APPROACH TO MYELODYSPLASTIC SYNDROMES IN THE ERA OF PRECISION MEDICINE Rashmi Kanagal-Shamanna, MD Assistant Professor Hematopathology & Molecular Diagnostics Department of Hematopathology The University of Texas M.D. Anderson Cancer Center Houston, Texas
No relevant COIs to disclose
Definition ounexplained cytopenia(s) oineffective hematopoiesis odysplasia ohigh risk of AML transformation Age-specific incidence rates (SEER)
Components for MDS diagnosis: 2016 WHO 1. Cytopenia(s) 2. Dysplasia(s) At least 1 cell lineage 3. MDS-defining cytogenetic abnormality References: 2016 WHO; NCCN 2017
2016 WHO criteria for diagnosis of of MDS Components for MDS diagnosis: 2016 WHO 1. Cytopenia(s) Original IPSS (prognostication) cut-off values Hemoglobin <10 g/dl Absolute neutrophilic count < 1.8x10 9 /L Platelets <100x10 9 /L Often incidental during routine lab work References: 2016 WHO; NCCN 2017
Greenberg et al. Blood. 2016 Oct 20;128(16):2096-2097
Suggestions Diagnosis possible with milder cytopenias if other definitive diagnostic criteria present Use individual laboratory reference ranges Account for ethnic variation Greenberg et al. Blood. 2016 Oct 20;128(16):2096-2097
2016 WHO criteria for diagnosis of MDS 2016 WHO criteria for diagnosis of MDS 2. Dysplasia Morphologic hallmark At least 1 cell lineage(s) Degree: at least 10% of cells of any lineage Number of dysplastic lineages No distinction between different morphologies except RS% and blast% References: 2016 WHO; NCCN 2017
Objective evaluation of dysplasia
Erythroid lineage Morphological abnormalities Cutoff values Variable weighted score Megaloblastoid changes > 5% 2 Megaloblastosis Pyknosis Bi or multinuclearity > 3% 1 > 5% 2 Multinuclearity Cytoplasmic fraying Nuclear lobulation or irregular contours > 3% 1 Pyknosis > 5% 1 Cytoplasmic fraying 7% 1 Ring sideroblasts > 5% 2 15% 3 Ferritin sideroblasts 30% 1 Nuc. Lobulation Ring sideroblast
Granulocytic lineage Morphological abnormalities Cutoff values Variable weighted score Myeloblasts Abnormal nuclear shape Myeloblasts > 3% 1 > 5% 3 Auer rods Auer rods 1% 3 Pseudo Pelger Hüet anomaly > 3% 1 > 5% 2 Hypolobulated nuclei Hypogranulated cytoplasm Abnormal nuclear shape 7% 1 Neutrophil hypogranulation > 3% 1 > 5% 2
Megakaryocytic lineage Morphological abnormalities Cutoff values Variable weighted score Micromegakaryocytes Monolobated megakaryocytes Micromegakaryocytes > 5% 3 Small binucleated megakaryocytes Megakaryocytes with multiple separated nuclei > 5% 1 > 5% 2 Small binucleated Separated nuclear lobes Hypolobated or monolobar megakaryocytes > 5% 2
Della Porta scoring system Sensitivity and specificity >90% Acceptable reproducibility Independently validated Della Porta et al. Leukemia 2015, 29, 66-75
Standardization Not practical for routine work-up Certain abnormalities have more weight Difficult cases with ambiguous findings: Hypocellular MDS MDS with fibrosis
Erythroid Granulocytic Megakaryocytic # of lineages
Non-clonal conditions show dysplasia Nutritional deficiencies: Folate Vitamin B12 Copper (Zinc induced) Medications Sulfa drugs (PPH changes) Chemotherapy Growth factors Toxins Heavy metals (arsenic), alcohol Viral infections HIV, EBV, CMV, hepatitis B, parvovirus B19 Autoimmune diseases Lupus etc Congenital hematologic disorders Congenital dyserythropoietic anemia Familial predisposing conditions RUNX1 mutation Ankyrin mutation
Never diagnose MDS in the absence of Clinical history Drug history Family history Never sub-classify MDS in the absence of Drug history (G-CSF/ EPO)
3. Cytogenetics: Essential component of MDS work-up Diagnostic Identification of a malignant clone ~50% de novo MDS; ~90% t-mds Biological distinct entity: isolated del(5q) Prognostic stratification Basis for Rx selection Clues for molecular pathogenesis of MDS Nybakken & Bagg. Journal of Molecular Diagnostics, 2014; 16:145-158
MDS-related cytogenetic abnormalities Patients with unexplained cytopenia(s) without dysplasia Presumptive evidence of MDS -Y, trisomy 8 and del(20q) not disease defining
Cytogenetic Scoring System in MDS J Clin Oncol. 2012 Mar 10;30(8):820-9.
FISH in MDS FISH abnormal in only 2.7% of 222 cases with adequate cytogenetic studies Coleman et al. Am J Clin Pathol 2011;135:915-920 915 915. Jiang et al. Leuk Res. 2012 Apr;36(4):448-52. Seegmiller et al. Leukemia & Lymphoma 2014;55:601-605.
MDS sub-classification: WHO Updates
Updated WHO sub-classification is prognostic in lower-risk MDS Kanagal-Shamanna et al. Am J Hematol. 2017 Aug;92(8):E168-E171
MDS with ring sideroblasts 2017 WHO update <5% BM blasts Absent del(5q) 5% RS with SF3B1 mutation 15% RS without SF3B1 mutation MDS-RS-SLD MDS-RS-MLD Prussian blue stain Mufti et al. Haematologica 2008; 93(11)
SF3B1 mutations in MDS SF3B1 mutations in ~30% MDS MDS patients with ring sideroblasts associated with a high frequency of mutation (65%) Papaemmanuil, et al. NEJM 2011 Yoshida, et al. Nature 2011
SF3B1 mut MDS have better OS & lower risk of disease progression Malcovati, et al. Blood 2015
MDS with RS and MLD Kanagal-Shamanna et al. Am J Hematol. 2017 Aug;92(8)
2017 WHO update MDS with isolated del(5q) Allow 1 additional cytogenetic abnormality except monosomy 7 or del(7q) Exclude >5% blasts Mallo et al. Leukemia (2011) 25, 110 120
2017 WHO update MDS with isolated del(5q) Recommend testing for TP53 mutation or p53 IHC Identify patients with poor response to lenalidomide Jadersten et al. J Clin Oncol 29:1971-1979.
2017 WHO update MDS-unclassifiable 1. MDS-SLD with pancytopenia (<IPSS recommendation) 2. MDS with isolated del(5q) with pancytopenia (<IPSS recommendation) 3. 1% PB blasts (2 separate occasions) + <5% BM blasts 4. Normal morphology with MDS-defining cytogenetic abnormality
2017 WHO update MDS with erythroid predominance 2008 WHO: blast% of non-erythroid lineage if >50% erythroid precursors Small changes in blast count between MDS and AEL Questionable benefit in AEL from intensive chemotherapy Blast% as a total of all nucleated cells (MDS-EB) Pure erythroid leukemia remains in AML
Genomic landscape of MDS Papaemmanuil et al. Blood. 2013 Nov 21;122(22):3616-27 Bejar et al. N Engl J Med. 2011;364(26):2496-2506 Haferlach T et al. Leukemia. 2014; 28(2):241-247
Somatic gene mutations DNA methylation Chromatin modification Splicing factors Transcription factors Tyrosine kinase signaling Tumor suppressor TET2, DNMT3A, IDH1, IDH2 ASXL1, EZH2 SF3B1, SRSF2, U2AF1 RUNX1, ETV6 RAS TP53 Bejar et al. N Engl J Med. 2011;364(26):2496-2506 Papaemmanuil et al. Blood. 2013 Nov 21;122(22):3616-27 Haferlach T et al. Leukemia. 2014; 28(2):241-247
Type of gene mutation & outcome Bejar et al. N Engl J Med 2011; 364:2496-2506
Type of gene mutation & outcome Favorable outcome: SF3B1 Bejar et al. N Engl J Med 2011; 364:2496-2506
Number of gene mutations & outcome Papaemmanuil et al. Blood. 2013 Nov 21; 122(22): 3616 3627.
Single gene assays to NGS Evidence of clonality in appropriate clinical context Define homogeneous MDS subtypes Predictors of outcome Targeted therapy Follow-up Multiple genes Semi-quantitative Better detection ability for low-level mutations Clonal evolution
Importance of NGS test results from a CLIA-certified laboratory 1. Reliable results every time, reproducible 2. Clinically actionable 3. Rigorous validation 4. Regular basis 5. Complex data interpreted by pathologist or equivalent qualification Kanagal-Shamanna et al. Expert Rev Mol Diagn. 2016;16(4):461-72
Age-related clonal hematopoiesis Jaiswal S. N Engl J Med. 2014;371:2488 Genovese et al. N Engl J Med 2014;371:2477-87
CHIP as a precursor state for hematological neoplasms Steensma et al. Blood 2015;126:9-16 Sperling et al. Nat Rev Cancer. 2017 Jan;7(1):5-19.
Spectrum of Indolent Myeloid Hematopoietic Disorders Feature ICUS IDUS CHIP CCUS MDS Somatic mutation - - +/- +/- +/- Clonal karyotypic abnormality - - +/- +/- +/- Marrow dysplasia - + - - + Cytopenia + - - + + Greenberg PL, et al. J Natl Compr Canc Netw 2017;15(1):60 87
Diff mutation characteristics in MDS vs. IMHD ICUS (4x) >>> MDS (cytopenic patients) MDS (71%) vs. ICUS (28%; CCUS) 1.5 2.5 Kwok B, et al. Blood. 2015;126:2355-2361 Cargo et a. Blood. 2015;126(21):2362-2365
Nature volume 559, pages400 404 (2018)
Familial Predisposition to MDS/AML Rare Recognized more commonly Pediatric onset Adults (anticipation) Pathognomic characteristics Subtle or absent Genomic sequencing + awareness
2016 WHO: Myeloid neoplasms with germline predisposition
Implications for the clinical diagnostics team Recognized after MDS/AML diagnosis in the proband Routine work-up similar to sporadic cases Limited knowledge regarding morphologic (and genetic) changes in BM Complexity in morphologic and genetic interpretation Monitoring for progression to hematologic malignancy
Germline predisposition syndromes Important to recognize Can present de novo and in late adulthood Dysmegakaryopoiesis frequent!! Caution while making a diagnosis of MDS Implications for family members Confirm by testing cultured skin fibroblasts and functional assays Kanagal-Shamanna et al. Haematologica 2017 102(10):1661-1670 Tsang et al. Modern Pathology (2017) 30, 486 498
Diagnosis of MDS in germline predisposition syndromes Kanagal-Shamanna et al. Haematologica 2017 102(10):1661-1670
Summary WHO revisions incorporating genetic findings provide improved sub-classification that is also prognostic Integrated pathology report incorporating all ancillary findings including clinical NGS results Appropriate categorization of cases with clonal hematopoiesis High alert to recognize MDS arising in germline settings and initiate appropriate work-up Frequent dysmegakaryopoiesis: exert caution in diagnosis MDS
THANK YOU Rkanagal@mdanderson.org