonitis, myocarditis, renal, neurologic, rheumatologic and ophthalmologic immune-mediated adverse reactions^(39-42).

2.3. Non-hematological immune-mediated complications of other monoclonal antibodies

Other monoclonal antibodies besides immune check-point inhibitors are less commonly associated with immune-mediated adverse reactions. The most frequent autoimmune disorders induced by monoclonal antibodies are psoriasis, inflammatory bowel disease, demyelinating diseases, interstitial lung disease and lupus⁽⁴⁴⁾. In severe cases of autoimmune-induced diseases, discontinuation of the monoclonal antibody is mandatory⁽⁴⁴⁾. Furthermore, corticotherapy or immunosuppressive therapy may be required in selected cases⁽⁴⁴⁾.

III. Conclusions

Monoclonal antibodies have become a widely used treatment not only in hemato-oncology, but also in other specialties. Their widespread use resulted in an increase in immune-mediated complications. These should be suspected in a patient with nonspecific symptoms who is being treated with monoclonal antibodies, thus rendering a detailed history, with extensive documentation of prior medication, paramount in the management of such patients. Knowledge of these complications allows for a prompt diagnosis and the proper medical treatment. 

 

Conflict of interest: none declared

Financial support: none declared

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