A Phase I/II Study of the mTOR Inhibitor Everolimus in Combination with HyperCVAD Chemotherapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia.
OBJECTIVE
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 HyperCVAD chemotherapy in relapsed/refractory acute lymphoblastic leukemia (ALL).


METHODS
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.
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Naval
N
Daver
Hematology/Oncology Fellowship Program, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Yanis
Y
Boumber
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Hagop
H
Kantarjian
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Farhad
F
Ravandi
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jorge
J
Cortes
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Michael E
ME
Rytting
Department of Pharmacy Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jitesh D
JD
Kawedia
Center for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, New South Wales, Australia.
Jordan
J
Basnett
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Kirk S
KS
Culotta
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Zhihong
Z
Zeng
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Hongbo
H
Lu
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Mary Ann
MA
Richie
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Rebecca
R
Garris
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Lianchun
L
Xiao
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Wenbin
W
Liu
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Keith A
KA
Baggerly
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Elias
E
Jabbour
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Susan
S
O'Brien
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jan
J
Burger
Center for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, New South Wales, Australia.
Linda J
LJ
Bendall
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas. mkonople@mdanderson.org debthomas@mdanderson.org.
Deborah
D
Thomas
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas. mkonople@mdanderson.org debthomas@mdanderson.org.
Marina
M
Konopleva
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers; D002648:Child; D003520:Cyclophosphamide; D003907:Dexamethasone; D004317:Doxorubicin; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D014750:Vincristine; D055815:Young Adult
D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D058570:TOR Serine-Threonine Kinases