Agents contributing to secondary immunodeficiency development in patients with multiple myeloma, chronic lymphocytic leukemia and non-Hodgkin lymphoma: A systematic literature review

Abstract

IntroductionPatients with hematological malignancies (HMs), like chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), have a high risk of secondary immunodeficiency (SID), SID-related infections, and mortality. Here, we report the results of a systematic literature review on the potential association of various cancer regimens with infection rates, neutropenia, lymphocytopenia, or hypogammaglobulinemia, indicative of SID.MethodsA systematic literature search was performed in 03/2022 using PubMed to search for clinical trials that mentioned in the title and/or abstract selected cancer (CLL, MM, or NHL) treatments covering 12 classes of drugs, including B-lineage monoclonal antibodies, CAR T therapies, proteasome inhibitors, kinase inhibitors, immunomodulators, antimetabolites, anti-tumor antibiotics, alkylating agents, Bcl-2 antagonists, histone deacetylase inhibitors, vinca alkaloids, and selective inhibitors of nuclear export. To be included, a publication had to report at least one of the following: percentages of patients with any grade and/or grade ≥3 infections, any grade and/or grade ≥3 neutropenia, or hypogammaglobulinemia. From the relevant publications, the percentages of patients with lymphocytopenia and specific types of infection (fungal, viral, bacterial, respiratory [upper or lower respiratory tract], bronchitis, pneumonia, urinary tract infection, skin, gastrointestinal, and sepsis) were collected.ResultsOf 89 relevant studies, 17, 38, and 34 included patients with CLL, MM, and NHL, respectively. In CLL, MM, and NHL, any grade infections were seen in 51.3%, 35.9% and 31.1% of patients, and any grade neutropenia in 36.3%, 36.4%, and 35.4% of patients, respectively. The highest proportion of patients with grade ≥3 infections across classes of drugs were: 41.0% in patients with MM treated with a B-lineage monoclonal antibody combination; and 29.9% and 38.0% of patients with CLL and NHL treated with a kinase inhibitor combination, respectively. In the limited studies, the mean percentage of patients with lymphocytopenia was 1.9%, 11.9%, and 38.6% in CLL, MM, and NHL, respectively. Two studies reported the proportion of patients with hypogammaglobulinemia: 0–15.3% in CLL and 5.9% in NHL (no studies reported hypogammaglobulinemia in MM).ConclusionThis review highlights cancer treatments contributing to infections and neutropenia, potentially related to SID, and shows underreporting of hypogammaglobulinemia and lymphocytopenia before and during HM therapies.

Screening for Antibody Deficiencies in Adults by Serum Electrophoresis and Calculated Globin

“…With an estimated prevalence 30 times greater than that of PADs [2,17], secondary antibody de ciencies (SADs) may be caused by underlying conditions and/or immunosuppressive treatments, frequently targeting B cells [2,[17][18][19][20]. The most common type of SAD arises from hematologic malignancies such as chronic lymphocytic leukemia, multiple myeloma, and lymphoma, where hypogammaglobulinemia can be present in up to 85% of patients [21,22]. Medication-associated SAD is a growing phenomenon related to immunosuppressive medications, mainly rituximab, veltuzumab, ibrutinib, and imatinib, to manage autoimmune and oncologic/hematologic diseases [17][18][19][20][21][22].…”

“…The most common type of SAD arises from hematologic malignancies such as chronic lymphocytic leukemia, multiple myeloma, and lymphoma, where hypogammaglobulinemia can be present in up to 85% of patients [21,22]. Medication-associated SAD is a growing phenomenon related to immunosuppressive medications, mainly rituximab, veltuzumab, ibrutinib, and imatinib, to manage autoimmune and oncologic/hematologic diseases [17][18][19][20][21][22]. Other conditions responsible for antibody de ciency are protein-losing disorders associated with renal, gastrointestinal, or cutaneous diseases [2,17,18].…”

“…Other conditions responsible for antibody de ciency are protein-losing disorders associated with renal, gastrointestinal, or cutaneous diseases [2,17,18]. The clinical presentation of SAD ranges from a restricted increased susceptibility to infections to severe conditions mainly characterized by airway recurrent chronic, complicated, or systemic infections [2,[17][18][19][20][21][22].…”

“…The years-long delay for diagnosis can lead to end-organ damage [26] and higher mortality [27], while timely correct treatment may decrease morbidity and improve survival [28]. In addition, early diagnosis of antibody de ciencies reduces healthcare expenses and leads to better health improvement for patients [21,29]. The factors impacting the delay in antibody de ciency diagnosis are not entirely understood, but the misconception that primary immunode ciencies are always childhood diseases, combined with the heterogeneity of disease presentation and the number of specialists caring for these patients, negatively impact the establishment of the diagnosis [5,6,10,34].…”

“…Secondary antibody de ciencies are often missed despite the occurrence of recurrent and even severe infections. In addition, a paucity of guidance related to its diagnosis screening and management and the diverse etiologies of SAD may contribute to the diagnostic delay in these patients [17][18][19][20][21]35].…”