Myelodysplastic syndromes

Transcription

1 Myelodysplastic syndromes Robert P Hasserjian Massachusetts General Hospital, Boston, MA

2 Disclosure of Relevant Financial Relationships Dr. Hasserjian declares he has no conflict(s) of interest to disclose.

3 Outline of presentation Review criteria required to establish a diagnosis of MDS according to the 2016 WHO Classification Review the WHO MDS disease categories Distinguishing features of each disease entity Challenges and pitfalls in the diagnosis of each entity

4 Myelodysplastic syndromes (MDS) Clonal hematopoietic stem cell neoplasms with ineffective hematopoiesis and intact maturation Peripheral blood cytopenias Morphologic dysplasia of hematopoietic elements Varying propensity to develop maturation arrest in hematopoietic cells, with accumulation of blasts and progression to AML Cutoff of 20% blasts in bone marrow or blood distinguishes MDS from AML

5 Low-grade MDS High-grade MDS

6 Challenges across the biologic spectrum of MDS Low-grade High-grade Non-neoplastic causes of cytopenia --Other neoplasms --Inherited --Extrinsic factors MDS 20% blasts AML Does the patient have a neoplasm? Should the patient be treated for MDS or should another diagnosis be sought? Risk-adapted therapy according to prognosis WHO subtype IPSS-R Molecular genetics Should the patient receive induction or other intensive chemotherapy with a goal of remission?

7 Components of MDS diagnosis and classification Unexplained cytopenias are a sine qua non of MDS 90% of MDS cases have a demonstrable clonal genetic abnormality Dysplasia Dysplasia is defining feature of MDS

8 Pathologists responsibility in evaluating cytopenias in a potential MDS case Know the complete CBC results (including WBC differential) at the time of the bone marrow sample Access key clinical information to provide guidance in interpreting the CBC values Duration of cytopenia Possible comorbid conditions that may be causing the cytopenia Possible causes of cytopenia that have not yet been clinically excluded

9 Dysplasia assessment WHO threshold: at least 10% of cells in any lineage must manifest dysplastic morphology to call that lineage dysplastic No distinction between different types of dysplastic morphologies Dysplasia is not always reproducible Dysplasia is not specific for MDS Significant dysplasia can be seen in bone marrow of normal volunteers and even more frequently in patients with non-neoplastic cytopenias Font P Ann Hematol 2013;92:19, Parmentier S Haematologica 2012;97:723, Matsuda A Leukemia 2007;21;678; Della Porta MG Leukemia 2014;29:66

10 Autoimmune hemolytic anemia Post-chemotherapy recovery

11 Tang G Let al. Leuk Res. 2012;36:974-81, Kern W et al. Haematologica 2013;98:201-7, Malcovati L et al. Blood 2013;122: , Porwit A et al. Leukemia 2014;28:1793 MDS Normal Flow cytometry assessment of MDS Abnormal flow cytometry patterns predict MDS with good sensitivity and specificity WHO 2016 and ELN guidelines do not permit a diagnosis of MDS solely based on flow cytometry Considered supportive of a diagnosis More data needed on findings in reactive conditions Flow is important to evaluate for lymphomas that can present with cytopenia mimicking MDS MACKEY JR BML_ fcs Clean blast 01 CD34 PerCP-Cy5-5-A % CD7 FITC-A MOORE BML_ fcs Clean blast 01 CD34 PerCP-Cy5-5-A Abnormalities in blasts % CD7 FITC-A MACKEY JR BML_ b f c CD13 APC-A Granulocy tes CD16 FITC-A MOORE BML_ b f cs CD13 APC-A Abnormalities in maturing elements Granulocy tes CD16 FITC-A Courtesy of Dr S Wang, MD Anderson Cancer Center

12 MDS-defining cytogenetic abnormalities Unbalanced Primary MDS Therapy-related MDS -7 or del(7q) 10% 50% del(5q) to t(5q) 10% 40% i(17q) or t(17p) 3-5% -13 or del(13q) 3% del(11q) 3% del(12p) or t(12p) 3% del(9q) 1-2% idic(x)(q13) 1-2% Balanced t(11;16)(q23;p13.3) 3% t(3;21)(q26.2;q22.1) 2% t(1;3)(p36.3;q21.2) 1% t(2;11)(p21;q23) 1% inv(3)(q21q26.2) 1% t(6;9)(p23;q34) 1% ~50% of MDS have a normal karyotype +8, -Y, and del(20q) are common in MDS, but can occur in non-neoplastic conditions and are not MDS-defining

13 Papaemmanuil E Blood. 2013;122:3616 Somatic mutations in MDS Some genetic abnormality is present in ~90% of MDS cases Similar mutations also occur in healthy older individuals (CHIP) CHIP appears to be a precursor state for MDS Many patients with CHIP never progress to MDS or a myeloid neoplasm Analogous to MGUS or monoclonal B-cell lymphocytosis

14 CHIP and anemia are frequent in elderly individuals, while MDS is rare Incidence of MDS per 100,000 <0.1% Frequency of CHIP 10-15% Frequency of anemia 12-25% Age at identification of CHIP (years) Mutant allele fraction 10% and spliceosome gene mutation or TET2, DNMT3A or ASXL1 mutation with at least one other mutation may be more indicative of an MDS-like disease Ma X Am J Medicine 2012; 125: S2, Rollison DE Blood 2008;112:45-52, Jaiswal S NEJM 2014; 371:2488, Steensma D Blood 2015; 126:9, Tettamanti M et al. Haematologica 2010;95:1849; Malcovati L et al. Blood 2017;129:3371

15 10,000 stem cells Clonal hematopoiesis High-risk clonal hematopoiesis Dysplastic hematopoiesis?? MDS

16 What is sufficient to diagnose MDS according to WHO 2016? Observation Dysplastic morphology ( 10%) Excess marrow blasts ( 5%) Sufficient to diagnose MDS in a cytopenic patient? Yes, provided possible secondary causes of cytopenia and dysplasia are excluded clinically Yes, provided marrow recovery or growth factor effect are excluded Cytogenetic abnormality Flow cytometry abnormality Yes, provided it is on the WHO list of approved abnormalities (excluding +8, -Y, del20q) No, but can support an MDS diagnosis suspected by other observations MDS-type mutation No, these can be found in normal individuals ( clonal hematopoiesis of indeterminate potential ); may support an MDS diagnosis suspected by other observations

17 Establishing a primary diagnosis of MDS remains a balancing act Morphologic dysplasia Lineages involved Number of dysplastic forms Severity of dysplasia Severity and persistence of cytopenia(s) Unexplained MCV Flow cytometry abnormalities MDS-type mutations Younger patients Co-morbid conditions Paucity of clinical history

18 2016 MDS with single lineage dysplasia (MDS-SLD) MDS with multilineage dysplasia (MDS-MLD) MDS with ring sideroblasts MDS-RS with single lineage dysplasia (MDS-RS-SLD) MDS-RS with multilineage dysplasia (MDS-RS-MLD) MDS with isolated del(5q) MDS, unclassifiable (MDS-U) MDS with excess blasts (MDS-EB) Refractory cytopenia of childhood (RCC)(provisional) MDS WHO classification 2008 Refractory cytopenia with unilineage dysplasia (RCUD) Refractory cytopenia with multilineage dysplasia (RCMD) Refractory anemia with ring sideroblasts (RARS) Refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS) MDS with isolated del(5q) MDS, unclassifiable (MDS-U) Refractory anemia with excess blasts (RAEB) Refractory cytopenia of childhood (RCC)(provisional)

19 MDS with single lineage dysplasia (MDS-SLD) Mildest form of MDS: median OS 66 months 1-2 cytopenias (usually macrocytic anemia), <1% PB and <5% BM blasts 1 lineage with 10% dysplastic cells <15% RS (<5% RS if SF3B1 mutated) Germing U et al. Leuk Res 2012;36:727, Maassen A et al. Leuk Res 2013;37:64 CHALLENGES Distinction from non-mds causes of cytopenia, especially reactive conditions If isolated neutropenia, consider hairy cell or LGL leukemia If isolated thrombocytopenia, consider ITP Dysplastic lineage is frequently different from the cytopenic lineage!

20 MDS with multilineage dysplasia (MDS-MLD) Lee JH et al. Leukemia 2003;17:305, Howe RB et al. Blood 2004;103:3255. Median OS 36 months, worse than MDS-SLD 1-3 cytopenias, <1% PB and <5% BM blasts 2-3 lineages with 10% dysplastic cells <15% RS (<5% RS if SF3B1 mutated) CHALLENGES Some reactive conditions may cause dysplasia in 2 lineages Iron stain needed to exclude MDS-RS-MLD Carefully examine blood smear and bone marrow for excess blasts Remember to exclude CMML (PB monocytes)

21 MDS with ring sideroblasts (MDS-RS) <1% PB blasts and <5% BM blasts 1-3 lineages with 10% dysplastic cells Divided into MDS-RS-SLD and MDS-RS-MLD 15% RS or 5% RS if SF3B1 mutated Germing U et al. Haematologica 2006;91:1596, Malcovati L et al. Blood 2015;126:233 CHALLENGES Keep in mind secondary causes of RS Alcohol, drugs, hereditary Iron stain should be done on an aspirate smear Insensitive in decalcified trephine biopsy By definition, if 15% RS are present, the erythroid lineage is dysplastic

22 MDS with ring sideroblasts: strong association with SF3B1 mutation RNA splicing factor Mutated in 70-80% of MDS with >15% ring sideroblasts Very rare in MDS lacking ring sideroblasts Appears to be an early founding mutation Associated with longer survival in MDS patients IPSS lower risk MDS patients Papaemmanuil E et al. NEJM 2011;365:1384, Patniak et al. MM Blood 2012;119:5674, Bejar R et al. JCO 2012;30:3376, Malcovati L et al. Blood 2011;118:6239, Malcovati L et al. Blood 2015;126:233, Woll PS et al. Cancer Cell 2014;25:794

23 MDS with isolated del(5q) Favorable prognosis (median OS >66 months) and good response to lenalidomide 1-2 cytopenias (usually macrocytic anemia) Often thrombocytosis <1% PB and <5% BM blasts 1 lineage with 10% dysplastic cells (usually megakaryocytes) Del(5q) alone or with 1 other abnormality (except -7 or del7q) CHALLENGES MPN and MDS/MPN may also have isolated del(5q) and thrombocytosis

24 Navigating the diagnosis of MDS with isolated del(5q) Dysmegakaryopoiesis, 1-2 cytopenias, and del(5q) Low or high platelets One additional cytogenetic abnormality, except -7 or del(7q) Ring sideroblasts or SF3B1 mutation JAK2 mutation Granulocytic dysplasia TP53 mutation Poorer prognosis Pancytopenia 1% PB or 5% BM blasts -7, del(7q), or 2 other cytogenetic abnormalities Another diagnosis

25 MDS with excess blasts (MDS-EB) 5% BM or 2% PB blasts or Auer rods Increased blasts are a strong and independent indicator of aggressive behavior in MDS CHALLENGES Increased PB blasts can upstage patients to MDS-EB1 or MDS-EB2 Do NOT calculate a non-erythroid blast % Do NOT use flow cytometry blast % Beware early AML with PML-RARA, t(8;21) or inv(16)/t(16;16) Low-grade MDS MDS-EB1 MDS-EB2 Malcovati L et al. Blood 2014;124:1513, Greenberg PL et al. Blood 2012;120:2454

26 CD34 Aspirate blast count is gold standard However, CD34 immunostaining of biopsy is critical to perform if the aspirate is compromised and may also be helpful even if the aspirate is adequate Valent P et al. Oncotarget 2010;1:483

27 MDS, unclassifiable (MDS-U): diseases on the fence between other entities Pancytopenia, but only one dysplastic lineage MDS-SLD or MDS-MLD? Clonal cytogenetic abnormality, but no dysplasia CHIP or MDS? 1% blood blasts, but <5% marrow blasts MDS-SLD/MLD or MDS-EB? Margolskee E et al. AJCP 2017;138:49, Knipp S et al. Leuk Res 2008;32:33

28 Special situations in MDS Hypoplastic MDS About 10% of cases Differential diagnosis with aplastic anemia; CD34 and CD61 stains MDS with fibrosis (MF2-3) 10-15% of cases; poorer prognosis Differential diagnosis with MPN and MDS/MPN Megakaryocyte morphology is critical; mutations also helpful CD34 helpful in disclosing cases with increased blasts MDS-MLD with fibrosis Orazi A AJCP 1997;107:268, Yue G Leuk Res 2008;32:553, Della Porta MG Leukemia 2015;29:66, Fu B Mod Pathol 2014;27:681

29 Erythroid-rich MDS >50% erythroids elements 10-15% of MDS cases Acute erythroid leukemia no longer diagnosed, even if blasts are >20% of the nonerythroids Consider pure erythroid leukemia (PEL) if large sheets of erythroids Almost all PEL cases have complex karyotype and TP53 mutation Wang SA and Hasserjian RP AJCP 2015;144:44 Erythroid-rich MDS-MLD TP53 E-cadherin

30 Diagnosis of MDS in children Diagnostic features of MDS (cytopenia, >10% dysplasia) History of cytotoxic therapy Therapy-related MDS 5% BM blasts or 2% PB blasts MDS-EB Dysplastic erythroids and micromegakaryocytes Clusters of erythroid precursors in biopsy <5% BM blasts, <2% PB blasts Hypocellular (usually) Refractory cytopenia of childhood Not fulfilling any of the above features Classify as for adult MDS All of the above diagnoses should be modified in the setting of a known germline predisposition, e.g.: Refractory cytopenia of childhood with germline GATA2 mutation MDS with excess blasts associated with Fanconi anemia Baumann I Histopathology 2012;61:10

31 What genetic studies should be done to diagnose and classify MDS? Conventional karyotype Need to evaluate for isolated del(5q)(+/- one other aberration) May allow diagnosis of MDS-U even in the absence of sufficient morphologic dysplasia Provides critical prognostic information (IPSS-R) FISH MDS panel is not indicated if 20 metaphases are obtained SF3B1 mutation MDS-RS still defined by iron stain, but mutation analysis can allow diagnosis a smaller number of ring sideroblasts are present TP53 mutation in MDS with isolated del(5q)

32 Prognostic influence of cytogenetic abnormalities in MDS Risk group Cytogenetic abnormality Very good Single del(11q) or -Y Good Intermediate Poor Very poor Normal del(5q)(single or with 1 other) Single del(12p) or del(20q) +8, i(17q), +19, single del(7q) Any other single or double -7, inv(3), t(3q), del(3q) del(7q) with 1 other 3 separate abnormalities 4 or more separate abnormalities (complex) Schanz et al, J Clin Oncol, :820-9

33 Prognostic impact of mutations in MDS Gene Frequency of mutation in MDS SF3B1 25% Good Prognostic impact TET % Unknown; may predict response to hypomethylating agents SRSF % Unknown; exclude CMML ASXL % Poor DNMT3A 10% Unknown; may predict response to hypomethylating agents RUNX1 5-10% Poor PPM1D 5% Poor EZH2 5% Poor ETV6 5% Poor IDH1/IDH2 5% Unknown; targeted therapies available U2AF1 5% Unknown TP53 5% Poor; poor outcome with hematopoietic cell transplant STAG2 5% Poor ZRSR2 5% Unknown

34 Summary and take-home messages MDS is still defined by dysplastic morphology, but accurate diagnosis requires taking into account possible reactive causes for dysplasia and cytopenias as well as genetic findings Integration of morphology (in blood and bone marrow), CBC results, and cytogenetics is critical in correctly classifying MDS Currently the presence of mutations and/or flow cytometry abnormalities do not establish a diagnosis of MDS, but can provide information to support an MDS diagnosis Mutations provide prognostic information and may predict response to certain therapies