First Steps When Evaluating a New Patient with AML

High grade myeloid neoplasms are a family of rapidly progressive cancers of the marrow stem and progenitor cells and are identified by the presence of an increased proportion of immature 'blast' cells (usually >10%) within a sample of peripheral blood or bone marrow aspirate. Identification can by either based on morphology or multiparameter flow cytometry. Patients may present with abnormal (either decreased or increased) cell counts, or a variety of symptoms such as night sweats, adenopathy, gingival swelling, purpuric rash, or organomegaly.

Prompt diagnosis is relies of careful characterization of the leukemia blast cells, which can become challenging following initial cytoreduction. Therefore initial management should not only aim to stabilize the patient, but also provide definitive diagnosis.

Several topics should be considered prior to recommending initial therapy. Then, once the patient is stabilized and required sampels obtained, a more careful consideration of tranplant and non-transplant therapies can be completed.

A general approach to evaluation should be methodical, and progresses as follows

1. *Initial Evaluation
   1. Obtain samples that will allow definitive diagnosis
   2. Evaluate the need for urgent interventions, including concurrent infection
2. Consider whether intensive induction therapy is appropriate
   1. Evaluate patient fitness for intensive induction therapy
   2. Consider outcomes with standard therapies including supportive care and/or hospice care, hypomethylating therapies, and standard intensive induction.
3. Formulation Initial Treatment Plan
4. Evaluate whether allogeneic stem cell transplant is appropriate
   • The likelihood of cure is dependent on a disease characteristics including genetic analyses that maybe available only days after initial presentation. Once definitive disease characterization is available, a careful consideration of the risks and benefits of allogeneic transplant is conducted as follows (usually after therapy is initiated).
     1. Prognostication of the outcomes of standard chemotherapy treatments
     2. Evaluation of the risk of allogeneic transplant including non-relapse mortality.
     3. Consideration of donor factors and risk of GVHD
     4. Consideration of the likelihood of successful (i.e. curative) allogenetic transplant
     5. Balancing these factors and quality of life with respect to patient preferences.

General workup

A physical exam is helpful to document site of disease, provide information regarding organ and marrow function, and to evaluate for evidence of infection. Additional information, such as the presence of liver or spleen enlargement may provide clues to disease history, e.g. prior myeloproliferative neoplasm resulting in marrow fibrosis and and indicating likely poor marrow recovery following intensive chemotherapy.

Special attention therefore is paid to examination of the chest (e.g. for ralles), volume status, skin (e.g. for rash), abdominal organs, oropharynx, and cardiac auscultation.

Laboratory testing should include:

• CBC
• Comprehensive metabolic panel
• HIV
• Hep B panel
• LDH & Uric Acid (to evaluate for TLS)
• EBV & CMV (these viral infections can reactivate at presentation)
• HLA typing (to aid in donor identification)

Blast Cutoffs for diagnosis by peripheral blood

We strongly recommend patients have samples obtained capable of rendering an exact diagnosis with risk stratification. As of 2022, this required at least some genetic sequencing approaches in addition to karyotyping. If the circulating blast concentration exceeds 2000/uL, it is likely that sufficient information for genetic characterization as well as metaphase karyotypic could be obtained from the peripheral blood. If this is not the case a bone marrow aspirate should be obtained.

Diagnosis is based on blast percentage - patients with 10-20% blasts are classified as "MDS/AML" reflecting the continuum of clinical disease and the high risk of patients with >10% blasts. These patients maybe enrolled on trials evaluating either MDS or AML-type therapy. Patients with >20% blasts are characterized as "AML".

Biobanks at FHCC

Two biobanks are currently operational at FHCC based on protocol numbers FH1690 (for AML) and FH1713 (for MDS). Contact the Tim Monahan for consent forms and sample aquisition.

General Patient Characterization

• family history of malignancy
• prior medical diagnosis especially:
  • heart disease
  • lung disease
  • renal disease
  • hepatobiliary disease
• ECOG performance status (should be carefully scrutinized!)
  • 0 = No limitations, fully activty, capable of working Note: patients with AML are rarely ECOG 0.
  • 1 = Slight limitations
  • 2 = Incapable of more than light activity. Up and about >50% of the day
  • 3 = Capable of all self care, in a bed or chair >50% of the day
  • 4 = Assitance needed for self care
  • 5 = Dead

Patient Fitness For Chemotherapy

Patient fitness is a key determinant of treatment, as fit patients have a lower risk of early death following intensive treatment. Non-intensive treatment is rarely curative.

Fitness can be assessed by calculating the Walter 'Treatment Related Mortality Score' (TRM) via an online calculator here: https://trmcalculator.fredhutch.org/.

Alternatively an affirmative answer to any of the following questions suggests lack of fitness for intensive treatments:

1. An age older than 75 years
2. Congestive heart failure or documented cardiomyopathy with an EF ≤50%
3. Documented pulmonary disease with DLCO ≤65% or FEV1 ≤65%, or dyspnea at rest or requiring oxygen, or any pleural neoplasm or uncontrolled lung neoplasm. Note that in the absence of prior pulmonary function tests, patients without a documented history of lung disease will not meet this criterion.
   • A useful question is "are you able today to walk up a full flight of stairs unaided?" An affirmative answer makes significant lung disease unlikely.
4. On dialysis and age older than 60 years, or uncontrolled renal carcinoma
5. Liver cirrhosis Child B or C, or documented liver disease with marked elevation of transaminases (>3 times normal values) and an age older than 60 years, or any biliary tree carcinoma or uncontrolled liver carcinoma or acute viral hepatitis
6. Active infection resistant to anti-infective therapy
7. Current mental illness requiring psychiatric hospitalization, institutionalization or intensive outpatient management, or current cognitive status that produces dependence (as confirmed by the specialist) not controlled by the caregiver
8. ECOG performance status ≥3 not related to leukemia
9. Any other comorbidity that the physician judges to be incompatible with conventional intensive chemotherapy