Humoral Dysfunction in Patients with Chronic Lymphocytic Leukemia on Ibrutinib As Evidenced By Suboptimal Vaccine Responses

Background:

Humoral and cell-mediated immune dysregulation is a hallmark of chronic lymphocytic leukemia (CLL) and predisposes these patients to recurrent infections, which remain the leading cause of mortality. Ibrutinib is widely used in both treatment-naive and relapsed CLL, and these patientshave a 48% cumulative rate of ≥grade 3 infections over a 5-year follow up (O'Brien et al.; Blood, April 2018). Our study evaluated humoral immunity in patients with CLL treated with ibrutinib by checking immunoglobulin (Ig) levels and vaccine responses.

Methods:

We measured serum IgG, IgM, IgA, and pre/post-vaccine IgG titers to diphtheria, tetanus, and Streptococcus pneumoniae in patients with CLL on treatment with ibrutinib. Patients were vaccinated with tetanus/diphtheria (Td) and the pneumococcal polysaccharide (PPV23) vaccines, with post-vaccination titers measured at four weeks. Descriptive statistics are reported with medians and interquartile ranges (IQR). Response to Td was defined as a two-fold increase in specific IgG into the protective range. Response to PPV23 was defined as a two-fold increase from baseline if pre-vaccination specific IgG ≥1.3 microgram per milliliter (mcg/ml), or if titers increased by four-fold from baseline if pre-vaccination specific IgG < 1.3 mcg/ml, for > 70% of the serotypes.

Results:

Ten patients were enrolled. The median age was 65 (IQR: 60-68) years; seven were male. The median time since diagnosis was 4.7 (IQR: 4-9.1) years. Patients were on ibrutinib for a median time of 1.3 (IQR: 0.4-2.8) years at the time of enrollment. Three patients had previously received treatment with rituximab monotherapy, while two patients had received prior combination therapy with fludarabine-rituximab-lenalidomide and fludarabine-cyclophosphamide-rituximab. Nine patients had received at least one course of antibiotics (ABx) in the year before enrollment; the median number of ABx courses was 2 (IQR 2-3). Four patients were on prophylactic antibiotics, and three had previously received immunoglobulin replacement therapy. The median serum IgG titer was 650 (IQR: 544-820) mg/dl. 40% (4/10) of patients responded to vaccination with diphtheria, 30% (3/10) of patients responded to vaccination with tetanus, and none of the patients responded to PPV23 (see Table 1).

Conclusion:

Patients with CLL treated with ibrutinib demonstrate a high prevalence of humoral dysfunction, as evidenced by suboptimal vaccine responses to both peptide and polysaccharide antigens despite adequate Ig levels. Clinicians should consider checking vaccine responses in conjunction with Ig levels for comprehensive evaluation of humoral dysfunction.

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