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First-in-human phase I/Ib open-label dose-escalation study of GWN323 (anti-GITR) as a single agent and in combination with spartalizumab (anti-PD-1) in patients with advanced solid tumors and lymphomas.
Piha-Paul, SA, Geva, R, Tan, TJ, Lim, DW, Hierro, C, Doi, T, Rahma, O, Lesokhin, A, Luke, JJ, Otero, J, et al
Journal for immunotherapy of cancer. 2021;(8)
Abstract
BACKGROUND GWN323 is an IgG1 monoclonal antibody (mAb) against the glucocorticoid-induced tumor necrosis factor receptor-related protein. This first-in-human, open-label phase I/Ib study aimed to investigate the safety and tolerability and to identify the recommended doses of GWN323 with/without spartalizumab, an anti-programmed cell death receptor-1 agent, for future studies. Pharmacokinetics, preliminary efficacy and efficacy biomarkers were also assessed. METHODS Patients (aged ≥18 years) with advanced/metastatic solid tumors with Eastern Cooperative Oncology Group performance status of ≤2 were included. GWN323 (10-1500 mg) or GWN323+spartalizumab (GWN323 10-750 mg+spartalizumab 100-300 mg) were administered intravenously at various dose levels and schedules during the dose-escalation phase. Dose-limiting toxicities (DLTs) were assessed during the first 21 days in a single-agent arm and 42 days in a combination arm. Adverse events (AEs) were graded per National Cancer Institute-Common Toxicity Criteria for Adverse Events V.4.03 and efficacy was assessed using Response Evaluation Criteria in Solid Tumors V.1.1. RESULTS Overall, 92 patients (single-agent, n=39; combination, n=53) were included. The maximum administered doses (MADs) in the single-agent and combination arms were GWN323 1500 mg every 3 weeks (q3w) and GWN323 750 mg+spartalizumab 300 mg q3w, respectively. No DLTs were observed with single-agent treatment. Three DLTs (6%, all grade ≥3) were noted with combination treatment: blood creatine phosphokinase increase, respiratory failure and small intestinal obstruction. Serious AEs were reported in 30.8% and 34.0%, and drug-related AEs were reported in 82.1% and 77.4% of patients with single-agent and combination treatments, respectively. Disease was stable in 7 patients and progressed in 26 patients with single-agent treatment. In combination arm patients, 1 had complete response (endometrial cancer); 3, partial response (rectal cancer, adenocarcinoma of colon and melanoma); 14, stable disease; and 27, disease progression. GWN323 exhibited a pharmacokinetic profile typical of mAbs with a dose-dependent increase in the pharmacokinetic exposure. Inconsistent decreases in regulatory T cells and increases in CD8+ T cells were observed in the combination arm. Gene expression analyses showed no significant effect of GWN323 on interferon-γ or natural killer-cell signatures. CONCLUSIONS GWN323, as a single agent and in combination, was well tolerated in patients with relapsed/refractory solid tumors. The MAD was 1500 mg q3w for single-agent and GWN323 750 mg+spartalizumab 300 mg q3w for combination treatments. Minimal single-agent activity and modest clinical benefit were observed with the spartalizumab combination. TRIAL REGISTRATION NUMBER NCT02740270.
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Rehabilitation in patients with lymphoma: An overview of Systematic Reviews.
Amatya, B, Khan, F, Lew, TE, Dickinson, M
Journal of rehabilitation medicine. 2021;(3):jrm00163
Abstract
OBJECTIVE To evaluate existing evidence from published systematic reviews for the effectiveness of rehabilitation interventions in patients with lymphoma. DATA SOURCES A comprehensive literature search was conducted using medical/health science databases up to 1 October 2020. Bibliographies of pertinent articles, journals and grey literature were searched. DATA EXTRACTION AND SYNTHESIS Two reviewers independently selected and reviewed potential reviews for methodological quality and graded the quality of evidence for outcomes using validated tools. Any discrepancies were resolved by final group consensus. RESULTS Twelve systematic reviews (n = 101 studies, 87,132 patients with lymphoma) evaluated 3 broad categories of rehabilitation interventions (physical modalities, nutrition and complementary medicine). Most reviews were of moderate-to-low methodological quality. The findings suggest: moderate-quality evidence for exercise programmes for improved fatigue and sleep disturbance; low-quality evidence for exercise therapy alone and qigong/tai chi for improved symptoms and overall quality of life, and an inverse association between sunlight/ultraviolet radiation exposure and incidence of non-Hodgkin's lymphoma; and very low-quality evidence for beneficial effects of yoga for sleep disturbances. Association between physical activity and lymphoma risk is indistinct. CONCLUSION Despite a range of rehabilitation modalities used for patients with lymphoma, high-quality evidence for many is sparse. Beneficial effects of exercise programmes were noted for fatigue, psychological symptoms and quality of life. More research with robust study design is required to determine the effective rehabilitation approaches.
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Urine volume to hydration volume ratio is associated with pharmacokinetics of high-dose methotrexate in patients with primary central nervous system lymphoma.
Isono, T, Hira, D, Morikochi, A, Fukami, T, Ueshima, S, Nozaki, K, Terada, T, Morita, SY
Pharmacology research & perspectives. 2021;(6):e00883
Abstract
High-dose methotrexate (HD-MTX)-based chemotherapy is the first-line treatment for primary central nervous system lymphoma (PCNSL), but is associated with severe adverse effects, including myelosuppression and renal impairment. MTX is primarily excreted by the kidneys. Renal function calculated using serum creatinine (Scr) derived from muscle may be overestimated in elderly PCNSL patients. Therefore, we aimed to construct a population pharmacokinetic model in PCNSL patients and explore the factors associated with MTX clearance. Sixteen PCNSL patients (median age, 66 years) treated with HD-MTX were included, and serum MTX concentrations were measured at 193 points in 49 courses. A population pharmacokinetic analysis was performed using NONMEM. A Monte Carlo simulation was conducted, in which serum MTX concentrations were stratified into three groups of creatine clearance (Ccr) (50, 75, and 100 ml/min) with three groups of the urine volume to hydration volume (UV/HV) ratio (<1, 1-2, and >2). The final model was constructed as follows: MTX clearance = 4.90·(Ccr/94.5)0.456 ·(UV/HV)0.458 . In the Monte Carlo simulation, serum MTX concentrations were below the standard values (10, 1, and 0.1 µM at 24, 48, and 72 h, respectively, after the start of the MTX administration) in most patients with UV/HV >2, even with Ccr of 50 ml/min. Conversely, half of the patients with UV/HV <1 and Ccr of 50 ml/min failed to achieve the standard values. The present results demonstrated that the UV/HV ratio was useful for describing the pharmacokinetics of MTX in PCNSL patients.
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Romidepsin and lenalidomide-based regimens have efficacy in relapsed/refractory lymphoma: Combined analysis of two phase I studies with expansion cohorts.
Mehta-Shah, N, Lunning, MA, Moskowitz, AJ, Boruchov, AM, Ruan, J, Lynch, P, Hamlin, PA, Leonard, J, Matasar, MJ, Myskowski, PL, et al
American journal of hematology. 2021;(10):1211-1222
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Abstract
Romidepsin (histone deacetylase inhibitor), lenalidomide (immunomodulatory agent), and carfilzomib (proteasome inhibitor), have efficacy and lack cumulative toxicity in relapsed/refractory lymphoma. We performed two investigator initiated sequential phase I studies to evaluate the maximum tolerated dose (MTD) of romidepsin and lenalidomide (regimen A) and romidepsin, lenalidomide, and carfilzomib (regimen B) in relapsed/refractory lymphoma. Cohorts in T-cell lymphoma (TCL), B-cell lymphoma (BCL) were enrolled at the MTD. Forty-nine patients were treated in study A (27 TCL, 17 BCL, 5 Hodgkin lymphoma (HL)) and 27 (16 TCL, 11 BCL) in study B. The MTD of regimen A was romidepsin 14 mg/m2 IV on days 1, 8, and 15 and lenalidomide 25 mg oral on days 1-21 of a 28-day cycle. The MTD of regimen B was romidepsin 8 mg/m2 on days 1 and 8, lenalidomide 10 mg oral on days 1-14 and carfilzomib 36 mg/m2 IV on days 1 and 8 of a 21-day cycle. In study A, 94% had AEs ≥Grade 3, most commonly neutropenia (49%), thrombocytopenia (53%), and electrolyte abnormalities (49%). In study B 59% had AEs ≥Grade 3, including thrombocytopenia (30%) and neutropenia (26%). In study A the ORR was 49% (50% TCL, 47% BCL, 50% HL). In study B the ORR was 48% (50% TCL, 50% BCL). For study A and B the median progression free survival (PFS) was 5.7 months and 3.4 months respectively with 11 patients proceeding to allogeneic transplant. The combinations of romidepsin and lenalidomide and of romidepsin, lenalidomide and carfilzomib showed activity in relapsed/refractory lymphoma with an acceptable safety profile.
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Characteristics of Lymphoma in Patients with Inflammatory Bowel Disease: A Systematic Review.
Muller, M, Broséus, J, Feugier, P, Thieblemont, C, Beaugerie, L, Danese, S, Arnone, D, Ndiaye, NC, Kokten, T, Houlgatte, R, et al
Journal of Crohn's & colitis. 2021;(5):827-839
Abstract
BACKGROUND Lymphoma is a dreaded complication of inflammatory bowel diseases [IBD]. Knowledge about lymphoma in patients with IBD is limited to epidemiological data and the description of risk factors. We performed a systematic review to describe the clinical characteristics and prognosis of lymphoma in patients with IBD. METHODS Electronic databases were searched up to June 1, 2020. All published clinical characteristics of lymphoma occurring in patients with IBD were collected. RESULTS Eleven studies were included. A total of 589 lymphomas were described in patients with IBD. As seen in de novo lymphoma, non-Hodgkin's lymphoma [NHL] was the most common histological subtype [83.9%]. Diffuse large B-cell lymphoma [DLBCL] and follicular lymphoma were the most well-represented NHL in patients with IBD [30% and 13% respectively]. Two main differences were observed in comparison with de novo lymphoma: primary intestinal lymphoma [PIL] represented a large proportion of lymphoma in patients with IBD [22-75%] whereas mucosa-associated lymphoid tissue [MALT] lymphoma was under-represented. Epstein-Barr virus [EBV]-positive status was observed in a large proportion of tumours [44-75%]. Survival data of lymphoma in patients with IBD were similar to those of de novo lymphoma. DISCUSSION This systematic review first highlights that PIL [especially DLBCL subtype] is significantly more frequent in patients with IBD and represents the most common entity. Conversely, MALT lymphoma is extremely rare in the IBD population. However, the overall quality of the evidence is low. Further studies are required to better define lymphoma characteristics in patients with IBD.
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Incidence of chemotherapy-induced peripheral neuropathy within 12 weeks of starting neurotoxic chemotherapy for multiple myeloma or lymphoma: a prospective, single-center, observational study.
Ajewole, VB, Cox, JE, Swan, JT, Chikermane, SG, Lamoth, B, Iso, T, Okolo, LO, Ford, CL, Schneider, AM, Hobaugh, EC, et al
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2020;(4):1901-1912
Abstract
PURPOSE Chemotherapy-induced peripheral neuropathy (CIPN) may necessitate chemotherapy dose reduction, delay, or discontinuation. This pilot study tested feasibility of patient enrollment, CIPN screening, and data collection in cancer patients for a future clinical study that will assess the safety and efficacy of an intervention that may prevent CIPN. METHODS This prospective, observational, single-center, pilot study included adults with newly diagnosed lymphoma or multiple myeloma receiving neurotoxic chemotherapy. Patients were enrolled between September 2016 and February 2017. The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire was completed by patients at 3 time points: baseline, week 6, and week 12. The primary outcome was change in the neurotoxicity score between these time points. RESULTS Of 33 patients approached for consent, 28 (85%) provided consent and were enrolled. The FACT/GOG-Ntx questionnaire was completed by 28 (100%) at baseline, 25 (89%) at week 6, and 24 (86%) at week 12. Average (standard deviation) neurotoxicity scores were 36.5 (6.6) at baseline, 34.0 (8.3) at week 6, and 30.6 (7.6) at week 12. Neurotoxicity scores changed from baseline by - 2.7 points (95% CI - 5.5 to 0.1; p = 0.061) at week 6 and - 6.0 points (95% CI - 5.6 to - 0.8; p = 0.012) at week 12. Clinically meaningful declines (decrease of > 10% from baseline) in neurotoxicity score were detected in 36% (9 of 25) at week 6 and in 67% (16 of 24) at week 12. CONCLUSION Sixty-seven percent of patients experienced clinically significant CIPN within 12 weeks of starting chemotherapy. Feasibility metrics for enrollment, consent, CIPN assessment, and follow-up were met.
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Primary Central Nervous System Lymphoma: Diagnostic Yield of Whole-Body CT and FDG PET/CT for Initial Systemic Imaging.
Suh, CH, Kim, HS, Park, JE, Jung, SC, Choi, CG, Kim, SJ
Radiology. 2019;(2):440-446
Abstract
Background Updated guidelines for suspected primary central nervous system lymphoma (PCNSL) are lacking. Purpose To investigate the diagnostic yield of initial systemic imaging in patients suspected of having PCNSL by using contrast material-enhanced chest and abdominopelvic CT and/or whole-body fluorine 18 fluorodeoxyglucose (FDG) PET/CT. Materials and Methods This retrospective study included 304 patients examined at a single tertiary hospital between January 1998 and October 2018. Consecutive adults (age >18 years) who were confirmed to have newly diagnosed PCNSL on the basis of findings at stereotactic brain biopsy were recruited. All patients were examined with contrast-enhanced chest and abdominopelvic CT and/or whole-body FDG PET/CT before initiation of PCNSL treatment. The diagnostic yield of CT and PET/CT was determined before therapy and at the time of recurrence in the brain. A χ2 test was performed to compare the diagnostic yield according to study date in order to assess for possible changes in technology during the study period. Results A total of 304 patients (180 men with a mean age [±standard deviation] of 58 years ± 13 and 124 women with a mean age of 59 years ± 13) were included. The diagnostic yield of CT and PET/CT for initial staging was 2% (six of 304 patients; 95% confidence interval [CI]: 0.7%, 4.3%), and these tests yielded false-positive findings in 13 of the 304 patients (4%; 95% CI: 2.3%, 7.2%). Diagnostic yield did not differ between patients evaluated before 2009 and those evaluated in 2009 and later (P = .82). The diagnostic yield of systemic imaging at recurrence was 1.5% (one of 68 patients; 95% CI: 0.0%, 7.9%), and these tests yielded false-positive findings in four of those 68 patients (6%; 95% CI: 1.6%, 14.4%). Conclusion Contrast-enhanced chest and abdominopelvic CT and/or whole-body fluorine 18 fluorodeoxyglucose PET/CT for initial staging, as well as for recurrence of suspected primary central nervous system lymphoma, had a low diagnostic yield. © RSNA, 2019 See also the editorial by Jara in this issue.
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Protocol for a randomised controlled trial to study cryoprevention of chemotherapy-induced oral mucositis after autologous stem cell transplantation.
Walladbegi, J, Svanberg, A, Gellerstedt, M
BMJ open. 2018;(10):e021993
Abstract
INTRODUCTION A majority of patients who receive myeloablative therapy prior to hematopoetic stem cell transplantation develop oral mucositis (OM). This adverse cytotoxic effect manifests as oral mucosal erythema and ulcerations and frequently necessitates high doses of morphine for pain alleviation. OM may also interfere with food intake and result in parenteral nutrition, weight loss and impaired quality of life. To date, there have been a few studies of evidence-based interventions for prevention of OM. Cooling the oral mucosa using ice chips in conjunction with chemotherapy is known to reduce the severity of OM although clinical application is still limited due to several disadvantages. The primary endpoint of this study is therefore to evaluate the efficacy of an innovative intraoral cooling device (Cooral) compared with ice cooling in reducing the degree of OM, in patients with myeloma or lymphoma. METHOD AND ANALYSIS A total of 180 patients from four different university hospitals in Sweden will be randomised to ice or Cooral in a proportion of 1:1. The degree of OM will be assessed at eight intraoral locations, in accordance with the Oral Mucositis Assessment Scale and WHO scale. Patients will be registered beginning at admission and will continue until discharge or until day +28. The primary variable is analysed in a multiple linear regression model. The significance level used is 5%. ETHICS AND DISSEMINATION The study protocol, questionnaire, diaries and letter of invitation to participants have been reviewed by the local ethical board in Göteborg. The trial results will be published in a peer-reviewed journal and disseminated to participants. TRIAL REGISTRATION NUMBER NCT03203733; Pre-results. PROTOCOL VERSION Version 4, 2017-06-05.
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Cellular and Molecular Targets of Resveratrol on Lymphoma and Leukemia Cells.
Frazzi, R, Guardi, M
Molecules (Basel, Switzerland). 2017;(6)
Abstract
Resveratrol (RSV) is a well known chemopreventive molecule featuring anti-cancer properties. Our paper describes the main molecular targets of RSV linked to its antiproliferative activity on lymphoma and leukemia experimental models. It discusses further the most recent and most promising among these molecular targets for a translational application.
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Neurologic Manifestations of Blood Dyscrasias.
Couriel, DR, Ricker, H, Steinbach, M, Lee, CJ
Hematology/oncology clinics of North America. 2016;(4):723-31
Abstract
Neurologic manifestations are common in blood diseases, and they can be caused by the hematologic disorder or its treatment. This article discusses hematologic diseases in adult patients, and categorizes them into benign and malignant conditions. The more common benign hematologic diseases associated with neurologic manifestations include anemias, particularly caused by B12 deficiency and sickle cell disease, and a variety of disorders of hemostasis causing bleeding or thrombosis, including thrombotic microangiopathy. Malignant conditions like multiple myeloma, leukemias, and lymphomas can have neurologic complications resulting from direct involvement, or caused by the different therapies to treat these cancers.