Gyermekkori indolens lymphomák differenciáldiagnosztikája

Összefoglaló. Bevezetés: A gyermekkorban előforduló hematológiai megbetegedések közül az indolens non-Hodgkin-lymphomák igen ritka entitásnak számítanak. A betegség általában körülírt nyirokcsomó-megnagyobbodással jelentkezik, mely jellemzően lokalizált marad, szisztémás tünetek megjelenése nélkül, a prognózis kifejezetten kedvező. Morfológiai képük igen változatos, ami miatt gyakran differenciáldiagnosztikai kihívást jelentenek. Sajátos klinikopatológiai megjelenésük és rendkívül kedvező gyógyhajlamuk miatt a 2016-os WHO klasszifikációban önálló entitásként szerepelnek, mint gyermekkori-típusú follikuláris lymphoma és gyermekkori nodális marginális zóna lymphoma. Jelen tanulmányunk célja volt átfogó képet adni a gyermekkori indolens lymphomákról, különös hangsúlyt fektetve a differenciáldiagnosztikai problematikára. Közleményünkben részletes ismertetésre kerülnek az egyes szövettani típusok, morfológiai, immunhisztokémiai, klinikai és genetikai jellemzők szerint. Summary. Introduction: Indolent non-Hodgkin lymphomas in the pediatric and young adult population are very rare. The disease usually presents as isolated, localized lymphadenopathy most often in the head and neck regions, without generalized symptoms. The histology mainly shows mature B-cell lymphoma phenotypes, distinction from reactive lymphoid hyperplasias can be often difficult. Pediatric indolent lymphomas show characteristic clinicopathological features with excellent prognosis that differ from the adult counterpart; these lymphomas can be found as a distinct entity in the 2016 WHO classification as the pediatric-type follicular lymphoma and the pediatric-type nodal marginal zone lymphoma. In this study we present the pathologic characteristics: morphology, immunophenotype and genetical features and the important differential diagnostics of these entities.

With Equal-Access, Service Members with Lymphoma Have Better Outcomes Than Their Civilian Counterparts

Introduction: The Military Health System (MHS) is a single-payer, equal-access healthcare system that provides healthcare to 1.4 million active-duty service members (ADSMs) from diverse socioeconomic backgrounds. ADSMs with cancer receive prompt care without copayments, deductibles, prior authorizations, or other insurance barriers. Lymphoma is the most common hematologic malignancy diagnosed in ADSMs. We sought to compare overall survival (OS) of ADSMs with lymphoma with matched civilian lymphoma patients. We also sought to identify variables among ADSMs that predicted OS. Methods: The Department of Defense Automated Central Tumor Registry (ACTUR) was retrospectively accessed to identify ADSMs with Hodgkin Lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), and indolent lymphomas over a 20-year span from 1997-2017. A comparator arm was created from the National Cancer Institute's Surveillance, Epidemiology and End-Result (SEER)-18 database and was matched in a 4:1 ratio by age, sex, race, ethnicity, year of diagnosis, and stage. OS was assessed with Cox proportional hazards models. Kaplan Meier curves were constructed and compared using log rank tests. Among ADSMs, univariate and multivariable analyses were performed to assess OS based on race, ethnicity, sex, age at diagnosis, stage, year of diagnosis, rank, branch of service, and geographic region at diagnosis. All data analyses were conducted using STATA/SE 15.1 for Windows; the alpha level for statistical significance was set to 0.05. Results: There were 1,170 ADSMs with HL, 443 with DLBCL, and 284 with indolent lymphomas identified from ACTUR. Most ADSMs were between ages 20-40, white/non-Hispanic, enlisted, and in the Army. All three groups of ADSMs had superior OS when compared with their matched civilian counterparts. There were 49%, 48%, and 35% reductions in the risk of death among ADSMs with DLBCL, indolent lymphoma and Hodgkin lymphoma, respectively (DLBCL hazard ratio [HR] 0.51, 95% CI 0.40-0.65, p<0.0001; indolent HR 0.52, 95% CI 0.33-0.81, p <0.002; HL HR 0.65, 95% CI 0.52-0.82, p <0.002). Among the ADSMs, variables that reached statistical significance in the univariate and/or the multivariable analyses for OS include increasing age (DLBCL, indolent), advanced stage (DLBCL, HL), and geographic residence at diagnosis (DLBCL, HL). Notably, there were no statistically significant differences in OS based on race, ethnicity, sex, rank, or branch of service. Discussion: ADSMs with lymphoma treated within the MHS have significantly better survival than their matched civilian counterparts. Further, disparities based on race/ethnicity and sex are not present in the MHS, despite being pervasive in the civilian sector. It is possible that better access to care within the equal-access MHS might explain our results. Alternatively, regular fitness tests and periodic health assessments may render ADSMs are more fit and less comorbid than their civilian counterparts, translating to a better chance of long-term survival. Although this study is limited by its retrospective design and possible coding inaccuracies, the finding of advanced age and stage impacting OS serves as a good internal control and confirms the quality of ACTUR data. Findings from this study reflect favorably on ADSMs with cancer. The absence of racial/ethnic or gender disparities reflects favorably on cancer care received within the equal-access MHS. Figure 1 Figure 1. Disclosures Thornton: Undisclosed Companies: Current equity holder in publicly-traded company.

Metabolic Tumor Volume and Total Lesion Glycolysis Can Predict Response to Very Low Dose Radiotherapy (4 Gy) in Indolent B-Cell Lymphomas

Numerous studies have established the role of very low dose radiotherapy (VLDRT), only 4 Gy in 2 fractions, in the management of indolent non-Hodgkin's lymphoma (NHL). While objective response rates to VLDRT are excellent, there are no widely accepted biomarkers of the depth and the durability of response after VLDRT. Radiosensitivity to VLDRT is not clearly linked to clinical features, such as tumor grade, histology, prior treatments or [18F]-FDG-PET standardized uptake values (SUV). Our group has recently demonstrated that pre-treatment tumor size greater than 6 cm may predict suboptimal response to VLDRT; however, this remains an imperfect predictor, and the majority of patients selected for VLDRT have lesions smaller than 6 cm. [18F]-FDG-PET metrics like baseline metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are shown to stratify patient response to chemotherapy for some NHLs, but neither has been shown to predict radiotherapy response to VLDRT. Therefore, we aimed to determine if these features could predict response to VLDRT in indolent B-cell NHLs. Between 2005 and 2018, 250 patients with follicular or marginal zone lymphoma were locally irradiated to 299 sites using 2 Gy x2. Response was assessed within 1.5-6 months of VLDRT (n=231), and local failure (LF) was assessed over a median follow-up of 29 months. Out of the 299 treated sites, 254 (85%) had a corresponding [18F]-FDG-PET/CT scan performed prior to radiotherapy. PET scans were imported into MIM, a radiotherapy contouring and planning software program, and pre-radiotherapy disease was manually defined. A uniform expansion of 0.5 cm was performed to define a larger region of interest containing the contoured lesion but accounting for technical variability in defining the tumor edges. Of the 254 lesions, 207 (81%) had a maximum SUV (SUVmax) greater than 2.5 and were considered for further analysis. PET parameters were obtained using an SUV of 2.5 as a cutoff for MTV (MTV2.5) and TLG (TLG2.5), which capture lesion bulk, and using 41% of the SUVmax as a cutoff for MTV (MTV41%) and TLG (TLG41%), which capture the most metabolically active parts of a lesion. Maximum lesion size was analyzed using 4 cm and 6 cm as predetermined cutoffs. Lesion response was analyzed using multivariate logistic LASSO regression to account for predictor multicollinearity, and receiver operating characteristic curve analysis to obtain estimates of the area under the curve (AUC). To analyze time to LF, we performed Cox proportional hazards multivariate regression using stepwise selection. PET parameters were divided in quartiles to aid in interpretability. Estimates are shown with 95% confidence intervals. A complete response (CR) was seen in 156 (68%) lesions and LF was seen in 81 (27%) lesions after VLDRT. Using size alone had similar predictive value for response (AUC: 0.57(0.49-0.65) compared to MTV2.5 (AUC:0.66 (0.57-0.74)), MTV41% (AUC:0.64 (0.56-0.73)), TLG2.5 (AUC:0.64 (0.54-0.74)), and TLG41% (AUC:0.64 (0.54,0.75)). Through LASSO logistic regression, we determined that only MTV41% > 75 th percentile was associated with lower odds of CR (odds ratio (OR):0.21 (0.08-0.53)) versus size ≥4 (OR: 0.94 (0.32, 2.73) ) with no interaction noted. Likewise, in a multivariate model of LF, TLG2.5> 75 th percentile was shown to be a better predictor of worse LF (HR: 2.44 (1.32, 4.52)) than size when considering lesions < 6 cm. In stratifying response and local control for patients receiving VLDRT for indolent lymphomas, MTV and TLG may aid in patient selection, especially for lesions smaller than 6 cm. As PET-based radiotherapy planning is routinely performed in the treatment of indolent lymphomas, these parameters are easily attained after contouring and may have immediate clinical utility. These findings may also be applicable to radiotherapy response with higher doses, and the incorporation of [18F]-FDG-PET metrics into treatment decisions is an area of active research. It remains to be seen in ongoing work whether higher-order PET radiomic features (which for instance capture heterogeneity of tumor glucose metabolism) can further improve the accuracy of [18F]-FDG-PET-based radiotherapy outcome prediction. Disclosures Mayerhoefer: Siemens: Other: Speaker Honoraria; General Electric: Other: Speaker Honoraria; Bristol Myers Squibb: Other: Speaker Honoraria.

Too much and not enough: revisiting maintenance rituximab in indolent lymphomas

Not available.

Antibody Responses after SARS-CoV-2 Vaccination in Lymphoma

Individuals with lymphoid malignancies have an increased mortality risk from COVID-19. Paradoxically, this population is least likely to be protected by SARS-CoV-2 vaccination as a result of disease- or treatment-related immunosuppression. Current data on vaccine responses in persons with lymphoid malignancies is limited. PROSECO is a UK multi-centre prospective observational study evaluating COVID-19 vaccine immune responses in individuals with lymphoma. This early interim analysis details the antibody responses to first- and second- SARS-CoV-2 vaccination with either BNT162b2 (Pfizer-BioNTech) and ChAdOx1 (AstraZeneca), in 129 participants. Responses are compared to those obtained in healthy volunteers. The key findings of this interim analysis are first, 61% of participants who are vaccinated during or within 6 months of receiving systemic anti-lymphoma treatment, do not have detectable antibodies despite two doses of vaccine. Second, individuals with curable disease such has Hodgkin (100%) and aggressive B-cell non-Hodgkin lymphoma (81%) develop robust antibody levels to either first or second doses, when vaccinated > 6 months after treatment completion. Third, participants incurable, indolent lymphomas have reduced antibody levels to first and second vaccine doses, irrespective of treatment history. Finally, whilst there was no difference in antibody responses between BNT162b2 and ChAdOx1 in lymphoma participants, BNT162b2 induces 11-fold higher antibody responses than ChAdOx1 after the second dose in healthy donors. These findings serve to reassure the community that individuals with treated Hodgkin and aggressive B-NHL can develop antibody responses to SARS-CoV-2 vaccine. Simultaneously it also highlights the critical need to identify an alternative strategy against COVID-19 for those undergoing systemic anti-lymphoma treatment, and for individuals with indolent lymphomas.

Clinical manifestations of, diagnostic approach to, and treatment of neurolymphomatosis in the rituximab era

Neurolymphomatosis (NL) is a rare manifestation of lymphoma, with limited evidence for optimal management. The largest patient series, 50 cases of lymphoma and leukemia, was published in 2010 with limited rituximab exposure. This study aims to evaluate the clinical presentation, diagnostic testing, and outcomes of NL in the rituximab era. Forty biopsy-proven cases of NL, in association with non-Hodgkin lymphoma (NHL), at the Mayo Clinic were retrospectively evaluated. B-cell NHL was associated with 97% of NL cases, of which diffuse large B-cell lymphoma (DLBCL) was the most common (68%). Primary NL, defined as neural involvement present at the time of diagnosis of lymphoma, was noted in 52% cases. Seventy percent of patients presented with sensorimotor weakness and neuropathic pain. Magnetic resonance imaging (MRI) was positive in 100% patients. Overall survival (OS) was significantly better for primary NL and NL associated with indolent lymphomas. Relapses were seen in 60% (24/40) of patients; 75% involved the peripheral or central nervous system at relapse. The use of rituximab in the frontline setting significantly impacted progression-free survival (PFS). Transplant consolidation was noted to be associated with improved OS. This study adds to the available literature on NL in the rituximab era. The overall outcomes have improved in recent years. In our experience, MRI and positron emission tomography/computed tomography may be required for accurate assessment of the extent of disease involvement and identification of an optimal biopsy site. The use of rituximab was associated with improvement in PFS, and autologous stem cell transplant was associated with OS.

Incorporating Novel Targeted and Immunotherapeutic Agents in Treatment of B-Cell Lymphomas

The introduction of novel targeted agents and immunotherapeutic modalities into the treatment of B-cell lymphomas has drastically shifted the treatment landscape. In diffuse large B-cell lymphoma, recent approvals of CAR T-cell therapy, the antibody-drug conjugate polatuzumab, and the anti-CD19 monoclonal antibody tafasitamab have provided efficacious options for patients with relapsed and refractory disease. These immunotherapies attempt to harness power from the patient’s own immune system to eradicate lymphoma. In chronic lymphocytic leukemia, oral targeted kinase inhibitors such as ibrutinib and acalabrutinib (Bruton tyrosine kinase inhibitors) and venetoclax (BCL2 inhibitor) are now favored over chemoimmunotherapy for upfront treatment because of improved progression-free survival across all subgroups (including high-risk subgroups such as unmutated immunoglobulin variable heavy chain and chromosome 17p deletion). In indolent lymphomas, several PI3K inhibitors are approved for treatment of relapsed disease. However, uptake of these agents has been limited because of toxicity concerns. Combination of lenalidomide and rituximab has been a safe and effective immune modality for patients with refractory indolent lymphomas; it is currently being used as a backbone to bring other targeted agents such as tazemetostat (EZH2 inhibitor) into earlier lines of treatment. In this article, we will review novel commercially available agents in the treatment of relapsed/refractory diffuse large B-cell lymphoma, treatment-naïve chronic lymphocytic leukemia, and relapsed/refractory indolent lymphomas. We will evaluate clinical trials that led to their approval and will provide an outlook into the future novel agents currently under investigation in B-cell malignancies.