TP53 mutation is frequent in mantle cell lymphoma with EZH2 expression and have dismal outcome when both are present.

Enhancer of zeste homolog 2 (EZH2) expression is found in about 40% of mantle cell lymphoma (MCL) patients, which is associated with aggressive histology, high Ki-67 proliferation rate, p53 mutant pattern and inferior overall survival (OS). We conducted 11-gene (ATM, BIRC3, CCND1, KMT2C, KMT2D, NOTCH1, NOTCH2, RB1, TP53, TRAF2 and UBR5) next generation sequencing panel to shed more light on MCL with EZH2 expression (EZH2+ MCL). EZH2+ MCL more frequently harbor TP53 mutation compared to EZH2(-) MCL (41.2% vs. 19.1%, respectively, p = 0.045). TP53 mutation and EZH2 expression demonstrated overlapping features including aggressive histology, high Ki-67 proliferation rate and p53 mutant pattern by immunohistochemistry. Comparative analysis disclosed that EZH2 expression correlates with high Ki-67 proliferation rate irrespective of TP53 mutation. Aggressive histology is associated with EZH2 expression or TP53 mutation, possibly via independent mechanisms. p53 mutant pattern is due to TP53 mutation. MCL patients with EZH2 expression or TP53 mutation show inferior outcome and when both are present, patients have dismal outcome.

Optical genomic mapping is a helpful tool for detecting CCND1 rearrangements in CD5-negative small B-cell lymphoma: Two cases of leukemic non-nodal mantle cell lymphoma.

Optical genome mapping (OGM) is a new DNA-based technology which provides comprehensive examination of the entire genome. We report two patients who presented with splenomegaly and leukocytosis with lymphocytosis including villous lymphocytes. Neither patient had lymphadenopathy. Bone marrow evaluation showed involvement by small B-cell lymphoma in a sinusoidal and interstitial distribution, and immunophenotypic analysis showed that the neoplastic cells were positive for B-cell markers and cyclin D1 but were negative for SOX11 and CD5. Initially, the clinicopathologic features in both patients were thought to be suspicious for hairy cell leukemia variant or splenic marginal zone lymphoma. However, OGM detected CCND1 rearrangement: t(2;11)/IGK::CCND1 in one case and t(11;14)/IGH::CCND1 in the other case. These cases illustrate the valuable role OGM can play in establishing the diagnosis of MCL. Case 1 also contributes to the paucity of literature on the rare occurrence of IGK::CCND1 in MCL.

SOX11+ Large B-Cell Neoplasms: Cyclin D1-Negative Blastoid/Pleomorphic Mantle Cell Lymphoma or Large B-Cell Lymphoma?

Large or blastoid B-cell neoplasms that are SOX11+ are a diagnostic dilemma and raise a differential diagnosis of cyclin D1-negative blastoid/pleomorphic mantle cell lymphoma (MCL) versus diffuse large B-cell lymphoma (DLBCL) or blastoid high-grade B-cell lymphoma (HGBL) with aberrant SOX11 expression. Here we report a study cohort of 13 SOX11+ large/blastoid B-cell neoplasms. Fluorescence in situ hybridization analysis was negative for CCND1 rearrangement in all 13 cases; 1 of 8 (12.5%) cases tested showed CCND2 rearrangement and 2 (25%) cases had extracopies of CCND2. Gene expression profiling showed that the study group had a gene expression signature similar to cyclin D1+ blastoid/pleomorphic MCL but different from DLBCL. Principal component analysis revealed that the cohort cases overlapped with cyclin D1+ blastoid/pleomorphic MCL but had minimal overlap with DLBCL. All patients in the cohort had clinicopathologic features similar to those reported for patients with cyclin D1+ MCL. We also performed a survey of SOX11 expression in a group of 85 cases of DLBCL and 24 cases of blastoid HGBL. SOX11 expression showed a 100% specificity and positive predictive value for the diagnosis of MCL. Overall, the results support the conclusion that large or blastoid B-cell neoplasms that are positive for SOX11 are best classified as cyclin D1-negative blastoid/pleomorphic MCL, and not as DLBCL or blastoid HGBL. We also conclude that SOX11 is a specific marker for the diagnosis of MCL, including cyclin D1-negative blastoid/pleomorphic MCL cases and should be performed routinely on blastoid/large B-cell neoplasms to help identify potential cases of cyclin D1-negative blastoid/pleomorphic MCL.

Potentiation of apoptosis in drug-resistant mantle cell lymphoma cells by MCL-1 inhibitor involves downregulation of inhibitor of apoptosis proteins.

Bruton's tyrosine kinase inhibitors (BTKi) and CAR T-cell therapy have demonstrated tremendous clinical benefits in mantle cell lymphoma (MCL) patients, but intrinsic or acquired resistance inevitably develops. In this study, we assessed the efficacy of the highly potent and selective MCL-1 inhibitor AZD5991 in various therapy-resistant MCL cell models. AZD5991 markedly induced apoptosis in these cells. In addition to liberating BAK from the antiapoptotic MCL-1/BAK complex for the subsequent apoptosis cascade, AZD5991 downregulated inhibitor of apoptosis proteins (IAPs) through a BAK-dependent mechanism to amplify the apoptotic signal. The combination of AZD5991 with venetoclax enhanced apoptosis and reduced mitochondrial oxygen consumption capacity in MCL cell lines irrespective of their BTKi or venetoclax sensitivity. This combination also dramatically inhibited tumor growth and prolonged mouse survival in two aggressive MCL patient-derived xenograft models. Mechanistically, the augmented cell lethality was accompanied by the synergistic suppression of IAPs. Supporting this notion, the IAP antagonist BV6 induced dramatic apoptosis in resistant MCL cells and sensitized the resistant MCL cells to venetoclax. Our study uncovered another unique route for MCL-1 inhibitor to trigger apoptosis, implying that the pro-apoptotic combination of IAP antagonists and apoptosis inducers could be further exploited for MCL patients with multiple therapeutic resistance.

Integrative Prognostic Machine Learning Models in Mantle Cell Lymphoma.

Patients with mantle cell lymphoma (MCL), an incurable B-cell malignancy, benefit from accurate pretreatment disease stratification. We curated an extensive database of 862 patients diagnosed between 2014 and 2022. A machine learning (ML) gradient-boosted model incorporated baseline features from clinicopathologic, cytogenetic, and genomic data with high predictive power discriminating between patients with indolent or responsive MCL and those with aggressive disease (AUC ROC = 0.83). In addition, we utilized the gradient-boosted framework as a robust feature selection method for multivariate logistic and survival modeling. The best ML models incorporated features from clinical and genomic data types highlighting the need for correlative molecular studies in precision oncology. As proof of concept, we launched our most accurate and practical models using an application interface, which has potential for clinical implementation. We designated the 20-feature ML model-based index the "integrative MIPI" or iMIPI and a similar 10-feature ML index the "integrative simplified MIPI" or iMIPI-s. The top 10 baseline prognostic features represented in the iMIPI-s are: lactase dehydrogenase (LDH), Ki-67%, platelet count, bone marrow involvement percentage, hemoglobin levels, the total number of observed somatic mutations, TP53 mutational status, Eastern Cooperative Oncology Group performance level, beta-2 microglobulin, and morphology. Our findings emphasize that prognostic applications and indices should include molecular features, especially TP53 mutational status. This work demonstrates the clinical utility of complex ML models and provides further evidence for existing prognostic markers in MCL. Significance: Our model is the first to integrate a dynamic algorithm with multiple clinical and molecular features, allowing for accurate predictions of MCL disease outcomes in a large patient cohort.

Safety of Concurrent Radiation Therapy With Brentuximab Vedotin in the Treatment of Lymphoma.

Purpose: Purpose: Radiation therapy (RT) and the antibody-drug conjugate brentuximab vedotin (BV) are standard-of-care treatment options for patients with certain B and T-cell lymphomas; however, there are limited data exploring the safety of concurrent BV and RT (BVRT). Methods and Materials: We performed a single institutional retrospective review of 44 patients who received BVRT. Results: Twenty percent of patients (9/44) developed new grade 2 or higher (G2+) hematologic toxicity (HT) after BVRT, which was associated with radiation dose (median dose of 35 Gy in those with new G2+ HT compared with 15 Gy in those without; P < .001). Acute G2+ elevation in aspartate transaminase or alanine transaminase level was associated with administration of concurrent chemotherapy with BVRT (57% vs 21%; P = .047) but was not associated with any RT factors. Local control (LC) was achieved in 24 of 42 patients (57%) with available follow-up. Ten patients (23%) proceeded to stem cell transplant or cellular therapy after BVRT at a median of 48 days (interquartile range, 27-188 days). At last follow-up, 10 patients (23%) remained without evidence of disease. Conclusions: Our analysis demonstrates that the combination of BV and RT is well tolerated, though care should be taken during RT planning to reduce the risk of HT. This combination can be considered for patients in need of both local and systemic disease control.

Blastoid and Pleomorphic Mantle Cell Lymphoma Demonstrate Distinct Clinicopathologic and Genetic Features.

The blastoid (B) and pleomorphic (P) variants of mantle cell lymphoma (MCL) are associated with aggressive clinical behavior. In this study, we collected 102 cases of B-MCL and P-MCL from untreated patients. We reviewed clinical data, analyzed morphologic features using an image analysis tool (ImageJ) and we assessed mutational and gene expression profiles. The chromatin pattern of lymphoma cells was assessed quantitatively by the pixel value. Cases of B-MCL showed a greater median pixel value with lower variation compared with P-MCL, indicating a homogeneously euchromatin-rich pattern in B-MCL. In addition, the Feret diameter of the nuclei was significantly smaller (median 6.92 vs. 8.49 µm per nucleus, P <0.001) and had a lesser degree of variation in B-MCL compared with P-MCL, indicating that B-MCL cells have smaller cells with a more monomorphic appearance. B-MCL showed a significantly higher median Ki-67 proliferation rate (60% vs. 40%, P =0.003), and affected patients had poorer overall survival compared with those with P-MCL (median overall survival: 3.1 vs. 8.8 y, respectively, P =0.038). NOTCH1 mutation was significantly more frequent in B-MCL compared with P-MCL (33% and 0%, respectively, P =0.004). Gene expression profiling showed 14 genes overexpressed in B-MCL cases and gene set enrichment assay for the overexpressed genes showed significant enrichment in the cell cycle and mitotic transition pathways. We also report a subset of MCL cases that has blastoid chromatin but a higher degree of pleomorphism in nuclear size and shape, designated here as hybrid MCL. Hybrid MCL cases had a similar Ki-67 proliferation rate, mutation profile, and clinical outcome to B-MCL and distinct from P-MCL. In summary, these data suggest biological differences between B-MCL and P-MCL cases justifying their separate designation when possible.

A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy.

Increasing evidence suggests that the gut microbiome may modulate the efficacy of cancer immunotherapy. In a B cell lymphoma patient cohort from five centers in Germany and the United States (Germany, n = 66; United States, n = 106; total, n = 172), we demonstrate that wide-spectrum antibiotics treatment ('high-risk antibiotics') prior to CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is associated with adverse outcomes, but this effect is likely to be confounded by an increased pretreatment tumor burden and systemic inflammation in patients pretreated with high-risk antibiotics. To resolve this confounding effect and gain insights into antibiotics-masked microbiome signals impacting CAR-T efficacy, we focused on the high-risk antibiotics non-exposed patient population. Indeed, in these patients, significant correlations were noted between pre-CAR-T infusion Bifidobacterium longum and microbiome-encoded peptidoglycan biosynthesis, and CAR-T treatment-associated 6-month survival or lymphoma progression. Furthermore, predictive pre-CAR-T treatment microbiome-based machine learning algorithms trained on the high-risk antibiotics non-exposed German cohort and validated by the respective US cohort robustly segregated long-term responders from non-responders. Bacteroides, Ruminococcus, Eubacterium and Akkermansia were most important in determining CAR-T responsiveness, with Akkermansia also being associated with pre-infusion peripheral T cell levels in these patients. Collectively, we identify conserved microbiome features across clinical and geographical variations, which may enable cross-cohort microbiome-based predictions of outcomes in CAR-T cell immunotherapy.

Brexucabtagene Autoleucel for Relapsed or Refractory Mantle Cell Lymphoma in Standard-of-Care Practice: Results From the US Lymphoma CAR T Consortium.

PURPOSE: Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication. PATIENTS AND METHODS: Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines. RESULTS: Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis. CONCLUSION: In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.

Exploiting PRMT5 as a target for combination therapy in mantle cell lymphoma characterized by frequent ATM and TP53 mutations.

Constant challenges for the treatment of mantle cell lymphoma (MCL) remain to be recurrent relapses and therapy resistance, especially in patients harboring somatic mutations in the tumor suppressors ATM and TP53, which are accumulated as therapy resistance emerges and the disease progresses, consistent with our OncoPrint results that ATM and TP53 alterations were most frequent in relapsed/refractory (R/R) MCL. We demonstrated that protein arginine methyltransferase-5 (PRMT5) was upregulated in R/R MCL, which predicted a poor prognosis. PRMT5 inhibitors displayed profound antitumor effects in the mouse models of MCL with mutated ATM and/or TP53, or refractory to CD19-targeted CAR T-cell therapy. Genetic knockout of PRMT5 robustly inhibited tumor growth in vivo. Co-targeting PRMT5, and ATR or CDK4 by using their inhibitors showed synergistic antitumor effects both in vitro and in vivo. Our results have provided a rational combination therapeutic strategy targeting multiple PRMT5-coordinated tumor-promoting processes for the treatment of R/R MCL with high mutation burdens.

Clinical impact of 5'MYC or 3'MYC gain/loss detected by FISH in patients with aggressive B-cell lymphomas.

FISH analysis using MYC break-apart probes is a widely used technique to assess for MYC rearrangement (MYC-R). Occasionally, FISH results in atypical signal patterns, such as gain or loss of 5'MYC or 3'MYC. The clinical impact and/or relationship of these atypical signal patterns to MYC-R are unknown. In this study, we assessed 35 patients who had aggressive B-cell lymphomas and exhibited atypical FISH signal patterns: 3'MYC deletion (n = 16) or 3'MYC deletion plus 5'MYC amplification (n = 5), 5'MYC gain (n = 10), 5'MYC deletion (n = 3), and 3'MYC gain (n = 1). For comparison, we also included 9 patients who showed an unbalanced MYC-R. Patients with 5'MYC gain showed MYC expression and were often refractory to chemotherapy (n = 7) or had early relapse (n = 2). By contrast, lymphomas with 3'MYC deletion were negative or had low expression of MYC (16 of 18), and patients often responded to chemotherapy (16 of 19). The median event-free survival was 24, 6, and 4 months for patients with 3'MYC deletion, 5'MYC gain and unbalanced MYC-R, respectively (p = 0.0048). We conclude that 5'MYC gain is associated with MYC expression and a poorer prognosis and likely represents an unbalanced MYC-R. By contrast, 3'MYC deletions are not associated with MYC expression or a poorer prognosis and this finding may be unrelated to MYC-R.

A polyamine-centric, blood-based metabolite panel predictive of poor response to CAR-T cell therapy in large B cell lymphoma.

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy for relapsed or refractory (r/r) large B cell lymphoma (LBCL) results in durable response in only a subset of patients. MYC overexpression in LBCL tumors is associated with poor response to treatment. We tested whether an MYC-driven polyamine signature, as a liquid biopsy, is predictive of response to anti-CD19 CAR-T therapy in patients with r/r LBCL. Elevated plasma acetylated polyamines were associated with non-durable response. Concordantly, increased expression of spermidine synthase, a key enzyme that regulates levels of acetylated spermidine, was prognostic for survival in r/r LBCL. A broad metabolite screen identified additional markers that resulted in a 6-marker panel (6MetP) consisting of acetylspermidine, diacetylspermidine, and lysophospholipids, which was validated in an independent set from another institution as predictive of non-durable response to CAR-T therapy. A polyamine centric metabolomics liquid biopsy panel has predictive value for response to CAR-T therapy in r/r LBCL.

Is There Still a Role for Transplant for Patients with Mantle Cell Lymphoma (MCL) in the Era of CAR-T Cell Therapy?

OPINION STATEMENT: For years, upfront autologous hematopoietic cell transplant (auto-HCT) has been the standard of care for younger and physically fit mantle cell lymphoma (MCL) patients after chemoimmunotherapy (CIT) induction. Bruton's tyrosine kinase (BTK) inhibitors have proven to be excellent salvage therapies, but their durability remains a question, especially in high-risk (HR) MCL. Allogeneic HCT (allo-HCT) was the only option for long-term remission and possibly cure for MCL relapse after auto-HCT and sometime as upfront consolidation for a young patient with HR MCL (debatable). We have seen a paradigm shift since the FDA approval in July 2020 of the brexucabtagene autoleucel chimeric antigen receptor T (CAR-T) cell therapy for relapsed and refractory (R/R) MCL with an preliminary evidence suggesting CAR-T may overcome known biological risk factors in MCL. Given its safety profile and excellent efficacy, the role of CAR-T among other approved therapies and HCT may need to be better defined. Based on the current evidence, auto-HCT remains a standard frontline consolidation therapy. CAR-T therapy is a preferred option for patients with relapsed/refractory (R/R) MCL, particularly those who failed BTK inhibitors. In certain high-risk MCL patients (such as high ki 67, TP53 alterations, complex karyotype, blastoid morphology, early relapse after initial diagnosis), CAR-T cell therapy may be considered before BTK inhibitors (preferably on a clinical trial). The role of allo-HCT is unclear in the CAR-T era, but remains a viable option for eligible patients who have no access or who have failed CAR-T therapy. Our review discusses current standards and the shifting paradigms in the indications for HCT and the role of CAR-T cell therapy for MCL. Prospective studies tailored based on risk factors are needed to better define the optimal sequences of HCT and cellular therapy and other approved novel therapies.

TIGIT is the central player in T-cell suppression associated with CAR T-cell relapse in mantle cell lymphoma.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy using brexucabtagene autoleucel (BA) induces remission in many patients with mantle cell lymphoma (MCL), and BA is the only CAR T-cell therapy approved by the FDA for MCL. However, development of relapses to BA is recognized with poor patient outcomes. Multiple CAR T-cell therapies have been approved for other lymphomas and the resistance mechanisms have been investigated. However, the mechanisms underlying BA relapse in MCL have not been investigated and whether any previously reported resistance mechanisms apply to BA-relapsed patients with MCL is unknown. METHODS: To interrogate BA resistance mechanisms in MCL, we performed single-cell RNA sequencing on 39 longitudinally collected samples from 15 BA-treated patients, and multiplex cytokine profiling on 80 serial samples from 20 patients. RESULTS: We demonstrate that after BA relapse, the proportion of T cells, especially cytotoxic T cells (CTLs), decreased among non-tumor cells, while the proportion of myeloid cells correspondingly increased. TIGIT, LAG3, and CD96 were the predominant checkpoint molecules expressed on exhausted T cells and CTLs; only TIGIT was significantly increased after relapse. CTLs expanded during remission, and then contracted during relapse with upregulated TIGIT expression. Tumor cells also acquired TIGIT expression after relapse, leading to the enhanced interaction of tumor cell TIGIT with monocyte CD155/PVR. In myeloid cells, post-relapse HLA-II expression was reduced relative to pretreatment and during remission. Myeloid-derived suppressor cells (MDSCs) were enriched after relapse with elevated expression of activation markers, including CLU (clusterin) and VCAN (versican). Extracellular chemokines (CCL4, CXCL9, CXCL13), soluble checkpoint inhibitors (sPD-L1, sTIM3, s4-1BB), and soluble receptors (sIL-2R, sTNFRII) were decreased during remission but elevated after relapse. CONCLUSIONS: Our data demonstrate that multiple tumor-intrinsic and -extrinsic factors are associated with T-cell suppression and BA relapse. Among these, TIGIT appears to be the central player given its elevated expression after BA relapse in not only CTLs but also MCL cells. The acquisition of TIGIT expression on tumor cells is MCL-specific and has not been reported in other CAR T-treated diseases. Together, our data suggest that co-targeting TIGIT may prevent CAR T relapses and thus promote long-term progression-free survival in MCL patients.

Brexucabtagene autoleucel: a breakthrough in the treatment of mantle cell lymphoma.

In July 2020, the U.S. Food and Drug Administration (FDA) approved brexucabtagene autoleucel (BA), the first anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for the treatment of relapsed/refractory mantle cell lymphoma (MCL). The pivotal ZUMA-2 trial led to the approval of BA in patients who experienced relapsed disease on prior therapies (chemotherapy and/or Bruton tyrosine kinase [BTK] inhibitors). The FDA approval of BA was based on excellent responses with this therapy in highly refractory patients with MCL, who conventionally had poor outcomes. Longer follow-up data from the ZUMA-2 study have been presented at recent international meetings. As is common with other CAR T-cell therapies in lymphomas, the main toxicities of BA therapy included cytokine release syndrome (CRS), infections, cytopenias and CAR-associated neurotoxicity. In this review, we provide a summary of the data in the development of BA and its impact on MCL patient survival and future directions.

Zanubrutinib in lymphoproliferative disorders: a comprehensive review.

The availability of Bruton tyrosine kinase (BTK) inhibitors has brought about a paradigm shift in the treatment of patients with B-cell lymphomas and chronic lymphocytic leukemia. BTK was clinically validated as a target by the efficacy of the first-in-class inhibitor ibrutinib. The extended survival conferred by BTK inhibitors has brought long-term tolerability to the foreground. To minimize toxicities thought to be attributable to off-target kinase inhibition, a next generation of BTK inhibitors with greater selectivity was developed. In the United States, zanubrutinib, a next-generation BTK inhibitor, has been approved for treating adults with mantle cell lymphoma who have received at least one prior therapy, for adults with Waldenström macroglobulinemia, and for adults with relapsed or refractory marginal zone lymphoma who have received at least one anti-CD20-based therapy. Because few head-to-head comparative trials of BTK inhibitors have so far been reported, no BTK 'inhibitor of choice' can be identified. Zanubrutinib has promising efficacy in its approved indications and appears to have reduced cardiac toxicities, particularly atrial fibrillation, which may influence the choice of BTK inhibitor treatment by prescribers. Further studies are needed to inform on optimal treatment sequencing of zanubrutinib and its combination with other agents. Here, we summarize existing clinical evidence for its efficacy and safety in mantle cell lymphoma, Waldenström macroglobulinemia, marginal zone lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and other B-lymphoproliferative indications. Plain Language Summary: Zanubrutinib is a drug that was shown to effectively treat cancer of B cells without causing excessive serious side effects Patients with certain B-cell malignancies (cancers of white blood cells) benefit from treatment with Bruton tyrosine kinase (BTK) inhibitors, drugs that block the BTK protein and keep cancer from growing and spreading. Patients experience extended survival with ibrutinib, the first-generation BTK inhibitor approved by US Food and Drug Administration (FDA); however, one in five patients quit treatment because of harmful side effects. Ibrutinib-related side effects such as increased risk of bleeding, atrial fibrillation (abnormal heart rhythm), and high blood pressure are thought to be caused by ibrutinib blocking other proteins besides the intended target protein BTK. To reduce these side effects, zanubrutinib, a next-generation BTK inhibitor, was designed to block BTK more specifically than ibrutinib. Results of clinical studies on zanubrutinib treatment appear promising in patients with several types of B-cell malignancies, including mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), marginal zone lymphoma (MZL), chronic lymphocytic leukemia, and small lymphocytic lymphoma. There are not yet enough clinical data to determine which BTK inhibitor is most effective in treating B-cell malignancies without causing harmful side effects. Early data from the phase 3 ALPINE clinical study suggest that zanubrutinib works better than ibrutinib, and fewer patients experience side effects and quit treatment. Zanubrutinib is currently approved for use for treatment of adult patients with MCL who have received at least one prior therapy, for adults with WM, and for adults with MZL who have received at least one anti-CD20-based therapy.