期刊论文详细信息
Journal of Hematology & Oncology
Rapid induction of complete molecular remission by sequential therapy with LDAC and sorafenib in FLT3-ITD-positive patients unfit for intensive treatment: two cases and review of the literature
Florian H Heidel2  Thomas Fischer2  Kathleen Jentsch-Ullrich1  Helga Luehr2  Tina M Schnoeder2  Christian Krogel2  Enrico Schalk2  Denise Wolleschak2 
[1] Private Practice for Hematology and Medical Oncology, Hasselbachplatz 2, Magdeburg D-39104, Germany;Department of Hematology and Oncology, Center of Internal Medicine, Otto-von-Guericke University Medical Center, Leipziger Str. 44, Magdeburg D-39120, Germany
关键词: Targeted therapy;    LDAC;    Small molecule;    Sorafenib;    AML;   
Others  :  806082
DOI  :  10.1186/1756-8722-6-39
 received in 2013-04-09, accepted in 2013-05-24,  发布年份 2013
PDF
【 摘 要 】

Treatment of acute myeloid leukemia remains a therapeutic challenge. Even in younger patients with a low rate of co-morbidities less than 50% of patients can be cured. For older patients or patients with significant co-morbidities, the situation appears even worse. In patients not eligible for intensive treatment approaches - e.g. due to underlying medical conditions - therapeutic approaches remain almost exclusively palliative. However, even with less intense treatment approaches, temporary remission can be achieved and this contributes to prolonged survival and improved quality of life of the respective patient. Targeted therapies have been widely used as palliative treatment in- and outside clinical trials as single agents. Combination with low-dose cytarabine (LDAC) potentially improves remission rates and can be safely administered in an outpatient setting.

Previous studies showed that additive hematologic toxicity of combinatory therapeutic approaches may arise from simultaneous treatment (e.g. chemotherapy plus targeted therapies). However, sequential therapies have already proven their feasibility in clinical trials. Here, we report two cases of rapid induction of complete molecular remission by sequential therapy with LDAC and sorafenib in patients unfit for intensive chemotherapy without significant long-term toxicity.

【 授权许可】

   
2013 Wolleschak et al.; licensee BioMed Central Ltd.

【 预 览 】
附件列表
Files Size Format View
20140708090143413.pdf 1161KB PDF download
Figure 3. 14KB Image download
Figure 2. 55KB Image download
Figure 1. 140KB Image download
【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】
  • [1]Godwin JE, Kopecky KJ, Head DR, Willman CL, Leith CP, Hynes HE, Balcerzak SP, Appelbaum FR: A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a southwest oncology group study (9031). Blood 1998, 91:3607-3615.
  • [2]Goldstone AH, Burnett AK, Wheatley K, Smith AG, Hutchinson RM, Clark RE: Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom medical research council AML11 trial. Blood 2001, 98:1302-1311.
  • [3]Lowenberg B, Suciu S, Archimbaud E, Haak H, Stryckmans P, de Cataldo R, Dekker AW, Berneman ZN, Thyss A, van der Lelie J, et al.: Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy–the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. European organization for the research and treatment of cancer and the Dutch-Belgian hemato-oncology cooperative hovon group. J Clin Oncol 1998, 16:872-881.
  • [4]Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, Omura GA, Moore JO, McIntyre OR, Frei E: The cancer and leukemia group B: intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 1994, 331:896-903.
  • [5]Mrozek K, Dohner H, Bloomfield CD: Influence of new molecular prognostic markers in patients with karyotypically normal acute myeloid leukemia: recent advances. Curr Opin Hematol 2007, 14:106-114.
  • [6]Mrozek K, Heerema NA, Bloomfield CD: Cytogenetics in acute leukemia. Blood Rev 2004, 18:115-136.
  • [7]Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, Van Vlierberghe P, Dolgalev I, Thomas S, Aminova O, et al.: Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012, 366:1079-1089.
  • [8]Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L, Habdank M, Spath D, Morgan M, Benner A, et al.: Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008, 358:1909-1918.
  • [9]Frohling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K, Dohner H, Dohner K: Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 2002, 100:4372-4380.
  • [10]Gale RE, Green C, Allen C, Mead AJ, Burnett AK, Hills RK, Linch DC: The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 2008, 111:2776-2784.
  • [11]Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U, Wermke M, Bornhauser M, Ritter M, Neubauer A, et al.: Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002, 99:4326-4335.
  • [12]Meshinchi S, Stirewalt DL, Alonzo TA, Boggon TJ, Gerbing RB, Rocnik JL, Lange BJ, Gilliland DG, Radich JP: Structural and numerical variation of FLT3/ITD in pediatric AML. Blood 2008, 111:4930-4933.
  • [13]Pratcorona M, Brunet S, Nomdedeu J, Ribera JM, Tormo M, Duarte R, Escoda L, Guardia R, Queipo de Llano MP, Salamero O, et al.: Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy. Blood 2013, 121:2734-2738.
  • [14]Bullinger L, Dohner K, Kranz R, Stirner C, Frohling S, Scholl C, Kim YH, Schlenk RF, Tibshirani R, Dohner H, Pollack JR: An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML. Blood 2008, 111:4490-4495.
  • [15]Cheson BD, Simon R: Low-dose ara-C in acute nonlymphocytic leukemia and myelodysplastic syndromes: a review of 20 years’ experience. Semin Oncol 1987, 14:126-133.
  • [16]Burnett AK, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK, Wheatley K: A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 2007, 109:1114-1124.
  • [17]Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, Fox E, Ehninger G, Feldman EJ, Schiller GJ, et al.: Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol 2010, 28:4339-4345.
  • [18]Levis M, Ravandi F, Wang ES, Baer MR, Perl A, Coutre S, Erba H, Stuart RK, Baccarani M, Cripe LD, et al.: Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood 2011, 117:3294-3301.
  • [19]Rollig C, Muller-Tidow C, Huttmann A, Kunzmann V, Baldus CD, Brandts C, Kramer A, Schafer-Eckart K, Neubauer A, Krause SW, et al.: Sorafenib versus placebo in addition to standard therapy in adult patients ≥60 years with newly diagnosed acute myeloid leukemia: results from the randomized-controlled soraml trial. Blood (ASH Annual Meeting Abstracts) 2012.
  • [20]Heidel F, Cortes J, Rucker FG, Aulitzky W, Letvak L, Kindler T, Huber C, Dohner H, Kantarjian H, Fischer T: Results of a multicenter phase II trial for older patients with c-kit-positive acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS) using low-dose ara-C and imatinib. Cancer 2007, 109:907-914.
  • [21]Macdonald DA, Assouline SE, Brandwein J, Kamel-Reid S, Eisenhauer EA, Couban S, Caplan S, Foo A, Walsh W, Leber B: A phase I/II study of sorafenib in combination with low dose cytarabine in elderly patients with acute myeloid leukemia or high-risk myelodysplastic syndrome from the National Cancer Institute of Canada Clinical Trials Group: trial IND.186. Leuk Lymphoma 2013, 54:760-766.
  • [22]Fischer T, Giles F, Paquette R, Schiller G, Ehninger G, Schiffer C, Cortes J, Kantarjian H, DeAngelo D, Heidel F, Cohen PS, Yu R, Bilic S, Zhang L, Phillips PS, Stone RM: Phase IB study of PKC412, an oral FLT3 kinase inhibitor, in sequential and simultaneous combinations with daunorubicin and cytarabine (DA) induction and high-dose cytarabine consolidation in newly diagnosed patients with AML. Haematologica 2006., 92((EHA Meeting Abstracts))
  • [23]Serve H, Wagner R, Sauerland C: Sorafenib in combination with standard induction and consolidation therapy in elderly AML patients: results from a randomized, placebo-controlled phase II trial. Blood (ASH Annual Meeting Abstracts) 2010., 116
  • [24]Smith CC, Wang Q, Chin CS, Salerno S, Damon LE, Levis MJ, Perl AE, Travers KJ, Wang S, Hunt JP, et al.: Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature 2012, 485:260-263.
  • [25]Borthakur G, Kantarjian H, Ravandi F, Zhang W, Konopleva M, Wright JJ, Faderl S, Verstovsek S, Mathews S, Andreeff M, Cortes JE: Phase I study of sorafenib in patients with refractory or relapsed acute leukemias. Haematologica 2011, 96:62-68.
  • [26]Man CH, Fung TK, Ho C, Han HH, Chow HC, Ma AC, Choi WW, Lok S, Cheung AM, Eaves C, et al.: Sorafenib treatment of FLT3-ITD(+) acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation. Blood 2012, 119:5133-5143.
  • [27]Metzelder S, Wang Y, Wollmer E, Wanzel M, Teichler S, Chaturvedi A, Eilers M, Enghofer E, Neubauer A, Burchert A: Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood 2009, 113:6567-6571.
  • [28]Rollig C, Brandts C, Shaid S, Hentrich M, Kramer A, Junghanss C, Schleyer E, Muller-Tidow C, Berdel WE, Ritter B, et al.: Survey and analysis of the efficacy and prescription pattern of sorafenib in patients with acute myeloid leukemia. Leuk Lymphoma 2012, 53:1062-1067.
  • [29]Scholl S, Loncarevic IF, Krause C, Kunert C, Clement JH, Hoffken K: Minimal residual disease based on patient specific Flt3-ITD and -ITT mutations in acute myeloid leukemia. Leuk Res 2005, 29:849-853.
  • [30]Al-Kali A, Cortes J, Faderl S, Jones D, Abril C, Pierce S, Brandt M, Kantarjian H, Ravandi F: Patterns of molecular response to and relapse after combination of sorafenib, idarubicin, and cytarabine in patients with FLT3 mutant acute myeloid leukemia. Clin Lymphoma Myeloma Leuk 2011, 11:361-366.
  文献评价指标  
  下载次数:11次 浏览次数:12次