Three Cases of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Involving Cerebrospinal Fluid (CSF)

2019 ◽  
Vol 152 (Supplement_1) ◽  
pp. S111-S112
Author(s):  
Anna Shestakova ◽  
Jayne Healey ◽  
Sheila (Xiaohui) Zhao ◽  
Sherif Rezk ◽  
Jamie Nakagiri
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Cerebrospinal Fluid ◽  
Chronic Lymphocytic Leukemia ◽  
Bone Marrow Involvement ◽  
Lymphocytic Leukemia ◽  
Lymphoid Tissues ◽  
Proliferative Index ◽  
Cns Involvement ◽  
Ki 67

Abstract Background Chronic lymphocytic leukemia (CLL) is a clonal disorder of B lymphocytes, characterized by proliferation of small mature lymphocytes involving the blood, bone marrow, and lymphoid tissues. CLL can rarely involve the central nervous system (CNS), either by involving brain parenchyma or cerebrospinal fluid (CSF). We present a series of three cases with clinically significant involvement of the CNS with CLL. Results During the past 2 years, our medical center managed three patients with CLL who presented with symptomatic CNS involvement, as determined by flow cytometry. The immunophenotypic profile was that of a typical CLL with light chain restricted small B cells positive for CD20 (dim) and coexpressing CD5 and CD23. In addition, two patients had brain involvement by SLL that was confirmed by brain biopsy. Notably, the brain lesions had a mildly elevated Ki-67 proliferative index (10%-30%). Bone marrow was involved in two patients, showing nodular, interstitial, and diffuse patterns. Bone marrow involvement ranged from 60% to 80% and showed very low Ki-67 proliferative index. None of the patients had features suggestive of a CLL transformation. FISH was performed on either bone marrow or CSF and demonstrated that patient 1 had Del11q(ATM) and Dell13q, patient 2 had trisomy 12, and patient 3 had del17(TP53) and IGH rearrangement. All of the patients showed persistent CSF involvement, ranging from 4 to 12 weeks, requiring aggressive treatment with intrathecal chemotherapy. At the end of treatment, all of the patients were clear of CNS involvement as judged by flow cytometry of CSF. Conclusion We report three patients who had persistent involvement of CSF. Only one patient had del17(TP53), a cytogenetic feature that is associated with high-risk CLL. It would be interesting to study clonal evolution of CLL to understand the mechanisms that underlie involvement of the CNS.

Mode of Action of the SDF-1/CXCL12 Inhibiting Spiegelmer® Nox-A12 and Its Impact On Chronic Lymphocytic Leukemia (CLL) Cell Motility and Chemosensitization

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 318-318
Author(s):  
Dirk Zboralski ◽  
Julia Hoellenriegel ◽  
Christian Maasch ◽  
Anna Kruschinski ◽  
Jan A. Burger
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Stromal Cells ◽  
Mode Of Action ◽  
Leukemia Cell ◽  
Lymphocytic Leukemia ◽  
Lymphoid Tissues ◽  
Cell Trafficking ◽  
Dependent Manner

Abstract Abstract 318 NOX-A12 is a novel Spiegelmer®-based antagonist of SDF-1/CXCL12, a chemokine involved in the regulation of chronic lymphocytic leukemia (CLL) cell trafficking. Spiegelmers® are mirror-image oligonucleotides that are identified to specifically bind to proteins in a manner conceptually similar to antibodies. Unlike aptamers, however, Spiegelmers® are built from the non-natural L-isomer form of nucleotides which confers resistance to the action of nucleases and avoids potential immunogenicity. CXCL12 is constitutively secreted and presented by bone marrow stromal cells (BMSC) via glycosaminoglycans (GAG) and acts as a homing factor for normal and malignant hematopoietic cells to the bone marrow (BM) and secondary lymphoid tissues via CXCR4 receptors that are expressed at high levels on circulating CLL cells. The microenvironment in the BM and secondary lymphoid tissues, in particular the CXCL12-CXCR4 axis, favors survival and chemotherapy-resistance of leukemic cells. We therefore investigated the effects of NOX-A12 in an in vitro co-culture system to model the interaction of CLL cells with their microenvironment. Surprisingly we observed that NOX-A12 increased pseudoemperipolesis in vitro, i.e. spontaneous leukemia cell migration beneath BMSC. Interestingly, this NOX-A12 induced trans-migration of CLL cells was completely inhibited by the CXCR4 antagonist AMD3100, suggesting a CXCL12/CXCR4 dependent mechanism. We postulated that this observation might result from a direct effect of NOX-A12 on CXCL12 release by the stromal cells. Therefore, we investigated this hypothesis in different BMSC lines (MS-5, R15C, and TSt-4) and we found that NOX-A12 induced a significant CXCL12 release in all three tested cell lines. We asked whether this NOX-A12 dependent increase of CXCL12 of BMSCs is due to release from either intracellular or extracellular storages. Intracellular staining of CXCL12 using flow cytometry did not reveal significant changes when BMSCs were incubated with NOX-A12. Furthermore, the transcription of CXCL12 was not found to be altered after NOX-A12 incubation over a period of three days as shown by quantitative RT-PCR. Rather, CXCL12 is released from extracellular storages of BMSCs. First hints were obtained through a rapid CXCL12 release within five minutes of incubation with NOX-A12. To confirm that CXCL12 is bound to the extracellular surface (by GAGs like heparin) and is being detached by NOX-A12 we first incubated BMSCs with NOX-A12, followed by a wash step and the addition of recombinant CXCL12. Recombinant CXCL12 was bound by BMSCs that were pre-incubated with NOX-A12 but not with a non-functional control (revNOX-A12), indicating that NOX-A12 strips off CXCL12. To corroborate the findings we incubated the BMSCs with heparin which also led to the release of CXCL12 in a dose dependent manner. Of note, the EC50 of heparin regarding CXCL12 release was much higher compared to the EC50 of NOX-A12 (≈ 12 μM vs. 5 nM) revealing the high affinity of NOX-A12 to CXCL12. The competition of NOX-A12 with heparin regarding CXCL12 binding was confirmed by Biacore experiments. Based on these findings, we developed a novel adapted co-culture approach to examine the ability of NOX-A12 to chemosensitize CLL cells. In this setting, we first strip off CXCL12 from BMSCs by NOX-A12 and subsequently add CLL cells which will be either non-treated or treated with chemotherapy (fludarabine combined with bendamustine). We found that NOX-A12 slightly decreased CLL cell viability. As expected, a strong viability decrease was observed with chemotherapy, which could be even further decreased by the combination with NOX-A12, suggesting synergistic effects. In conclusion, we propose that NOX-A12's mode of action is the release of extracellular bound CXCL12 and its subsequent inhibition. Since CXCL12 induces leukemia cell trafficking and homing to tissue microenvironment and also favors leukemia cell survival, we believe that targeting CXCL12 is an attractive approach to remove the protective effects of CXCL12-secreting BMSCs in order to sensitize CLL cells for subsequent chemotherapy. Thus, NOX-A12 represents a very promising agent to significantly improve the treatment of CLL. The compound is currently being tested in a Phase IIa study in relapsed CLL patients. Disclosures: Zboralski: NOXXON Pharma AG, Berlin, Germany: Employment. Maasch:NOXXON Pharma AG: Employment. Kruschinski:NOXXON Pharma AG: Employment. Burger:NOXXON Pharma AG: Consultancy, Research Funding.

Azacytidine and Vorinostat in Patients with Chronic Lymphocytic Leukemia (CLL) Diagnosed with Therapy-Related Myelodysplastic Syndromes/Acute Myeloid Leukemia (t-MDS/AML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5627-5627
Author(s):  
Yesid Alvarado ◽  
Michael J Keating ◽  
Susan O'Brien ◽  
Hagop M. Kantarjian ◽  
William G. Wierda ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Median Time ◽  
Stable Disease ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Bone Marrow Involvement ◽  
Lymphocytic Leukemia ◽  
Cycle Number ◽  
Prognostic Features

Abstract Background: There is evidence of a leukemogenic effect of purine analogues, mainly when combined with DNA-damaging agents. Various series report an approximately 5% rate of t-MDS/AML in patients treated with a fludarabine-based regimen. Patients are generally old, and old age is associated with worse outcomes. To date, there is no established standard therapy recommendation for this group of patients, and results of prospective treatment evaluations are scarce. Aim: To determine the characteristics and treatment outcomes of patients with CLL and t-MDS/AML. Methods: We analyzed a group of 6 patients with newly diagnosed t-MDS/AML who were treated in our institution from September 2011 to July 2014. Patients were enrolled in a phase II trial of azacitidine (75 mg/m2 IV daily x 5 days) in combination with vorinostat (200 mg orally three times daily x 5 days) (Arm A) or azacitidine alone (Arm B), with courses repeated every 3-8 weeks. This trial was designed to uniformly treat patients not eligible for other leukemia protocols due to comorbidities. Results: At baseline, all patients had an underlying diagnosis of CLL that was in remission or minimally active. The median percentage of CLL bone marrow involvement was 10% (range 0-60%), and ALC was 0.9 K/uL (range 0.2-9.79). The median number of prior CLL treatments was 2 (range 0-3). All patients had previously received fludarabine-based regimens. The median time from chemotherapy to t-MDS/AML diagnosis was 10 years (range 4-10). All patients were male, and the median age was 72 years (range 52-72). All patients had 3-line cytopenia, with median WBC 2.3 K/uL (range 0.8-8.9), ANC 0.55 K/uL (range 0-1.22), hemoglobin 9.6 G/DL (range 8.3-10.4), platelets 39 K/uL (range 6-80), and bone marrow blast percentage of 5% (range 1-18%). The karyotype was complex in all patients. Molecular studies showed that 3 patients had TP53 gene mutations. Five patients received treatment in Arm A, and only 1 patient was randomized to Arm B. Patients received a median of 4 cycles (range 2-7) and remained in the study for a median time of 216 days (range 86-329) before progression. None of the patients achieved remission, but stable disease was observed in 5 out of 6 patients. At the time of this analysis, 4 patients are dead and 2 are still alive: one discontinued treatment because of prolonged myelosuppression and is receiving best supportive care, and the other is recovering from cycle number 4 of treatment. The median survival in the group from the time of treatment initiation was 10.1 months and from the time of study discontinuation was 3.1 months. Further therapy was attempted in 3 patients without response. Conclusion: This is a group of patients with poor prognostic features. Azacytidine and vorinostat have been previously reported to be a safe combination (Garcia-Manero et al. ASH 2010, abstract 604) and may constitute a reasonable treatment alternative. Further prospective studies involving larger numbers of patients are required. Abstract 5627. Table 1: Baseline Patient Characteristics. Patient Age WBC K/uL Hb G/DL Plt K/uL BM Blast % CLL BM % Cytogenetic Molecular Prior CLL Treatments Treatment Arm Best Response 1 52 11 9.6 6 18 60 -3,-4,-5q,-6,-7, -7p,-12, +16 TP53 mutation 1.FCR x 62. Rituximab + Lenalidomide A NR 2 74 1 10 41 3 10 -3p,-5q,-7,-15,-17,-19 TP53 mutation 1. FCR x 42. FCR x 53. BR x 2 A SD 3 68 2.2 9.4 27 6 30 +7,-7p,t(7,21) Negative 1. FCR x 62. FCR x 4 B SD 4 73 2.3 9.7 39 6 0 +2,-5q,+8,-17,-18,+19,+20,-Y Negative 1. FCR x 6 A SD 5 71 0.8 8.3 39 4 0 +2,+4,t(5;17),+6,-7,-9, +13, +15,-16,-17,+18,+19,-20,+21 Negative 1. FR x 12. BR x43. MEDI-551 A SD 6 74 2.4 10.4 80 1 10 t(1;3),inv3,-5q,-18 TP53 mutation 1. R-CHOP x 62. BR x 13. FCR x 4 A SD WBC: White blood cells, Hb: hemoglobin, Plt: Platelets, BM: Bone Marrow, CLL: Chronic Lymphocytic Leukemia, F: Fludarabine, C: Cyclophosphamide, R: Rituximab, B: Bendamustine, MEDI-551: anti-CD19 antibody, NR: no response, SD: stable disease. Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding.

Plasma Circulating Ki-67 Index as a Biomarker and Prognostic Indicator in Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1261-1261
Author(s):  
Jean-Marie Bruey ◽  
Zeev Estrov ◽  
Hagop M. Kantarjian ◽  
Wanlong Ma ◽  
Chen-Hsiung Yeh ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Peripheral Blood ◽  
Performance Status ◽  
Bone Marrow Involvement ◽  
Lymphocytic Leukemia ◽  
Nuclear Antigen ◽  
Proliferation Index ◽  
Ki 67 ◽  
Control Subjects ◽  
Healthy Control

Abstract Abstract 1261 Poster Board I-283 Ki-67 is a nuclear antigen that is expressed in all stages of the cell cycle except G0 and is widely used as a marker of cellular proliferation in human tumors. We recently demonstrated that levels of plasma circulating Ki-67 (cKi-67) are significantly higher in patients with newly diagnosed acute lymphoblastic leukemia (ALL) than in healthy control subjects, and that elevated levels of cKi-67 are associated with a shorter survival in ALL patients. Here we examined the associations of cKi-67 levels with laboratory and clinical variables in patients with chronic lymphocytic leukemia (CLL). The study included 194 patients with CLL and 96 healthy control subjects. The cKi-67 levels in plasma were determined using electro-chemiluminescence-based immunoassay using the Mesoscale Discovery platform. Since usually Ki-67 is used as an index of tumor cell proliferation, we took into account the lymphocyte count of the CLL patients in peripheral blood and normalized the levels of the cKi67 to the absolute number of lymphocytes in the peripheral blood establishing plasma cKI-67 index (cKi-67 level ng/1000 circulating lymphocytes/μL plasma). Median (range) levels of absolute cKi-67 were significantly higher in patients with CLL than in control subjects (914.65 [102.0-4975.12] ng/mL vs 353 [35.76-2830.65] ng/mL; P<0.0001). However, absolute levels did not correlate with clinical or other laboratory variables (white cell count, hemoglobin, platelets, beta-2 microglobulin, or Rai stage, performance status). In contrast, the cKI-67 index correlated significantly with bone marrow involvement (p<0.001), number of lymph node sites involved (p<0.001), and Rai stage (p=0.05), but not with IgVH mutation (P=0.62) or performance status (p=0.71) The cK-I67 index was significantly associated with survival when used as either as a continuous variable (P=0.002) or as a dichotomous variable (P=0.005). Multivariate Cox proportional hazards analysis incorporating cKi67 index with IgVH mutation status and B2M, demonstrated that only cKi-67 and B2M were independent predictors of survival. This data shows that there variability in proliferation between patients with CLL and those patients high relative proliferation (index) have more aggressive disease. Furthermore, plasma cKi-67 index and B2M levels are strong predictors of clinical behavior in CLL. Disclosures No relevant conflicts of interest to declare.

Diagnostic and Clinical Considerations in Concomitant Bone Marrow Involvement by Plasma Cell Myeloma and Chronic Lymphocytic Leukemia/Monoclonal B-Cell Lymphocytosis: A Series of 15 Cases and Review of Literature

2013 ◽  
Vol 137 (4) ◽  
pp. 503-517 ◽  
Author(s):  
Christopher L. Alley ◽  
Endi Wang ◽  
Cherie H. Dunphy ◽  
Jerald Z. Gong ◽  
Chuanyi M. Lu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Correct Diagnosis ◽  
Bone Marrow Involvement ◽  
Rare Event ◽  
Lymphocytic Leukemia ◽  
Plasma Cell Myeloma

Context.—Plasma cell myeloma and chronic lymphocytic leukemia are both common hematologic malignancies, sharing many epidemiologic features. Concomitant detection of the 2 conditions poses special diagnostic challenges for the pathologist. Objective.—To describe the pathologic findings in cases of concomitant bone marrow involvement by myeloma and CD5+ monoclonal B cells and to outline the differential diagnostic possibilities, suggest a workup for correct diagnosis, and examine clinical outcome. Design.—Fifteen cases that met the diagnostic criteria were identified from pathology databases at 4 participating institutions. Morphologic findings were reviewed, additional immunohistochemical stains performed, and flow cytometric, cytogenetic, and relevant laboratory and clinical information was summarized. Previously published cases were searched from electronic databases and cross-references. Results.—Most patients (13 of 15) were older males. Often (11 of 15) they presented clinically with myeloma, yet had both monotypic plasma cells and B cells in the diagnostic marrow. In 4 patients, myeloma developed 24 months or later after chronic lymphocytic leukemia. In 7 patients, myeloma and CD5+ B cells showed identical immunoglobulin light-chain restriction. Primary differential diagnoses include lymphoplasmacytic lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia with plasmacytoid differentiation. CD56 and/or cyclin D1 expression by plasma cells was helpful for correct diagnosis. Most patients in our cohort and published reports were treated for plasma cell myeloma. Conclusions.—Concomitant detection of myeloma and chronic lymphocytic leukemia in the bone marrow is a rare event, which must be carefully differentiated from lymphomas with lymphoplasmacytic differentiation for correct treatment.

scholarly journals The pattern of bone marrow involvement among chronic lymphocytic leukemia patients and its impact on the disease outcome in Kurdistan Region of Iraq

2021 ◽  
Vol 10 (2) ◽  
pp. 158
Author(s):  
MarwaNadhim Karam ◽  
KawaM Hasan ◽  
NawsherwanS Mohammed ◽  
AhmedK Yassin ◽  
ShokhanMohammad Mustafa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Bone Marrow Involvement ◽  
Lymphocytic Leukemia ◽  
Disease Outcome ◽  
Kurdistan Region

Validation of Minimal Residual Disease Flow Cytometry Method for Residual Disease Monitoring in Chronic Lymphocytic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4196-4196
Author(s):  
Shabnam Tangri ◽  
Annalee Estrellado ◽  
Julie Ranuio ◽  
Elisa Romeo ◽  
Jonathan Lawson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Chronic Lymphocytic Leukemia ◽  
Light Chain ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
Normal Cells ◽  
Chain Analysis ◽  
Minimal Residual

Abstract Monitoring Minimal Residual Disease (MRD) of Chronic Lymphocytic Leukemia (CLL) patients who achieved complete remission has been difficult and challenging using flow cytometry detection methods in peripheral blood Earlier flow cytometry methods described for detection of MRD relied on the assessment of CD20 expression that maybe compromised during rituximab therapy (CD5/19/20/79B and light chain analysis) or were done using the classic CLL staining panel (CD5/19/23 and light chain analysis) that had a low sensitivity. To facilitate the development of methods that would be suitable for rituximab containing regimens and have better sensitivity, a panel of antibody combinations was identified for use in an internationally standardized flow cytometric approach for MRD detection in CLL-treated patients (Rawstron et al., 2007). This panel consists of 5 combinations of antibodies specific for 1-sIgKappa/sIgLambda/CD19/CD5, 2-CD45/CD14/CD19/CD5, 3-CD43/CD79b/CD19/CD5, 4-CD22/CD81/CD19/CD5 and 5-CD20/CD38/CD19/CD5 antigens. The first two combinations are utilized for confirmation of clonality and assessment of Tcell contamination rate within the B cell gate, whereas combinations 3, 4 and 5 are specific for MRD detection. This standardized 5-combination panel was technically validated by Genoptix Medical Laboratory for use in BiogenIdec’s clinical trials in CLL with Lumiliximab. To validate this panel assay, selected CLL samples were mixed with normal donor blood or “disease-free” bone marrow specimens, to achieve 1%, 0.1%, 0.05% and 0.01% of CLL cells in “non-CLL” leukocytes. Our results show that it is possible to identify up to 1 CLL cell in 10,000 normal cells in some but not all cases, and that on a consistent basis our analysis is able to identify 1 CLL cell in 1000 normal cells. In comparison, the classic screening panel commonly used to diagnose CLL has a limit of detection (LOD) of about 1% (1 leukemic cell in 100 normal cells); thus this new method provides a 10 to 100 fold improvement in sensitivity. The enhanced sensitivity and LOD of the new assay is mainly due to the reduction of the non-CLL cell background in peripheral blood and bone marrow Furthermore, to make analysis guidelines consistent among analysts, an internal semi-quantitative clustering scoring analysis system was developed for this assay. The cluster scoring scheme assigns a negative score to scattered events with no clearly visible clone; well grouped events with tight visible clones are assigned positive scores and those gated events are considered for MRD final call. To reliably define the presence of MRD, at least 2 of the 3 MRD specific antibody combinations must have a positive clustering score. Due to the small number of cells to be analyzed, collection of 500,000 events is recommended. Finally, the results of additional studies showed that the anticoagulant employed may impact the stability of the antigens over a period of 7 days, and for accurate MRD determination blood specimens should be drawn into Heparin vacutainer tubes when long shipping times are expected.

Low Expression of ROR1 on Chronic Lymphocytic Leukemia Is Associated with Other Atypical Findings

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4588-4588
Author(s):  
H. Elizabeth Broome ◽  
Laura Z. Rassenti ◽  
Michael Y. Choi ◽  
Thomas J. Kipps
Keyword(s):  
Flow Cytometry ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Confidence Interval ◽  
Lymphocytic Leukemia ◽  
Lymphoid Tissues ◽  
Neoplastic Cells ◽  
Atypical Features ◽  
Trisomy 12 ◽  
Low Levels

Abstract Abstract 4588 ROR1 is a developmental embryonic surface antigen that also is expressed on chronic lymphocytic leukemia (CLL) cells, but not on most tissues or cells of healthy adults, including secondary lymphoid tissues or normal CD5 B cells. Studies involving relatively small numbers of patients have identified expression of ROR1 on the neoplastic cells of nearly all patients examined. However, it is not established whether there are cases of bona fide CLL that lack expression of this antigen or whether cases of putative CLL that lack expression of ROR1 actually represent a disease subset that has biologic and/or clinical features distinct from that of CLL that express ROR1. To further explore the significance of low levels of ROR1 on CLL, we analyzed 268 cases of CLL for surface expression of ROR1 via multiparameter flow cytometry using a fluorochrome-conjugated mAb specific for ROR1. The percentage of CLL cells with ROR1 for each case had a median of 94, mean of 81 and a standard deviation of 26. By visual inspection of the histograms, the distribution of ROR1 expression for each case approximated that of a Gaussian distribution. For 14 of these cases (5.2%), less than 20% of their neoplastic B cells expressed ROR1. Three of these 14 cases (21%) had features of “typical” CLL by immunophenotype. These cases did not have cytogenetic abnormalities as detected by fluorescence in situ hybridization (FISH), were negative for ZAP-70, and expressed mutated IGHV genes (Table 1). The 11 other cases had some features in common with that of typical CLL including small, mature, lymphocyte morphology, a persistent absolute lymphocyte count of greater than 5K/ul, expression of CD5, and lack of translocations characteristic of mantle cell lymphoma [e.g t(11;14)]. However, these 11 cases also showed variably atypical features. Three cases had dim or partial expression of CD23 (cases #1, 8, 11), one case lacked expression of CD23 (#4). Trisomy 12 was detected in three of the 14 cases (21%; 95% confidence interval 8–48%), not significantly different than the reported frequency of 14%. 13qdel as the sole cytogenetic/ FISH abnormality was present in another three of the 14 cases (21%; 95% confidence interval 8–48%), which is significantly lower than the reported frequency of 60% (p<0.05). The clonal IGHV gene had somatic mutations in 9 of 12 cases analyzed (75%; 95% confidence interval 47–91%). These findings indicate that low levels of ROR1 are rare in typical CLL, and that CLL with low level expression of ROR1 have a high frequency of other atypical immunophenotypic and cytogenetic findings.Table 1Case% ROR1Atypical features of ImmunophenotypeCytogenetics/ FISH% ZAP- 70% IGHV homologyALC1*1.6partial 23+, bright 79b+, dim 81+, FMC7+Normal FISH2691.740.322.0dim 5+, 13+, FMC7+46, XX, t(13;18) (q14q21) [4]/46,XX916); 13qdel by FISHNANA12.133.138+47, XY, del(2)(p23),+12(14) (?q24); trisomy 12 by FISH1100.017.34*3.4dim 5+, bright 20+, 23-neg, FMC7+, bright sIg+46, XY; 13qdel by FISH194.7193.454.0Typical46,XY; normal FISH195.58.46*5.7TypicalNormal FISH2194.028.177.4TypicalNormal FISH1592.716.38*7.7Dim 23+, bright 79b+, variable 81+, bright sIg+46 XY; 13qdel by FISH7491.03.098.3NANA1093.454.61013.713+, bright 20+, 38+, FMC7+NA1098.614.61114.1weak 5+, 13+, dim 23+, FMC7+del13q by FISH2793.13.012*14.138+Trisomy 1287100.046.813*15.2mod 20+, partial FMC7+NA1897.912.514*16.413+, 38+, FMC7+,47, XX,+12[7]/47,idem,?2q,-8,add(10(p13),+mar[3]; trisomy 12 by FISHNANA5.2*= splenomegaly%4A5 is percentage of CD19+ lymphocytes with 4A5 fluorescence greater than threshold set with 99% of fluorescence from isotype control staining.Immunophenotype is considered “typical” for CLL if neoplastic cells express CD5, CD19, CD20 (dim), CD23, CD43 (dim), CD79b(dim) and do NOT express CD38, CD81 and FMC-7. Only the atypical features for each case are noted in table.Cytogenetics/FISH: 20 metaphase karyotype and/or 200 interphase FISH for CCND1/IGH [translocation (11;14)(q13;q32)], ATM (11q22.3), D12Z3 (12 centromere), D13S319 (13q14.3), LAMP1 (13q34), p53 (17p13.1).% Zap-70 is percentage of CD19+ neoplastic cells that express ZAP70 by flow cytometry.% IgH mut. is the percentage homology of the neoplastic clone with germline IgHV geneALC is absolute lymphocyte countNA: not available Disclosures: No relevant conflicts of interest to declare.

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