Isolated Neutropenia Due to Immune Checkpoint Inhibitors

In this article, we explore the correlation between immune checkpoint inhibitors (ICIs) and neutropenia. Immune checkpoint inhibitors have revolutionized cancer treatment and management by maximizing the innate abilities of the immune system. However, this therapeutic potential is accompanied by a range of immune-related adverse effects (irAEs), including neutropenia, which is a rare but potentially life-threatening side effect of this mode of cancer treatment. Through an in-depth analysis of various case reports, we have compiled a detailed table summarizing the occurrences of neutropenia associated with different ICIs, the grades of neutropenia, treatments used, and patient outcomes. Management of neutropenia must include an approach based on early diagnosis of the condition and a treatment based on its severity. This review discusses different therapeutic interventions, ranging from the administration of corticosteroids and intravenous immunoglobulin (IVIG) to the use of granulocyte colony-stimulating factor (filgrastim) and, in very severe cases, a stem cell transplant. We have also enlisted salient side effects caused by these interventions. Our findings emphasize that while neutropenia is a relatively rare adverse effect of ICIs, its severity necessitates increased awareness among healthcare professionals. As ICIs continue to be seen as an integral component of cancer therapy, a comprehensive understanding of neutropenia as a side effect and its management is critical for optimizing patient outcomes. A crucial purpose of this review is to highlight the need to achieve a balance between acquiring the therapeutic benefits of various treatment strategies for irAEs and considering their potential side effects, especially with the use of steroids. Achieving this equilibrium is very important in optimizing patient care during immunotherapy, as these irAE management options can both mitigate the neutropenia triggered by ICIs and potentially give rise to secondary complications. Therefore, a careful assessment of the risks and benefits associated with each treatment approach is essential in tailoring irAE management.


Introduction And Background
Immune checkpoint inhibitors (ICIs) are a class of regulatory drugs that are designed to block specific proteins on the surface of immune cells or cancer cells, thereby enhancing the immune system's ability to recognize and destroy cancer cells.Two of the most well-known immune checkpoint proteins targeted by ICIs are programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).ICIs targeting these two proteins are involved in inhibiting T-cell activation and, therefore, attack the malignant cells.In the realm of medicine, ICIs have demonstrated significant clinical benefits across a wide range of malignancies, establishing them as one of the most gratifying breakthroughs in this field.However, immunotherapies operate through modulating the immune system, which can adversely trigger immunerelated adverse events (irAEs) [1].These irAEs can manifest as dermatologic, gastrointestinal, hepatic, and pulmonary reactions.Hematologic immune-related adverse events (heme-irAEs), in particular, have been progressively reported in the literature with a reported fatality rate of 12%.According to the French pharmacovigilance databases, neutropenia, autoimmune hemolytic anemia, and immune thrombocytopenia were the most commonly occurring heme-irAEs [2].
Recent research has revealed isolated neutropenia to be the rarest but the most deleterious manifestation resulting from the use of ICI [3].According to the National Cancer Institute Common Terminology Criteria for Adverse Events, chemotherapy-induced neutropenia (CIN) can be divided into four grades: Grade 1 with an absolute neutrophil count (ANC) of 1500-2000 cells/mm 3 , Grade 2 with an ANC of 1000-1500 cells/mm 3 , Grade 3 with an ANC of 500-1000 cells/mm 3 , Grade 4 with an ANC <500 cells/mm 3 [4].Isolated neutropenia secondary to ICI use presents a reasonable concern to patients' safety given the limited amount of literature related to it.It is important to note that the incidence and severity of these heme-irAEs can vary among individuals and depend on factors such as the type of cancer being treated, the specific ICI used and the overall health of the patient [5].In this review, we have compiled a summary of 20 published cases of ICIinduced neutropenia for the treatment of various cancers, encompassing lung cancer, melanoma, multiple myeloma, bladder cancer, and Hodgkin lymphoma.Furthermore, we have explored several aspects of irNeutropenia, which include the number of cycles before onset of neutropenia, the infectious complications that may arise from low neutrophil levels as well as effective strategies for managing this condition.Despite terminating the immune checkpoint blockade, neutropenia persisted in most of the cases, which calls for careful consideration and management.

Review
According to this review of 20 published cases (Table 1), ICI-induced neutropenia had an equal occurrence rate in males and females.The youngest individual reported to experience neutropenia was 32 years old, while the oldest patient was 82 years old.In terms of underlying oncological conditions, lung cancer accounted for the highest number of cases treated with immunotherapy followed by melanoma and bladder cancer.A singular instance of Hodgkin's lymphoma was also documented.The most frequently utilized ICIs were pembrolizumab and nivolumab.Nivolumab was commonly prescribed for cases involving lung cancer, melanoma, and even Hodgkin's lymphoma.Pembrolizumab was initiated for a variety of cancers including carcinoma of the lungs, multiple myeloma, and bladder cancer.Ipilimumab, primarily, was administered for the treatment of melanoma, and durvalumab showed effectiveness in treating squamous cell lung carcinoma.Development of abnormal LFTs was seen in a few patients on nivolumab for lung cancer.Immunoglobulins. Cyclosporine

TABLE 1: Summary of published cases with isolated neutropenia due to immune checkpoint inhibitor therapy
The most popular treatment modalities include steroids, IVIG, GM-CSF, and immunosuppressants like cyclosporine, mycophenolate, etc.The choice of therapies and their combinations can vary widely based on the individual patient's condition, the underlying cause, and the severity of the neutropenia.Multidisciplinary collaboration between different physicians including hematologists, infectious disease specialists, and other healthcare providers is often necessary to tailor treatment plans to each patient's unique needs.
Steroids have the most important role in mitigating neutropenia, caused by ICI therapy, based on current published literature.Needless to say, stopping the offending ICI with the onset of neutropenia is imperative.Steroids can present challenges due to their side effects when used for a long period of time and thus, balancing with their desired effects can be tricky.A case study by Patel et al. [19] exemplifies this, where the administration of steroids led to severe myopathy in a 75-year-old female who was taking nivolumab for Stage IIIB melanoma.This case is particularly interesting as the patient initially developed severe neuropathy while taking immunotherapy.Later, the introduction of steroid therapy resulted in marked improvement in the neuropathy but the use of steroids also caused severe myopathy, complicating the patient's clinical course.Attempting to taper the steroid dosage would exacerbate the neuropathy.Thus, it proved difficult to decide between whether to keep her on steroids or taper them off.However, despite the incorporation of steroids, intravenous immunoglobulin (IVIG), and other immunosuppressive agents into the treatment regimen, the patient's neutropenia persisted.Ultimately, comfort care was initiated and this was reported as a mortality.This case serves as a reminder of the difficulty faced in managing neutropenia and its associated complications, where the use of therapeutic agents can introduce significant side effects.It brings into focus the critical need for personalized treatment strategies and the consideration of individual patient factors when deciding on a management plan.
As noted above, the initial treatment for immune-mediated neutropenia is discontinuing the suspected ICI, except for one case presented by Laurain et al. [7], where ICI therapy was continued despite neutropenia.An interesting aspect of this case was that the patient developed pulmonary nodules as a side effect of immunotherapy as confirmed on biopsy, which revealed hypersensitivity pneumonitis due to immunotherapy.The patient showed improvement on steroids and co-trimoxazole.
In certain severe instances where standard therapies like steroids, IVIG, and G-CSF do not yield positive results in addressing neutropenia, the option of immunosuppressive agents is available.Cyclosporine [6,8,22], mycophenolate [11,19], and tocilizumab [8] have been used to combat irNeutropenia (immunerelated neutropenia).In all of these reports, the patients already were on steroids.Immunosuppressive agents were not used as monotherapy in any of the cases.Bryant et al. [8] showed that with the use of immunosuppressants, patients had infectious complications, e.g., pseudomonal facial cellulitis with the use 2023 Jalil et al.Cureus 15(9): e45674.DOI 10.7759/cureus.45674 of cyclosporine [8].
In rare instances, a stem cell transplant may be considered.One such case, as detailed by Bryant et al. [8] involves the application of pembrolizumab to treat multiple myeloma.In this scenario, a 49-year-old female patient encountered Grade 4 neutropenia after undergoing 2 cycles of pembrolizumab treatment.As a result, the administration of pembrolizumab was stopped, and the patient's initial treatment plan included the use of steroids, IVIG, and G-CSF, along with rituximab, cyclosporine, and tocilizumab.Throughout the treatment duration, the patient experienced several infections, including a very aggressive case of pseudomonal facial cellulitis.Eventually, due to the persistence of neutropenia for over two months, the patient received an autologous hematopoietic stem cell transplant after which the neutropenia resolved.
Filgrastim, a form of G-CSF, was a common intervention across all cases, but its effectiveness was limited in almost all cases.Bulbul et al. [18] did not utilize GM-CSF and resorted only to IVIG and dexamethasone, resulting in a favorable response.Clearly, in almost all of the other cases, GM-CSF was utilized and two published cases reported no significant response when GM-CSF was used as monotherapy [6,8].GM-CSF, which plays a crucial role in the production and activation of white blood cells, holds promise in various clinical contexts, but its effectiveness as a single treatment modality may not be enough to cause considerable improvement for immunotherapy-related neutropenia.
In cases where patients developed febrile neutropenia, a condition characterized by a fever accompanying a low absolute neutrophil count, antimicrobial therapy was prescribed as a low neutrophil count left the patients vulnerable to infections.The initial step in managing febrile neutropenia involved the administration of broad-spectrum antibiotics.The choice of a broad-spectrum antibiotic is based on the need to quickly address the infection while waiting for more specific information about the causative agent.
Once the patient's condition stabilized and laboratory tests yielded results, efforts were made to isolate the infectious agent responsible for the fever and neutropenia.Identifying the specific microorganism causing the infection is essential for tailoring the treatment regimen to be as targeted and effective as possible.However, it is important to note here that a study performed by Derosa et al. [25] showed that the application of antibiotics can disturb the distribution of gut microbes, leading to the development of resistance to ICIs, especially anti-PD-1 inhibitors.Another study suggested that antibiotic therapy used before starting patients on ICI is associated with worse rates of response to immunotherapy and survival.An antibiotic therapy taken concurrently with ICI therapy appeared to be safe [26].Therefore, care must be taken while prescribing antibiotics especially if they are being prescribed prior to ICI treatment.

Conclusions
Extensive research endeavors are crucial to understanding the complete spectrum of immune-related adverse events and identifying the most effective strategies for managing these occurrences, especially when dealing with the rarest manifestations, one of which is isolated neutropenia, and assessing the overall risk/benefit profile of utilizing ICIs in cancer patients.Heightened awareness regarding neutropenia can lead to earlier detection, improved management, and ultimately better outcomes for patients.Since neutropenia is a multifaceted phenomenon, addressing it demands a collaborative effort among specialists from diverse fields to work together as a cohesive team to revolutionize the understanding of these complexities.The goal is to optimize the use of ICIs, minimize toxicity, and maximize their beneficial effects.
With the available limited literature, generally, stopping the offending immunotherapy and steroids with or without IVIG seems to be the mainstay and commonly employed first step in the management of isolated neutropenia.The preferred steroids are either methylprednisolone at a dose of at least 1-2 mg/kg or prednisone at a dose of at least 1-2 mg/kg.IVIG is of particular interest and monotherapy has not been tried, but still, we conclude that in severe neutropenia, IVIG should not be tried as a stand-alone therapy.A general reflex is to give GM-CSF; however, interestingly, GM-CSF did not show promising effects in all of the cases.The same could be said about immunosuppressants in general.Where these drugs are beneficial to have in the arsenal, monotherapy has never been tried and complications have frequently been reported.
We also conclude that neutropenia may last several days to a week before any response can be substantiated.This can lead to prolonged hospitalization and/or frequent visits to outpatient clinics which can result in caregiver fatigue on top of psychological dismay of the patient.When dealing with complications of neutropenia, patients need to be hospitalized and management should be done under isolation especially when infective organisms are involved.Our review aims to highlight the importance of early recognition of neutropenia among patients on ICI treatment through a review of published cases on this side effect.
Stopping the ICI treatment is the most effective initial step followed by other therapies like corticosteroids, IVIG, G-CSF, and immunosuppressants; depending upon the grade of neutropenia.Mostly, corticosteroids are able to treat neutropenia based on our review.In patients who develop secondary infections, antimicrobials may be prescribed according to the nature of the infection.When all of the other therapies fail to produce recovery, an autologous stem cell transplant (ASCT) could become necessary.A multidisciplinary approach is always warranted and a hematologist should always be consulted.
A crucial aspect of this exploration is to understand the relationship between autoimmune conditions and the administration of ICIs.It is essential to discern whether irAEs from ICIs trigger autoimmunity or if preexisting autoimmune conditions may exacerbate after initiating ICI therapy.Understanding this association holds profound significance for tailoring cancer treatments and influencing patient outcomes in a positive and impactful manner.
following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
febrile grade 3 neutropenia on day 32 after the first dose of nivolumab, improved with stopping ICI and concurrent treatment with G-CSF.However, on day 77, the patient had to be retreated with G-CSF as neutrophil count became 500/mL, antifungals (e.g., fluconazole) prednisone (1mg/kg).Change of corticosteroid to dexamethasone (8mg IV every 6 hours) on Stopped 3 courses of IVIG and multiple infusions of G-CSF before pancytopenia resolved.Neutrophil count became normal 2 weeks after the last treatment with G-CSF and 4 weeks after the last IVIG Patient developed pancytopenia due to ICI 2023 Jalil et al.Cureus 15(9): e45674.DOI 10.7759/cureus.