Why Lymphoproliferative Disorders Increase Infection Risk
Lymphoproliferative disorders (LPD) dramatically increase infection risk through multiple simultaneous mechanisms: the malignant cells themselves cause profound immune dysfunction by producing hypogammaglobulinemia and T-cell exhaustion, while simultaneously infiltrating the bone marrow to cause neutropenia and functional immune cell defects.
Disease-Related Immune Dysfunction
Humoral Immunity Defects
Patients with chronic lymphocytic leukemia (CLL) frequently develop hypogammaglobulinemia, leading to increased susceptibility to encapsulated bacteria, principally Streptococcus pneumoniae, with recurrent sinopulmonary infections and septicemia 1.
Multiple myeloma patients are functionally hypogammaglobulinemic despite elevated total immunoglobulin levels, because the repertoire of antibody production is severely restricted 1.
The antibody failure in LPD is progressive and cumulative, worsening with disease duration and treatment exposure 2.
Cellular Immunity Impairment
T-cell exhaustion occurs in LPD, particularly CLL, where CD8+ T cells exhibit features of dysfunction and impaired functionality 1.
Lymphoproliferative malignancies cause infiltration of the bone marrow with malignant cells, resulting in leukopenia and dysfunctional marrow production of normal immune cells 1.
Severe lymphopenia is a significant independent risk factor for severe infections (OR 4.7,95% CI 1.3-17) 3.
Treatment-Related Immunosuppression
Chemotherapy Effects
Patients with advanced or refractory LPD receiving multiple chemotherapeutic regimens face dramatically increased infection risk—nearly 90% of heavily pretreated patients (median 3 prior regimens) with fludarabine-refractory CLL experience serious infectious complications requiring hospitalization 1.
Prior treatment with rituximab and fludarabine emerged as specific risk factors for viral infections (OR 1.8,95% CI 1.05-3.3 for previous rituximab) 1, 3.
Refractory hematologic malignancies develop marrow failure from both the underlying disease and cumulative effects of multiple lines of cytotoxic or immunosuppressive therapy 1.
Targeted Therapy Considerations
Combined targeted treatment versus single-agent treatment significantly increases severe infection risk (OR 2.2,95% CI 1.1-4.2) 3.
BTK inhibitors, PI3K inhibitors, and BCL-2 inhibitors carry infection risks, with severe infection incidence of 23% during median 17-month follow-up, though this is not superior to the chemotherapy era 3.
The cumulative incidence of infections is highest in the first 3-6 months of targeted drug treatment, then decreases 3.
Spectrum of Infectious Pathogens
Bacterial Infections
Bacterial pathogens account for 54% of severe infections in LPD patients, with encapsulated organisms (S. pneumoniae, H. influenzae) predominating early in disease course 1, 3.
Staphylococcus aureus and gram-negative pathogens occur more commonly in advanced disease and during neutropenia 1.
Opportunistic Infections
Heavily pretreated LPD patients develop infections from bacterial, viral (HSV, VZV, CMV), fungal, and opportunistic pathogens including Pneumocystis jirovecii 1.
Invasive fungal infections occurred in 6% of patients, predominantly in CLL patients treated with ibrutinib 3.
Viral Reactivations
EBV-associated lymphoproliferative disorder represents a severe complication, particularly in patients with specific immune defects such as interleukin-10 receptor defects, altered regulatory T cell function, and decreased FOXp3 protein levels 1.
CMV reactivations, while uncommon in untreated LPD patients, can occur with treatment-induced immunosuppression 1.
Clinical Impact and Mortality
Infection-related mortality in LPD patients reaches 6%, with definitive discontinuation of targeted drugs required in 22% of patients experiencing severe infections 3.
The mortality rate for COVID-19 in hematologic malignancies, particularly lymphoproliferative disorders like NHL, CLL, and multiple myeloma, ranged from 13.8% to 37% during the first pandemic wave 1.
Critical Pitfalls to Avoid
Do not underestimate infection risk in patients who appear to be responding to therapy—even patients experiencing disease response remain at elevated risk due to persistent immune dysfunction 1.
Avoid assuming that newer targeted therapies eliminate infection risk; while they may have different toxicity profiles than chemotherapy, severe infections still occur in approximately one-quarter of patients 3.
Never overlook the additive effect of multiple immunosuppressive agents—combination therapy exponentially increases infection risk compared to monotherapy 3.