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Summary: Diagnosis of primary central nervous system lymphoma (PCNSL) is challenging, and although brain biopsy remains the gold standard, cerebrospinal fluid (CSF) constitutes a less invasive source of lymphomatous biomarkers. In a retrospective cohort of 54 PCNSL cases tested at diagnosis or relapse, we evaluated the contribution of immunoglobulin heavy chain (IGH) gene clonality and MYD88 L265P detection on both CSF cell pellets and supernatants, in comparison with cytology, flow cytometry, interleukin (IL)‐10 and IL‐6 quantification. Clonality assessment included a new assay to detect partial IGH‐DJ rearrangements. Clonal IGH rearrangements and/or MYD88 L265P mutation were detected in 27 (50%) cell pellets and 24 (44%) supernatant cell‐free (cf) DNA. Combining analyses on both compartments, 36 (66%) cases had at least one detectable molecular marker, present only in cfDNA for 9 (16%) of them. While cytology and flow cytometry were positive in only 7 (13.0%) and 9 (17.3%) cases respectively, high IL‐10 levels were observed in 36 (66.7%) cases. Overall, taking into account molecular and cytokine results, 46/54 (85%) cases had at least one lymphomatous biomarker detectable in the CSF. These results show that this combination of biomarkers evaluated on both cell pellet and supernatant CSF fractions improves significantly the biological diagnosis of PCNSL. [ABSTRACT FROM AUTHOR]

Keywords: IGHV somatic hyper mutation; chronic lymphocytic leukaemia; chronic lymphocytic leukaemia subgroups EN IGHV somatic hyper mutation chronic lymphocytic leukaemia chronic lymphocytic leukaemia subgroups 809 810 2 06/08/20 20200601 NES 200601 Since the introduction of the I IGHV i gene somatic hypermutation (SHM) status as prognostic marker in chronic lymphocytic leukaemia (CLL) patients in the two 1999 landmark publications from the Stevenson and Chiorazzi groups (Damle I et al. i , [1]; Hamblin I et al. i , [5]), its value has been consistently confirmed in virtually all CLL cohorts analysed thus far. To distinguish good from poor prognostic CLL subgroups, a threshold of 98% identity to the closest germline (=unrearranged) immunoglobulin heavy variable ( I IGHV i ) gene was introduced. CLL cases showing a clonally rearranged I IGHV i gene with <98% identity to the closest I IGHV i gene (classified as IG-mutated CLL, M-CLL) constitute the more favourable group, while those with >=98% identity (unmutated CLL, U-CLL) represent the adverse group. [Extracted from the article]

Nucleotide insertions/duplications or deletions in immunoglobulin heavy chain genes have been found in 24/760 patients (3.15%) with chronic lymphocytic leukemia (CLL). In 21/24 cases, the inserted/duplicated or lost nucleotides occurred in multiples of 3; therefore, the original reading frame was maintained and a potentially intact receptor was coded. The pattern and location of insertions/duplications or deletions in CLL and their restriction to mutated IGHV rearranged genes strongly suggests that they resulted from somatic hypermutation. Their incidence in CLL is consistent with previous reports in normal, auto-reactive and neoplastic human B cells, thus seemingly indicating that these modifications generally arise without any particular disease-specific associations. A striking exception to this rule was identified in CLL IGHV3-21-expressing cases: one amino acid was deleted from the CDR2 region in 16/63 (25.4%) mutated CLL IGHV3-21 sequences (including public database-derived IGHV3-21 CLL cases + the present series) vs. only 2/257 (0.78%) public database-derived mutated non-CLL IGHV3-21 sequences; 15/16 CLL IGHV3-21 sequences carrying this deletion belonged to a subset with unique, shared HCDR3 and light chain CDR3 motifs. This finding further supports the idea of selective antigenic pressures playing a pathogenetic role in some CLL cases. [ABSTRACT FROM AUTHOR]

We report the unusual transformation of a case of Waldenström's macroglobulinemia (WM) into IgM multiple myeloma (MM). The initial clinical and biological presentation of the disease was typical smouldering WM, with lymphocytic infiltration of the bone marrow. Five years later, signs of transformation appeared: the patient presented with diffuse osteolytic bone lesions without organomegaly, and the bone marrow was infiltrated with characteristic malignant plasma cells. Electron microscopy (EM) examination showed that the endoplasmic reticulum (ER) of the dysmorphic plasma cells contained monoclonal IgM. Immunolabeling for calreticulin, a resident protein of the ER, demonstrated unequivocally that the characteristic intranuclear inclusions were indeed part of ER. Flow cytometry revealed an MM profile for the cellular proliferation. Molecular biology performed on the final marrow could only retrieve a single cellular clone. In conclusion, this is the first documented description of the transformation of typical WM into an aggressive form of MM. [ABSTRACT FROM AUTHOR]

Primary intraocular lymphoma (PIOL) is a rare presentation of lymphoma that is particularly difficult to recognize. In our institution, 36 cases of PIOL were diagnosed between March 1997 and July 2002. The recognition of lymphoma cells by cytology with or without immunophenotyping on slides generated a strong suspicion of the diagnosis in 34 of 36 cases. The diagnosis was confirmed by measurement of interleukin-10 (IL-10) in the vitreous humour or aqueous humour; high levels were observed in 35 of 36 cases, all were of B-cell origin. As expected, the only case with T-cell lymphoma had a very low level of IL-10. Furthermore, IL-10 levels excluded this diagnosis in two cases that were incorrectly suspected of PIOL after cytological examination. Finally, detection of clonality by polymerase chain reaction techniques, performed in 29 cases, represented a helpful tool in diagnosing PIOL as this approach definitively confirmed the diagnosis of B- or T-cell lymphoma in 17 cases. [ABSTRACT FROM AUTHOR]

Alteration of the tumour suppressor gene p53 is frequent in AIDS-related non-Hodgkin's lymphomas (AIDS-NHL), particularly in Burkitt's or Burkitt's-like lymphomas (BL/BLL). Since mechanisms of inactivation other than mutations have been advanced, the transcriptional activity of the p53 protein was studied in a functional assay in yeast in a series of AIDS-NHL lesions and compared with their morphology, immunohistochemistry (IHC) and single-strand conformation polymorphism (SSCP) analysis detection of other p53 abnormalities, Epstein-Barr virus (EBV) status, MDM-2 oncoprotein expression and c-MYC rearrangement. Polymorphic lymphoproliferations (PL), identified as precursors of NHL in HIV-patients, were also analysed in attempt to detect p53 modifications related to clonal progression. The functional assay detected p53 mutants in 40% (12/30) of the tumours: 50% (6/12) of BL/BLL, 40% (4/10) of diffuse large cell lymphomas (DLCL) and 25% (2/8) of PL. An oligoclonal or monoclonal population was identified in the two PL cases with mutant p53. An accumulation of the p53 protein was detected by IHC in 26% (8/30) of the tumours (five BL/BLL and three DLCL) and was associated with positive functional assay. In the 20 lesions tested by both of the screening methods for mutations, a p53 mutant pattern was detected in 55% of cases (11/20) and in 25% of cases (5/20) respectively with the functional assay and SSCP analysis of exons 5–8. There was no inverse correlation between the detection of EBV genome and the presence of p53 mutations and no overexpression of MDM-2 protein for the whole series. In conclusion, the functional assay was more sensitive than IHC and SSCP for the detection of p53 mutations in tumour samples. The mutations identified in AIDS-NHL lesions inactivate the p53 protein and in PL they could represent a selection of an aggressive clone. [ABSTRACT FROM AUTHOR]

The prognosis of relapsed primary central nervous system lymphoma (PCNSL) remains dismal. CAR T-cells are a major contributor to systemic lymphomas, but their use in PCNSL is limited. From the LOC network database, we retrospectively selected PCNSL who had leukapheresis for CAR-T cells from the third line of treatment, and, as controls, PCNSL treated with any treatment, at least in the third line and considered not eligible for ASCT. Twenty-seven patients (median age: 68, median of three previous lines, including ASCT in 14/27) had leukapheresis, of whom 25 received CAR T-cells (tisa-cel: N = 16, axi-cel: N = 9) between 2020 and 2023. All but one received a bridging therapy. The median follow-up after leukapheresis was 20.8 months. The best response after CAR-T cells was complete response in 16 patients (64%). One-year progression-free survival from leukapheresis was 43% with a plateau afterward. One-year relapse-free survival was 79% for patients in complete or partial response at CAR T-cell infusion. The median overall survival was 21.2 months. Twenty-three patients experienced a cytokine release syndrome and 17/25 patients (68%) a neurotoxicity (five grade ≥3). The efficacy endpoints were significantly better in the CAR T-cell group than in the control group (N = 247) (median PFS: 3 months; median OS: 4.7 months; p < 0.001). This series represents the largest cohort of PCNSL treated with CAR T-cells reported worldwide. CAR T-cells are effective in relapsed PCNSL, with a high rate of long-term remission and a reassuring tolerance profile. The results seem clearly superior to those usually observed in this setting., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Hepatitis C virus (HCV) infection increases the risk of B-cell non-Hodgkin lymphomas (B-NHL). Antiviral treatment (AT) can induce hematological responses in patients with marginal zone lymphomas (MZL). The ANRS HC-13 Lympho-C study aimed at a better understanding of the impact of AT on HCV associated B-NHL. This multicentric study enrolled 116 HCV-positive patients with B-NHL between 2006 and 2012. Cytological and histological samples were collected for centralized review. At lymphoma diagnosis, median age was 61 years and gender ratio M/F was 1. Cytohistological distribution was marginal zone lymphoma (MZL) n = 45 (39%), diffuse large B-cell lymphoma (DLBCL) n = 45 (39%), and other types n = 26 (22%). MZL patients had more frequent detection of rheumatoid factor (68% vs. 35%; P = 0.001) and more frequently mixed cryoglobulinemia (74% vs. 44%; P = 0.021) than patients with DLBCL. Among patients receiving AT, a sustained virologic response was achieved in 23 of 38 (61%) patients with MZL and in 9 of 17 (53%) with DLBCL (P = 0.42). Three-year overall survival (OS) and progression-free survival were 78% 95%CI [63-88] and 64% [48-76], respectively, without difference between cytohistological groups. Outcome analysis showed a favorable association between OS and AT in all patients (P = 0.05) and in the subgroup of MZL patients only (P = 0.04). Our data support that AT improves the outcomes of HCV-associated NHLs. The impact of new AT regimen with protease inhibitor needs to be investigated in this setting. [clinicalTrials.gov Identification number NCT01545544], (© 2014 Wiley Periodicals, Inc.)

Objective: The association of hepatitis C virus (HCV) infection with type II mixed cryoglobulinemia is well established, but the role of HCV in B cell lymphoma remains controversial. The objective of this study was to determine the frequency of circulating and liver-infiltrating monoclonal B cells in patients with HCV infection., Methods: One hundred sixty patients were studied prospectively, including 115 HCV-positive patients and 45 HCV-negative patients with other nonimmune chronic liver disease(s). B cell clonality was determined by DNA amplification of the IgH rearrangements, followed by polyacrylamide gel electrophoresis., Results: A clonal B cell population was detected in the blood of 21 (26%) of 81 HCV-positive patients whose cryoglobulin status was known, including 12 of 25 patients with type II cryoglobulinemia, 2 of 12 patients with type III cryoglobulinemia, and 7 of 44 patients without cryoglobulins. A clonal IgH rearrangement was detected in 26 (32%) of 81 liver biopsy specimens from HCV- infected patients, including 16 patients with a circulating clonal population. A clonal B cell population was not observed in the blood of 40 patients with non-HCV liver diseases and was present in only 1 (3%) of 30 liver biopsy specimens. Logistic regression analysis showed that HCV-infected patients with clonal B cell proliferation in both the blood and liver were older (P = 0.004) and had longer duration of HCV infection (P = 0.009), higher serum cryoglobulin levels (P = 0.001) that were more frequently symptomatic (P < 0.03), and liver disease that was more severe than that in patients without a clonal B cell population in the blood or liver (P = 0.05). In 4 of 16 patients with a clonal B cell population in both the blood and liver, a definite B cell malignancy was finally diagnosed., Conclusion: Clonal B lymphocytes are frequently detected in the blood and liver of patients with chronic HCV infection, in the absence of overt B cell malignancy. These clones are usually, but not always, associated with the presence of type II cryoglobulins. A high percentage of patients with B cell clonality in both the blood and liver were finally diagnosed as having a definite B cell malignancy.

Primary intraocular lymphoma (PIOL) is a rare presentation of lymphoma that is particularly difficult to recognize. In our institution, 36 cases of PIOL were diagnosed between March 1997 and July 2002. The recognition of lymphoma cells by cytology with or without immunophenotyping on slides generated a strong suspicion of the diagnosis in 34 of 36 cases. The diagnosis was confirmed by measurement of interleukin-10 (IL-10) in the vitreous humour or aqueous humour; high levels were observed in 35 of 36 cases, all were of B-cell origin. As expected, the only case with T-cell lymphoma had a very low level of IL-10. Furthermore, IL-10 levels excluded this diagnosis in two cases that were incorrectly suspected of PIOL after cytological examination. Finally, detection of clonality by polymerase chain reaction techniques, performed in 29 cases, represented a helpful tool in diagnosing PIOL as this approach definitively confirmed the diagnosis of B- or T-cell lymphoma in 17 cases.