Lessons From Pneumococcal Vaccine Responses in Patients With CLL in an Evolving Vaccine Landscape

Get Permission

The role of vaccines in mitigating the significant morbidity and mortality associated with infections in chronic lymphocytic leukemia (CLL) is a developing field of study, punctuated by the advent of novel therapeutic agents and pressing questions regarding the global SARS–CoV-2 vaccination efforts. Patients with CLL suffer from impaired innate and adaptive immunity, with functional defects in T cells, natural killer cells, and humoral response, leading to abrogated vaccine efficacy.1,2

The recently published study by Mauro et al3 in Leukemia—also reviewed in this issue of The ASCO Post—elucidates key themes for assessing immune response to the conjugate pneumococcal vaccine (PCV13) in patients with CLL.

Raamis Khwaja, MD

Raamis Khwaja, MD

Philip A. Thompson, MBBS (Hons)

Philip A. Thompson, MBBS (Hons)

Nitin Jain, MD

Nitin Jain, MD

Study Findings and Clinical Questions

In a prospective study conducted at four hematology institutions in Italy, Mauro and colleagues investigated immune response to a single dose of PCV13 vaccine in 112 patients with CLL. When measured 3 and 6 weeks after vaccination, just 9 of 112 (8%) met the criteria for serologic response (defined as a twofold increase in the pneumococcal IgG levels), including 8 of 22 (36%) previously untreated patients with CLL and 1 of 11 (9%) patients on front-line ibrutinib therapy. Notably, none of the patients who had received prior chemoimmunotherapy (fludarabine, cyclophosphamide, and rituximab, n = 32; bendamustine and rituximab, n =13) or patients with IgG levels less than 400 mg/dL (n = 26) had a serologic response. Additionally, patients aged ≥ 60 years and those with signs of disease progression had lower serologic response. This study concluded that PCV13 vaccination should be offered to patients with CLL in the early stage of the disease, preferably at diagnosis, when they have a better chance of mounting an immune response.

Several previous studies have explored the question of immune response to PCV13 vaccine in patients with CLL. In a randomized study from the Swedish CLL group, 128 previously untreated patients with CLL received PCV13 vaccine (n = 63) or the polysaccharide pneumococcal vaccine (PPSV23; n = 65).4 A total of 12 serotype-specific IgG antibodies common to both vaccines were measured at baseline and at 1 and 6 months after the vaccination. Results demonstrated a more robust response for PCV13 vs PPSV23: 40% vs 21% at 1 month and 33% vs 17% at 6 months, respectively.

Another study evaluated antibody response to PCV13 in 24 previously untreated patients with CLL compared with 15 healthy control subjects.5 Adequate serologic response was noted in 58% of patients with CLL and 100% of the control group 1 month after vaccination. The comparatively higher response rate noted in patients with CLL in this study may be reflective of early-stage disease.

As Bruton’s tyrosine kinase (BTK) inhibitors have now become standard therapy for CLL, Andrick and colleagues measured antibody response in four patients with CLL receiving ibrutinib vs four patients with CLL who were not receiving ibrutinib (control group).6 None of the patients on ibrutinib therapy mounted a serologic response, whereas all four patients in the control group met the response criteria.

Interestingly, a study evaluating early administration of ibrutinib in asymptomatic, previously untreated patients with high-risk CLL noted improved efficacy of PCV13 when patients started ibrutinib at the same time.7 The antibody response waned after 12 months, indicating a possible benefit of revaccination to boost titers. Congruent to the findings by Mauro et al, these studies highlight that advanced disease seems to dampen serologic response to the PCV13 vaccine and stress the importance of vaccination earlier in the disease course, especially prior to the initiation of anti-CLL therapy.

The Advisory Committee on Immunization Practices (ACIP) recommends that adults with immunocompromising conditions (such as CLL) should receive a dose of PCV13 first, followed by a dose of PPSV23 at least 8 weeks later.8 A second PPSV23 dose is recommended 5 years after the first PPSV23 dose. Similar to the ACIP guidelines, the European Conference on Infections in Leukemia (ECIL) consortium recommends one dose of PCV13 followed by PPSV23 after 8 weeks.9 Additionally, the guidelines advocated vaccination prior to the start of therapy, in accordance with the studies previously mentioned that showed improved response rates in treatment-naive patients. Notably, the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for CLL recommend PPSV23 every 5 years (no recommendation provided for PCV13).10

Similar to the low rates of immune response to the pneumococcal vaccine, low rates of vaccine response to the influenza vaccine have been noted in patients with CLL, with response rates ranging from 7% to 26% for those receiving BTK inhibitor therapy.11,12 A recent study investigated humoral response to the adjuvant hepatitis B (HepB-CpG) and recombinant zoster (RZV) vaccines for previously untreated patients with CLL vs those receiving BTK inhibitor therapy.13 Only 4% of patients receiving BTK inhibitor therapy developed a serologic response to the HepB-CpG vaccine, compared with 28% of previously untreated patients, suggestive of an impaired de novo immune response. In contrast, there was no significant difference in response to the RZV vaccine between those who did and did not receive BTK inhibitors, attributed to the recall antigenic response from prior pathogenic exposure.

COVID-19 Vaccination and CLL

These findings have important implications for the immune response to the novel mRNA vaccines for SARS–CoV-2 for patients with CLL. Current data indicate reduced efficacy of mRNA vaccines for COVID-19 in these patients. One study evaluated 167 patients with CLL who received BNT162b2 mRNA COVID-19 vaccine and noted an antibody response rate of 39.5% (55% among those with previously untreated CLL); only 8 of 50 patients (16%) who were receiving a BTK inhibitor had an antibody response.14 Moreover, none of the 22 patients who had received anti-CD20 antibodies within 12 months of vaccination mounted an immune response.

Given suboptimal response to COVID-19 vaccines, there is a need to measure postvaccine serologic responses in patients with CLL to truly evaluate vaccine-conferred protection.
— Raamis Khwaja, MD; Philip A. Thompson, MBBS (Hons); and Nitin Jain, MD

Tweet this quote

In another study, 44 patients with CLL were evaluated for serologic response to mRNA (BNT162b2 or mRNA-1273) vaccination; 52% of the patients produced a serologic response, with a higher proportion of treatment-naive vs treated patients (17/18 = 94% vs 6/26 = 23%), including a lower proportion of patients treated with a BTK inhibitor (3/14 = 21%) or venetoclax (0/7 = 0%).15 Given suboptimal response to the COVID-19 vaccines, there is a need to measure postvaccine serologic responses in patients with CLL to truly evaluate vaccine-conferred protection. This is being investigated in several multicenter trials at this time.

Closing Thoughts

The results reported by Mauro and colleagues and additional studies summarized here suggest impaired vaccine immune response in patients with CLL, especially those receiving active therapy. Efforts should be made to administer the vaccines earlier in the disease course. Additional work is needed to evaluate other strategies (eg, booster vaccinations) where feasible in patients with CLL and other immunocompromised states. 

Dr. Khwaja works in the Department of Internal Medicine at The University of Texas Health Science Center, Houston. Dr. Thompson works in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Dr. Jain works in the Department of Leukemia at The University of Texas MD Anderson Cancer Center.

DISCLOSURE: Dr. Khwaja reported no conflicts of interest. Dr. Thompson has received honoraria from and served as a consultant or advisor to Janssen, Adaptive Biotechnologies, and AbbVie; and has received institutional research funding from ­AbbVie, Pharmacyclics, Genentech, and Adaptive Biotechnologies. Dr. Jain has received honoraria from and served as a consultant or advisor to AbbVie/Genentech, Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca/MedImmune, BeiGene, Bristol Myers Squibb/Celgene, Cellectis, Janssen, Pharmacyclics, Precision Biosciences, Servier, and TG Therapeutics; and has received institutional research funding from AbbVie, Adaptive Biotechnologies, ADC Therapeutics, Aprea Therapeutics, AstraZeneca/MedImmune, Bristol Myers Squibb, Celgene, Cellectis, Fate Therapeutics, Genentech/Roche, Incyte, Kite, Pfizer, Pharmacyclics, Precision Biosciences, and Servier.


1. Riches JC, Gribben JG: Immunomodulation and immune reconstitution in chronic lymphocytic leukemia. Semin Hematol 51:228-234, 2014.

2. Whitaker JA, Shanafelt TD, Poland GA, et al: Room for improvement: Immunizations for patients with monoclonal B-cell lymphocytosis or chronic lymphocytic leukemia. Clin Adv Hematol Oncol 12:440-450, 2014.

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

4. Svensson T, Kättström M, Hammarlund Y, et al: Pneumococcal conjugate vaccine triggers a better immune response than pneumococcal polysaccharide vaccine in patients with chronic lymphocytic leukemia: A randomized study by the Swedish CLL group. Vaccine 36:3701-3707, 2018.

5. Pasiarski M, Rolinski J, Grywalska E, et al: Antibody and plasmablast response to 13-valent pneumococcal conjugate vaccine in chronic lymphocytic leukemia patients—Preliminary report. PLoS One 9:e114966, 2014.

6. Andrick B, Alwhaibi A, DeRemer DL, et al: Lack of adequate pneumococcal vaccination response in chronic lymphocytic leukaemia patients receiving ibrutinib. Br J Haematol 182:712-714, 2018.

7. Woyach J, Thangavadivel S, Weiss DM, et al: Final results of a phase 2 trial of early intervention ibrutinib with vaccinations in patients with asymptomatic, high-risk CLL. Blood 134(suppl 1):1759, 2019.

8. Centers for Disease Control and Prevention: Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 61;816-819, 2012.

9. Mikulska M, Cesaro S, de Lavallade H, et al: Vaccination of patients with haematological malignancies who did not have transplantations: Guidelines from the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis 19:e188-e199, 2019.

10. Wierda WG, Byrd JC, Abramson JS, et al: NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 4.2021–April 29, 2021. Available at Accessed May 26, 2021.

11. Douglas AP, Trubiano JA, Barr I, et al: Ibrutinib may impair serological responses to influenza vaccination. Haematologica 102:e397-e399, 2017.

12. Sun C, Gao J, Couzens L, et al: Seasonal influenza vaccination in patients with chronic lymphocytic leukemia treated with ibrutinib. JAMA Oncol 2:1656-1657, 2016.

13. Pleyer C, Ali MA, Cohen JI, et al: Effect of Bruton tyrosine kinase inhibitor on efficacy of adjuvanted recombinant hepatitis B and zoster vaccines. Blood 137:185-189, 2021.

14. Herishanu Y, Avivi I, Aharon A, et al: Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. Blood. April 16, 2021 (early release online).

15. Roeker LE, Knorr DA, Thompson MC, et al: COVID-19 vaccine efficacy in patients with chronic lymphocytic leukemia. Leukemia. May 13, 2021 (early release online).


Related Articles

Low Response Rates to Conjugate Pneumococcal Vaccine in Patients With Chronic Lymphocytic Leukemia

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...