In a large randomized trial that compares regimens in which brentuximab vedotin replaced bleomycin, the group receiving the brentuximab had a 4.9 percentage-point improvement in modified ...progression-free survival, less pulmonary toxicity, and more myelotoxicity and neurotoxicity.
In addition to chimeric antigen receptor T-cell (CAR-T) therapy, antibody–drug conjugates, and targeted therapies such as Bruton's tyrosine kinase inhibitors and PI3 kinase inhibitors, bispecific ...T-cell redirectors have shown promising activity in this setting. The next generation of bispecific T-cell redirectors for non-Hodgkin lymphoma target CD20 (ie, epcoritamab, mosunetuzumab, glofitamab, odronextamab, plamotamab) and have defined pharmacokinetic properties and longer half-lives, enabling intermittent dosing and potentially subcutaneous administration, fewer serious toxic effects, and encouraging overall (39–96%) and complete (19–77%) response rates.4 In The Lancet, Martin Hutchings and colleagues5 report the results of the phase 1 dose-escalation part of an ongoing trial of the CD3xCD20 bispecific T-cell redirector, epcoritamab, in patients with CD20+ relapsed or refractory B-cell non-Hodgkin lymphoma (NCT03625037). Four patients developed transient neurological complications, including grade 1 partial seizure, grade 1 agraphia, grade 3 hypersomnia, and grade 3 confusion; however, immune effector cell-associated neurotoxicity syndrome (ICANS) grading was not used, limiting cross-product or cross-trial comparisons (grade 1 partial seizure would be considered grade 3 ICANS).6 Fever was the only serious treatment-related adverse event occurring in more than 5% of participants and no patient had febrile neutropenia or discontinued therapy due to adverse events.
Most patients with follicular lymphoma (FL) experience multiple relapses necessitating subsequent lines of therapy. Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor approved for the treatment of ...several B-cell malignancies, showed promising activity in FL in a phase 1 study. We report the results of a phase 2 trial evaluating ibrutinib in recurrent FL. Forty patients with recurrent FL were treated with ibrutinib 560 mg/d until progression or intolerance. The primary end point was overall response rate (ORR). Exploratory analyses included correlations of outcome with recurrent mutations identified in a cancer gene panel that used next-generation sequencing in pretreatment biopsies from 31 patients and results of early interim positron emission tomography/computed tomography scans in 20 patients. ORR was 37.5% with a complete response rate of 12.5%, median progression-free survival (PFS) of 14 months, and 2-year PFS of 20.4%. Response rates were significantly higher among patients whose disease was sensitive to rituximab (52.6%) compared with those who were rituximab refractory (16.7%) (P = .04). CARD11 mutations were present in 16% of patients (5 of 31) and predicted resistance to ibrutinib with only wild-type patients responding (P = .002). Maximum standardized uptake value at cycle 1 day 8 correlated with response and PFS. Ibrutinib was well-tolerated with a toxicity profile similar to labeled indications. Ibrutinib is a well-tolerated treatment with modest activity in relapsed FL. Evaluation of BTK inhibitors in earlier lines of therapy may be warranted on the basis of improved response rates in rituximab-sensitive disease. Somatic mutations such as CARD11 may have an impact on response to ibrutinib, may inform clinical decisions, and should be evaluated in larger data sets. This trial was registered at www.clinicaltrials.gov as #NCT01849263.
•Ibrutinib has modest activity in FL with low response rates in rituximab-refractory patients.•CARD11 mutations predict for lack of response to ibrutinib.
Treating unfit patients with aggressive B-cell lymphoma poses the dilemma of balancing potential cure while minimizing toxicity because of frailty and comorbidities. Age greater than 80 years and ...common comorbidities such as cardiovascular disease and poorly controlled diabetes mellitus often preclude the use of full-dose anthracyclines and steroids, the backbones of standard regimens for aggressive B-cell lymphomas. Assessing patient fitness remains subjective, with no consensus on best practice or how to integrate assessment tools into decision making. Incorporation of prephase steroids for all unfit patients may markedly improve performance status with consideration of standard dose therapy, especially in patients less than age 80. Although randomized studies are lacking, current data suggest patients age ≥ 80 years are considered unfit a priori and should receive dose-reduced anthracycline regimens or anthracycline-free regimens. Severe toxicity is highest after the first cycle of chemotherapy. Dose reductions for cycle 1 in unfit patients with plans to escalate as tolerated is often an effective strategy. Unfit patients often benefit from comanagement with gerontologists, cardio-oncologists, and endocrinologists depending on age and the nature of comorbidities. Palliative therapy for patients with newly diagnosed aggressive B-cell lymphoma results in median survivals of less than 3 months, and in general, should only be considered in patients with untreatable comorbidities such as advanced dementia or refractory metastatic solid tumors. Incorporating new, potentially less toxic agents such as novel antibodies, antibody-drug conjugates, and bispecific antibodies into first-line therapy is an exciting future direction with potential for substantial benefit in less fit patients.
Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma, yet it remains only partially characterized at the genomic level. To improve our understanding of the genetic ...underpinnings of this incurable and clinically heterogeneous disease, whole-exome sequencing was performed on tumor/normal pairs from a discovery cohort of 24 patients with FL. Using these data and mutations identified in other B-cell malignancies, 1716 genes were sequenced in 113 FL tumor samples from 105 primarily treatment-naive individuals. We identified 39 genes that were mutated significantly above background mutation rates. CREBBP mutations were associated with inferior PFS. In contrast, mutations in previously unreported HVCN1, a voltage-gated proton channel-encoding gene and B-cell receptor signaling modulator, were associated with improved PFS. In total, 47 (44.8%) patients harbor mutations in the interconnected B-cell receptor (BCR) and CXCR4 signaling pathways. Histone gene mutations were more frequent than previously reported (identified in 43.8% of patients) and often co-occurred (17.1% of patients). A novel, recurrent hotspot was identified at a posttranslationally modified residue in the histone H2B family. This study expands the number of mutated genes described in several known signaling pathways and complexes involved in lymphoma pathogenesis (BCR, Notch, SWitch/sucrose nonfermentable (SWI/SNF), vacuolar ATPases) and identified novel recurrent mutations (EGR1/2, POU2AF1, BTK, ZNF608, HVCN1) that require further investigation in the context of FL biology, prognosis, and treatment.
•FLs harbor more recurrent mutations in the BCR signaling pathway, SWI/SNF complex, and histone genes than previously known.•Novel recurrent mutations affecting BTK, SYK, and HVCN1 may have therapeutic and prognostic implications for FL.
Diffuse large B-cell lymphoma, the most common subtype of non-Hodgkin lymphoma, comprises a heterogenous group of morphologically, genetically, and clinically distinct diseases. Several recent ...advances have affected the treatment landscape, which had been mostly stagnant for the past few decades. We will review the practice-changing studies in frontline (POLARIX), early relapse (ZUMA-7 and TRANSFORM), and multiple recurrent (ZUMA-1, JULIET, TRANSCEND, L-MIND, and LOTIS-2) stages and discuss how the treatment landscape may evolve with the emergence of bispecific antibodies.
Addition of brentuximab vedotin, a CD30-targeted antibody–drug conjugate, and the programmed death 1 (PD-1) inhibitors nivolumab and pembrolizumab to the armamentarium for transplant-ineligible ...relapsed/refractory classical Hodgkin lymphoma has resulted in improved outcomes, including the potential for cure in a small minority of patients. For patients who have failed prior transplant or are unsuitable for dose-intense approaches based on age or comorbidities, an individualized approach with sequential use of single agents such as brentuximab vedotin, PD-1 inhibitors, everolimus, lenalidomide, or conventional agents such as gemcitabine or vinorelbine may result in prolonged survival with a minimal or modest effect on quality of life. Participation in clinical trials evaluating new approaches such as combination immune checkpoint inhibition, novel antibody–drug conjugates, or cellular therapies such as Epstein-Barr virus–directed cytotoxic T lymphocytes and chimeric antigen receptor T cells offer additional options for eligible patients.
Natural killer (NK) cells are a promising cellular immunotherapy for cancer. Cytokine-induced memory-like (ML) NK cells differentiate after activation with interleukin-12 (IL-12), IL-15, and IL-18, ...exhibit potent antitumor responses, and safely induce complete remissions in patients with leukemia. However, many cancers are not fully recognized via NK cell receptors. Chimeric antigen receptors (CARs) have been used to enhance tumor-specific recognition by effector lymphocytes. We hypothesized that ML differentiation and CAR engineering would result in complementary improvements in NK cell responses against NK-resistant cancers. To test this idea, peripheral blood ML NK cells were modified to express an anti-CD19 CAR (19-CAR-ML), which displayed significantly increased interferon γ production, degranulation, and specific killing against NK-resistant lymphoma lines and primary targets compared with nonspecific control CAR-ML NK cells or conventional CAR NK cells. The 19-CAR and ML responses were synergistic and CAR specific and required immunoreceptor tyrosine-based activation motif signaling. Furthermore, 19-CAR-ML NK cells generated from lymphoma patients exhibited improved responses against their autologous lymphomas. 19-CAR-ML NK cells controlled lymphoma burden in vivo and improved survival in human xenograft models. Thus, CAR engineering of ML NK cells enhanced responses against resistant cancers and warrants further investigation, with the potential to broaden ML NK cell recognition against a variety of NK cell–resistant tumors.
•ML NK cell differentiation and CAR engineering synergistically combine to enhance NK cell responses to resistant leukemia/lymphoma.•CAR-ML NK cells expand and control NK-resistant leukemia/lymphoma in vivo in xenograft models.
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Brentuximab vedotin is a drug immunoconjugate with an antibody targeting CD30, an antigen expressed mainly on Hodgkin's and anaplastic large-cell lymphomas, linked to a potent microtubule inhibitor. ...In a study involving 45 patients after relapse, 11 complete remissions were observed.
Approximately 15 to 30% of patients with Hodgkin's lymphoma do not have a long-term remission with conventional therapy,
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resulting in an estimated 1300 deaths annually in the United States alone.
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Autologous hematopoietic stem-cell transplantation (ASCT) represents a potentially curative treatment for some patients with recurrent or progressive Hodgkin's lymphoma after failure of initial combination chemotherapy. Unfortunately, ASCT is only effective in approximately 50% of such patients.
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Among those who have a relapse after ASCT, overall survival is 55% at 2 years and 32% at 5 years.
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Because the incidence of Hodgkin's lymphoma peaks during young adulthood, these premature deaths . . .
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