WHO Classification of Tumours of the Hematopoietic and Lymphoid Tissues, 4th Ed.

(with emphasis on the myeloid neoplasms)

J. Vardiman, University of Chicago, Chicago, IL

The WHO Classification, 4th Edition

Why classify?
Classification is the language of medicine: diseases must be described, defined and named before they can be diagnosed, treated and studied. Furthermore, a consensus on definitions and terminology is essential for both clinical practice and investigation.
N.L. Harris, et al. Introduction to the WHO classification of tumours of haematopoietic and lymphoid tissues, in WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, (Eds), IARC, Lyon

Discussion Outline
1. Background/Principles of the WHO Classification 2. Unique features of the 4th edition:
- Acknowledges the need for better minimal diagnostic criteria to distinguish reactive and/or pre-neoplastic lesions from early or overt neoplasms -Acknowledges some cases may have biologic features that overlap classification subgroups and thus will be difficult or impossible to classify into existing nomenclature

3. Controversial / confusing issues in the myeloid neoplasms:

- MPN, prefibrotic PMF vs. ET - Classification issues in MDS - New categories in AML and old categories redefined

The WHO Classification was a joint effort of the EAHP and the SH, sponsored by the WHO. The WHO and the Societies selected editors to propose a list of diseases; authors for the individual chapters were chosen for their expertise in various areas. All editors and authors volunteered their efforts.

Clinical Advisory Committees Lymphoid (top) and Myeloid (below)

Two clinical advisory committees one for lymphoid and one for myeloid neoplasms each comprised of ~50 internationally recognized clinicians/clinical scientists, met with the pathologists to discuss the merits of the proposed classification More than 150 pathologists, clinicians and scientists participated in the final writing of the 4th edition

Principles of the WHO Classification:

1) Utilizes all available information clinical findings, morphology, immunophenotype, and genetic features in an attempt to define disease entities of clinical significance; the relative importance of each feature may vary among different diseases 2) It is a consensus classification in which a majority of experts have agreed, not necessarily unanimously, to the criteria for the definition and classification of specific disease entities

CML a prototype for the integration of clinical, morphologic, and genetic data:
Disease -> chromosome-> genes-> pathways-> designed Rx
BCR-ABL fusion gene

imatinib
tyrosine kinase constitutive act.

But, mysteries still remain ..

Karyotype: 46 XX, t(9:22)(q34;q11.2), PCR: BCR-ABL1 fusion detected

Karyotype: 46 XX; PCR: BCR-ABL1 NOT DETECTED

Karyotype: 46 XX; PCR: BCR-ABL1 NOT DETECTED; JAK2 V617F DETECTED

Karyotype: 46 XX, t(9:22)(q34;q11.2), PCR: BCR-ABL1 fusion is present JAK2 V617F is present

Discussion Outline
1. Background/Principles of the WHO Classification 2. Unique features of the 4th edition:
- Acknowledges the need for better minimal diagnostic criteria to distinguish reactive and/or pre-neoplastic lesions from early or overt neoplasms; attempts to provide workable criteria for diagnosis and further study -Acknowledges some cases may have biologic features that overlap classification subgroups and thus will be difficult or impossible to classify into existing nomenclature; attempts to identify these gray zones such as B-cell lymphoma, unclassifiable with features intermediate between DLBCL and Burkitt or between DLBCL and classical HL

3. Controversial / confusing issues in the myeloid neoplasms:

- MPN, prefibrotic PMF vs. ET - Classification issues in MDS - New categories in AML and old categories redefined

. the frequent application of immunophenotypic and genetic studies to blood, bone marrow and lymph node samples often lead to the discovery of abnormalities where there is no clear cut evidence of disease at least of a neoplastic disease and the question arises whether these may be predisposing, pre-neoplastic, or early neoplastic lesions, or, be even inconsequential.

MGUS
-Approx. 3% of pts. >50 yrs. of age, 9% >85 yrs. -M component less than myeloma (<30 g/L) -Marrow plasmacytosis <10% -No lytic bone lesions -No myeloma-related symptoms -Plasma cells may have similar phenotype, genetic abnormalities as those with overt myeloma -~1% progress to overt myeloma / year -Risk factors favoring progression include higher M protein concentration, IgA M-protein, plasma cell mass, light chain proteinuria, serum free light-chain ratio -All cases of myeloma preceded by MGUS

ficolled specimen

WBC=6.8K/uL 69% lymphs 4.69 K/uL abs lymphs 45% of lymphs: CD19+,CD5+,CD23+,Lambda 2100 clonal B-lymphocytes/uL

Monoclonal B-cell lymphocytosis of undetermined significance (MBCL)

-3-12% of the population >40 years of age (an incidence more than 100 times the incidence of CLL in the general population) -Size of clone may range from <0.2-4.9 x 109/L -Same immunophenotypic/genetic abnormalities seen in CLL may be seen in MBCL, including ZAP70, CD38, (20%), and 17p-, 11q- (5%), but are of unknown prognostic significance -All patients with CLL have a preceding MBCL -Should some cases of MBCL be considered/ diagnosed as early CLL?
Shanafelt T, Hanson CA. Monoclonal B-cell lymphocytosis. Leukemia & Lymphoma 2009;50:493-497 Marti GE, Rawstron AC, Ghia P, et al. Diagnostic criteria for monclonal B-cell lymphocytosis. Br J Haematol 2005;130:325-332 Nieto WG, Almeida J, Romero A, et al. Increased frequency (12%) of circulating chronic lymphocytic leukemia like B-cell clones in healthy subjects. Blood 2009;114:33-37

Rossi D, et al. The prognosis of clinical monoclonal B cell lymphocytosis* differs from prognosis of Rai 0 chronic lymphocytic leukemia and is recapitulated by biological risk factors. British Journal of Hematology 2009;146:64-75
* Clinical monoclonal B cell lymphocytosis is diagnosed during evaluation of lymphocytosis, whereas low count monoclonal B lymphocytosis is found in patients with normal lymphocyte counts

WHO Definition of CLL/SLL

In the absence of extramedullary tissue involvement, there must be

> 5 x 109/L monoclonal B-lymphocytes* with a CLL phenotype in the peripheral blood to make the diagnosis of CLL. In such cases, the lymphocytosis should be present for at
least 3 months. The diagnosis of CLL may also be made with lower lymphocyte counts if there is cytopenia or disease-related symptoms. SLL is used for non-leukemic cases with the tissue morphology and immunophenotype of CLL; lymphadenopathy, no cytopenias due to BM infiltration by CLL/SLL, and <5 x 109/L. * Adapted from the recommendations of the Familial CLL consortium; Br J Haematol 2005;130:325-332

Genotypic and/or immunophenotypic findings of an entity but no clinical disease. Precursor or predisposing factor?
Monoclonal gammopathy of undetermined significance Monoclonal lymphocytosis of uncertain significance Isolated in situ follicular lymphoma
Normal lymphoid tissue with isolated follicles showing BCL2 expression, with or without evidence of lymphoma elsewhere. Significance as an isolated finding (no lymphoma elsewhere) remains uncertain.

BCL2

CD10

BCL2

CD10

Minimal Diagnostic Criteria for MDS

* Neutrophil granularity depends on optimal staining

34 yr. old woman with refractory anemia

CDA Type II

68 yr. old woman with refractory macrocytic anemia

60 year old man with pancytopenia: MDS or Aplastic Anemia?

Major questions at CAC meeting regarding MDS

1. Can minimal diagnostic criteria for MDS be better defined? 2. Some patients dont fit into previous WHO categories, e.g., patients with refractory thrombocytopenia. Can refinements be made to provide better correlation with specific clinical features? 3. Does there need to be a separate classification for childhood MDS?

MDS Minimal Diagnostic Criteria WHO 2001, 2008

The diagnosis of MDS is made when 10% or more of the cells of at least one myeloid lineage shows unequivocal morphologic dysplasia, and when all causes of secondary or transient dysplasia (nutritional deficiency, viral disorders, medication, growth factor therapy, copper deficiency, heavy metal poisoning, etc.) have been adequately excluded.

MDS-minimal criteria, 2008

In the presence of a persistent, refractory cytopenia but inconclusive diagnostic morphologic findings, the following cytogenetic abnormalities can be considered as presumptive evidence of MDS:
Unbalanced: -7 or del(7q) -5 or del (5q) i(17q) or t(17p) -13 or del(13q) del (11q) del(12p) or t(12p) del(9q) idic (X)(q13) Other: Complex abn (3 or more) Balanced: t(11;16)(q23;p13.3) t(3;21)(q26.2;q22.1) t(1;3)(p36.3;q21.2) t(1;22)(p21;q23) inv(3)(q21q26.2) t(6;9)(p23;q24)

Multiparameter flow cytometry in MDS

-Abnormal light scatter properties -Abnormal antigen density -Abnormal expression of non-myeloid antigens -Abnormal maturation pattern, with dyssynchronous/abnormal expression of antigens normally expressed during maturation

FCI Erythroid Abnormalities in MDS Stetler-Stevenson, M. et al. Blood 2001;98:979

SSC

Erythroid Gate

CD45

Normal

MDS

MDS

Gly A

Gly A

Gly A

CD71

CD71

CD71

MDS: Minimal Diagnostic Criteria, WHO 2008

FC results are highly suggestive of MDS if there are three or more aberrant features in erythroid, granulocytic or monocytic maturation. They are not sufficient, however, for the diagnosis of MDS. Cases with inconclusive morphologic and cytogenetic findings and three or more aberrant features by flow cytometry should be re-evaluated over several months for definitive morphologic or cytogenetic evidence of MDS.

68 yr. old woman with refractory macrocytic anemia

Idiopathic cytopenia of undetermined significance (ICUS)

-Is not a myelodysplastic classification category -May be used to describe patients with a refractory cytopenia of undetermined cause; follow-up in some cases may show sufficient evidence to classify them as MDS

Enumeration of Blasts in MDS

Pic of CD34 biopsy here
CD34

- Blast % should be determined from a visual 500 cell differential performed on cellular aspirate smears - CD34 by flow cytometry is not recommended as a substitute for visual inspection; not all blasts are CD34+ and the specimen for flow may be hemodilute - CD34 by IHC on bone marrow biopsy may be helpful when the aspirate is hemodilute or cannot be obtained

Discussion Outline
1. Background/Principles of the WHO Classification 2. Unique features of the 4th edition:
predisposing or pre-neoplastic lesions from truly neoplastic disorders; attempts to establish workable criteria for classification and further evaluation of such lesions - Acknowledges that in some cases there may be morphologic and biologic overlap between subgroups, and attempts to identify these gray zones in classification, e.g., Burkitt vs. DLBCL, Classical HL vs. DLBCL

- Acknowledges difficulties in distinguishing some

3. Controversial / confusing issues in the myeloid neoplasms:

- MPN, prefibrotic PMF vs. ET - Classification issues in MDS - New categories in AML and old categories redefined

WHO Classification of Myeloid Neoplasms

I. Myeloproliferative Neoplasms* II. Myeloid/Lymphoid Neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1** III. Myelodysplastic / Myeloproliferative Neoplasms* IV. Myelodysplastic Syndromes V. Acute myeloid Leukemia
* Name change * * New category

Myeloproliferative Neoplasms
Chronic myelogenous leukemia, BCR-ABL1 positive Chronic neutrophilic leukemia Polycythemia vera* Primary myelofibrosis* Essential thrombocythemia* Chronic eosinophilic leukemia, not otherwise specified* Mastocytosis* Myeloproliferative neoplasm, unclassifiable
* name change, new addition and/or change in diagnostic criteria

Changes in the Criteria for Diagnosis and Classification of the MPN influenced by:
1) Acquired somatic gene mutations and rearrangements that encode abnormal tyrosine kinases involved in the pathogenesis of MPN can also be used as diagnostic markers 2) Relatively recent appreciation that histologic features in the bone marrow biopsy often correlate with clinical features and outcome in MPN, particularly PV, ET and PMF, and can be used as diagnostic criteria in conjunction with other clinical and laboratory parameters

Any of these abnormalities identifies the case as neoplastic

JAK2 V617F
1. How does one mutation lead to three different diseases? A. Mutated JAK2 is the sole event and the phenotype depends on Genetic background of the patient Level of JAK2 V617F allele burden B. Mutated JAK2 is a secondary event to an earlier genetic defect that predisposes to the mutation and determines the phenotype C. Any of, all of, or none of the above

Genetic background of the patient determines the phenotype

1. PV is more common in men, ET is more common in women 2. Analysis of single nucleotide polymorphisms in JAK2, MPL, EPOR and G-CSFR showed specific SNPS in germline JAK2 and EPOR that were associated with either PV or ET 3. Families with a predilection to develop MPN acquire the JAK2 V617F as a somatic mutation, indicating an inherited predilection for the disease; in some families only PV, ET or PMF occurs, but in others all diseases are represented.

Dosage of JAK2 V617F determines the phenotype

1. Homozygosity of JAK2 V617F is found in ~30% of PV, ~5% of ET, and ~15% of PMF patients 2. Transgenic models with low JAK2 V617F expression leads to thrombocytosis, and ET-like phenotype; not PV 3. Analysis of erythroid colonies from patients with PV always shows homozygous cells regardless of allele burden of patient; analysis of ET patients almost never shows homozygous cells Sooooo maybe PV, ET and PMF are a single disease process, and the phenotype just depends on the gene dosage?

The JAK 2 mutation is a secondary event, and an unknown pre-JAK2 lesion determines the phenotype
1. Discrepancy between clonal vs. JAK2 mutated cells; by Xinactivation studies a number of women have been shown to have 100% clonal granulopoiesis, but to have a JAK2 V617F / JAK2 less than 25% in the granulocytes 2. Commonly, in patients with mutated JAK2 who develop blast transformation, the acute phase blasts lack the mutation

TET2 mutations?

JAK2 V617F
1. How does one mutation lead to three different diseases? A. Mutated JAK2 is the sole event and the phenotype depends on Genetic background of the patient Level of JAK2 V617F allele burden B. Mutated JAK2 is a secondary event to an earlier genetic defect that predisposes to the mutation and determines the phenotype C. Any of, all of, or none of the above

Any of these abnormalities identifies the case as neoplastic

Pertinent Histopathologic Findings in MPN

Lineages involved in the proliferation Maturation pattern within the lineages Megakaryocyte topography Megakaryocyte cytology Reticulin/Collagen Fibrosis correlate with other clinical and laboratory findings and with disease progression

Polycythemia vera, (polycythemic stage)

-Panmyelosis

-Megakaryocytes of variable sizes, lacking significant cytologic dysplasia, often loosely clustered

PV

Panmyelosis in a patient with polycythemia vera

Fibrotic phase, PMF

Primary myelofibrosis, Prefibrotic phase

Essential thrombocythemia
- Variably cellular bone marrow, often normally cellular -Increased numbers of large megakaryocytes with hyperlobulated nuclei, minimal granulocytic or erythroid proliferation

Revised WHO criteria for PV

1. Hemoglobin > 18.5 g/dL in men, >16.5 g/dL in women or other evidence of increased red cell volume/mass* 2. JAK2 V617F or other functionally similar JAK2 mutation
MINOR CRITERIA: 1. Bone marrow biopsy hypercellular for age with panmyelosis 2. Low serum EPO
3. Endogenous erythroid colony formation in vitro Diagnosis requires: or Major criteria 1 & 2 plus one minor criterion, Major criterion 1 plus two minor criteria

MAJOR CRITERIA:

*Hb or Hct >99th percentile of method specific reference range for age, sex, altitude of residence, red cell mass >25% above normal predicted mean value,

If you suspect PV: Hb >18.5 g/dL (M), >16.5g/dL (F) Peripheral Blood Mutation screening for JAK2 V617F & Serum EPO measurement

V617F (+) EPO Decr

V617F (+) EPO Nl or Inc

V617F (-) EPO Decr

V617F (-) EPO Nl or Inc

PV highly likely

PV likely

PV possible

PV unlikely

JAK2 exon 12 screen, Bm Bx Bm Bx encouraged, not essential Bm Bx recommended to confirm If not c/w PV, ? congenital PV EpoR mutation Consider secondary PV

Revised WHO criteria for ET

1. Sustained platelet count 450 x 109/L 2. Bone marrow biopsy showing proliferation of enlarged, mature megakaryocytes; no significant granulocytic or erythroid proliferation 3. Not meeting WHO criteria for PV, PMF, CML, BCR-ABL1+, or MDS 4. Demonstration of JAK2 V617F or similar activating mutation, or demonstration that the thrombocytosis is not reactive All 4 criteria must be met

Revised WHO criteria for PMF

Major criteria: 1. Not meeting WHO criteria for PV, CML, MDS, or other MPN 2. Megakaryocyte proliferation/ atypia accompanied by reticulin and/or collagen fibrosis, or in absence of fibrosis, atypical megakaryocyte proliferation and marrow hypercellularity with granulocytic proliferation 3. Demonstration of JAK2 V617F, or that bone marrow fibrosis is not secondary to infection, autoimmune disorder or other chronic inflammatory condition, lymphoproliferative disorder, metastatic cancer, or toxic myelopathy Minor criteria 1. Leukoerythroblastosis 3. Increase in LDH 2. Anemia 4. Palpable splenomegaly Diagnosis requires meeting all 3 major and 2 minor criteria

Primary myelofibrosis, Prefibrotic phase

Comparison of classification of cases of ET according to PVSG vs WHO Criteria for MPDs

Theile J, Kvasnicka HM Ann Hematol 2003;82:148

WHO Criteria PVSG Criteria 483 pts PMF, Prefibrotic* = 321 (66.5) *grade 0 or 1 reticulin fibrosis ET=162 (33.55)

Survival in early MPNs with thrombocythemia

100

80

ET PMF-0

% Survival

60

PMF-1
40 Relative survival according to WHO (%) 5 yrs. 10 yrs. 15 yrs. ET 100.0 4.4 99.1 7.8 83.9 17.6 PMF-0 92.1 7.1 80.8 11.7 67.9 23.7 PMF-1 83.0 9.5 67.3 17.8 55.4 29.8 0 2 4 6 8 10 Years after diagnosis 12

20

n=476
14

- Evaluated 370 patients with ET diagnosed according to PVSG criteria -Three experienced observers used the WHO criteria for diagnosis of ET and pre-fibrotic PMF -The diagnoses were not reproducible among the three observers -Concluded that WHO histologic criteria are difficult to apply, and they found no survival differences between ET and PMF, indicating there is no validity to the distinction of ET from pre-fibrotic PMF with thrombocythemia the WHO criteria are not reproducible - Of note is that nearly 25% of the patients in the study diagnosed as ET by PVSG guidelines had 3+ to 4+ fibrosis (scale 1-4); some had osteosclerosis* Blood 2008;111:60-70 *Campbell P, et al. J Clin Oncol 2009;27:2991-2119

ET:

PMF:

Representative fields from 10 of 145 cases of MPN evaluated independently by four observers (JT, AO, CH, JV) and classified at ET or pre-fibrotic PMF Observer reproducibility on these 10 cases was 100%, with observer reproducibility of about 80-85% of all cases

Myeloid/lymphoid neoplasms with eosinophilia

Abnormalities of: PDGFRA, PDGFRB, or FGFR1

1. All result from formation of a fusion gene encoding an abnormal tyrosine kinase, usually but not invariably with > 1500 eos/uL. 2. Cases with rearranged PDGFRA usually present as CEL, often with mast cell proliferation as well; rare cases present as T-LBL with eosinophilia 3. Cases with rearranged PDGFRB have features of CMML with eosinophilia or CEL 4. Patients with rearranged PDGFRA or PDGFRB respond to imatinib 5. Cases with FGFR1 rearrangements may present as CEL (8p11 myeloproliferative syndrome) but presentation as T- or B-lymphoblastic leukemia/lymphoma with eosinophilia is also common 6. Their similarities yet variable clinical and morphologic presentations argued for their placement in a separate and unique subgroup

Summary of changes in MPN

1. Name change from MPD to MPN 2. Mastocytosis included in the MPN category 3. Cases previously diagnosed as CEL may be diagnosed in the category Myeloid/Lymphoid Neoplasm with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1when these specific abnormalities are present and when not present, in the MPN category CEL, NOS 4. Diagnostic algorithms of PV, ET and PMF now incorporate information about mutated JAK2 and similar activating mutations as well as pertinent histologic features 5. The threshold for platelet count for ET has been lowered to 450 x 109/L

Major questions at CAC meeting regarding MDS

1. Can minimal diagnostic criteria for MDS be better defined? 2. Some patients dont fit into previous WHO categories, e.g., patients with refractory thrombocytopenia. Can refinements be made to provide better correlation with specific clinical features? 3. Does there need to be a separate classification for childhood MDS?

Myelodysplastic Syndromes
Refractory cytopenia with unilineage dysplasia (RCUD) Refractory anemia Refractory neutropenia Refractory thrombocytopenia Refractory anemia with ring sideroblasts Refractory cytopenia with multilineage dysplasia Refractory anemia with excess blasts Refractory anemia with excess blasts-1* Refractory anemia with excess blasts-2 Myelodysplastic syndrome with isolated del (5q) Childhood myelodysplastic syndrome Provisional entity: Refractory cytopenia of childhood * Change in criteria

Provisional entity: Refractory cytopenia of childhood (RCC)

Rationale: Isolated refractory anemia is very uncommon in children, most kids will present with neutropenia and/or thrombocytopenia, with/without anemia. RARS is virtually never seen in children In contrast to adult MDS, most children with RCC usually have hypocellular bone marrow RCC: Evidence of multilineage dysplasia required Blasts <2% in blood, Blasts <5% in marrow Children with 2% or more blasts in blood and/or 5% or more in marrow classified as adult MDS

Read the classification guidelines for MDS carefully !!

A case of RCUD may have bicytopenia despite unilineage dysplasia, but if there is pancytopenia, the dx is MDS, U Cases of RCUD and RCMD have <1% blasts (200 cell count) in blood; if 1%, the dx is MDS, U Cases with <5% blasts in the marrow but 2-4% in the blood are classified as RAEB-1 Cases with Auer rods and <5% blasts in the blood and <10% in the bone marrow are RAEB-2

Summary of major changes in MDS

1. Patients who lack convincing morphologic evidence of dysplasia but who have specific MDS-related cytogenetic abnormalities should be considered as having presumptive evidence of MDS 2. Refractory neutropenia and refractory thrombocytopenia are added, along with refractory anemia, to the group of Refractory cytopenia with unilineage dysplasia category 3. Patients with <5% blasts in their bone marrow but 2% or more in the blood can be diagnosed as refractory anemia with excess blasts-1 if other findings of dysplasia are present. 4. A provisional entity, Refractory cytopenia of childhood, has been added; its distinction from aplastic anemia can be difficult

Acute Myeloid Leukemia and Related Precursor Neoplasms, WHO 2008

Acute myeloid leukemia with recurrent genetic abnormalities Acute myeloid leukemia with myelodysplasia-related changes Therapy-related myeloid neoplasms Acute myeloid leukemia, not otherwise specified Myeloid sarcoma Myeloid proliferations related to Down Syndrome Blastic plasmacytoid dendritic cell neoplasm

WHO, 2001 AML with recurrent genetic abnormalities

AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 AML with inv(16)(p13.1q22) or t(16;16)(p13.1q22); CBFB-MYH11 APL with t(15;17)(q22;q12); PML-RARA AML with 11q23 abnormalities; MLL

AML with recurrent genetic abnormalities

AML with t(8;21)(q22;q22); RUNX1-RUNX1T1** AML with inv(16)(p13.1q22) or t(16;16)(p13.1q22); CBFB-MYH11** APL with t(15;17)(q22;q12); PML-RARA** AML with t(9;11)((p22q23); MLLT3-MLL AML (megakaryoblastic) with t(1;22)(p13;q13); RBV15-MKL1 AML with t(6;9)(p23;q34); DEK-NUP214 AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN-EVI1 Provisional entities: AML with mutated NPM1 AML with mutated CEBPA
** Diagnosed as AML, regardless of blast count; others require >20% blasts

Class I Mutations

Class II Mutations

proliferation and/or survival advantage; not affecting differentiation

AML

impaired hematopoietic differentiation and subsequent apoptosis

Gilliland and Griffin, Blood 100:1532, 2002 (modified by H. Dohner)

Prognostic significance of mutations in cytogenetically normal AML

Genetic alteration Favorable: NPM1 mutation CEBPA mutation Unfavorable: FLT3-ITD mutation MLL-PTD mutation WT1 mutation *NPM1+FLT3 ITD ~32% ~7% ~10% ~40% of mutated NPM1 ~24% ~25% ~10-25% 25% ~50% ~15% ~60%* ~62% Incidence 4-yr survival

Schlenk, et al. New Engl J Med 2008:358:1909

AML with myelodysplasia-related features

Ref

-Diagnose when >20% blasts and myelodysplasia-related cytogenetic abnormalities are present -Diagnose when >20% blasts are present and there is a history of a preceding myelodysplastic syndrome -Diagnose when >20% blasts are present and >50% of two or more myeloid lineages are dysplastic
Figure: Wandt H, et al. Blood 2008;111:1855