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Erschienen in: Annals of Hematology 10/2016

27.04.2016 | Review Article

Emerging strategies for the treatment of older patients with acute myeloid leukemia

verfasst von: Miguel A. Sanz, Gloria Iacoboni, Pau Montesinos, Adriano Venditti

Erschienen in: Annals of Hematology | Ausgabe 10/2016

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Abstract

Acute myeloid leukemia (AML) is the most common acute leukemia in adults, and its incidence increases with age. Clinical outcomes in younger patients have improved over the years but, unfortunately, there is little evidence for an equivalent improvement in outcome for older patients. Approximately 50 % of older patients who are able to receive intensive chemotherapy will achieve a complete remission; however, they face a much higher relapse rate than younger patients, and survival rates for this group are low. Therefore, there is an urgent need to improve outcomes in older patients with AML. In this article, we discuss current treatment paradigms for older patients with AML including the challenges faced when determining which patients are eligible for intensive chemotherapy. We then highlight new treatments in development that may benefit this patient group. Cytotoxic agents, hypomethylating agents, molecularly targeted agents, and cell cycle kinase inhibitors are discussed, with a focus on novel agents that have achieved an advanced stage of development. Overall, the treatment of AML in older patients remains a challenge and, whenever possible, treatment should be offered in the context of clinical trials and should be planned with curative intent.
Literatur
1.
Zurück zum Zitat Pollyea DA, Kohrt HE, Medeiros BC (2011) Acute myeloid leukaemia in the elderly: a review. Br J Haematol 152:524–542CrossRefPubMed Pollyea DA, Kohrt HE, Medeiros BC (2011) Acute myeloid leukaemia in the elderly: a review. Br J Haematol 152:524–542CrossRefPubMed
2.
Zurück zum Zitat Hoffman R, Benz EJ, Shattil S et al (2000) Hematology: basic principles and practice 3rd edition. Churchill Livingstone, London Hoffman R, Benz EJ, Shattil S et al (2000) Hematology: basic principles and practice 3rd edition. Churchill Livingstone, London
4.
Zurück zum Zitat Fey MF, Buske C, on behalf of the ESMO Guidelines Working Group (2013) Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 24:vi138–vi143CrossRefPubMed Fey MF, Buske C, on behalf of the ESMO Guidelines Working Group (2013) Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 24:vi138–vi143CrossRefPubMed
5.
Zurück zum Zitat Burnett AK (2012) Treatment of acute myeloid leukemia: are we making progress? Am Soc Hematol Educ Program Book 2012:1–6 Burnett AK (2012) Treatment of acute myeloid leukemia: are we making progress? Am Soc Hematol Educ Program Book 2012:1–6
6.
Zurück zum Zitat Burnett A, Wetzler M, Löwenberg B (2011) Therapeutic advances in acute myeloid leukemia. J Clin Oncol 29:487–494CrossRefPubMed Burnett A, Wetzler M, Löwenberg B (2011) Therapeutic advances in acute myeloid leukemia. J Clin Oncol 29:487–494CrossRefPubMed
7.
Zurück zum Zitat Deschler B, de Witte T, Mertelsmann R, Lubbert M (2006) Treatment decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches. Haematologica 91:1513–1522PubMed Deschler B, de Witte T, Mertelsmann R, Lubbert M (2006) Treatment decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches. Haematologica 91:1513–1522PubMed
8.
Zurück zum Zitat Döhner H, Estey EH, Amadori S et al (2010) Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 115:453–474CrossRefPubMed Döhner H, Estey EH, Amadori S et al (2010) Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 115:453–474CrossRefPubMed
9.
Zurück zum Zitat Lowenberg B, Ossenkoppele GJ, van Putten W et al (2009) High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 361:1235–1248CrossRefPubMed Lowenberg B, Ossenkoppele GJ, van Putten W et al (2009) High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 361:1235–1248CrossRefPubMed
10.
Zurück zum Zitat Juliusson G, Antunovic P, Derolf A et al (2009) Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood 113:4179–4187CrossRefPubMed Juliusson G, Antunovic P, Derolf A et al (2009) Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood 113:4179–4187CrossRefPubMed
11.
Zurück zum Zitat National Institute for Health and Care Excellence. Azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia. NICE technology appraisal guidance [TA218]. In. 2011 National Institute for Health and Care Excellence. Azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia. NICE technology appraisal guidance [TA218]. In. 2011
12.
Zurück zum Zitat Fenaux P, Mufti GJ, Hellstrom-Lindberg E et al (2010) Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 28:562–569CrossRefPubMed Fenaux P, Mufti GJ, Hellstrom-Lindberg E et al (2010) Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 28:562–569CrossRefPubMed
13.
Zurück zum Zitat Dombret H, Seymour JF, Butrym A et al (2015) International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 126:291–299CrossRefPubMedPubMedCentral Dombret H, Seymour JF, Butrym A et al (2015) International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 126:291–299CrossRefPubMedPubMedCentral
14.
Zurück zum Zitat Pleyer L, Burgstaller S, Girschikofsky M et al (2014) Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group. Ann Hematol 93:1825–1838CrossRefPubMedPubMedCentral Pleyer L, Burgstaller S, Girschikofsky M et al (2014) Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group. Ann Hematol 93:1825–1838CrossRefPubMedPubMedCentral
15.
Zurück zum Zitat Breccia M, Frustaci AM, Cannella L et al (2009) Comorbidities and FLT3-ITD abnormalities as independent prognostic indicators of survival in elderly acute myeloid leukaemia patients. Hematol Oncol 27:148–153CrossRefPubMed Breccia M, Frustaci AM, Cannella L et al (2009) Comorbidities and FLT3-ITD abnormalities as independent prognostic indicators of survival in elderly acute myeloid leukaemia patients. Hematol Oncol 27:148–153CrossRefPubMed
16.
Zurück zum Zitat Etienne A, Esterni B, Charbonnier A et al (2007) Comorbidity is an independent predictor of complete remission in elderly patients receiving induction chemotherapy for acute myeloid leukemia. Cancer 109:1376–1383CrossRefPubMed Etienne A, Esterni B, Charbonnier A et al (2007) Comorbidity is an independent predictor of complete remission in elderly patients receiving induction chemotherapy for acute myeloid leukemia. Cancer 109:1376–1383CrossRefPubMed
17.
Zurück zum Zitat Giles FJ, Borthakur G, Ravandi F et al (2007) The haematopoietic cell transplantation comorbidity index score is predictive of early death and survival in patients over 60 years of age receiving induction therapy for acute myeloid leukaemia. Br J Haematol 136:624–627CrossRefPubMed Giles FJ, Borthakur G, Ravandi F et al (2007) The haematopoietic cell transplantation comorbidity index score is predictive of early death and survival in patients over 60 years of age receiving induction therapy for acute myeloid leukaemia. Br J Haematol 136:624–627CrossRefPubMed
18.
Zurück zum Zitat Kantarjian H, Ravandi F, O’Brien S et al (2010) Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood 116:4422–4429CrossRefPubMedPubMedCentral Kantarjian H, Ravandi F, O’Brien S et al (2010) Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood 116:4422–4429CrossRefPubMedPubMedCentral
19.
Zurück zum Zitat Krug U, Rollig C, Koschmieder A et al (2010) Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes. Lancet 376:2000–2008CrossRefPubMed Krug U, Rollig C, Koschmieder A et al (2010) Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes. Lancet 376:2000–2008CrossRefPubMed
20.
Zurück zum Zitat Malfuson JV, Etienne A, Turlure P et al (2008) Risk factors and decision criteria for intensive chemotherapy in older patients with acute myeloid leukemia. Haematologica 93:1806–1813CrossRefPubMed Malfuson JV, Etienne A, Turlure P et al (2008) Risk factors and decision criteria for intensive chemotherapy in older patients with acute myeloid leukemia. Haematologica 93:1806–1813CrossRefPubMed
21.
Zurück zum Zitat Oosterveld M, Suciu S, Muus P et al (2015) Specific scoring systems to predict survival of patients with high-risk myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML) after intensive antileukemic treatment based on results of the EORTC-GIMEMA AML-10 and intergroup CRIANT studies. Ann Hematol 94:23–34CrossRefPubMed Oosterveld M, Suciu S, Muus P et al (2015) Specific scoring systems to predict survival of patients with high-risk myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML) after intensive antileukemic treatment based on results of the EORTC-GIMEMA AML-10 and intergroup CRIANT studies. Ann Hematol 94:23–34CrossRefPubMed
22.
Zurück zum Zitat Pastore F, Dufour A, Benthaus T et al (2014) Combined molecular and clinical prognostic index for relapse and survival in cytogenetically normal acute myeloid leukemia. J Clin Oncol 32:1586–1594CrossRefPubMedPubMedCentral Pastore F, Dufour A, Benthaus T et al (2014) Combined molecular and clinical prognostic index for relapse and survival in cytogenetically normal acute myeloid leukemia. J Clin Oncol 32:1586–1594CrossRefPubMedPubMedCentral
23.
Zurück zum Zitat Rollig C, Thiede C, Gramatzki M et al (2010) A novel prognostic model in elderly patients with acute myeloid leukemia: results of 909 patients entered into the prospective AML96 trial. Blood 116:971–978CrossRefPubMed Rollig C, Thiede C, Gramatzki M et al (2010) A novel prognostic model in elderly patients with acute myeloid leukemia: results of 909 patients entered into the prospective AML96 trial. Blood 116:971–978CrossRefPubMed
24.
Zurück zum Zitat Wheatley K, Brookes CL, Howman AJ et al (2009) Prognostic factor analysis of the survival of elderly patients with AML in the MRC AML11 and LRF AML14 trials. Br J Haematol 145:598–605CrossRefPubMed Wheatley K, Brookes CL, Howman AJ et al (2009) Prognostic factor analysis of the survival of elderly patients with AML in the MRC AML11 and LRF AML14 trials. Br J Haematol 145:598–605CrossRefPubMed
25.
Zurück zum Zitat Yoon JH, Cho BS, Kim HJ et al (2013) Outcomes of elderly de novo acute myeloid leukemia treated by a risk-adapted approach based on age, comorbidity, and performance status. Am J Hematol 88:1074–1081CrossRefPubMed Yoon JH, Cho BS, Kim HJ et al (2013) Outcomes of elderly de novo acute myeloid leukemia treated by a risk-adapted approach based on age, comorbidity, and performance status. Am J Hematol 88:1074–1081CrossRefPubMed
26.
Zurück zum Zitat Ross K, Gillespie-Twardy AL, Agha M et al (2015) Intensive chemotherapy in patients aged 70 years or older newly diagnosed with acute myeloid leukemia. Oncol Res Feat Preclin Clin Cancer Ther 22:85–92 Ross K, Gillespie-Twardy AL, Agha M et al (2015) Intensive chemotherapy in patients aged 70 years or older newly diagnosed with acute myeloid leukemia. Oncol Res Feat Preclin Clin Cancer Ther 22:85–92
27.
Zurück zum Zitat Buckley SA, Othus M, Vainstein V et al (2014) Prediction of adverse events during intensive induction chemotherapy for acute myeloid leukemia or high-grade myelodysplastic syndromes. Am J Hematol 89:423–428CrossRefPubMedPubMedCentral Buckley SA, Othus M, Vainstein V et al (2014) Prediction of adverse events during intensive induction chemotherapy for acute myeloid leukemia or high-grade myelodysplastic syndromes. Am J Hematol 89:423–428CrossRefPubMedPubMedCentral
29.
Zurück zum Zitat Bello C, Yu D, Komrokji RS et al (2011) Outcomes after induction chemotherapy in patients with acute myeloid leukemia arising from myelodysplastic syndrome. Cancer 117:1463–1469CrossRefPubMed Bello C, Yu D, Komrokji RS et al (2011) Outcomes after induction chemotherapy in patients with acute myeloid leukemia arising from myelodysplastic syndrome. Cancer 117:1463–1469CrossRefPubMed
30.
Zurück zum Zitat Shin SH, Yahng SA, Yoon JH et al (2013) Survival benefits with transplantation in secondary AML evolving from myelodysplastic syndrome with hypomethylating treatment failure. Bone Marrow Transplant 48:678–683CrossRefPubMed Shin SH, Yahng SA, Yoon JH et al (2013) Survival benefits with transplantation in secondary AML evolving from myelodysplastic syndrome with hypomethylating treatment failure. Bone Marrow Transplant 48:678–683CrossRefPubMed
31.
Zurück zum Zitat Amadori S, Del Principe MI, Venditti A (2014) Advances in the treatment of elderly and frail patients with acute myeloid leukemia. Curr Opin Oncol 26:663–669CrossRefPubMed Amadori S, Del Principe MI, Venditti A (2014) Advances in the treatment of elderly and frail patients with acute myeloid leukemia. Curr Opin Oncol 26:663–669CrossRefPubMed
32.
Zurück zum Zitat de la Rubia J, Regadera A, Martin G et al (2002) FLAG-IDA regimen (fludarabine, cytarabine, idarubicin and G-CSF) in the treatment of patients with high-risk myeloid malignancies. Leuk Res 26:725–730CrossRefPubMed de la Rubia J, Regadera A, Martin G et al (2002) FLAG-IDA regimen (fludarabine, cytarabine, idarubicin and G-CSF) in the treatment of patients with high-risk myeloid malignancies. Leuk Res 26:725–730CrossRefPubMed
33.
Zurück zum Zitat Kadia TM, Ravandi F, O’Brien S et al (2015) Progress in acute myeloid leukemia. Clin Lymphoma Myeloma Leuk 15:139–151CrossRefPubMed Kadia TM, Ravandi F, O’Brien S et al (2015) Progress in acute myeloid leukemia. Clin Lymphoma Myeloma Leuk 15:139–151CrossRefPubMed
34.
Zurück zum Zitat Burnett AK, Russell NH, Hills RK et al (2013) Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial. J Clin Oncol 31:3360–3368CrossRefPubMed Burnett AK, Russell NH, Hills RK et al (2013) Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial. J Clin Oncol 31:3360–3368CrossRefPubMed
35.
Zurück zum Zitat Holowiecki J, Grosicki S, Robak T et al (2004) Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study. Leukemia 18:989–997CrossRefPubMed Holowiecki J, Grosicki S, Robak T et al (2004) Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study. Leukemia 18:989–997CrossRefPubMed
36.
Zurück zum Zitat Holowiecki J, Grosicki S, Giebel S et al (2012) Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol 30:2441–2448CrossRefPubMed Holowiecki J, Grosicki S, Giebel S et al (2012) Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol 30:2441–2448CrossRefPubMed
37.
38.
Zurück zum Zitat Faderl S, Ravandi F, Huang X et al (2008) A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood 112:1638–1645CrossRefPubMedPubMedCentral Faderl S, Ravandi F, Huang X et al (2008) A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood 112:1638–1645CrossRefPubMedPubMedCentral
39.
Zurück zum Zitat Nazha A, Kantarjian H, Ravandi F et al (2013) Clofarabine, idarubicin, and cytarabine (CIA) as frontline therapy for patients ≤60 years with newly diagnosed acute myeloid leukemia. Am J Hematol 88:961–966CrossRefPubMedPubMedCentral Nazha A, Kantarjian H, Ravandi F et al (2013) Clofarabine, idarubicin, and cytarabine (CIA) as frontline therapy for patients ≤60 years with newly diagnosed acute myeloid leukemia. Am J Hematol 88:961–966CrossRefPubMedPubMedCentral
40.
Zurück zum Zitat Martinez-Cuadron D, Montesinos P, Oriol A et al (2014) Phase II trial to assess the safety and efficacy of clofarabine in combination with low-dose cytarabine in elderly patients with acute myeloid leukemia. Ann Hematol 93:43–46CrossRefPubMed Martinez-Cuadron D, Montesinos P, Oriol A et al (2014) Phase II trial to assess the safety and efficacy of clofarabine in combination with low-dose cytarabine in elderly patients with acute myeloid leukemia. Ann Hematol 93:43–46CrossRefPubMed
41.
Zurück zum Zitat Kantarjian H, Faderl S, Garcia-Manero G et al (2012) Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients: a randomised phase 2 study. Lancet Oncol 13:1096–1104CrossRefPubMedPubMedCentral Kantarjian H, Faderl S, Garcia-Manero G et al (2012) Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients: a randomised phase 2 study. Lancet Oncol 13:1096–1104CrossRefPubMedPubMedCentral
42.
Zurück zum Zitat Burnett AK, Russell N, Hills RK et al (2015) A randomised comparison of the novel nucleoside analogue sapacitabine with low-dose cytarabine in older patients with acute myeloid leukaemia. Leukemia 29:1312–1319CrossRefPubMed Burnett AK, Russell N, Hills RK et al (2015) A randomised comparison of the novel nucleoside analogue sapacitabine with low-dose cytarabine in older patients with acute myeloid leukaemia. Leukemia 29:1312–1319CrossRefPubMed
43.
Zurück zum Zitat Pigneux A, Harousseau JL, Witz F et al (2010) Addition of lomustine to idarubicin and cytarabine improves the outcome of elderly patients with de novo acute myeloid leukemia: a report from the GOELAMS. J Clin Oncol 28:3028–3034CrossRefPubMed Pigneux A, Harousseau JL, Witz F et al (2010) Addition of lomustine to idarubicin and cytarabine improves the outcome of elderly patients with de novo acute myeloid leukemia: a report from the GOELAMS. J Clin Oncol 28:3028–3034CrossRefPubMed
44.
Zurück zum Zitat Giles F, Rizzieri D, Karp J et al (2007) Cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, in patients age 60 years or older with previously untreated acute myeloid leukemia. J Clin Oncol 25:25–31CrossRefPubMed Giles F, Rizzieri D, Karp J et al (2007) Cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, in patients age 60 years or older with previously untreated acute myeloid leukemia. J Clin Oncol 25:25–31CrossRefPubMed
45.
Zurück zum Zitat Schiller GJ, O’Brien SM, Pigneux A et al (2010) Single-agent laromustine, a novel alkylating agent, has significant activity in older patients with previously untreated poor-risk acute myeloid leukemia. J Clin Oncol 28:815–821CrossRefPubMed Schiller GJ, O’Brien SM, Pigneux A et al (2010) Single-agent laromustine, a novel alkylating agent, has significant activity in older patients with previously untreated poor-risk acute myeloid leukemia. J Clin Oncol 28:815–821CrossRefPubMed
46.
Zurück zum Zitat Giles F, Vey N, DeAngelo D et al (2009) Phase 3 randomized, placebo-controlled, double-blind study of high-dose continuous infusion cytarabine alone or with laromustine (VNP40101M) in patients with acute myeloid leukemia in first relapse. Blood 114:4027–4033CrossRefPubMed Giles F, Vey N, DeAngelo D et al (2009) Phase 3 randomized, placebo-controlled, double-blind study of high-dose continuous infusion cytarabine alone or with laromustine (VNP40101M) in patients with acute myeloid leukemia in first relapse. Blood 114:4027–4033CrossRefPubMed
47.
Zurück zum Zitat Freeman C, Keane N, Swords R, Giles F (2013) Vosaroxin: a new valuable tool with the potential to replace anthracyclines in the treatment of AML? Expert Opin Pharmacother 14:1417–1427CrossRefPubMed Freeman C, Keane N, Swords R, Giles F (2013) Vosaroxin: a new valuable tool with the potential to replace anthracyclines in the treatment of AML? Expert Opin Pharmacother 14:1417–1427CrossRefPubMed
48.
Zurück zum Zitat Hoch U, Lynch J, Sato Y et al (2009) Voreloxin, formerly SNS-595, has potent activity against a broad panel of cancer cell lines and in vivo tumor models. Cancer Chemother Pharmacol 64:53–65CrossRefPubMed Hoch U, Lynch J, Sato Y et al (2009) Voreloxin, formerly SNS-595, has potent activity against a broad panel of cancer cell lines and in vivo tumor models. Cancer Chemother Pharmacol 64:53–65CrossRefPubMed
49.
Zurück zum Zitat Stuart RK, Cripe LD, Maris MB et al (2015) REVEAL-1, a phase 2 dose regimen optimization study of vosaroxin in older poor-risk patients with previously untreated acute myeloid leukaemia. Br J Haematol 168:796–805CrossRefPubMed Stuart RK, Cripe LD, Maris MB et al (2015) REVEAL-1, a phase 2 dose regimen optimization study of vosaroxin in older poor-risk patients with previously untreated acute myeloid leukaemia. Br J Haematol 168:796–805CrossRefPubMed
50.
Zurück zum Zitat Lancet JE, Roboz GJ, Cripe LD et al (2015) A phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia. Haematologica 100:231–237CrossRefPubMedPubMedCentral Lancet JE, Roboz GJ, Cripe LD et al (2015) A phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia. Haematologica 100:231–237CrossRefPubMedPubMedCentral
51.
Zurück zum Zitat Ravandi F, Ritchie EK, Sayar H et al (2015) Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. Lancet Oncol 16:1025–1036CrossRefPubMed Ravandi F, Ritchie EK, Sayar H et al (2015) Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. Lancet Oncol 16:1025–1036CrossRefPubMed
52.
Zurück zum Zitat Dennis M, Russell N, Hills RK et al (2015) Vosaroxin and vosaroxin plus low-dose Ara-C (LDAC) vs low-dose Ara-C alone in older patients with acute myeloid leukemia. Blood 125:2923–2932CrossRefPubMedPubMedCentral Dennis M, Russell N, Hills RK et al (2015) Vosaroxin and vosaroxin plus low-dose Ara-C (LDAC) vs low-dose Ara-C alone in older patients with acute myeloid leukemia. Blood 125:2923–2932CrossRefPubMedPubMedCentral
53.
Zurück zum Zitat Lim WS, Tardi PG, Dos SN et al (2010) Leukemia-selective uptake and cytotoxicity of CPX-351, a synergistic fixed-ratio cytarabine:daunorubicin formulation, in bone marrow xenografts. Leuk Res 34:1214–1223CrossRefPubMed Lim WS, Tardi PG, Dos SN et al (2010) Leukemia-selective uptake and cytotoxicity of CPX-351, a synergistic fixed-ratio cytarabine:daunorubicin formulation, in bone marrow xenografts. Leuk Res 34:1214–1223CrossRefPubMed
54.
Zurück zum Zitat Lancet JE, Cortes JE, Hogge DE et al (2014) Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood 123:3239–3246CrossRefPubMedPubMedCentral Lancet JE, Cortes JE, Hogge DE et al (2014) Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood 123:3239–3246CrossRefPubMedPubMedCentral
55.
Zurück zum Zitat Cashen AF, Schiller GJ, O’Donnell MR, DiPersio JF (2010) Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol 28:556–561CrossRefPubMed Cashen AF, Schiller GJ, O’Donnell MR, DiPersio JF (2010) Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol 28:556–561CrossRefPubMed
56.
Zurück zum Zitat Kantarjian HM, Thomas XG, Dmoszynska A et al (2012) 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 30:2670–2677CrossRefPubMedPubMedCentral Kantarjian HM, Thomas XG, Dmoszynska A et al (2012) 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 30:2670–2677CrossRefPubMedPubMedCentral
57.
Zurück zum Zitat Quintás-Cardama A, Ravandi F, Liu-Dumlao T et al (2012) Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia. Blood 120:4840–4845CrossRefPubMedPubMedCentral Quintás-Cardama A, Ravandi F, Liu-Dumlao T et al (2012) Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia. Blood 120:4840–4845CrossRefPubMedPubMedCentral
58.
Zurück zum Zitat Blum W, Garzon R, Klisovic RB et al (2010) Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A 107:7473–7478CrossRefPubMedPubMedCentral Blum W, Garzon R, Klisovic RB et al (2010) Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A 107:7473–7478CrossRefPubMedPubMedCentral
59.
Zurück zum Zitat Ritchie EK, Feldman EJ, Christos PJ et al (2013) Decitabine in patients with newly diagnosed and relapsed acute myeloid leukemia. Leuk Lymphoma 54:2003–2007CrossRefPubMed Ritchie EK, Feldman EJ, Christos PJ et al (2013) Decitabine in patients with newly diagnosed and relapsed acute myeloid leukemia. Leuk Lymphoma 54:2003–2007CrossRefPubMed
60.
Zurück zum Zitat Kottaridis PD, Gale RE, Frew ME et al (2001) The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 98:1752–1759CrossRefPubMed Kottaridis PD, Gale RE, Frew ME et al (2001) The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 98:1752–1759CrossRefPubMed
61.
Zurück zum Zitat Smith BD, Levis M, Beran M et al (2004) Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 103:3669–3676CrossRefPubMed Smith BD, Levis M, Beran M et al (2004) Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 103:3669–3676CrossRefPubMed
62.
Zurück zum Zitat Knapper S, Burnett AK, Littlewood T et al (2006) A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood 108:3262–3270CrossRefPubMed Knapper S, Burnett AK, Littlewood T et al (2006) A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood 108:3262–3270CrossRefPubMed
63.
Zurück zum Zitat Levis M, Ravandi F, Wang ES et al (2011) Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood 117:3294–3301CrossRefPubMedPubMedCentral Levis M, Ravandi F, Wang ES et al (2011) Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood 117:3294–3301CrossRefPubMedPubMedCentral
64.
Zurück zum Zitat Serve H, Krug U, Wagner R et al (2013) Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol 31:3110–3118CrossRefPubMed Serve H, Krug U, Wagner R et al (2013) Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol 31:3110–3118CrossRefPubMed
65.
Zurück zum Zitat Fischer T, Stone RM, DeAngelo DJ et al (2010) 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 28:4339–4345CrossRefPubMedPubMedCentral Fischer T, Stone RM, DeAngelo DJ et al (2010) 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 28:4339–4345CrossRefPubMedPubMedCentral
66.
Zurück zum Zitat Stone RM, DeAngelo DJ, Klimek V et al (2005) Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 105:54–60CrossRefPubMed Stone RM, DeAngelo DJ, Klimek V et al (2005) Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 105:54–60CrossRefPubMed
67.
Zurück zum Zitat Stone RM, Mandrekar S, Sanford BL et al. (2015) The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18–60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). Blood (ASH Annual Meeting Abstracts) 126: Abstract 6 Stone RM, Mandrekar S, Sanford BL et al. (2015) The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18–60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). Blood (ASH Annual Meeting Abstracts) 126: Abstract 6
68.
Zurück zum Zitat Zarrinkar PP, Gunawardane RN, Cramer MD et al (2009) AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 114:2984–2992CrossRefPubMedPubMedCentral Zarrinkar PP, Gunawardane RN, Cramer MD et al (2009) AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 114:2984–2992CrossRefPubMedPubMedCentral
69.
Zurück zum Zitat Levis MJ, Perl AE, Dombret H et al. (2012) Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation. Blood (ASH Annual Meeting Abstracts) 120: Abstract 673 Levis MJ, Perl AE, Dombret H et al. (2012) Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation. Blood (ASH Annual Meeting Abstracts) 120: Abstract 673
70.
Zurück zum Zitat Martinelli G, Perl AE, Dombret H et al (2013) Effect of quizartinib (AC220) on response rates and long-term survival in elderly patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia. ASCO Meeting Abstracts 31:7021 Martinelli G, Perl AE, Dombret H et al (2013) Effect of quizartinib (AC220) on response rates and long-term survival in elderly patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia. ASCO Meeting Abstracts 31:7021
71.
Zurück zum Zitat Perl AE, Dohner H, Rousselot PH et al (2013) Efficacy and safety of quizartinib (AC220) in patients age > = 70 years with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia (AML). ASCO Meeting Abstracts 31:7023 Perl AE, Dohner H, Rousselot PH et al (2013) Efficacy and safety of quizartinib (AC220) in patients age > = 70 years with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia (AML). ASCO Meeting Abstracts 31:7023
72.
Zurück zum Zitat Cortes JE, Tallman MS, Schiller G et al. (2013) Results of a phase 2 randomized, open-label, study of lower doses of quizartinib (AC220; ASP2689) in subjects with FLT3-ITD positive relapsed or refractory acute myeloid leukemia (AML). Blood (ASH Annual Meeting Abstracts) 122: Abstract 494 Cortes JE, Tallman MS, Schiller G et al. (2013) Results of a phase 2 randomized, open-label, study of lower doses of quizartinib (AC220; ASP2689) in subjects with FLT3-ITD positive relapsed or refractory acute myeloid leukemia (AML). Blood (ASH Annual Meeting Abstracts) 122: Abstract 494
73.
Zurück zum Zitat Wennerberg K, Rossman KL, Der CJ (2005) The Ras superfamily at a glance. J Cell Sci 118:843–846CrossRefPubMed Wennerberg K, Rossman KL, Der CJ (2005) The Ras superfamily at a glance. J Cell Sci 118:843–846CrossRefPubMed
74.
Zurück zum Zitat Harousseau JL, Lancet JE, Reiffers J et al (2007) A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib in patients with refractory or relapsed acute myeloid leukemia. Blood 109:5151–5156CrossRefPubMed Harousseau JL, Lancet JE, Reiffers J et al (2007) A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib in patients with refractory or relapsed acute myeloid leukemia. Blood 109:5151–5156CrossRefPubMed
75.
Zurück zum Zitat Lancet JE, Gojo I, Gotlib J et al (2007) A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood 109:1387–1394CrossRefPubMedPubMedCentral Lancet JE, Gojo I, Gotlib J et al (2007) A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood 109:1387–1394CrossRefPubMedPubMedCentral
76.
Zurück zum Zitat Karp JE, Lancet JE, Kaufmann SH et al (2001) Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood 97:3361–3369CrossRefPubMed Karp JE, Lancet JE, Kaufmann SH et al (2001) Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood 97:3361–3369CrossRefPubMed
77.
Zurück zum Zitat Laubach J, Rao AV (2008) Current and emerging strategies for the management of acute myeloid leukemia in the elderly. Oncologist 13:1097–1108CrossRefPubMed Laubach J, Rao AV (2008) Current and emerging strategies for the management of acute myeloid leukemia in the elderly. Oncologist 13:1097–1108CrossRefPubMed
78.
Zurück zum Zitat Harousseau JL, Martinelli G, Jedrzejczak WW et al (2009) A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older. Blood 114:1166–1173CrossRefPubMed Harousseau JL, Martinelli G, Jedrzejczak WW et al (2009) A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older. Blood 114:1166–1173CrossRefPubMed
79.
Zurück zum Zitat Karp JE, Smith BD, Gojo I et al (2008) Phase II trial of tipifarnib as maintenance therapy in first complete remission in adults with acute myelogenous leukemia and poor-risk features. Clin Cancer Res 14:3077–3082CrossRefPubMedPubMedCentral Karp JE, Smith BD, Gojo I et al (2008) Phase II trial of tipifarnib as maintenance therapy in first complete remission in adults with acute myelogenous leukemia and poor-risk features. Clin Cancer Res 14:3077–3082CrossRefPubMedPubMedCentral
80.
Zurück zum Zitat Janning M, Fiedler W (2014) Volasertib for the treatment of acute myeloid leukemia: a review of preclinical and clinical development. Future Oncol 10:1157–1165CrossRefPubMed Janning M, Fiedler W (2014) Volasertib for the treatment of acute myeloid leukemia: a review of preclinical and clinical development. Future Oncol 10:1157–1165CrossRefPubMed
81.
Zurück zum Zitat Bug G, Müller-Tidow C, Schlenk RF et al. (2011) Phase I/II study of volasertib (BI 6727), an intravenous polo-like kinase (Plk) inhibitor, in patients with acute myeloid leukemia (AML): updated results of the dose finding phase I part for volasertib in combination with low-dose cytarabine (LD-Ara-C) and as monotherapy in relapsed/refractory AML. Blood 118: Abstract 1549 Bug G, Müller-Tidow C, Schlenk RF et al. (2011) Phase I/II study of volasertib (BI 6727), an intravenous polo-like kinase (Plk) inhibitor, in patients with acute myeloid leukemia (AML): updated results of the dose finding phase I part for volasertib in combination with low-dose cytarabine (LD-Ara-C) and as monotherapy in relapsed/refractory AML. Blood 118: Abstract 1549
82.
Zurück zum Zitat Döhner H, Lübbert M, Fiedler W et al (2014) Randomized, phase 2 trial comparing low-dose cytarabine with or without volasertib in AML patients not suitable for intensive induction therapy. Blood 124:1426–1433CrossRefPubMedPubMedCentral Döhner H, Lübbert M, Fiedler W et al (2014) Randomized, phase 2 trial comparing low-dose cytarabine with or without volasertib in AML patients not suitable for intensive induction therapy. Blood 124:1426–1433CrossRefPubMedPubMedCentral
83.
Zurück zum Zitat Kantarjian HM, Martinelli G, Jabbour EJ et al (2013) Stage I of a phase 2 study assessing the efficacy, safety, and tolerability of barasertib (AZD1152) versus low-dose cytosine arabinoside in elderly patients with acute myeloid leukemia. Cancer 119:2611–2619CrossRefPubMedPubMedCentral Kantarjian HM, Martinelli G, Jabbour EJ et al (2013) Stage I of a phase 2 study assessing the efficacy, safety, and tolerability of barasertib (AZD1152) versus low-dose cytosine arabinoside in elderly patients with acute myeloid leukemia. Cancer 119:2611–2619CrossRefPubMedPubMedCentral
Metadaten
Titel
Emerging strategies for the treatment of older patients with acute myeloid leukemia
verfasst von
Miguel A. Sanz
Gloria Iacoboni
Pau Montesinos
Adriano Venditti
Publikationsdatum
27.04.2016
Verlag
Springer Berlin Heidelberg
Erschienen in
Annals of Hematology / Ausgabe 10/2016
Print ISSN: 0939-5555
Elektronische ISSN: 1432-0584
DOI
https://doi.org/10.1007/s00277-016-2666-2

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