General AML

ESH 2018 | How to use standard therapy in AML

An oral session took place at the European School of Hematology (ESH) Clinical Updates on Acute Leukemias Meeting on 4–6 May 2018, in Budapest, Hungary. During this session, an educational talk was presented by Bob Löwenberg, Professor of hematology at Erasmus University Medical Center, Rotterdam, Netherlands, on standard therapy in acute myeloid leukemia (AML) with some practical aspects.1

Remission induction

Anthracyclines

Professor Löwenberg started his talk by highlighting the currently used anthracyclines, especially the two most commonly used chemotherapeutic drugs, daunorubicin and idarubicin. There are ongoing discussions about the schedule and dose of these regimens. The speaker discussed the findings of a phase III randomized study (NCT00049517),  which evaluated the use of cytarabine plus either standard-dose (45 mg/m2/day) or high-dose daunorubicin (90 mg/m2/day) as induction therapy in 657 patients under the age of 60 years with untreated AML. It was demonstrated that 90 mg/m2/day daunorubicin results in superior outcomes in comparison with standard dose (45 mg/m2/day). Furthermore, in a study published in the New England Journal of Medicine (NEJM) by Professor Löwenberg and colleagues found that in 813 patients older than 60 years, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, results in a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects.2,3

Bob Löwenberg continued his talk by discussing a Japanese study (JALSG) by Ohtake et al. which was published in Blood in 2011. The study investigated whether daunorubicin (50 mg/m2 daily for 5 days) or idarubicin (12 mg/m2 daily for 3 days) is more efficient in 1,057 patients (median age = 47 years) with de novo AML.4 The two anthracyclines resulted in similar overall survival (OS), relapse free survival (RFS), and complete remission (CR) rate. Additionally, Pautas et al. studied daunorubicin in a dosing schedule of 80 mg/m2 for 3 days (DNR) versus idarubicin on two dose levels (12 mg/m2/day for 3 days [IDA3] vs 12 mg/m2/day for 4 days [IDA4]). Significant difference was observed in CR rates for patients in the DNR, IDA3 and IDA4 arms (70% vs 83% vs 78% respectively, P = 0.04) However, no significant differences were observed in event free survival (EFS) or OS among the three arms.5

Then, a question was discussed whether 60 mg/m2 dose of daunorubicin can be given with curative intent instead of 90 mg/m2, thus a study by Burnett and colleagues was referred. The study investigated 60 mg/m2 versus 90 mg/m2 of daunorubicin in AML induction.6 As a result, the study group found that there was no subgroup that showed significant benefit from the modified induction chemotherapy. Based on these studies, Professor Löwenberg recommended 80–90 mg/m2 (maybe 60 mg/m2) daunorubicin or 12 mg/m2 idarubicin for 3 days as a regular dose of anthracyclines for AML induction.

Cytarabine

Cytarabine therapy was the next subject of the talk, which has another debated dosing approach. Conventionally, ara-C can be added in a dose of 100 to 400 mg per square meter. However, in order to get higher rates of RFS, study groups have examined whether higher doses of ara-C can show superior outcomes, if it is administered at a dose of 1000 mg/m2 up to 3000 mg/m2. In a study published in NEJM by Bob Löwenberg and colleagues, two doses of ara-C (200 mg/m2 vs 1000 mg/m2) in patients 18–60 years were compared in patients with newly diagnosed AML. It was found that induction therapy with cytarabine at the lower (regular) dose level already provides maximal anti-leukemic effect for all response endpoints, showing a plateau in the dose–response relationship above the regular dose level. Consequently, using high-dose ara-C far above the maximally effective dose possibly enhances toxicity without providing increased anti-leukemic effects in AML patients.7 He further added that “we would like to deliver our backbone with minimal toxicity.” Professor Löwenberg recommended 7 days of cytarabine 100–200 mg/m2 continuous intravenous infusion for induction regimen in AML.

Addition of clofarabine

Professor Löwenberg and colleagues, in a previous trial, compared two induction regimens in newly diagnosed AML patients (age = 18–65 years), idarubicin-cytarabine (cycle I) and amsacrine-cytarabine (cycle II) with or without clofarabine (10 mg/m2 on Days 1–5 of each cycles). Consolidation involved chemotherapy with or without hematopoietic stem cell transplantation. The results of this study showed improved anti-leukemic effect of clofarabine on top of an anthracycline-cytarabine-based remission-induction regimen.8

Post-remission therapy

Chemotherapy, allo- or autologous transplant consolidation?

Different intensive post-remission therapies have been assessed including intensive consolidation chemotherapy and high-dose therapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is another option for AML patients, although allo-HSCT provides the most effective anti-leukemic activity but with an increased risk of death.

Vellenga et al. conducted a prospective, randomized phase III trial evaluating auto-HSCT versus intensive consolidation chemotherapy in newly diagnosed AML patients in complete remission (CR). The results of this study showed a relapse benefit for ASCT as post-remission therapy but similar survival rates as more relapsed patients on the chemotherapy cohort were salvaged with a late transplantation.9

The decision to perform allo-HSCT depends on the assessment of the risk-benefit ratio. This ratio depends on molecular and cytogenetic features, as well as patient, donor and transplant factors.

Novel therapies

Recent therapeutic and diagnostic developments evolving at the interface of clinical and laboratory research create an emerging perspective of personalized therapeutics in AML. Professor Löwenberg continued his talk by mentioning the phase III RATIFY study, which investigated whether the addition of midostaurin, an oral multi-targeted kinase inhibitor, that is active in patients with a FLT3 mutation, to standard chemotherapy would prolong OS in patients with FLT3 mutated AML. The findings of the RATIFY trial showed that the addition of midostaurin to standard chemotherapy significantly prolonged OS and EFS among patients with FLT3 positive AML.10

Professor Löwenberg concluded his talk by suggesting that the standard care of AML should start with genetic diagnosis, followed by 7 + 3 induction therapy with cytarabine for 7 days, and anthracyclines such as daunorubicin or idarubicin for 3 days. For newly diagnosed AML that is FLT3 mutation positive, midostaurin may be included. There are variable options for post-remission therapy, based on a patient’s risk of relapse. Consolidation may include high-dose cytarabine with or without ASCT, allo-HSCT or enrolment in an ongoing clinical trial.

References
  1. Löwenberg B. How to use standard treatment in AML? European School of Hematology (ESH) Clinical Updates on Acute Leukemias Meeting, Budapest, Hungary. 2018 May 4–6.
  2. Fernandez H. F. et al. Anthracycline Dose Intensification in Acute Myeloid Leukemia. N Engl J Med. 2009 Sept 24. DOI: 10.1056/NEJMoa0904544.
  3. Löwenberg B. et al. High-Dose Daunorubicin in Older Patients with Acute Myeloid Leukemia. N Engl J Med. 2009 Sept 24; 361(13): 1249–59. DOI: 10.1056/NEJMoa0901409.
  4. Ohtake S. et al. Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study. Blood. 2011 Feb 24; 117(8): 2358–65. DOI: 10.1182/blood-2010-03-273243.
  5. Pautas C. et al. Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study. J Clin Oncol. 2010 Feb 10; 28(5): 808–14. DOI: 10.1200/JCO.2009.23.2652.
  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 Jun 18; 125(25): 3878–85. DOI: 10.1182/blood-2015-01-623447.
  7. Löwenberg B. et al. Cytarabine dose for acute myeloid leukemia. N Engl J Med. 2011 Mar 17; 364(11): 1027–36. DOI: 10.1056/NEJMoa1010222.
  8. Löwenberg B. et al. Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML. Blood. 2017 Mar 23; 129(12): 1636–1645. DOI: 10.1182/blood-2016-10-740613.
  9. Vellenga E. et al. Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. Blood. 2011 Dec 1;118(23):6037-42. DOI: 10.1182/blood-2011-07-370247.
  10. Stone R. M. et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017 Aug 3; 377(5): 454–464. DOI: 10.1056/NEJMoa1614359. [Epub ahead of print 2017 Jun 23].