Pocket Oncology (Pocket Notebook Series), 1st Ed.

ACUTE MYELOID LEUKEMIA (AML)

Justin M. Watts and Martin S. Tallman

Epidemiology

• Incidence: Estimated 13800 new cases in the United States in 2012 (10200 death)

• Most common myeloid malignancy in adults

• Median age of onset: 70 y

• RF: Cytotoxic chemotherapy, IR, benzene exposure, trisomy 21, rare congenital syndrome (eg, Fanconi anemia, Klinefelter, dyskeratosis congenita)

Disease Biology/Natural History

• Heterogeneous clonal disorder of hematopoietic stem cells (“blasts”)

• Many genotypic variants (many w/prognostic relevance)

• W/o Rx: ↑ blasts in BM & circulation & ↓ ANC/Hb/Plt; typically fatal in wks to mos d/t BM failure (infxn, bleeding) or organ infiltration

Clinical Presentation/Emergencies

• Presenting s/s reflect ↓ hematopoiesis: Most commonly fatigue and/or infxn

• Most pts are pancytopenic w/circulating blasts at dx → ∼50% have ↓ or nl WBC; ∼20% have WBC >100000/μL

• Leukostasis can occur if WBC >50000/μL → vascular occlusion/hemorrhage (esp. of microcirculation) → visual disturbance/retinopathy, dyspnea/pulm infiltrates, myocardial ischemia, TIA/CVA → Rx w/hydration, hydroxyurea, leukapheresis

• DIC: Very common in APL & frequent cause of early death (cerebral hemorrhage) → early admin. of ATRA critical at first suspicion of APL (ie, in the ER)

• Tumor lysis syndrome (TLS) (more common w/ALL but can occur in AML): Ppx w/IVF & allopurinol, Rx includes forced diuresis, rasburicase, HD if sev.

• CNS involvement in 2–3% of cases (RF: ↑ WBC, relapsed APL); w/u incl. eye exam, CT/MRI, usu defer LP until CR1 unless symptomatic (theoretical risk of CNS seeding)

Diagnosis

• BM aspirate & bx w/flow cytometry, cytogenetics, & molecular studies (KITFLT3NPM1CEBPA are standard)

• AML confirmed if ≥20% myeloblasts in BM or blood or recurrent cytogenetic abnormality

• R/o ALL → morphology (Auer rods are pathognomonic for AML; N:C ratio often higher in ALL); immunophenotyping by IHC/flow; cytogenetics/molecular genetic studies

• Common myeloid Ag: CD13, CD33, CD34, CD117, MPO

WHO Classification of AML (Blood 2009;114:937)

FAB classification no longer used

Prognosis

Determined primarily by age & cytogenetic/molecular risk

• Age >60 y is an independent poor-risk feature

• Poor PS, high presenting WBC, antecedent hematologic disorder, Rx-related AML → poor-risk

• Good-risk: APL (10–15% of all AML), +core binding factor (∼12%)

• Most pts have an intermediate or unfavorable risk at presentation

AML Genetics and Risk (Blood Rev 2004;18:115; Blood 2010;116:354)

45% pts have nl cytogenetics

• Favorable karyotypic abnls are considered favorable regardless of other cytogenetic abnls

• c-KIT Mt portends less favorable prognosis in pts w/t(8;21) [but probably not in pts w/inv(16)/t(16;16)]

• Some data that NPM1 & IDH co-Mt may be very favorable, & that FLT3-ITD confers an esp poor prognosis in presence of other, newly discovered “poor-risk” Mt (eg, TET2ASXL1, & DNMT3A) (NEJM2012;366:1079)

• A monosomal karyotype (≥2 monosomies or 1 w/other structural abnl) carries an extremely poor prognosis

Treatment

• Induction chemo (“7 + 3”): 7 d of infusional cytarabine & 3 d of dauno or idarubicin; RCTs confirmed high-dose dauno (90 mg/m2) superior (OS benefit) to standard dose (45 mg/m2) (NEJM 2009;361:1235); can use dauno 60 mg/m2in older pts w/good PS

• Confirm CR (<5% blasts) w/BM bx upon peripheral count recovery; persistent cytopenias >28 d after chemo → likely residual leukemia

• Can repeat 1 course of induction w/“5 + 2” or alternative regimen if no CR

• Postremission (consolidation) Rx: High-dose cytarabine (HiDAC) → optimal dose under debate → in younger pts current standard is 3 g/m2 × 6 doses for 3–4 cycles (cerebellar tox rare but potential SE; modify dose in older pts)

• No proven benefit to multiple courses of HiDAC, esp. in older pts & non-CBF leukemias

• Allogeneic HCT in appropriate pts (unfavorable prognosis, strongly consider if intermediate-risk) w/suitable donor (RIC for pts >50–60 y)

• Autologous HCT rarely used, though may benefit pts w/favorable or intermediate risk who received high-dose dauno (Blood 2011;117:5306)

• No proven role for maintenance chemotherapy in AML (despite numerous studies)

• If relapse → salvage chemo (eg, MEC → mitoxantrone, etoposide, cytarabine) vs. clinical trial → goal to achieve CR2 & consolidate w/alloHCT

• MUD & matched sibling donor (MRD) HCT now have similar outcomes; UCB has expanded donor pool (Blood 2010;116:4693)

• Hypomethylating agents (5-aza, decitabine) have benefit in older pts not candidates for intensive chemo (J Clin Oncol 2010;28:562)

• Supportive care: IVF, abx for FN, antimold antifungal ppx if prolonged neutropenia, TLS ppx w/allopurinol (rasburicase if ↑ UA & risk for tumor lysis), RBC & plt transfusions, hydroxyurea if ↑ WBCs (leukapheresis rarely needed)

Outcomes (Blood 2005;106:1154; J Clin Oncol 2009;27:61)

• ∼70–80% of younger pts (<60 y) & ∼40–50% of older pts (>60 y) will achieve CR w/induction chemo (+CR correlates w/survival)

• OS ∼35–40% in younger adults; better prognosis in APL & CBF leukemias

• Older pts have dismal prognosis (OS ∼10%), d/t medical comorbidities & underlying disease biology/genetics (eg, ↑ risk of antecedent MDS, monosomal karyotype)

Acute Promyelocytic Leukemia (APL)

• Unique subtype of AML w/excellent prognosis & distinct biology

• Characterized by atypical promyelocytes (w/c are blast “equivalents”)

• Driven/defined by translocation of RAR gene [t(15;17)] → aberrant fusion protein PML-RARα → blocks nl myeloid differentiation at promyelocyte stage

• High early mortality rate from characteristic DIC → start ATRA early & aggressively correct coagulopathy w/FFP & cryoprecipitate

• Most pts are now cured w/the differentiating agents ATRA & ATO → almost all pts achieve CR, OS ∼90%

• Standard Rx: Induction w/ATRA & idarubicin (or dauno + cytarabine) → consolidation w/ATRA & ATO → maintenance w/ATRA, 6-MP, oral MTX; autoHCT if relapse

• Pts treated w/ATRA/ATO only (no chemotherapy) also appear to have excellent outcomes → idarubicin still used if elevated WBC to prevent hyperleukocytosis, w/c ↑ induction mortality & risk of relapse (J Clin Oncol 2009;27:504)

• Differentiation syndrome: Fever, edema, serositis, ARDS, HoTN → Rx w/high-dose steroids & temporary cessation of ATRA/ATO (potentially life-threatening)