WHO 2016 Myeloid and acute leukemia

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THE UPDATED WHO CLASSIFICATION OF HEMATOLOGICAL MALIGNANCIES The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia:

THE UPDATED WHO CLASSIFICATION OF HEMATOLOGICAL MALIGNANCIES The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia Dr. Hasmukh R. Balar Department of Haematology Sahyadri Speciality Hospital Pune Blood , 19 May 2016; Volume 127, number 20

Slide2:

This revision has been influenced by several factors : The discovery of recently identified molecular features has yielded new perspectives regarding diagnostic and prognostic markers 2. Improved characterization and standardization of morphological features aiding in the reliability and reproducibility of diagnosis. 3. A number of clinical-pathological studies have now validated the WHO postulate of an integrated approach that includes hematologic, morphologic, cytogenetic, and molecular genetic findings

Myeloproliferative neoplasms:

Myeloproliferative neoplasms Chronic myeloid leukemia (CML), BCR-ABL+ Chronic Neutrophilic leukemia (CNL) Polycythemia Vera (PV) Primary myelofibrosis (PMF) Essential thrombocythemia (ET) Chronic eosinophilic leukemia, not otherwise specified (NOS) MPN, unclassifiable Mastocytosis PMF, prefibrotic /early stage PMF, overt fibrotic stage

CML:

CML

CNL:

CNL Removed hepatosplenomegaly as criteria

PV:

PV 2016 2008

ET:

ET

Pre PMF / Overt PMF:

Pre PMF / Overt PMF

Mastocytosis:

Mastocytosis Considered as separate disease category. Shorting of “Systemic mastocytosis with associated clonal hematological non mast cell lineage disease” (SH-AHNMD) to systemic mastocytosis with an associated hematological neoplasm (SM-AHN).”

Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2:

Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2 Myeloid/lymphoid neoplasms with PDGFRA rearrangement Myeloid/lymphoid neoplasms with PDGFRB rearrangement Myeloid/lymphoid neoplasms with FGFR1 rearrangement . Provisional entity: Myeloid/lymphoid neoplasms with PCM1-JAK2

Why new entity Myeloid/lymphoid neoplasms with PCM1-JAK2 ?:

Why new entity Myeloid/lymphoid neoplasms with PCM1-JAK2 ? t(8;9)(p22;q24.1);PCM1-JAK2 with Combination of eosinophilia with BM findings of left-shifted erythroid predominance, lymphoid aggregates, and often myelofibrosis, at times mimicking PMF. It can also rarely present as T/B ALL Responds to JAK inhibition .

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN):

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) Chronic myelomonocytic leukemia (CMML) Atypical chronic myeloid leukemia (aCML), BCR-ABL- Juvenile myelomonocytic leukemia (JMML) . MDS/MPN, unclassifiable MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)

CMML:

CMML Due to the discovery of molecular and clinical differences between the so-called “P roliferative type” of CMML (WBC count>= 13X10’9/L) and the “Dysplastic type” (WBC <13X10’9/L), particularly those differences related to aberrancies in the RAS/MAPK signaling pathways Recent evidence has shown that a more precise prognostication can be obtained with 3 blast-based groupings: CMML-0, a category for cases with < 2% blasts in PB and <5% blasts in BM; CMML-1 for cases with 2% to 4% blasts in PB and/or 5% to 9% blasts in BM; and CMML-2 for cases with 5% to 19% blasts in PB, 10% to 19% in BM, and/or when any Auer rods are present

Atypical CML:

Atypical CML No changes in criteria Assess for CSF3R mutation (If positive strongly consider CNL)

Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis:

Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis Considered full entity under MDS/MPN The name RARS-T is changed to MDS/MPN-RS-T . MDS like MPN like Clinical Macrocytic anemia Transfusion requirement Thrombocytosis Need for cytoreduction Morphological Erythroid dysplasia Ring sideroblasts Large megakaryocytes with bulbous nuclei Genetic SF3B1 mutation (80-90%) JAK2 mutation (50-60%) Rarely CALR/MPL

Slide16:

Blood 2011 118:6239-6246; doi:10.1182/blood-2011-09-377275

Juvenile myelomonocytic leukemia:

Juvenile myelomonocytic leukemia

Myelodysplastic syndromes (MDS):

Myelodysplastic syndromes (MDS) MDS with single lineage dysplasia MDS with multilineage dysplasia MDS with ring sideroblasts (MDS-RS) MDS-RS and single lineage dysplasia MDS-RS and multilineage dysplasia MDS with isolated del(5q) MDS with excess blasts MDS –EB -1 MDS -EB- 2 MDS, unclassifiable Provisional entity: Refractory cytopenia of childhood 2016 2008 RCUD RCMD RARS RCMD-RS RAEB-1 RAEB-2

Why MDS nomenclature changed? :

Why MDS nomenclature changed? Classification relies mainly on the degree of dysplasia and blast % and specific cytopenias have only minor impact. The lineage's manifesting significant morphologic dysplasia frequently do not correlate with the specific cytopenias in individual MDS cases MDS has changed to remove terms such as “refractory anemia” and “refractory cytopenia” and replaces them with “myelodysplastic syndrome” followed by the appropriate modifiers: single vs multilineage dysplasia, ring sideroblasts, excess blasts, or the del(5q) cytogenetics abnormality

New handling of MDS with ring sideroblasts:

New handling of MDS with ring sideroblasts MDS with multilineage dysplasia and ring sideroblast will be reinstated (MLD-RS) MDS with SF3B1 mutation can be classified as SLD- RS/ MLD-RS if >5% ring sideroblasts are present Will not require >15% RS SF3B1 mutation will not affect MDS –EB or isolated del(5q)

Changes in MDS del(5q):

Changes in MDS del(5q) Allow one additional cytogenetic abnormality Excluding high risk abnormalities TP53 mutation study or p53 immunostain Exclusions >5% blasts in PB/BM Significant granulocytic dysplasia

When erythroid precursors comprise >=50% of BM nucleated cells:

When erythroid precursors comprise >=50% of BM nucleated cells In the updated classification, the denominator used for calculating blast percentage in all myeloid neoplasms is all nucleated BM cells, not just the “nonerythroid cells.” This will result in most cases previously diagnosed as the erythroid/myeloid subtype of acute erythroid leukemia now being classified as Myelodysplastic Syndrome with excess blasts

Myeloid neoplasms with germ line predisposition:

Myeloid neoplasms with germ line predisposition A major changes to the 2016 revision

Acute myeloid leukemia (AML) and related neoplasms:

Acute myeloid leukemia (AML) and related neoplasms

AML with recurrent genetic abnormalities:

AML with recurrent genetic abnormalities AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1 AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11 APL with PML-RARA AML with t(9;11)(p21.3;q23.3);MLLT3-KMT2A AML with t(6;9)(p23;q34.1);DEK-NUP214 AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM AML (megakaryoblastic) with t(1;22)(p13.3;q13.3);RBM15-MKL1 . AML with mutated NPM1 AML with biallelic mutations of CEBPA . Provisional entity: AML with BCR-ABL1 Provisional entity: AML with mutated RUNX1

Reason to include AML RUNX1 mutation as separate entity:

Reason to include AML RUNX1 mutation as separate entity Jason H. Mendler et al. JCO 2012;30:3109-3118

Reason for including “Biallelic” to CEBPA mutation:

Reason for including “ Biallelic ” to CEBPA mutation Kaplan-Meier curves for overall survival stratified by (A) CEBPA–wild-type (WT) or CEBPA-mutant status, (B) CEBPA-WT, CEBPA-single, or CEBPA-double mutant status Claire L. Green et al. JCO 2010;28:2739-2747 7-20% AML has CEBPA mutation 12-47% are monoallelic, rest biallelic

AML with myelodysplasia-related changes:

AML with myelodysplasia-related changes No prognostic significance of multilineage dysplasia (MLD), IF- No prior h/o Myelodysplastic Syndrome NPM1 or CEBPA dm positive Normal karyotype Classified under AML with NPM1 m / CEBPA dm Del9q is an MDS related entity only in the absence of NPM1 mutations NPM1 commonly associated with del9q and is likely not adverse in this setting If prior h/o MDS, MDS/MPN, MPN or tMDS/AML or cytogenetic abnormalities (other than del9q)- No survival benefit of NPM1 Considered as AML -MRC

Therapy-related myeloid neoplasms:

Therapy-related myeloid neoplasms No Changes

AML, NOS:

AML, NOS AML with minimal differentiation AML without maturation AML with maturation Acute myelomonocytic leukemia Acute monoblastic/monocytic leukemia Pure erythroid leukemia Acute megakaryoblastic leukemia Acute basophilic leukemia Acute panmyelosis with myelofibrosis

Myeloid sarcoma:

Myeloid sarcoma No changes

Myeloid proliferations related to Down syndrome:

Myeloid proliferations related to Down syndrome No changes.

Acute leukemias of ambiguous lineage:

Acute leukemias of ambiguous lineage Acute undifferentiated leukemia Mixed phenotype acute leukemia (MPAL) with t(9;22)(q34.1;q11.2); BCR-ABL1 MPAL with t(v;11q23.3); KMT2A rearranged MPAL, B/myeloid, NOS MPAL, T/myeloid, NOS Natural killer (NK) cell lymphoblastic leukemia/lymphoma

B-lymphoblasticleukemia/lymphoma:

B-lymphoblasticleukemia/lymphoma B-lymphoblastic leukemia/lymphoma, NOS B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2);BCR-ABL1 B-lymphoblastic leukemia/lymphoma with t(v;11q23.3);KMT2A rearranged B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1 B-lymphoblastic leukemia/lymphoma with hyperdiploidy B-lymphoblastic leukemia/lymphoma with hypodiploidy B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3) IL3-IGH B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3);TCF3-PBX1 . . Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21

T-Lymphoblastic leukemia/lymphoma:

T-Lymphoblastic leukemia/lymphoma . . Provisional entity: Early T-cell precursor lymphoblastic leukemia Provisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymphoma

Thank you:

Thank you This 2016 classification is not a major overhaul of the disease categories. Rather, it is intended to incorporate new knowledge of these disorders obtained since the 2008 publication and is a revision of that classification.

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B-ALL with intrachromosomal amplification of chromosome 21 Occurs in about 2% of children with Acute Lymphoblastic leukemia Especially older children Low WBC count Associated with an adverse prognosis B-ALL with translocations involving tyrosine kinases or cytokine receptors (“BCR-ABL1–like ALL”) association with an adverse prognosis responses of some cases to TKI therapies

Early T-precursor (ETP) ALL leukemia :

Early T-precursor (ETP) ALL leukemia Early T-cell differentiation, with retention of some myeloid and stem cell characteristics at both the immunophenotypic and genetic level By definition, blasts in ETP ALL express CD7 but lack CD1a andCD8, and are positive for 1 or more of the myeloid/stem cell markers CD34, CD117, HLADR, CD13, CD33, CD11b, or CD65. They typically also express CD2 and cytoplasmic CD3 and may express CD4, but these are not part of the definition. CD5 is often negative and when positive is present on 75% of the blast population; Initial small series of ETP ALL suggested that outcome was very poor, more recent larger series with more effective therapy showed either a small but statistically non significant difference in outcome, in the largest series to date, no prognostic significance