Ixazomib, daratumumab and low-dose dexamethasone in intermediate-fit patients with newly diagnosed multiple myeloma: an open-label phase 2 trial.

Background: The outcome of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients is heterogeneous, partly depending on frailty level. The aim of this study was to prospectively investigate the efficacy and safety of Ixazomib-Daratumumab-low-dose dexamethasone (Ixa-Dara-dex) in NDMM intermediate-fit patients. Methods: In this phase II multicenter HOVON-143 study, IMWG Frailty index based intermediate-fit patients, were treated with 9 induction cycles of Ixa-Dara-dex, followed by maintenance with ID for a maximum of 2 years. The primary endpoint was overall response rate on induction treatment. Patients were included from October 2017 until May 2019. Trial Registration Number: NTR6297. Findings: Sixty-five patients were included. Induction therapy resulted in an overall response rate of 71%. Early mortality was 1.5%. At a median follow-up of 41.0 months, median progression-free survival (PFS) was 18.2 months and 3-year overall survival 83%. Discontinuation of therapy occurred in 77% of patients, 49% due to progression, 9% due to toxicity, 8% due to incompliance, 3% due to sudden death and 8% due to other reasons. Dose modifications of ixazomib were required frequently (37% and 53% of patients during induction and maintenance, respectively), mainly due to, often low grade, polyneuropathy. During maintenance 23% of patients received daratumumab alone. Global quality of life (QoL) improved significantly and was clinically relevant, which persisted during maintenance treatment. Interpretation: Ixazomib-Daratumumab-low-dose dexamethasone as first line treatment in intermediate-fit NDMM patients is safe and improves global QoL. However, efficacy was limited, partly explained by ixazomib-induced toxicity, hampering long term tolerability of this 3-drug regimen. This highlights the need for more efficacious and tolerable regimens improving the outcome in vulnerable intermediate-fit patients. Funding: Janssen Pharmaceuticals, Takeda Pharmaceutical Company Limited.

Effects of potent neutralizing antibodies from convalescent plasma in patients hospitalized for severe SARS-CoV-2 infection.

In a randomized clinical trial of 86 hospitalized COVID-19 patients comparing standard care to treatment with 300mL convalescent plasma containing high titers of neutralizing SARS-CoV-2 antibodies, no overall clinical benefit was observed. Using a comprehensive translational approach, we unravel the virological and immunological responses following treatment to disentangle which COVID-19 patients may benefit and should be the focus of future studies. Convalescent plasma is safe, does not improve survival, has no effect on the disease course, nor does plasma enhance viral clearance in the respiratory tract, influence SARS-CoV-2 antibody development or serum proinflammatory cytokines levels. Here, we show that the vast majority of patients already had potent neutralizing SARS-CoV-2 antibodies at hospital admission and with comparable titers to carefully selected plasma donors. This resulted in the decision to terminate the trial prematurely. Treatment with convalescent plasma should be studied early in the disease course or at least preceding autologous humoral response development.

Ixazomib, Daratumumab, and Low-Dose Dexamethasone in Frail Patients With Newly Diagnosed Multiple Myeloma: The Hovon 143 Study.

PURPOSE: Frail patients with newly diagnosed multiple myeloma have an inferior outcome, mainly because of a high discontinuation rate due to toxicity. We designed a phase II trial specifically for frail patients, evaluating the efficacy and tolerability of ixazomib-daratumumab-low-dose-dexamethasone (Ixa-Dara-dex). METHODS: Sixty-five patients, who were frail according to the International Myeloma Working Group frailty index, were treated with nine induction cycles Ixa-Dara-dex followed by maintenance with Ixa-Dara for a maximum of 2 years. RESULTS: The overall response rate on induction therapy was 78%. After a median follow-up of 22.9 months, median progression-free survival (PFS) was 13.8 months and 12-month overall survival (OS) was 78%. Median PFS and 12-month OS were 21.6 months and 92% in patients who were frail based on age > 80 years alone, versus 13.8 months and 78%, and 10.1 months and 70% in patients who were frail based on additional frailty parameters either ≤ 80 or > 80 years of age, respectively. In 51% of patients, induction therapy had to be discontinued prematurely, of which 6% because of noncompliance to study treatment, 9% because of toxicity, and 9% because of death (8% within 2 months, of which 80% because of toxicity). Quality of life improved during induction treatment, being clinically meaningful already after three induction cycles. CONCLUSION: Ixa-Dara-dex lead to a high response rate and improved quality of life. However, treatment discontinuation because of toxicity and early mortality, negatively influencing PFS and OS, remains a concern in frail patients. The outcome was heterogeneous across frail subpopulations. This should be taken into account in the design and interpretation of future studies in frail patients, to pave the way for more precise treatment guidance.

Computed Tomography Observer Agreement in Staging Malignant Lymphoma.

OBJECTIVE: To determine pretreatment computed tomography observer agreement in patients with newly diagnosed lymphoma. METHODS: Forty-nine computed tomography scans were reviewed by 3 experienced radiologists, with each scan assessed twice by 1 observer. Predefined nodal and extranodal regions were assessed, and Ann Arbor stages were assigned. K-statistics were defined as poor (κ < 0.2), fair (κ > 0.2 to κ ≤ 0.4), moderate (κ > 0.4 to κ ≤ 0.6), substantial (κ > 0.6 to κ ≤ 0.8), and almost perfect (κ > 0.8 to κ ≤ 1). RESULTS: Nodal interobserver agreement varied from 0.09 for infraclavicular involvement to 0.95 for para-iliac involvement; intraobserver agreement was substantial to almost perfect, except for infraclavicular nodes. Extranodal interobserver agreement varied from 0.56 to 0.88; intraobserver agreement was substantial to almost perfect. Ann Arbor stage interobserver agreement varied from 0.57 to 0.69; intraobserver agreement was substantial. CONCLUSION: Computed tomography observer agreement in staging malignant lymphoma appears to be suboptimal.

Relationship between pretreatment FDG-PET and diffusion-weighted MRI biomarkers in diffuse large B-cell lymphoma.

The purpose of this study was to determine the correlation between the (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) standardized uptake value (SUV) and the diffusion-weighted magnetic resonance imaging (MRI) apparent diffusion coefficient (ADC) in newly diagnosed diffuse large B-cell lymphoma (DLBCL). Pretreatment FDG-PET and diffusion-weighted MRI of 21 patients with histologically proven DLBCL were prospectively analyzed. In each patient, maximum, mean and peak standardized uptake value (SUV) was measured in the lesion with visually highest FDG uptake and in the largest lesion. Mean ADC (ADCmean, calculated with b-values of 0 and 1000 s/mm(2)) was measured in the same lesions. Correlations between FDG-PET metrics (SUVmax, SUVmean, SUVpeak) and ADCmean were assessed using Pearson's correlation coefficients. In the lesions with visually highest FDG uptake, no significant correlations were found between the SUVmax, SUVmean, SUVpeak and the ADCmean (P=0.498, P=0.609 and P=0.595, respectively). In the largest lesions, there were no significant correlations either between the SUVmax, SUVmean, SUVpeak and the ADCmean (P=0.992, P=0.843 and P=0.894, respectively). The results of this study indicate that the glycolytic rate as measured by FDG-PET and changes in water compartmentalization and water diffusion as measured by the ADC are independent biological phenomena in newly diagnosed DLBCL. Further studies are warranted to assess the complementary roles of these different imaging biomarkers in the evaluation and follow-up of DLBCL.

Whole-body MRI vs. CT for staging lymphoma: patient experience.

OBJECTIVE: To assess and compare patient experience of whole-body magnetic resonance imaging (MRI) to that of computed tomography (CT) for staging newly diagnosed lymphoma. MATERIALS AND METHODS: A total of 36 patients with newly diagnosed lymphoma prospectively underwent whole-body MRI and CT for staging purposes. Patients were asked to fill in a short questionnaire with regard to the burden and experience of the examination on a Likert scale (range 1-4). Wilcoxon signed rank tests were used to determine statistically significant differences in patient (dis)comfort between the two examinations. RESULTS: Patients reported to be significantly (P=0.007) less worried before undergoing whole-body MRI compared to CT. Patients also experienced whole-body MRI as significantly (P=0.010) less unpleasant and felt significantly (P=0.003) better shortly after the scan. The necessary preparations before CT scanning (i.e. insertion of intravenous line, drinking of contrast fluid), which are not required for whole-body MRI, were reported to be a considerable burden. CONCLUSION: In this study in patients with newly diagnosed lymphoma, whole-body MRI was experienced as a more patient-friendly technique than CT.

Whole-body MRI, including diffusion-weighted imaging, for staging lymphoma: comparison with CT in a prospective multicenter study.

PURPOSE: To compare whole-body magnetic resonance imaging (MRI), including diffusion-weighted imaging (DWI), to computed tomography (CT) for staging newly diagnosed lymphoma. MATERIALS AND METHODS: In all, 108 patients with newly diagnosed lymphoma prospectively underwent whole-body MRI (T1-weighted and T2-weighted short inversion time inversion recovery [n = 108], and DWI [n = 104]) and CT. Ann Arbor stages were assigned according to whole-body MRI and CT findings. Staging disagreements were resolved using bone marrow biopsy, FDG-PET, and follow-up studies. The results were descriptively analyzed. RESULTS: Staging results of whole-body MRI without DWI were equal to those of CT in 66.6%, higher in 24.1%, and lower in 9.3%, with correct/incorrect/unresolved higher staging and incorrect/unresolved lower staging relative to CT in 15/7/4 and 9/1 patient(s), respectively. Staging results of whole-body MRI with DWI were equal to those of CT in 65.4%, higher in 27.9%, and lower in 6.7%, with correct/incorrect/unresolved higher staging and incorrect/unresolved lower staging relative to CT in 18/6/5 and 6/1 patient(s), respectively. CONCLUSION: The results of this study suggest that whole-body MRI staging equals CT staging in the majority of patients with newly diagnosed lymphoma. No advantage of additional DWI was demonstrated. Whole-body MRI can be a good alternative to CT if radiation exposure should be avoided.

MRI for staging lymphoma: whole-body or less?

PURPOSE: To assess whether whole-body MRI detects more clinically relevant lesions (i.e., leading to a change in Ann Arbor stage) than an MRI protocol that only includes the head/neck and trunk (i.e., from cranial vertex to groin, excluding the arms) in patients with lymphoma. MATERIALS AND METHODS: One hundred consecutive patients with newly diagnosed lymphoma prospectively underwent T1-weighted and T2-weighted short inversion time inversion recovery whole-body MRI. The number of lymphomatous sites at MRI with a field of view (FOV) limited to the head/neck and trunk, and the additional number of lymphomatous sites at whole-body MRI and their influence on Ann Arbor stage were determined. RESULTS: At MRI with a FOV limited to the head/neck and trunk, 507 sites were classified as lymphomatous. At whole-body MRI, 7 additional sites outside the head/neck and trunk in 7 patients (7.0%; 95% confidence interval: 3.4-13.8%) were classified as lymphomatous, but Ann Arbor stage never changed. CONCLUSION: Whole-body MRI did not detect any clinically relevant lesions outside the FOV of an MRI protocol that only includes the head/neck and trunk. Therefore, it may be sufficient to only include the head/neck and trunk when using MRI for staging lymphoma.

ADC measurements in the evaluation of lymph nodes in patients with non-Hodgkin lymphoma: feasibility study.

OBJECT: To determine whether apparent diffusion coefficient (ADC) measurements allow discrimination of normal lymph nodes from lymphomatous lymph nodes, and indolent lymphomas from aggressive lymphomas in patients with non-Hodgkin lymphoma (NHL). MATERIALS AND METHODS: Eighteen healthy volunteers and thirty-two patients with newly diagnosed NHL (indolent: n = 16; aggressive: n = 16) underwent diffusion-weighted imaging. ADCs of normal lymph nodes were compared to those of lymphomatous lymph nodes, and ADCs of indolent lymphomas were compared to those of aggressive lymphomas. Receiver operating characteristic (ROC) analysis was performed when ADCs were significantly different between two of the aforementioned groups. RESULTS: ADCs (in 10(-3) mm(2)/s) of lymphomatous lymph nodes (0.70 ± 0.22) were significantly lower (P < 0.0001) than those of normal lymph nodes (1.00 ± 0.15). Area under the ROC curve was 0.865. Sensitivity and specificity were 78.1 and 100% when using an optimal cutoff ADC value of 0.80. On the other hand, ADCs of indolent lymphomas (0.67 ± 0.21) were not significantly different (P = 0.2997) from those of aggressive lymphomas (0.74 ± 0.23). CONCLUSION: ADC measurements show promise as a highly specific tool for the discrimination of normal lymph nodes from lymphomatous lymph nodes, but appear to be of no utility in differentiating indolent from aggressive lymphomas.

Whole-body MRI, including diffusion-weighted imaging, for the initial staging of malignant lymphoma: comparison to computed tomography.

PURPOSE: To assess the value of whole-body magnetic resonance imaging (MRI), including diffusion-weighted imaging (DWI), for the initial staging of malignant lymphoma, compared with computed tomography (CT). MATERIALS AND METHODS: Thirty-one consecutive patients with newly diagnosed malignant lymphoma prospectively underwent whole-body MRI (T1-weighted and short inversion time inversion recovery [n = 31], and DWI [n = 28]) and CT. Ann Arbor stages were assigned by 1 radiologist according to whole-body MRI findings, and by another radiologist according to CT findings. Differences in staging between whole-body MRI (without and with DWI) and CT were resolved using other (imaging) studies (including 18F-fluoro-2-deoxyglucose positron emission tomography and bone marrow biopsy) and follow-up studies as reference standard. RESULTS: Staging results of whole-body MRI without DWI were equal to those of CT in 74% (23/31), higher in 26% (8/31), and lower in 0% (0/31) of patients, with correct/incorrect/unresolved overstaging relative to CT in 3, 2, and 2 patients, respectively, and incorrect staging of both modalities in 1 patient. Staging results of whole-body MRI with DWI were equal to those of CT in 75% (21/28), higher in 25% (7/28), and lower in 0% (0/28) of patients, with correct/incorrect overstaging relative to CT in 6 and 1 patient(s), respectively. CONCLUSION: Our results suggest that initial staging of malignant lymphoma using whole-body MRI (without DWI and with DWI) equals staging using CT in the majority of patients, whereas whole-body MRI never understaged relative to CT. Furthermore, whole-body MRI mostly correctly overstaged relative to CT, with a possible advantage of using DWI.

Poor outcomes of chronic active Epstein-Barr virus infection and hemophagocytic lymphohistiocytosis in non-Japanese adult patients.

Chronic active Epstein-Barr virus infection manifests as a combination of persistent infectious mononucleosis-like symptoms and high viral load in apparently immunocompetent patients. It is closely related to Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. These 2 abnormal Epstein-Barr virus-associated diseases are seldom reported in individuals other than Japanese children and adolescents. We report a series of 2 adult non-Japanese patients with fatal chronic active Epstein-Barr virus and 1 adult non-Japanese patient with Epstein-Barr virus hemophagocytic lymphohistiocytosis and discuss its pathogenesis and treatment options.