W.B.C. Stevens

Reduced PTLD-related mortality in patients experiencing EBV infection following allo-SCT after the introduction of a protocol incorporating pre-emptive rituximab

The mortality associated with post-transplant lymphoproliferative disorder (PTLD) induced by EBV infection can be reduced by monitoring EBV by polymerase-chain-reaction and rituximab given pre-emptively. We performed a retrospective analysis of the risk factors for the occurrence of EBV infection/disease and EBV-related mortality among 273 consecutive recipients of a T-cell-depleted allo-SCT during two periods: (a) before the implementation of a comprehensive protocol (2006–2008) and (b) afterwards (2009–2011). EBV infection was detected in 61 (22%) cases, and 28 cases were considered to have had EBV disease. Treatment with antithymocyte globulin was the most important risk factor (odds ratio (OR) 2.4; 95% confidence interval (CI) 1.3–4.2, P=0.001). After implementation of the protocol, in patients experiencing EBV infection, pre-emptive therapy was started more often and sooner (median 3 vs 6 days, P=0.002). Moreover, there were fewer cases of monomorphic PTLD (4/33 (12%) vs 11/28 (39%), P=0.01), and the EBV-related mortality was lower for patients experiencing EBV infection (2/33 (6%) vs 8/28 (29%), OR 0.2; 95% CI 0.05–0.9, P=0.03). The EBV protocol proved feasible and resulted in faster initiation of pre-emptive therapy, the diagnosis in an earlier stage of EBV disease, and decreased EBV-related mortality.

Clinical features of patients with nodal marginal zone lymphoma compared to follicular lymphoma: similar presentation, but differences in prognostic factors and rate of transformation.

Abstract Nodal marginal zone lymphoma (NMZL) is a rare type of B-cell non-Hodgkin lymphoma. This study assessed the clinical features of 56 patients with NMZL in comparison to 46 patients with follicular lymphoma (FL). Patients with NMZL and FL had a largely similar clinical presentation, but patients with FL had a higher disease stage at presentation, more frequent abdominal lymphadenopathy and bone marrow involvement, and showed more common transformation into diffuse large B-cell lymphoma (DLBCL) during the course of disease. Overall survival and event-free survival were similar for patients with NMZL and FL, but factors associated with worse prognosis differed between the two groups. Transformation into DLBCL was associated with a significantly poorer outcome in both groups, but the phenotypes were different: DLBCL arising in FL was mainly of germinal center B-cell phenotype, whereas DLBCL arising in NMZL was mainly of non-germinal center B-cell phenotype.

Prognostic relevance of CD163 and CD8 combined with EZH2 and gain of chromosome 18 in follicular lymphoma: A study by the Lunenburg Lymphoma Biomarker Consortium.

In follicular lymphoma, studies addressing the prognostic value of microenvironment-related immunohistochemical markers and tumor cell-related genetic markers have yielded conflicting results, precluding implementation in practice. Therefore, the Lunenburg Lymphoma Biomarker Consortium performed a validation study evaluating published markers. To maximize sensitivity, an end of spectrum design was applied for 122 uniformly immunochemotherapy-treated follicular lymphoma patients retrieved from international trials and registries. The criteria were: early failure, progression or lymphoma-related death <2 years versus long remission, response duration of >5 years. Immunohistochemical staining for T cells and macrophages was performed on tissue microarrays from initial biopsies and scored with a validated computer-assisted protocol. Shallow whole-genome and deep targeted sequencing was performed on the same samples. The 96/122 cases with complete molecular and immunohistochemical data were included in the analysis. EZH2 wild-type (P=0.006), gain of chromosome 18 (P=0.002), low percentages of CD8+ cells (P=0.011) and CD163+ areas (P=0.038) were associated with early failure. No significant differences in other markers were observed, thereby refuting previous claims of their prognostic significance. Using an optimized study design, this Lunenburg Lymphoma Biomarker Consortium study substantiates wild-type EZH2 status, gain of chromosome 18, low percentages of CD8+ cells and CD163+ area as predictors of early failure to immunochemotherapy in follicular lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP [-like]), while refuting the prognostic impact of various other markers.

Recurrent mutations in genes involved in nuclear factor-κB signalling in nodal marginal zone lymphoma—diagnostic and therapeutic implications

To investigate the spectrum of mutations in 20 genes involved in B‐cell receptor and/or Toll‐like receptor signalling resulting in activation of nuclear factor‐κB (NF‐κB) in 20 nodal marginal zone lymphomas (NMZLs), 20 follicular lymphomas (FLs), and 11 cases of B‐cell lymphoma, unclassifiable (BCL‐u).

'Trained immunity': consequences for lymphoid malignancies

In hematological malignancies complex interactions exist between the immune system, microorganisms and malignant cells. On one hand, microorganisms can induce cancer, as illustrated by specific infection-induced lymphoproliferative diseases such as Helicobacter pylori-associated gastric mucosa-associated lymphoid tissue lymphoma. On the other hand, malignant cells create an immunosuppressive environment for their own benefit, but this also results in an increased risk of infections. Disrupted innate immunity contributes to the neoplastic transformation of blood cells by several mechanisms, including the uncontrolled clearance of microbial and autoantigens resulting in chronic immune stimulation and proliferation, chronic inflammation, and defective immune surveillance and anti-cancer immunity. Restoring dysfunction or enhancing responsiveness of the innate immune system might therefore represent a new angle for the prevention and treatment of hematological malignancies, in particular lymphoid malignancies and associated infections. Recently, it has been shown that cells of the innate immune system, such as monocytes/macrophages and natural killer cells, harbor features of immunological memory and display enhanced functionality long-term after stimulation with certain microorganisms and vaccines. These functional changes rely on epigenetic reprogramming and have been termed ‘trained immunity’. In this review the concept of ‘trained immunity’ is discussed in the setting of lymphoid malignancies. Amelioration of infectious complications and hematological disease progression can be envisioned to result from the induction of trained immunity, but future studies are required to prove this exciting new hypothesis.

High prevalence of MYD88 and CD79B mutations in intravascular large B-cell lymphoma

TO THE EDITOR: Intravascular large B-cell lymphoma (IVLBCL) is a rare variant of extranodal diffuse large B-cell lymphoma (DLBCL). It is characterized by proliferation of blastic, neoplastic B cells within the lumina of small- or intermediate-sized blood vessels and capillaries.[1][1] IVLBCL may

High prevalence ofandmutations in intravascular large B-cell lymphoma

TO THE EDITOR: Intravascular large B-cell lymphoma (IVLBCL) is a rare variant of extranodal diffuse large B-cell lymphoma (DLBCL). It is characterized by proliferation of blastic, neoplastic B cells within the lumina of small- or intermediate-sized blood vessels and capillaries.[1][1] IVLBCL may

Identification of IG-clonality status as a pre-treatment predictor for mortality in patients with immunodeficiency-associated Epstein-Barr virus-related lymphoproliferative disorders

Immunodeficiency-associated Epstein-Barr (EBV)-related lymphoproliferative disorders (EBV-LPD), including the post-transplant lymphoproliferative disorders (PTLD), are aggressive hematologic malignancies which, despite improvements in therapy, including the use of anti-CD20 monoclonal antibody, result in considerable morbidity and mortality.1–3 Retrospective analyses have revealed several clinical risk factors, including therapeutic interventions, that predict outcome in patients with EBV-LPD. However, pre-treatment risk stratification that can be used to guide therapeutic decisions remains difficult and algorithms are lacking.1 Although morphology is regarded to be a cornerstone in therapy decision making, immunoglobulin (IG) clonality might help prognostication. Despite efforts to standardize the pathological classification of EBV-LPD,4 neither histology nor IG clonality has been shown to consistently predict outcome.5–7 Nevertheless, comprehensive IG clonality testing, with a high detection rate of clonality, allows an objective pathological parameter to be re-evaluated in risk stratification of EBV-LPD.8

A “body armor” of leukemia cutis

A 25-year old female was diagnosed with an acute myeloid leukemia (AML: FAB classification M2) with very poor-risk cytogenetic abnormalities i.e. monosomal karyotype (including monosomy 17p resulting in loss of the tumor suppressor gene p53). At presentation, she had enlarged lymph nodes and tonsils that were at that time designated reactive to infection. After remission-induction and consolidation chemotherapy, which contained cytarabine and an anthracycline (idarubicin and daunorubicin, respectively), she achieved a complete morphological and cytogenetic remission on bone marrow evaluation. During consolidation chemotherapy, she had experienced an episode of fluctuating skin changes mainly consisting of a bluish discoloration and no particular suspicion was raised. Two weeks later and prior to the start of conditioning treatment for an allogeneic hematopoietic stem cell transplantation (HSCT), she again reported skin changes that consisted of cyanotic discoloration and progressive thickening which gave her the feeling that she was getting stuck in some kind of body armor. The skin changes were most pronounced at her forehead, cheeks, and upper body (Image 1). On physical examination, there was hardening and roughness of the skin and also cervical and axillary lymphadenopathy was noticed. Histological examination of a skin biopsy showed dermal infiltration by leukemic blasts (Image 2) with immunophenotypical evaluation expression of CD34, CD43, CD68, and myeloperoxidase. Therefore, she was diagnosed with an extramedullary relapse of the AML, also designated leukemia cutis or myeloid sarcoma. Positron-emission tomography (Image 3) revealed extensive skin (red arrow) and regional lymph node enhancement (green arrow). Examination of cerebrospinal fluid revealed myeloblasts confirming central nervous system involvement. Shortly thereafter salvage, high-dose chemotherapy was initiated with normalization of her face and resolution of lymphadenopathy. Unfortunately after a myeloablative T cell replete allogeneic HSCT, she experienced an early relapse and died. In retrospect at initial diagnosis, the AML already had extramedullary manifestations, which might have had increased the vigilance for extramedullary relapse and initiation of prophylactic intrathecal chemotherapy. Image 1.