key: cord-0997611-hfkp5k8m
authors: Gong, Inna Y.; Vijenthira, Abi; Betschel, Stephen D.; Hicks, Lisa K.; Cheung, Matthew C.
title: COVID‐19 vaccine response in patients with hematologic malignancy: A systematic review and meta‐analysis
date: 2022-01-13
journal: Am J Hematol
DOI: 10.1002/ajh.26459
sha: abb7e29c2c3e827c522219a127375adbe00cb7f4
doc_id: 997611
cord_uid: hfkp5k8m

nan

To the editor:

Hematologic malignancies encompass a group of heterogenous diseases with variable effects on immune function, and the degree of immune dysfunction may be further exacerbated by therapies used to treat specific diseases. Emerging real-world data suggest that patients with hematologic malignancy, particularly B-cell malignancies and those receiving B-cell depleting therapies, likely do not elicit robust immunologic responses following COVID-19 vaccination; however, existing studies include modest sample sizes and uncertainty remains.

Thus, we performed a systematic review and meta-analysis aggregating data on anti-SARS-CoV-2 IgG antibody seroresponse (SR) to COVID-19 vaccination in patients with hematologic malignancy.

PubMed and EMBASE were searched from January 1, 2021 to November 4, 2021 , to identify studies of vaccine immunogenicity following COVID-19 vaccination in patients with hematologic malignancy (Supplementary Methods; Tables S1 and S2; Figure S1 ). The primary outcomes were pooled SR in all studies, and pooled relative benefit ratio (RB) compared to controls in studies with a comparator group. Secondary outcomes were pooled SR and pooled RB by hematologic malignancy subtype and treatment status and type. Pooled estimates, RBs, along with 95% confidence intervals (CIs) were calculated using a random-effects model using MetaXL and Review Manager 5.4. (Table S3) . Full results are provided in Supplementary Results. Figure 1 provides a visual depiction of pooled SR and RB for outcomes. Pooled SR of all included patients was 59% (95% CI 55%-64%, with considerable heterogeneity I 2 95%; Figure S2 ). RB when compared to controls (either health care workers, healthy volunteers, or age-matched cancer-free controls) in available reports was 0.61 (95% CI 0.55-0.66, I 2 91%; Figure S3) Figure S4 ). This was particularly notable for prior anti-CD20 therapy with RB 0.16 (95% CI 0.08-0.30) when comparing receipt of anti-CD20 therapy <9-12 months of vaccination to >9-12 months after vaccination (Table S4 and Figure S5 ). Similarly, poor SR was observed in patients receiving novel targeted therapies Bruton tyrosine kinase inhibitor (BTKi) or venetoclax (37%, 95% CI 22%-54%) and anti-CD38 therapy (48%, 95% CI 27%-68%) ( Figures S20 and S21 ). (Table S5) .

We identified three studies reporting on SR following booster (third) dose in hematologic malignancy patients. These studies demonstrated that a booster dose could achieve SR up to 55% of patients who were seronegative following initial vaccination series. 1 Overall, our data support the rapidly emerging evidence demonstrating impaired humoral response following vaccination in hematologic malignancy patients. Patients with B-cell malignancies, particularly CLL and lymphoma, had the lowest SR. This likely reflects the disease-specific biology which causes underlying immune dysfunction in many patients as well as therapies used to treat lymphoid malignancies, including B-cell depleting therapies such as anti-CD20 and BTK inhibitors. Indeed, patients receiving treatment with B-cell depleting therapy had markedly impaired antibody responses compared to noncancer controls and disease patients, with reported SR ranging from 0% to 25% for those who received anti-CD20 within 3 months of vaccination. Response rates following COVID-19 vaccination improved with the passage of time, with higher serologic responses observed in those who received vaccination more than 9-12 months following anti-CD20 therapy. These findings are in keeping with prior studies suggesting that B-cell reconstitution following anti-CD20 antibody treatment requires 9-12 months. 2 Similarly, studies reporting on oral B-cell depleting therapies also observed impaired antibody response, with reported SR ranging from 14% to 57%. Importantly, seroconversion from seronegative to seropositive following booster vaccinations was evaluated in several studies, support the role of this strategy in achieving seroconversion. Furthermore, a study evaluating the kinetics of antibody titers demonstrated a rapid decline in titers from 36 days onward, and resulted in conversion from seropositive to seronegative in patients with hematologic malignancy while SR was conserved in patients with solid malignancies. 3 Collectively, these data support the use of booster doses to achieve optimal serologic response in patients with hematologic malignancy.

Although PCD can also suppress the immune system and affect nor- NPM1 mutation status was also tested in all samples by a standardized RNA-based assay (MutaQuant™ Kit, Ipsogen). According to manufacture's statements, the analytical (limit of detection) was determined on known low positive samples and found to be equal to 10.7 NPM1-A copies (n = 52 measures), 15.7 NPM1-B copies (n = 36 measures), and 10.2 NPM1-D copies (n = 36 measures), respectively, corresponding to approximately 0.009 NPM1-A copies, 0.008 NPM1-B copies, and 0.008 NPM1-D copies normalized to 100 ABL copies. A sample was considered MRD positive when 2 of 3 replicates had Ct <40.

For mutation profiling details and statistical analysis see Supplementary Material and Table S2 .

After a median follow-up of 34 months (interquartile range [IQR] 9-60), the median overall survival was 43.4 months (IQR 10-not reached) and the median relapse-free survival was 22 months (IQR 8-90). A total of 24 patients (50%) eventually relapsed (20 hematological and 4 molecular relapses), the observed relapse incidence is higher

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We thank patient participant in the included studies.

The authors declare no potential conflict of interest.