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Simple Summary: This review article provides an update on the current knowledge surrounding mantle cell lymphoma (MCL), focusing on the disease's complexity and heterogeneity, as well as its prognostic factors. Advancements in risk stratification scoring systems are reviewed, and the emerging role of genomic technologies and their potential to inform risk profiling are also highlighted. In addition, the article discusses novel therapies, including Bruton's tyrosine kinase inhibitors, BCL-2 inhibitors, ROR1 inhibitors, and bispecific T-cell engagers, which could become cornerstones of MCL treatment in the future. Advancements in mantle cell lymphoma (MCL) have illuminated the disease's molecular diversity, leading to a wide variation in the outcomes observed in MCL. Current prognostic risk scores are continuously revised to incorporate new updates in the mechanistic or biologic understanding of MCL. Nevertheless, key high-risk features of MCL associated with rapid disease progression and poor survival, such as TP53 mutations, complex karyotypes, and blastoid or pleomorphic morphologies, remain absent from available prognostic tools. The greater accessibility of genomic technologies, such as next-generation sequencing (NGS), has enabled clinicians to identify specific genetic alterations that serve as prognostic signals and disease monitoring parameters, cultivating accurate risk profiling that is illustrative of MCL heterogeneity. Through an increased understanding of distinct MCL behaviors, novel therapies that mechanistically target disease biology, including Bruton's tyrosine kinase inhibitors, BCL-2 inhibitors, ROR1 inhibitors, and bispecific T-cell engagers, have broadened the treatment armamentarium for relapsed/refractory MCL cases. These interventions, in addition to chemoimmunotherapy and autologous stem cell transplantation mainstays, confer the individualization of treatment and improved survival outcomes. Further exploration of the considerable biological heterogeneity of MCL can enhance knowledge, management, and the treatment of this rare lymphoma subtype. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a rare non-Hodgkin lymphoma that frequently becomes chemoresistant over time. The distinct mechanisms of ibrutinib and lenalidomide provided a judicious rationale to explore the combination with anti-CD20 immunotherapy. In this phase 1b study (NCT02446236), patients (n=25) with relapsed/refractory MCL received rituximab with escalating doses of lenalidomide (days 1–21) and ibrutinib 560mg (days 1–28) of 28-day cycles. The MTD for lenalidomide was 20mg; most common grade ≥3 adverse events were skin rashes (32%) and neutropenic fever (24%). The best ORR was 88%, CR rate was 83%, and median duration of response (DOR) was 36.92months (95% CI 33.77, 51.37). Responses were seen even in refractory patients or with high-risk features (e.g. blastoid variant, TP53 mutation, Ki-67>30%). R2I was safe and tolerable in patients with R/R MCL. [ABSTRACT FROM AUTHOR]

To evaluate the trend in cytogenetic/molecular testing rate in chronic lymphocytic leukemia (CLL) and assess the clinical and economic burden of first-line (1 L) treatment with chemoimmunotherapy (CIT) by risk status. This retrospective cohort study identified patients with CLL from a U.S. managed care population. Medical records were obtained for eligible patients who initiated 1 L CIT between 1/1/2007 and 7/31/2019 and underwent prognostic testing to classify them as high risk (del(17p), TP53 mutation, del(11q), unmutated IGHV or complex karyotype) or as non-high risk by FISH only (non-del(17p) and non-del(11q)). Study outcomes included testing rate, time to next treatment (TTNT) or death, time to treatment failure (defined as time to change of therapy, non-chemotherapy intervention, hospice care or death), and total plan paid costs (medical + pharmacy) per patient per month (PPPM) in the 1 L period. Cox proportional hazard models and generalized linear models were used to calculate adjusted hazard ratio or rate ratio. Among the 1,808 patients with CLL, 612 were FISH or IGHV tested and the rate of testing increased from 30% to 44% from 2007–2019. High-risk patients (n = 119) had 65% higher risk of next treatment or death (median time: 2.4 vs 3.7 years), 65% higher risk of treatment failure (median time: 3.0 vs 4.9 years), and 33% higher costs ($12,194 vs $9,055, p = 0.027) during 1 L treatment than non-high risk patients (n = 134). High-risk CLL patients treated with 1 L chemoimmunotherapy have poorer clinical and economic outcomes compared to non-high risk patients. Assessment of genetic risk remains suboptimal. [ABSTRACT FROM AUTHOR]

Patients with hematologic malignancies have poor outcomes from COVID infection and are less likely to mount an antibody response after COVID infection. This is a retrospective study of adult lymphoma patients who received the COVID vaccine between 12/1/2020 and 11/30/2021. The primary endpoint was a positive anti-COVID spike protein antibody level following the primary COVID vaccination series. The primary vaccination series was defined as 2 doses of the COVID mRNA vaccines or 1 dose of the COVID adenovirus vaccine. Subgroups were compared using Fisher's exact test, and unadjusted and adjusted logistic regression models were used for univariate and multivariate analyses. A total of 243 patients were included in this study; 72 patients (30%) with indolent lymphomas; 56 patients (23%) with Burkitt's, diffuse large B-cell lymphoma (DLBCL), and primary mediastinal B-cell lymphoma (PMBL) combined; 55 patients (22%) with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL); 44 patients (18%) with Hodgkin and T-cell lymphomas (HL/TCL) combined; 12 patients (5%) with mantle cell lymphoma; and 4 patients (2%) with other lymphoma types. One-hundred fifty-eight patients (65%) developed anti-COVID spike protein antibodies after completing the primary COVID vaccination series. Thirty-eight of 46 (83%) patients who received an additional primary shot and had resultant levels produced anti-COVID spike protein antibodies. When compared to other lymphoma types, patients with CLL/SLL had a numerically lower seroconversion rate of 51% following the primary vaccination series whereas patients with HL/TCL appeared to have a robust antibody response with a seropositivity rate of 77% (p = 0.04). Lymphoma patients are capable of mounting a humoral response to the COVID vaccines. Further studies are required to confirm our findings, including whether T-cell immunity would be of clinical relevance in this patient population. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with lymphoma are at greater risk of complications from COVID-19 infection. However, limited data exists on COVID-19-related outcomes in lymphoma patients since the use of COVID-19 vaccines and treatments began. Our study reports the real-world outcomes of 68 lymphoma or CLL patients who developed COVID-19 infection during the omicron surge in the US. We found that 34% of patients were hospitalized due to COVID-19 infection. The COVID-19-associated death rate was 9% (6/68) in all patients and 26% (6/23) in hospitalized patients, which was much lower compared to rates earlier in the pandemic prior to the introduction of COVID-19 vaccines and treatments. In 30 patients with data available, 60% did not make antibodies after COVID-19 vaccination. Most patients (74%, 17/23) who were hospitalized did not receive COVID-19 monoclonal antibody treatment. Our results pointed to important differences and the need for a new approach to treating cancer patients with COVID-19 infection. Lymphoma patients are at greater risk of severe consequences from COVID-19 infection, yet most reports of COVID-19-associated outcomes were published before the advent of COVID-19 vaccinations and monoclonal antibodies (mAbs). In this retrospective study, we report the real-world outcomes of 68 lymphoma or CLL patients who developed COVID-19 infection during the omicron surge in the US. We found that 34% of patients were hospitalized as a result of COVID-19 infection. The death rate due to COVID-19 was 9% (6/68) in the overall population and 26% (6/23) in hospitalized patients. During the preintervention COVID-19 era, the mortality rate reported in cancer patients was 34%, which increased to 60.2% in hospitalized patients. Thus, the death rates in our study were much lower when compared to those in cancer patients earlier in the pandemic, and may be attributed to modern interventions. In our study, 60% (18/30) of patients with serology data available did not develop anti-COVID-19 spike protein antibodies following vaccination. Most patients (74%, 17/23) who were hospitalized due to COVID-19 infection did not receive COVID-19 mAb treatment. Our results pointed to the importance of humoral immunity and the protective effect of COVID-19 mAbs in improving outcomes in lymphoma patients. [ABSTRACT FROM AUTHOR]

Introduction: Certain genetic features in chronic lymphocytic leukemia (CLL) are associated with inferior outcomes after chemoimmunotherapy (CIT). This retrospective study evaluated treatment patterns and clinical outcomes of patients with CLL, stratified into high-risk and non-high-risk groups, who received first-line ibrutinib or CIT therapy. Methods: High-risk group included confirmed presence of del(17p), del(11q), unmutated IGHV, TP53 mutations, or complex karyotype. Weighted high-risk ibrutinib and CIT groups were compared for treatment effects using inverse probability of treatment weighting. Hazard ratios [95% CI] (HR) for time to next treatment (TTNT) were analyzed using Kaplan–Meier curves. Results: Bendamustine/rituximab was the most common CIT regimen initiated for high-risk patients. During the available follow-up (median 34–35 months), 74.7% of the weighted high-risk ibrutinib group received only one line of treatment, compared with 47.2% of the weighted high-risk CIT group. The most common second-line treatment was ibrutinib for those in the CIT groups and venetoclax for the ibrutinib groups. The weighted high-risk ibrutinib group had a significantly longer TTNT (median not reached) than the weighted high-risk CIT group (median 34.4 months) and was 54% less likely to start a new treatment (HR 0.5 [0.3–0.6], P < 0.010). Among CIT-treated groups, high-risk patients had significantly shorter median TTNT than non-high-risk patients (P < 0.010). However, within the ibrutinib-treated groups, the median TTNT was similar between high-risk and non-high-risk patients (HR 2.2 [1.0–5.0]; P = 0.060). Conclusion: This study found that first-line single-agent ibrutinib therapy was associated with significantly longer TTNT than CIT regimens in real-world patients with high-risk CLL. The results support the use of ibrutinib in high-risk patients. Infographic: [ABSTRACT FROM AUTHOR]

Opinion Statement: When selecting therapy for patients with indolent non-Hodgkin lymphoma (iNHL) including follicular (FL), marginal zone (MZL), small lymphocytic (SLL), and lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM), there are several factors to consider. With a median age around 70 at diagnosis, many patients have accumulated comorbid conditions that may limit treatment options. Although incurable for most, iNHL is a chronic disease with a median overall survival measured in years to decades. This long natural history changes the risk-to-benefit balance with a lower acceptance of toxicity early in the treatment course compared to that of aggressive lymphomas. Despite a recent rapid increase in available therapies, overall progress in iNHL has been slow for several reasons. Initial trials grouped iNHLs together making it challenging to appreciate the differential activity among subtypes. We have not been able to develop prognostic models that maintain validity in the era of chemotherapy-free options. Predictive markers have been elusive and without identified molecular signatures, it is challenging to select and sequence therapy. With these clinical factors in mind, in addition to the heterogeneity among and within iNHLs, I do not have a standard treatment algorithm and feel each patient should have an individualized treatment approach. This review focuses on recent updates and controversies in the management of iNHL with a focus on FL and MZL. [ABSTRACT FROM AUTHOR]

Background: Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown.Methods: Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy.Results: In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse <12 months from completion of first-line therapy) experienced inferior median PFS (2.8 vs 23 months; P < .001) and OS (6 months vs not reached; P < .001) compared with patients with late treatment failure. Although the 17% of patients with early failure who achieved a complete response to second-line immunochemotherapy experienced prolonged survival, this outcome could not be predicted by clinicopathologic features at the start of second-line immunochemotherapy.Conclusions: Patients with early treatment failure after intensive first-line immunochemotherapy experience poor outcomes after receiving standard second-line immunochemotherapy. The use of standard-of-care or experimental therapies currently available in the third-line setting and beyond should be investigated in the second-line setting for these patients. [ABSTRACT FROM AUTHOR]

Introduction. The diagnosis of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin's lymphoma (cHL), also referred to as grey zone lymphoma (GZL), is a challenging diagnosis. There are no standardized guidelines; however, evidence strongly suggests that DLBCL-based regimens are effective in the treatment of GZL. Brentuximab vedotin (BV) is an anti-CD30 antibody drug conjugate that has established efficacy in relapsed/refractory Hodgkin and some T-cell lymphomas. There is some evidence that BV has a positive response in non-Hodgkin lymphoma (NHL) with a wide range of CD30 expressions—including GZL. Case. We present a case of a patient initially diagnosed with cHL who underwent repeat biopsy which was revealed to be GZL. Based on PET scanning and immunohistochemical studies, she was classified as a stage IIIA CD20+/CD30+ GZL patient. Given her strong CD30 expression, she underwent 6 cycles of R-BV-CHP (rituximab, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone) chemotherapy and achieved complete response (CR) both clinically and radiographically. Discussion. Given the rarity of GZL, this case illustrates the immense challenges in making the diagnosis, discusses the current treatment options, and suggests that BV may be a viable therapeutic candidate in the treatment of GZL. [ABSTRACT FROM AUTHOR]

Hodgkin lymphoma (HL) is an uncommon, highly curable subtype of lymphoma with a bimodal incidence; it affects mostly young adults, with a second peak in older adults. To decrease the risk of long-term toxicity without compromising efficacy and to identify patients with poor prognoses, early interim PET scan is being used as a predictive and prognostic marker to adapt treatment. With improved understanding of the pathobiology of HL, several novel agents have recently entered the treatment armamentarium including immunological blockade checkpoint inhibitors and the anti-CD30 antibody--drug conjugate brentuximab vedotin. Older patients, defined as those over age 60 years, have inferior outcomes compared with younger patients, including remission rate, relapse-free survival, and overall survival. The treatment of older patients with HL represents an area of unmet need, and is a focus of ongoing clinical trials. [ABSTRACT FROM AUTHOR]

In recent years, several genetic and epigenetic alterations have been identified and linked with deregulated signaling pathways that promote growth and survival of lymphoma cells. These discoveries have raised hopes that a new era of targeted therapy will eventually improve treatment outcome of lymphoma. In this focused review, we summarize emerging preclinical and clinical data supporting the development of novel agents targeting B cell receptor signaling, phosphoinositol-3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) oncogenic pathways. Furthermore, we discuss new data on targeting chromatin modulating mechanisms. [ABSTRACT FROM AUTHOR]