Aggressive Lymphoma Research Articles

Predictors of severe hematotoxicity after CAR T-cell therapy.

7024 Background: The EHA/EBMT immune effector cell-associated hematotoxicity (ICAHT) grading system characterizes hematotoxicity after CAR T-cell therapy based on depth and duration of neutropenia (Rejeski et al, Blood, 2023). We evaluated pre- and post-infusion factors associated with grade 3-4 ICAHT and developed a predictive model in 602 patients with hematologic malignancies undergoing CAR T-cell therapy at Fred Hutch Cancer Center. Methods: Grading of early hematotoxicity (day-0-30 after CAR T-cell cell infusion) was automated using the heatwaveR package. Associations with 50 patient, disease-related, and laboratory factors, and grade 3-4 ICAHT were modeled using univariate and multivariable logistic regression. Results: The most common disease types were aggressive non-Hodgkin lymphoma (NHL; n = 293; 49%), indolent NHL (n = 150; 25%), and acute lymphoblastic leukemia (ALL; n = 94; 16%). The most common CAR T-cell products were the investigational CD19 CAR T-cell product JCAR014 (n = 197; 33%), axicabtagene ciloleucel (n = 129; 21%), and lisocabtagene maraleucel (n = 73; 12%). Incidences of early ICAHT grades 1, 2, 3, and 4 were 319 (53%), 96 (16%), 60 (10%), and 35 (6%) patients, respectively. Baseline patient factors associated with grade 3-4 ICAHT included ALL (reference: aggressive NHL, OR = 4.18, 95% CI, 2.41-7.26, p < 0.001) , Hispanic or Latino ethnicity (OR = 2.17, 95% CI, 1.07-4.20, p = 0.025), and lower age (OR = 1.03, 95% CI, 1.02-1.05, p < 0.001). Pre-lymphodepletion (LD) laboratory factors associated with grade 3-4 ICAHT in univariate analyses included lower ANC (OR = 6.67 per log10 cells/μL, 95% CI, 4.0-11.1, p < 0.001), LDH (OR = 8.70per log10U/L, 95% CI, 4.03-19.4, p < 0.001), CRP (OR = 3.18 per log10mg/L, 95% CI, 2.06-5.07, p < 0.001), and ferritin (OR = 6.07 per log10mg/L, 95% CI, 3.65-10.6, p < 0.001). Peak CRP (OR = 15.6, 95% CI, 7.27-36.4, p < 0.001), peak ferritin (OR = 7.41, 95% CI, 5.02-11.3, p < 0.001), peak CRS grade (OR = 2.01, 95% CI, 1.59-2.56, p < 0.001), and peak ICANS grade (OR = 1.51, 95% CI, 1.29-1.77, p < 0.001) after CAR T-cell infusion were also strongly associated with grade 3-4 ICAHT. A multivariable model using restricted cubic splines and including disease type, pre-LD ANC, pre-LD LDH, peak CRP, peak ferritin, and CRS grade demonstrated high discrimination to predict grade 3-4 ICAHT (C-index = 0.89). Internal validation using bootstrapping showed near-perfect calibration without overfitting. Sensitivity and specificity based on the Youden criteria was 74% and 90%, respectively. The sensitivity and specificity of the CAR-HEMATOTOX score in predicting grade 3-4 ICAHT was 93% and 30%, respectively. Conclusions: We identified pre- and post-infusion predictors of grade 3-4 ICAHT and internally validated a multivariable logistic regression model including disease-type, pre-LD ANC, pre-LD LDH, peak CRP, peak ferritin, and CRS grade. We plan to further evaluate our model in an external cohort.

Burkitt lymphoma in a scalp region: a case report of it’s recurrence in a 13-year-old child

Introduction: Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma characterized by chromosome 8 MYC gene translocation. It manifests in three clinical types: immunodeficiency-related, sporadic (nonendemic), and endemic (African), each differing in epidemiology and clinical behavior. Treatment typically involves enrollment in clinical trials or intensive chemotherapy regimens like R-CODOX-M/IVAC. The authors present a case of recurrent BL following treatment. Case report: A 13-year-old female presented with a gradually progressive swelling in the left parieto-occipital region. Examination revealed normal vital signs and a Glasgow coma scale, with seronegative findings on investigations. An excision of a subganglion soft tissue tumor was performed, revealing histopathological features suggestive of a small round blue cell tumor. After chemotherapy, the patient experienced a recurrence in the scalp region, diagnosed as BL. Discussion: While scarce reports exist on BL in the scalp region, cases have been documented in various body locations. Treatment strategies, including chemotherapy and surgery, have shown promising results in managing the disease and improving symptoms. Conclusion: The recurrence of BL is rare, highlighting the importance of vigilance in monitoring patients post-treatment. The authors report a case of recurrent BL in a 13-year-old female, emphasizing the need for continued research and surveillance in managing this aggressive malignancy.

Incidence of any infections and SARS-CoV-2 infections in patients receiving treatment for follicular lymphoma and diffuse large B-cell lymphoma: Real-world evidence from a large US national claims database.

e19061 Background: Non-Hodgkin’s lymphoma is a heterogeneous group of conditions, including the indolent subtype follicular lymphoma (FL) and the aggressive subtype diffuse large B-cell lymphoma (DLBCL). Infections associated with NHL are a major concern due to effects of the underlying disease and its treatment and have been reported to increase with increasing lines of therapy (LoT). However, the risk of infections overall and SARS-COV-2 infections specifically is not well characterized in patients who have received multiple LoTs. The goal of the study was to estimate the exposure-adjusted incidence rates (EAIR) of infections during the COVID-19 pandemic by type, severity and LoT received in patients treated for FL or DLBCL in the real-world setting. Methods: We identified patients in the Optum Clinformatics claims data from October 1, 2015, to June 30, 2023. Patients were aged ≥18 years, enrolled continuously for 365 days before index (start of LoT), and had ≥2 ICD-10 diagnosis codes for FL or DLBCL in the 365 days before index. The EAIR (per 100 person-years, PY) was estimated for infections by type (any infections and SARS-COV-2 [after 1/1/2020]), severity (hospitalized or fatal hospitalizations), and number of LoTs received. Results: A total of 4,799, 1,025 and 510 FL patients were included in the 1L (1 LoT), 2L, and 3L+ cohorts, respectively. The EAIR of infections resulting in hospitalization in 1L, 2L, and 3L+ cohorts were 20.6 (95% confidence interval (CI): 19.0-22.3), 30.2 (25.5-35.9), and 44.2 (35.4-55.3) per 100-PY for any infection; and 4.6 (4.0-5.4), 4.4 (3.0-6.5) and 8.3 (5.3-13.2) per 100-PY for SARS-COV-2 infections, respectively. The EAIR of fatal hospitalizations were 4.0 (3.4-4.8), 8.6 (6.4-11.5), and 13.9 (9.7-20.0) per 100-PY for any infection; and 1.3 (1.0-1.7), 1.6 (0.8-3.0), and 4.1 (2.2-7.9) per 100-PY for SARS-COV-2 infections. A total of 8,058, 2,114 and 977 DLBCL patients were included in 1L, 2L, and 3L+ cohorts, respectively. The EAIR of infections resulting in hospitalization in 1L, 2L, and 3L+ cohorts were 64.2 (60.7-67.8), 85.2 (76.9-94.3), and 113.4 (98.4-130.7) per 100-PY for any infection; and 6.3 (5.5-7.2), 7.3 (5.6-9.6), and 15.1 (11.3-20.2) per 100-PY for SARS-COV-2 infections respectively. The EAIR of fatal hospitalizations were 12.0 (10.8-13.3), 23.0 (19.5-27.1), and 27.8 (22.1-34.9) per 100-PY for any infection; and 1.6 (1.2-2.1), 2.7 (1.7-4.2), and 4.8 (2.9-8.0) per 100-PY for SARS-COV-2 infections in 1L, 2L and 3L+ cohorts, respectively. Conclusions: This real-world analysis demonstrated substantial morbidity and mortality associated with overall and SARS-COV-2 infections among NHL patients, with a higher incidence in DLBCL compared to FL, and with increasing LoTs.

Impact of military deployment on non-Hodgkin lymphoma subtype.

e19070 Background: Approximately 3.5 million activity duty service members (ADSM) have deployed to Afghanistan or Iraq from 2001-2022. During deployments, ADSMs are potentially exposed to deployment-related toxins and carcinogens, which could theoretically alter cancer biology. In terms of non-Hodgkin lymphoma (NHL), it is unclear whether deployment affects NHL subtype or cancer-specific survival. Methods: Deployment and occupation data from the Defense Manpower Data Center was merged with data from the Department of Defense Tumor Registry. Documented cases of NHL diagnosed from 2001-2022 were identified. ADSMs and retirees were included; dependents and those under the age of 18 were excluded. Differences in NHL subtype (aggressive B-cell, indolent B-cell, T-cell) and cancer-specific survival were assessed by deployment status (previously deployed vs. never deployed). Occupation was assessed among those who deployed. Propensity score matching (2:1) for age at diagnosis, year of diagnosis, and gender was performed to minimize confounding. All data were carried out using SAS and Jump statistical software. This study was approved by the IRB. Results: There were 2,599 ADSMs and retirees diagnosed with NHL between 2001-2022. Approximately 15% had previously deployed (n=398). Compared with never deployed, military personnel who had previously deployed were more likely to have aggressive B-cell NHL (45% vs. 34%) and less likely to have indolent B-cell NHL (50% vs. 54%) or T-cell NHL (6% vs. 12%), p<0.001. Deployment to Iraq or Afghanistan did not impact NHL subtype. During deployment, occupations of Infantry, Engineering and Healthcare did not impact NHL subtype, whereas occupations of Pilot/Aircrew and Intelligence did, with less T-cell lymphoma diagnosed (0 vs. 7%, and 3% vs. 8%, respectively). When evaluating NHL subtype by race, it was noted that in comparison to White, Asian, Pacific Islander and Other Race, Black Race was associated with more T-cell NHL (21%), largely comprised of cutaneous T-cell lymphoma. Conclusions: After propensity score matching, prior deployment was associated with more aggressive B-cell lymphoma than military personnel who had never deployed. Deployment occupation affected NHL subtype diagnosed, with Pilots/Aircrew and Intelligence personnel being less likely to have T-cell lymphoma, whereas Black Race was associated with a higher likelihood of having T-cell lymphoma. This study sheds insights into the impact of deployment on cancer subtype. Ongoing investigations are assessing mortality differences by deployment as well as causes of death.

Patterns of vancomycin use in high-risk febrile neutropenia.

e23224 Background: Febrile neutropenia (FN) is a common complication in patients with hematologic malignancy. ASCO guidelines on the management of FN endorse empiric anti-Pseudomonas coverage while reserving the use of agents targeting gram-positive organisms and methicillin-resistant Staphylococcus aureus (MRSA) for select criteria-defined patients such as those with severe mucositis, hemodynamic instability, radiographic pneumonia, or history of MRSA colonization among others. We sought to examine our institutional management of FN, hypothesizing that local use of empiric vancomycin for high-risk FN will deviate from ASCO guidelines reflected in institutional policy. Methods: Case data from 1/1/2016 – 6/1/2023 was collected retrospectively, comprising patients admitted to the general medical floor with known leukemia, lymphoma, or multiple myeloma meeting ASCO criteria for FN. Patients admitted to intensive care at time of FN or for less than 48-hours were excluded. For each patient, use of vancomycin at time of FN diagnosis (t0) and 48-hours later (t48) was evaluated for congruence with society guidelines. Results: 91 patients were reviewed with a median age of 68 years old (IQR 59-74, 15). Median length of stay (LOS) was 20 days (IQR 7-29, 22) with FN occurring on day seven of hospitalization on average. Most patients receiving vancomycin were admitted to the hematology specialty unit at time of diagnosis (63%). Acute leukemia was the most common malignancy represented (62.8%), while high grade lymphoma comprised 23.1%. 98.9% of patients were on active chemotherapy at time of FN. 81 patients (89%) received vancomycin as empiric treatment for FN with 76 (93.8%) receiving vancomycin at t0. Of this latter cohort, 29.7% of patients received vancomycin at t0 without indication. At t48, vancomycin was discontinued in 28.4% of patients, 44.4% received vancomycin with true indication, and 27.2% were continued on vancomycin without indication. The median duration of therapy for patients receiving vancomycin incongruently at t48 was 4 days. Of those meeting criteria for vancomycin use at t48, severe mucositis and soft tissue infection were each cited in 22.2% of cases, followed by pneumonia, persistent fever, and hemodynamic instability. Notably, the presence of any grade mucositis was significantly associated with the continued use of empiric vancomycin at t48 (p = .025). Admission to hematology specialty unit did not significantly affect adherence to FN management guidelines. Conclusions: These data suggest that the use of vancomycin for FN at our institution deviates from society guidelines including on specialized hematology wards. This study was underpowered to assess adverse outcomes seen with vancomycin use such as renal injury, prolonged LOS and greater cost of care. Given the high complexity of this patient population, detailed provider education is indicated to promote safe, evidence-based care and broader antimicrobial stewardship.

Real world outcomes in patients with follicular lymphoma treated with RCHOP vs BR.

e19038 Background: In patients (pts) with (w) follicular lymphoma (FL), BR is associated w improved progression free survival (PFS) compared to RCHOP. In clinical practice, RCHOP is frequently utilized in pts w grade (G) 1-2 FL w high SUVs or Ki-67% proliferation index, and G 3A FL due to concern for transformation. Using real world data, we compared treatment trends and outcomes in pts w FL treated w first line (1L) BR versus (vs) RCHOP. Methods: This study used the nationwide Flatiron Health electronic health record-derived de-identified database. Pts diagnosed w FL G 1-2 or 3A and treated between (bt) 2011-2022 w 1L BR or RCHOP were included. The primary objective was to compare time to next treatment or death (TTNT) bt the two cohorts. Overall survival (OS), and transformation and POD24 rate were also analyzed. Univariable and multivariable Cox regression models were used to evaluate the impact of various clinical factors (sex, ethnicity, ECOG PS, treatment center type, FL G, FLIPI, rituximab maintenance [mtn]) on TTNT and OS. Results: The study included 2,089 pts; 1,475 pts received BR (BR n=1387, BO [obinutuzumab] n=88,), and 614 pts received RCHOP (RCHOP n=459, OCHOP n=8, RCEOP [etoposide] n=4, RCHP n=1, RCEP n=1, RCVP n=137, OCVP n=4). Median age at diagnosis was 64. Most patients were male (53%), non-Hispanic (90%), had advanced stage disease (82%), ECOG PS 0 (57%), G 1-2 FL (85%), intermediate FLIPI (62%), were treated at a community practice (83%), and did not receive rituximab mtn (54%). At median follow up of 90 mos, median TTNT bt BR and RCHOP was 96 vs 78 mos (HR 1.146, 95% CI 0.986-1.332, p = 0.076). In a multivariable model, there was no significant association bt RCHOP and TTNT. Male sex, ECOG PS ≥ 2, and high FLIPI were associated w worse TTNT, and Rituximab mtn w improved TTNT. Among G 3A pts (n=304), more pts received RCHOP (57% vs 43%), and median TTNT bt BR and RCHOP was 73 vs 78 mos (HR 0.787, 95% CI 0.542-1.142, p=0.207). Median OS bt BR vs RCHOP was 126 vs 138 months (HR 0.878, 95% CI 0.718-1.075, p=0.207). Male sex, ECOG PS ≥ 2, high FLIPI, and treatment in community setting were associated w worse OS. Rituximab mtn was associated w improved OS. 115 (5.5%) pts had transformation to aggressive lymphoma. Transformation rates bt BR vs RCHOP were 4.83% vs 6.50% (p=0.2) among all G 1-2 pts (n=1785), and 3.85% vs 9.2% (p=0.069) among all G 3A pts (n=304). 310 (14.8%) pts had POD 24, including 13.3% of all pts treated with BR and 18.6% with RHCOP (p=0.002). Autologous stem cell transplant (ASCT) was used in 26 (8.4%) POD 24 pts, among whom there was no difference in ASCT rate bt BR vs RCHOP (8.2% vs 8.8%, p=0.9). Conclusions: This retrospective analysis of real-world data showed clinical improvement in TTNT w BR compared to RCHOP in all FL patients. Among patients w G 3A FL, there was no significant improvement in TTNT with RCHOP. Rituximab mtn was associated w improved OS. Rate of transformation was higher in G 3A patients treated with RCHOP. There was low rate of ASCT in POD24 pts.

Long term results of a new treatment strategy for follicular low grade lymphoma (FLGL).

e19035 Background: FLGL usually presents with widespread but asymptomatic lymphadenopathy, low SUVs on PET and normal LDH. It's considered incurable and standard of care has been 'watch and wait' (W&W) followed later by treatment if necessary. We have described a subset of patients that we termed clinically discordant indolent histology (“CDIH”) whose behavior is more aggressive. CDIH is defined as presence of any of these: B symptoms, high LDH, SUV >14 on PET, Ki-67 index >30% or involvement of areas such as lung, pleura, soft-tissue, CNS and bones. Our study aims to assess real-world long-term outcome of managing FLGL with and without CDIH. Methods: We analyzed 186 previously untreated FLGL cases treated at our center from June 2002-July 2023, without opting for W&W. CDIH cases typically received R-CHOP x6, then 4 FND. Non-CDIH mainly received FND-R. All received 2 years maintenance rituximab. Main objective was to assess 10-year PFS and OS of stage IV cases, comparing it in a real-world setting against our previously published MD Anderson (MDACC) data. Secondary objectives were to compare our 10-year PFS and OS in stage IV cases against historical controls based on the FLIPI-2 score. We also sought to determine prognostic value of CDIH as compared to FLIPI-2, evaluate early relapse rate (2 yrs), and assess rate of transformation to aggressive lymphoma. Results: Median age: 58 (26-93). Median follow up: 96 mos (6-261). Stage III-IV: 76%. CDIH was present in 56%. Our PFS 10 yrs for non-CDIH=96% vs CDIH=77% (p=0.002). For stage IV, PFS 10 yrs = 82% vs MDACC's 50% using FND-R. OS 10-yr= 90% vs MDACC's 85%. 67 pts were followed >10 years; a relapse occurred in only 5 (7%). Our PFS 10 yr for favorable FLIPI-2 (score 0)= 97%, for intermediate (1-2) =88%, unfavorable (3-5)= 72% (p=.15). Our PFS results were consistently superior to literature data across all FLIPI-2 scores. Transformation to DLBCL= 6/186 (3%) compared to 20-30% historical controls; 5 of 6 transformations were in cases with CDIH and 4 occurred within 3 yrs. Early (<2 yr) relapse rate= 2% in contrast with 20% literature data; all 4 early relapses were CDIH. Conclusions: Our findings emphasize several advantages of initiating treatment early and basing it on presence or absence of CDIH. Our data highlight the need to 1- identify CDIH for potential use of doxorubicin treatment. 2- CDIH as prognostic factor seems more effective than FLIPI-2. 3- PFS 10 yr results are remarkably superior to both literature controls and to our previous experience at MDACC with FND-R. 4- Only 7% relapses beyond 10 yrs suggest potential for cure, according to our results and those from MDACC. [Table: see text]

Identification of a prognostic signature based on five ferroptosis-related genes for diffuse large B-cell lymphoma.

Therapies for diffuse large B-cell lymphoma (DLBCL) are limited due to the diverse gene expression profiles and complicated immune microenvironments, making it an aggressive lymphoma. Beyond this, researches have shown that ferroptosis contributes to tumorigenesis, progression, and metastasis. We thus are interested to dissect the connection between ferroptosis and disease status of DLBCL. We aim at generating a valuable prognosis gene signature for predicting the status of patients of DLBCL, with focus on ferroptosis-related genes (FRGs). To examine the connection between ferroptosis-related genes (FRGs) and clinical outcomes in DLBCL patients based on public datasets. An expression profile dataset for DLBCL was downloaded from GSE32918 (https://www.ncbi.nlm.nih.gov/geo/ query/acc.cgi?acc=gse32918), and a ferroptosis-related gene cluster was obtained from the FerrDb database (http://www. zhounan.org/ferrdb/). A prognostic signature was developed from this gene cluster by applying a least absolute shrinkage and selection operator (LASSO) Cox regression analysis to GSE32918, followed by external validation. Its effectiveness as a biomarker and the prognostic value was determined by a receiver operator characteristic curve mono factor analysis. Finally, functional enrichment was evaluated by the package Cluster Profiler of R. Five ferroptosis-related genes (FRGs) (GOP1, GPX2, SLC7A5, ATF4, and CXCL2) associated with DLBCL were obtained by a multivariate analysis. The prognostic power of these five FRGs was verified by TCGA (https://xenabrowser.net/datapages/?dataset=TCGA.DLBC.sampleMap%2FHiSeqV2_PANCAN&host=https%3A%2F%2Ftcga.xenahubs.net&removeHub=https%3A%2F%2Fxena.treehouse.gi.ucsc.edu%3A44) and GEO (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=gse 32918) datasets, with ROC analyses. KEGG and GO analyses revealed that upregulated genes in the high-risk group based on the gene signature were enriched in receptor interactions and other cancer-related pathways, including pathways related to abnormal metabolism and cell differentiation. The newly developed signature involving GOP1, GPX2, SLC7A5, ATF4, and CXCL2 has the potential to serve as a prognostic biomarker. Furthermore, our results provide additional support for the contribution of ferroptosis to DLBCL.

New classifications of B-cell neoplasms: a comparison of 5th WHO and International Consensus classifications.

In 2024, the World Health Organization (WHO) launched a new classification of lymphoid neoplasms, a revision of the previously used Revised 4th Edition of their classification (WHO-4R). However, this means that two classifications are now in simultaneous use: the 5th Edition of the WHO classification (WHO-5) and the International Consensus Classification (ICC). Instead of a comprehensive review of each disease entity, as already described elsewhere, this review focuses on revisions made in both the WHO-5 and ICC from WHO-4R and discrepancies between them regarding B-cell neoplasms. Similarities include cutaneous marginal zone lymphoma, cold agglutinin disease, non-primary effusion lymphoma-type effusion-based lymphoma, and gray zone lymphoma. Differences include plasma cell neoplasms, high-grade B-cell lymphoma (double hit lymphoma), follicular lymphoma, LPD with immune deficiency and dysregulation, extranodal large B-cell lymphoma, transformations of indolent B-cell lymphomas, and diffuse large B-cell lymphoma, not otherwise specified. Understanding the similarities and differences between the two latest classifications will aid daily diagnostic practice and future research on lymphoid neoplasms.

MALT1 substrate cleavage: what is it good for?

CARD-BCL10-MALT1 (CBM) signalosomes connect distal signaling of innate and adaptive immune receptors to proximal signaling pathways and immune activation. Four CARD scaffold proteins (CARD9, 10, 11, 14) can form seeds that nucleate the assembly of BCL10-MALT1 filaments in a cell- and stimulus-specific manner. MALT1 (also known as PCASP1) serves a dual function within the assembled CBM complexes. By recruiting TRAF6, MALT1 acts as a molecular scaffold that initiates IκB kinase (IKK)/NF-κB and c-Jun N-terminal kinase (JNK)/AP-1 signaling. In parallel, proximity-induced dimerization of the paracaspase domain activates the MALT1 protease which exerts its function by cleaving a set of specific substrates. While complete MALT1 ablation leads to immune deficiency, selective destruction of either scaffolding or protease function provokes autoimmune inflammation. Thus, balanced MALT1-TRAF6 recruitment and MALT1 substrate cleavage are critical to maintain immune homeostasis and to promote optimal immune activation. Further, MALT1 protease activity drives the survival of aggressive lymphomas and other non-hematologic solid cancers. However, little is known about the relevance of the cleavage of individual substrates for the pathophysiological functions of MALT1. Unbiased serendipity, screening and computational predictions have identified and validated ~20 substrates, indicating that MALT1 targets a quite distinct set of proteins. Known substrates are involved in CBM auto-regulation (MALT1, BCL10 and CARD10), regulation of signaling and adhesion (A20, CYLD, HOIL-1 and Tensin-3), or transcription (RelB) and mRNA stability/translation (Regnase-1, Roquin-1/2 and N4BP1), indicating that MALT1 often targets multiple proteins involved in similar cellular processes. Here, we will summarize what is known about the fate and functions of individual MALT1 substrates and how their cleavage contributes to the biological functions of the MALT1 protease. We will outline what is needed to better connect critical pathophysiological roles of the MALT1 protease with the cleavage of distinct substrates.

L-LOP/LOPP for the treatment of canine gastrointestinal/hepatosplenic lymphoma

Canine gastrointestinal (GI) and hepatosplenic (HS) high-grade (large cell) lymphomas are uncommon forms of canine lymphomas, with a very poor response to chemotherapy and a very poor prognosis. Currently, there are no established effective chemotherapy protocols for canine GI/HS lymphomas. This case series aimed to retrospectively evaluate the efficacy of lomustine-based protocols L-LOP (L-asparaginase, lomustine, vincristine, and prednisolone) and L-LOPP (with the addition of procarbazine) for treatment of canine GI/HS lymphomas. Medical records of dogs with cytologically or histologically diagnosed lymphoma at CityU Veterinary Medical Centre from 2019 to 2022 were retrospectively reviewed. The L-LOP/LOPP treatment protocol was well tolerated with rare severe adverse events. Median progression-free survival for GI and HS lymphoma was 56 days (range, 10–274 days) and 57 days (range 8–135 days) respectively; while median survival time for GI and HS lymphoma was 93 days (range 10–325 days) and 210 days (range 8–240 days) respectively.

Primary cutaneous, epidermotropic mycosis fungoides-like presentation: critical appraisal and description of two novel cases, broadening the spectrum of ALK+ T-cell lymphoma.

Leading from a two-case series, including two patients receiving a diagnosis of epidermotropic T-cell lymphoma, featuring a mycosis fungoides (MF)-like clinical pattern and ALK expression and molecular alteration, we performed a critical appraisal of ALK+ primary cutaneous T-cell lymphomas (pcTCL). Considering our patients and the literature, 32 cases were retrieved, 7 of which featured an MF-like clinical picture over a 4-to-20-year period. MF-like cases show distinctive histology, comprising a predominantly epidermotropic infiltration of small-to-large, atypical-to-pleomorphic, with few anaplastic cells, negligible-to-intense CD30-expression, and a CD4+/cytotoxic granule+ phenotype. These features should prompt a search for ALK expression captured by the ALK D5F3 clone. Bona fide ALK+ pcTCL is very rare, and existent data suggest the presence of a broader pattern of disease, including instances mimicking MF and/or primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma. The major challenges in dealing with this subset include prodromal phases, misinterpreted as inflammatory dermatosis or parapsoriasis/early phase MF both clinically and histologically, while recognition of its ALK-driven biology is hampered both by the unusual clinic-pathologic pattern of the disease, which stands apart from the classical (i.e., nodal) picture of ALK+ anaplastic large cell lymphoma and by the low sensitivity of ALK1 clone. Data on its optimal management are far from being conclusive: An MF-like approach is currently chosen, but depending on CD30 and, most notably, ALK expression, a targeted therapy could be envisaged in advanced stages, as clinical response to ALK inhibition was documented in one patient.

Semimethylation is a feature of diffuse large B-cell lymphoma, and subgroups with poor prognosis are characterized by global hypomethylation and short telomere length

BackgroundLarge B-cell lymphoma (LBCL) is the most common lymphoma and is known to be a biologically heterogeneous disease regarding genetic, phenotypic, and clinical features. Although the prognosis is good, one-third has a primary refractory or relapsing disease which underscores the importance of developing predictive biological markers capable of identifying high- and low-risk patients. DNA methylation (DNAm) and telomere maintenance alterations are hallmarks of cancer and aging. Both these alterations may contribute to the heterogeneity of the disease, and potentially influence the prognosis of LBCL.ResultsWe studied the DNAm profiles (Infinium MethylationEPIC BeadChip) and relative telomere lengths (RTL) with qPCR of 93 LBCL cases: Diffuse large B-cell lymphoma not otherwise specified (DLBCL, n = 66), High-grade B-cell lymphoma (n = 7), Primary CNS lymphoma (n = 8), and transformation of indolent B-cell lymphoma (n = 12). There was a substantial methylation heterogeneity in DLBCL and other LBCL entities compared to normal cells and other B-cell neoplasms. LBCL cases had a particularly aberrant semimethylated pattern (0.15 ≤ β ≤ 0.8) with large intertumor variation and overall low hypermethylation (β > 0.8). DNAm patterns could not be used to distinguish between germinal center B-cell-like (GC) and non-GC DLBCL cases. In cases treated with R-CHOP-like regimens, a high percentage of global hypomethylation (β < 0.15) was in multivariable analysis associated with worse disease-specific survival (DSS) (HR 6.920, 95% CI 1.499–31.943) and progression-free survival (PFS) (HR 4.923, 95% CI 1.286–18.849) in DLBCL and with worse DSS (HR 5.147, 95% CI 1.239–21.388) in LBCL. These cases with a high percentage of global hypomethylation also had a higher degree of CpG island methylation, including islands in promoter-associated regions, than the cases with less hypomethylation. Additionally, telomere length was heterogenous in LBCL, with a subset of the DLBCL-GC cases accounting for the longest RTL. Short RTL was independently associated with worse DSS (HR 6.011, 95% CI 1.319–27.397) and PFS (HR 4.689, 95% CI 1.102–19.963) in LBCL treated with R-CHOP-like regimens.ConclusionWe hypothesize that subclones with high global hypomethylation and hypermethylated CpG islands could have advantages in tumor progression, e.g. by inactivating tumor suppressor genes or promoting treatment resistance. Our findings suggest that cases with high global hypomethylation and thus poor prognosis could be candidates for alternative treatment regimens including hypomethylating drugs.

Prognostic role of the updated Kiel classification in canine high-grade T-cell lymphomas.

The aim of this study was to determine and describe the prognostic role of the morphological subtype determined according to the updated Kiel classification in dogs with high-grade T-cell lymphomas (HGTCLs) depending on the treatment applied. The HGTCLs were classified into three subtypes according to the updated Kiel classification: pleomorphic mixed (PM), lymphoblastic lymphoma/acute lymphoblastic leukaemia and plasmacytoid (P). The treatment was divided into a palliative therapy (PlT) group and a chemotherapy (ChT) group. The study was conducted between 2009 and 2017, and it enrolled 58 dogs in which cytomorphological and immunocytochemistry diagnoses were HGTCL. Overall survival (OS) was significantly longer in the ChT group (median OS-4 months, interquartile range [IQR] from 2 to 8 months) than in the PlT group (median OS-6 weeks, IQR from 1 week to 3 months). In the PlT group, PM subtype and glucocorticosteroids (GCSs) treatment proved significantly and independently linked to longer OS and approximately three-fold lower risk of death during the study period (adjusted hazard ratio [HRadj] = 0.26, confidence interval [CI] 95%: 0.08-0.81; p = 0.020 and HRadj = 0.30, CI 95%: 0.11-0.77; p = 0.013, respectively), although due to small group size, precision of estimations was poor (wide CI 95%). In the ChT group, >7 days elapsing between diagnosis and the beginning of chemotherapy and GCS treatment prior to chemotherapy were significantly associated with lower chance of complete remission (CR; p = 0.034 for both); GCS treatment prior to chemotherapy was significantly associated with shorter OS (p = 0.016); chemotherapy based on the modified CHOP protocol was significantly associated with higher chance of CR (p = 0.034) and longer OS (p = 0.039); and CR was significantly linked to longer OS (p = 0.001). The morphological subtype of HGTCL has some prognostic value in dogs treated palliatively (with PM subtype associated with longer OS than P subtype); however, this effect is no longer visible when a dog is treated with chemotherapy.

Plasmablastic lymphoma: 2024 update on diagnosis, risk stratification, and management.

Plasmablastic lymphoma (PBL) is a rare CD20-negative aggressive lymphoma with a poor prognosis under standard treatment options. Though PBL is associated with human immunodeficiency virus infection and other immunosuppressed states, it can also affect immunocompetent individuals. The diagnosis requires a high clinical suspicion and pathological confirmation. EBER expression and MYC gene rearrangements are frequently detected. The differential diagnosis includes EBV+ diffuse large B-cell lymphoma, extracavitary primary effusion lymphoma, ALK+ DLBCL, and HHV8+ large B-cell lymphoma, among others. Age ≥60 years, advanced clinical stage, and high intermediate and high International Prognostic Index scores are associated with worse survival. Combination chemotherapy regimens, such as EPOCH, are recommended. The addition of bortezomib, lenalidomide, or daratumumab might improve outcomes. Including PBL patients and their participation in prospective clinical trials is warranted.

Generation and External Validation of a Histologic Transformation Risk Model for Patients with Follicular Lymphoma

Follicular lymphoma (FL) is the most frequent indolent lymphoma. Some patients (10%-15%) experience histologic transformation (HT) to a more aggressive lymphoma, usually diffuse large B-cell lymphoma (DLBCL). This study aimed to validate and improve a genetic risk model to predict HT at diagnosis.We collected mutational data from diagnosis biopsies of 64 FL patients. We combined them with the data from a previously published cohort (total n = 104; 62 from nontransformed and 42 from patients who did transform to DLBCL). This combined cohort was used to develop a nomogram to estimate the risk of HT. Prognostic mutated genes and clinical variables were assessed using Cox regression analysis to generate a risk model. The model was internally validated by bootstrapping and externally validated in an independent cohort. Its performance was evaluated using a concordance index and a calibration curve.The clinicogenetic nomogram included the mutational status of 3 genes (HIST1HE1, KMT2D, and TNFSR14) and high-risk Follicular Lymphoma International Prognostic Index and predicted HT with a concordance index of 0.746. Patients were classified as being at low or high risk of transformation. The probability HT function at 24 months was 0.90 in the low-risk group vs 0.51 in the high-risk group and, at 60 months, 0.71 vs 0.15, respectively. In the external validation cohort, the probability HT function in the low-risk group was 0.86 vs 0.54 in the high-risk group at 24 months, and 0.71 vs 0.32 at 60 months. The concordance index in the external cohort was 0.552. In conclusion, we propose a clinicogenetic risk model to predict FL HT to DLBLC, combining genetic alterations in HIST1H1E, KMT2D, and TNFRSF14 genes and clinical features (Follicular Lymphoma International Prognostic Index) at diagnosis. This model could improve the management of FL patients and allow treatment strategies that would prevent or delay transformation.

Clinical analysis of 18 children with aggressive mature B-cell lymphoma after liver transplantation

Objective: To summarize the clinical characteristics, prognostic factors and treatment outcomes of childhood aggressive mature B-cell lymphoma after liver transplantation. Methods: This retrospective study included 18 children with newly diagnosed aggressive mature B-cell lymphoma after liver transplantation and treated from June 2018 to June 2022 in the Department of Hematology and Oncology of Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine. Clinical characteristics, treatment and outcomes of patients at last evaluation were analyzed. Overall survival (OS) and event free survival (EFS) rates were calculated by Kaplan-Meier method and Log-Rank analysis was performed to find factors of poor prognosis. Results: Among all 18 patients, there were 6 males and 12 females, and the age of onset was 40 (35, 54) months. The interval from transplant to tumor diagnosis was 21 (17, 35) months and 5 patients had early onset disease (<1 year since transplant). Seventeen patients had abdominal lesions. Diarrhea, vomiting and abdominal masses were the main clinical manifestations. All patients were Epstein-Barr virus (EBV) related posttransplant lymphoproliferative disorders (PTLD). One patient received individualized therapy due to critical sick at diagnosis, and the remaining 17 patients received CP (cyclophosphamide, methylprednisolone plus rituximab) and/or modified EPOCH (prednisone, etoposide, doxorubicin, vincristine, cyclophosphamide plus rituximab) regimens. Of all 18 patients, 15 cases got complete response, 2 cases got partial response, 1 patient died of severe infection. The 2-year OS and EFS rates of 18 patients were (94±5)% and (83±8)%, respectively. None of age, gender or early onset disease had effect on OS and EFS rates in univariate analysis (all P>0.05). Conclusions: The symptoms of PTLD were atypical. Close surveillance of EBV-DNA for patients after liver transplantation was crucial to early stage PTLD diagnosis. CP or modified EPOCH regimen was efficient for pediatric patients with aggressive mature B cell lymphoma after liver transplantation.

Molecular Mechanisms and Treatment Strategies for Helicobacter pylori-Induced Gastric Carcinogenesis and Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma.

Helicobacter pylori has been classified as a class I carcinogen by WHO because of its primary involvement in the development of gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. This review focuses on understanding the molecular pathophysiological mechanisms that operate within intracellular transduction pathways and their relevance in the treatment strategies for the two main diseases caused by H. pylori. H. pylori virulence factors such as cytotoxin-associated gene A and vacuolating cytotoxin A genotypes, inflammatory mediators, H. pylori-induced microRNA deregulation, alterations in autophagy proteins and regulators, and changes in DNA methylation are some of the molecular mechanisms that play essential roles in H. pylori infection and gastric carcinogenesis. The discovery of novel treatment strategies that target the deregulated intracellular transduction pathways in gastric carcinogenesis and MALT lymphoma is critical. H. pylori eradication (HPE) is not limited to H. pylori-dependent low-grade MALT lymphoma and may be used in patients with high-grade diffuse large B-cell lymphoma (DLBCL) (de novo or DLBCL-MALT lymphoma). The loss of H. pylori dependency and high-grade transformation appear to be distinct events in the progression of gastric lymphoma. Interestingly, patients with H. pylori-positive gastric DLBCL without histological evidence of MALT lymphoma (pure gastric DLBCL) may respond to HPE therapy.

A Rare Case of Aggressive Non-Hodgkin's Lymphoma of the Muscle in a Young Male Presenting as Necrotizing Myofasciitis

A Rare Case of Aggressive Non-Hodgkin's Lymphoma of the Muscle in a Young Male Presenting as Necrotizing Myofasciitis

Relapse after glofitamab has a poor prognosis and rates of CD20 loss are high.

We reviewed cases with aggressive B-cell non-Hodgkin lymphoma who relapsed or progressed following glofitamab. The prognosis was poor, with low rates of response to subsequent salvage therapies, and a median overall survival of 4.1 months from the time of progression. There were high rates of CD20 loss (59%) at the time of relapse. In a field where CD20 × CD3 bispecific antibodies are entering routine clinical use, our experience highlights a potential means of resistance. It illustrates both the need to further characterise mechanisms of CD20 loss, and to pursue clinical trials of novel non-CD20-directed treatments in this cohort.