Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation

被引：201

作者：

Metzelder, Stephan ^{[1
]}

Wang, Ying ^{[1
]}

Wollmer, Ellen ^{[1
]}

Wanzel, Michael ^{[2
]}

Teichler, Sabine ^{[1
]}

Chaturvedi, Anuhar ^{[1
]}

Eilers, Martin ^{[3
]}

Enghofer, Erich ^{[4
]}

Neubauer, Andreas ^{[1
]}

Burchert, Andreas ^{[1
]}

机构：

[1] Univ Marburg, Med Ctr Univ Giessen & Marburg, Dept Hematol Oncol & Immunol, Marburg, Germany

[2] Inst Mol Biol & Tumor Res, Marburg, Germany

[3] Univ Wurzburg, Dept Physiol Chem, Bioctr, Wurzburg, Germany

[4] Bayer Schering Pharma, BU Oncol, Leverkusen, Germany

来源：

BLOOD | 2009年 / 113卷 / 26期

关键词：

INTERNAL TANDEM DUPLICATION; ACUTE MYELOGENOUS LEUKEMIA; FLT3; GENE; MYELODYSPLASTIC SYNDROME; RISK GROUP; CHEMOTHERAPY; MUTATIONS; PROGNOSIS; IMATINIB; TRIALS;

D O I：

10.1182/blood-2009-03-208298

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Acute myeloid leukemia (AML) patients with internal tandem duplication (ITD) mutations in the Fms-like tyrosine-3 (FLT3) gene have a dismal prognosis. Here we report compassionate-use results with the multikinase and FLT3-ITD inhibitor sorafenib for the treatment of relapsed or refractory FLT3-ITD-positive AML. Sorafenib induced clinically meaningful and very rapid responses in all 6 patients treated either before (n = 2), after (n = 3), or both before and after (n = 1) allogeneic stem cell transplantation (allo-SCT). Sorafenib-induced remissions facilitated allo-SCT in 2 of the 3 refractory patients. Two of the 4 patients who were treated after allo-SCT survived 216 and 221 days, respectively, whereas the other 2 remain in ongoing complete molecular remission. Sorafenib response was associated with an inhibition of the antiapoptotic FLT3-ITD target Stat-5 in vivo. Together, sorafenib monotherapy before or after allo-SCT has remarkable clinical activity in poor risk FLT3-ITD-positive AML and deserves further evaluation in prospective clinical trials. (Blood. 2009; 113: 6567-6571)

引用

页码：6567 / 6571

页数：5

共 18 条

[11] Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia [J].

Schlenk, Richard F. ;

Doehner, Konstanze ;

Krauter, Juergen ;

Froehling, Stefan ;

Corbacioglu, Andrea ;

Bullinger, Lars ;

Habdank, Marianne ;

Spaeth, Daniela ;

Morgan, Michael ;

Benner, Axel ;

Schlegelberger, Brigitte ;

Heil, Gerhard ;

Ganser, Arnold ;

Doehner, Hartmut .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (18) :1909-1918

[12] Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome [J].

Schmid, C ;

Schleuning, M ;

Ledderose, G ;

Tischer, J ;

Kolb, HJ .

JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (24) :5675-5687

[13] Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation [J].

Schmid, Christoph ;

Schleuning, Michael ;

Schwerdtfeger, Rainer ;

Hertenstein, Bernd ;

Mischak-Weissinger, Eva ;

Bunjes, Donald ;

v. Harsdorf, Stephanie ;

Scheid, Christoph ;

Holtick, Udo ;

Greinix, Hildegard ;

Keil, Felix ;

Schneider, Barbara ;

Sandherr, Michael ;

Bug, Gesine ;

Tischer, Johanna ;

Ledderose, Georg ;

Hallek, Michael ;

Hiddemann, Wolfgang ;

Kolb, Hans-Jochem .

BLOOD, 2006, 108 (03) :1092-1099

[14] Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia:: association with FAB subtypes and identification of subgroups with poor prognosis [J].

Thiede, C ;

Steudel, C ;

Mohr, B ;

Schaich, M ;

Schäkel, U ;

Platzbecker, U ;

Wermke, M ;

Bornhäuser, M ;

Ritter, M ;

Neubauer, A ;

Ehninger, G ;

Illmer, T .

BLOOD, 2002, 99 (12) :4326-4335

[15] Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT 5 pathway activation [J].

Wang, Ying ;

Cai, Dali ;

Brendel, Cornelia ;

Barett, Christine ;

Erben, Philipp ;

Manley, Paul W. ;

Hochhaus, Andreas ;

Neubauer, Andreas ;

Burchert, Andreas .

BLOOD, 2007, 109 (05) :2147-2155

[16] Early molecular response to posttransplantation imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) [J].

Wassmann, B ;

Pfeifer, H ;

Stadler, M ;

Bornhäuser, M ;

Bug, G ;

Scheuring, UJ ;

Brück, P ;

Stelljes, M ;

Schwerdtfeger, R ;

Basara, N ;

Perz, J ;

Bunjes, D ;

Ledderose, G ;

Mahlberg, R ;

Binckebanck, A ;

Gschaidmeier, H ;

Hoelzer, D ;

Ottmann, OG .

BLOOD, 2005, 106 (02) :458-463

[17] Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines [J].

Yokota, S ;

Kiyoi, H ;

Nakao, M ;

Iwai, T ;

Misawa, S ;

Okuda, T ;

Sonoda, Y ;

Abe, T ;

Kahsima, K ;

Matsuo, Y ;

Naoe, T .

LEUKEMIA, 1997, 11 (10) :1605-1609

[18] Mutant FLT3:: A direct target of sorafenib in acute myelogenous leukemia [J].

Zhang, Weiguo ;

Konopleva, Marina ;

Shi, Yue-Xi ;

McQueen, Teresa ;

Harris, David ;

Ling, Xiaoyang ;

Estrov, Zeev ;

Quintas-Cardama, Alfonso ;

Small, Donald ;

Cortes, Jorge ;

Andreeff, Michael .

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2008, 100 (03) :184-198

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