Characteristics of aggressive B-cell lymphoma

Aggressive B-cell lymphomas are a heterogeneous group of mature B-cell neoplasms with morphological similarities, but phenotypic and genetic differences. This thesis investigated the aggressive lymphomas from bench-to-bedside aiming to enhance insight into its pathobiology, to investigate mechanisms underlying therapy resistance, and to explore novel treatment combinations. We focused on the role of MYC gene rearrangements, impact of DNA mutations, and altered protein expression. We observed that MYC rearrangements functioned as drivers of transformation in one third of cases in transformed follicular lymphoma. Next, we described loss of human leukocyte antigen (HLA) DM with loss of antigen expression by HLA class II as a novel mechanism of immune escape in Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL). Mutational analysis of paired DLBCL tumor samples indicated variable mutational heterogeneity at relapse, with PIM1 and SOCS1 potentially related to resistance. Focusing on treatment, we observed that necrosis as assessed by 18F-FDG PET-scans was associated with metabolic active DLBCL irrespectively of MYC rearrangements and this might identify patients at increased risk of relapse. The combination of the JAK2 inhibitor ruxolitinib and the checkpoint inhibitor pembrolizumab showed a remarkable response in a patient with a primary chemo- and radiotherapy refractory primary mediastinal B-cell lymphoma. Finally, we studied the treatment outcomes of patient groups with rare poor risk lymphoma (relapsed stage I DLBCL and central nervous system DLBCL). The results and considerations from this thesis form the basis for ongoing Dutch HOVON trials, in several of which the PhD candidate plays a central role

Zoonotic Transmission of Vaccine-Derived Bordetella bronchiseptica.

We describe a unique case of a 43-year-old-female with a Bordetella bronchiseptica infection caused by zoonotic transmission following vaccination of her dog. With this report, we want to raise awareness of potential zoonotic transmission of live attenuated vaccines from animals to patients with impaired immunity.</p

Treatment of initial parenchymal central nervous system involvement in systemic aggressive B-cell lymphoma

Central nervous system (CNS) involvement in systemic B-cell non-Hodgkin lymphoma (B-NHL) at diagnosis (sysCNS) is rare. We investigated the outcome of 21 patients with sysCNS, most commonly diffuse large B-cell lymphoma, treated with high dose methotrexate (HD-MTX) and R-CHOP. The median number of cycles of HD-MTX and R-CHOP was 4 (range 1–8) and 6 (range 0–8), respectively. Consolidative whole brain radiotherapy (WBRT) was given to 33% (7/21) patients. With a median follow-up of 44 months the 3-year progression free survival (PFS) and overall survival (OS) were 45% (95%CI 34–56%) and 49% (95%CI 38–60%), respectively. Over 90% of patients had an unfavorable international prognostic index score, reflected by treatment-related mortality of 19% (4/21) and relapse-related mortality of 28% (6/21). The outcome of these patients was, however, unexpectedly good when compared to secondary CNS relapses. Prospective studies are needed to define the optimal treatment for patients with sysCNS, but its rarity might be challenging

A patient with a large renal tumor:not always for the urologist

A 68-year old patient presented with flank pain caused by a large renal mass. A nephrectomy was performed because renal cell carcinoma was suspected. Pathological examination showed a diffuse large B‑cell lymphoma. Primary renal manifestation of a lymphoma is rare. The diagnosis is often missed or only recognized after a nephrectomy is performed. A primary renal lymphoma must be considered when radiologically a hypovascular, diffuse growing process is seen, without the characteristic signs of renal cell carcinoma, like calcifications and vascular invasion. Diagnosis can be confirmed by biopsies and, once histologically proven, curative treatment with chemo-immunotherapy is possible. In this article the diagnostic considerations and characteristics of a renal lymphoma are described

Heterogeneous Pattern of Dependence on Anti-Apoptotic BCL-2 Family Proteins upon CHOP Treatment in Diffuse Large B-Cell Lymphoma

Expression of the anti-apoptotic B-cell lymphoma 2 (BCL-2) protein in patients with diffuse large B-cell lymphoma (DLBCL) strongly correlates with resistance to standard therapy with cyclophosphamide, vincristine, doxorubicin, prednisolone, and rituximab (R-CHOP). Although studies focus mainly on the contribution of BCL-2, here we also investigate the contribution of other anti-apoptotic proteins to CHOP-therapy resistance in DLBCL. Functional dynamic BCL-2 homology (BH)3 profiling was applied to DLBCL cell lines upon CHOP treatment or single CHOP compounds. Cell-specific anti-apoptotic dependencies were validated with corresponding BH3-mimetics. We found high expression of anti-apoptotic BCL-2, MCL-1, and BCL-XL in DLBCL cell lines and patients. CHOP treatment resulted in both enhanced and altered anti-apoptotic dependency. Enhanced sensitivity to different BH3-mimetics after CHOP treatment was confirmed in specific cell lines, indicating heterogeneity of CHOP-induced resistance in DLBCL. Analysis of single CHOP compounds demonstrated that similar changes could also be induced by doxorubicin or vincristine, providing evidence for clinical combination therapies of doxorubicin or vincristine with BH3-mimetics in DLBCL. In conclusion, we show for the first time that CHOP treatment induces increased anti-apoptotic dependency on MCL-1 and BCL-XL, and not just BCL-2. These results provide new perspectives for the treatment of CHOP-resistant DLBCL and underline the potential of BH3 profiling in predicting therapy outcomes