Late-Onset Hematological Toxicity (LOHT) in Patients with B-Cell Lymphomas: A Survey in 758 Cases

ABSTRACT Background: The increasing survival of patients with non-Hodgkin lymphoma has allowed the diagnosis of long-term complications, including late-onset hematological toxicity (LOHT), transitory cytopenias, or therapy-related myeloid neoplasm (t-MDS/t-AML). Objective: The objective of the study was to determine the frequency and clinical evolution of LOHT in patients with lymphoproliferative malignancies. Materials and Methods: Two cohorts of patients B-cell lymphomas were reviewed. Patients who achieved full hematologic recovery at the end of treatment, and thereafter developed any degree of cytopenia were included in the study. Clinical and biochemical parameters were compared between patients with and without cytopenias with X2 test. Bi- and multivariate analyses were performed to evaluate factors associated with the development of late-onset cytopenias. Results: Of 758 patients enrolled, 19 developed cytopenias (2.5%). Transitory cytopenia was documented in 6 cases, 3 developed ICUS, 8 t-MDS, and 2 t-AML. In patients with FL, only hemoglobin < 12 g/dL (p = 0.032) and >6 nodal areas (p = 0.037) at diagnosis were factors statistically significant for the development of cytopenia. During cytopenias, 55% of patients died. Conclusions: LOHT constitutes a cause of morbidity and mortality in 2.5% of lymphoma patients treated with different therapy regimens.

Brentuximab vedotin demonstrates an objective response in a patient with refractory CD30+ primary mediastinal B-cell lymphoma

Diffuse large B-cell lymphomas (DLBCL) with MYC translocations combined with translocations involving BCL-2 or BCL-6 are referred to as double-hit lymphomas. These lymphomas are generally refractory to currently available therapies and have a poor prognosis. Primary mediastinal B-cell lymphoma (PMBL) is a rare subtype of DLBCL, which shares clinical, pathologic, and genetic similarities with classical Hodgkin's lymphoma. Unlike DLBCL, rearrangements involving MYC, BCL-2, and BCL-6 are typically absent in PMBL. We present a patient with PMBL who had increased gene copy numbers of MYC and BCL-2 along with increased protein expression of BCL-2 (c-Myc expression was about 15%–20% by immunostain). The disease was refractory to standard and salvage chemotherapies. The lymphoma, however, responded to brentuximab vedotin, a CD30-directed chemoimmunoconjugate

HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma

Immunotherapy has been applied successfully to treat B-cell lymphomas in preclinical models or clinical settings. However, immunotherapy resistance is a major challenge for B-cell lymphoma treatment. To overcome this issue, combinatorial therapeutic strategies have been pursued to achieve a better efficacy for treating B-cell lymphomas. One of such strategies is to combine immunotherapy with histone deacetylase (HDAC) inhibitors. HDAC inhibitors can potentially increase tumor immunogenicity, promote anti-tumor immune responses, or reverse immunosuppressive tumor environments. Thus, the combination of HDAC inhibitors and immunotherapy has drawn much attention in current cancer treatment. However, not all HDAC inhibitors are created equal and their net effects are highly dependent on the specific inhibitors used and the HDACs they target. Hence, we suggest that optimal treatment efficacy requires personalized design and rational combination based on prognostic biomarkers and unique profiles of HDAC inhibitors. Here, we discuss the possible mechanisms by which B-cell lymphomas acquire immunotherapy resistance and the effects of HDAC inhibitors on tumor cells and immune cells that could help overcome immunotherapy resistance.

HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma

Immunotherapy has been applied successfully to treat B-cell lymphomas in preclinical models or clinical settings. However, immunotherapy resistance is a major challenge for B-cell lymphoma treatment. To overcome this issue, combinatorial therapeutic strategies have been pursued to achieve a better efficacy for treating B-cell lymphomas. One of such strategies is to combine immunotherapy with histone deacetylase (HDAC) inhibitors. HDAC inhibitors can potentially increase tumor immunogenicity, promote anti-tumor immune responses, or reverse immunosuppressive tumor environments. Thus, the combination of HDAC inhibitors and immunotherapy has drawn much attention in current cancer treatment. However, not all HDAC inhibitors are created equal and their net effects are highly dependent on the specific inhibitors used and the HDACs they target. Hence, we suggest that optimal treatment efficacy requires personalized design and rational combination based on prognostic biomarkers and unique profiles of HDAC inhibitors. Here, we discuss the possible mechanisms by which B-cell lymphomas acquire immunotherapy resistance and the effects of HDAC inhibitors on tumor cells and immune cells that could help overcome immunotherapy resistance.

Chromatin remodeling factor lymphoid-specific helicase links with Epstein-Barr virus associated the follicular germinal center B cell lymphomas

Background: We assessed the frequency of epigenetic lesions, including lymphoid-specific helicase (LSH), 5-hydroxymethylcytosine (5-hmC) and E2F1, and the possible correlations among molecular findings, phenotype, clinical features, and outcome. Methods: We investigated 181 paraffin-embedded B-cell lymphoma samples using immunohistochemistry and in situ hybridization. Results: The levels of Ki67, LSH, 5-hmC, and E2F1 were all increased in germinal center B-cell lymphomas when compared with those in normal lymph nodes, and LSH was highly expressed in diffuse large B-cell lymphomas (DLBCLs) and Burkitt lymphomas (BLs) that were positive for Epstein-Barr virus (EBV) infection, indicating that LSH is linked to EBV infection in DLBCL and BL. Interestingly, LSH was mainly localized in the germinal centers of lymph nodes whereas 5-hmC staining localized to areas surrounding the germinal centers. Conclusions: These findings indicate a critical role for LSH as a biomarker and therapeutic target in follicular germinal center B-cell lymphoma.

Prognostic impact of MYD88 mutation, proliferative index and cell origin in diffuse large B cell lymphoma

Abstract Background Diffuse large B-cell lymphoma, among non-Hodgkin lymphomas, is one of the most frequent subtypes. Clinical laboratory data and post-treatment outcomes are scarce in the Brazilian population. Objective The main objective of this retrospective study was to assess the impact of tumor markers, including the Myeloid differentiation primary response 88 (MYD88) mutation. Method Eighty-three patients were included and treated with R-CHOP or R-CHOP-like regimens. Results Median age was 64-years old and 58% were female patients. The median follow-up was 42 months. The progression free survival (PFS) at this time was 63% and overall survival (OS), 66%. In the patients with tumors expressing Myc proto-oncogene protein (MYC) and B-cell lymphoma 2 (BCL2), assessed by immunohistochemistry (IHC), known as dual protein expressers, median post-progression survival was 31 (15-45) months. An increased proliferative index were associated with a high rate of progression (hazard ratio 2.31 [95% confidence interval [1.05-5.12]; p = 0.04). The cell of origin (COO), identified by IHC, was not able to predict PFS (p = 0.76). The MYD88 L265P mutation was present in 10.8% (9/83) of patients and did not show a prognostic correlation. Conclusion In conclusion, the MYD88 mutation, although an important tool for diagnosis and a possible target drug, presented at a low frequency and was not a prognostic marker in this population.

Expression of a recombinant protein by fusing anti-CD20 ScFv with dominant antigen epitopes and its anti-tumor activity / 中国免疫学杂志

Objective:To artificially design and express a recombinant protein named as ScFv-pLLO by fusing ScFv gene of Rituximab(C2B8)and dominant antigen epitopes from listeriolysin O(LLO),and studying its anti-tumor activity.Methods:VH and VL gene sequences of C2B8 against CD20 were acquired by searching United States Patent database,and ScFv sequence was constructed by linking VL and VH with a short peptide linker.Two CD4+T cell epitopes from LLO were selected and designed to splice ScFv sequence.The recombinant gene of ScFv-pLLO was cloned into prokaryotic expression vector and purified after induction.The capacity of ScFv-pLLO target-binding to B-cell lymphomas was evaluated by flow cytometry ( FCM ) and co-immunoprecipitation ( Co-IP ) .The effects of ScFv-pLLO on B-cell lymphomas proliferation and apoptosis were detected respectively.The immunogenicity of ScFv-pLLO was assessed by lymphocyte proliferation assay.Results: ScFv-pLLO was successfully expressed.It could bind to different B-cell lymphomas cell lines and obviously inhibit the growth of Raji cells as well as inducing apoptosis.Moreover,ScFv-pLLO was able to stimulate proliferation of spleen lymphocytes of immunized mice.Conclusion: The recombinant protein ScFv-pLLO can target-bind to B-cell lymphomas,and perform inhibitory effect and induce apoptosis on Raji cells that indicate ScFv-pLLO retain the capacity of ScFv derived from monoclonal antibody against CD20.Besides, ScFv-pLLO can induce immune response.This study provides a basis for further research about the role of ScFv-pLLO on simulating tumor cell antigens as well as being tumor vaccine adjuvant.

Case for diagnosis

We report the case of a 81-year-old female patient who had a two-year history of violet-colored erythematous tumors on both legs. Histopathological and immunohistochemical examinations confirmed the diagnosis of primary cutaneous large B-cell lymphoma, leg type. This rare, cutaneous lymphoma affects predominantly elderly females. Clinically, patients present with tumoral lesions on one or both legs (worst prognosis). Diagnosis is based on clinical, histopathological and immunohistochemical findings. The strong expression of BCL2, BCL6, MUM-1 and CD20, and the positivity for Ki67 antigen confirm the diagnosis. R-CHOP chemotherapy regimen (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) is the most widely accepted treatment.