Acute Myeloid Leukemia

Dr. Tjatur Winarsanto SpPD2012

Hematologic MalignanciesLymphoid Cell Line (B or T cells)ALLCLLLymphomaMyelomaMyeloid Cell Line (granulocytes, monocytes, erythrocytes, megakaryocytes)CMLPolycythemia VeraEssential ThrombocythemiaMyelofibrosis with metaplasiaAtypical chronic myeloid disordersAML

Acute Myeloid LeukemiaWhat is it?- Clonal expansion of myeloid precursor cells with reduced capacity to differentiate- As opposed to ALL/CLL, it is limited to the myeloid cell line differentiated from ALL based on morphology, cytogenetics, cytochemical analysis, cell surface markers

MyelopoiesisMyeloid Progenitor cell Myeloblast Promyelocyte Myelocyte Metamyelocyte Band GranulocyteMyeloid Progenitor cell Myeloblast Monoblast Promonocyte MonocyteMyeloid Progenitor cell ProerythroblastMyeloid Progenitor cell Megakaryoblast

EpidemiologyIncidence 2.7 per 100,00012.6 per 100,000 in those over 65 yomedian age of presentation : 65 yoMore prevalent:MalesEuropean descentHispanic/Latino background (promyelocytic leukemia (AML M3))

EpidemiologyIncreased incidenceGenetic fragilityBloom syndromeFaconi anemiaWiskott Aldrich Down, Klinefelter, Patau syndromestobacco use?herbicides?, pesticides?benzene exposureXRT Topoisomerase II inhibitors (e.g etopisode), alkylating agentsMDSother cell proliferation disorders CML, polycythemia vera, primary thrombocytosis, PNH

Clinical symptomsDue to the excessive proliferation of myeloid precursor cells in bone marrow, certain symptoms/lab findings are expected (e.g. as a result of pancytopenia)Functional neutropenia fever, chills (INFECTION)Thrombocytopenia bleeding, bruising Anemia weakness, fatigue

Clinical symptomsOther findings bone pain (sternum, lower extremities) infrequent but thought to be secondary to expansion of medullary cavity

Physical FindingsGingival involvement (especially in the monocytic variants (M4 or M5))Rare hepatosplenomegaly Pallor, petechiae, ecchymosesBone tendernessRetinal hemorrhageCNS infiltration (more common in M4 and M5)Skin, soft tissue infiltration

Gingival Infiltration in Monocytic (AML M4 eos) Variant of AMLMani, A, Lee, DA. Leukemic Gingival Infiltration. N Engl J Med 2008; 358(3): 274. Copyright 2008 Massachusetts Medical Society

Clinical symptoms/Physical FindingsExtramedullary disease (ie, myeloid sarcoma)Can also have involvement of lymph nodes, intestine, mediastinum, ovaries, uterus

DiagnosisPreviously >30% blasts on BM aspirate (per FAB criteria)Recently changed to > 20% blasts on BM aspirate (per WHO criteria)patients with certain cytogenic abnormalities are considered to have AML regardless of blast percentaget(8;21)(q22;q22), inversion (16)(p13q22)t(16;16)(p13;q22), and t(15;17)(q22;q12)

FAB Classification of AMLM0 undifferentiated acute myeloblastic leukemia (5%)M1 AML with minimal maturation (20%)M2 AML with maturation (30%) t(8;21)M3 Acute promyelocytic leukemia (5%) t(15;17)M4 Acute myelomonocytic leukemia (20%)M4 eos Acute myelomonocytic leukemia with eosinophilia (5%) inv (16)M5 Acute monocytic leukemia (10%) t(9;11)M6 Acute erythroid leukemia (3%)M7 Acute megakaryoblastic leukemia (3%)

WHO ClassificationAML with certain genetic abnormalities t(8;21), t(16), inv(16), chromosome 11 changest(15;17) as usually seen with AML M3 AML with multilineage dysplasia (more than one abnormal myeloid cell type is involved) AML related to previous chemotherapy or radiation AML not otherwise specifiedundifferentiated AML (M0) AML with minimal maturation (M1) AML with maturation (M2) acute myelomonocytic leukemia (M4) acute monocytic leukemia (M5) acute erythroid leukemia (M6) acute megakaryoblastic leukemia (M7) acute basophilic leukemia acute panmyelosis with fibrosis myeloid sarcoma (also known as granulocytic sarcoma or chloroma) Undifferentiated or biphenotypic acute leukemias (leukemias that have both lymphocytic and myeloid features. Sometimes called ALL with myeloid markers, AML with lymphoid markers, or mixed lineage leukemias.)

AML M2

Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994, Washington, DC. Armed Forces Institute of Pathology.

AML M3 (Promyelocytic)Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994, Washington, DC. Armed Forces Institute of Pathology.

AML M3 (Promyelocytic)Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994, Washington, DC. Armed Forces Institute of Pathology.

AML M4 eosFrom Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994, Washington, DC. Armed Forces Institute of Pathology.

LeukostasisLeukostasis predominantly in those with WBC counts > 100,000 (10% of patients); can also be seen in patients with WBC > 50,000Most common in those with M4 or M5 leukemiaFunction of the blast cells being less deformable than mature myeloid cells. As a result, intravascular plugs develop.High metabolic activity of blast cells and local production of various cytokines contribute to underlying hypoxia

Treatment of AMLGoal for complete remissionplatelet count greater than 100neutrophil count greater than 1000BM with 5% or less blastsMolecular complete remission : no evidence of leukemic cells in BM even with sensitive tests (eg, PCR, flow cytometry)If in complete remission for >3 yrs without relapse potentially cured (

TreatmentAssess need for emergent therapyAPL with blast > 50,000 and evidence of DICleukemic crisis with organ dysfunction (pulmonary, CNS) seen most often with M4 or M5 variant

Prognostic Factors in AMLFavorableyounger age (80% AML M3Unfavorableolder age (>60)Poor performance statusWBC >100,000Elevated LDHprior MDS or hematogic malignancyCD34 positive phenotype, MRD1 postive phenotypedel (5), del (7)trisomy 8t(6;9), t(9;22)t(9;11) seen in AML M5FLT3 gene mutation (seen in 30% of patients)

TreatmentRemission induction therapyCommonly anthracycline (ie, daunorubicin, idarubicin) and cytarabine (3+7 regimen)Cytarabine has ample CNS penetration so no need for prophylactic intrathecal chemotx (also, risk in patients with AML compared to ALL)60-80% achieve complete remissionPostremission therapyConsolidation longer survival than maintence alonetypically high dose cytarabineMaintenance continue chemotx monthly for 4-12 monthsnonmyelosuppressive doses

TreatmentIncreasingly, hematopoietic cell transplantation is used in patients with AML after 1st remission in those with poor/intermediate prognostic factors.Also allogenic/autologous transplant in those with relapse or 2nd remissionautologous with higher relapse rates. Used in those without HLA matched donor

TreatmentStandard therapy remission rates of 60-80% with median remission durations of 1 yrless than 20% achieve long-term remission free survivalTherapy is altered in older individuals (esp. those with poor performance status)AML believed to be a clinically/biologically distinct entity in older individuals remission rates of 45% in those > 60 yo with less than 10% long-term remission free survivallow dose cytarabine +/- hydroxyureainvestigational therapypalliative care

Survival in AMLJabbour EJ, Estery E, Kantarjian HM. Adult Acute Myeloid Leukemia. Mayo Clin Proc. 2006;81:247-260.

Treatment in Refractory or Relapsed AMLMost important predictive factor for outcome in relapsed/refractory AML = duration of 1st remissionRelapse is defined by >5% blasts in bone marrowSalvage therapy produces remission rates of 40-60% in pts with remission rates >1 yr, but only 10-15% in those with shorter remissionAllogenic transplant appears superior to cytarabine based chemotx in those with remission 60 yo with remission > 3 months

TreatmentSupportive careG-CSF platelet transfusionsPRBCs (leukodepleted, irradiated)Prophylactic antibioticsfluconazole (candidiasis)acyclovir (HSV, VZV)

Future Therapeutic TargetsSurface antigens using monoclonal antibodiesSignal transduction targeting (eg, FLT3, methylation, angiogenesis)Multidrug resistance reversing agentsGene expression profiling