A pilot trial of the mTOR (mammalian target of rapamycin) inhibitor RAD001 in patients with advanced B-CLL

Decker, Thomas; Sandherr, Michael; Goetze, Katharina; Oelsner, Madlen; Ringshausen, Ingo; Peschel, Christian

doi:10.1007/s00277-008-0582-9

Cited by 55 publications

(34 citation statements)

References 32 publications

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“…Finally, the ability of CAL-101 to induce apoptosis and to antagonize multiple environmental stimuli shows true potential for the treatment of CLL and related lymphoid malignancies. Other compounds targeting proximal or distal signaling involved in PI3K have shown clinical activity in patients with CLL, including the Syk inhibitor fostamatinib disodium 47 and the mTOR (mammalian target of rapamycin) inhibitor RAD001, 48,49 providing strong rational for targeting this pathway. The data put forward here from our laboratory data clearly justify clinical development of CAL-101 in CLL and related lymphoid malignancies, which is now well under way.…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals

Herman

Gordon²,

Wagner³

et al. 2010

Blood

515

477

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IntroductionChronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the United States, with approximately 15 000 new cases and approximately 4500 deaths per year. 1 CLL is characterized by a B1 monoclonal lymphocyte immunophenotype with expression of the surface antigens CD19, CD5, CD20, CD23, and dim surface immunoglobulin G. The cell of origin of CLL is uncertain, but a gene expression pattern most similar to a mature memory B cell has been hypothesized. 2 In addition, CLL cells display disrupted apoptosis that is caused by both primary tumor features and codependent stromal elements. 3 Although many patients are asymptomatic at diagnosis, CLL is a progressive disease that in most patients eventually will require treatment. Once they become symptomatic, patients have a relatively short overall survival, ranging from 18 months to 6 years, with a 22.5% 10-year survival expectation. 4 Common treatments for CLL include alkylating chemotherapeutic drugs (such as chlorambucil and cyclophosphamide), purine analogs (such as fludarabine), and rituximab (used in combination with fludarabine, fludarabine and cyclophosphamide, or pentostatin and cyclophosphamide). Newer studies with either single-agent bendamustine or alemtuzumab have been shown to have improved response and progression-free survival over alkylator-based therapy. However, no current treatment option results in curative therapy, and all patients eventually relapse. This provides strong justification for developing additional types of therapies for CLL. Of particular interest are therapies that target signal transduction pathways essential to CLL cell survival mechanisms that are known to be aberrantly activated.One such pathway is the phosphoinositide 3-kinase (PI3K) pathway. The PI3K pathway is acknowledged as a key component of cell survival in many cancers, including CLL. It is activated by receptors, or the small guanosine triphosphatase Ras, and is made up of various classes of PI3K isoforms. 5 There are 3 classes of PI3K isoforms; however, only the class I isoforms phosphorylate inositol lipids to form second messenger phosphoinositides. Specifically, class I PI3K enzymes convert PtdIns(3,4)P 2 into PtdIns(3,4,5)P 3 , in the cell membrane that recruit, via binding to the amino-terminal pleckstrin homology domain, downstream signaling proteins such as Tec kinases, phosphatidylinositol-dependent kinase, Akt, integrin-linked kinase, and Rac guanine exchange factor. Class I isoforms are made up of 2 subsets (IA and IB). Class IA encompasses p110␣, p110␤, and p110␦ (catalytic domains), bound by p85, p50, or p55 (regulatory domains). Class IB is made up solely of the p110␥ (catalytic domain) bound by the regulatory domain p101. The p110␣ and p110␤ isoforms are ubiquitously expressed, and knock-out mice for both are embryonic lethal. 6 It is thought that this widespread functionality of PI3K signaling is at An Inside Blood analysis of this article appears at the front of this issue.The publication costs of this article were defrayed ...

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Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals

Herman

Gordon²,

Wagner³

et al. 2010

Blood

515

477

View full text Add to dashboard Cite

show abstract

“…Decker and colleagues tested the effect of RAD001 5 mg per day in patients with advanced B-CLL and reported one partial response and three patients with stable disease. 93 However, this trial was stopped after treatment of seven patients because of the development of opportunistic infections. In the study of Zent and colleagues, 22 patients with refractory CLL were treated with everolimus 10 mg per day and a partial remission was observed in 4 patients (18%).…”

Section: Chronic Lymphocytic Leukemiamentioning

confidence: 99%

Perspectives on inhibiting mTOR as a future treatment strategy for hematological malignancies

et al. 2010

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“…A second brief report of single-agent everolimus in seven patients with heavily pretreated chronic lymphocytic leukemia showed significant infectious complications without objective responses, although all patients were heavily pretreated and had received significant prior immunosuppressive therapy. 24 The largest study of everolimus in lymphomas was a phase II study conducted by the Mayo Clinic group, and recently reported in abstract format. 25 One hundred forty-five patients with aggressive and indolent lymphomas were accrued, and the study included an exploratory arm with T-cell lymphomas and Hodgkin's lymphomas.…”

Section: Temsirolimus In Nonmcl Lymphomasmentioning

confidence: 99%

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

Smith

Besien

Karrison

et al. 2010

JCO

183

129

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A B S T R A C T PurposeDespite high initial remission rates, most lymphomas relapse and require further therapy. The mammalian target of rapamycin (mTOR) pathway is a validated target in mantle cell lymphoma, but has not been extensively evaluated in other lymphomas. Patients and MethodsWe performed a phase II trial of single-agent temsirolimus 25-mg weekly in patients with relapsed aggressive and indolent lymphomas. The primary objective was overall and complete response rate. Patients were stratified by histology: group A (diffuse large B-cell lymphoma, transformed follicular lymphoma), group B (follicular lymphoma), and group C (chronic lymphocytic leukemia/ small lymphocytic lymphoma, and other indolent lymphomas). ResultsEighty-nine patients were treated, with outcome strongly dependent on histology. Group A had an overall and complete response rate of 28.1% and 12.5%, respectively, and median progressionfree survival (PFS) of 2.6 months and median overall survival (OS) of 7.2 months. Group B had overall and complete response rates of 53.8% and 25.6%, respectively, and median PFS of 12.7 months; median OS has not yet been reached. Group C had a partial response rate of 11% with no complete responders. Toxicity was mainly mild and/or reversible myelosuppression and mucositis; however, four patients developed pneumonitis. ConclusionsSingle-agent temsirolimus has significant activity in both diffuse large B-cell lymphoma and follicular lymphoma, although the durability of responses and PFS are longer for patients with follicular lymphoma. This is the first report of substantial activity of temsirolimus in lymphomas other than mantle cell lymphoma, and supports further evaluation of mTOR as a target in these diseases.

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A pilot trial of the mTOR (mammalian target of rapamycin) inhibitor RAD001 in patients with advanced B-CLL

Cited by 55 publications

References 32 publications

Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals

Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals

Perspectives on inhibiting mTOR as a future treatment strategy for hematological malignancies

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

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