Aspasia Stamatoullas

TET2 and TP53 mutations are frequently observed in blastic plasmacytoid dendritic cell neoplasm

918. Dunleavy, K., Hakim, F., Kim, H.K., Janik, J.E., Grant, N., Nakayama, T., White, T., Wright, G., Kwak, L., Gress, R., Tosato, G. & Wilson, W.H. (2005) B-cell recovery following rituximab-based therapy is associated with perturbations in stromal derived factor-1 and granulocyte homeostasis. Blood, 106, 795–802. Hirayama, Y., Kohda, K., Konuma, Y., Hirata, Y., Kuroda, H., Fujimi, Y., Shirao, S., Kobune, M., Takimoto, R., Matsunaga, T. & Kato, J. (2009) Late onset neutropenia and immunoglobulin suppression of the patients with malignant lymphoma following autologous stem cell transplantation with rituximab. Internal Medicine, 48, 57– 60. Lai, G.G., Lim, S.T., Tao, M., Chan, A., Li, H. & Quek, R. (2009) Late-onset neutropenia following RCHOP chemotherapy in diffuse large B-cell lymphoma. American Journal of Hematology, 84, 414–417. Lemieux, B., Tartas, S., Traulle, C., Espinouse, D., Thieblemont, C., Bouafia, F., Alhusein, Q., Antal, D., Salles, G. & Coiffier, B. (2004) Rituximab-related late-onset neutropenia after autologous stem cell transplantation for aggressive non-Hodgkin’s lymphoma. Bone Marrow Transplantation, 33, 921–923. Nitta, E., Izutsu, K., Sato, T., Ota, Y., Takeuchi, K., Kamijo, A., Takahashi, K., Oshima, K., Kanda, Y., Chiba, S., Motokura, T. & Kurokawa, M. (2007) A high incidence of late-onset neutropenia following rituximab-containing chemotherapy as a primary treatment of CD20-positive B-cell lymphoma: a single-institution study. Annals of Oncology, 18, 364–369. Voog, E., Morschhauser, F. & Solal-Céligny, P. (2003) Neutropenia in patients treated with rituximab. New England Journal of Medicine, 348, 2691–2694. Wolach, O., Bairey, O. & Lahav, M. (2010) Late-onset neutropenia after rituximab treatment; case series and comprehensive review of the literature. Medicine (Baltimore), 89, 308–318.

Detection and prognostic value of recurrent exportin 1 mutations in tumor and cell-free circulating DNA of patients with classical Hodgkin lymphoma

Classical Hodgkin lymphoma is one of the most common lymphomas and shares clinical and genetic features with primary mediastinal B-cell lymphoma. In this retrospective study, we analyzed the recurrent hotspot mutation of the exportin 1 (XPO1, p.E571K) gene, previously identified in primary mediastinal B-cell lymphoma, in biopsies and plasma circulating cell-free DNA from patients with classical Hodgkin lymphoma using a highly sensitive digital PCR technique. A total of 94 patients were included in the present study. This widely expressed XPO1 E571K mutation is present in one quarter of classical Hodgkin lymphoma patients (24.2%). Mutated and wild-type classical Hodgkin lymphomas were similar regarding the main clinical features. Patients with a detectable XPO1 mutation at the end of treatment displayed a tendency toward shorter progression-free survival, as compared to patients with undetectable mutation in plasma cell-free DNA (2-year progression-free survival: 57.1%, 95% confidence interval: 30.1–100% versus 2-year progression-free survival: 90.5%, 95% confidence interval: 78.8–100%, respectively, P=0.0601). To conclude, the detection of the XPO1 E571K mutation in biopsy and plasma cell-free DNA by digital PCR may be used as a novel biomarker in classical Hodgkin lymphoma for both diagnosis and minimal residual disease, and pinpoints a crucial role of XPO1 in classical Hodgkin lymphoma pathogenesis. The detection of somatic mutation in the plasma cell-free DNA of patients represents a major technological advance in the context of liquid biopsies and noninvasive management of classical Hodgkin lymphoma.

Digital PCR for quantification of recurrent and potentially actionable somatic mutations in circulating free DNA from patients with diffuse large B-cell lymphoma.

Abstract Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous malignancy harboring frequent targetable activating somatic mutations. Emerging evidence suggests that circulating cell-free DNA (cfDNA) can be used to detect somatic variants in DLBCL using Next-Generation Sequencing (NGS) experiments. In this proof-of-concept study, we chose to develop simple and valuable digital PCR (dPCR) assays for the detection of recurrent exportin-1 (XPO1) E571K, EZH2 Y641N, and MYD88 L265P mutations in DLBCL patients, thereby identifying patients most likely to potentially benefit from targeted therapies. We demonstrated that our dPCR assays were sufficiently sensitive to detect rare XPO1, EZH2, and MYD88 mutations in plasma cfDNA, with a sensitivity of 0.05%. cfDNA somatic mutation detection by dPCR seems to be a promising technique in the management of DLBCL, in addition to NGS experiments.

Somatic mutations of cell-free circulating DNA detected by targeted next-generation sequencing and digital droplet PCR in classical Hodgkin lymphoma

Lucile Bessi, Pierre-Julien Viailly, Elodie Bohers, Philippe Ruminy, Catherine Maingonnat, Philippe Bertrand, NasrinSarafan Vasseur, Ludivine Beaussire, Marie Cornic, Pascaline Etancelin, Vincent Camus, Jean-Michel Picquenot, Herv e Tilly, Aspasia Stamatoullas and Fabrice Jardin INSERM U1245, Centre Henri Becquerel and Rouen University, Rouen, France; Department of Pathology, Centre Henri Becquerel, Rouen, France; Department of Clinical Hematology, Centre Henri Becquerel, Rouen, France