Mature B-cell Research Articles

Perturbations in spike-specific peripheral T follicular helper cells in SARS-CoV2 breakthrough convalescent individuals immunized by BBV152 vaccine.

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) infection has caused an increase in mortality and morbidity, but with vaccination, the disease severity has significantly reduced. With the emergence of various variants of concern (VOCs), the vaccine breakthrough infection has also increased. Here we studied circulating spike-specific T follicular response (cTfh) in infection-naïve vaccinees and convalescent vaccinees (individuals who got the Delta breakthrough infection after two doses of BBV152 vaccine) to understand their response as they are the most crucial cells that are involved in vaccine-mediated protection by helping in B-cell maturation. Our results indicated that cTfh cells in both the groups recognized the wild-type and Delta spike protein but memory response to the wild-type spike was superior in infection-naïve than in the convalescent group. The cytokine response, particularly interleukin-21 (IL-21) from cTfh, was also higher in infection-naïve than in convalescent vaccinees, indicating a dampened cTfh response in convalescent vaccinees after breakthrough infection. Also, there was a positive correlation between IL-21 from cTfh cells and neutralizing antibodies of infection-naïve vaccinees. Multiple cytokine analysis also revealed higher inflammation in convalescent vaccinees. Our data indicated that the necessity of a third booster dose may be individual-specific depending on the steady-state functional phenotype of immune cells.

MM-374 Efficacy and Safety of Elranatamab in Patients With Relapsed/Refractory Multiple Myeloma (RRMM) and Prior B-Cell Maturation Antigen (BCMA)-Directed Therapies: Pooled Analysis From MagnetisMM Studies

MM-374 Efficacy and Safety of Elranatamab in Patients With Relapsed/Refractory Multiple Myeloma (RRMM) and Prior B-Cell Maturation Antigen (BCMA)-Directed Therapies: Pooled Analysis From MagnetisMM Studies

POSTER: MM-374 Efficacy and Safety of Elranatamab in Patients With Relapsed/Refractory Multiple Myeloma (RRMM) and Prior B-Cell Maturation Antigen (BCMA)- Directed Therapies: Pooled Analysis From MagnetisMM Studies

POSTER: MM-374 Efficacy and Safety of Elranatamab in Patients With Relapsed/Refractory Multiple Myeloma (RRMM) and Prior B-Cell Maturation Antigen (BCMA)- Directed Therapies: Pooled Analysis From MagnetisMM Studies

Chronic lymphocytic leukemia

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a mature B-cell neoplasm characterized by progressive accumulation of monoclonal B lymphocytes. CLL is considered being identical to SLL. Malignant cells seen in CLL and SLL have the same pathological and immunophenotypic features. The term CLL is used when the disease occurs mainly in the blood, while the term SLL is used when the involvement is mainly nodal.

Early B-cell development and B-cell maturation are impaired in patients with active hemophagocytic lymphohistiocytosis

AbstractHemophagocytic lymphohistiocytosis (HLH) is characterized by hyperinflammation and multiorgan dysfunction. Infections, including the reactivation of viruses, contribute to significant disease mortality in HLH. Although T-cell and natural killer cell–driven immune activation and dysregulation are well described, limited data exist on the status of B-cell compartment and humoral immune function in HLH. We noted marked suppression of early B-cell development in patients with active HLH. In vitro B-cell differentiation studies after exposure to HLH-defining cytokines, such as interferon gamma (IFN-γ) and tumor necrosis factor, recapitulated B-cell development arrest. Messenger RNA sequencing of human CD34+ cells exposed to IFN-γ demonstrated changes in genes and pathways affecting B-cell development and maturation. In addition, patients with active HLH exhibited a marked decrease in class-switched memory B (CSMB) cells and a decrease in bone marrow plasmablast/plasma cell compartments. The decrease in CSMB cells was associated with a decrease in circulating T follicular helper (cTfh) cells. Finally, lymph node and spleen evaluation in a patient with HLH revealed absent germinal center formation and hemophagocytosis with associated lymphopenia. Reassuringly, the frequency of CSMB and cTfh improved with the control of T-cell activation. Taken together, in patients with active HLH, these changes in B cells may affect the humoral immune response; however, further immune studies are needed to determine its clinical significance.

Exploiting the CD200-CD200R immune checkpoint axis in multiple myeloma to enhance CAR T-cell therapy

AbstractPatients with multiple myeloma (MM) treated with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T cells usually relapse with BCMA+ disease, indicative of CAR T-cell suppression. CD200 is an immune checkpoint that is overexpressed on aberrant plasma cells (aPCs) in MM and is an independent negative prognostic factor for survival. However, CD200 is not present on MM cell lines, a potential limitation of current preclinical models. We engineered MM cell lines to express CD200 at levels equivalent to those found on aPCs in MM and show that these are sufficient to suppress clinical-stage CAR T-cells targeting BCMA or the Tn glycoform of mucin 1 (TnMUC1), costimulated by 4-1BB and CD2, respectively. To prevent CD200-mediated suppression of CAR T cells, we compared CRISPR-Cas9–mediated knockout of the CD200 receptor (CD200RKO), to coexpression of versions of the CD200 receptor that were nonsignaling, that is, dominant negative (CD200RDN), or that leveraged the CD200 signal to provide CD28 costimulation (CD200R-CD28 switch). We found that the CD200R-CD28 switch potently enhanced the polyfunctionality of CAR T cells, and improved cytotoxicity, proliferative capacity, CAR T-cell metabolism, and performance in a chronic antigen exposure assay. CD200RDN provided modest benefits, but surprisingly, the CD200RKO was detrimental to CAR T-cell activity, adversely affecting CAR T-cell metabolism. These patterns held up in murine xenograft models of plasmacytoma, and disseminated bone marrow predominant disease. Our findings underscore the importance of CD200-mediated immune suppression in CAR T-cell therapy of MM, and highlight a promising approach to enhance such therapies by leveraging CD200 expression on aPCs to provide costimulation via a CD200R-CD28 switch.

Factors determining whether diffuse large B-cell lymphoma samples are detected by flow cytometry.

Flow cytometry (FCM) is widely used in the diagnosis of mature B-cell neoplasms (MBN), and FCM data are usually consistent with morphological findings. However, diffuse large B-cell lymphoma (DLBCL), a common MBN, is sometimes not detected by FCM. This study aimed to explore factors that increase the likelihood of failure to detect DLBCL by FCM. Cases with a final diagnosis of DLBCL that were analysed by eight-colour FCM were retrospectively collated. Clinical, FCM, histopathological and genetic data were compared between cases detected and cases not detected by FCM. DLBCL cases from 135 different patients were analysed, of which 22 (16%) were not detected by FCM. In samples not detected by flow cytometry, lymphocytes were a lower percentage of total events (p = 0.02), and T cells were a higher percentage of total lymphocytes (p = 0.01). Cases with high MYC protein expression on immunohistochemistry were less likely to be missed by FCM (p = 0.011). Detection of DLBCL was not different between germinal centre B-cell (GCB) and non-GCB subtypes, not significantly affected by the presence of necrosis or fibrosis, and not significantly different between biopsy specimens compared to fine-needle aspirates, or between samples from nodal compared to extranodal tissue. The study identifies several factors which affect the likelihood of DLBCL being missed by FCM. Even with eight-colour analysis, FCM fails to detect numerous cases of DLBCL.

Single-agent belantamab mafodotin in patients with relapsed/refractory multiple myeloma: Final analysis of the DREAMM-2 trial.

Patients with relapsed/refractory multiple myeloma (RRMM) have a high unmet treatment need. Belantamab mafodotin (belamaf), a first-in-class, B-cell maturation antigen-binding antibody-drug conjugate, eliminates myeloma cells through direct cell killing and an anti-myeloma immune response. DREAMM-2 (NCT03525678) was a phase 2, two-arm, open-label trial in patients with heavily pretreated RRMM who had three or more prior therapies, were refractory to an immunomodulatory agent and a proteasome inhibitor, and refractory or intolerant to an anti-CD38 monoclonal antibody. Belamaf was given at 2.5 or 3.4mg/kg every 3weeks. The primary end point was overall response rate (ORR); secondary end points included progression-free survival (PFS), overall survival (OS), safety, ocular symptoms, and health-related quality of life (HRQOL). This final analysis (cutoff date, March 31, 2022), N=223, with median follow-up of 12.5 and 13.8months, demonstrated an ORR of 32% and 35%, median PFS of 2.8 and 3.9months, and median OS of 15.3 and 14.0months in the 2.5mg/kg and 3.4mg/kg cohorts, respectively. Median duration of response was 12.5 and 6.2months. No new safety signals were observed; the most common Grade 3 and 4 adverse events were keratopathy (29% vs. 25%), thrombocytopenia (22% vs. 29%), and anemia (21% vs. 28%). HRQOL outcomes suggest that overall global health status/quality of life, physical and role functioning, and overall disease symptoms were maintained or improved during treatment. This final analysis of DREAMM-2 confirms that in patients with triple-class refractory RRMM, single-agent belamaf results in durable and clinically meaningful responses with a manageable safety profile.

Epcoritamab: First Approval.

Epcoritamab (epcoritamab-bysp; Epkinly™; Tepkinly®) is a subcutaneously administered CD3×CD20 T-cell-engaging bispecific antibody being co-developed by Genmab and AbbVie for the treatment of mature B-cell non-Hodgkin lymphoma subtypes (B-NHLs), including diffuse large B-cell lymphoma (DLBCL). Epcoritamab received its first (conditional) approval on 19 May 2023, in the USA, for the treatment of adult patients with relapsed or refractory (R/R) DLBCL, not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥ 2 lines of systemic therapy. Elsewhere, epcoritamab has received a positive opinion in the EU as a monotherapy for the treatment of adults with R/R DLBCL after ≥ 2 lines of systemic therapy, and is currently under regulatory review in Japan for the treatment of adults with R/R large B-cell lymphoma after ≥ 2 lines of systemic therapy. Clinical development of epcoritamab as monotherapy and in combination with standard of care agents for the treatment of mature B-NHLs is ongoing globally. This article summarizes the milestones in the development of epcoritamab leading to this first approval for R/R DLBCL.

Post-infusion Costs Associated with Idecabtagene Vicleucel Treatment for Patients with Relapsed/Refractory Multiple Myeloma in the KarMMa Trial.

Patients with triple-class exposed relapsed/refractory multiple myeloma (RRMM) have poor outcomes with substantial healthcare costs. Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy, showed deep, durable responses in patients with RRMM in the pivotal phase 2 KarMMa trial (NCT03361748). Healthcare resource utilization (HCRU) and costs were estimated for ide-cel-treated patients in the KarMMa trial. Post-infusion costs were estimated based on HCRU data, including facility care, diagnostics, medications, and procedures. Length of stay (LOS) was extracted for inpatient and intensive care unit (ICU) care. All patients had a 14-day post-infusion inpatient stay per trial protocol. Analyses were conducted for patients treated in the United States (US), who received the ide-cel target dose of 450×106 CAR+T cells and assuming a 7-day inpatient stay. Overall, 128 patients received ide-cel and were included in this analysis. Mean age was 60years, 59% were men, and 81% were white. Mean total LOS was 23.9days. Total estimated costs over 24months post-infusion were US$115,614 per patient, driven by facility costs (75%; $86,385). Most costs were incurred in the first month (58%; $67,259). The scenario analysis assuming a 7-day inpatient stay showed estimated 24-month costs of $92,294. For the 54 (42%) patients who received ide-cel high dose, total costs over 24months were $113,298 per patient. Extrapolation of costs based on HCRU data from patients receiving single-infusion of ide-cel in the KarMMa trial showed substantially reduced HCRU and costs over 2years after initial treatment. Most costs were incurred during the first month after ide-cel infusion, likely attributable to the 14-day inpatient stay required by the trial protocol. These findings suggest a nominal, incremental monthly cost of care immediately after treatment, which may be lower in routine clinical practice.

Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results

Elranatamab is a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the ongoing phase 2 MagnetisMM-3 trial, patients with relapsed or refractory multiple myeloma received subcutaneous elranatamab once weekly after two step-up priming doses. After six cycles, persistent responders switched to biweekly dosing. Results from cohort A, which enrolled patients without prior BCMA-directed therapy (n = 123) are reported. The primary endpoint of confirmed objective response rate (ORR) by blinded independent central review was met with an ORR of 61.0% (75/123); 35.0% ≥complete response. Fifty responders switched to biweekly dosing, and 40 (80.0%) improved or maintained their response for ≥6 months. With a median follow-up of 14.7 months, median duration of response, progression-free survival and overall survival (secondary endpoints) have not been reached. Fifteen-month rates were 71.5%, 50.9% and 56.7%, respectively. Common adverse events (any grade; grade 3–4) included infections (69.9%, 39.8%), cytokine release syndrome (57.7%, 0%), anemia (48.8%, 37.4%), and neutropenia (48.8%, 48.8%). With biweekly dosing, grade 3–4 adverse events decreased from 58.6% to 46.6%. Elranatamab induced deep and durable responses with a manageable safety profile. Switching to biweekly dosing may improve long-term safety without compromising efficacy. ClinicalTrials.gov identifier: NCT04649359.

Heterogeneous diffuse large B-cell lymphoma: accurate diagnosis as a key to successful therapy. A review

Diffuse large B-cell lymphoma (DLBCL) is the most common variant of non-Hodgkin's lymphoma and accounts for about 1/3 of all non-Hodgkin's lymphomas in Western countries and about 40% of B-cell tumors worldwide. Correct diagnosis of clinically distinct subgroups of aggressive mature B-cell lymphomas is crucial for the choice of adequate treatment. Currently, the identification of DLBCL subtype depends on a combination of morphologic, immunophenotypic, and cytogenetic/molecular features. The classification covers the most common unspecified variant of DLBCL, also referred to as "not otherwise specified" (NOS), and a number of other rare forms. Over the past two decades, DLBCL NOS which accounts for more than 80% of all cases, has been the subject of a growing number of molecular studies that have identified prognostic factors that are being actively introduced into real-world clinical practice. Only the integration of morphological, immunohistochemical and molecular features of DLBCL will lead to the achievement of the long-term goal of curing the majority of patients with minimal or no toxic manifestations with the aid of personalized healthcare.

Bioanalytical Methods for Characterization of CAR-T Cellular Kinetics: Comparison of PCR Assays and Matrices.

Recently, multiple chimeric antigen receptor T-cell (CAR-T)-based therapies have been approved for treating hematological malignancies, targeting CD19 and B-cell maturation antigen. Unlike protein or antibody therapies, CAR-T therapies are "living cell" therapies whose pharmacokinetics are characterized by expansion, distribution, contraction, and persistence. Therefore, this unique modality requires a different approach for quantitation compared with conventional ligand binding assays implemented for most biologics. Cellular (flow cytometry) or molecular assays (polymerase chain reaction (PCR)) can be deployed with each having unique advantages and disadvantages. In this article, we describe the molecular assays utilized: quantitative PCR (qPCR), which was the initial platform used to estimate transgene copy numbers and more recently droplet digital PCR (ddPCR) which quantitates the absolute copy numbers of CAR transgene. The comparability of the two methods in patient samples and of each method across different matrices (isolated CD3+ T-cells or whole blood) was also performed. The results show a good correlation between qPCR and ddPCR for the amplification of same gene in clinical samples from a CAR-T therapy trial. In addition, our studies show that the qPCR-based amplification of transgene levels was well-correlated, independent of DNA sources (either CD3+ T-cells or whole blood). Our results also highlight that ddPCR can be a better platform for monitoring samples at the early phase of CAR-T dosing prior to expansion and during long-term monitoring as they can detect samples with very low copy numbers with high sensitivity, in addition to easier implementation and sample logistics.

Real-world experience of patients with multiple myeloma receiving ide-cel after a prior BCMA-targeted therapy

Most patients with multiple myeloma experience disease relapse after treatment with a B-cell maturation antigen-targeted therapy (BCMA-TT), and data describing outcomes for patients treated with sequential BCMA-TT are limited. We analyzed clinical outcomes for patients infused with standard-of-care idecabtagene vicleucel, an anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, at 11 US medical centers. A total of 50 patients with prior BCMA-TT exposure (38 antibody-drug conjugate, 7 bispecific, 5 CAR T) and 153 patients with no prior BCMA-TT were infused with ide-cel, with a median follow-up duration of 4.5 and 6.0 months, respectively. Safety outcomes between cohorts were comparable. The prior BCMA-TT cohort had a lower overall response rate (74% versus 88%; p = 0.021), median duration of response (7.4 versus 9.6 months; p = 0.03), and median progression-free survival (3.2 months versus 9.0 months; p = 0.0002) compared to the cohort without prior BCMA-TT. All five patients who received a prior anti-BCMA CAR T responded to ide-cel, and survival outcomes were best for this subgroup. In conclusion, treatment with ide-cel yielded meaningful clinical responses in real-world patients exposed to a prior BCMA-TT, though response rates and durability were suboptimal compared to those not treated with a prior BCMA-TT.

Prognostics of Systemic Malignancy ICD-O Topography and Morphology Types on Brain Metastases: An NCDB Time-to-event Cohort.

The primary site and histology of systemic malignancy are known predictors of progression to brain metastases (BM). We investigated the combinational interactions of International Classification of Diseases for Oncology (ICD-O) primary topography and morphology types on the survival of BM after adjusting for relevant clinical and demographic prognostic factors. The cohort included all adult patients with BM at diagnosis of an invasive malignancy in the National Cancer Database (2010 to 2018). The sample consisted of 180,150 entries out of 14,279,749 cancer patients screened. A survival analysis of the topography-specific and histology-specific time to death was performed. Multivariate Cox regression revealed violations of the proportional hazard assumption for multiple covariates. Parametric models using a log-logistic distribution best described the population survival pattern. The primary topography "prostate" and morphology "choriocarcinoma" provided the strongest survival benefit among ICD-O types, whereas BM from prostate demonstrated a 14-month median overall increase in survival probability. Favorable prognostics were BM from breast, bone/joints, and testis; also, the morphologies of carcinoid tumor, mature B-cell lymphoma, and papillary adenocarcinoma. Poor prognostics were BM from gastrointestinal (liver, biliary tree, pancreas, and gallbladder) and gynecologic malignancies. All morphologies of spindle cell carcinoma, hemangiosarcoma, undifferentiated carcinoma, Ewing sarcoma, pseudosarcomatous carcinoma, renal cell carcinoma/sarcomatoid, signet ring cell carcinoma, spindle cell sarcoma, and squamous cell carcinoma/spindle cell were associated with poor survival. This is the largest cohort providing an unbiased estimate of the adjusted ICD-O topography and morphology effect sizes. The results can be summarized as a booklet for prognostic classification of disease in patients with BM secondary to systemic malignancy.

Use of a hybrid intelligence decision tree to identify mature B-cell neoplasms.

Mature B-cell neoplasms are challenging to diagnose due to their heterogeneity and overlapping clinical and biological features. In this study, we present a new workflow strategy that leverages a large amount of flow cytometry data and an artificial intelligence approach to classify these neoplasms. By combining mathematical tools, such as classification algorithms and regression tree (CART) models, with biological expertise, we have developed a decision tree that accurately identifies mature B-cell neoplasms. This includes chronic lymphocytic leukemia (CLL), for which cytometry has been extensively used, as well as other non-CLL subtypes. The decision tree is easy to use and proposes a diagnosis and classification of mature B-cell neoplasms to the users. It can identify the majority of CLL cases using just three markers: CD5, CD43, and CD200. This approach has the potential to improve the accuracy and efficiency of mature B-cell neoplasm diagnosis.

Expansion of the immature B lymphocyte compartment in Graves' disease.

The specific mechanisms driving autoimmunity in Graves' disease (GD) remain largely unknown. Kappa-deleting recombination excision circles (KRECs) are circular DNA molecules generated during B cell maturation in the bone marrow which provide a measure of B cell production and proliferation. We aimed to investigate the association between KRECs and B cell subpopulations, with thyroid status and clinical outcome in GD patients. Kappa-deleting recombination excision circles were measured by quantitative real-time PCR using a triple-insert plasmid control in 132 GD patients and 140 healthy controls. In addition, KRECs in GD patients on withdrawal of antithyroid drug (ATD) and 6-10 weeks later were analysed according to a clinical outcome at 1 year. Flow cytometry was performed on isolated CD19+ B cells to quantitate 7 B lymphocyte subpopulations in 65 GD patients. Circulating KRECs were higher in GD vs. controls (P = 1.5 × 10-9) and demonstrated a positive correlation to thyroid hormones and autoantibodies (free thyroxine: P = 2.14 × 10-5, rho = .30; free triiodothyronine: P = 1.99 × 10-7, rho = .37; thyroid stimulating hormone receptor autoantibodies: P = 1.36 × 10-5, rho = .23). Higher KRECs in GD patients 6-10 weeks after ATD withdrawal were associated with relapse of hyperthyroidism at 1 year (P = .04). The KRECs were positively correlated to the total CD19+ B cell count (P = 3.2 × 10-7). This study reports a robust association between KRECs and GD, highlighting the importance of B cells in the pathogenesis of GD and the influence of thyroid status on B cell activity. The findings indicate a potential role for KRECs as a marker of disease activity and outcome in GD.

Machine learning models-based on integration of next-generation sequencing testing and tumor cell sizes improve subtype classification of mature B-cell neoplasms.

Next-generation sequencing (NGS) panels for mature B-cell neoplasms (MBNs) are widely applied clinically but have yet to be routinely used in a manner that is suitable for subtype differential diagnosis. This study retrospectively investigated newly diagnosed cases of MBNs from our laboratory to investigate mutation landscapes in Chinese patients with MBNs and to combine mutational information and machine learning (ML) into clinical applications for MBNs, especially for subtype classification. Samples from the Catalogue Of Somatic Mutations In Cancer (COSMIC) database were collected for ML model construction and cases from our laboratory were used for ML model validation. Five repeats of 10-fold cross-validation Random Forest algorithm was used for ML model construction. Mutation detection was performed by NGS and tumor cell size was confirmed by cell morphology and/or flow cytometry in our laboratory. Totally 849 newly diagnosed MBN cases from our laboratory were retrospectively identified and included in mutational landscape analyses. Patterns of gene mutations in a variety of MBN subtypes were found, important to investigate tumorigenesis in MBNs. A long list of novel mutations was revealed, valuable to both functional studies and clinical applications. By combining gene mutation information revealed by NGS and ML, we established ML models that provide valuable information for MBN subtype classification. In total, 8895 cases of 8 subtypes of MBNs in the COSMIC database were collected and utilized for ML model construction, and the models were validated on the 849 MBN cases from our laboratory. A series of ML models was constructed in this study, and the most efficient model, with an accuracy of 0.87, was based on integration of NGS testing and tumor cell sizes. The ML models were of great significance in the differential diagnosis of all cases and different MBN subtypes. Additionally, using NGS results to assist in subtype classification of MBNs by method of ML has positive clinical potential.

Primary Burkitt Lymphoma of the Rectum

Abstract Burkitt lymphoma (BL) is a highly aggressive mature B-cell neoplasm with the highest incidence in a pediatric population. Three clinical subtypes of BL are known: sporadic, endemic, and immune deficiency associated. The most common site of involvement in the case of the sporadic form is an ileocecal region. We describe a rare case of sporadic BL in a 71-year-old male with a primary localisation in the rectum presenting with progressive bowel obstruction and rectal bleeding. The clinical evaluation involved colonoscopy, biopsy with a following morphological examination, computerised tomography of thorax, abdomen and pelvis, magnetic resonance imaging of pelvis, and laboratory analysis. Due to the unclear tumorous mass and progressive clinical symptoms, surgical treatment was applied – laparotomy, total mesorectal excision with the formation of permanent colostomy. Morphological examination of the specimen revealed a phenotype characteristic to BL. One month after the surgery, two single liver metastasis were detected. The patient received six courses of DA-EPOCH chemotherapy. Post-treatment radiological examinations revealed full clinical remission and disease-free survival for 68 months (5 years and 8 months).

Hepatitis B virus reactivation in seronegative occult hepatitis B patient receiving ibrutinib therapy

BackgroundIbrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor approved for the treatment for several mature B-cell malignancies. Reactivation of hepatitis B virus (HBV) is a well-described complication in patients with chronic HBV infection or prior HBV exposure undergoing cytotoxic or immunosuppressive chemotherapy for hematologic malignancies. This phenomenon has been frequently reported with rituximab. However, published data on the risk of HBV reactivation induced by ibrutinib are scarce. Cases of HBV reactivation in hematologic patients receiving ibrutinib therapy have recently been described, but limited only to overt hepatitis B patients or seropositive occult hepatitis B patients.Case presentationWe report the first case of HBV reactivation during ibrutinib treatment in an asymptomatic 82-year-old woman with seronegative occult hepatitis B patient (i.e., negative for HBsAg, anti-HBc and anti-HBs). Four months after ibrutinib treatment, her liver function test (LFT) was deranged, with seroconversion to HBsAg positivity. Serum hepatitis B virus DNA was quantified to be 1.92 × 108 IU/ml. Antiviral treatment was initiated, and viral load was gradually suppressed with improvement in LFT.ConclusionsOur case illustrated that in populations with a high incidence of HBV exposure, systematic screening for HBV exposure is essential prior to ibrutinib treatment, followed by serial monitoring of serologic and molecular markers of hepatitis B. There is a need for an international consensus to support the recommendation of antiviral prophylaxis against HBV reactivation in patients using ibrutinib.