Mathieu Wemeau

MYD88 L265P mutation contributes to the diagnosis of Bing Neel syndrome

Bing‐Neel syndrome (BNS), a rare neurological syndrome associated with Waldenström macroglobulinaemia (WM), is a direct involvement of the central nervous system by lymphoplasmacytoid cells characterized with an adverse prognostic. The MYD88 L265P mutation has been identified in the vast majority of patients with WM. The diagnosis of BNS is often challenging because of the variety of clinical presentations associated with difficult histological techniques. We hypothesized that identification of MYD88 L265P mutation in the cerebrospinal fluid (CSF) would contribute to the diagnosis of BNS in addition to imaging, flow cytometry and cytology. We identified MYD88 L265P mutation in the CSF and the bone marrow of all cases of BNS using quantitative polymerase chain reaction qPCR and Sanger sequencing. Copy neutral loss of heterozygosity including MYD88 was observed in one case. No mutation of CXCR4, CD79A and CD79B was observed in parallel. We further showed that monitoring the quantitative expression of MYD88 L265P mutation might be a useful molecular tool to monitor response to chemotherapy using qPCR. In conclusion, identification of MYD88 L265P mutation might be a new molecular‐based biomarker tool to add to the diagnostic and monitoring armamentarium for BNS.

Impact of Initial FDG-PET/CT and Serum-Free Light Chain on Transformation of Conventionally Defined Solitary Plasmacytoma to Multiple Myeloma

Purpose: Solitary plasmacytoma (SP) is a localized proliferation of monoclonal plasma cells in either bone or soft tissue, without evidence of multiple myeloma (MM), and whose prognosis is marked by a high risk of transformation to MM. Experimental Design: We studied the impact of FDG-PET/CT (2[18F]fluoro-2-deoxy-D-glucose positron emission tomography–computed tomography) on the risk of transformation of SP to overt MM among other markers in a series of 43 patients diagnosed with SP. Results: Median age was 57.5 years; 48% of patients had an abnormal involved serum-free light chain (sFLC) value, and 64% had an abnormal sFLC ratio at diagnosis. Thirty-three percent had two or more hypermetabolic lesions on initial PET/CT, and 20% had two or more focal lesions on initial MRI. With a median follow-up of 50 months, 14 patients transformed to MM with a median time (TTMM) of 71 months. The risk factors that significantly shortened TTMM at diagnosis were two or more hypermetabolic lesions on PET/CT, abnormal sFLC ratio and involved sFLC, and to a lesser extent at completion of treatment, absence of normalized involved sFLC and PET/CT or MRI. In a multivariate analysis, abnormal initial involved sFLC [OR = 10; 95% confidence interval (CI), 1–87; P = 0.008] and PET/CT (OR = 5; 95% CI, 0–9; P = 0.032) independently shortened TTMM. Conclusions: An abnormal involved sFLC value and the presence of at least two hypermetabolic lesions on PET/CT at diagnosis of SP were the two predictors of early evolution to myeloma in our series. This data analysis will need confirmation in a larger study, and the study of these two risk factors may lead to a different management of patients with SP in the future. Clin Cancer Res; 20(12); 3254–60. ©2014 AACR.

Prognostic value of PINI index in patients with multiple myeloma.

Background:  The Prognostic Inflammatory and Nutritional Index (PINI) is a simple scoring system that aggregates two blood markers of inflammatory [C‐reactive protein (CRP) and orosomucoid] and of nutritional (albumin and prealbumin) states. It is used in routine practice in geriatric medicine, especially in hospitalized elderly patients. This study was undertaken to evaluate the usefulness of PINI index in multiple myeloma (MM), a malignancy of the elderly.

Absence of CALR mutations in JAK2-negative polycythemia

Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) responsible for increased hematopoiesis, mainly affecting the erythroid lineage. The diagnosis of PV has been simplified enormously by the description of JAK2 mutations, affecting the canonical V617 in exon 14 in more than 95% of cases,

Combination of t(4;14), del(17p13), del(1p32) and 1q21 gain FISH probes identifies clonal heterogeneity and enhances the detection of adverse cytogenetic profiles in 233 newly diagnosed multiple myeloma

BackgroundOur aim was to set the FISH combination of del(17p13), t(4;14), 1q21 gain and del(1p32), four adverse cytogenetic factors rarely evaluated together, and compare our technical thresholds with those defined in the literature.MethodsTwo hundred thirty-three patients with MM at diagnosis were studied using FISH to target 4 unfavorable cytogenetic abnormalities: 17p13 deletion, t(4;14) translocation, 1p32 deletion and 1q21 gain. Technical thresholds were determined for each probe using isolated CD138-expressing PC from patients without MM.ResultsThe FISH analysis identified abnormalities in 79.0% of patients. Del(17p13) was detected in 15.0% of cases, t(4;14) in 11.5%, 1q21 gain in 37.8% and del(1p32) in 8.7%. Adding 1p32/1q21 FISH probes has enabled us to identify adverse cytogenetic profiles in 39.0% of patients without del(17p13) or t(4;14). Clonal heterogeneity was observed in 51.1% of patients as well as an increase in the number of adverse abnormalities when related clones were greater than or equal to 2 (85.1% against 45.6%).ConclusionFISH allowed detecting accumulation of adverse abnormalities and clonal heterogeneity in MM with a combination of 4 probes. The impacts of these two parameters need to be evaluated, and could be included in future cytogenetic classifications.

IMiD en hématologie

IMiDs belong to a new pharmalogical class, whose principal therapeutic agents are the thalidomide and the lenalidomide. They have immunomodulatory and antiangiogenic properties, as well as a direct effect on tumor cells. Thalidomide and lenalidomide were first approved for multiple myeloma, and in 5q-myelodysplastic syndrome for lenalidomide. Several studies have shown the efficacy of these drugs in others hematologic malignancies. A third component has been developed, the pomalidomide, which may be more effective in certain indications. Here we present an overview of IMiDs in hematology, including mechanisms of action and known significant side effects.

Microparticle phenotypes are associated with driver mutations and distinct thrombotic risks in essential thrombocythemia

Essential thrombocythemia (ET) is a Philadelphia-negative myeloproliferative neoplasm with high platelet counts and an increased risk of thrombosis. Acquired somatic mutations delineate four ET subtypes: JAK2-V617F , CALR -mutated, MPL -mutated, and “Triple-Negative” (TN).[1][1] CALR mutations

Carrefour des spécialitésMacroglobulinémie de WaldenströmWaldenström's macroglobulinemia

Waldenströms macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with the presence of an IgM monoclonal gammopathy in the blood. WM remains incurable with a median of 8-year of overall survival for patients with symptomatic WM. Treatment is postponed for asymptomatic patients and progressive anemia is the most common indication for initiation of treatment. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab, either alone or in combination. Studies involving new combination chemotherapy are ongoing and preliminary results are encouraging. However, there are several limitations to these approaches. The complete response rate is low and the treatment free survival is short in many patients, no specific agent or regimen has been shown to be superior to another, and no treatment has been specifically approved for WM. As such, new therapeutic agents are needed for the treatment of WM. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of WM so as to better target therapeutics for this malignancy. These efforts have led to the development of proteasome inhibitors as bortezomib, several Akt/mTor inhibitors, such as perifosine and Rad001. Many other agents and monoclonal antibodies are currently being tested in clinical trials and seem promising. This article provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM.

Macroglobulinémie de Waldenström

Waldenströms macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with the presence of an IgM monoclonal gammopathy in the blood. WM remains incurable with a median of 8-year of overall survival for patients with symptomatic WM. Treatment is postponed for asymptomatic patients and progressive anemia is the most common indication for initiation of treatment. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab, either alone or in combination. Studies involving new combination chemotherapy are ongoing and preliminary results are encouraging. However, there are several limitations to these approaches. The complete response rate is low and the treatment free survival is short in many patients, no specific agent or regimen has been shown to be superior to another, and no treatment has been specifically approved for WM. As such, new therapeutic agents are needed for the treatment of WM. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of WM so as to better target therapeutics for this malignancy. These efforts have led to the development of proteasome inhibitors as bortezomib, several Akt/mTor inhibitors, such as perifosine and Rad001. Many other agents and monoclonal antibodies are currently being tested in clinical trials and seem promising. This article provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM.

Traitement du myélome multiple

Résumé:Nous assistons depuis 20 ans à des progrès continus dans la prise en charge des patients atteints de myélome multiple (MM). Le traitement intensif avec autogreffe de cellules souches du sang périphérique constitue maintenant le traitement de référence des patients de moins de 65 ans. Depuis 1999, l’arsenal thérapeutique s’est renforcé de trois molécules majeures, le thalidomide, le bortézomib (Velcade®) et le lénalidomide (Revlimid®), qui vont à l’évidence améliorer le pronostic des patients. Selon toute vraisemblance, les associations melphalan-prednisone-thalidomide, melphalan-prednisone-bortézomib ou melphalan-prednisone-lénalidomide seront amenées à remplacer l’association historique melphalanprednisone comme traitement de référence du MM du sujet âgé. Ces molécules prendront également leur place dans les procédures de traitement intensif, dans la réduction tumorale avant greffe ou en traitement d’entretien. Le traitement du MM bénéficie aussi des traitements par bisphosphonates, pour prise en charge de l’ostéopathie, et des érythropoïétines recombinantes pour traitement ou prévention de l’anémie. Toutes ces avancées ne doivent pas faire oublier que le traitement symptomatique conserve une importance majeure.Abstract:The past twenty years have brought continuous progress in the management of care for patients suffering from multiple myeloma (MM). Intensive treatment by autologous peripheral blood stem cell transplantation is now a reference treatment for patients under the age of 65. Since 1999, three new molecules have become available: thalidomide, bortezomib (Velcade®) and lenalidomide (Revlimid®), which will certainly improve patient prognosis. In all likelihood, the association of melphalan-prednison-thalidomide, melphalan-prednisone-bortezomib or melphalan-prednisone-lenalidomide will come to replace the known melphalan-prednisone association as a reference for treating MM in older patients. These molecules will also find their place in intensive treatment procedures, in pre-transplant tumor reduction or in maintenance treatment. Treatment of MM also benefits from bisphosphonate treatment, used to manage bone pathologies, and from recombinant erythropoietin for the treatment or prevention of anemia. All of these advances should not blind us to the fact that symptomatic treatment still plays an important role.