Safety and Efficacy of Immune Checkpoint Inhibitors in the Treatment of Hodgkin Lymphoma in People Living with Human Immunodeficiency Virus: A Case Series
Authors: Graeter Allison , Bowles Kristina E , Coghill Anna 
Published: December 2023

Introduction:
Immune checkpoint inhibitors (ICI) have changed the landscape of cancer treatment. They work by disrupting the binding of immune checkpoint proteins, such as PD-1, PD-L1, and CTLA-4, which function to prevent over-activation of the immune system. By interrupting this binding, the body's natural immune response against cancer cells is enhanced. Nivolumab and pembrolizumab, two ICIs that target PD-1, are approved for use in relapsed/refractory Hodgkin lymphoma (HL). HIV is associated with higher rates of cancer, including HL. Several studies have demonstrated the safety of ICI in people with HIV (PWH) in many types of cancer. Unfortunately, many cancer clinical trials continue to exclude PWH without consideration of long-term adherence to highly active antiretroviral therapy (HAART), normal CD4+ counts, or undetectable viral loads because of fear regarding increased adverse events (AEs) and poor outcomes. In addition, studies have shown that PWH diagnosed with cancer are less likely to receive any cancer treatment. Here, we present three cases of PWH diagnosed with HL and treated with an ICI and examine their outcomes and ICI-related AEs. In addition, we discuss five matched cases of people without HIV infection diagnosed with HL and treated with an ICI.
Methods:
A retrospective study was performed for HL patients at an NCI-designated comprehensive cancer center from 2015 to 2022, diagnosed with HIV (confirmed with antibody testing) and treated with an ICI. Three patients met these criteria. HIV-negative matches for the above patients were identified based on diagnosis, treatment, stage, sex, and age. Five patients with HL without HIV infection were identified as appropriate matches based on these criteria. Demographic data and clinical outcomes data were collected from the electronic medical record. The common terminology criteria for adverse events (CTCAE) were used to classify and grade AEs. Due to a small sample size, statistical analyses and comparisons were not performed between PWH and PWOH
Results:
Demographic data (Table 1) and clinical response/outcome data (Table 2) are shown for all patients. Patients 1, 2, and 3 were HIV positive, while patients 4, 5, 6, 7, and 8 were HIV negative. ICI-related AEs were documented in three patients, one with and two without HIV. Patient 1, who was not compliant with HAART (CD4+ 70, viral load 1.39x10 6), experienced grade 4 myocarditis (confirmed on cardiac MRI) after cycle 2 with nivolumab, with pulseless electrical activity requiring pressor support and mechanical ventilation for four days, along with high-dose steroid taper, IV diuresis, and initiation of guideline-directed medical therapy (GDMT). Nivolumab was discontinued, and the patient was lost to follow-up with reported death three months later, attributed to HL. Patient 7 developed symptomatic grade 2 hypothyroidism on nivolumab after two cycles, requiring levothyroxine, to which the patient responded appropriately. Nivolumab was continued. Patient 8 experienced grade 3 myocarditis (confirmed on cardiac MRI) after cycle 7 of pembrolizumab, with hospitalization for IV diuretics and GDMT initiation. Pembrolizumab was discontinued.
Discussion:
In conclusion, ICIs are a therapeutic option for the treatment of HL in PWH. This limited case series suggests that PWH on long-term HAART tolerate ICIs well. The patient in our study who was not compliant with HAART experienced grade 4 myocarditis, with death attributed to lymphoma three months later. This may suggest an increased risk of ICI-related AEs and poorer outcomes in patients not on HAART and/or with poorly controlled HIV. However, further studies are required to investigate this risk, as our sample size was too small to draw statistically meaningful conclusions. Interestingly, one patient without HIV infection also experienced ICI-related myocarditis, but of less severe grade (grade 3 versus grade 4) than the patient with HIV. Most patients from both groups had an overall survival (OS) of more than two years, which may suggest that ICIs are not associated with decreased OS in patients with HIV infection. Unfortunately, our study was limited by the sample size, and statistical comparison of patients with and without HIV infection could not be performed. Further research is needed to investigate the tolerance and efficacy of ICIs as therapeutic options in PWH with Hodgkin lymphoma.