With the exception of the use of all trans-retinoic acid (ATRA) for patients with acute pro-myelocytic leukemia (APL), relatively few changes in the therapy of acute myeloid leukemia (AML) have been made since the introduction of the so-called “7 and 3” regimen in 1973.1, 2 The regimen is made up of 3 daily doses of daunorubicin at a dose of 45 mg/m2 combined with cytarabine for seven continuous daily doses at 100 mg/m2.1, 2
The outcome to current therapy is suboptimal with only 60-70% of patients achieving their first complete remission. The median survival of patients who achieve remission is 12-24 months and the five year survival is achieved in only 20% of those patients.3 Attempts to find a superior alternative or improve the 7 and 3 induction regimen have been disappointing.4, 5 Both, the intensification of cytarabine dose6-8 and the addition of other drugs, have failed to improve outcome when compared to “7 and 3”.9
That all changed this week, with the publication of the first conclusive evidence for better overall survival in patients receiving higher doses of daunorubicin (90 mg/m2) compared to the conventional dose (45 mg/m2) regimen. The Eastern Cooperative Oncology Group (ECOG) study, which appears this week in the New England Journal of Medicine,10 assigned 657 patients between the ages of 17 and 60 years with newly diagnosed AML to receive either the 7 and 3 induction regimen with conventional dose of daunorubicin versus the higher dose. Those that achieved a complete remission were then given post remission therapy according to their risk stratification as well as the availability of an HLA matched sibling. Patients with unfavorable or intermediate risk profile were offered allogeneic transplant if they had an HLA matched sibling.11, 12 The remainder were offered high dose cytarabine with or without gemtuzumab ozgamicin, followed by an autologous transplant.13
An intention to treat analysis, with a median follow up of 25.2 months, revealed that 90 mg/m2 daunorubicin resulted in higher complete remission rates (70.6% vs. 57.3%, P=0.001) as well as improved median survival (23.7 vs. 15.7 months, P=0.003).
Interestingly, the rates of serious (grade 3 to 5) adverse events were similar in the two groups. Serious cardiac toxicity was observed in 7.2% in the standard dose arm compared to 7.9% in the high dose arm. A reduced left ventricular ejection fraction was observed in 1.3% of patients in the high dose group and none of the standard regimen group. The rate of treatment related mortality was 4.5% in the standard arm compared to 5.5% in the high dose arm (P=0.60). The most common cause of death was from infections and pulmonary failure.
For those patients with a favorable cytogenetic profile that received the high dose, the median survival had not been reached at the time of the final analysis (median follow up of 25.2 months); thus, exceeding the current median survival of 12-24 months in patients who achieve remission.3 The largest difference was seen in those with intermediate risk who received the daunorubicin 90 mg/m2. Patients with unfavorable cytogenetic profile, however, did not experience any benefit from higher doses.
Patients with low and intermediate risk de novo AML should be offered 7 and 3 induction therapy with daunorubicin dose intensification at 90 mg/m2. This is both safe and effective in these patients but not associated with any benefit in patients with poor prognostic features. However, as the authors note, it is not yet clear what the optimal dose of intensification is. Whether 90 mg/m2 is better than 60 mg/m2, requires further study.
Conflict of interest statementNo financial conflicts or disclosures to report.
CITE THIS ARTICLE:
Tamer M. Fouad, M.D.. Improved survival in AML with higher anthracycline doses. Doctors Lounge. Available at: https://www.doctorslounge.com/index.php/articles/page/300. Accessed June 27 2019.
1. Yates J, Wallace JJ, Ellison R, Holland J. Cytosine arabinoside (MSC A63878) and daunorubicin (NSC A83142) in acute non-lymphocytic leukemia. Cancer Chemother Rep. 1973.
2. Stone RM, Mayer RJ. Treatment of the newly diagnosed adult with de novo acute myeloid leukemia. Hematol Oncol Clin North Am. Feb 1993;7(1):47-64.
3. Jabbour EJ, Estey E, Kantarjian HM. Adult acute myeloid leukemia. Mayo Clin Proc. Feb 2006;81(2):247-260.
4. Preisler H, Bjornsson S, Henderson ES, et al. Remission induction in acute nonlymphocytic leukemia: comparison of a seven-day and ten-day infusion of cytosine arabinoside in combination with adriamycin. Med Pediatr Oncol. 1979;7(3):269-275.
5. Berman E, Heller G, Santorsa J, et al. Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood. Apr 15 1991;77(8):1666-1674.
6. Schiller G, Gajewski J, Nimer S, et al. A randomized study of intermediate versus conventional-dose cytarabine as intensive induction for acute myelogenous leukaemia. Br J Haematol. Jun 1992;81(2):170-177.
7. Weick JK, Kopecky KJ, Appelbaum FR, et al. A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood. Oct 15 1996;88(8):2841-2851.
8. Bishop JF, Matthews JP, Young GA, Bradstock K, Lowenthal RM. Intensified induction chemotherapy with high dose cytarabine and etoposide for acute myeloid leukemia: a review and updated results of the Australian Leukemia Study Group. Leuk Lymphoma. Jan 1998;28(3-4):315-327.
9. Preisler H, Davis RB, Kirshner J, et al. Comparison of three remission induction regimens and two postinduction strategies for the treatment of acute nonlymphocytic leukemia: a cancer and leukemia group B study. Blood. May 1987;69(5):1441-1449.
10. Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. Sep 24 2009;361(13):1249-1259.
11. Clift RA, Buckner CD, Thomas ED, et al. The treatment of acute non-lymphoblastic leukemia by allogeneic marrow transplantation. Bone Marrow Transplant. Oct 1987;2(3):243-258.
12. Keating S, de Witte T, Suciu S, et al. The influence of HLA-matched sibling donor availability on treatment outcome for patients with AML: an analysis of the AML 8A study of the EORTC Leukaemia Cooperative Group and GIMEMA. European Organization for Research and Treatment of Cancer. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto. Br J Haematol. Sep 1998;102(5):1344-1353.
13. Farag SS, Ruppert AS, Mrozek K, et al. Outcome of induction and postremission therapy in younger adults with acute myeloid leukemia with normal karyotype: a cancer and leukemia group B study. J Clin Oncol. Jan 20 2005;23(3):482-493.