Disease Overview
Epstein Barr virus‐positive (EBV+) diffuse large B‐cell lymphoma (DLBCL), not otherwise specified (NOS) is an entity included in the WHO classification of lymphoid neoplasms since ...2016. EBV+ DLBCL, NOS, is an aggressive B‐cell lymphoma associated with EBV infection, and a poor prognosis with standard chemotherapeutic approaches.
Diagnosis
The diagnosis is made through a careful pathological evaluation. Detection of EBV‐encoded RNA (EBER) is considered standard for diagnosis; however, a clear cutoff for percentage of positive cells has not been defined. The differential diagnosis includes plasmablastic lymphoma (PBL), DLBCL associated with chronic inflammation, primary effusion lymphoma (PEL), among others.
Risk‐Stratification
The International Prognostic Index (IPI) and the Oyama score can be used for risk‐stratification. The Oyama score includes age >70 years and presence of B symptoms. The expression of CD30 and PD‐1/PD‐L1 are emerging as potential adverse but targetable biomarkers.
Management
Patients with EBV+ DLBCL, NOS, should be staged and managed following similar guidelines than patients with EBV‐negative DLBCL. EBV+ DLBCL, NOS, however, might have a worse prognosis than EBV‐negative DLBCL in the era of chemoimmunotherapy. Therefore, the inclusion of patients in clinical trials when available is recommended. There is an opportunity to study and develop targeted therapy in the management of patients with EBV+ DLBCL, NOS.
Resistance to standard immunochemotherapy remains an unmet challenge in diffuse large B-cell lymphoma (DLBCL), and aberrant DNA methylation may contribute to chemoresistance. Promising early-phase ...results were reported with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus subcutaneous azacitidine, a hypomethylating agent. In this phase 1 study, we evaluated CC-486 (oral azacitidine) plus 6 cycles of R-CHOP in patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. CC-486 doses of 100, 150, 200, or 300 mg given 7 days before cycle 1 and on days 8-21 of cycles 1-5 were evaluated; additional patients were enrolled in the expansion phase to examine preliminary efficacy. The primary objectives were to determine the safety and the maximum tolerated dose (MTD) of CC-486 in combination with R-CHOP. The most common grade 3/4 toxicities were hematologic, including neutropenia (62.7%) and febrile neutropenia (25.4%); grade 3/4 nonhematologic toxicities were uncommon (<7%). The MTD was not established; 2 patients had dose-limiting toxicities (1 with grade 4 febrile neutropenia; 1 with grade 4 prolonged neutropenia). The recommended phase 2 dose was established as 300 mg. The overall response rate was 94.9%, with 52 patients (88.1%) achieving complete responses. With a median follow-up of 28.9 months, estimated 1- and 2-year progression-free survival rates were 84.1% and 78.6%, respectively. Overall, epigenetic priming with CC-486 before R-CHOP can be delivered with acceptable safety to patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. ClinicalTrials.gov: NCT02343536.
•Epigenetic priming with oral azacitidine (CC-486) before R-CHOP demonstrated an acceptable safety profile.•CC-486 plus R-CHOP showed clinical activity in previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed FL.
Display omitted
Chimeric antigen receptor T-cell (CAR-T) therapy represents the most important advances in cancer immunotherapy, especially in hematological malignancies such as B-cell lymphomas. CAR-T cell therapy ...has significant activity in poor risk B-cell lymphomas. CAR-T cell therapy is associated with potentially life-threatening toxicities such as cytokine release syndrome (CRS) and neurotoxicity (NT). While CRS pathophysiology and management are well established, the understanding and treatment of NT continues to develop. All current CAR-T products approved for DLBCL have been associated with NT with some differences in their severity. As cell therapies continue to advance and its access broadening, it will be imperative for clinicians to be aware of the signs and symptoms of NT, its stratification and basic management. Keywords: CAR-T, neurotoxicity, ICANS, encephalopathy
Chimeric antigen receptor (CAR) T-cell therapy with axicabtagene ciloleucel (axi-cel) continues to make its way in the treatment of B-cell lymphomas. Follicular lymphoma (FL) is the second most ...common non-Hodgkin’s lymphoma. While its prognosis is usually good, the disease is considered incurable and patients still relapse. High-risk subgroups such as high FLIPI score or early relapses (POD24) face poor outcomes. Current treatment options with phosphatidylinositol 3-kinase (Pi3K) inhibitors or other novel agents have clinical activity but short remission with cures remaining elusive. The ZUMA-5 study of axi-cel has shown high response rates with durable remissions with manageable toxicities, particularly in poor risk FL, replicating the outcomes in smaller and earlier studies. Long-term follow up will demonstrate the real impact of axi-cel in relapsed FL.
•Axi-cel showed clinically meaningful improvements in QoL in 2L LBCL over SOC at days 100 and 150.•There was a trend toward faster recovery to baseline QoL in patients who received axi-cel.
Display ...omitted
Here, we report the first comparative analysis of patient-reported outcomes (PROs) with chimeric antigen receptor T-cell therapy vs standard-of-care (SOC) therapy in second-line relapsed/refractory large B-cell lymphoma (R/R LBCL) from the pivotal randomized phase 3 ZUMA-7 study of axicabtagene ciloleucel (axi-cel) vs SOC. PRO instruments were administered at baseline, day 50, day 100, day 150, month 9, and every 3 months from randomization until 24 months or an event-free survival event. The quality of life (QoL) analysis set comprised patients with a baseline and ≥1 follow-up PRO completion. Prespecified hypotheses for Quality of Life Questionnaire-Core 30 (QLQ-C30) physical functioning, global health status/QoL, and EQ-5D-5L visual analog scale (VAS) were tested using mixed-effects models with repeated measures. Clinically meaningful changes were defined as 10 points for QLQ-C30 and 7 for EQ-5D-5L VAS. Among 359 patients, 296 (165 axi-cel, 131 SOC) met inclusion criteria for QoL analysis. At day 100, statistically significant and clinically meaningful differences in mean change of scores from baseline were observed favoring axi-cel over SOC for QLQ-C30 global health status/QoL (estimated difference 18.1 95% confidence interval (CI), 12.3-23.9), physical functioning (13.1 95% CI, 8.0-18.2), and EQ-5D-5L VAS (13.7 95% CI, 8.5-18.8; P < .0001 for all). At day 150, scores significantly favored axi-cel vs SOC for global health status/QoL (9.8 95% CI, 2.6-17.0; P = .0124) and EQ-5D-5L VAS (11.3 95% CI, 5.4-17.1; P = .0004). Axi-cel showed clinically meaningful improvements in QoL over SOC. Superior clinical outcomes and favorable patient experience with axi-cel should help inform treatment choices in second-line R/R LBCL. This trial was registered at www.clinicaltrials.gov as #NCT03391466.
Elsawy et al present the patient-reported outcomes after axicabtagene ciloleucel (axi-cel) administered as second-line therapy in large B-cell lymphoma compared to salvage chemotherapy followed by autologous stem cell transplantation (ASCT) in the ZUMA-7 trial. In clinical responders, treatment with axi-cel delivers better quality-of-life and an earlier return to baseline functioning compared to salvage chemotherapy followed by ASCT. The results imply that, in addition to improving progression-free survival, axi-cel is better tolerated than the previous standard.
The sperm acrosome reaction (AR), an essential event for mammalian fertilization, involves Ca2+ permeability changes leading to exocytosis of the acrosomal vesicle. The acrosome, an intracellular ...Ca2+ store whose luminal pH is acidic, contains hydrolytic enzymes. It is known that acrosomal pH (pHacr) increases during capacitation and this correlates with spontaneous AR. Some AR inducers increase intracellular Ca2+ concentration (Ca2+i) through Ca2+ release from internal stores, mainly the acrosome. Catsper, a sperm specific Ca2+ channel, has been suggested to participate in the AR. Curiously, Mibefradil and NNC55‐0396, two CatSper blockers, themselves elevate Ca2+i by unknown mechanisms. Here we show that these compounds, as other weak bases, can elevate pHacr, trigger Ca2+ release from the acrosome, and induce the AR in both mouse and human sperm. To our surprise, μM concentrations of NNC55‐0396 induced AR even in nominally Ca2+ free media. Our findings suggest that alkalization of the acrosome is critical step for Ca2+ release from the acrosome that leads to the acrosome reaction.
We show evidence that an elevation of acrosomal pH triggers Ca2+ release from the acrosome and induce the acrosomal reaction in both, mouse and human spermatozoa.
Abstract Disease overview Epstein Barr virus‐positive (EBV+) diffuse large B‐cell lymphoma (DLBCL), not otherwise specified (NOS) is an aggressive B‐cell lymphoma associated with EBV infection ...included in the WHO classification of lymphoid neoplasms since 2016. Although historically associated to poor prognosis, outcomes seem to have improved in the era of chemoimmunotherapy. Diagnosis The diagnosis is established through meticulous pathological evaluation. Detection of EBV‐encoded RNA (EBER) is the standard diagnostic method. The ICC 2022 specifies EBV+ DLBCL, NOS as occurring when >80% of malignant cells express EBER, whereas the WHO‐HAEM5 emphasizes that the majority of tumor cells should be EBER positive without setting a defined threshold. The differential diagnosis includes plasmablastic lymphoma, DLBCL associated with chronic inflammation, primary effusion lymphoma, among others. Risk‐stratification The International Prognostic Index (IPI) and the Oyama score can be used for risk‐stratification. The Oyama score includes age >70 years and presence of B symptoms. The expression of CD30 and PD‐1/PD‐L1 are emerging as potential adverse but targetable biomarkers. Management Patients with EBV+ DLBCL, NOS, should be staged and managed following similar guidelines than patients with EBV‐negative DLBCL. EBV+ DLBCL, NOS, however, might have a worse prognosis than EBV‐negative DLBCL in the era of chemoimmunotherapy. Therefore, inclusion of patients in clinical trials when available is recommended. There is an opportunity to study and develop targeted therapy in the management of patients with EBV+ DLBCL, NOS.
Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated remarkable anti-tumor activity in B-cell malignancies and is under investigation in other hematologic malignancies and solid ...tumors. While highly efficacious, post-infusion T cell activity often results in massive cytokine release precipitating cytokine release syndrome (CRS), the signature toxicity of CAR T cells. This toxicity is characterized by systemic immune activation resulting in fever, hypotension, respiratory insufficiency and capillary leak. Either in conjunction with or in the absence of CRS, a subset of patients may also develop mild to severe neurotoxicity. Although the precise pathogenesis of CRS and neurotoxicity aren't fully elucidated, risk factors and mitigation strategies have been reported. Areas covered: This manuscript provides an in-depth overview of the pathogenesis, clinical characteristics, current toxicity management strategies, and future perspectives pertaining to CRS and neurotoxicity. Expert Opinion: As CAR T cell based therapies gain popularity in the management of various malignancies, the complimentary toxicities of CRS and neurotoxicity pose a clinical challenge in practice. Risk adaptive modeling incorporating disease profile, patient demographics, lymphodepletion, cell dosing, CAR T construct, and potentially cytokine gene polymorphisms may be instructive to assess individualized risk and optimal CRS/neurotoxicity management.
In this issue of Blood, Jain et al reported on the poor outcomes of patients with chronic lymphocytic leukemia (CLL) after the discontinuation of ibrutinib.
Adoptive T-cell immunotherapy is a rapidly growing field and is shifting the paradigm of clinical cancer treatment. Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor T-cell ...therapy that was initially developed at the National Cancer Institute and has recently been commercially approved by the US Food and Drug Administration for relapsed or refractory aggressive non-Hodgkin's lymphomas including diffuse large B-cell lymphoma and its variants. The ZUMA-1 Phase I and II clinical trials formed the basis of the US Food and Drug Administration approval of this product, and we discuss the particulars of the clinical trials and the pharmacology of axi-cel. In addition, we review the CD19 chimeric antigen receptor T-specific toxicities of cytokine release syndrome and neurotoxicity, which remain the challenges to the safe delivery of this important therapy for aggressive B-cell lymphomas with poor prognosis.
PDF
