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acute myeloid leukemia (AML)

Malignancy of myeloid cells; clonal expansion of myeloblasts in bone marrow, blood or other tissue. Classification: World Health Organization (WHO) 1) acute myeloid leukemia with recurrent genetic abnormalities a) AML with t[8;21][q22;q22]; AML1/ETO b) AML with abnormal bone marrow eosinophils, inv(16)(p13.1;q22.1) or t[16;16][p13;q22]; CBF-beta/MYH11 c) acute promyelocytic leukemia (AML-M3) (AML with t[15;17][q22;q12]; PML/RAR-alpha and variants) d) AML with 11q23 (MLL) abnormalities e) AML with mutated RUNX1 [15] f) AML with BCR-ABL1 [15] 2) acute myeloid leukemia with myelodysplasia-related changes a) following myelodysplastic syndrome/myeloproliferative disorder b) without preceding myelodysplastic syndrome 3) acute myeloid leukemia, therapy related a) alkylating agent related b) topoisomerase type 2 inhibitor related c) other 4) acute myeloid leukemia not otherwise categorised a) acute myeloid leukemia minimally differentiated (AML-M0) b) acute myeloid leukemia without maturation (AML-M1) c) acute myeloid leukemia with matuation (AML-M2) d) acute myelomonocytic leukemia (AML-M4) e) acute monoblastic & monocytic leukemia (AML-M5a, 5b) f) acute erythroid leukemia (AML-M6a, 6b) g) acute megakaryoblastic leukemia (AML-M7) h) acute basophilic leukemia i) acute panmyelosis with myelofibrosis j) myeloid sarcoma French-American-Brittish (FAB) classification: - acute myeloid leukemia minimally differentiated (AML-M0) 3-5% - acute myeloid leukemia without maturation (AML-M1) 15-20% - acute myeloid leukemia with matuation (AML-M2) 25-30% - acute promyelocytic leukemia (AML-M3) 10-15% - acute myelomonocytic leukemia (AML-M4) 20-30% - acute monoblastic leukemia (AML-M5a) 2-9%* - acute monocytic leukemia (AML-M5b) 2-9%* - acute erythroid leukemia (AML-M6a, 6b) 3-5% - acute megakaryoblastic leukemia (AML-M7) 3-5% * combined incidence AML-5 (AML-M5a + AML-M5b) 2-9% Etiology: (risk factors): - age is greatest risk factor - prior alkylating agent therapy - benzene exposure - radiation - type 2 topoisomerase inhibitors - Fanconi's anemia - Bloom syndrome - Down syndrome - neurofibromatosis - myeliproliferative neoplasm Epidemiology: 1) worldwide, approximately 2.8/100,000 population per year 2) most cases diagnosed in January, implying seasonal factors such as infectious agents or environmental triggers [32] 3) more common in adults a) ~80% of adult leukemias b) ~20% of childhood leukemias 4) mean age at presentation is 67 years [7] 5) in adults, 90% of acute leukemia is myeloblastic, 10% is lymphoblastic [7]* * the reverse is true of children & adolescents [7] Pathology: 1) bone marrow is hypercellular a) monomorphic population of cells, arrested development b) proliferation of myeloblasts & or promyelocytes in bone marrow & peripheral blood c) WHO recommendation for diagnosis: myeloblasts >= 20% in blood or bone marrow 2) may evolve from myelodysplastic syndrome 3) leukemic myeloblasts divide hourly & the patient becomes symptomatic over days to weeks [7] 4) functional neutropenia due to myeloblast replacement of normal bone marrow Genetics: > 20 known genetic aberrations associated with AML - chromosomal abnormalities generally involve chromsomes 5 & 7 - mutations in genes encoding epigenetic modifiers, such as DNMT3A, ASXL1, TET2, IDH1, & IDH2, are commonly acquired early & are present in the founding clone [15] typically are secondary events that occur later during leukemogenesis [15] - constitutively-activated FLT3 associated with poor prognosis - mutations involving NPM1 or signaling molecules (FLT3, RAS) - ~1/4 of adult AML patients with FLT3-ITD (Internal Tandem Duplication) - defects in NPM1 most common genetic defect in AML (30%) [35] - KMT2A rearrangements in 15% of childen & adults with AML [35] - early-onset AML may be associated with germline defects in MBD4 [18] - overexpression of ZFP91, MSI2 - mutations in RUNX1, ASXL1, TP53 - translocation t(5;11)(q35;p15.5), NUP98 & NSD1 genes - translocation t(6;9)(p23;q34) involving DEK with NUP214/CAN - translocation t(7;11)(p15;p15) involving HOXA9 with NUP98 - translocation t(8;11)(p11.2;p15), WHSC1L1 & NUP98 genes - translocation t(8;16)(p11;p13) involving MYST3 with CREBBP - t(8;21)(q22;q22) (AML/ETO) involving AML1 & ETO (favorqble prognosis) - translocation t(8;22)(p11;q13) involving MYST3 with EP300 - translocation t(12;22)(q13;q11) involving MN1 & TEL genes - translocation t(11;17)(q23;q25) involving SEPT9 & MLL genes - translocation t(11;17)(q23;p13) involving GAS7 with MLL genes - translocation t(4;12)(q12;p13) involving CHIC2 & ETV6 genes - translocation t(9;11)(q34;q23) involving DAB2IP & MLL genes - translocation t(11;17)(p15;p13) involving PHF23 & NUP98 genes - translocation t(3;21)(q26;q22) involving EVI1 & RUNX1/AML1 - translocation t(3,11)(q25,q23) involving GMPS with MLL - translocation t(1;3)(p36;q21) involving PRDM16 - translocation t(16;21)(p11;q22) involving FUS with ERG - inversion inv(8)(p11;q13) generates the MYST3-NCOA2 oncogene - inversion inv(16) (favorable prognosis) [7] - other implicated genes: - CDCA7, JAK2, KRAS, NT5DC3, LHX1, IRF1, S100A6, RGS2, SPAG9 Gene expression profiling clusters [8] non-coding RNA profiles may provide prognostic information [19] - some such non-coding RNAs may be located in close proximity to hematopoietic coding genes [19] * multiple (> 5 genetic aberrations) associated with poor prognosis [7] Clinical manifestations: 1) AML-related bone marrow failure a) fatigue (anemia) b) dyspnea c) mucosal & cutaneous bleeding (thrombocytopenia) d) gingival hyperplasia (monocytic leukemias) e) leukemia cutis f) extramedullary tumors g) develops over weeks to months 2) fever 3) opportunistic infections (neutropenia) 4) skin & mucous membrane lesions [3] - petechiae when platelet count < 20,000/uL [7] - gingival hypertrophy & leukemia cutis common 5) most likely among leukemias to develop petechiae, bruising, bleeding, & infection [7] 6) sternal tenderness (bone marrow expansion) 7) hepatosplenomegaly uncommon, suggests another diagnosis [7] 8) lymphadenopathy uncommon, suggests another diagnosis [7] Laboratory: 1) complete blood count (CBC) - leukocytosis with circulating blasts [7] - absolute neutrophil count may be low [7] - anemia - thrombocytopenia - in the elderly, typically long-standing pancytopenia 2) peripheral blood smear* a) Auer rods in myeloblasts pathognomonic b) >= 20% blasts is diagnostic 3) bone marrow aspiration & bone marrow biopsy a) Auer rods in myeloblasts pathognomonic b) >= 20% blasts is diagnostic 4) flow cytometry: CD33 [7], CD117 [5] 5) cytogenetics (only definitive diagnosis) 6) gene expression profiling using microarray technology predicts prognosis [8] 7) detection of mutations during AML remission with targeted next-generation sequencing, excluding mutations associated with age-related clonal hematopoiesis, predicts likelihood of relapse [20] 8) specific mutation testing - FLT3 gene mutation - NPM1 gene mutation - IDH1 gene mutation - IDH2 gene mutation 10) C5-cytosine DNA methyltransferase-3A (DNMT3A) gene mutation testing (see NGC guideline, Program in Evidence-based Care) 11) reduction of ERK 1/2 & p38 MAPK phosphorylation in the myeloid cell compartment 24 hour post-chemotherapy predicts 5-year overall survival [34] 12) see ARUP consult [9] * image of myeloblasts in a patient with refractory acute myeloid leukemia [29] * images of myeloblast in mitosis & in apoptosis [29] Complications: - leukostasis & hyperviscosity syndrome (WBC count is > 50,000/uL) - tumor lysis syndrome may occur spontaneously or especially with treatment [7] - may be 1st manifestation of AML [7] Differential diagnosis: - acute lymphoblastic leukemia (children, adolecents) - acute promyelocytic leukemia (DIC) Management: 1) within 1st 24 hours of diagnosis - confirm acute leukemia - confirm AML vs ALL - exclude acute promyelocytic leukemia - leukapheresis if WBC count is > 50,000/uL 2) chemotherapy induction a) daunorubicin (Cerubidine) for 3 days b) cytarabine (Cytosar) for 7 days c) daunorubicin + cytarabine referred to as "7 + 3 regimen" - patients > 70 years do not tolerate 7 + 3 well [7] - addition of sorafenib (Nexavar) in patients < 60 years of age may be of benefit [16] d) idarubicin may substitute for daunorubicin e) high dose cytarabine (ARA-C) (HiDAC) is used in patients with refractory, relapsed or therapy-related AML f) flotetuzumab may induce remission [14] g) vigorous hydration & pretreatment with allopurinol to prevent tumor lysis syndrome h) urine alkalinization to reduce hyperuricemia i) prophylaxis with posaconazole for aspergillosis [22] 3) chemotherapy consolidation & maintenance a) high dose ARA-C 1-3 gm/m2 BID b) addition of sorafenib (Nexavar) in patients < 60 years of age may be of benefit [16] c) oral azacitidine (Onureg) as maintenance therapy after first remission [28] d) consolidation after completed remission for low risk patients - no prior chemotherapy, candidates for targeted therapy e) allogeneic stem cell transplantation reserved for "salvage therapy" & for first complete remission in younger patients (51 years is younger) [7] f) for patients who fail induction therapy, allogeneic stem cell transplantation without intensive salvage induction may be an option [31] 4) targeted therapy - FLT3 inhibitor midostaurin (Rydapt) in combination with standard cytarabine & daunorubicin induction & cytarabine consolidation for constitutively-activated FLT3 mutation [17] - gilteritinib (another FLT3 inhibitor) shows promise [17] - quizartinib (Vanflyta) FDA-approved for adults with FLT3-ITD (Internal Tandem Duplication) [36] - IDH1 inhibitor ivosidenib for AML patients (6-10%) with IDH1 mutations (FDA-approval pending) [23] - addition of ivosidenib (Tibsovo) to azacitidine increases survival 3-fold [30] - IDH2 inhibitor enasidenib (Idhifa) for AML patients (20%) with IDH2 mutations [21] - response rate ~ 30% + another 30% with stable disease - investigational menin inhibitor revumenib promising for patients with relapsed or refractory KMT2A-rearranged or NPM1-mutant acute leukemia [35 - CD33(+) AML - gemtuzumab ozogamicin (Mylotarg) - may induce remission in elderly patients with CD33(+) AML - not associated with profound myelosuppression - more harm than benefit; US market removal June 2010 - FDA approval for CD33+ AML Sept 2017 - all trans-retinoic acid for AML-M3 (acute promyelocytic leukemia) - therapy-related AML or myelodysplasia-related AML - CPX-351 (Vyxeos) 5) considerations in older patients - older, fit patients pretreated with 10-days of decitabine (Dacogen) prior to allogeneic hematopoietic stem cell transplantation with similar overall survival & fewer severe adverse events vs conventional intensive chemotherapy [33] - older patients with high-risk AML or comorbidities precluding use of intensive chemotherapy may be treated with supportive care & low-dose outpatient chemotherapy (azacytidine or decitabine) [7] 6) supportive care a) blood transfusions - use only filtered & irradiated blood products b) platelet transfusion 1] hemorrhage 2] platelet count < 10,000/uL c) leukopheresis & chemotherapy for treatment of leukostasis (WBC > 50,000/uL) d) prophylaxis for invasive fungal disease - caspofungin more effective than fluconazole [26] e) palliative care integrated with oncology care improves quality of life, psychological distress, & end of life care [27] 7) autologous vs allogeneic stem cell transplantation - indicated for first complete remission in younger patients (<=51 years) [7] - IFN-gamma may induce stealth leukemia cells to reveal themselves after stem cell transplantation [24] 8) prognosis: a) 30-50% remission in the elderly with induction therapy b) 10% of elderly who achieve remission sustain remission > 5 years [4] c) a favorable prognosis for AML in patients is - 34% 5 year survival for patients > 55 years - 65% 5 year survival for patients < 55 years d) a unfavorable prognosis for AML in patients is - 2% 5 year survival for patients > 55 years - 14% 5 year survival for patients < 55 years 9) genetic classification of AML may better estimate prognosis & facilitate treatment [10] - genetic profile of leukemic cells with greatest influence on survival [7] 10) routine medical care of family members

Interactions

disease interactions

Related

AML1 or CBFA2 gene chromosomal translocation t3q26:21q22 (AML1)

Specific

acute basophilic leukemia acute eosinophilic leukemia acute myeloid leukemia t[16;16][p13;q22] or inv[16][p13;q22];(CBF-beta/MYH11) acute myeloid leukemia t[18;21][q22;q22];(AML1/ETO) acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) acute myeloid leukemia, 11q23 (MLL) abnormalities acute myeloid leukemia, therapy related acute panmyelosis with myelofibrosis AML gene expression profiling clusters AML-M0; acute myeloblastic leukemia minimally differentiated AML-M1; acute myeloblastic leukemia without maturation AML-M2; acute myeloblastic leukemia with maturation AML-M3; acute promyelocytic leukemia AML-M4; acute myelomonocytic leukemia AML-M5; acute monocytic leukemia AML-M6; acute erythroblastic leukemia AML-M7; acute megakaryoblastic leukemia chronic myeloid leukemia (CML) blast crisis

General

acute leukemia myeloid leukemia

Database Correlations

OMIM correlations

References

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