Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory waldenström macroglobulinemia

Irene M. Ghobrial, Morie Gertz, Betsy LaPlant, John K Camoriano, Suzanne Hayman, Martha Lacy, Stacey Chuma, Brianna Harris, Renee Leduc, Meghan Rourke, Stephen Maxted Ansell, Daniel DeAngelo, Angela Dispenzieri, Peter Leif Bergsagel, Craig Reeder, Kenneth C. Anderson, Paul G. Richardson, Steven P. Treon, Thomas Elmer Witzig

Research output: Contribution to journalArticle

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Abstract

Purpose: The phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR) signal transduction pathway controls cell proliferation and survival. Everolimus is an oral agent targeting raptor mTOR (mTORC1). The trial's goal was to determine the antitumor activity and safety of single-agent everolimus in patients with relapsed/refractory Waldenström macroglobulinemia (WM). Patients and Methods: Eligible patients had measurable disease (immunoglobulin M monoclonal protein > 1,000 mg/dL with > 10% marrow involvement or nodal masses > 2 cm), a platelet count more than 75,000 × 106/L, a neutrophil count more than 1,000 × 106/L, and a creatinine and bilirubin less than 2 x the laboratory upper limit of normal. Patients received everolimus 10 mg orally daily and were evaluated monthly. Tumor response was assessed after cycles 2 and 6 and then every three cycles until progression. Results: Fifty patients were treated. The median age was 63 years (range, 43 to 85 years). The overall response rate (complete response plus partial remission [PR] plus minimal response [MR]) was 70% (95% CI, 55% to 82%), with a PR of 42% and 28% MR. The median duration of response and median progression-free survival (PFS) have not been reached. The estimated PFS at 6 and 12 months is 75% (95% CI, 64% to 89%) and 62% (95% CI, 48% to 80%), respectively. Grade 3 or higher related toxicities were observed in 56% of patients. The most common were hematologic toxicities with cytopenias. Pulmonary toxicity occurred in 10% of patients. Dose reductions due to toxicity occurred in 52% of patients. Conclusion: Everolimus has high single-agent activity with an overall response rate of 70% and manageable toxicity in patients with relapsed WM and offers a potential new therapeutic strategy for this patient group.

Original languageEnglish (US)
Pages (from-to)1408-1414
Number of pages7
JournalJournal of Clinical Oncology
Volume28
Issue number8
DOIs
StatePublished - Mar 10 2010

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Waldenstrom Macroglobulinemia
Sirolimus
Disease-Free Survival
Everolimus
Phosphatidylinositol 3-Kinase
Raptors
Platelet Count
Bilirubin
Immunoglobulin M
Signal Transduction
Creatinine
Cell Survival
Neutrophils
Bone Marrow
Cell Proliferation
Safety

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory waldenström macroglobulinemia. / Ghobrial, Irene M.; Gertz, Morie; LaPlant, Betsy; Camoriano, John K; Hayman, Suzanne; Lacy, Martha; Chuma, Stacey; Harris, Brianna; Leduc, Renee; Rourke, Meghan; Ansell, Stephen Maxted; DeAngelo, Daniel; Dispenzieri, Angela; Bergsagel, Peter Leif; Reeder, Craig; Anderson, Kenneth C.; Richardson, Paul G.; Treon, Steven P.; Witzig, Thomas Elmer.

In: Journal of Clinical Oncology, Vol. 28, No. 8, 10.03.2010, p. 1408-1414.

Research output: Contribution to journalArticle

Ghobrial, Irene M. ; Gertz, Morie ; LaPlant, Betsy ; Camoriano, John K ; Hayman, Suzanne ; Lacy, Martha ; Chuma, Stacey ; Harris, Brianna ; Leduc, Renee ; Rourke, Meghan ; Ansell, Stephen Maxted ; DeAngelo, Daniel ; Dispenzieri, Angela ; Bergsagel, Peter Leif ; Reeder, Craig ; Anderson, Kenneth C. ; Richardson, Paul G. ; Treon, Steven P. ; Witzig, Thomas Elmer. / Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory waldenström macroglobulinemia. In: Journal of Clinical Oncology. 2010 ; Vol. 28, No. 8. pp. 1408-1414.
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abstract = "Purpose: The phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR) signal transduction pathway controls cell proliferation and survival. Everolimus is an oral agent targeting raptor mTOR (mTORC1). The trial's goal was to determine the antitumor activity and safety of single-agent everolimus in patients with relapsed/refractory Waldenstr{\"o}m macroglobulinemia (WM). Patients and Methods: Eligible patients had measurable disease (immunoglobulin M monoclonal protein > 1,000 mg/dL with > 10{\%} marrow involvement or nodal masses > 2 cm), a platelet count more than 75,000 × 106/L, a neutrophil count more than 1,000 × 106/L, and a creatinine and bilirubin less than 2 x the laboratory upper limit of normal. Patients received everolimus 10 mg orally daily and were evaluated monthly. Tumor response was assessed after cycles 2 and 6 and then every three cycles until progression. Results: Fifty patients were treated. The median age was 63 years (range, 43 to 85 years). The overall response rate (complete response plus partial remission [PR] plus minimal response [MR]) was 70{\%} (95{\%} CI, 55{\%} to 82{\%}), with a PR of 42{\%} and 28{\%} MR. The median duration of response and median progression-free survival (PFS) have not been reached. The estimated PFS at 6 and 12 months is 75{\%} (95{\%} CI, 64{\%} to 89{\%}) and 62{\%} (95{\%} CI, 48{\%} to 80{\%}), respectively. Grade 3 or higher related toxicities were observed in 56{\%} of patients. The most common were hematologic toxicities with cytopenias. Pulmonary toxicity occurred in 10{\%} of patients. Dose reductions due to toxicity occurred in 52{\%} of patients. Conclusion: Everolimus has high single-agent activity with an overall response rate of 70{\%} and manageable toxicity in patients with relapsed WM and offers a potential new therapeutic strategy for this patient group.",
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T1 - Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory waldenström macroglobulinemia

AU - Ghobrial, Irene M.

AU - Gertz, Morie

AU - LaPlant, Betsy

AU - Camoriano, John K

AU - Hayman, Suzanne

AU - Lacy, Martha

AU - Chuma, Stacey

AU - Harris, Brianna

AU - Leduc, Renee

AU - Rourke, Meghan

AU - Ansell, Stephen Maxted

AU - DeAngelo, Daniel

AU - Dispenzieri, Angela

AU - Bergsagel, Peter Leif

AU - Reeder, Craig

AU - Anderson, Kenneth C.

AU - Richardson, Paul G.

AU - Treon, Steven P.

AU - Witzig, Thomas Elmer

PY - 2010/3/10

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N2 - Purpose: The phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR) signal transduction pathway controls cell proliferation and survival. Everolimus is an oral agent targeting raptor mTOR (mTORC1). The trial's goal was to determine the antitumor activity and safety of single-agent everolimus in patients with relapsed/refractory Waldenström macroglobulinemia (WM). Patients and Methods: Eligible patients had measurable disease (immunoglobulin M monoclonal protein > 1,000 mg/dL with > 10% marrow involvement or nodal masses > 2 cm), a platelet count more than 75,000 × 106/L, a neutrophil count more than 1,000 × 106/L, and a creatinine and bilirubin less than 2 x the laboratory upper limit of normal. Patients received everolimus 10 mg orally daily and were evaluated monthly. Tumor response was assessed after cycles 2 and 6 and then every three cycles until progression. Results: Fifty patients were treated. The median age was 63 years (range, 43 to 85 years). The overall response rate (complete response plus partial remission [PR] plus minimal response [MR]) was 70% (95% CI, 55% to 82%), with a PR of 42% and 28% MR. The median duration of response and median progression-free survival (PFS) have not been reached. The estimated PFS at 6 and 12 months is 75% (95% CI, 64% to 89%) and 62% (95% CI, 48% to 80%), respectively. Grade 3 or higher related toxicities were observed in 56% of patients. The most common were hematologic toxicities with cytopenias. Pulmonary toxicity occurred in 10% of patients. Dose reductions due to toxicity occurred in 52% of patients. Conclusion: Everolimus has high single-agent activity with an overall response rate of 70% and manageable toxicity in patients with relapsed WM and offers a potential new therapeutic strategy for this patient group.

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