Temsirolimus Has Activity in Non–Mantle Cell Non-Hodgkin's Lymphoma Subtypes: The University of Chicago Phase II Consortium

Smith, Sonali M.; Besien, Koen van; Karrison, Theodore; Dancey, Janet; McLaughlin, Peter; Younes, Anas; Smith, Scott E.; Stiff, Patrick J.; Lester, Eric P.; Modi, Sanjiv; Doyle, L. Austin; Vokes, Everett E.; Pro, Barbara

doi:10.1200/jco.2010.29.2813

Cited by 180 publications

(127 citation statements)

References 30 publications

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“…Further improvement may be expected using drugs effectively inhibiting both mTOR-complexes (so called dual inhibitors). 16,17,26,27 Taken together, we found that diffuse large B-cell lymphomas with active mTOR-signaling have a poor prognosis, and Rictor overexpression may predict low or no responsiveness to conventional rapalog (mTORC1 inhibitor) therapy in these cases. Predicting the sensitivity and the potential cost/benefit of mTOR-inhibitor treatment requires individual attention in every patient.…”

Section: Discussionmentioning

confidence: 66%

“…Factors behind responsiveness or resistance are also largely obscure at present. [15][16][17] The analysis of targeted molecules (expression levels, phosphorylation and/or localization of proteins, indicating their activation state) or of proteins related to their activity can help predict the outcome of molecular targeted therapy. Therefore we need to find markers to determine the activation level of the mTOR pathway and to predict response to mTOR inhibitor therapy in diffuse large B-cell lymphomas for the selection of patients who may further benefit from mTOR inhibition.…”

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confidence: 99%

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Activity and complexes of mTOR in diffuse large B-cell lymphomas—a tissue microarray study

et al. 2012

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Diffuse large B-cell lymphoma is a heterogeneous group of diseases with different responses to therapy. Targeting mTOR (mammalian target of rapamycin) offers a new approach to improve the treatment. mTOR inhibitors are being developed and are in clinical use in mantle cell lymphoma therapy and clinical trials are ongoing in other high-grade lymphomas as well. However, there is limited data about mTOR activity and the expression of its different complexes in diffuse large B-cell lymphomas. Tissue microarray blocks were constructed from paraffin-embedded biopsy specimens. More than 700 immunohistochemical stainings (mTOR signaling-related proteins and phosphoproteins, markers for lymphoma classification) were evaluated from 68 diffuse large B-cell lymphoma biopsies from conventionally treated and followed patients. Approximately 30% of cases were characterized as germinal center-derived diffuse large B-cell lymphomas, which showed virtually no mTOR activity, as determined by phospho-ribosomal S6 expression, the most sensitive marker of mTOR activity. In about 80% of non-germinal center-derived diffuse large B-cell lymphoma cases, positivity of mTOR-related phosphoproteins was observed, denoting mTOR activity. Moreover, Rictor (a characteristic protein of the mTOR complex2) was overexpressed in 43% of all diffuse large B-cell lymphomas and in 63% of mTOR-active nongerminal center diffuse large B-cell lymphoma samples. Rictor overexpression with mTOR activity indicated significantly worse survival for patients than mTOR inactivity or mTOR activity with low Rictor expression. These results suggest that mTOR activity is characteristic in most non-germinal center-derived diffuse large B-cell lymphomas with potentially variable mTOR-inhibitor sensitivity. Taken together, mTOR inhibitors may be useful in addition to regular therapy in diffuse large B-cell lymphomas, however, patient and inhibitor selection criteria must be carefully considered.

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Section: Discussionmentioning

confidence: 66%

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confidence: 99%

Activity and complexes of mTOR in diffuse large B-cell lymphomas—a tissue microarray study

et al. 2012

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“…[194][195][196] These results have been validated in early-stage clinical trials in adults, finding single-agent ORR of 28-30%, using everolimus or temsirolimus. [197,198] Hodgkin's disease is a highly curable tumor in children; however, more aggressive or relapsed Hodgkin's disease can be difficult to treat. Preclinical studies have demonstrated that AKT is often constitutively activated in Hodgkin's disease cell lines; however, no studies have confirmed or refuted this finding in primary tumors.…”

Section: Lymphomasmentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen.Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual-and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignanc...

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“…In some cases, dramatic responses have been observed; however, in general these agents have shown modest activity in relapsed and refractory DLBCL, with overall response rates ranging from 11 to 47%, CR rates from 1 to 16% and median durations of remission generally in the 2-6 months range (Table 1). [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] For many of these agents, studying specific subtypes of DLBCL (for example, the activated B cell subtype), or cases in which the target of the agent is known to be present, will likely prove to be more effective than simply enrolling all DLBCL cases. Therefore, some subtypes of DLBCL may ultimately prove to be amenable to maintenance therapy post transplant.…”

Section: Modification Of Salvage Therapymentioning

confidence: 99%

Allogeneic hematopoietic cell transplantation for diffuse large B cell lymphoma: who, when and how?

Klyuchnikov

Bacher

Kroll

et al. 2013

Bone Marrow Transplant

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Despite overall improvements in outcomes of patients with diffuse large B cell lymphoma (DLBCL), B30-40% of patients develop relapsed or refractory disease. For patients with chemo refractory disease, or recurrent disease following autologous hematopoietic SCT (auto-HCT), the prognosis is poor, with no consensus on the optimal therapy. Currently, owing to the graft vs lymphoma effect, hematopoietic allogeneic hematopoietic cell transplantation (allo-HCT) is the only potentially curative option for such patients. In addition, many patients who are considered today for auto-HCT actually have a low likelihood of benefit. For example, a patient with prior rituximab exposure who relapses within 1 year of diagnosis and has a second-line age-adjusted International Prognosis Index of 2 or 3 at relapse has a o25% chance of being cured by auto-HCT. It is possible that such patients may be better served with an allo-HCT. Unfortunately, in many cases, allo-HCT applicability is limited by patient age, comorbidities, performance status and treatment-related toxicities. Recent attempts to improve the efficacy of auto-HCT, such as incorporating radio-immunotherapy into the conditioning regimen, have not resulted in improved outcomes. However, incorporation of novel agents such as antiprogrammed death-1 antibodies as maintenance therapy after auto-HCT show promise. Allo-HCT in relapsed/refractory DLBCL patients can result in a 30-40% PFS rate at 3 years, in part due to a graft vs DLBCL effect. While reduced-intensity/nonmyeloablative conditioning is increasingly being used, certain patients may benefit from myeloablative conditioning. We present an algorithm intended to discriminate which relapsed and refractory DLBCL patients are most likely to benefit from auto-HCT vs allo-HCT. New approaches, using novel agents that target the molecular heterogeneity in DLBCL, will be an essential component of moving the field forward. Lastly, we propose a prospective registry-based study as the only feasible mechanism to define the optimal position of allo-HCT in the overall treatment strategy for DLBCL. It is hoped that this review will promote the development of prospective multicenter efforts to determine whether such patients do, in fact, benefit from earlier and/or more effective implementation of allo-HCT.

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Temsirolimus Has Activity in Non–Mantle Cell Non-Hodgkin's Lymphoma Subtypes: The University of Chicago Phase II Consortium

Cited by 180 publications

References 30 publications

Activity and complexes of mTOR in diffuse large B-cell lymphomas—a tissue microarray study

Activity and complexes of mTOR in diffuse large B-cell lymphomas—a tissue microarray study

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

Allogeneic hematopoietic cell transplantation for diffuse large B cell lymphoma: who, when and how?

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