General AML|FLT3

Revised Canadian consensus guidelines for diagnosis and treatment of elderly patients with AML – Comments from Andre Schuh

On 25th July 2017, Joseph M Brandwein, member of our North America Steering Committee, from the University of Alberta, Edmonton, Canada, et al. published revised clinical practice guidelines for the management of Acute Myeloid Leukemia (AML) in patients age 60 years and over in the American Journal of Blood Research.

Based on recent studies, Brandwein et al. made the following recommendations:

Patients fit for induction chemotherapy
  • Intensive induction chemotherapy (anthracycline or anthracenedione for 3 days plus cytarabine [100–200 mg/m2] for 7 days) was recommended for all patients below the age of 80 with de novo AML except for patients with high co-morbidity scores and patients with adverse-risk cytogenetics who are not candidates for Hematopoietic Stem Cell Transplantation (HSCT)
  • Recommended anthracyclines include daunorubicin (60 mg/m2 daily for 3 days), idarubicin (12 mg/m2 daily for 3 days), and mitoxantrone (12 mg/m2 daily for 3 days)
  • Older de novo AML patients (up to the age of 70) with intermediate- or favorable-risk cytogenetics should receive induction therapy in combination with gemtuzumab ozogamicin (GO) if available
  • For patients with contraindications to anthracyclines, fludarabine, cytarabine, and filgrastim (FLAG) regimen was recommended
  • Midostaurin should be added to induction, consolidation, and continued as maintenance in Fms Like Tyrosine Kinase 3 (FLT3) mutated patients (up to the age of 70)
  • For adverse-risk patients eligible for HSCT in Complete Remission (CR), induction therapy should be administered
  • HSCT should be considered for all patients up to the age 75
  • Haploidentical donor should be considered as an alternative to a matched related or unrelated donor HSCT
  • For patients (60–75 years) with Secondary AML (sAML), CPX-351 should be administered if available as induction and post-remission therapy
Unfit patients for induction chemotherapy
  • Cytogenetic results should be provided within one week and are important in determining the optimal treatment
  • Azacitidine should be administered as standard treatment for patients with 20–30% bone marrow blasts with myelodysplasia-related changes
  • Azacitidine should be the preferred front-line treatment for patients with adverse-risk cytogenetics who are not eligible for HSCT
  • Treatment options for favorable- and intermediate-risk patients include: azacitidine, decitabine, or Low-Dose cytarabine (LDAC)
  • For patients with sAML, enrolment in a clinical trial or a Hypomethylating Agent (HMA) was recommended
Elderly Acute Promyelocytic Leukemia (APL) patients
  • A chemo-free regimen consisting of ATRA and arsenic trioxide (ATO) should be administered for patients with low-risk intermediate APL
  • Patients should be monitored closely for treatment-related complications 
  • For high-risk APL patients, with a White Blood Cell (WBC) > 10 x 109/L, cytoreductive therapy should be added early during induction therapy

Brandwein et al. concluded by encouraging older patients to be enrolled in clinical trial studies, which they hope would lead to “new standards of care which would necessitate further revisions to the guidelines” in the future.

Abstract

The treatment of acute myeloid leukemia (AML) in older patients is undergoing rapid changes, with a number of important publications in the past five years. Because of this, a group of Canadian leukemia experts has produced an update to the Canadian Consensus Guidelines that were published in 2013, with several new agents recommended, subject to availability. Recent studies have supported the survival benefit of induction chemotherapy for patients under age 80, except those with major co-morbidities or those with adverse risk cytogenetics who are not candidates for allogeneic hematopoietic stem cell transplantation (HSCT). Midostaurin should be added to induction therapy for patients up to age 70 with a FLT3 mutation, and gemtuzumab ozogamicin for de novo AML up to age 70 with favorable or intermediate risk cytogenetics. Daunorubicin 60 mg/m2 is the recommended dose for 3+7 induction therapy. Acute promyelocytic leukemia should be treated with arsenic trioxide plus all-trans retinoic acid, regardless of age, with cytotoxic therapy added upfront only for those with initial white blood count > 10. HSCT may be considered for selected suitable patients up to age 70-75. Haploidentical donor transplants may be considered for older patients. For non-induction candidates, azacitidine is recommended for those with adverse risk cytogenetics, while either a hypomethylating agent (HMA) or low-dose cytarabine can be used for others. HMA may also be used for relapsed/refractory disease after chemotherapy. For patients with secondary AML, CPX-351 is recommended for fit patients age 60-75.

References
  1. Brandwein J.M. et al. Treatment of older patients with acute myeloid leukemia (AML): revised Canadian consensus guidelines. Am J Blood Res. 2017 Jul 30; 7(4): 30–40. Epub 2017 Jul 25.

Expert Opinion

A cross-country group of Canadian Hematologists with particular expertise in the treatment of adult acute leukemia, originally met in 2012 to create consensus guidelines for the treatment of AML in older patients (ages ≥ 60 years). These guidelines, published in 20131, incorporated a comprehensive literature review of relevant institutional, cooperative group, and cancer registry data, as well as relevant clinical trials and meta-analyses, published between 1991 and 2012. The 2013 guidelines presented an evidence-based, algorithmic approach to AML treatment in patients ≥ 60 years, which advanced the notion of more-aggressive treatment approaches in older patients, but was speculative in some areas due to the absence of data from ongoing clinical trials. Notably, in addition to advocating clinical trial enrolment whenever possible, these guidelines recommended approaches that were not necessarily funded in all Canadian jurisdictions.

 Since the publication of these guidelines in 2013, the approach to older patients with AML has evolved considerably. First, there has been a progressively wider acceptance of the notion that selected older patients with AML are candidates for aggressive AML treatment, as well as for allogeneic alloSCT.2,3 Second, the completion and publication of several clinical trials (and of subsequent updates) have clarified the approach to older patients with AML receiving induction therapy4,5,6, as well as to those deemed not suitable for induction chemotherapy.7 Third, a consensus approach to low- and high-risk APL has been defined.8,9,10,11 Fourth, the role of comprehensive molecular profiling in prognostication in AML has been refined.12 And fifth, a number of recent clinical trials and drug approvals13 have suggested alternative approaches to the treatment of AML in the older patient.

Due to the above changes in the Canadian AML treatment landscape, the Canadian expert panel met in 2016 to develop revised guidelines for the treatment of AML in the older patient, which were published in 2017.14 These new guidelines recommend the consideration of induction chemotherapy for suitably fit patients up to age 80, the consideration of clinical trial approaches, if available, and include strategies that are not necessarily funded in all (or any) Canadian jurisdictions. As in the 2013 guidelines, specific treatment algorithms are suggested:

 In low/intermediate risk APL, a chemo-free ATRA/ATO approach8,9 is recommended. In high risk APL, the idarubicin/ATRA/ATO APML4 protocol10,11 is recommended.

 For induction candidates with non-APL AML, the addition of midostaurin to standard 3+7 induction therapy for patients with a FLT3 mutation up to age 70; the addition of gemtuzumab ozogamicin to 3+7 induction chemotherapy up to age 70 with favourable or intermediate risk cytogenetics; or the use of CPX-351 for patients with sAML aged 60-75, are recommended.

 For patients with non-APL AML not eligible for induction chemotherapy, azacitidine and low dose cytarabine are considered equivalent in cases with standard risk cytogenetics, in the absence of myelodysplasia-related morphologic features. If the latter features are present, azacitidine is favoured. Azacitidine is recommended in cases with adverse risk cytogenetics.

 While other recent guideline revisions such as ELN 201715 and NCCN16 also have incorporated recent developments in AML treatment, the Canadian consensus guidelines differ somewhat in that they are structured as targeted answers to selected questions, focus primarily on changes that have occurred since the 2013 version, and present treatment options in practical terms as simple, user-friendly algorithms shaped by expert opinion.  

 References
  1.  Brandwein J.M. et al. Treatment of older patients with acute myeloid leukemia (AML): a Canadian consensus. Am J Blood Res. 2013 May 5; 3(2):141–64.
  2. Juliusson G. 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: 4179–4187. DOI: 1182/blood-2008-07-172007.
  3. Sorror M.L. et al. Intensive versus non-intensive induction therapy for patients (Pts) with newly diagnosed acute myeloid leukemia (AML) using two different novel prognostic models. Blood. 2016; 128:216.
  4. Stone R.M. et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017 August 3; 377(5): 454–464. DOI: 1056/NEJMoa1614359. Epub 2017 Jun 23.
  5. Hills R. K. 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(9): 986–96. DOI: 1016/S1470-2045(14)70281-5. Epub 2014 Jul 6.
  6. Burnett A.K. et al. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood. 2015;125(25): 3878–85. DOI: 1182/blood-2015-01-623447. Epub 2015 Apr 1.
  7. Dombret H. 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(3): 291–9. DOI: 1182/blood-2015-01-621664. Epub 2015 May 18.
  8. Lo-Coco F. et al. Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11; 369(2): 111–21. DOI: 1056/NEJMoa1300874.
  9. Platzbecker U. et al. Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial. J Clin Oncol. 2017;35(6): 605–612. DOI: 1200/JCO.2016.67.1982. Epub 2016 Oct 31
  10. Iland H.J. et al. Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570–80.
  11. Iland H.J. et al. Australasian Leukaemia and Lymphoma Group. Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial. Lancet Haematol. 2015; 2(9):e357-66. DOI: 1016/S2352-3026(15)00115-5. Epub 2015 Aug 20.
  12. Papaemmanuil E. et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med. 2016; 374(23):2209-2221. DOI: 1056/NEJMoa1516192.
  13. Lancet J. E et al. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin. Oncol. 2016; 34(Suppl):7000a.
  14. Brandwein J. M. et al. Treatment of older patients with acute myeloid leukemia (AML): revised Canadian consensus guidelines. Am J Blood Res. 2017 Jul 25; 7(4): 30–40.
  15. Döhner H. et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4): 424–447. DOI: 1182/blood-2016-08-733196. Epub 2016 Nov 28.
  16. NCCN Acute Myeloid Leukemia v. 3.2017 - June 6, 2017.