Neue Therapieoptionen bei der Akuten Myeloischen Leukämie

Während das „7+3“-Regime bestehend aus Cytarabin und Anthracyclin lange Zeit das Rückgrat der Behandlung der Akuten Myeloischen Leukämie (AML) war, wurden in den letzten 5 Jahren mehrere neuartige Medikamente zugelassen. Trotz dieser vielversprechenden neuartigen Therapieoptionen bleibt die Behandlung der AML angesichts des biologisch heterogenen Charakters der Erkrankung eine Herausforderung. Diese Übersicht bietet ein Update zu neuen Behandlungsstrategien der AML.

Abstract

Background While the “7+3” regimen of cytarabine + anthracycline has been the backbone of acute myeloid leukemia (AML) treatment for four decades, several novel drugs have been approved in the past five years. Despite these promising novel therapeutic options, treatment of AML remains challenging, given the biologically heterogenous character of the disease.

Aim This review provides an update on novel treatment strategies for AML.

Material and Methods This article is based on the current European LeukemiaNet (ELN) recommendations and the DGHO «Onkopedia» guideline on AML treatment.

Results and Conclusion The treatment algorithm is based on patient-related and disease-specific factors, such as patient age and fitness as well as AML molecular profile. Younger patients considered fit for intensive chemotherapy receive 1–2 courses of induction therapy (“7+3” regimen, eg. cytarabine/daunorubicin, or CPX-351 for patients with myelodysplasia-related AML or therapy-related AML). For CD33+ patients or those with evidence of an FLT3 mutation “7+3” in combination with Gemtuzumab-Ozogamicin (GO) or Midostaurin is recommended, respectively. For consolidation, patients receive either high-dose chemotherapy (± GO/± Midostaurin) or undergo allogeneic hematopoietic cell transplantation (HCT), based on ELN risk stratification. In some cases, maintenance therapy with oral azacytidine or FLT3 inhibitor is indicated. Patients experiencing relapse should receive chemotherapy-based re-induction therapy or, in case of an FLT3 mutation, Gilteritinib and subsequently undergo allogeneic HCT. For older patients or those considered unfit for intensive therapy, azacytidine in combination with Venetoclax is a promising novel treatment strategy. Although not yet approved by the European Medical Agency (EMA), for patients with IDH1IDH1 or IDH2 mutations treatment with the IDH1 and IDH2 inhibitors Ivosidenib and Enasidenib should be considered.

Schlüsselwörter

myeloische Neoplasien - akute myeloische Leukämie - Risikostratifizierung - molekularzielgerichtete Therapie

Keywords

myeloid neoplasms - acute myeloid leukemia - risk stratification - molecular-guided treatment

Publication History

Article published online:
29 March 2023

• Literatur

• 1 Stone RM, Mandrekar SJ, Sanford BL. et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med 2017; 377 (05) 454-464 DOI: 10.1056/NEJMoa1614359. (PMID: 28644114)
• 2 Perl AE, Martinelli G, Cortes JE. et al. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med 2019; 381 (18) 1728-1740 DOI: 10.1056/NEJMoa1902688. (PMID: 31665578)
• 3 Lancet JE, Uy GL, Cortes JE. et al. CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia. J Clin Oncol Off J Am Soc Clin Oncol 2018; 36 (26) 2684-2692
• 4 DiNardo CD, Jonas BA, Pullarkat V. et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med 2020; 383 (07) 617-629 DOI: 10.1056/NEJMoa2012971. (PMID: 32786187)
• 5 Döhner H, Wei AH, Appelbaum FR. et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 2022; 140 (12) 1345-1377
• 6 Röllig C, Ayuk FA, Heuser JB. et al. Akute Myeloische Leukämie (AML). Onkopedia 2022. Accessed December 19, 2022 at: https://www.onkopedia.com/de/onkopedia/guidelines/akute-myeloische-leukaemie-aml/@@guideline/html/index.html
• 7 Röllig C, Kramer M, Schliemann C. et al. Does time from diagnosis to treatment affect the prognosis of patients with newly diagnosed acute myeloid leukemia?. Blood 2020; 136 (07) 823-830
• 8 Burchert A, Bug G, Fritz LV. et al. Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With FLT3-Internal Tandem Duplication Mutation (SORMAIN). J Clin Oncol Off J Am Soc Clin Oncol 2020; 38 (26) 2993-3002
• 9 Xuan L, Wang Y, Huang F. et al. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. Lancet Oncol 2020; 21 (09) 1201-1212
• 10 Wei AH, Döhner H, Pocock C. et al. Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission. N Engl J Med 2020; 383 (26) 2526-2537 DOI: 10.1056/NEJMoa2004444. (PMID: 33369355)
• 11 DeWolf S, Tallman MS. How I treat relapsed or refractory AML. Blood 2020; 136 (09) 1023-1032 DOI: 10.1182/blood.2019001982. (PMID: 32518943)
• 12 Schneidawind D, Federmann B, Faul C. et al. Allogeneic hematopoietic cell transplantation with reduced-intensity conditioning following FLAMSA for primary refractory or relapsed acute myeloid leukemia. Ann Hematol 2013; 92 (10) 1389-1395 DOI: 10.1007/s00277-013-1774-5. (PMID: 23652585)
• 13 Burnett AK, Milligan D, Prentice AG. 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; 109 (06) 1114-1124 DOI: 10.1097/moh.0b013e3283366bb8. (PMID: 20178141)
• 14 Kantarjian HM, Thomas XG, Dmoszynska A. 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 Off J Am Soc Clin Oncol 2012; 30 (21) 2670-1677
• 15 Dombret H, Seymour JF, Butrym A. et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015; 126 (03) 291-299
• 16 Lambert J, Pautas C, Terré C. et al. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica 2019; 104 (01) 113-119
• 17 Castaigne S, Pautas C, Terré C. et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet Lond Engl 2012; 379: 1508-1516
• 18 Burnett AK, Hills RK, Milligan D. et al. Identification of Patients With Acute Myeloblastic Leukemia Who Benefit From the Addition of Gemtuzumab Ozogamicin: Results of the MRC AML15 Trial. J Clin Oncol 2011; 29 (04) 369-377
• 19 Hills RK, Castaigne S, Appelbaum FR. 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; 15 (09) 986-996
• 20 Schlenk RF, Paschka P, Krzykalla J. et al. Gemtuzumab Ozogamicin in NPM1-Mutated Acute Myeloid Leukemia: Early Results From the Prospective Randomized AMLSG 09–09 Phase III Study. J Clin Oncol Off J Am Soc Clin Oncol 2020; 38 (06) 623-632
• 21 Kapp-Schwoerer S, Weber D, Corbacioglu A. et al. Impact of gemtuzumab ozogamicin on MRD and relapse risk in patients with NPM1-mutated AML: results from the AMLSG 09–09 trial. Blood 2020; 136 (26) 3041-3050
• 22 Feldman EJ, Lancet JE, Kolitz JE. et al. First-in-man study of CPX-351: a liposomal carrier containing cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory acute myeloid leukemia. J Clin Oncol Off J Am Soc Clin Oncol 2011; 29 (08) 979-985 DOI: 10.1200/JCO.2010.30.5961. (PMID: 21282541)
• 23 Lancet JE, Uy GL, Newell LF. et al. CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol 2021; 8 (07) e481-491 DOI: 10.1016/S2352-3026(21)00134-4. (PMID: 34171279)
• 24 Roboz GJ, DiNardo CD, Stein EM. et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood 2020; 135 (07) 463-471 DOI: 10.1182/blood.2019002140. (PMID: 31841594)
• 25 DiNardo CD, Stein EM, de Botton S. et al. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N Engl J Med 2018; 378 (25) 2386-2398 DOI: 10.1056/NEJMoa1716984. (PMID: 29860938)
• 26 Montesinos P, Recher C, Vives S. et al. Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia. N Engl J Med 2022; 386 (16) 1519-1531 DOI: 10.1056/NEJMoa2117344. (PMID: 35443108)
• 27 Stein EM, DiNardo CD, Pollyea DA. et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 2017; 130 (06) 722-731 DOI: 10.1182/blood-2017-04-779405. (PMID: 28588020)
• 28 Cortes JE, Heidel FH, Hellmann A. et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia 2019; 33 (02) 379-389 DOI: 10.1016/S2352-3026(21)00192-7. (PMID: 34329576)