UNASSIGNED: Fluorescence in situ hybridization (FISH) is an essential ancillary study used to identify clinically aggressive subsets of large B-cell lymphomas that have MYC, BCL2, or BCL6 rearrangements. Small-volume biopsies such as fine needle aspiration biopsy (FNAB) and core needle biopsy (CNB) are increasingly used to diagnose lymphoma and obtain material for ancillary studies such as FISH. However, the performance of FISH in small biopsies has not been thoroughly evaluated or compared to surgical biopsies.
UNASSIGNED: We describe the results of MYC, BCL2, and BCL6 FISH in a series of 222 biopsy specimens, including FNAB with cell blocks, CNBs, and surgical excisional or incisional biopsies from 208 unique patients aggregated from 6 academic medical centers. A subset of patients had FNAB followed by a surgical biopsy (either CNB or excisional biopsy) obtained from the same or contiguous anatomic site as part of the same clinical workup; FISH results were compared for these paired specimens.
UNASSIGNED: FISH had a low hybridization failure rate of around 1% across all specimen types. FISH identified concurrent MYC and BCL2 rearrangements in 20 of 197 (10%) specimens and concurrent MYC and BCL6 rearrangements in 3 of 182 (1.6%) specimens. The paired FNAB and surgical biopsy specimens did not show any discrepancies for MYC or BCL2 FISH; of the 17 patients with 34 paired cytology and surgical specimens, only 2 of the 49 FISH probes compared (4% of all comparisons) showed any discrepancy and both were at the BCL6 locus. One discrepancy was due to necrosis of the CNB specimen causing a false negative BCL6 FISH result when compared to the FNAB cell block that demonstrated a BCL6 rearrangement.
UNASSIGNED: FISH showed a similar hybridization failure rate in all biopsy types. Ultimately, MYC, BCL2, or BCL6 FISH showed 96% concordance when compared across paired cytology and surgical specimens, suggesting FNAB with cell block is equivalent to other biopsy alternatives for evaluation of DLBCL or HGBCL FISH testing.

High-grade B-cell lymphoma with 11q aberrations (HGBL-11q) has been classified for the first time as a high-grade mature B-cell neoplasm according to the 5th edition of the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues. HGBL-11q is morphologically and immunohistochemically similar to Burkitt lymphoma (BL) or HGBL; it is characterized by gain in the 11q23.2-11q23.3 region and loss in the 11q24.1-qter region but it lacks MYC translocation. HGBL-11q is a rare tumor, and its exact frequency in Japan remains unclear. In this study, we classified 113 Germinal center B-cell (GCB) type aggressive B-cell lymphomas (BCLs), which were divided into BL, high-grade (HG), and large cell (LC) morphologies. We performed fluorescence in situ hybridization (FISH) to identify 11q aberrations. Nine patients had 11q aberrations (7.96%, 9/113), including six HGBL-11q. The age range was from 8 to 87 years, and all were male. Six out of 14 patients with HG morphology were diagnosed with HGBL-11q (6/14, 42.9%). HGBL-11q has been found to occur primarily in children and young adults but also in middle-aged and older adults. Patients with HG morphology without MYC translocation should undergo FISH for 11q aberrations regardless of age. However, the pathogenesis, clinical findings, and prognosis of HGBL-11q remain unclear. The accumulation of cases with an accurate HGBL-11q diagnosis in daily practice and accurate and detailed data on HGBL-11q will contribute to further understanding of 11q aberrations.

UNASSIGNED: The optimal treatment of patients with systemic diffuse large B-cell (DLBCL) or high-grade B-cell (HGBL) lymphomas with synchronous central nervous system (CNS) involvement at diagnosis is not well defined. High-dose methotrexate administered concurrently with R-CHOP (RM-CHOP) is a commonly used regimen, but data on outcomes achieved with this regimen are limited.
UNASSIGNED: To report our experience with RM-CHOP in patients with systemic DLBCL or HGBL with synchronous CNS involvement at diagnosis.
UNASSIGNED: A single-center retrospective analysis.
UNASSIGNED: We identified consecutive patients with systemic DLBCL or HGBL with synchronous CNS involvement at diagnosis who were treated with RM-CHOP from January 2012 to January 2021.
UNASSIGNED: Fifty patients were included with a median age of 62 years; 82% had DLBCL (n = 41) and 18% had HGBL (n = 9). Treatment with RM-CHOP was followed by consolidative autologous hematopoietic cell transplantation in 14 patients (28%). The complete response (CR) rate following RM-CHOP was 62%. With a median follow-up of 40 months, the median progression-free (PFS) and overall (OS) survivals were 16 and 58 months, and the 2-year PFS and OS were 41% and 57%, respectively. The 2-year cumulative incidence of CNS progression/relapse was 29%. Outcomes were particularly poor in HGBL, with median PFS and OS of 6 and 7 months, compared with median PFS and OS of 22 months and not reached in DLBCL, respectively. The outcomes of patients with relapsed/progressive disease were poor, with only 63% of patients receiving subsequent treatments and only 21% achieving CR to next subsequent treatment. Most patients (58%) with disease relapse/progression had CNS involvement which was associated with very poor outcomes (median OS of 2 months).
UNASSIGNED: CNS involvement in aggressive B-cell non-Hodgkin lymphoma at diagnosis dictates clinical outcomes and requires more effective treatment options.

OBJECTIVE: It is unknown whether Epstein-Barr virus (EBV) infection can occur in high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit or triple-hit lymphoma (DHL/THL).
RESULTS: Here we report 16 cases of EBV+ DHL/THL from screening 846 cases of DHL/THL and obtaining additional EBV+ cases through multi-institutional collaboration: 8 MYC/BCL2 DHL, 6 MYC/BCL6 DHL, and 2 THL. There were 8 men and 8 women with a median age of 65 years (range, 32-86). Two patients had a history of follicular lymphoma and one had AIDS. Nine of 14 patients had an International Prognostic Index of ≥3. Half of the cases showed high-grade/Burkitt-like morphology and the other half diffuse large B-cell lymphoma morphology. By immunohistochemistry, the lymphoma cells were positive for MYC (n=14/16), BCL2 (n=12/16), BCL6 (n=14/16), CD10 (n=13/16), and MUM1 (n=6/14). By Hans algorithm, 13 cases were classified as GCB and 3 as non-GCB. The lymphomas frequently showed an EBV latency type I with a median EBV-encoded small RNAs of 80% positive cells (range, 20-100%). After a median follow-up of 36.3 months (range, 2.0-41.6), 7 patients died with a median survival of 15.4 months (range, 3.4-47.3) after diagnosis of EBV+ DHL/THL. Five of 6 patients with MYC/BCL6 DHL were alive including 4 in complete remission. In contrast, only 4/10 patients with MYC/BCL2 DHL or THL were alive including 2 in complete remission. The median survival in patients with MYC/BCL6 DHL was unreached and was 21.6 months in patients with MYC/BCL2 DHL or THL.
CONCLUSIONS: EBV infection in DHL/THL is rare (~1.5%). Cases of EBV+ DHL/THL are largely similar to their EBV-negative counterparts clinicopathologically. Our findings expand the spectrum of EBV+ B-cell lymphomas currently recognized in the WHO classification and suggest differences between EBV+ MYC/BCL2 and MYC/BCL6 DHL that may have therapeutic implications.

A few prospective trials in HIV-positive patients with Burkitt lymphoma (BL) or high-grade B-cell lymphoma (HGBL) have been reported. Investigated therapies have shown good efficacy but relevant safety problems, with high rates of interruptions, severe mucositis, septic complications, and fungal infections. Here, we report the results of a multicentre phase II trial addressing a new dose-dense, short-term therapy aimed at maintaining efficacy and improving tolerability. The experimental programme included a 36-day polychemotherapy induction followed by high-dose cytarabine-based consolidation and response-tailored BEAM (carmustine, etoposide, cyatarabine, and melphalan)- conditioned autologous stem cell transplantation (ASCT). This therapy would be considered active if ≥11 complete remissions (CR) after induction (primary endpoint) were recorded among 20 assessable patients. HIV-positive adults (median age 42, range 26-58; 16 males) with untreated BL (n = 16), HGBL (n = 3) or double-hit lymphoma (n = 1) were enrolled. All patients had high-risk features, with meningeal and bone marrow infiltration in five and nine patients respectively. The experimental programme was safe and active in a multicentre setting, with only two episodes of grade 4 non-haematological toxicity (hepatotoxicity and mucositis), and no cases of systemic fungal infections; two patients died of toxicity (bacterial infections). Response after induction (median duration: 47 days; interquartile range 41-54), was complete in 13 patients and partial in five [overall response rate = 90%; 95% confidence interval (CI) = 77-100]. All responders received consolidation, and five required autologous stem cell transplant. At a median follow-up of 55 (41-89) months, 14 patients are relapse-free and 15 are alive, with a five-year progression-free survival and an overall survival of 70% (95% CI = 60-80%) and 75% (95% CI = 66-84) respectively. No patient with cerebrospinal fluid (CSF)/meningeal lymphoma experienced central nervous system recurrence. With respect to previously reported regimens, this programme was delivered in a shorter period, and achieved the main goal of maintaining efficacy and improving tolerability.

Diffuse large B-cell lymphoma (DLBCL) is the most common histological transformation (HT) of follicular lymphoma (FL). Other types of HT are very rare, and their incidence, histopathology, and patient outcomes have not been sufficiently described. Here, we assessed the clinicopathological characteristics of 19 cases of non-DLBCL HT of FL in a single institution in Japan to advance the understanding of the disease. Among 889 consecutive patients diagnosed with FL between 2000 and 2018, 191 suffered HT (21%). The median follow-up period was 94 months (range = 3-225). A total of 172 patients (90%) had DLBCL transformation, whereas the remaining 19 patients (10%) exhibited non-DLBCL transformation. In the latter cases, the following diagnoses were made based on morphology, immunohistochemistry, flow cytometry, and fluorescence in situ hybridization analyses: classic Hodgkin lymphoma (7 patients; 4%); high-grade B-cell lymphoma (HGBL) with MYC and BCL2 rearrangements (4 patients; 2%); HGBL, not otherwise specified (4 patients; 2%); B-cell lymphoblastic leukemia/lymphoma (2 patients; 1%); anaplastic large-cell lymphoma-like lymphoma (1 patient; 0.5%); and plasmablastic lymphoma (1 patient; 0.5%). Epstein-Barr virus-encoded RNA-1 did not associate with HT in any of the cases tested (n = 8). Patients with non-DLBCL transformation showed poor outcomes, with a median overall survival of 13 months (range = 2 days-107 months); 10 of the patients (53%) died of HT. In conclusions, non-DLBCL transformation was observed in 10% of patients with HT from FL. Our data show that timely, accurate, and comprehensive histopathological diagnosis is needed to ensure optimal treatment and improve the outcome of these patients.

Objectives: Primary breast diffuse large B-cell lymphoma (PB-DLBCL) and primary breast high-grade B-cell lymphoma (PB-HGBCL) are rare extranodal aggressive B-cell lymphomas with distinct characteristics. Reliable data regarding appropriate treatment of these specific entities are lacking due to their rarity.Methods: We reviewed 36 patients diagnosed at four Chinese medical centres between January 2008 and December 2018. Data regarding clinicopathological features, therapeutic evaluation and central nervous system (CNS) relapse were collected, and overall survival (OS) and progression-free survival (PFS) were calculated.Results: Among the 36 patients, there were 29 PB-DLBCL patients and 7 PB-HGBCL patients. The 5-year OS for PB-DLBCL and PB-HGBCL was 75.9% and 28.6%, respectively. The 5-year PFS for PB-DLBCL and PB-HGBCL was 69.0% and 14.3%, respectively. The R-DAEPOCH regimen was significantly more effective in PB-DLBCL patients than the R-CHOP regimen (5-year OS: 78.9% vs 62.5%, P=0.024; 5-year PFS: 73.7% vs 50.0%, P=0.037) but resulted in more severe myelosuppression (P=0.025). The rate of CNS relapse was 17.2% in PB-DLBCL patients and 28.6% in PB-HGBCL patients; the difference was not significant (P=0.602). The R-DAEPOCH regimen did not predominantly reduce CNS recurrence as expected (P=0.616). The Cox proportional hazards model revealed that risk stratification and triple expression were independent prognostic factors.Conclusion: Current treatments, including more intensive chemotherapy regimens, achieve good control of the disease. Novel drugs combined with cellular immunotherapy initially show promising therapeutic effects, and more clinical trials are required to confirm these effects further.

Outcomes for patients with high-risk diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP chemotherapy are suboptimal but, to date, no alternative regimen has been shown to improve survival rates. This phase 2 trial aimed to assess the efficacy of a Burkitt-like approach for high-risk DLBCL using the dose-intense R-CODOX-M/R-IVAC regimen.
Eligible patients were aged 18-65 years with stage II-IV untreated DLBCL and an International Prognostic Index (IPI) score of 3-5. Patients received alternating cycles of CODOX-M (cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate) alternating with IVAC chemotherapy (ifosfamide, etoposide and high-dose cytarabine) plus eight doses of rituximab. Response was assessed by computed tomography after completing all four cycles of chemotherapy. The primary end point was 2-year progression-free survival (PFS).
A total of 111 eligible patients were registered; median age was 50 years, IPI score was 3 (60.4%) or 4/5 (39.6%), 54% had a performance status ≥2 and 9% had central nervous system involvement. A total of 85 patients (76.6%) completed all four cycles of chemotherapy. There were five treatment-related deaths (4.3%), all in patients with performance status of 3 and aged >50 years. Two-year PFS for the whole cohort was 67.9% [90% confidence interval (CI) 59.9-74.6] and 2-year overall survival was 76.0% (90% CI 68.5-82.0). The ability to tolerate and complete treatment was lower in patients with performance status ≥2 who were aged >50 years, where 2-year PFS was 43.5% (90% CI 27.9-58.0).
This trial demonstrates that R-CODOX-M/R-IVAC is a feasible and effective regimen for the treatment of younger and/or fit patients with high-risk DLBCL. These encouraging survival rates demonstrate that this regimen warrants further investigation against standard of care.
ClinicalTrials.gov (NCT00974792) and EudraCT (2005-003479-19).