Outlines. Disclosures. Updates on B-cell Chronic Lymphoproliferative Disorders of the Blood and Bone Marrow
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1 Updates on B-cell Chronic Lymphoproliferative Disorders of the Blood and Bone Marrow Sa A, Wang MD Jeffrey L. Jorgensen, MD, PhD Department of Hematopathology, UT M.D. Anderson Cancer Center, Houston, TX Disclosures Grant/Research Support from Seattle Genetics and Glaxosmithkline. Outlines Chronic lymphocytic leukemia/small lymphocytic lymphoma; Monoclonal B cell lymphocytosis; Mantle cell leukemia, non nodal leukemic variant; Hairy cell leukemia, hairy cell leukemia variant and gray zone hairy cell leukemia CLL/SLL Most common leukemia in the Western Hemisphere ~25% of all leukemias in the U.S. 18,960 estimated new cases in ,660 estimated deaths in 2016 Median age ~70 years Incidence increases with advancing age ~30% under 60 y, ~15% under 50 y 1
2 CLL/SLL Immunophenotype of CLL/SLL Pan B-cell antigens+, most dim (CD20, CD22, CD79b, surface light chains) CD5+, CD23+ Morphology Small, mature appearing lymphocytes Pale staining proliferation centers in lymph nodes, bone marrow in some cases CLL/SLL with atypical phenotype May show decreased CD5, and/or brighter than usual pan-b-cell markers (CD20, CD22, FMC-7, and/or CD79b/light chain) Often associated with trisomy 12 Differential diagnosis includes mantle cell lymphoma, marginal zone lymphoma, other lowgrade lymphomas Newer markers: LEF1 (Lymphoid enhancer binding factor 1) Transcription factor, WNT/ β catenin pathway Normally expressed in some T and pro B cells but not mature B cells. Largest series: 100% positive in CLL, not in other small B cell LPD (total of 290 B LPD) 1 Rare MCL reported as positive 2 1 Tandon et al. Mod Pathol 2011; 24: O'Malley et al. Ann Diagn Pathol 2017; 26:57. 2
3 Composite mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma Ig superfamily member Widely expressed (B cells, activated T cells, thymocytes, endothelial l cells and neurons) Positive in nearly all CLL cases, strong in most, including those with an atypical phenotype Most MCL are negative Newer markers: CD200 cyclind1 SOX11 LEF1 Cytometry Part B: Clinical Cytometry 24 FEB 2017 DOI: /cyto.b Challagundla et al. Am J Clin Pathol 2014; 142:837. CD200 in Atypical CLL/SLL Chronic lymphocytic leukemia with del(13q) (CD23 negative, CD5very dim) Chronic lymphocytic y leukemia with Trisomy 12 (CD20bright, FMC7+) Small B cell lymphoma by flow cytometry markers CLL/SLL Mantle cell Marginal zone Follicular Hairy cell leukemia CD CD CD CD / CD /+ - CD / /+ CD /- -/ Hairy cell variant Others FMC7- CD103+, CD25+ CD11c+ CD200 Uniform, moderate to strong Neg Partial, dim Neg, or dim+ Bright+ CD103+ CD25- CD11c+/- Neg, dim+ 3
4 Newer markers: CD49d Integrin family (α subunit), surface molecule Promotes microenvironmentmediated proliferation of CLL leukemic cells Prognostic value independent of CD38/ ZAP updates on Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) Update #1 CLL requires a cut off of 5 X10 9 /L In the absence of tissue (lymph node, spleen, extramedullary tissue) involvement there must be 5 X 10 9 /L monoclonal lymphocytes with a CLL phenotype in peripheral blood. Otherwise, they are Monoclonal B cell Lymphocytosis (MBL) Bulian et al. J Clin Oncol 2014; 32:897. Monoclonal B cell Lymphocytosis (MBL) Monoclonal B cells <5 x 10 9 /L in peripheral blood Not SLL, or other B cell LPD: No lymphadenopathy, organomegaly, other extramedullary involvement Assess carefully for lymphoma if non CLL phenotype Present in up to 12% of adults with normal CBC, using highly sensitive flow cytometry MBL subtypes by phenotype CLL like (70%) Typical phenotype, CD5+, CD20 (dim), Ig (dim) Usually mutated IGHV; spectrum of FISH findings similar to CLL; Atypical CLL like (15%) CD5+, CD20 (bright) or CD23, must rule out MCL (FISH) Rawstron et al. Blood 2002; 100:635, Nieto et al. Blood 2009; 114:33. Karube et al. Semin Cancer Biol 2014; 24:3, Xochelli et al. Blood 2014; 123:
5 MBL subtypes by phenotype Non CLL like (15%) CD20 (mod to bright+), CD5 /+ (20% of cases weak) Subset with genotype suggestive of splenic MZL: del(7q), t(7q), i(17q) 17% progression in 5 years Karube et al. Semin Cancer Biol 2014; 24:3, Xochelli et al. Blood 2014; 123:1199 Xochelli A et al, Blood Feb 20;123(8): , 206, MBL subtypes by cell count Low count (<0.5 x 10 9 /L, most <50/μl) Very low risk of progression, no monitoring required High count (0.5 5 x 10 9 /L): Annual progression requiring treatment 1 2% Subset (5 9%) with high risk cytogenetic alterations Requires clinical monitoring, similar to Rai stage 0 CLL Rawstron et al. Blood 2002; 100:635, Nieto et al. Blood 2009; 114:33. Nodal based MBL of a CLL/SLL immunophenotype Atypical B cells with a CLL immunophenotype identified in otherwise reactive lymph node LN largest dimension <1.5 cm Absence of proliferation centers Very indolent clinical course N=36; median 23 months, 21 untreated patients had noor or stable lymphadenopathy, 3 had regressed lymphadenopathy, and 12 had developed progressive lymphadenopathy and/or received therapy for chronic lymphocytic leukemia/small lymphocytic lymphoma.) Examples of lymph nodes with subtle follicular and perifollicular involvement by CLL/SLL cells in patients with <5x10 9 /L peripheral blood monoclonal B-cells CD3 CD20 CD3 CD5 CD20 CD5 Gibson SE et al, Haematologica Aug;96(8): Sarah E. Gibson et al. Haematologica 2011;96:
6 2016 WHO Update #2 on CLL/SLL Clinical importance of expanded proliferation centers Terminology Accelerated CLL Proliferation center rich-cll Histological aggressive CLL CLL with expanded proliferation center Expanded (>one 20x field) and confluent proliferation centers Ki67>30%, can show cyclind1, and MYC protein expression Del(11q), del(17p), t(14q) Proliferation centers of CLL Ki67 Ki67 1 Gradowski et al. Am J Clin Pathol 2012; 138: Gine et al. Haematologica 2010; 95:1526, Ciccone et al. Leukemia 2012; 26:499, Falchi et al. Blood 2014; 123:2783. Molecular genetic findings in CLL/SLL No disease-defining mutations Most common: NOTCH1, SF3B1, TP53, ATM, BIRC3, POT1, and MYD88 Worse prognosis: TP53, ATM, NOTCH1, SF3B1, and BIRC3 IGVH3-21 gene usage Predictive factors for response to therapy in CLL/SLL Abnormalities in TP53 predict lack of response to fludarabine therapy Deletions detected by conventional cytogenetics or FISH Mutations detected by PCR, NGS Non-genotoxic therapies are preferred Puente et al. Nature 2011; 475:101, Landau et al. Nature 2015; 526:525. Rossi et al. Blood 2013; 121:1403, Rossi et al. Leuk Lymphoma 2017; 58:
7 Non-genotoxic therapies for CLL/SLL B-cell receptor signaling inhibition Bruton s tyrosine kinase inhibitor: ibrutinib PI-3-kinase inhibitor: idelalisib BCL-2 inhibition: venetoclax Combination therapy with these and immunotherapy Anti-CD20: rituximab, ofatumumab Mantle cell lymphoma Classical MCL Lymph nodes and extranodal sites; CD20+, CD22+, CD5+, CD23, CD43 (50 75%), CD200 IGHV unmutated or minimally mutated B cells SOX11+ (80 90%) Included blastoid or pleomorphic variant Rossi et al. Leuk Lymphoma 2017; 58:1548. Classic MCL Classic type Small cell variant Blastoid variant Pleomorphic variant 10 5 CD23 PE-A CD19 PE-Cy7-A 7
8 Mantle cell lymphoma, lymphomagenesis Mantle Cell Lymphoma leukemic non nodal variant Non nodal Leukemic MCL Involving I l i the peripheral lblood, bone marrow and often spleen; no lymph node or extranodal/tissue involvement; IGHV mutated; Often SOX11 negative; Secondary abnormalities, often involving TP53, may occur and lead to aggressive disease Swerdlow SH et al, BLOOD, 19 MAY 2016 x VOLUME 127, NUMBER 20 CD200 Expression Patterns in MCL Demographic and Clinical Data of Patients with CD200+ MCL PE-A CD200 PE E-A CD20 APC-H7-A CD20 APC-H7-A E-A CD200 PE CD200 PE-A % 30% CD20 APC-H7-A CD20 APC-H7-A CD200 PE-A PE E-A CD20 APC-H7-A 19 men, 6 women Age: 63 years (36 79 years) B symptoms: 12% (3 patients) Non nodal nodal leukemic MCL (BM, PB and/or spleen): n=11 (44%) Nodal/extranodal involvement CD200+, 3.7% CD200-, 96.3% CD200 Negative: 96.3%(643/668) CD200 +: 3.7%(25/668) Partial +: Uniform +: 68% (17/25) 32%(8/25) (besides PB and BM): n=14 (Stage IV) 8
9 All 25 patients had Bone Marrow Involvement Comparison between CD200+ (n=25) and CD200- MCL (n=157) Interstitial: 52% (12/23), SOX11-negative 14/19, LEF1 negative 19/19 Treatment of CD200+ MCL Summary & Conclusions CD200 expression in MCL is uncommon (3.7%) Refused therapy (n=2) Tonsilectomy (n=1) No therapy 1 or 2 agents (n=2) CD200+ MCL often shows a CLL-like immunophenotype, frequent small cell morphology, an interstitial BM involvement pattern and SOX11 negativity; A large proportion of these cases belong to non-nodal leukemic subtype MCL, and showing IgH hypermutation (4/4) Many patients with CD200+ MCL have an indolent clinical course and do not require immediate treatment 9
10 Naïve B cells CD200 in the scheme of mantle cell pathogenesis In situ MCL+ like B cells Unmutated IG SOX11+ GC Classical type Progression Hairy cell leukemia (HCL) Older patients, splenomegaly, usually pancytopenic Monocytopenia is characteristic Infections lead to morbidity/mortality Hypermutated IG SOX11- Indolent including Non-nodal leukemic subtype Hu Z et al and Wang SA. Modern Pathology, 2017, Oct 6 HCL on touch prep HCL in bone marrow core biopsy 10
11 HCL phenotype: TRAP HCL phenotype: TRAP Tartrate-resistant acid phophatase (TRAP) by cytochemistry on smears: HCL strongly (+), but may be only in a few cells Not specific: some marginal zone lymphomas (MZL) are weakly (+) HCL: Classic IHC markers DBA.44: B-cell marker, sensitive but not specific [LPL, MZL, mantle cell lymphoma may be (+)] Cyclin D1 is (+) in most cases Usually weak, not associated with t(11;14) Useful for distinction from marginal zone lymphoma (MZL) Miranda, et al. (2000), Mod Pathol 13:1308 Sherman, et al. (2011), Am J Clin Pathol 136:390 HCL Classic IHC markers: Annexin A1 Involved in phagocytosis, cell signaling Gene expression profiling: overexpressed in HCL Highly specific for HCL among B-cell LPD Granulocytes (+), some T cells also (+) Must correlate with a B-cell marker Background too high for minimal residual disease detection Falini, et al. (2004), Lancet 363:1869 Sherman, et al. (2011), Am J Clin Pathol 136:390 11
12 HCL: Annexin A1 by IHC HCL - Newer IHC marker: TBX21 T-box transcription factor, expressed in Th1 cells Regulates IgG class switching, induced by CpG in Bcells HCL: Most reported cases (+), often strong/uniform Other small B-cell LPDs: Many cases (+), often weaker Normal BM: rare scattered interstitial i i T cells (+) Low background, OK for MRD (2-5% level) Grans+ Dorfman, et al. (2004), Am J Clin Pathol 122:292 Sherman, et al. (2011), Am J Clin Pathol 136:390 Flow cytometry of hairy cell leukemia HCL - Flow cytometry Characteristic immunophenotype: CD11c bright+, CD22 bright+, CD25+, CD103+, CD123+, CD200 bright+ Also CD19 bright+, CD20 bright+ Subset of cases may be CD10+ (10-20% cases); CD5+ (0-2%) 12
13 HCL: Insights from whole exome sequencing Index case: BRAF V600E mutation identified d Mutational hotspot in melanoma, papillary thyroid ca., Langerhans -cell histiocytosis Kinase upstream of MEK and ERK 47/47 HCL cases also positive 195/195 other peripheral B-cell LPDs negative Tiacci, et al. (2011), N Engl J Med 364:2305 HCL: Detection of BRAF V600E PCR with allele specific oligonucleotide primers 1,2 0.1% sensitivity in treated patients 1 IHC for mutant BRAF 3 Suitable for diagnosis, potentially MRD 1 Arcaini, et al. (2012),Blood 119:188, 2 Tiacci, et al. (2012),Blood 119:192 3 Turakhia et al. Am J Clin Pathol 2015; 144:87. HCL: Therapy Highly sensitive to purine nucleoside analogs Pentostatin, t ti cladribine These are immunosuppressive Relapse often responds to re-treatment Investigational: BRAF inhibitors (vemurafenib, dabrafenib) BTK inhibitor (ibrutinib) Immunotoxins (anti-cd22+toxin) HCL variant CBC: often higher white count, no monocytopenia Morphology: may have irregular nuclei, prominent nucleoli Grever et al. Blood 2017; 129: WHO 13
14 Facts of HCL variant A form of splenic B cell lymphoma, NOS; Unmutated IGHV, preferential use of IGHV4-34 Immunophenotype: Often CD103+, CD11c+, DBA.44+ Absent CD25, CD123, Annexin A1, TRAP; CD200 dim or negative Genotype: No BRAF V600E mutation; ti recurrent MAP2K1 mutation; Not responsive to HCL front-line therapy HCL gray zone? Small subset of cases unmutated IGHV, with IGHV4-34 gene usage HCL-classic phenotype (CD25+, CD123+, annexin A1+) Absent BRAF V600E mutations Worse response to cladribine By WHO 2008 criteria, these are HCL-classic, but WHO 2016 suggests that they may be more closely related to HCL-variant; Arons et al. Leuk Lymphoma 2011; 52 Suppl 2:99, Xi et al. Blood 2012; 119:3330, Waterfall et al. Nat Genet 2014; 46:8. Questions Acknowledgements Lynne Abruzzo, MD PhD, Ohio State University Jian He, MD PhD (fellow), MD Anderson Cancer Center Both kindly provided selected slides 14
Small, mature-appearing appearing
B-cell Chronic Lymphoproliferative Disorders of the Blood and Bone Marrow Disclosures I have nothing to disclose. Jeffrey L. Jorgensen, MD, PhD Department of Hematopathology, UT M.D. Anderson Cancer Center,
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