A phase I/II study of the mTOR inhibitor everolimus in combination with hyperCVAD chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia

Naval Daver, Yanis Boumber, Hagop Kantarjian, Farhad Ravandi, Jorge Cortes, Michael E. Rytting, Jitesh D. Kawedia, Jordan Basnett, Kirk S. Culotta, Zhihong Zeng, Hongbo Lu, Mary Ann Richie, Rebecca Garris, Lianchun Xiao, Wenbin Liu, Keith A. Baggerly, Elias Jabbour, Susan O'Brien, Jan Burger, Linda J. BendallDeborah Thomas, Marina Konopleva

Research output: Contribution to journalArticle

Abstract

Purpose: Previous studies suggest a potential therapeutic role for mTOR inhibition in lymphoid malignancies. This single-center phase I/II study was designed to test the safety and efficacy of the mTOR inhibitor everolimus in combination with HyperC-VAD chemotherapy in relapsed/refractory acute lymphoblastic leukemia (ALL). Experimental Design: Twenty-four patients were treated; 15 received everolimus 5 mg/day and 9 received 10 mg/day with HyperCVAD. Results: The median age of patients was 25 years (range, 11-64) and median number of prior treatments was 2 (range, 1-7). Grade 3 mucositis was the dose-limiting toxicity and the maximum tolerated everolimus dose was 5 mg/day. Responses included complete remission (CR) in 6 patients (25%), CR without platelet recovery (CRp) in 1 (4%), and CR without recovery of counts (CRi) in 1 (4%), for an overall response rate of 33%. In addition, partial response (PR) was noted in 2 patients (8%). Seven of 11 patients treated in first salvage achieved CR/CRp (64%). The median OS was 29 weeks for patients in first salvage versus 15 weeks for patients in second salvage and beyond (P > 0.001). A response was noted in 5 of 10 (50%) heavily pretreated T-ALL patients (median of 4 prior salvage regimens). Everolimus significantly inhibited phosphorylation of S6RP, but this did not correlate with response. No significant decreases in p4EBP1 and pAkt levels were noted. Responders had higher everolimus dose-adjusted area under the curve (P = 0.025) and lower clearance (P = 0.025) than nonresponders. Conclusions: The combination of HyperCVAD and everolimus is well tolerated and moderately effective in relapsed ALL, specifically T-ALL.

Original languageEnglish (US)
Pages (from-to)2704-2714
Number of pages11
JournalClinical Cancer Research
Volume21
Issue number12
DOIs
StatePublished - Jun 15 2015
Externally publishedYes

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Drug Therapy
Mucositis
Maximum Tolerated Dose
Everolimus
Area Under Curve
Research Design
Blood Platelets
Phosphorylation
Safety
Therapeutics
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A phase I/II study of the mTOR inhibitor everolimus in combination with hyperCVAD chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia. / Daver, Naval; Boumber, Yanis; Kantarjian, Hagop; Ravandi, Farhad; Cortes, Jorge; Rytting, Michael E.; Kawedia, Jitesh D.; Basnett, Jordan; Culotta, Kirk S.; Zeng, Zhihong; Lu, Hongbo; Richie, Mary Ann; Garris, Rebecca; Xiao, Lianchun; Liu, Wenbin; Baggerly, Keith A.; Jabbour, Elias; O'Brien, Susan; Burger, Jan; Bendall, Linda J.; Thomas, Deborah; Konopleva, Marina.

In: Clinical Cancer Research, Vol. 21, No. 12, 15.06.2015, p. 2704-2714.

Research output: Contribution to journalArticle

Daver, N, Boumber, Y, Kantarjian, H, Ravandi, F, Cortes, J, Rytting, ME, Kawedia, JD, Basnett, J, Culotta, KS, Zeng, Z, Lu, H, Richie, MA, Garris, R, Xiao, L, Liu, W, Baggerly, KA, Jabbour, E, O'Brien, S, Burger, J, Bendall, LJ, Thomas, D & Konopleva, M 2015, 'A phase I/II study of the mTOR inhibitor everolimus in combination with hyperCVAD chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia', Clinical Cancer Research, vol. 21, no. 12, pp. 2704-2714. https://doi.org/10.1158/1078-0432.CCR-14-2888
Daver, Naval ; Boumber, Yanis ; Kantarjian, Hagop ; Ravandi, Farhad ; Cortes, Jorge ; Rytting, Michael E. ; Kawedia, Jitesh D. ; Basnett, Jordan ; Culotta, Kirk S. ; Zeng, Zhihong ; Lu, Hongbo ; Richie, Mary Ann ; Garris, Rebecca ; Xiao, Lianchun ; Liu, Wenbin ; Baggerly, Keith A. ; Jabbour, Elias ; O'Brien, Susan ; Burger, Jan ; Bendall, Linda J. ; Thomas, Deborah ; Konopleva, Marina. / A phase I/II study of the mTOR inhibitor everolimus in combination with hyperCVAD chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 12. pp. 2704-2714.
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T1 - A phase I/II study of the mTOR inhibitor everolimus in combination with hyperCVAD chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia

AU - Daver, Naval

AU - Boumber, Yanis

AU - Kantarjian, Hagop

AU - Ravandi, Farhad

AU - Cortes, Jorge

AU - Rytting, Michael E.

AU - Kawedia, Jitesh D.

AU - Basnett, Jordan

AU - Culotta, Kirk S.

AU - Zeng, Zhihong

AU - Lu, Hongbo

AU - Richie, Mary Ann

AU - Garris, Rebecca

AU - Xiao, Lianchun

AU - Liu, Wenbin

AU - Baggerly, Keith A.

AU - Jabbour, Elias

AU - O'Brien, Susan

AU - Burger, Jan

AU - Bendall, Linda J.

AU - Thomas, Deborah

AU - Konopleva, Marina

PY - 2015/6/15

Y1 - 2015/6/15

N2 - Purpose: Previous studies suggest a potential therapeutic role for mTOR inhibition in lymphoid malignancies. This single-center phase I/II study was designed to test the safety and efficacy of the mTOR inhibitor everolimus in combination with HyperC-VAD chemotherapy in relapsed/refractory acute lymphoblastic leukemia (ALL). Experimental Design: Twenty-four patients were treated; 15 received everolimus 5 mg/day and 9 received 10 mg/day with HyperCVAD. Results: The median age of patients was 25 years (range, 11-64) and median number of prior treatments was 2 (range, 1-7). Grade 3 mucositis was the dose-limiting toxicity and the maximum tolerated everolimus dose was 5 mg/day. Responses included complete remission (CR) in 6 patients (25%), CR without platelet recovery (CRp) in 1 (4%), and CR without recovery of counts (CRi) in 1 (4%), for an overall response rate of 33%. In addition, partial response (PR) was noted in 2 patients (8%). Seven of 11 patients treated in first salvage achieved CR/CRp (64%). The median OS was 29 weeks for patients in first salvage versus 15 weeks for patients in second salvage and beyond (P > 0.001). A response was noted in 5 of 10 (50%) heavily pretreated T-ALL patients (median of 4 prior salvage regimens). Everolimus significantly inhibited phosphorylation of S6RP, but this did not correlate with response. No significant decreases in p4EBP1 and pAkt levels were noted. Responders had higher everolimus dose-adjusted area under the curve (P = 0.025) and lower clearance (P = 0.025) than nonresponders. Conclusions: The combination of HyperCVAD and everolimus is well tolerated and moderately effective in relapsed ALL, specifically T-ALL.

AB - Purpose: Previous studies suggest a potential therapeutic role for mTOR inhibition in lymphoid malignancies. This single-center phase I/II study was designed to test the safety and efficacy of the mTOR inhibitor everolimus in combination with HyperC-VAD chemotherapy in relapsed/refractory acute lymphoblastic leukemia (ALL). Experimental Design: Twenty-four patients were treated; 15 received everolimus 5 mg/day and 9 received 10 mg/day with HyperCVAD. Results: The median age of patients was 25 years (range, 11-64) and median number of prior treatments was 2 (range, 1-7). Grade 3 mucositis was the dose-limiting toxicity and the maximum tolerated everolimus dose was 5 mg/day. Responses included complete remission (CR) in 6 patients (25%), CR without platelet recovery (CRp) in 1 (4%), and CR without recovery of counts (CRi) in 1 (4%), for an overall response rate of 33%. In addition, partial response (PR) was noted in 2 patients (8%). Seven of 11 patients treated in first salvage achieved CR/CRp (64%). The median OS was 29 weeks for patients in first salvage versus 15 weeks for patients in second salvage and beyond (P > 0.001). A response was noted in 5 of 10 (50%) heavily pretreated T-ALL patients (median of 4 prior salvage regimens). Everolimus significantly inhibited phosphorylation of S6RP, but this did not correlate with response. No significant decreases in p4EBP1 and pAkt levels were noted. Responders had higher everolimus dose-adjusted area under the curve (P = 0.025) and lower clearance (P = 0.025) than nonresponders. Conclusions: The combination of HyperCVAD and everolimus is well tolerated and moderately effective in relapsed ALL, specifically T-ALL.

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