12.3 Acute Myeloid Leukemia (AML)

AML is a heterogeneous hematologic malignancy characterized by what?

the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, & other tissues

Leukemia cells have limited ability to differentiate and are therefore not capable of performing the functions of normal white blood cell

Most common form of acute leukemia

acute myelogenous leukemia

AML Signs and Symptoms

• AML is rapidly fatal if not treated

• Cytopenias:

  • Anemia

    • Fatigue, malaise, weakness

  • Thrombocytopenia

    • Easy bruising, petechiae, ecchymosis

    • Heavy and / or prolonged menses

    • Bleeding such as epistaxis, gingival bleeding, conjunctival hemorrhage

  • Neutropenia

    • Infection

    • Signs and symptoms may be absent due to non-functioning nature of the malignant WBC clone

• High “Blast” Count

AML Workup

• Laboratory tests

  • CBC with differential, chemistries, coagulation studies

• Examination of peripheral blood smear

• Bone marrow biopsy

  • Cytogenetics, immunophenotyping and cytochemistry

• Cardiac echocardiogram or MUGA

  • Treatment often includes anthracyclines

Diagnosis of AML

• BLASTS = BAD!

  • Peripheral blasts

  • Blasts in bone marrow biopsy sample

• Greater than 20% = a diagnosis of AML

AML Risk Assessment and and Predictors of Outcomes

• Age – outcomes are better in patients less than 60 years old.

• Performance status – “fitter” patients do better

• Duration of first remission

• Cytogenetics and molecular abnormalities – MOST IMPORTANT

General Treatment Plan for AML

• Initiate immediately after definitive diagnosis is made.

• Chemotherapy:

  • Intensive chemotherapy

    • When goal is cure

    • Most patients, unless considered unfit

  • Low-intensity chemotherapy

    • When goal is altering the natural course of the disease

    • Less fit or elderly patients

• Appropriate supportive care

  • Blood/Platelet transfusions, pain control, antinauseants with chemotherapy, infection prevention

Fit patient Treatment plan with High Risk AML in Alberta

Induction Chemo (trying for remission)

then

Consolidation Chemo (trying to hold remission)

then

Allogenic Stem Cell Transplant

Induction Chemo Goals

Goal is to “Induce” a complete remission (CR)

• disappearance of clinical and bone marrow evidence of leukemia

  • Bone marrow to have normal cellularity with < 5% blasts and no leukemic clone

  • No “Blasts” in the peripheral blood

• AND restoration of normal hematopoiesis

  • Neuts ≥1.0 and Plt >100

AML Induction Protocol

7+3” or “three and seven”

7+3” or “three and seven” Regimen includes

• 3 days of daily IV push anthracycline:

  • Calgary uses Idarubicin 12 mg/m2 IV push over 5 minutes once daily X 3 days

  • Some centres use Daunorubicin

  • Toxicities similar to those discussed for doxorubicin

• 7 days of daily continuous infusion cytarabine

  • Cytarabine 100-200 mg/m2/day IV continuous infusion for 7 days

  • Patients commonly get a rash

AML Supportive Care Includes

• INFECTIONS!!!

  • After giving “induction” chemotherapy, patients experience a very deep and extended period of deep neutropenia

  • Prophylaxis of opportunistic infections:

  • Febrile Neutropenia – High risk Category - Refer to CRI/FN lecture

• TLS prophylaxis: Typically lower risk than ALL patients but usually still need allopurinol

• Mucositis

AML Consolidation, when is it given

Given after a CR (complete remission) is achieved with induction therapy

AML Consolidation Regimen

• HIDAC = HIgh Dose Ara-C (cytarabine)

• 3000 mg/m2 IV over 2-3 hours q12h on days 1,3,5 (6 doses)

HIDAC AEs

• Ocular Toxicity!

  • Doses of cytarabine that are greater than 1g/m2 for 2 doses will lead to corneal toxicity in most patients

  • Symptoms include excessive tearing, pain, photophobia and sensation of foreign body

  • Steroid eye drops are absolutely necessary for duration of HIDAC therapy and continuing until 48 hours after the last dose. (Dexamethasone eye drops or Prednisolone eye drops)

• Cerebellar Toxicity

  • Neurologic assessment (including handwriting assessment)

What is an Allogeneic HSCT?

stems cells come from someone else

Allogeneic Transplant Process 

1) Collection from donor’s bone marrow or blood 

2) Processing of stem cells

3) Cryopreservation of stem cells until needed to be infused (doen’’t need to happen if being infused shortly)

4) Chemotherapy (high dose chemo or radiation is given to patient)

5) Infusion of stem cells to patient 

Purpose of Allogeneic HSCT

• To rescue the recipient from myeloablative therapy given for treatment of malignant disease

  • Same rationale as Autologous HSCT

• To replace the abnormal hematopoietic component

  • AKA to replace malignant progenitor cells with health progenitor cells from a donor

• To establish a graft-versus-leukemia (tumor) effect

  • Donor cells recognize and destroy the residual malignant cells in the host

  • Advantage over Autologous HSCT

• In Alberta, Allo-HSCT is part of the clinical guidelines for treatment of appropriate patients with AML or ALL, select patients with CML, and select patients with other hematologic malignancies

Stem Cell sources for Allogeneic HSCT

• Bone Marrow

  • Cells are obtained through a bone marrow harvest

  • Procured through multiple needle aspirations into the posterior iliac crest

  • Obtained under general or regional anesthesia

• Peripheral Blood

  • Cells are obtained using apheresis

• Umbilical Cord Blood

Overview of Allo HSCT

1) Search for a suitable donor (MRD, MUD, Cord)

2) Obtain donor stem cells (timing depends on source, location, fresh/frozen)

3) Conditioning Chemotherapy

4) Start Immunosuppression (Example: Cyclosporine)

5) Infuse STEM CELLS (DAY 0)

6) Supportive Care (opportunistic infections, treatment related toxicities)

7) Engraftment (Count Recovery around DAY 10-20)

8) Wean off immunosuppression if no GVHD

9) Immunoreconstitution (occurs much later after transplant)

Pharmacist Role in the Transplant Team

• Chemotherapy toxicity management:

  • Seizure prophylaxis

    • Some chemo agents in high dose can reduce seizure threshold

  • Mucositis

    • Mouth care, pain control

  • Nausea/vomiting

    • Antinauseants

  • Organ toxicities (hepatic, renal, etc)

    • Dose adjustments

  • Pharmacokinetic monitoring of chemotherapy agents (busulfan)

• GVHD prophylaxis/treatment (allo):

  • Immunosuppression

    • Cyclosporine therapeutic drug monitoring

    • Prednisone Tapers

  • GVHD Symptom Management

• Infection prophylaxis/treatment:

  • Management of febrile neutropenia

  • Prophylaxis for Pneumocystis, Herpes viruses, fungal infection

  • Treatment of infections