Morphology of AML.

Yesterday and today I read an literature by Gail J. Roboz in the Education Program Book by American Society of Hematology (ASH), which is named “Hematology” and published annually by the ASH in one volume per year. The name is “Novel Approaches to the Treatment of Acute Myeloid Leukemia”. In this article the author discussed several aspects of Acute Myeloid Leukemia (AML) including: the general, the chemotherapy regimen, the stem cell transplantation, and the prognostic of AML. Now let’s get into this article.

In the introduction section. Approximately 12,000 adults are diagnosed with acute myeloid leukemia (AML) in the United States annually, with a median age of 67 years. Despite advances in therapeutics and supportive care, the majority of patients with AML die from their disease. But among the subtypes acute promyelocytic leukemia (APL) is an important exception to the general statement of AML. In this subtype >75% of patients are cured with a combination of anthracycline-based chemotherapy, all-trans retinoic acid, and arsenic trioxide. For some APL patients, it is possible to eliminate cytotoxic chemotherapy altogether and to achieve cure with arsenic and all-trans retinoic acid alone. In this article we don’t discuss this subtype of AML in detail.

For all other subtypes of AML, the mainstay of initial treatment was developed nearly 40 years ago as a combination of cytosine arabinoside (ara-C) with an anthracycline, and this regimen remains the worldwide standard of care. Without stem cell transplantation, the age of patients is an in dependent major determinant indicator of the prognostic. For patients <60 years of age approximately 70%-80% of those will achieve complete remission, but most ultimately relapse and overall survival is only 40%-45% at 5 years. Among patients >60 years of age, 40%-50% of those with a good performance status can achieve complete remission, but cure rates are <10% and median survival is <1 year. Later in another section we will discuss the older AML patients in detail.

Advances in genomics technologies have identified AML as a genetically highly heterogeneous disease. As the technologies is well developed today, we are able to assign AML patients to many subgroups based on their molecular genetic defects. First we can assign AML patients to two subgroups which are cytogenetically normal and cytogenetically abnormal.

Cytogenetically normal patients comprise the largest subgroup of AML. This subgroup can now be further divided into a myriad of molecular subgroups too. Some subtypes of molecular genetic defects are know to have significant prognostic implications. For example, mutations in FLT3-ITD have been associated with an aggressive disease phenotype and poor outcomes. In contrast, patients with biallelic mutations in CEBPA and NPM1 without concomitant mutations in FLT3-ITD have significantly more favorable outcomes.

Also there is subgroup with abnormal cytogenetics. For example, mutations in KIT may negate the “favorable” classification previously associated with t(8;21).

Treatment of Acute Myeloid Leukemia

The treatment paradigm for AML generally includes remission induction, followed by consolidation with either 1-4 cycles of chemotherapy or stem cell transplantation.

The drugs for remission and consolidation have been variations on a theme of ara-C combined with an anthracycline or anthracenedione. In 1973 Yates et al first reported the result of a pilot trial of infusional cytarabine combined with daunorubicin in AML. The treatment was called “7&3 DNR 45” to indicate the dose of daunorubicin, 45 mg/m2. And there are many former studies to show the effects of the anthracyclines. There are five recommands for the treatment of AML.

  • Cumulative anthracycline dose for induction should be at least 180 mg/mof daunorubicin or 36 mg/m2 of idarubicin and consider daunorubicin 270 mg/m(It’s called intensive therapy, we will discuss about it later) for patients up to 65 years of age with a good performance status and adequate cardiac function.
  • Consider carefully if offering intensive consolidation to patients >60 years of age because this has not been shown to prolong survival and is associated with significant toxicity.
  • Refer potential transplantation candidates immediately at time of diagnosis to allow adequate time for donor identification and transplantation planning.
  • Age is not a major determinant of outcome after reduced intensity allogeneic transplantation; do not exclude patients on the basis of chronological age alone and refer older patients with good performance status early.
  • Almost every patient with AML should be considered for a clinical trial, including those who are already in remission. (more…)