In an Italian study reported in Leukemia, Francesca Romana Mauro, MD, of the Department of Translational and Precision Medicine, Sapienza University, Rome, and colleagues found that only a small minority of patients with chronic lymphocytic leukemia (CLL) developed an adequate immune response to pneumococcal vaccination; responses were more likely in patients who were younger, had previously untreated and stable disease, and normal immunoglobulin G (IgG) levels prior to vaccination.¹

As stated by the investigators: “Pneumococcal vaccination is recommended for patients with CLL. However, response to vaccines has been investigated [only] in a small series of patients with CLL.”

Francesca Romana Mauro, MD

Study Details

Between November 2015 and February 2018, 112 patients enrolled from four hematology institutions received a single-dose 0.5-mL intramuscular injection of the 13-valent pneumococcal conjugate vaccine (PCV13). The primary endpoint was the proportion of patients who developed an immune response to the PCV13, defined as a twofold increase in anti–pneumococcal IgG (PC-IgG) levels. PC-IgG levels were assessed with a commercial enzyme-linked immunoassay kit prior to vaccination and at 3 and 6 weeks after vaccination. Protective PC-IgG levels were defined as ≥ 40 mg/L, based on data from the literature.

Median patient age was 68 years (range = 43–87 years), 80 (71%) were male, and 26 (23%) had IgG levels ≤ 400 mg/L. Overall, 7 (6%) had progressive disease, 51 of 98 (52%) with available data had unmutated IGHV, 19 of 81 (24%) with available data had del17p or TP53 mutation, (23%) had an episode of pneumonia within the past 24 months, and 34 patients (30%) had PC-IgG levels ≥ 40 mg/L at baseline.

Overall, 22 patients (19.6%) were treatment-naive. Among the 90 previously treated patients, 45 had received front-line chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR, n = 32), or bendamustine plus rituximab (BR, n = 13) and 45 had received B-cell receptor (BCR) pathway kinase inhibitors, including ibrutinib in 35 (first- and advanced-line in 11 and 24 patients) and idelalisib in 10 (all advanced-line). The median time from discontinuation of chemoimmunotherapy to vaccination was 40 months among patients receiving FCR and 8 months among those receiving BR. The median time between the start of ibrutinib and idelalisib and vaccination was 34 and 22 months.

Responses

Overall, PC-IgG levels were evaluated in 104 patients at week 3 (8 patients evaluated at week 6 only) from vaccination and in 104 at week 6 (8 evaluated at week 3 only).

Overall, adequate immune response was observed in 9 patients (8%), including in 8 of 22 (36%) treatment-naive patients and 1 of 11 (9%)  vaccinated while on front-line therapy with ibrutinib. All patients with immune response had baseline IgG levels > 400 mg/dL with PC-IgG levels ≥ 40 mg/L. Among 78 patients with baseline PC-IgG levels < 40 mg/L, 4 (5%) exhibited increases to ≥ 40 mg/L after vaccination.

Median PC-IgG levels before vs after vaccination were 26.4 mg/L (range = 3–270 mg/L) vs 27.6 mg/L (range = 3–288/mg/L). The highest median levels of PC-IgG after vaccination were observed in treatment-naive patients (85 mg/dL, range = 12–288 mg/dL) followed by patients treated with front-line ibrutinib (54 mg/dL, range = 13–136 mg/dL). There was no apparent increase in median PC-IgG levels after vaccination in other patient groups.

Factors associated with increased likelihood of adequate immune response were age < 60 years (P = .007), IgG levels > 400 mg/L at baseline (P = .07), PC-IgG levels ≥ 40 mg/dL at baseline (P < .0001), treatment-naive status (P < .0001), and absence of clinical signs of disease progression (P = .04).

Clinical Outcomes After Vaccination

Median follow-up from PCV13 vaccination was 16 months (range = 6–38 months). A total of 14 patients with hypogammaglobulinemia received immunoglobulin support after a median of 13 months (range = 4–28 months) from vaccination due to recurrent infections (pneumonia in 8, other infections in 6).

Overall, 29 patients (26%) developed pneumonia after PCV13 vaccination, with radiologic findings being consistent with pneumonia of bacterial etiology in all cases. Pneumonia was observed in 2 of 9 patients (22%) with an effective immune response and in 6 of 40 patients (15%) with PC-IgG levels ≥ 40 mg/mL.

In the entire cohort, 36-month pneumonia-free survival after vaccination was 54.7%. No significant effect on pneumonia-free survival was observed for immune response to PCV13 or baseline PC-IgG or IgG levels. Factors associated with poorer pneumonia-free survival were pneumonia within 24 months before PCV13 (P < .0001), clinical signs of progressive disease (P < .0001), low neutrophil count (< 1.0 × 10⁹/L, P = .04), TP53 mutation (P = .01), and prior treatment with BR vs FCR (P = .009). No patients on front-line ibrutinib developed pneumonia after vaccination. Among patients with relapsed or refractory disease, 12-month pneumonia-free survival was 87.1% for patients on ibrutinib and 63.5% for those on idelalisib (P = .02).

In a multivariate analysis, presence of clinical signs of progressive disease at vaccination (hazard ratio [HR] = 8.39, 95% confidence interval [CI] = 2.71–25.97) and a prior pneumonia event (HR = 7.03, 95% CI = 3.33–14.86) were associated with poorer pneumonia-free survival. In an analysis restricted to patients with available del17p or TP53 mutation status, TP53 mutation was associated with poorer pneumonia-free survival (HR = 2.91, 95% CI = 1.22–6.99).

Estimated overall survival at 36 months was 86.7%. Poorer survival was associated with prior vs no prior pneumonia (68.5% vs 97.6%, P < .0001). No differences in survival probability were observed according to PC-IgG levels or adequate immune response to PCV13.

The investigators concluded: “[Our] results suggest that vaccination should be offered at diagnosis to CLL patients with early stage and stable disease who have better resources for an effective immune response.” 

DISCLOSURE: Dr. Mauro reported no conflicts of interest.

REFERENCE

1. Mauro FR, Giannarelli D, Galluzzo CM, et al: Response to the conjugate pneumococcal vaccine (PCV13) in patients with chronic lymphocytic leukemia (CLL). Leukemia 35:737-746, 2021.