Chemotherapy with rituximab followed by high‐dose therapy and autologous stem cell transplantation in patients with mantle cell lymphoma

Abstract

A hallmark of neoplasia is dysregulated apoptosis, programmed cell death. Apoptosis is crucial for normal tissue homeostasis. Dysregulation of apoptotic pathways leads to reduced cytocidal responses to chemotherapeutic drugs or radiation and is a frequent contributor to therapeutic resistance in cancer. The literature pertaining to detection of apoptotic pathway constituents in cytologic specimens is reviewed herein. Virtually all methods for detecting apoptosis, including classic cytomorphologic evaluation, TUNEL assay, immunocytochemistry, and gene sequence analysis, may be applied to cytologic samples as well as tissue. Components of both intrinsic and extrinsic apoptotic pathways have been studied, including many reports examining p53 and bcl‐2, as well as studies of caspase inhibitory proteins XIAP and survivin, death receptors and ligands such as Fas, Fas‐ligand, and TRAIL. p53 undergoes oncogenic alteration more than any other protein; its immunocytochemical detection almost always connotes loss of its physiologic role as an inducer of apoptosis in response to a damaged genome. Several reports establish cytologic sampling as being as useful as tissue sampling. In one respect cytologic sampling is superior to tissue sampling in particular, by allowing clinicians to repeat sampling of the same tumor before and after administration of therapy; a number of reports use this approach to attempt to predict tumor response by assaying the effect of chemotherapy on the induction of apoptosis. Diagn. Cytopathol. 2010;38:685–697. © 2010 Wiley‐Liss, Inc.

Ten‐year follow‐up after intense chemoimmunotherapy with Rituximab‐HyperCVAD alternating with Rituximab‐high dose methotrexate/cytarabine (R‐MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma

“…Proposed reasons for this include the addition of doxorubicin and/or rituximab, the use of more intense therapy and better supportive care. A majority of published reports suggest a need for therapy with aggressive frontline chemotherapy, with or without high-dose chemotherapy and autologous stem cell transplantation, in order to improve overall outcome (Vandenberghe et al, 2003;Lefrère et al, 2004;Dreyling et al, 2005;Thieblemont et al, 2005;Vigouroux et al, 2005;De Guibert et al, 2006;Kahl et al, 2006;Vose et al, 2006;Fayad et al, 2007;Delarue et al, 2008;Evens et al, 2008;Geisler et al, 2008;Magni et al, 2008;Van't Veer et al, 2008;Tam et al, 2009). At our institution, patients with newly diagnosed aggressive (nodular and diffuse) MCL and their blastoid variants received a regimen of intense chemo-immunotherapy without consolidation stem cell transplantation between 1999 and 2002, in which the monoclonal antibody rituximab was added to an intense chemotherapy regimen reported by Cortes et al (1995), for the treatment of acute lymphoblastic leukaemias.…”

Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma

“…20 Although rituximab monotherapy has been shown to yield modest results, combination chemotherapy plus rituximab has demonstrated more promising effects. 21,22 Thus, we chose to evaluate the combined activity of RAD001-rituximab therapy on our MCL cell lines. Although we did not observe any antiproliferative effects against NCEB1 and Jeko1 in response to rituximab treatment, SP49 cells cultured with rituximab exhibited approximately 30% inhibition of proliferation (Figure 4b, left panel).…”

“…22,29 However, combination therapies of CHOP/CVP, rituximab and total body irradiation, followed by autologous stem cell transplantation, have demonstrated an improvement in complete remission and overall survival rates. 21,30 MCL is characterized by a balanced translocation t(11;14)(q13;q32) and overexpression of cyclin D1, 4 a G 1 cyclin regulated by the PI3K/Akt/mTOR signaling pathway. 31 Studies have presented encouraging results utilizing the mTOR inhibitor rapamycin and its derivatives in various hematological malignancies and solid tumors, [11][12][13][14][15]32 with one recent report identifying substantial anti-tumor activity in MCL.…”

A multicenter phase II trial (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma

“…[7][8][9] Early aggressive therapy appears to provide an advantage to some young patients but the impact on overall survival is not yet defined. 10 R-CHOP-like, R-HyperCVAD, R-DHAP or R-VAD+C polychemotherapy regimens are most frequently used as front-line therapies for young and/or fit MCL patients. 7,9,11 Those patients achieving a good response to initial therapy should be considered for consolidation by high-dose chemotherapy followed by autologous stem cell transplantation.…”