Habermann, Thomas

Abstract Introduction: Castleman disease (CD) is a heterogeneous group of lymphoproliferative disorders classified anatomically as unicentric (UCD), oligocentric (OligoCD), or multicentric (MCD). Human herpesvirus 8 (HHV-8)-negative MCD is referred to as idiopathic MCD (iMCD), which includes clinical subtypes with distinct phenotypes and treatment responses: TAFRO (thrombocytopenia, anasarca, fever, renal dysfunction and/or reticulin fibrosis, and organomegaly), idiopathic plasmacytic lymphadenopathy (IPL), and not otherwise specified (NOS). While UCD and iMCD, including TAFRO, have been more clearly defined, OligoCD and iMCD-IPL remain under-characterized, particularly in Western cohorts. This study aimed to validate the updated clinical classification of CD using a large institutional cohort by retrospectively reclassifying patients based on lymph node distribution and clinicopathologic criteria. We further examined whether OligoCD and IPL represent clinically and prognostically distinct entities compared to UCD or iMCD, and other iMCD subtypes. Methods: This study included 217 patients evaluated for CD at our institution between January 2004 and August 2024. All cases were reclassified based on the extent of lymph node involvement and iMCD subtype. UCD was defined as the involvement of a single lymph node region. OligoCD was defined as involvement of ≥2 contiguous lymph node stations without sufficient systemic symptoms to meet iMCD criteria. Patients with POEMS syndrome or HIV/HHV-8–associated CD, or lacking pathologic confirmation, were excluded. We evaluated clinical presentation, laboratory data, histopathology, treatment regimens, and outcomes. The primary endpoint was overall survival (OS), and the secondary endpoint was event-free survival (EFS), defined as time from first-line treatment to progression, change in therapy, or death. Survival outcomes were assessed using the log-rank test. Results: Among 217 CD patients, 123 (57%) had UCD, 43 (20%) had OligoCD, and 51 (23%) had iMCD. iMCD-defining symptoms were more common in iMCD compared to UCD and OligoCD. Among all, only fatigue and organomegaly were more common in OligoCD than in UCD. Laboratory values related to CD disease activities, including hemoglobin, serum creatinine, albumin, CRP, and plasma IL-6, showed significant differences in iMCD compared to UCD and OligoCD. No significant difference in the laboratory findings was observed between UCD and OligoCD, although patients with OligoCD had intermediate values between UCD and iMCD. With median follow-up of 4.0, 7.6, and 4.6 years for UCD, OligoCD, and iMCD, respectively, the 5-year OS was 99.0%, 97.7%, and 89.5% without differences among groups. Corresponding 2-year EFS rates were 95.2% for UCD, 68.0% for OligoCD, and 53.8% for iMCD. With OligoCD being the reference, UCD had a significantly lower hazard ratio (HR) of 0.20 (95% CI 0.10–0.41), and iMCD had a significantly higher HR of 2.0 (95% CI 1.1–3.6). Among OligoCD patients initially treated with surgery (40%), none required systemic therapy thereafter. Those treated with rituximab or glucocorticoid monotherapy required subsequent therapy in 50% and 43%, respectively. Within iMCD subtypes (TAFRO (n=16), IPL (n=9), and NOS (n=26)), the 5-year OS was 80.4%, 100%, and 91.0%, respectively, without significant differences among the subtypes. However, 1-year EFS rates were 40.2%, 100%, and 65.6%, respectively, with an HR of 4.3 (95% CI 1.2–15.2; p = 0.02) in TAFRO and 1.6 (95% CI 0.77–3.5) in NOS compared to IPL. Patients with IPL had a high rate of symptomatic improvement assessed by a physician of 89% with a longer time-to-next treatment. Conclusions: This extensive, retrospective cohort study supports the clinical relevance of updated CD subtype classification. As the present study spans two decades, it reflects evolving diagnostic criteria and therapeutic standards, including the 2014 FDA approval of siltuximab, the iMCD consensus criteria in 2017, with the addition of OligoCD and iIPL. The findings confirm the aggressive clinical nature of iMCD and suggest that OligoCD demonstrated intermediate features between UCD and iMCD, though closer to UCD in outcome. Also, the results reconfirmed that TAFRO is associated with severe symptomatic diseases, and validated that patients with IPL, even in the Western cohort, likely have favorable responses to treatment. Continued prospective efforts are warranted to confirm the clinical distinctions.

Abstract Introduction Marginal zone lymphoma (MZL) is an indolent and heterogenous disease. Several prognostic models have been proposed to assess outcomes in MZL, including FLIPI, IPI (primarily designed for overall survival [OS]), and MZL-specific scores such as MALT-IPI (event-free survival [EFS]) and MZL-IPI (progression-free survival). FLIPI24 is a recently developed prognostic index for patients with follicular lymphoma (FL) treated with first-line (1L) immunochemotherapy (IC), identifying a high-risk population with inferior survival and increased risk of lymphoma-related death. FLIPI24 has also demonstrated robust performance in the entire FL population, including patients under observation. This study aimed to evaluate the prognostic utility of FLIPI24 in patients with MZL and to compare its performance with other established indices (FLIPI, MZL-IPI, IPI, MALT-IPI). Methods We pooled harmonized data from newly diagnosed MZL patients with complete available FLIPI24 variables (age, white blood cell count [WBC], hemoglobin [HGB], serum lactate dehydrogenase [LDH], and beta-2-microglobulin [B2M] levels) treated with 1L IC. Data were collected from three prospective international cohorts: NiHiL (Czech Republic; n=897; enrolled 2005–2023), LEO (USA; n=62; 2015–2020), and MER (USA; n=32; 2010–2015), forming a pooled cohort of 991 1L IC-treated patients. The analysis was then extended to include all newly diagnosed MZL patients (n=2,116), regardless of treatment. The primary endpoint in the 1L IC-treated cohort was EFS at 24 months (EFS24), and for all MZL patients, it was OS. Secondary endpoints included OS24 for 1L IC treated cohort, lymphoma-related mortality by FLIPI24 risk groups, and comparative prognostic performance of FLIPI, IPI, and MALT-IPI, by C-statistics; performance of MZL-IPI was assessed on a subgroup of NiHiL patients with available data (n=877 all MZL, n=485 1L IC-treated). Results Among the 991 1L IC-treated patients, the median age at diagnosis was 66 years (range 22–94); 47% were male; 11% had ECOG performance status ≥2, 68% clinical stage III–IV, 42% elevated LDH, 40% IPI 3–5, 42% FLIPI 3–5, and 62% MALT-IPI 2–3. The median B2M level was 2.8 mg/L, WBC 7.0 × 10⁹/L, and HGB 13.1 g/dL. MZL subtypes were: 64% extranodal (EMZL), 22% nodal (NMZL), and 14% splenic (SMZL). Most common 1L IC regimens were R-CVP (46%), R-CHOP-like (32%), R-chlorambucil (9%), and B-R (9%). FLIPI24 stratified patients into low- (18%), intermediate- (37%), and high-risk (45%) groups. High-risk patients were older (median 54 vs 65 vs 71 years for low-, intermediate-, and high-risk groups, respectively; P<0.01), had more frequent adverse baseline features, and were more likely to have the SMZL subtype (2% vs 7% vs 25% for low-, intermediate-, and high-risk groups, respectively; P<0.01). After a median follow-up of 7.2 years, EFS24 was 89%, 85%, and 65% (P<0.01) across low-, intermediate-, and high-risk groups; OS at 2 years was 98%, 97%, and 79%; and OS at 5 years was 96%, 91%, and 62%, resp. (P<0.01). The 5-year cumulative incidence of lymphoma-related death was 13% in high-risk vs 6% in low-/intermediate-risk groups. FLIPI24 showed better prognostic accuracy for EFS compared with FLIPI, MZL-IPI, IPI and MALT-IPI (C-index: 0.640 vs 0.630, 0.622, 0.620 and 0.603, resp.), as well as for OS (C-index: 0.710 vs 0.672, 0.641, 0.663, 0.652, resp.). Prognostic performance was consistent across MZL subtypes. In the extended cohort of 2,116 newly diagnosed MZL patients (47% receiving IC, 17% rituximab monotherapy, 11% radiotherapy, 8% surgery, 2% antibiotics; 15% observed), FLIPI24 stratified patients into low- (24%), intermediate- (39%), and high-risk (37%) groups. OS at 2 year was 99%, 97%, and 83%, at 5 years it was 96%, 91%, and 62%, resp. (P<0.01). The 5-year cumulative incidence of lymphoma-related death was 12% in high-risk vs 4% in low-/intermediate-risk patients. FLIPI24 outperformed other indices (OS C-index: 0.754 vs MZL-IPI 0.654, FLIPI 0.700, MALT-IPI 0.694, IPI 0.699). Conclusion FLIPI24 demonstrates strong and consistent prognostic performance across all MZL subtypes, identifying ~40% of patients as high-risk with significantly worse survival and increased lymphoma-related mortality. The FLIPI24 outperforms FLIPI, MZL-IPI, IPI, and MALT-IPI in predicting outcomes and may serve as a practical tool to guide risk-adapted management and selection of patients for novel therapies in MZL. Funding: NU21-03-00411, P50 CA97274, U01 CA195568.

With improved medical treatments, the prognosis for many malignancies has improved, and more patients are presenting for transplant evaluation with a history of treated cancer. Solid organ transplant (SOT) recipients with a prior malignancy are at higher risk of posttransplant recurrence or de novo malignancy, and they may require a cancer surveillance program that is individualized to their specific needs. There is a dearth of literature on optimal surveillance strategies specific to SOT recipients. A working group of transplant physicians and cancer-specific specialists met to provide expert opinion recommendations on optimal cancer surveillance after transplantation for patients with a history of malignancy. Surveillance strategies provided are mainly based on general population recurrence risk data, immunosuppression effects, and limited transplant-specific data and should be considered expert opinion based on current knowledge. Prospective studies of cancer-specific surveillance models in SOT recipients should be supported to inform posttransplant management of this high-risk population.