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Aktueller Stand der Therapiekonzepte bei Akuter Myeloischer Leukämie (S. 17–25)
Christoph Röllig, Universitätsklinikum Dresden

  1. Hellenbrecht A, Messerer D, Gökbuget N. Häufigkeit von Leukämien bei Erwachsenen in Deutschland. Kompetenznetzwerk Leukämien 2008 [cited 2011 Jul 29]; Available from: URL: www.kompetenznetz-leukaemie.de/content/aerzte/epidemiologie/leukaemiehaeufigkeit/
  2. Juliusson G, Antunovic P, Derolf A, Lehmann S, Mollgard L, Stockelberg D, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood 2009 Apr 30; 113(18): 4179–87
  3. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood 2016 Apr 11
  4. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2016 Nov 28
  5. Shah A, Andersson TM, Rachet B, Bjorkholm M, Lambert PC. Survival and cure of acute myeloid leukaemia in England, 1971– 2006: a population-based study. Br J Haematol 2013 Aug; 162(4): 509–16
  6. Thein MS, Ershler WB, Jemal A, Yates JW, Baer MR. Outcome of older patients with acute myeloid leukemia: an analysis of SEER data over 3 decades. Cancer 2013 Aug 1; 119(15): 2720–7
  7. Juliusson G, Lazarevic V, Horstedt AS, Hagberg O, Hoglund M. Acute myeloid leukemia in the real world: why population-based registries are needed. Blood 2012 Apr 26; 119(17): 3890–9
  8. Atallah E, Cortes J, O'brien S, Pierce S, Rios MB, Estey E, et al. Establishment of baseline toxicity expectations with standard frontline chemotherapy in acute myelogenous leukemia. Blood 2007 Nov 15; 110(10): 3547–51
  9. Kantarjian H, O'brien S, Cortes J, Giles F, Faderl S, Jabbour E, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer 2006 Mar 1; 106(5): 1090–8
  10. Krug U, Berdel WE, Gale RP, Haferlach C, Schnittger S, Muller-Tidow C, et al. Increasing intensity of therapies assigned at diagnosis does not improve survival of adults with acute myeloid leukemia. Leukemia 2016 Feb 9
  11. Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010 Jan 21; 115(3): 453–74
  12. Rollig C, Bornhauser M, Thiede C, Taube F, Kramer M, Mohr B, et al. Long-term prognosis of acute myeloid leukemia according to the new genetic risk classification of the European LeukemiaNet recommendations: evaluation of the proposed reporting system. J Clin Oncol 2011 Jul 10; 29(20): 2758–65
  13. Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009 Feb 26; 113(9): 1875– 91
  14. Lo-Coco F, Avvisati G, Orlando SM, Ferrara F, Vignetti M, Fazi P, et al. ATRA and Arsenic Trioxide (ATO) Versus ATRA and Idarubicin (AIDA) for Newly Diagnosed, Non High-Risk Acute Promyelocytic Leukemia (APL): Results of the Phase III, Prospective, Randomized, Intergroup APL0406 Study by the Italian-German Cooperative Groups Gimema-SAL-AMLSG. ASH Annual Meeting Abstracts 2012 Nov 16; 120(21): 6
  15. Lengfelder E, Lambert J-F, Nachbaur D, Niederwieser D, Platzbecker U, Schlenk RF, et al. Onkopedia-Leitlinie Akute Promyelozyten Leukämie.  1-1-2014. 21-4-2017 
  16. Röllig C, Beelen DW, Braess J, Greil R, Niederwieser D, Passweg JR, et al. Onkopedia-Leitlinie Akute Myeloische Leukämie.  12-1-2017. 24-1-2017
  17. Mielcarek M, Furlong T, O'Donnell PV, Storer BE, McCune JS, Storb R, et al. Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood 2016 Mar 17; 127(11): 1502–8
  18. Shayegi N, Kramer M, Bornhauser M, Schaich M, Schetelig J, Platzbecker U, et al. The level of residual disease based on mutant NPM1 is an independent prognostic factor for relapse and survival in AML. Blood 2013 Jul 4; 122(1): 83– 92
  19. Kronke J, Schlenk RF, Jensen KO, Tschurtz F, Corbacioglu A, Gaidzik VI, et al. Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group. J Clin Oncol 2011 Jul 1; 29(19): 2709– 16
  20. Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 2012 Jul 20; 30(21): 2670– 7
  21. Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015 Jul 16; 126(3): 291– 9
  22. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009 Mar; 10(3): 223– 32
  23. Burnett AK, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK, et al. 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 Mar 15; 109(6): 1114–24
  24. Cabrero M, Jabbour E, Ravandi F, Bohannan Z, Pierce S, Kantarjian HM, et al. Discontinuation of hypomethylating agent therapy in patients with myelodysplastic syndromes or acute myelogenous leukemia in complete remission or partial response: retrospective analysis of survival after long-term follow-up. Leuk Res 2015 May; 39(5): 520–4
  25. Thol F, Schlenk RF, Heuser M, Ganser A. How I treat refractory and early relapsed acute myeloid leukemia. Blood 2015 Apr 7
  26. Fathi AT, Chen YB. Treatment of relapse of acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation. Curr Hematol Malig Rep 2014 Jun; 9(2): 186–92
  27. Ritchie EK, Feldman EJ, Christos PJ, Rohan SD, Lagassa CB, Ippoliti C, et al. Decitabine in patients with newly diagnosed and relapsed acute myeloid leukemia. Leuk Lymphoma 2013 Sep; 54(9): 2003–7
  28. Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 2009 Sep 24; 361(13): 1249–59
  29. Lee JH, Joo YD, Kim H, Bae SH, Kim MK, Zang DY, et al. A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia. Blood 2011 Oct 6; 118(14): 3832–41
  30. Burnett AK, Russell NH, Hills RK, Kell J, Cavenagh J, Kjeldsen L, et al. A randomised comparison of daunorubicin 90mg/m2 vs 60mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood 2015 Apr 1
  31. Ommen HB. Monitoring minimal residual disease in acute myeloid leukaemia: a review of the current evolving strategies. Ther Adv Hematol 2016 Feb; 7(1): 3–16
  32. Ehninger A, Kramer M, Rollig C, Thiede C, Bornhauser M, von BM, et al. Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. Blood Cancer J 2014 Jun 13; 4: e218
  33. Kharfan-Dabaja MA, Hamadani M, Reljic T, Pyngolil R, Komrokji RS, Lancet JE, et al. Gemtuzumab ozogamicin for treatment of newly diagnosed acute myeloid leukaemia: a systematic review and meta-analysis. Br J Haematol 2013 Nov; 163(3): 315–25
  34. Loke J, Khan JN, Wilson JS, Craddock C, Wheatley K. Mylotarg has potent anti-leukaemic effect: a systematic review and meta-analysis of anti-CD33 antibody treatment in acute myeloid leukaemia. Ann Hematol 2015 Mar; 94(3): 361–73
  35. Hills RK, Castaigne S, Appelbaum FR, Delaunay J, Petersdorf S, Othus M, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol 2014 Aug; 15(9): 986–96
  36. Li X, Xu SN, Qin DB, Tan Y, Gong Q, Chen JP. Effect of adding gemtuzumab ozogamicin to induction chemotherapy for newly diagnosed acute myeloid leukemia: a meta-analysis of prospective randomized phase III trials. Ann Oncol 2014 Feb; 25(2): 455–61
  37. Montalban-Bravo G, Garcia-Manero G. Novel drugs for older patients with acute myeloid leukemia. Leukemia 2015 Apr; 29(4): 760–9
  38. Dohner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med 2015 Sep 17; 373(12): 1136–52

UPDATE
Aktuelle Therapie des Adenokarzinoms des Pankreas (S. 45–49)
Angelika Kestler und Thomas Seufferlein, Universitätsklinikum Ulm

  1. Robert-Koch-Institut. 2015. Krebs in Deutschland 2011/2012. Edited by Robert-Koch-Institut and Gesellschaft der epidemiologischen Krebsregister in Deutschland. 10. Ausg. Beiträge Zur Gesundheitsberichterstattung Des Bundes. Berlin
  2. Shaib, W. L., A. Ip, K. Cardona, O. B. Alese, S. K. Maithel, D. Kooby, J. Landry, and B. F. El-Rayes. 2016. Contemporary Management of Borderline Resectable and Locally Advanced Unresectable Pancreatic Cancer. The Oncologist; 21 (2): 178–87
  3. Lutz, M. P., J. R. Zalcberg, M. Ducreux, D. Aust, M. J. Bruno, M. W. Büchler, J.R. Delpero, et al. 2017. 3rd St. Gallen EORTC Gastrointestinal Cancer Conference: Consensus Recommendations on Controversial Issues in the Primary Treatment of Pancreatic Cancer. Eur J Cancer; 79 (July): 41–49
  4. Wang-Gillam, Andrea, Chung-Pin Li, György Bodoky, Andrew Dean, Yan-Shen Shan, Gayle Jameson, Teresa Macarulla, et al. 2016. Nanoliposomal Irinotecan with Fluorouracil and Folinic Acid in Metastatic Pancreatic Cancer after Previous Gemcitabine-Based Therapy (NAPOLI-1): A Global, Randomised, Open-Label, Phase 3 Trial. Lancet (London, England); 387 (10018): 545–57
  5. Hosein, P. J., G. de Lima Lopes, V. H. Pastorini, C. Gomez, J. Macintyre, G. Zayas, I. Reis, A. J. Montero, J. R. Merchan, and C. M. Rocha Lima. 2013. A Phase II Trial of Nab-Paclitaxel as Second-Line Therapy in Patients With Advanced Pancreatic Cancer. J Clin Oncol; 36 (2): 151–56
  6. MacKenzie, S., H. Zeh, L. E. McCahill, T. D. Sielaff, N. Bahary, T. E. Gribbin, J. E. Seng, et al. 2013. A Pilot Phase II Multicenter Study of Nab-Paclitaxel (Nab-P) and Gemcitabine (G) as Preoperative Therapy for Potentially Resectable Pancreatic Cancer (PC). J Clin Oncol; 31: 2013 suppl; abstr 4038
  7. Suker, Mustafa, Berend R Beumer, Eran Sadot, Lysiane Marthey, Jason E Faris, Eric A Mellon, Bassel F El-Rayes, et al. 2016. FOLFIRINOX for Locally Advanced Pancreatic Cancer: A Systematic Review and Patient-Level Meta-Analysis. Lancet Oncol; 17 (6): 801–10
  8. Hammel, Pascal, Florence Huguet, Jean-Luc van Laethem, David Goldstein, Bengt Glimelius, Pascal Artru, Ivan Borbath, et al. 2016. Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib: The LAP07 Randomized Clinical Trial. JAMA; 315 (17): 1844–53
  9. Seufferlein, T., M. Porzner, T. Becker, V. Budach, G. Ceyhan, I. Esposito, R. Fietkau, et al. 2013. S3-Leitlinie zum exokrinen Pankreaskarzinom. Zeitschrift für Gastroenterologie; 51 (12): 1395–1440
  10. Oettle, Helmut, Peter Neuhaus, Andreas Hochhaus, Jörg Thomas Hartmann, Klaus Gellert, Karsten Ridwelski, Marco Niedergethmann, et al. 2013. Adjuvant Chemotherapy With Gemcitabine and Long-Term Outcomes Among Patients With Resected Pancreatic Cancer: The CONKO-001 Randomized Trial. JAMA; 310 (14): 1473
  11. Neoptolemos, John P., Deborah D. Stocken, Claudio Bassi, Paula Ghaneh, David Cunningham, David Goldstein, Robert Padbury, et al. 2010. Adjuvant Chemotherapy With Fluorouracil Plus Folinic Acid vs Gemcitabine Following Pancreatic Cancer Resection: A Randomized Controlled Trial. JAMA; 304 (10): 1073
  12. Uesaka, K., N. Boku, A. Fukutomi, Y. Okamura, M. Konishi, I. Matsumoto, Y. Kaneoka, et al. 2016. Adjuvant Chemotherapy of S-1 versus Gemcitabine for Resected Pancreatic Cancer: A Phase 3, Open-Label, Randomised, Non-Inferiority Trial (JASPAC 01). Lancet; 388 (10041): 248–57
  13. Valle, J. W., D. Palmer, R. Jackson, T. Cox, J. P. Neoptolemos, P. Ghaneh, C. L. Rawcliffe, et al. 2014. Optimal Duration and Timing of Adjuvant Chemotherapy After Definitive Surgery for Ductal Adenocarcinoma of the Pancreas: Ongoing Lessons From the ESPAC-3 Study. J Clin Oncol; 32 (6): 504–12
  14. Neoptolemos JP, Palmer DH, Ghaneh P, et al.; European Study Group for Pancreatic Cancer. 2017. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet; 389: 1011–1024
  15. Sahin, I. H., A. I. Geyer, D. W. Kelly, and E. M. O’Reilly. 2016. Gemcitabine-Related Pneumonitis in Pancreas Adenocarcinoma – An Infrequent Event: Elucidation of Risk Factors and Management Implications. Clinical Colorectal Cancer; 15 (1): 24–31
  16. Moore, Malcolm J., David Goldstein, John Hamm, Arie Figer, Joel R. Hecht, Steven Gallinger, Heather J. Au, et al. 2007. Erlotinib plus Gemcitabine Compared with Gemcitabine Alone in Patients with Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol; 25 (15): 1960–66
  17. Von Hoff, Daniel D., Thomas Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey Infante, Malcolm Moore, Thomas Seay, et al. 2013. Increased Survival in Pancreatic Cancer with Nab-Paclitaxel plus Gemcitabine. New Eng J Med; 369 (18): 1691–1703
  18. Bachet, J. B., P. Hammel, J. Desramé, A. Meurisse, B. Chibaudel, T. André, P. Debourdeau, et al. 2017. Nab-Paclitaxel plus Either Gemcitabine or Simplified Leucovorin and Fluorouracil as First-Line Therapy for Metastatic Pancreatic Adenocarcinoma (AFUGEM GERCOR): A Non-Comparative, Multicentre, Open-Label, Randomised Phase 2 Trial. The Lancet Gastroenterology & Hepatology; 2 (5): 337–46
  19. Conroy, Thierry, Françoise Desseigne, Marc Ychou, Olivier Bouché, Rosine Guimbaud, Yves Bécouarn, Antoine Adenis, et al. 2011. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. New Eng J Med; 364 (19): 1817–25
  20. Gourgou-Bourgade, S., C. Bascoul-Mollevi, F. Desseigne, M. Ychou, O. Bouché, R. Guimbaud, Y. Bécouarn, et al. 2013. Impact of FOLFIRINOX Compared With Gemcitabine on Quality of Life in Patients With Metastatic Pancreatic Cancer: Results From the PRODIGE 4/ACCORD 11 Randomized Trial. J Clin Oncol; 31 (1): 23–29
  21. Oettle, Helmut, Hanno Riess, Jens M. Stieler, Gerhard Heil, Ingo Schwaner, Jörg Seraphin, Martin Görner, et al. 2014. Second-Line Oxaliplatin, Folinic Acid, and Fluorouracil versus Folinic Acid and Fluorouracil Alone for Gemcitabine-Refractory Pancreatic Cancer: Outcomes from the CONKO-003 Trial. J Clin Oncol; 32 (23): 2423–29
  22. Pelzer, U., I. Schwaner, J. Stieler, M. Adler, J. Seraphin, B. Dörken, H. Riess, and H. Oettle. 2011. Best Supportive Care (BSC) versus Oxaliplatin, Folinic Acid and 5-Fluorouracil (OFF) plus BSC in Patients for Second-Line Advanced Pancreatic Cancer: A Phase III-Study from the German CONKO-Study Group. Eur J Cancer; 47 (11): 1676–81
  23. Gill et al. 2014. PANCREOX: A Randomized Phase 3 Study of 5FU/LV with or without Oxaliplatin for Second-Line Advanced Pancreatic Cancer (APC) in Patients (Pts) Who Have Received Gemcitabine (GEM)-Based Chemotherapy (CT). J Clin Oncol; 32:5s, (suppl; abstr 4022)
  24. Portal A, Pernot S, Tougeron D, Arbaud C, et al., 2015. Nab-paclitaxel plus gemcitabine for metastatic pancreatic adenocarcinoma after Folfirinox failure: an AGEO prospective multicentre cohort. Br J Cancer 2015; 113:989-95
  25. Kalra, A. V., J. Kim, S. G. Klinz, N. Paz, J. Cain, D. C. Drummond, U. B. Nielsen, and J. B. Fitzgerald. 2014. Preclinical Activity of Nanoliposomal Irinotecan Is Governed by Tumor Deposition and Intratumor Prodrug Conversion. Cancer Res; 74 (23): 7003–13
  26. Middleton, G., D. H. Palmer, W. Greenhalf, P. Ghaneh, R. Jackson, T. Cox, A. Evans, et al. 2017. Vandetanib plus Gemcitabine versus Placebo plus Gemcitabine in Locally Advanced or Metastatic Pancreatic Carcinoma (ViP): A Prospective, Randomised, Double-Blind, Multicentre Phase 2 Trial. Lancet Oncol; 18 (4): 486–99
  27. Kindler, H. L., T. Ioka, D. J. Richel, J. Bennouna, R. Létourneau, T. Okusaka, A. Funakoshi, et al. 2011. Axitinib plus Gemcitabine versus Placebo plus Gemcitabine in Patients with Advanced Pancreatic Adenocarcinoma: A Double-Blind Randomised Phase 3 Study. Lancet Oncol; 12 (3): 256–62
  28. Janavičius, R. 2010. Founder BRCA1/2 Mutations in the Europe: Implications for Hereditary Breast-Ovarian Cancer Prevention and Control. EPMA Journal; 1 (3): 397–412
  29. Kaufman, B., R. Shapira-Frommer, R. K. Schmutzler, M. W. Audeh, M. Friedlander, J. Balmaña, G. Mitchell, et al. 2015. Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation. J Clin Oncol; 33 (3): 244–50
  30. Hingorani, S. R., W. P. Harris, T. Beck, B. A. Berdov, S. A. Wagner, P. Jiang, D. C. Maneval, J. Zhu, and C. E. Devoe. 2013. A Phase Ib Study of Gemcitabine plus PEGPH20 (Pegylated Recombinant Human Hyaluronidase) in Patients with Stage IV Previously Untreated Pancreatic Cancer. J Clin Oncol; 31 (15 Suppl 4010): 4010
  31. Le Dung, T., J. N. Uram, H. Wang, B. R. Bartlett, H. Kemberling, A. D. Eyring, A. D. Skora, et al. 2015. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. New Eng J Med; 372 (26): 2509–20
  32. Dung, L. T., A. H. Ko, Z. A. Wainberg, V. J. Picozzi, H. L. Kindler, A. Wang-Gillam, P. E. Oberstein, et al. 2017. Results from a Phase 2b, Randomized, Multicenter Study of GVAX Pancreas and CRS-207 Compared to Chemotherapy in Adults with Previously-Treated Metastatic Pancreatic Adenocarcinoma (ECLIPSE Study). J Clinl Oncol; 35 (4_suppl): 345–345
  33. Dung, L. T., A. Wang-Gillam, V. Picozzi, Jr, T. F. Greten, T. S. Crocenzi, G. M. Springett, M. Morse, et al. 2014. A Phase 2, Randomized Trial of GVAX Pancreas and CRS-207 Immunotherapy versus GVAX Alone in Patients with Metastatic Pancreatic Adenocarcinoma: Updated Results. J Clin Oncol; 32 (3_suppl): 177–177