Citations

Abstract Background Dementia with Lewy bodies (DLB) is a prevalent form of dementia associated with neuronal alpha‐synuclein aggregates (Lewy bodies). Symptoms include cognitive impairment, fluctuations, neuropsychiatric features including psychosis, sleep disorders, and dysautonomia. DLB is the most expensive form of dementia, and there are currently no treatments approved by the US FDA. Given the advent of sensitive and specific in vivo biomarkers for synuclein aggregation, drug developers are increasingly interested in DLB. FDA instituted Patient‐Focused Drug Development (PFDD) meetings in 2012 with the purpose of ensuring that patients’ experiences, perspectives, needs, and preferences are captured and meaningfully incorporated into drug development and evaluation. Method In October 2024, the Lewy Body Dementia Association (LBDA) and the Alzheimer’s Association (ALZ) co‐hosted an externally‐led PFDD (EL‐PFDD) meeting on DLB. Thirty days before the event, LBDA solicited public comment on the lived experience of DLB, the current state of treatment, and what people with DLB value in potential future therapies. During the live meeting, people with DLB, care partners and family members described their experiences and responded to live polling questions. Result The EL‐PFDD was attended by 347 people with DLB and care partners, drug developers (both industry and academic), FDA staff, and NIH staff. Preliminary analysis of the discussion content and survey responses shows several themes emerging from the meeting. The most bothersome and impactful symptoms varied over the course of the disease, but included cognitive impairment and fluctuations, neuropsychiatric symptoms, and sleepiness. Concerns for the future included progressive decline in cognition, changes in behavior/mood, and cost of care. Limitations to current treatments included lack of FDA‐approved medications, and side effects and lack of efficacy associated with “off label” medications. Priorities for future treatments included symptomatic treatments that do not worsen other DLB symptoms, slowing disease progression, accessibility/insurance coverage, and avoiding side effects. Conclusion The EL‐PFDD on DLB provided valuable information for drug developers and regulators to understand the lived experience of people with DLB and care partners. The results will be documented in a “Voice of the Patient” report that will be hosted at www.lbda.org/el‐pfdd .

Abstract Background: For LS-DLBCL, clinical trials (FLYER, LYSA/GOELAMS 02-03, LYSA LNH09-1B, S1001) have shown that 4 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP4) without radiation (RT) leads to durable remissions in >90% of cases. However, only patients (pts) with non-bulky disease and/or international prognostic index (IPI) of 0 and complete metabolic response (CMR) on interim positron emission tomography (PET) scan, if performed, were eligible for RCHOP4 alone in these studies. Outcomes in trial-ineligible LS-DLBCL and the appropriate real-world candidates for RCHOP4 are still undefined. Methods: We conducted a multicenter retrospective study of adult pts with stage I/II DLBCL of any tumor bulk, IPI and with or without B-symptoms diagnosed after 2011 and treated with RCHOP4 +/- 2 cycles R from 21 U.S. centers. Pts with PMBCL, PTLD or receiving non-standard dose RCHOP for cycle (C) 1 or planned consolidative RT were excluded. The primary endpoint was PFS from C1 by Kaplan-Meier method, not counting indolent lymphoma relapse. Event free survival (EFS) was time to next therapy without progression (including unplanned RT for non-CR), progression or death. A competing risks analysis of non-relapse mortality (NRM) vs. DLBCL progression was performed. Results: The characteristics of the 428 pts were: median age 60 (18-88), 60% male, 11% Hispanic and 4% non-Hispanic Black, 62% stage I, 15% elevated LDH, 3% ECOG PS>1, 5% tumor bulk >7cm, 9% had B-symptoms and median Charlson Comorbidity Index (CCI) was 4 (2-12). IPI was 0, 1 and 2-3 in 42%, 46% and 12% and stage-modified IPI (smIPI) was 0, 1, 2 and 3-4 in 25%, 48%, 21% and 6% of pts. 66% had nodal (59% head/neck, 11% pelvic, 9% multiple above diaphragm, 7% abdominal) and 46% extranodal sites (37% head/neck, 20% gastric/intestinal, 9% spleen, 8% skin/soft tissue); 6% had transformed/concurrent FL/MZL or grade 3B FL, 33% (138/408) were non-GCB cell of origin (COO), 25% (90/357) double expressor (DEL) and 0.5% (2/379) double-hit. 13% had completely resected disease, 97% staging PET and 47% bone marrow biopsy. Median diagnosis to treatment interval was 30 days (IQR 20-43), 6% had dose reductions after C1, 77% had an interim PET (iPET) after C2 (33%) or C3 (67%), 15% received 2 additional cycles R and 4% CNS prophylaxis. CMR rates by iPET were 83% after C2 and 94% after C3, and 95% by end-of-treatment PET. iPET PMR was more likely if smIPI>2 or bulky disease. Median follow-up time was 2.7 years. There were 32 progression events: 14 occurred at the primary site and 17 at distant sites (1 unknown), and 12 occurred after 2 years. Another 11 pts received unplanned RT after RCHOP4 for non-CR. There were 24 deaths, 12 without prior progression. Cause of death was DLBCL in 7 and non-DLBCL in 17 cases (6 infection, 2 ILD, 2 heart failure, 2 second cancer, 1 seizure, 4 unknown). EFS, PFS and OS rates were 88%, 90% and 96% at 3 years. By univariable Cox regression, Black race, elevated LDH, smIPI>2, DEL, increasing CCI, multiple subdiaphragmatic nodal sites and iPET PMR were associated with worse PFS. Non-significant variables of note included COO, extranodal sites, complete resection, missing bone marrow biopsy, missing iPET and additional cycles R. By multivariable analysis (including age>60, stage, ECOG PS>1, elevated LDH, bulky disease, CCI, B-symptoms and DEL), ECOG PS>1 (HR 3.95 p=0.050), CCI (HR 1.29 p=0.003) and DEL (HR 2.02 p=0.069) were associated with worse PFS. Cumulative incidence of DLBCL progression and NRM were 8% and 2% at 3 years. Competing risk analysis by univariable models found that age>60, ECOG PS>1, smIPI>2, elevated LDH, CCI and bulky disease were associated with NRM, while DEL and B-symptoms were associated with DLBCL progression.Conclusion: Presented is the largest retrospective cohort of LS-DLBCL treated uniformly with RCHOP4 to date. Despite modest follow-up time and lack of an “intention-to-treat“ population, this study shows that abbreviated RCHOP4 leads to excellent outcomes in the real-world, albeit with continuous risk of late relapse. smIPI risk factors were associated with worse PFS, though this may in part be driven by risk of non-lymphoma death. As pts with advanced age, poor performance status or comorbidities may benefit from reduced treatment exposure, RCHOP4 should still be considered for these and other “trial-ineligible” pts, particularly if other high-risk features (iPET PMR, DEL or B-symptoms) are absent.

ABSTRACT The characteristics at diagnosis and clinical course of primary extranodal follicular lymphoma (EFL) have not been extensively described. The International Extranodal Lymphoma Study Group (IELSG) conducted an international retrospective survey aimed to describe the clinical features at diagnosis and the outcomes of FL cases with a clinically dominant extranodal component. The dataset included 605 pathologically reviewed cases from 19 different countries, and their outcomes were compared to those of nodal follicular lymphomas. The two most common presentation sites for EFL were the skin ( n = 334) and the gastrointestinal tract ( n = 72), with 22 cases having primary duodenal localization. These subsets exhibited unique features at diagnosis and significantly different overall survival (OS) patterns. After a median follow‐up of 5.5 years, primary cutaneous lymphomas showed a superior outcome [10‐year OS: 89% (95% CI, 83%–93%)], while primary gastrointestinal lymphomas had an intermediate outcome [10‐year OS: 79% (95% CI, 59%–90%)]. Among the gastrointestinal lymphomas, primary duodenal lymphomas tended toward the best outcome [10‐year OS: 95% (95% CI, 69%–99%)]. Other primary extranodal sites had inferior outcomes [10‐year OS: 59% (95% CI, 48%–68%)], similar to primary nodal lymphomas [10‐year OS: 57% (95% CI, 49%–64%)]. These findings support the identification of specific primary FL localizations as distinct entities with particular clinical and biological characteristics.

PURPOSE Lymphomas are a heterogeneous group of diseases that develop in individuals of all ages and have variable prognoses. Improved survival resulting from therapy advances has led to the emergence of diverse late effects. Although several (US)–based organizations have developed survivorship guidelines, the distinct features of lymphoma subtypes and diverse therapies used raise concerns regarding their applicability to lymphoma survivors. We compared survivorship recommendations (outside primary disease monitoring) between US clinical guidelines. METHODS We extracted information from 17 guidelines from five US-based organizations: ASCO (n = 11), American Cancer Society (n = 1), Children's Oncology Group (n = 1), Center for International Blood and Marrow Transplant Research (n = 1), and the National Comprehensive Cancer Network (n = 3). Guidelines were evaluated to determine whether they offer recommendations on physical effects , psychosocial and quality of life ( QOL ), and health promotion and prevention . Comparisons were focused on second primary malignancy, cardiovascular complications, and vaccination. RESULTS Survivorship recommendations on physical effects and psychosocial and QOL mainly differ in the timing and approaches for screening. Vaccination recommendations were primarily derived from other cancer populations. Identified research gaps were a lack of understanding of the risk of late effects across lymphoma subtypes, the role of social determinants of health in survivorship, and the lack of a survivorship care model that integrates lymphoma subtypes and treatment exposures. CONCLUSION This study raises awareness about the complexity and challenges of managing survivors under the umbrella diagnosis of lymphoma. The inconsistency and incompleteness of existing guidelines may lead to suboptimal survivorship care. We propose expert-based research priorities to address gaps and unmet needs to help develop risk-based follow-up recommendations to optimize survivorship care for lymphoma survivors.

Abstract Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of T-cell lymphoma associated with an aggressive clinical course and a worse prognosis. HSTCL develops in the setting of chronic immune suppression or immune dysregulation in up to 20% of cases and is most often characterized by spleen, liver, and bone marrow involvement. Diagnosis and management of HSTCL pose significant challenges given the rarity of the disease along with the absence of lymphadenopathy and poor outcome with conventional chemotherapy regimens. These Guidelines Insights focus on the diagnosis and treatment of HSTCL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL), and Sézary syndrome (SS) is a rare erythrodermic and leukemic subtype of CTCL characterized by significant blood involvement. Although early-stage disease can be effectively treated predominantly with skin-directed therapies, systemic therapy is often necessary for the treatment of advanced-stage disease. Systemic therapy options have evolved in recent years with the approval of novel agents such as romidepsin, brentuximab vedotin, and mogamulizumab. These NCCN Guidelines Insights discuss the diagnosis and management of MF and SS (with a focus on systemic therapy).

Abstract Background Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of non-Hodgkin’s lymphomas (NHL) characterized by poor treatment outcomes with conventional chemotherapy, including CHOP [complete remission (CR) ∼40%]. Retrospective studies suggest that the incorporation of etoposide into chemotherapy regimens may improve outcomes compared to CHOP. In contrast, anthracyclines appear to have a limited role in PTCL, largely attributed to p-glycoprotein related resistance. Pralatrexate was the first drug approved for patients (pts) with relapsed PTCL, providing a rationale to evaluate it in the front-line setting. Herein, we evaluated the efficacy of a novel combination for the primary therapy of pts with PTCL whereby the anthracycline in CHOP backbone was replaced with etoposide (CEOP) alternating with pralatrexate (P). Methods Pts > 18 years (yrs) with PTCL stages II-IV with no prior therapy and adequate end organ function were eligible. Eligible histologies included, PTCL-NOS, AILT, ALCL (ALK positive pts only allowed if IPI >3). CEOP (Cycle A) was administered as: cyclophosphamide 750 mg/m2 IV d1, etoposide 100 mg/m2 IV d1-3 (or 100 mg/m2 IV d1 and 200 mg/m2 PO days 2-3), vincristine 2 mg IV day 1 and prednisone 100 mg/day X 5 alternating with P (cycle B) 30 mg/m2 IV d 15, 22 and 29 (with vitamin B12 and folate supplementation). Growth factors were used to support both cycles of therapy. Imaging to assess response was done after cycle 2B, 4B and 6B. Pts achieving a remission were eligible for consolidative autologous stem cell transplant (ASCT) after cycle 4B at physician discretion. The primary statistical aim was to improve the CR rate from 40 to 63% with CEOP-P and optional transplant. Secondary objectives included assessment of event free survival (EFS), overall survival (OS) and toxicity of the regimen. A two-stage Simon design (alpha=0.10, 90% power) tested the null hypothesis that the CR rate would be </= to 40%. For the first stage of 20 evaluable pts, the trial would be terminated if 8 or fewer pts experienced a CR after course 2B of chemotherapy. For the second stage, a total of 34 pts were required with at least 17 achieving a CR at the end of therapy to consider the regimen useful. Results 34 pts were enrolled and one withdrew consent before starting therapy, leaving 33 pts enrolled between 7/2011 and 1/2013. Characteristics are shown in Table 1. 27 pts received at least 2 cycles of therapy. 6 pts received only 1 cycle due to early disease progression in 4 and adverse events in 2. Grade 3-4 toxicities attributed to therapy included, anemia (27%), thrombocytopenia (12%), febrile neutropenia (18%), mucositis (18%), sepsis (15%), increased creatinine (12%) and liver transaminases (12%). At the end of stage 1, 10 of 20 pts (50%) achieved a CR; therefore accrual proceeded to stage 2. At the time of this initial analysis, the overall response rate is 70%. To date 15 pts (45%) have achieved a CR with two additional pts pending evaluation. Overall, the 1-yr EFS is 48% (95% CI 28-64), and 1-yr OS 70% (95% CI 47-84) (Figures 1 and 2). 6 pts (18%) to date (n=3 CR, n=2 PR and 1 with stable disease) have received consolidation with ASCT and all are in CR post-transplant. Pts who proceeded to ASCT were younger than the non-transplant cohort (median age 58 versus 64 yrs) with other clinical characteristics being similar. On exploratory bivariate analyses, age <60 yrs, absence of B symptoms, low IPI score (0,1), achieving a CR, and receiving a ASCT were associated with better EFS. Attaining a CR was the only factor associated with better OS and was highest in patients with low IPI (78%) and those with ALCL histology (75%). Conclusions CEOP-P met the pre-defined stage 1 response criteria. Longer follow-up is needed to assess the impact on the final CR rate and secondary objectives of EFS and OS. Defining optimal front line therapy in PTCL continues to be a challenge and an unmet need. Disclosures: Advani: Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Spectrum Pharmaceuticals: Research Funding. Off Label Use: Pralatrexate is currently only approved for relapsed/refractory PTCL. Lechowicz:Allos Therapeutics: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Carson:Spectrum Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau. Foss:merck: Research Funding; spectrum: Research Funding; eisai: Membership on an entity’s Board of Directors or advisory committees; millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees; celgene: Honoraria, Research Funding; seattle genetics: Research Funding. Horwitz:Celgene : Consultancy, Research Funding; Spectrum Pharamaceuticals: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Kyowa Hakko Kirn Pharma: Consultancy; Genzyme : Research Funding; Janssen: Research Funding; Millennium: Consultancy, Research Funding. Pro:Spectrum Pharmaceuticals: Honoraria. Pinter-Brown:Spectrum Pharmaceuticals: Consultancy, Honoraria. Smith:Micromet: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Allos: Consultancy; Genentech: Consultancy; Onyx: Consultancy. Shustov:Spectrum Pharmaceuticals: Consultancy, Honoraria. Savage:Spectrum Pharmaceuticals: Research Funding. Vose:Spectrum Pharmaceuticals: Research Funding.