Waldenstrom's 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. (C) 2010 Societe nationale francaise de medecine interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.

La macroglobulinémie de Waldenström (MW) est un syndrome lymphoprolifératif B caractérisé par une infiltration médullaire lymphoplasmocytaire et la présence d’un pic monoclonal IgM circulant. Cette hémopathie reste à l’heure actuelle incurable. La médiane de survie globale est de huit ans pour les patients symptomatiques. Il n’y a pas d’indication de traitement habituellement reconnue pour les patients asymptomatiques. Un traitement est le plus souvent initié en raison de l’aggravation d’une anémie. Les principales options thérapeutiques comprennent les agents alkylants, les analogues nucléosidiques et le rituximab, en monothérapie ou en association. Les résultats préliminaires des études testant de nouvelles combinaisons de chimiothérapies sont encourageants, mais aucune association thérapeutique n’a fait la preuve de sa supériorité. De plus, une réponse complète est très rarement obtenue et la survie sans traitement reste courte pour la plupart des patients. Il faut donc développer de nouveaux agents thérapeutiques dans la MW. Les travaux de plusieurs équipes de recherche ont permis récemment de mieux comprendre la biologie de cette maladie, de définir de nouvelles cibles et de développer de nouveaux agents thérapeutiques, tels que les inhibiteurs du protéasome, dont le bortézomib et les inhibiteurs de la voie Akt/mTor comme la périfosine et Rad001. De nombreuses autres molécules et des anticorps monoclonaux sont en cours d’expérimentation et semblent prometteurs. Cette revue présente les dernières études cliniques et différents résultats précliniques de nouveaux agents thérapeutiques en cours de développement dans la MW.

Waldenstrom's 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.