COVID‐19 vaccination: Evaluation of risk for protection failure in chronic lymphocytic leukemia patients

To the Editor Chronic lymphocytic leukemia (CLL) is one of the most frequent B cell malignancies and the most frequent leukemia in Western countries. The disease is clinically characterized by the accumulation of CD5 +/CD19+ B lymphocytes, which are diverted from their immuno‐ protection role, therefore resulting in an inherent risk for CLL patient to develop infections, such a predisposition being further potentiated as the result of chemo‐immuno therapies (CIT). Although Italy was one of the countries most severely affected by the COVID‐19 outbreak, the prevalence of symptomatic COVID‐ 19 cases in CLL was overall in keeping with the advanced median age, and the known associated immunosuppression of CLL patients. According to multicenter studies, however, higher rates of severe COVID‐19 and of COVID‐19‐associated mortality were observed in these patients. In this context, CLL patients may represent an interesting model of immuno‐compromised oncological elderly patients in which the efficacy of the novel vaccines against COVID‐19 can be verified. The Italian vaccination program starting December 2020, although progressing slower than in other states, for example Israeli, United Kingdom, and United States, reached about 19% of vaccinated population of at the end of April 2021, when Israeli, United Kingdom, and United States had percentages of vaccinated population as high as 62%, 49%, and 40%, respectively. Therefore, as in similar studies carried out on US and Israeli CLL cohorts, we have recently had the chance to investigate whether the COVID‐19 vaccine is capable to trigger a specific antibody‐ mediated response in CLL by taking advantage of a well‐ characterized cohort of CLL patients from a single Italian institution reaching a complete two‐dose vaccination at the end of April 2021. The study included 46 CLL patients, diagnosed between 1993 and 2020, followed in a single institution (Hematology Unit of the University of Tor Vergata in Rome, Italy), who received two doses of the mRNA vaccine Comirnaty (BMT162b2 BioNTech/Pfizer GmbH). None of these patients had a documented history of SARS‐CoV‐2 infection. After providing informed consent for data collection, patients were tested for the development of antibodies against the SARS‐CoV‐2 S protein after a median of 26 days (interquartile range, IQR, 25–27) from the booster vaccination, without difference between patients scored negative (26 days, IQR 24–27) or positive (27 days, IQR 25–27) for antibody detection (see below). Serum samples were evaluated by the chemo‐luminescence Anti‐ SARS‐CoV‐2 immunoassay (Maglumi 2019‐nCOV IgG) on the analyzer MAGLUMITM 2000 Plus, a fully auto chemo‐luminescence immunoassay analyzer for the quantitative detection of IgG class antibodies (Ab) against the SARS‐CoV‐2 S protein. This assay has a linear measurement range of 0.180–100 AU/ml, with a concentration <0.90 AU/ml considered as not reactive and ≥1.10 AU/ml considered as positive, with values between such cutoff being considered as ambiguous; no cases had values between 0.90 and 1.10 AU/ml in our series. When sample results exceeded the upper limit of the measuring range, samples were on‐board diluted 1:10 or 1:20, following manufacturer's indications. CLL patients were all characterized for sex, age, Rai staging, B2M serum levels, IgG levels, immunoglobulin‐heavy‐variable (IGHV) gene mutational status, NOTCH1 mutations, CD49d expression, and interphase fluorescence in situ hybridization for 17p13.1 (17p) deletion, 11q22.3 (11q) deletion, 13q14 deletion, and trisomy 12 by following standard methods, as previously reported. Correlation between CLL features and positive/negative serology testing was estimated through unconditional logistic regression model. Among CLL patients, 29/46 were males, and, at the time of vaccination, 20/46 patients had an age ≥ 70 years. Known CLL clinico‐biological features found in their detrimental configuration at the time of vaccination included advanced (i.e., >0) Rai staging (35/46 cases), B2M > upper level of normal (24/46 cases), IgG < lower level of normal (26/46 cases), unmutated IGHV gene status (22/46 cases), presence of 17p and/or 11q deletions (16/46 cases), high CD49d expression (22/46 cases), and detection of NOTCH1 mutations (9/46 cases) (Figure 1). Regarding therapies at the time of vaccination, 29/46 patients were on active treatment, whilst the remaining 17 patients were not treated (Figure 1), being either in the watch‐and‐wait CLL phase (7 cases), or off therapy (10 cases) from previous chemo‐ immunotherapy (CIT) or chemo‐free regimens (median previous lines of therapy 1, range 1–2; median time from end of treatment to vaccination 28 months, IQR, 19–114 months). All treated patients were under chemo‐free regimens with either ibrutinib (21 cases) or venetoclax (8 cases), both given as single agent. Among treated patients, 5 were treatment naïve (TN, all on ibrutinib), and 24 were