Inferior Outcome of Addition of the Aminopeptidase Inhibitor Tosedostat to Standard Intensive Treatment for Elderly Patients with AML and High Risk MDS

被引：9

作者：

Janssen, Jeroen ^{[1
]}

Lowenberg, Bob ^{[2
]}

Manz, Markus ^{[3
]}

Bargetzi, Mario ^{[4
]}

Biemond, Bart ^{[5
]}

Borne, Peter von Dem ^{[6
]}

Breems, Dimitri ^{[7
]}

Brouwer, Rolf ^{[8
]}

Chalandon, Yves ^{[9
,10
]}

Deeren, Dries ^{[11
]}

Efthymiou, Anna ^{[12
]}

Gjertsen, Bjorn-Tore ^{[13
]}

Graux, Carlos ^{[14
]}

Gregor, Michael ^{[15
]}

Heim, Dominik ^{[16
]}

Hess, Urs ^{[17
]}

Hoogendoorn, Mels ^{[18
]}

Jaspers, Aurelie ^{[19
]}

Jie, Asiong ^{[20
]}

Jongen-Lavrencic, Mojca ^{[2
]}

Klein, Saskia ^{[21
]}

van der Klift, Marjolein ^{[22
]}

Kuball, Jurgen ^{[23
]}

van Lammeren-Venema, Danielle ^{[24
]}

Legdeur, Marie-Cecile ^{[25
]}

van de Loosdrecht, Arjan ^{[1
]}

Maertens, Johan ^{[26
]}

Kooy, Marinus van Marwijk ^{[27
]}

Moors, Ine ^{[28
]}

Nijziel, Marten ^{[29
]}

van Obbergh, Florence ^{[30
]}

Oosterveld, Margriet ^{[31
]}

Pabst, Thomas ^{[32
]}

van der Poel, Marjolein ^{[33
]}

Sinnige, Harm ^{[34
]}

Spertini, Olivier ^{[35
]}

Terpstra, Wim ^{[36
]}

Tick, Lidwine ^{[37
]}

van der Velden, Walter ^{[38
]}

Vekemans, Marie-Christiane ^{[39
]}

Vellenga, Edo ^{[40
]}

de Weerdt, Okke ^{[41
]}

Westerweel, Peter ^{[42
]}

Stussi, Georg ^{[43
]}

van Norden, Yvette ^{[44
]}

Ossenkoppele, Gert ^{[1
]}

机构：

[1] Univ Amsterdam, Med Ctr, Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands

[2] Erasmus MC, NL-3015 GD Rotterdam, Netherlands

[3] Univ Spital Zurich, CH-8091 Zurich, Switzerland

[4] Kantonsspital Aarau, CH-5001 Aarau Aarau, Switzerland

[5] Univ Amsterdam, Med Ctr, NL-1105 AZ Amsterdam, Netherlands

[6] Leiden Univ, Med Ctr, NL-2333 ZA Leiden, Netherlands

[7] Ziekenhuis Netwerk Antwerpen, B-2000 Antwerp, Belgium

[8] Reinier Graaf Hosp, NL-2625 AD Delft, Netherlands

[9] Univ Geneva, Geneva Univ Hosp, Div Hematol, Dept Oncol, CH-1211 Geneva, Switzerland

[10] Univ Geneva, Fac Med, CH-1211 Geneva, Switzerland

[11] AZ Delta, B-8800 Roeselare, Belgium

[12] Hop Fribourgeois, CH-1708 Fribourg, Switzerland

[13] Haukeland Hosp, N-5021 Bergen, Norway

[14] Mont Godinne, B-5530 Yvoir, Belgium

[15] Luzerner Kantonsspital, CH-6004 Luzern, Switzerland

[16] Univ Hosp Basel, CH-4031 Basel, Switzerland

[17] Kantonsspital St Gallen, CH-9007 St Gallen, Switzerland

[18] Medisch Ctr Leeuwarden, NL-8934 AD Leeuwarden, Netherlands

[19] Citadelle Hosp, B-4000 Liege, Belgium

[20] Zuyderland MC, Postbus 5500, NL-6130 MB Sittard, Netherlands

[21] Meander Med Ctr, NL-3813 TZ Amersfoort, Netherlands

[22] Amphia Hosp, NL-4819 EV Breda, Netherlands

[23] Univ Med Ctr, NL-3584 CX Utrecht, Netherlands

[24] Haga Hosp, NL-2545 AA The Hague, Netherlands

[25] Medisch Spectrum Twente, NL-7512 KZ Enschede, Netherlands

[26] Univ Hosp Gasthuisberg, B-3000 Leuven, Belgium

[27] Isala Clin, NL-8025 AB Zwolle, Netherlands

[28] Ghent Univ Hosp, B-9000 Ghent, Belgium

[29] Catharina Hosp, NL-5623 EJ Eindhoven, Netherlands

[30] Hosp Jolimont, B-7100 Haine St Paul, Belgium

[31] Canisius Wilhelmina Hosp, NL-6532 SZ Nijmegen, Netherlands

[32] Univ Hosp, Inselspital, CH-3010 Bern, Switzerland

[33] Maastricht Univ, Med Ctr, NL-6229 HX Maastricht, Netherlands

[34] Jeroen Bosch Ziekenhuis, NL-5223 GZ Den Bosch, Netherlands

[35] CHU Vaudois, CH-1011 Lausanne, Switzerland

[36] OLVG, NL-1091 AC Amsterdam, Netherlands

[37] Maxima Med Ctr, NL-5631 BM Eindhoven, Netherlands

[38] Radboud Univ Nijmegen, Med Ctr, NL-6525 GA Nijmegen, Netherlands

[39] Hop St Luc, B-1200 Brussels, Belgium

[40] Univ Med Ctr Groningen, NL-9713 GZ Groningen, Netherlands

[41] Antonius Hosp, NL-3435 CM Nieuwegein, Netherlands

[42] Albert Schweitzer Hosp, NL-3318 AT Dordrecht, Netherlands

[43] Ist Oncol Svizzera Italiana, CH-6500 Bellinzona, Switzerland

[44] Erasmus MC, Hovon Data Ctr, NL-3015 GD Rotterdam, Netherlands

来源：

CANCERS | 2021年 / 13卷 / 04期

关键词：

AML; high-risk MDS; tosedostat; clinical trial; aminopeptidase inhibitor; elderly;

D O I：

10.3390/cancers13040672

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Simple Summary Treatment results of acute myeloid leukemia (AML) in elderly patients are unsatisfactory. We investigated in an open label randomized phase II study whether addition of tosedostat, an aminopeptidase inhibitor, to intensive chemotherapy would improve outcome in this population. 231 AML patients > 65 years of age were randomly assigned to receive standard chemotherapy with or without tosedostat for two cycles. We found that complete bone marrow leukemia clearance was not significantly different between both arms. After two years, survival was 33% for the standard arm versus 18% for the tosedostat arm. More patients died due to infectious complications in the tosedostat arm than after standard treatment. Also, a cardiac rhythm abnormality called atrial fibrillation was more often seen in the tosedostat arm. We conclude that the addition of tosedostat to standard chemotherapy does negatively affect the therapeutic outcome of elderly patients with acute myeloid leukemia. Treatment results of AML in elderly patients are unsatisfactory. We hypothesized that addition of tosedostat, an aminopeptidase inhibitor, to intensive chemotherapy may improve outcome in this population. After establishing a safe dose in a run-in phase of the study in 22 patients, 231 eligible patients with AML above 65 years of age (median 70, range 66-81) were randomly assigned in this open label randomized Phase II study to receive standard chemotherapy (3+7) with or without tosedostat at the selected daily dose of 120 mg (n = 116), days 1-21. In the second cycle, patients received cytarabine 1000 mg/m(2) twice daily on days 1-6 with or without tosedostat. CR/CRi rates in the 2 arms were not significantly different (69% (95% C.I. 60-77%) vs 64% (55-73%), respectively). At 24 months, event-free survival (EFS) was 20% for the standard arm versus 12% for the tosedostat arm (Cox-p = 0.01) and overall survival (OS) 33% vs 18% respectively (p = 0.006). Infectious complications accounted for an increased early death rate in the tosedostat arm. Atrial fibrillation was more common in the tosedostat arm as well. The results of the present study show that the addition of tosedostat to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients.

引用

页码：1 / 11

页数：11

共 50 条

[1] Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS
G. J. Ossenkoppele
D. A. Breems
G. Stuessi
Y. van Norden
M. Bargetzi
B. J. Biemond
P. A von dem Borne
Y. Chalandon
J. Cloos
D. Deeren
M. Fehr
B. Gjertsen
C. Graux
G. Huls
J. J. J. W. Janssen
A. Jaspers
M. Jongen-Lavrencic
E. de Jongh
S. K. Klein
M. van der Klift
M. van Marwijk Kooy
J. Maertens
L. Michaux
M. W. M. van der Poel
A. van Rhenen
L. Tick
P. Valk
M. C. Vekemans
W. J. F. M. van der Velden
O. de Weerdt
T. Pabst
M. Manz
B. Löwenberg
[J]. Leukemia, 2020, 34 : 1751 - 1759
[2] Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS
Ossenkoppele, G. J.
Breems, D. A.
Stuessi, G.
Van Norden, Y.
Bargetzi, M.
Biemond, B. J.
A von dem Borne, P.
Chalandon, Y.
Cloos, J.
Deeren, D.
Fehr, M.
Gjertsen, B.
Graux, C.
Huls, G.
Janssen, J. J. J. W.
Jaspers, A.
Jongen-Lavrencic, M.
De Jongh, E.
Klein, S. K.
Van der Klift, M.
Van Marwijk Kooy, M.
Maertens, J.
Micheaux, L.
Van der Poel, M. W. M.
Van Rhenen, A.
Tick, L.
Valk, P.
Vekemans, M. C.
Van der Velden, W. J. F. M.
De Weerdt, O.
Pabst, T.
Manz, M.
Lowenberg, B.
Havelange
Vekemans, M-C
Moors, I.
Van Obberg, F.
Maertens, J. A.
Hodossy, B.
Vansteenweghen, S.
Lammertijn, L.
Sonet, A.
Triffet, A.
Gjertsen, B. T.
Passweg, J.
Heim, D.
Giovanni, San
Stuessi, Georg
Betticher, D.
Chalandon, Y.
[J]. LEUKEMIA, 2020, 34 (07) : 1751 - 1759
[3] Correction: Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS
G. J. Ossenkoppele
D. A. Breems
G. Stuessi
Y. van Norden
M. Bargetzi
B. J. Biemond
P. A von dem Borne
Y. Chalandon
J. Cloos
D. Deeren
M. Fehr
B. Gjertsen
C. Graux
G. Huls
J. J. J. W. Janssen
A. Jaspers
M. Jongen-Lavrencic
E. de Jongh
S. K. Klein
M. van der Klift
M. van Marwijk Kooy
J. Maertens
L. Michaux
M. W. M. van der Poel
A. van Rhenen
L. Tick
P. Valk
M. C. Vekemans
W. J. F. M. van der Velden
O. de Weerdt
T. Pabst
M. Manz
B. Löwenberg
[J]. Leukemia, 2020, 34 : 2820 - 2820
[4] The influence of cytogenetic abnormalities on treatment outcome after intensive antileukemic therapy for patients with high risk MDS and AML following MDS.
DeWitte
Suciu, S
Boogaerts, M
Labar, B
Archimbaud, E
Aul, C
Selleslag, D
Ferrant, A
Weijermans, P
Mandelli, F
Amadori, S
Jehn, U
Muus, P
DeMuynck, H
Dardenne, M
Willemze, R
Gratwohl, A
Apperley, J
[J]. BLOOD, 1996, 88 (10) : 1806 - 1806
[5] Addition of the nuclear export inhibitor selinexor to standard intensive treatment for elderly patients with acute myeloid leukemia and high risk myelodysplastic syndrome
Janssen, J. J. W. M.
Loewenberg, B.
Manz, M.
Biemond, B. J.
Westerweel, P. E.
Klein, S. K.
Fehr, M.
Sinnige, H. A. M.
Efthymiou, A.
Legdeur, M. C. J. C.
Pabst, T.
Gregor, M.
van der Poel, M. W. M.
Deeren, D.
Tick, L. W.
Jongen-Lavrencic, M.
van Obbergh, F.
Boersma, R. S.
de Weerdt, O.
Chalandon, Y.
Heim, D.
Spertini, O.
van Sluis, G.
Graux, C.
Stuessi, G.
van Norden, Y.
Ossenkoppele, G. J.
[J]. LEUKEMIA, 2022, 36 (09) : 2189 - 2195
[6] Addition of the nuclear export inhibitor selinexor to standard intensive treatment for elderly patients with acute myeloid leukemia and high risk myelodysplastic syndrome
J. J. W. M. Janssen
B. Löwenberg
M. Manz
B. J. Biemond
P. E. Westerweel
S. K. Klein
M. Fehr
H. A. M. Sinnige
A. Efthymiou
M. C. J. C. Legdeur
T. Pabst
M. Gregor
M. W. M. van der Poel
D. Deeren
L. W. Tick
M. Jongen-Lavrencic
F. van Obbergh
R. S. Boersma
O. de Weerdt
Y. Chalandon
D. Heim
O. Spertini
G. van Sluis
C. Graux
G. Stüssi
Y. van Norden
G. J. Ossenkoppele
[J]. Leukemia, 2022, 36 : 2189 - 2195
[7] Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS (vol 66, pg 813, 2020)
Ossenkoppele, G. J.
Breems, D. A.
Stuessi, G.
van Norden, Y.
Bargetzi, M.
Biemond, B. J.
von dem Borne, P.
Chalandon, Y.
Cloos, J.
Deeren, D.
Fehr, M.
Gjertsen, B.
Graux, C.
Huls, G.
Janssen, J. J. J. W.
Jaspers, A.
Jongen-Lavrencic, M.
de Jongh, E.
Klein, S. K.
van der Klift, M.
van Marwijk Kooy, M.
Maertens, J.
Michaux, L.
van der Poel, M. W. M.
van Rhenen, A.
Tick, L.
Valk, P.
Vekemans, M. C.
van der Velden, W. J. F. M.
de Weerdt, O.
Pabst, T.
Manz, M.
Lowenberg, B.
[J]. LEUKEMIA, 2020, 34 (10) : 2820 - 2820
[8] A Phase I/II Study Of Cytarabine Or Azacitidine In Combination With Tosedostat In Older Patients With AML Or High-Risk MDS
DiNardo, Courtney D.
Kantarjian, Hagop M.
Ravandi, Farhad
Konopleva, Marina
Kadia, Tapan M.
Borthakur, Gautam
Daver, Naval G.
Durand, Mends
Rivera, Silvia
Quintas-Cardama, Alfonso
Garcia-Manero, Guillermo
Cortes, Jorge E.
[J]. BLOOD, 2013, 122 (21)
[9] Fetal hemoglobin induction during decitabine treatment of elderly high-risk MDS and AML patients: A potential dynamic biomarker for outcome
Stomper, J.
Ihorst, G.
Suciu, S.
Sander, P. N.
Becker, H.
Wijermans, P. W.
Bisse, E.
Claus, R.
Luebbert, M.
[J]. ONCOLOGY RESEARCH AND TREATMENT, 2018, 41 : 19 - 19
[10] A pilot study of bendamustine in elderly patients with high-risk MDS and AML
Strupp, C.
Knipp, S.
Hartmann, J.
Gattermann, N.
Haas, R.
Germing, U.
[J]. LEUKEMIA & LYMPHOMA, 2007, 48 (06) : 1161 - 1166

← 1 2 3 4 5 →