Acute Myeloid Leukemia: Drug Therapy

Therapeutic targets

  • Destruction of the majority of leukemia cells
  • Achievement of remission (disappearance of disease symptoms; percentage of leukemia cells < 5%, return to normal hematopoiesis), possibly also partial remission or full remission (in blood and bone marrow are no longer detectable leukemia cells).

Therapy recommendations

If serious complications are already present at diagnosis, it is important to start treatment immediately:

  • Polychemotherapy, in a few cases supplemented by radiotherapy (CNS radiatio) of the head [total duration of treatment: up to approximately 1.5 years]:
    • Induction therapy, consisting of a preliminary phase designed to initiate treatment (induction phase I) (only in patients who, at the time of diagnosis, have a primary leukocyte (white blood cell) count >50. 000 per microliter of blood or whose organs are severely enlarged due to infestation with leukemia cells); this preliminary phase (treatment with two drugs) is followed by the actual induction therapy (induction phase II; duration of therapy: 2 months, consisting of two therapy blocks including interposed recovery breaks of several weeks); this phase serves to achieve a remission
    • Consolidation or intensification therapy (three therapy blocks, each six to eight days, interspersed with treatment breaks of about three to four weeks) to destroy more leukemia cells and maintain remission;
    • Maintenance or continuous therapy (duration of therapy: about 1 year) serves to prevent a relapse (recurrence of the disease); constitutes a mild chemotherapy
    • CNS therapy (intrathecal chemotherapy), if necessary, also radiotherapy (radiatio) of the head: CNS radiatio (depending on age 15-24 Gy / children 15-18 Gy) if there is evidence of involvement of the CNS (central nervous system).
  • The intensity and duration of therapy and its prognosis depend on: AML subtype, degree of spread of leukemia cells and response to therapy.
  • Allogeneic stem cell transplantation (from HLA-matched family or unrelated donor) in patients, if appropriate.
      • Who suffer a relapse (recurrence of the disease).
      • As post-remission therapy in patients with intermediate and unfavorable karyotype.
  • See also under “Further therapy”.

Active substances (main indication)

Cytostatic agents

The following agents are used in chemotherapy for AML.

  • Induction phase I (preliminary phase): e.g., 6-thioguanine (6-TG) and cytarabine (ARA-C).
  • Induction phase II; cytosine arabinoside (also cytarabine; ARA-C), anthracyclines such as idarubicin (IDR) or liposomal daunorubicin (L-DNR), and etoposide (VP-16) and mitoxantrone.
  • Consolidation and intensification therapy: cytarabine (Ara-C; normal to high dose), mitoxantrone (MITOX), 2-chloro-2-deoxyadenosine, etoposide (VP-16), and idarubicin (IDR)
  • CNS therapy: cytarabine (ARA-C) alone or a combination of cytarabine, prednisone (PRED), and methotrexate (MTX) [triple therapy].
  • No dosage information is provided here because changes in the respective regimens are common with chemotherapy.

Elderly patients who cannot tolerate intensive chemotherapy receive the DNA methyltransferase inhibitors decitabine and azacitidine instead.The enzyme SAMHD1 converts the activated form of decitabine back to its inactive parent form. Determining the amount of SAMHD1 in AML cells can predict how sensitive they are to decitabine. Note: Azacitidine is not affected by SAMHD1. Weakened elderly patients are also helped by the following combination therapy: decitabine and the vitamin A drug tretinoin. Further notes

  • New therapeutic regimens include.
  • Currently, an international study (multicenter phase III trial) is investigating in acute promyelocytic leukemia (APL) (rare subtype of AML) the extent to which arsenic (arsenic trioxide, ATO) in combination with a vitamin A derivative (all-trans-retinoic acid, ATRA; this promotes differentiation of immature tumor cells into mature blood cells) can replace chemotherapy; an initial study was very successful in this regard in promyelocytic leukemia. The standard of care to date is ARTA plus chemotherapy.
  • Midostaurin in addition to standard therapy has prolonged the median overall survival of AML patients with a mutation of the FLT3 gene from 25.6 to 74.7 months.
  • Gilteritinib (selective FLT3 inhibitor; dosage: 120 mg daily): approved for monotherapy of relapsed or refractory acute myeloid leukemia (AML) with FLT3 mutation; in a comparison of monotherapy versus various salvage chemotherapies in adult patients, overall survival was improved by nearly one-quarter (median OS: 9.3 months versus 5.6 months). The one-year survival rate was 37.1 percent versus 16.7 percent, more than twice as high.
  • Venetoclax: oral BCL-2 inhibitor to restore natural apoptosis (programmed cell death) processes in altered CLL cells. This is prevented by overexpression of BCL-2.Venetoclax combined with azacitidine showed significantly improved treatment response and overall survival: median life expectancy 14.7 months versus control group at 9.7 months and frequency of treatment response from 28 to 66 percent.

Other agents

  • Androgen treatment with the low-dose anabolic steroid norethandrolone (10 or 20 mg/day) as maintenance therapy prolongs life to disease progression and overall survival in elderly patients with AML:
    • With complete remission at five years: Group with androgen therapy was still alive 31.2% (95% confidence interval: 22.8- 40.0%); comparison group without treatment only 16.2
    • Event-free survival at five years: Group with androgen treatment significantly higher (21.5% versus 12.9%).
    • Overall survival: significant difference between both groups (26.3% versus 17.2%).