Ansell, Stephen M.

AbstractPredicting early clinical failure in patients with untreated follicular lymphoma (FL) is important but difficult. This study aimed to determine the incidence and patterns of extranodal (EN) and spleen disease using PET/CT, and assess their utility in predicting early clinical failure. PET/CT images from 613 cases of untreated FL (2003‐2016) were reviewed. The location and number of EN sites, patterns of bone involvement, and splenic involvement were recorded. Outcomes were assessed using event‐free survival (EFS), overall survival (OS), and early clinical failure at 24 months (EFS24). So, 49% (301/613) of patients had PET/CT‐detected EN involvement, and 28% (171/613) had spleen involvement. The presence of ≥2 EN sites, spleen, bone or soft tissue involvement all predicted failure to achieve EFS24. Presence of ≥2 EN sites and bone involvement pattern were also predictive of OS in a univariate analysis. In a multivariate analysis with FLIPI‐2 factors, spleen involvement, pattern of bone involvement, and soft tissue involvement independently predicted a lower EFS (HR 1.49 (1.11‐2.00),P= .007; HR 1.71 (1.10‐2.65),P= .017; and HR 1.67 (1.06‐2.62),P= .026, respectively). When the multivariate analysis was performed using PRIMA‐PI factors (marrow and B2M), the number of EN sites was an independent prognostic factor for inferior OS (HR 2.28;P= .05). Baseline PET/CT identifies EN involvement in nearly half of patients with untreated FL. The presence of ≥2 EN sites, bone, soft tissue, or splenic involvement predicts early clinical failure. These results, when combined with other factors, may better identify high‐risk patients and guide therapy.

Abstract Non-Hodgkin lymphoma is a malignancy of B lymphocytes that typically infiltrate sites of disease, including the lymph nodes, spleen, and bone marrow. Beyond the presence of malignant cells, many immune cells are also present within the tumor microenvironment. Although these immune cells have the potential to regulate the growth of malignant B cells, intratumoral immune cells are unable to eradicate lymphoma cells and most patients with lymphoma have clinical evidence of disease progression. Recent data have identified some of the mechanisms that account for the suppressed antitumor immune response and have created opportunities for treatment to overcome the deficiencies. Two general categories of immunological therapies are available. The first approach is to use agents that prevent inhibitory signals via immune checkpoint receptors that downregulate immune cell function. Blockade of suppressive programmed cell death 1 (PD-1) or CTLA-4 signaling has resulted in significant clinical activity by allowing intratumoral T cells to remain activated and target malignant cells. A second approach is to additionally activate T cells that are suboptimally active or suppressed, by providing signals through costimulatory molecules including CD27 or CD40 or by adding immunostimulatory cytokines. There has been significant heterogeneity in the responses to these treatment approaches. Clinical responses are seen in many diseases, but the most promising responses have been with PD-1 blockade in Hodgkin lymphoma. In other lymphomas, responses are seen but only in a subset of patients. Further research is needed to identify the mechanisms that account for response and to identify patients most likely to benefit from immune modulation.

BACKGROUND Waldenström macroglobulinemia (WM) is preceded by asymptomatic WM (AWM), for which the risk of progression to overt disease is not well defined. METHODS We studied 439 patients with AWM, who were diagnosed and observed at Dana-Farber Cancer Institute between 1992 and 2014. RESULTS During the 23-year study period, with a median follow-up of 7.8 years, 317 patients progressed to symptomatic WM (72%). Immunoglobulin M 4,500 mg/dL or greater, bone marrow lymphoplasmacytic infiltration 70% or greater, β2-microglobulin 4.0 mg/dL or greater, and albumin 3.5 g/dL or less were all identified as independent predictors of disease progression. To assess progression risk in patients with AWM, we trained and cross-validated a proportional hazards model using bone marrow infiltration, immunoglobulin M, albumin, and beta-2 microglobulin values as continuous measures. The model divided the cohort into three distinct risk groups: a high-risk group with a median time to progression (TTP) of 1.8 years, an intermediate-risk group with a median TTP of 4.8 years, and a low-risk group with a median TTP of 9.3 years. We validated this model in two external cohorts, demonstrating robustness and generalizability. For clinical applicability, we made the model available as a Web page application ( www.awmrisk.com ). By combining two cohorts, we were powered to identify wild type MYD88 as an independent predictor of progression (hazard ratio, 2.7). CONCLUSION This classification system is positioned to inform patient monitoring and care and, for the first time to our knowledge, to identify patients with high-risk AWM who may need closer follow-up or benefit from early intervention.

Background: Patients (pts) with classical Hodgkin lymphoma (cHL) frequently experience reduced health-related quality of life (HRQoL) (Oerlemans et al, Ann Hematol 2011). Nivolumab, a fully human IgG4 anti-programmed death-1 (PD-1) immune checkpoint inhibitor monoclonal antibody, demonstrated efficacy and clinically meaningful improvement in pt-reported outcomes (PROs) in pts with relapsed/refractory cHL in cohorts A, B, and C of CheckMate 205 (NCT02181738) (Armand et al, J Clin Oncol 2018; Engert et al, ASH 2017). Nivolumab monotherapy followed by nivolumab + doxorubicin, vinblastine and dacarbazine (N-AVD) demonstrated an objective response rate of 84% in newly diagnosed cHL (cohort D of CheckMate 205; Ramchandren et al, EHA 2018). We present PROs in CheckMate 205 cohort D. Methods: Pts ≥18 years of age with untreated, advanced-stage cHL, with ECOG performance status (PS) of 0–1 received 4 doses of nivolumab monotherapy (240 mg IV Q2W) followed by N-AVD for 6 cycles (12 doses). Pts then entered the follow-up (FU) period. PROs were an exploratory endpoint, assessed using the EuroQol 5 Dimensions-3 level (EQ-5D-3L) and associated visual analog scale (EQ-VAS) in all treated pts who had both a baseline (monotherapy cycle 1) and post-baseline assessment. EQ-VAS ranges from 0–100, with higher scores indicating better HRQoL. In EQ-5D-3L, pts can report no, some, or extreme problems in each of 5 dimensions (mobility, self-care, activity, pain, and anxiety). Results: 51 pts were treated. At baseline, median age was 37 years, 63% were male, 59% had ECOG PS of 0. 49 pts (96%) completed baseline EQ-VAS. Mean EQ-VAS scores exceeded the mean baseline score at the end of monotherapy, after 2 combination cycles, at the end of therapy, and during follow-up (Table 1). The proportion of pts reporting some or extreme problems in EQ-5D-3L was numerically lower than or similar to baseline after monotherapy for all dimensions, but was numerically higher than baseline (dimensions of mobility and activity) after 2 combination cycles, and remained close to or numerically below baseline during follow-up (dimensions of self-care, activity, pain, and anxiety). Conclusions: Pt-reported HRQoL, as assessed by observed mean EQ-VAS scores, did not deteriorate from baseline during treatment with nivolumab followed by N-AVD. Proportions of pts reporting problems in individual EQ-5D-3L dimensions were generally similar to baseline during treatment and follow-up.