Brentuximab vedotin, an antibody-drug conjugate (ADC), selectively delivers the microtubule-disrupting agent monomethyl auristatin E (MMAE) into CD30-expressing cells. The pharmacokinetics of brentuximab vedotin have been characterized in patients with CD30-positive haematologic malignancies. The primary objective of this phase 1 open label evaluation was to assess the pharmacokinetics of brentuximab vedotin in patients with hepatic or renal impairment.

Recent randomized trials have demonstrated the efficacy of ibrutinib-based therapy in the treatment of patients with CLL. In Alliance A041202, a higher than expected number of unexplained deaths were reported with front-line ibrutinib in a patient population aged at least 65 years compared to ECOG 1912, which included patients up to 70 years of age.

Early detection of ovarian cancer remains a challenge due to widespread metastases and a lack of biomarkers for early-stage disease. This study was conducted to identify relevant biomarkers for both laparoscopic and serum diagnostics in ovarian cancer.

Isolation and amplification of primary lymphoma cells in vitro setting is technically and biologically challenging task. To optimize culture environment and mimic in vivo conditions, lymphoma cell lines were used as a test case and were grown in 3-dimension (3D) using a novel 3D tissue culture polystyrene scaffold with neonatal stromal cells to represent a lymphoma microenvironment. In this model, the cell proliferation was enhanced more than 200-fold or 20,000% neoplastic surplus in 7 days when less than 1% lymphoma cells were cocultured with 100-fold excess of neonatal stroma cells, representing 3.2-fold higher proliferative rate than 2D coculture model. The lymphoma cells grew and aggregated to form clusters during 3D coculture and did not maintained the parental phenotype to grow in single-cell suspension. The cluster size was over 5-fold bigger in the 3D coculture by day 4 than 2D coculture system and contained less than 0.00001% of neonatal fibroblast trace. This preliminary data indicate that novel 3D scaffold geometry and coculturing environment can be customized to amplify primary cancer cells from blood or tissues related to hematological cancer and subsequently used for personalized drug screening procedures.

Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off-label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10-14 day treatment course, acalabrutinib improved oxygenation in a majority of patients, often within 1-3 days, and had no discernable toxicity. Measures of inflammation - C-reactive protein and IL-6 - normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4/8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2/8 (25%) discharged on room air. Ex vivo analysis revealed significantly elevated BTK activity, as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. These results suggest that targeting excessive host inflammation with a BTK inhibitor is a therapeutic strategy in severe COVID-19 and has led to a confirmatory international prospective randomized controlled clinical trial.

Relapsed/refractory primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) are associated with short survival and represent an unmet need, requiring novel effective strategies. Anti-CD19 chimeric antigen receptor (CAR) T cells, effective in systemic large B-cell lymphoma (LBCL), have shown responses in PCNSL and SCNSL in early reports, but with limited sample size. We, therefore, performed a comprehensive systematic review and meta-analysis of all published data describing CAR T-cell use in PCNSL and SCNSL. This identified 128 patients with PCNSL (30) and SCNSL (98). Our primary objectives were to evaluate CAR T-cell specific toxicity (immune effector cell-associated neurotoxicity syndrome [ICANS] and cytokine release syndrome [CRS]) as well as response rates in these 2 populations. Seventy percent of patients with PCNSL had CRS of any grade (13% grade 3-4) and 53% had ICANS of any grade (18% grade 3-4). Comparatively, 72% of the SCNSL cohort experienced CRS of any grade (11% grade 3-4) and 48% had ICANS of any grade (26% grade 3-4). Of the patients with PCNSL, 56% achieved a complete remission (CR) with 37% remaining in remission at 6 months. Similarly, 47% of patients with SCNSL had a CR, with 37% in remission at 6 months. In a large meta-analysis of central nervous system (CNS) lymphomas, toxicity of anti-CD19-CAR T-cell therapy was similar to that of registrational studies in systemic LBCL with no increased signal of neurotoxicity observed. Encouraging efficacy was demonstrated in patients with CNS lymphoma with no discernible differences between PCNSL and SCNSL.

Here, we report on a phase IIa study to determine the intubation rate, survival, viral clearance, and development of endogenous Abs in patients with COVID-19 pneumonia treated with convalescent plasma (CCP) containing high levels of neutralizing anti-SARS-CoV-2 Abs. Radiographic and laboratory evaluation confirmed all 51 treated patients had COVID-19 pneumonia. Fresh or frozen CCP from donors with high titers of neutralizing Abs was administered. The nonmechanically ventilated patients (n = 36) had an intubation rate of 13.9% and a 30-day survival rate of 88.9%, and the overall survival rate for a comparative group based on network data was 72.5% (1625/2241). Patients had negative nasopharyngeal swab rates of 43.8% and 73.0% on days 10 and 30, respectively. Patients mechanically ventilated had a day-30 mortality rate of 46.7%; the mortality rate for a comparative group based on network data was 71.0% (369/520). All evaluable patients were found to have neutralizing Abs on day 3 (n = 47), and all but 1 patient had Abs on days 30 and 60. The only adverse event was a mild rash. In this study on patients with COVID-19 disease, we show therapeutic use of CCP was safe and conferred transfer of Abs, while preserving endogenous immune response.

The aim of this study was to determine the apoptotic effects, toxicity, and radiosensitization of total low dose irradiation delivered at a high dose rate in vitro to melanoma cells, normal human epidermal melanocytes (HEM), or normal human dermal fibroblasts (HDF) and to study the effect of mitochondrial inhibition in combination with radiation to enhance apoptosis in melanoma cells. Cells irradiated using 10X flattening filter-free (FFF) 10 MV X-rays at a dose rate of 400 or 2400 MU/min and a total dose of 0.25-8 Gy were analyzed by cell/colony counting, MitoTracker, MTT, and DNA-damage assays, as well as by quantitative real-time reverse transcriptase PCR in the presence or absence of mitochondrial respiration inhibitors. A dose rate of 2400 MU/min killed on average five-fold more melanoma cells than a dose rate 400 MU/min at a total dose of 0.5 Gy and preserved 80% survival of HEM and 90% survival of HDF. Increased apoptosis at the 2400 MU/min dose rate is mediated by greater DNA damage, reduced cell proliferation, upregulation of apoptotic genes, and downregulation of cell cycle genes. HEM and HDF were relatively unharmed at 2400 MU/min. Radiation induced upregulation of mitochondrial respiration in both normal and cancer cells, and blocking the respiration with inhibitors enhanced apoptosis only in melanoma cells. A high dose rate with a low total dose (2400 MU/min, 0.5 Gy/10X FFF 10 MV X-rays) enhances radiosensitivity of melanoma cells while reducing radiotoxicity toward HEM and HDF. Selective cytotoxicity of melanoma cells is increased by blocking mitochondrial respiration.

The observational MCL-004 study evaluated outcomes in patients with relapsed/refractory mantle cell lymphoma who received lenalidomide-based therapy after ibrutinib failure or intolerance.

Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) is associated with a poor prognosis. Outcomes are particularly poor following immunochemotherapy failure or relapse within 12 months of induction. We conducted a Phase I/II trial of lenalidomide plus RICE (rituximab, ifosfamide, carboplatin, and etoposide) (RICER) as a salvage regimen for first-relapse or primary refractory DLBCL. Dose-escalated lenalidomide was combined with RICE every 14 d. After three cycles of RICER, patients with chemosensitive disease underwent stem cell collection and consolidation with BEAM [BCNU (carmustine), etoposide, cytarabine, melphalan] followed by autologous stem cell transplantation (autoSCT). Patients who recovered from autoSCT toxicities within 90 d initiated maintenance treatment with lenalidomide 25 mg daily for 21 d every 28 d for 12 months. No dose-limiting or unexpected toxicities occurred with lenalidomide 25 mg plus RICE. Grade 3/4 haematological toxicities resolved appropriately, and planned dose density and dose intensity of RICER were preserved. No lenalidomide or RICE dose reductions were required in any of the three cycles. After two cycles of RICER, nine of 15 patients (60%) achieved a complete response, and two achieved a partial response (13%). Combining lenalidomide with RICE is feasible, and results in promising response rates (particularly complete response rates) in high-risk DLBCL patients.

High risk, unfavorable classical Hodgkin lymphoma (cHL) includes those patients with primary refractory or early relapse, and progressive disease. To improve the availability of biomarkers for this group of patients, we investigated both tumor biopsies and peripheral blood leukocytes (PBL) of untreated (chemo-naïve, CN) Nodular Sclerosis Classic Hodgkin Lymphoma (NS-cHL) patients for consistent biomarkers that can predict the outcome prior to frontline treatment.

Multiple studies have demonstrated that diffuse large B-cell lymphoma (DLBCL) can be divided into subgroups based on their biology; however, these biological subgroups overlap clinically. Using machine learning, we developed an approach to stratify patients with DLBCL into four subgroups based on survival characteristics. This approach uses data from the targeted transcriptome to predict these survival subgroups. Using the expression levels of 180 genes, our model reliably predicted the four survival subgroups and was validated using independent groups of patients. Multivariate analysis showed that this patient stratification strategy encompasses various biological characteristics of DLBCL, and only TP53 mutations remained an independent prognostic biomarker. This novel approach for stratifying patients with DLBCL, based on the clinical outcome of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone therapy, can be used to identify patients who may not respond well to these types of therapy, but would otherwise benefit from alternative therapy and clinical trials.

Despite advances in the development of clinical agents for treating Mantle Cell Lymphoma (MCL), treatment of MCL remains a challenge due to complexity and frequent relapse associated with MCL. The incorporation of conventional and novel diagnostic approaches such as genomic sequencing have helped improve understanding of the pathogenesis of MCL, and have led to development of specific agents targeting signaling pathways that have recently been shown to be involved in MCL. In this review, we first provide a general overview of MCL and then discuss about the role of biomarkers in the pathogenesis, diagnosis, prognosis, and treatment for MCL. We attempt to discuss major biomarkers for MCL and highlight published and ongoing clinical trials in an effort to evaluate the dominant signaling pathways as drugable targets for treating MCL so as to determine the potential combination of drugs for both untreated and relapse/refractory cases. Our analysis indicates that incorporation of biomarkers is crucial for patient stratification and improve diagnosis and predictability of disease outcome thus help us in designing future precision therapies. The evidence indicates that a combination of conventional chemotherapeutic agents and novel drugs designed to target specific dysregulated signaling pathways can provide the effective therapeutic options for both untreated and relapse/refractory MCL.

Ovarian cancer (OVC) is the deadliest of all gynecologic cancers, primarily as a consequence of asymptomatic progression. The complex nature of OVC creates challenges for early detection, and there is a lack of specific and sensitive biomarkers suitable for screening and detecting early stage OVC.

Clinical trials that led to ibrutinib's approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58 versus 61 years, P=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85 versus 87 months, P=0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure.

Mapping of allele-specific DNA methylation (ASM) can be a post-GWAS strategy for localizing regulatory sequence polymorphisms (rSNPs). The advantages of this approach, and the mechanisms underlying ASM in normal and neoplastic cells, remain to be clarified.

This phase 1b/2, multicenter, open-label study evaluated ibrutinib plus durvalumab in relapsed/refractory follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL). Patients were treated with once-daily ibrutinib 560 mg plus durvalumab 10 mg/kg every 2 weeks in 28-day cycles in phase 1b without dose-limiting toxicities, confirming the phase 2 dosing. Sixty-one patients with FL (n = 27), germinal center B-cell (GCB) DLBCL (n = 16), non-GCB DLBCL (n = 16), and unspecified DLBCL (n = 2) were treated. Overall response rate (ORR) was 25% in all patients, 26% in patients with FL, 13% in patients with GCB DLBCL, and 38% in patients with non-GCB DLBCL. Overall, median progression-free survival was 4.6 months and median overall survival was 18.1 months; both were longer in patients with FL than in patients with DLBCL. The most frequent treatment-emergent adverse events (AEs) in patients with FL and DLBCL, respectively, were diarrhea (16 [59%]; 16 [47%]), fatigue (12 [44%]; 16 [47%]), nausea (9 [33%]; 12 [35%]), peripheral edema (7 [26%]; 13 [38%]), decreased appetite (8 [30%]; 11 [32%]), neutropenia (6 [22%]; 11 [32%]), and vomiting (5 [19%]; 12 [35%]). Investigator-defined immune-related AEs were reported in 12/61 (20%) patients. Correlative analyses were conducted but did not identify any conclusive biomarkers of response. In FL, GCB DLBCL, and non-GCB DLBCL, ibrutinib plus durvalumab demonstrated similar activity to single-agent ibrutinib with the added toxicity of the PD-L1 blockade; the combination resulted in a safety profile generally consistent with those known for each individual agent.

Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated IGHV, 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients, the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study.