In an Italian study reported in Leukemia, Mauro et al found that only a small minority of patients with chronic lymphocytic leukemia (CLL) developed an adequate immune response to pneumococcal vaccination, with response being more likely in patients who were younger, had previously untreated and stable disease, and had normal IgG levels prior to vaccination.

Study Details

In the study, 112 patients enrolled from four hematology institutions between November 2015 and February 2018 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 using ELISA. PC-IgG levels were assessed prior to vaccination, as well as at 3 and 6 weeks after vaccination. Protective PC-IgG levels were defined as ≥ 40 mg/L, based on data from the literature.

Among all patients:

• Median age was 68 years (range = 43–87 years)
• Eighty (71%) were male,
• 26 (23%) had IgG levels ≤ 400 mg/L
• Seven (6%) had progressive disease
• Fifty-one (52%) of 98 with available data had unmutated IGHV,
• Nineteen (24%) of 81 with available data had a del17p or TP53 mutation
• Twenty-three percent had an episode of pneumonia within the past 24 months
• Thirty-four (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); 45 had received B-cell receptor (BCR) pathway kinase inhibitors, including ibrutinib in 35 (first- and advanced-line in 11 and 24 patients, respectively) 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).

Adequate immune response was observed in 9 patients (8%), including in 8 (36%) of 22 treatment-naive patients and 1 (9%) of 11 patients vaccinated while on front-line ibrutinib. All patients with an 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 < 0.0001), 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). Overall, 29 patients (26%) developed pneumonia after PCV13 vaccination. Pneumonia was observed in 2 (22%) of 9 patients with an effective immune response and in 6 (15%) of 40 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/refractory disease, 12-month pneumonia-free survival was 87.1% for patients on ibrutinib and 63.5% for those on idelalisib (P = .02).

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 [patients with] CLL with early-stage and stable disease who have better resources for an effective immune response.”

Disclosure: For full disclosures of the study authors, visit nature.com.