Addition of AEG35156 XIAP Antisense Oligonucleotide in Reinduction Chemotherapy Does Not Improve Remission Rates in Patients With Primary Refractory Acute Myeloid Leukemia in a Randomized Phase II Study

被引：42

作者：

Schimmer, Aaron D. ^{[1
]}

Herr, Wolfgang ^{[2
]}

Haenel, Mathias ^{[3
]}

Borthakur, Gautham ^{[4
]}

Frankel, Arthur ^{[5
]}

Horst, Heinz-August ^{[6
]}

Martin, Sonja ^{[7
]}

Kassis, Jeannine ^{[8
]}

Desjardins, Pierre ^{[9
]}

Seiter, Karen ^{[10
]}

Fiedler, Walter ^{[11
]}

Noppeney, Richard ^{[12
]}

Giagounidis, Aristoteles ^{[13
]}

Jacob, Christine ^{[14
]}

Jolivet, Jacques ^{[14
]}

Tallman, Martin S. ^{[15
]}

Koschmieder, Steffen ^{[16
]}

机构：

[1] Princess Margaret Hosp, Ontario Canc Inst, Toronto, ON M4X 1K9, Canada

[2] Univ Med Mainz, Mainz, Germany

[3] Klinikum Chemnitz gGmbH, Chemnitz, Germany

[4] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[5] Scott & White Hosp, Temple, TX USA

[6] Univ Klinikum Schleswig Holstein, Kiel, Germany

[7] Robert Bosch Krankenhaus Stuttgart, Stuttgart, Germany

[8] Hop Maison Neuve Rosemont, Montreal, PQ, Canada

[9] Hosp Charles Lemoyne, Greenfield Pk, PQ, Canada

[10] New York Med Coll, Valhalla, NY 10595 USA

[11] Univ Klinikum Hamburg Eppendorf, Hamburg, Germany

[12] Univ Klinikum Essen, Essen, Germany

[13] St Johannes Hosp, Katholisches Klinikum Duisburg, Duisburg, Germany

[14] Aegera Therapeut, Montreal, PQ, Canada

[15] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA

[16] Univ Klinikum Munster, Munster, Germany

来源：

CLINICAL LYMPHOMA MYELOMA & LEUKEMIA | 2011年 / 11卷 / 05期

关键词：

Antisense; Leukemia; Phase II clinical trial; XIAP; X-LINKED INHIBITOR; INTERNATIONAL WORKING GROUP; CANCER CELLS; IN-VITRO; INDUCTION CHEMOTHERAPY; APOPTOSIS PROTEIN; RESPONSE CRITERIA; DOWN-REGULATION; TARGETING XIAP; EXPRESSION;

D O I：

10.1016/j.clml.2011.03.033

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

XIAP is over-expressed in AML and may contribute to chemoresistance. We report an open-label randomized phase II trial of reinduction chemotherapy with and without the XIAP antisense oligonucleotide AEG35156 in patients with AML patients. The addition of AEG35156 to re-induction chemotherapy did not improve rates of remission. Therefore, alternate therapeutic strategies should be explored in these patients. Background: XIAP (X-linked inhibitor of apoptosis protein) is an inhibitor of caspases 3 and 9 that is overexpressed in acute myeloid leukemia (AML) and may contribute to chemoresistance. We report an open-label randomized phase II trial of reinduction chemotherapy with and without the XIAP antisense oligonucleotide AEG35156 in patients with AML who did not achieve remission with initial induction chemotherapy. Methods: Twenty-seven patients with AML who were refractory to initial induction chemotherapy were randomized and treated with AEG35156 (650 mg) in combination with high-dose cytarabine and idarubicin. Thirteen patients were randomized and treated with high-dose cytarabine and idarubicin alone. The rates of response and toxicity were determined. Results: Of the 27 patients assigned to AEG35156 in combination with high-dose cytarabine and idarubicin, 3 died during reinduction chemotherapy, 5 achieved complete remission (CR), and 6 achieved CR with incomplete platelet count recovery (CRp), for an overall response rate of 41%. Of the 13 patients assigned to the control arm of the study, none died during reinduction, 6 achieved CR, and 3 achieved CRp, for an overall response rate of 69%. The differences in response rates between patients in the AEG35156 and control arms were not statistically different (P = 0.18 by the chi(2) test). Conclusions: The addition of AEG35156 to reinduction chemotherapy was well tolerated but did not improve rates of remission. Therefore alternative therapeutic strategies should be explored in patients with AML refractory to induction chemotherapy.

引用

页码：433 / 438

页数：6

共 25 条

[1] Outcome after induction chemotherapy for older patients with acute myeloid leukemia is not improved with mitoxantrone and etoposide compared to cytarabine and daunorubicin: a Southwest Oncology Group study [J].

Anderson, JE ;

Kopecky, KJ ;

Willman, CL ;

Head, D ;

O'Donnell, MR ;

Luthardt, FW ;

Norwood, TH ;

Chen, IM ;

Balcerzak, SP ;

Johnson, DB ;

Appelbaum, FR .

BLOOD, 2002, 100 (12) :3869-3876

[2] Increased expression of apoptosis inhibitor protein XIAP contributes to anoikis resistance of circulating human prostate cancer metastasis precursor cells [J].

Berezovskaya, O ;

Schimmer, AD ;

Glinskii, AB ;

Pinilla, C ;

Hoffman, RM ;

Reed, JC ;

Glinsky, GV .

CANCER RESEARCH, 2005, 65 (06) :2378-2386

[3] Predictors of response to reinduction chemotherapy for patients with acute myeloid leukemia who do not achieve complete remission with frontline induction chemotherapy [J].

Brandwein, Joseph M. ;

Gupta, Vikas ;

Schuh, Andre C. ;

Schimmer, Aaron D. ;

Yee, Karen ;

Xu, Wei ;

Messner, Hans A. ;

Lipton, Jeffrey H. ;

Minden, Mark D. .

AMERICAN JOURNAL OF HEMATOLOGY, 2008, 83 (01) :54-58

[4] 6-thioguanine, cytarabine, and daunorubicin (TAD) and high-dose cytarabine and mitoxantrone (HAM) for induction, TAD for consolidation, and either prolonged maintenance by reduced monthly TAD or TAD-HAM-TAD and one course of intensive consolidation by sequential HAM in adult patients at all ages with de novo acute myeloid leukemia (AML):: A randomized trial of the German AML cooperative group [J].

Büchner, T ;

Hiddemann, W ;

Berdel, WE ;

Wörmann, B ;

Schoch, C ;

Fonatsch, C ;

Löffler, H ;

Haferlach, T ;

Ludwig, WD ;

Maschmeyer, G ;

Staib, P ;

Aul, C ;

Grüneisen, A ;

Lengfelder, E ;

Frickhofen, N ;

Kern, W ;

Serve, HL ;

Mesters, RM ;

Sauerland, MC ;

Heinecke, A .

JOURNAL OF CLINICAL ONCOLOGY, 2003, 21 (24) :4496-4504

[5] Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells [J].

Carter, BZ ;

Gronda, M ;

Wang, ZL ;

Welsh, K ;

Pinilla, C ;

Andreeff, M ;

Schober, WD ;

Nefzi, A ;

Pond, GR ;

Mawji, IA ;

Houghten, RA ;

Ostresh, J ;

Brandwein, J ;

Minden, MD ;

Schuh, AC ;

Wells, RA ;

Messner, H ;

Chun, K ;

Reed, JC ;

Schimmer, AD .

BLOOD, 2005, 105 (10) :4043-4050

[6] Caspase-independent cell death in AML: caspase inhibition in vitro with pan-caspase inhibitors or in vivo by XIAP or Survivin does not affect cell survival or prognosis [J].

Carter, BZ ;

Kornblau, SM ;

Tsao, T ;

Wang, RY ;

Schober, WD ;

Milella, M ;

Sung, HG ;

Reed, JC ;

Andreeff, M .

BLOOD, 2003, 102 (12) :4179-4186

[7] Regulation and targeting of antiapoptotic XIAP in acute myeloid leukemia [J].

Carter, BZ ;

Milella, M ;

Tsao, T ;

McQueen, T ;

Schober, WD ;

Hu, W ;

Dean, NM ;

Steelman, L ;

McCubrey, JA ;

Andreeff, M .

LEUKEMIA, 2003, 17 (11) :2081-2089

[8] Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia [J].

Cheson, BD ;

Bennett, JM ;

Kopecky, KJ ;

Büchner, T ;

Willman, CL ;

Estey, EH ;

Schiffer, CA ;

Döhner, H ;

Tallman, MS ;

Lister, TA ;

LoCocco, F ;

Willemze, R ;

Biondi, A ;

Hiddemann, W ;

Larson, RA ;

Löwenberg, B ;

Sanz, MA ;

Head, DR ;

Ohno, R ;

Bloomfield, CD .

JOURNAL OF CLINICAL ONCOLOGY, 2003, 21 (24) :4642-4649

[9] Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia [J].

Cheson, Bruce D. ;

Greenberg, Peter L. ;

Bennett, John M. ;

Lowenberg, Bob ;

Wijermans, Pierre W. ;

Nimer, Stephen D. ;

Pinto, Antonio ;

Beran, Miloslav ;

de Witte, Theo M. ;

Stone, Richard M. ;

Mittelman, Moshe ;

Sanz, Guillermo F. ;

Gore, Steven D. ;

Schiffer, Charles A. ;

Kantarjian, Hagop .

BLOOD, 2006, 108 (02) :419-425

[10] X-linked IAP is a direct inhibitor of cell-death proteases [J].

Deveraux, QL ;

Takahashi, R ;

Salvesen, GS ;

Reed, JC .

NATURE, 1997, 388 (6639) :300-304

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