Chapter 4: Acute Myeloid Leukemias (AML)

· AML with recurrent genetic abnormalities

· AML with multilineage dysplasia

· AML and MDS, therapy-related

· AML not otherwise categorized

· Acute leukemia of ambiguous lineage

AML with recurrent genetic abnormalities

· t(8;21)(q22;q22)(AML/ETO)

· inv(16) or t(16;16)(p13q22); (CBFβ/MYH11)

· t(15;17)(q22;q21)

· 11q23(MLL)

AML with multilineage dysplasia

· AML plus dysplasia

· Dysplasia: >50% of cells of 2 or more myeloid lines in a pre-treatment specimen

· May occur de novo or following MDS or MDS/MPD

· Mainly in elderly and rare in children

· Often severe pancytopenia

· Dysgranulopoiesis, dyserythropoiesis, dysmegakaryopoiesis

· Blasts positive for CD34 and pan-myeloid markers (CD13 and CD33)

· Frequently: aberrant expression of CD56 and CD7

· Increased incidence of multidrug resistance glycoprotein: MDR-1

· Genetics : similar to MDS

o Often: -7/del(7q), -5/del(5q), +8, +9, +11, del(11q), del(12p), -18, +19,
del(20q), +21

o Less often: t(2;11), t(1;7), 3q21 and 3q26

o t(3;21)(q21;q26): usually therapy related, or associated with CML as a 2^nd
event at blastic crisis

o t(3;5)(q25;q34) is associated with mutilineage dysplasia but no thrombocytosis

· Prognosis: multilineage dysplasia has adverse effect on remission

Therapy-Related AML/MDS

· After cytotoxic chemotherapy and/or radiation therapy

· Two types

o Alkylating agent and radiation therapy related

o Topoisomerase II inhibitor related

Alkylating Agent/Radiation Therapy Related AML/MDS

· Occur 5-6 years after initiation of treatment

· Range: 10-192 months

· Risk related to age and cumulative dosage

· Mutagenic effects of ionizing radiation and alkylating agents

· Two-thirds of cases present as MDS

· One-third of cases present as overt AML with MDS features

· All myeloid cell lines affected

· Dyserythropoiesis

· Ringed sideroblasts in 60% of cases (one-third in excess of 15% of erythroids)

· Hypogranulation and nuclear hypolobation in granulocytes

· Dysplastic megakaryocytes, increased in 25% of cases

· Basophils increased in 25% of cases

· Auer rods in a minority of cases

· Bone marrow biopsy: hypercellular in 50%, normocellular in 25%, hypocellular in 25%, fibrosis in 15%

· Types of AML: M2, M4, M5, M6, M7

· Immunophenotype

o Blasts often CD34+, CD33+, CD13+, frequent aberrant expression of CD56+ and CD7+

o Increased incidence of MDR-1 expression in blasts

· Genetics

o Increased cytogenetic abnormalities

o Similar to de novo MDS, RCMD, RAEB

o Unbalanced translocations

o Deletions of chromosomes 5 and 7 (long arms)

o Chromosomes 1, 4, 12, 14, 18

o Complex chromosomal abnormalities

· Prognosis: Poor response to therapy, poor survival

Topoisomerase II Inhibitor Related AML/MDS

· Epipodophyllotoxins and related compounds that target DNA-Topoisomerase II, examples etoposide and teniposide, also anthracyclines, such as doxorubicin and 4-epi-doxorubicin

· All ages

· Shorter latency: 12-130 months (median: 33-34 months)

· Latency can be less than 6 months

· Usually presents as overt AML without a previous MDS phase

· Significant monocytic component

· Most are acute monoblastic or myelomonocytic, occasionally acute promyelocytic leukemia or acute megakaryoblastic leukemia

· Bone marrow usually hypercellular

· Acute lymphoblastic leukemia also possible, usually associated with t(4;11)(q21;q23) chromosome abnormality

· Genetics:

o Usually balanced translocation involving 11q23 (MLL gene) and primarily t(9;11), t(11;19), and t(6;11)

o Others t(8;21), t(3;21), inv(16), t(8;16), and t(6;9)

o t(4;11)(q21;q23) (associated with ALL)

o t(15;17)(q22;p21) (APL)

· Prognosis: good initial response to therapy, but relapses frequent and survival variable (especially poor with 11q23)

AML not otherwise categorized

· Cases that do not fulfill criteria for inclusion in:

o AML with recurrent genetic abnormalities

o AML with multilineage dysplasia

o AML and MDS, therapy-related

· Basis for subclassification in this category

o Morphology

o Cytochemistry

o Degree of maturation

§ Defining criterion for AML is ³20% myeloblasts in PB or BM (differential for 500 cells in BM, or 200 leukocytes in PB). PB smear and BM aspirate provide the major criteria required for categorization. BM biopsy is for assessment of marrow cellularity in pre- and post-therapy, also for diagnosis of hypocellular acute leukemia cases and leukemia associated with fibrosis

§ Blast equivalents

· Promyelocytes in APL

· Promonocytes in AML with monocytic differentiation

o Megakaryoblasts

· Recommendations for classification are applicable only to specimens obtained prior to chemotherapy.

· Subtypes

o Acute myeloblastic leukemia, minimally differentiated (M0)

o Acute myeloblastic leukemia without maturation (M1)

o Acute myeloblastic leukemia with maturation (M2)

o Acute myelomonocytic leukemia (M4)

o Acute monoblastic leukemia (M5a) and Acute monocytic leukemia (M5b)

o Acute erythroid leukemia (M6)

o Acute megakaryoblastic leukemia (M7)

o Acute basophilic leukemia

o Acute panmyelosis with myelofibrosis

o Myeloid sarcoma

Acute myeloblastic leukemia, minimally differentiated (M0)

· Definition

o Acute leukemia with no evidence of myeloid differentiation by

§ Morphology, and Light microscopic cytochemistry

o Myeloid nature of blasts demonstrated by

§ Immunologic markers, and/or

§ Ultrastructural studies

o Immunophenotyping studies essential to rule out ALL

· Epidemiology

o 5% of cases of AML

o Mostly adults

· Clinical

o Present with marrow failure: anemia, neutropenia, thrombocytopenia

o May have leukocytosis with increased blasts

· Blasts

o Medium size

o Round or slightly indented nuclei

o Dispersed nuclear chromatin

o 1 or 2 nucleoli

o Agranular cytoplasm

o Myeloperoxidase (MPO): negative

o Sudan Black B (SBB): negative

o Naphthol ASD chloroacetate esterase: negative

o Alpha naphthyl butyrate esterase: negative or weak reactivity

· BM: markedly hypercellular with poorly differentiated blasts

· Ultrastructural studies: may demonstrate MPO activity

· Blast immunophenotype: positive for

o One or more pan-myeloid antigen

§ CD13, CD33, CD117 (all cases)

o Primitive hematopoietic associated antigens

§ CD34, CD38 and HLA-DR (most cases)

o TdT (1/3 of cases or more)

o Antigens associated with, but not specific for, lymphoid differentiation

§ CD7, CD2, CD19 (frequently)

· Blast immunophenotype: negative for

o B and T lymphoid restricted antibodies

§ cCD3, cC79a, and cCD22

o MPO often negative (may be positive in a few blasts)

o Antigens associated with myelomonocytic maturation

§ CD11b, CD15, CD14, CD65

· Genetics

o No unique abnormality

o Most common: complex karyotypes, +13, +8, +4, -7

· Prognosis is poor: lower remission rate, more frequent early relapse, shorter survival

Acute myeloblastic leukemia without maturation (M1)

· Definition

o Characterized by a high percentage of BM blasts without significant evidence of maturation to more mature neutrophils

o Blasts ³90% of non-erythroid cells

o The myeloid nature of blasts is demonstrated by: MPO or SBB positivity (>3%) and/or Auer rods

· Epidemiology

o 10% of cases of AML

o Adults (median age 46 y/o), but can occur at any age

· Clinical

o Present with marrow failure: anemia, neutropenia, thrombocytopenia

o May have leukocytosis with markedly increased blasts

· Blasts

o Typical myeloblasts with azurophilic granules, and /or Auer rods

o Lymphoblast-like with no granules

· MPO and SBB variably positive (but always positive in ³3% of blasts)

· BM

o Usually markedly hypercellular

o Blasts in BM sections may react with antibodies to MPO, Lysozyme, CD117, and/or CD34

· Differential diagnosis

o ALL, if

§ Blasts have no granules

§ Low percentage of MPO positivity

§ Resolution: TdT, MPO, SBB

o AML with maturation (M2), with a high percentage of blasts

§ Resolution: % promyelocytes and more mature neutrophils more than 10% of nucleated cells

o Acute monoblastic leukemia (M5a)

§ Resolution: NSE, MPO, SBB

o Acute megakaryoblastic leukemia (M7)

§ Resolution: CD41, CD61, MPO, SBB

· Blast immunophenotype: positive for

o Two or more myelomonocytic antigens (CD13, CD33, CD117) and/or

o MPO

o CD34

· Blast immunophenotype: negative for

o Markers associated with monocytic maturation

§ CD11b, CD14

o Lymphoid antigens

§ CD3, CD20, CD79a

· Genetics

o No specific chromosomal abnormalities

· Prognosis

o Aggressive course (particularly with hyperleukocytosis)

Acute Myeloblastic Leukemia with Maturation (M2)

· At least 20% blasts in bone marrow or blood (but less than 90%)

· Granulocytic elements (promyelocytes through PMNs) at least 10% of non-erythroid cells

Chapter 4: Acute Myeloid Leukemias (AML)

· AML with recurrent genetic abnormalities

· AML with multilineage dysplasia

· AML and MDS, therapy-related

· AML not otherwise categorized

· Acute leukemia of ambiguous lineage

AML with recurrent genetic abnormalities

· AML plus dysplasia

· Dysplasia: >50% of cells of 2 or more myeloid lines in a pre-treatment specimen

· May occur de novo or following MDS or MDS/MPD

· Mainly in elderly and rare in children

· Often severe pancytopenia

· Dysgranulopoiesis, dyserythropoiesis, dysmegakaryopoiesis

· Blasts positive for CD34 and pan-myeloid markers (CD13 and CD33)

· Frequently: aberrant expression of CD56 and CD7

· Increased incidence of multidrug resistance glycoprotein: MDR-1

o Often: -7/del(7q), -5/del(5q), +8, +9, +11, del(11q), del(12p), -18, +19, del(20q), +21

o Less often: t(2;11), t(1;7), 3q21 and 3q26

o t(3;21)(q21;q26): usually therapy related, or associated with CML as a 2nd event at blastic crisis

o t(3;5)(q25;q34) is associated with mutilineage dysplasia but no thrombocytosis

· Prognosis: multilineage dysplasia has adverse effect on remission

Therapy-Related AML/MDS

· After cytotoxic chemotherapy and/or radiation therapy

· Two types

o Alkylating agent and radiation therapy related

o Topoisomerase II inhibitor related

Alkylating Agent/Radiation Therapy Related AML/MDS

· Occur 5-6 years after initiation of treatment

· Range: 10-192 months

· Risk related to age and cumulative dosage

· Mutagenic effects of ionizing radiation and alkylating agents

· Two-thirds of cases present as MDS

· One-third of cases present as overt AML with MDS features

· All myeloid cell lines affected

· Dyserythropoiesis

· Ringed sideroblasts in 60% of cases (one-third in excess of 15% of erythroids)

· Hypogranulation and nuclear hypolobation in granulocytes

· Dysplastic megakaryocytes, increased in 25% of cases

· Basophils increased in 25% of cases

· Auer rods in a minority of cases

· Bone marrow biopsy: hypercellular in 50%, normocellular in 25%, hypocellular in 25%, fibrosis in 15%

· Types of AML: M2, M4, M5, M6, M7

· Immunophenotype

o Blasts often CD34+, CD33+, CD13+, frequent aberrant expression of CD56+ and CD7+

o Increased incidence of MDR-1 expression in blasts

· Genetics

o Increased cytogenetic abnormalities

o Similar to de novo MDS, RCMD, RAEB

o Unbalanced translocations

o Deletions of chromosomes 5 and 7 (long arms)

o Chromosomes 1, 4, 12, 14, 18

o Complex chromosomal abnormalities

· Prognosis: Poor response to therapy, poor survival

Topoisomerase II Inhibitor Related AML/MDS

· Epipodophyllotoxins and related compounds that target DNA-Topoisomerase II, examples etoposide and teniposide, also anthracyclines, such as doxorubicin and 4-epi-doxorubicin

· All ages

· Shorter latency: 12-130 months (median: 33-34 months)

· Latency can be less than 6 months

· Usually presents as overt AML without a previous MDS phase

· Significant monocytic component

· Most are acute monoblastic or myelomonocytic, occasionally acute promyelocytic leukemia or acute megakaryoblastic leukemia

· Bone marrow usually hypercellular

· Acute lymphoblastic leukemia also possible, usually associated with t(4;11)(q21;q23) chromosome abnormality

· Genetics:

o Usually balanced translocation involving 11q23 (MLL gene) and primarily t(9;11), t(11;19), and t(6;11)

o Others t(8;21), t(3;21), inv(16), t(8;16), and t(6;9)

o t(4;11)(q21;q23) (associated with ALL)

o t(15;17)(q22;p21) (APL)

· Prognosis: good initial response to therapy, but relapses frequent and survival variable (especially poor with 11q23)

AML not otherwise categorized

· Cases that do not fulfill criteria for inclusion in:

o AML with recurrent genetic abnormalities

o AML with multilineage dysplasia

o AML and MDS, therapy-related

· Basis for subclassification in this category

o Morphology

o Cytochemistry

o Degree of maturation

§ Blast equivalents

· Promyelocytes in APL

o Often: -7/del(7q), -5/del(5q), +8, +9, +11, del(11q), del(12p), -18, +19,
del(20q), +21

o t(3;21)(q21;q26): usually therapy related, or associated with CML as a 2^nd
event at blastic crisis