- Email: [email protected]
Signal transducer and activator of transcription (STAT)-3 is a double edged sword in CLL cells
Abstracts analysis. Results: Trisomy12 (38-80% of cells) and NOTCH1 mutation (53-100% of cells) was detected in all patients. All patients had two or more cell populations defined by NOTCH1 mutation, Trisomy12 or both (major clone in 2/5 cases). Two patients demonstrated further intra-clonal diversity through either convergent or parallel evolution of two different or identical NOTCH1 mutations in Trisomy12 sub-clones, respectively. Conclusions: Trisomy12-NOTCH1 evolution is more complex than previously thought and may provide insight into progression and transformation. Grant Acknowledgements: Wessex Medical Research Innovation award, Kay Kendal Leukaemia Fund. Keywords: Singlecell, Genetics, CLL, Cancer.
302 Adherence To The Ibrutinib 420 mg Dose Administered To Patients With Previously Treated CLL Jan A. Burger, MD, PhD,1 Paul M. Barr, MD,2 Jennifer R. Brown, MD, PhD,3 Peter Hillmen, MB ChB, PhD,4 Susan O’Brien, MD,1 Jacqueline C. Barrientos, MD,5 Nishitha M. Reddy, MBBS, MScl,6 Steven Coutre, MD,7 Stephen P. Mulligan, MBBS, MD, FRACP, FRCPA,8 Ulrich Jaeger, MD,9 Richard R. Furman, MD,10 Florence Cymbalista, MD,11 Marco Montillo, MD,12 Claire Dearden, MD,13 Tadeusz Robak, MD, PhD,14 Carol Moreno, MD,15 John Pagel, MD, PhD,16 Samuel Suzuki, MS, MBA,17 Juthamas Sukbuntherng, PhD,17 George Cole, MD,17 Danelle F. James, MD, MAS,17 John C. Byrd, MD18 1
University of Texas MD Anderson Cancer Center, Houston, TX; Wilmot Cancer Institute, University of Rochester, NY; 3Dana-Farber
2
Signal transducer and activator of transcription (STAT)-3 is a double edged sword in CLL cells
Nashville, TN; 7Stanford University School of Medicine, Stanford, CA; 8
1
5
James Institute of Oncology, Leeds, UK; North Shore-LIJ Cancer Institute, Lake Success, NY; 6Vanderbilt-Ingram Cancer Center, Royal North Shore Hospital, Sydney, Australia; 9Medical University of
Vienna, Vienna, Austria;
10
Weill Cornell Medical College/New York
Presbyterian Hospital, New York, NY; 11Hôpital Avicenne, Paris, France; 12Niguarda Ca’ Granda Hospital, Milan, Italy; 13Royal Marsden Hospital, London, UK; Poland;
14
Medical University of Lodz, Lodz,
15
Hospital de la Santa Creu Sant Pau, Barcelona, Spain;
16
Swedish Cancer Institute, Seattle, WA;
Abbvie Company, Sunnyvale, CA;
17
Pharmacyclics LLC, an
18
The Ohio State University Med-
ical Center, Columbus, OH
Context: Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton’s tyrosine kinase (BTK). BTK active site occupancy (median 90%) is achieved at 4 and maintained at 24 hours with ibrutinib 420 mg once-daily (Lancet Oncology 2013). Using simulated 140 or 280 mg doses, fewer patients attained complete BTK occupancy (Poggesi, AACR 2014). Objective: To evaluate ibrutinib dose adherence parameters on IRC-assessed progression-free survival (PFS), in accordance with iwCLL criteria, in patients with previously
-
303
Uri Rozovski,1 David M. Harris,2 Ping Li,2 Zhiming Liu,2 Srdana Grgurevic,2 Alessandra Ferrajoli,2 William G. Wierda,2 Srdan Verstovsek,2 Michael Keating,2 Zeev Estrov2
Cancer Institute, Boston, MA; 4The Leeds Teaching Hospitals, St.
S24
treated CLL. Design: Phase 3, randomized, open-label multicenter study of ibrutinib versus ofatumumab (RESONATE). Patients/ Intervention: Analysis included patients (1 prior treatment for CLL/SLL) who received ibrutinib 420 mg once-daily dose. Main Outcome Measures: Overall mean dose intensity (DI) defined as the proportion of administered vs. planned doses of 420 mg, and in first 8 weeks to avoid confounding (8-week mean dose intensity); PFS beyond 8 weeks; steady-state AUC/Cmax estimated using week 1 and 4 timepoints; missed doses 8 consecutive days with ibrutinib restarting after missed dose. Results: Overall mean DI was 95% (median 100%) with median 8.6 months of ibrutinib treatment (N¼195). 8-week mean DI was 96%. 73 of 79 patients (92%) with dose holds restarted at 420 mg. 3.6% of patients had dose reduction to 280 mg and 0.5% dose reduction to 140 mg. Fewer progression events occurred with overall mean DI above vs. below mean (12% vs. 33%). PFS was longer with 8-week mean DI above vs. below mean (median not reached vs. 6.9 months, P¼0.0127), and shorter in patients missing 8 (n¼57) vs. <8 (n¼136) consecutive days of ibrutinib (median 10.9 months vs. not reached). Higher mean DI was associated with fewer PFS events regardless of del17p, or TP53 mutation. No difference was seen in median PFS with lower vs. higher ibrutinib exposure (AUC or Cmax) in patients receiving ibrutinib 420 mg with pharmacokinetic assessment (n¼179) at weeks 1 and 4. Conclusions: Higher mean ibrutinib DI is associated with improved PFS, with patients missing 8 consecutive days experiencing more PFS events. These results support the clinical importance of sustained adherence to continuous once-daily 420 mg ibrutinib dosing in patients with previously treated CLL.
Clinical Lymphoma, Myeloma & Leukemia September 2015
Institute of Hematology, Davidoff Cancer Center, Beilinson Hospital,
Sackler School of Medicine, Tel-Aviv University, Israel; 2The University of Texas MD Anderson Cancer Center
In CLL STAT3 is constitutively phosphorylated on serine 727 residues and activates anti-apoptotic genes. Therefore, we hypothesized that STAT3 levels and rate of spontaneous apoptosis would be inversely correlated. To test levels of STAT3 we used quantitative western immunoblotting and found that levels were significantly higher in patients with high (N ¼ 32) compared to low (N ¼ 32) WBC counts (P ¼ 0.007). To test the rate of spontaneous apoptosis we stained the cells of 19 CLL patients with Annexin V and PI and found that apoptosis rates were highly correlated with white blood cell (WBC) counts (rp¼0.88, P< 0.0001). Accordingly, levels of cleaved PARP were 3 times higher in patients with high (N ¼ 32) compared to low (N ¼ 32) WBC counts (P ¼ 0.007). Hence, contrary to our hypothesis in high-count CLLs levels of STAT3 and rate of spontaneous apoptosis are both increased. Intrigued by these
Abstracts findings we wondered whether when present at high levels STAT3 induces apoptosis of CLL cells. To test this theory we first overexpress STAT3 in MM1 cells and found that overexpression of STAT3 upregulated caspase3 levels and induced apoptosis of MM1 cells. Because sequence analysis revealed that the promoter of caspase3 harbors putative STAT3 binding sites, we sought to determine whether STAT3 activates caspase-3. Chromatin immunoprecipitation (ChIP) and an electrophoretic mobility shift essay (EMSA) confirmed that STAT3 binds the caspase-3 promoter, and a Luciferase assay validated that STAT3 activates the caspase-3 promoter in IL-6-treated MM1 cells. To assess STAT3’s binding affinity to the promoter of caspase-3, we prepared serial dilutions of CLL cell DNA and, using ChIP and EMSA, found that STAT3’s binding affinities to p21 and c-Myc were 8 and 4 times higher than STAT’s binding affinity to caspase-3, suggesting that at high levels STAT3 are required to activate caspase-3. Taken together, these findings suggest that STAT3 has a previously unknown pro-apoptotic function. When present at high levels, STAT3 activates Caspase3 and induces apoptosis rather than providing CLL cells with survival advantage.
304 Therapeutic inhibition of HAUSP-PTEN network in chronic lymphocytic leukemia Giovanna Carrà,1,5 Cristina Panuzzo,1,5 Davide Torti,1,2 Guido Parvis,2 Sabrina Crivellaro,1 Mara Brancaccio,3 Angelo Guerrasio,1 Pier Paolo Pandolfi,4 Giuseppe Saglio,1,2 Alessandro Morotti1 1
Department of Clinical and Biological Sciences, University of Turin,
San Luigi Gonzaga Hospital, Orbassano, Italy; 2Division of Internal Medicine e Hematology, San Luigi Gonzaga Hospital, Orbassano, Italy; 3Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy; 4Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Boston, MA; 5Department of Medicine and Pathology, Beth Israel Deaconess Medical Center,
in CLL. Results: most primary CD19+ CLL lymphocytes display nuclear excluded and/or predominantly cytosolic PTEN compartmentalization when compared to PTEN “diffuse” normal lymphocytes. Loss of nuclear PTEN affects CLL cell growth, apoptosis and genomic stability, while genetic restoration of nuclear PTEN in CLL cell lines promotes growth arrest and apoptosis. PTEN nuclear exclusion is mediated by aberrant HAUSP over-expression/phosphorylation by Casein Kinase II. The CKII/HAUSP/PTEN network harbors therapeutic potentials. In primary CLL lymphocytes treatment with HAUSP inhibitors restores or enriches PTEN nuclear pool, with consequent growth arrest and apoptosis induction. Notably, HAUSP is also able to regulate the stability of an additional tumor suppressors: p53. Therefore, HAUSP inhibition is associated with either PTEN nuclear accumulation and p53 stabilization. Finally, in TP53 deleted CLL HAUSP inhibitors maintains pro-apoptotic role through the re-activation of PTEN nuclear functions. Conclusion: HAUSP-PTEN network is a new therapeutic target in CLL. HAUSP inhibitors promote PTEN nuclear pool restoration with consequent CLL selective and strong apoptosis induction. Grant Acknowledgement: Giovani Ricercatori, Ricerca finalizzata, Italian Ministero della Salute. Keywords: PTEN; HAUSP; Chronic lymphocytic leukemia; P53; tumor suppressor.
305 Diagnostic Role of Lumbar Puncture (LP) for the diagnosis of Central Nervous System (CNS) Involvement by Chronic Lymphocytic Leukemia(CLL)/Richter Syndrome (RS) Paolo Strati,1 Joon H. Uhm,1 Timothy Kaufmann,1 Sameer A. Parikh,1 Curtis A. Hanson,1 Kari G. Chaffee,1 Sara J. Achenbach,1 Timothy G. Call,1 Tait D. Shanafelt1 1
The Mayo Clinic
Harvard Medical School, Boston, MA
Context: Chronic Lymphocytic Leukemia (CLL) is a B-cell malignancy for which current therapies are effective in disease control but not in disease eradication. Lack of reliable treatment options for refractory and relapsing patients represents a primary unmet clinical need. The tumor suppressor PTEN plays an essential role in CLL pathogenesis. PTEN can be functionally inactivated in cancer, upon protein down-regulation/phosphorylation/delocalization with important therapeutic implications. In particular, loss of PTEN nuclear pool is a novel and challenging mechanism of PTEN inactivation. Nuclear PTEN is indeed able to regulate in a phosphatese independent manner cell growth and genome integrity maintenance. PTEN nuclear pool is preserved by mono-ubiquitination, with the de-ubiquitinase HAUSP acting as the major regulator of PTEN nuclear loss. Objective: 1) characterization of PTEN functional inactivation in CLL; 2) development of strategies to reactivate PTEN in CLL with consequent cancer selective apoptosis induction. Design: in primary CD19+ CLL lymphocytes evaluation of PTEN expression/localization/activity and mechanisms of regulation. Development of strategies to reactivate PTEN
Introduction: The CNS is the most common site of involvement by “extra-medullary” CLL and RS. The role of LP in its diagnosis remains controversial, and only case reports are available in literature to guide its interpretation. Methods: We used the Mayo Clinic CLL database to identify all patients with CLL/small lymphocytic lymphoma who were followed at our center between 01/1995 and 11/2014. Only patients for whom adequate treatment was recommended by a Mayo hematologist were considered to have a final diagnosis of CNS CLL/RS. Descriptive statistics were gathered, and correlations between these diagnoses and LP findings were evaluated. Categorical and continuous variables were evaluated using the 2 or Fisher exact tests and the Mann-Whitney test, as appropriate. Results: Of 4317 identified patients, 176 (4%) underwent a LP because of neurological symptoms. The final diagnosis was CNS CLL in 17 (10%) patients, CNS RS in 12 (7%), infection in 40 (23%), autoimmunity in 31 (18%), other cancer in 5 (2%), and other etiology in 70 (40%). Among the 145 patients who had a negative CSF cytology for CLL/RS, 11% were diagnosed with clinically significant CNS involvement by CLL or RS on tissue biopsy. Among the 31 patients with CSF cytology demonstrating CNS CLL/RS, 18 (58%)
Clinical Lymphoma, Myeloma & Leukemia September 2015
- S25
302 Adherence To The Ibrutinib 420 mg Dose Administered To Patients With Previously Treated CLL Jan A. Burger, MD, PhD,1 Paul M. Barr, MD,2 Jennifer R. Brown, MD, PhD,3 Peter Hillmen, MB ChB, PhD,4 Susan O’Brien, MD,1 Jacqueline C. Barrientos, MD,5 Nishitha M. Reddy, MBBS, MScl,6 Steven Coutre, MD,7 Stephen P. Mulligan, MBBS, MD, FRACP, FRCPA,8 Ulrich Jaeger, MD,9 Richard R. Furman, MD,10 Florence Cymbalista, MD,11 Marco Montillo, MD,12 Claire Dearden, MD,13 Tadeusz Robak, MD, PhD,14 Carol Moreno, MD,15 John Pagel, MD, PhD,16 Samuel Suzuki, MS, MBA,17 Juthamas Sukbuntherng, PhD,17 George Cole, MD,17 Danelle F. James, MD, MAS,17 John C. Byrd, MD18 1
University of Texas MD Anderson Cancer Center, Houston, TX; Wilmot Cancer Institute, University of Rochester, NY; 3Dana-Farber
2
Signal transducer and activator of transcription (STAT)-3 is a double edged sword in CLL cells
Nashville, TN; 7Stanford University School of Medicine, Stanford, CA; 8
1
5
James Institute of Oncology, Leeds, UK; North Shore-LIJ Cancer Institute, Lake Success, NY; 6Vanderbilt-Ingram Cancer Center, Royal North Shore Hospital, Sydney, Australia; 9Medical University of
Vienna, Vienna, Austria;
10
Weill Cornell Medical College/New York
Presbyterian Hospital, New York, NY; 11Hôpital Avicenne, Paris, France; 12Niguarda Ca’ Granda Hospital, Milan, Italy; 13Royal Marsden Hospital, London, UK; Poland;
14
Medical University of Lodz, Lodz,
15
Hospital de la Santa Creu Sant Pau, Barcelona, Spain;
16
Swedish Cancer Institute, Seattle, WA;
Abbvie Company, Sunnyvale, CA;
17
Pharmacyclics LLC, an
18
The Ohio State University Med-
ical Center, Columbus, OH
Context: Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton’s tyrosine kinase (BTK). BTK active site occupancy (median 90%) is achieved at 4 and maintained at 24 hours with ibrutinib 420 mg once-daily (Lancet Oncology 2013). Using simulated 140 or 280 mg doses, fewer patients attained complete BTK occupancy (Poggesi, AACR 2014). Objective: To evaluate ibrutinib dose adherence parameters on IRC-assessed progression-free survival (PFS), in accordance with iwCLL criteria, in patients with previously
-
303
Uri Rozovski,1 David M. Harris,2 Ping Li,2 Zhiming Liu,2 Srdana Grgurevic,2 Alessandra Ferrajoli,2 William G. Wierda,2 Srdan Verstovsek,2 Michael Keating,2 Zeev Estrov2
Cancer Institute, Boston, MA; 4The Leeds Teaching Hospitals, St.
S24
treated CLL. Design: Phase 3, randomized, open-label multicenter study of ibrutinib versus ofatumumab (RESONATE). Patients/ Intervention: Analysis included patients (1 prior treatment for CLL/SLL) who received ibrutinib 420 mg once-daily dose. Main Outcome Measures: Overall mean dose intensity (DI) defined as the proportion of administered vs. planned doses of 420 mg, and in first 8 weeks to avoid confounding (8-week mean dose intensity); PFS beyond 8 weeks; steady-state AUC/Cmax estimated using week 1 and 4 timepoints; missed doses 8 consecutive days with ibrutinib restarting after missed dose. Results: Overall mean DI was 95% (median 100%) with median 8.6 months of ibrutinib treatment (N¼195). 8-week mean DI was 96%. 73 of 79 patients (92%) with dose holds restarted at 420 mg. 3.6% of patients had dose reduction to 280 mg and 0.5% dose reduction to 140 mg. Fewer progression events occurred with overall mean DI above vs. below mean (12% vs. 33%). PFS was longer with 8-week mean DI above vs. below mean (median not reached vs. 6.9 months, P¼0.0127), and shorter in patients missing 8 (n¼57) vs. <8 (n¼136) consecutive days of ibrutinib (median 10.9 months vs. not reached). Higher mean DI was associated with fewer PFS events regardless of del17p, or TP53 mutation. No difference was seen in median PFS with lower vs. higher ibrutinib exposure (AUC or Cmax) in patients receiving ibrutinib 420 mg with pharmacokinetic assessment (n¼179) at weeks 1 and 4. Conclusions: Higher mean ibrutinib DI is associated with improved PFS, with patients missing 8 consecutive days experiencing more PFS events. These results support the clinical importance of sustained adherence to continuous once-daily 420 mg ibrutinib dosing in patients with previously treated CLL.
Clinical Lymphoma, Myeloma & Leukemia September 2015
Institute of Hematology, Davidoff Cancer Center, Beilinson Hospital,
Sackler School of Medicine, Tel-Aviv University, Israel; 2The University of Texas MD Anderson Cancer Center
In CLL STAT3 is constitutively phosphorylated on serine 727 residues and activates anti-apoptotic genes. Therefore, we hypothesized that STAT3 levels and rate of spontaneous apoptosis would be inversely correlated. To test levels of STAT3 we used quantitative western immunoblotting and found that levels were significantly higher in patients with high (N ¼ 32) compared to low (N ¼ 32) WBC counts (P ¼ 0.007). To test the rate of spontaneous apoptosis we stained the cells of 19 CLL patients with Annexin V and PI and found that apoptosis rates were highly correlated with white blood cell (WBC) counts (rp¼0.88, P< 0.0001). Accordingly, levels of cleaved PARP were 3 times higher in patients with high (N ¼ 32) compared to low (N ¼ 32) WBC counts (P ¼ 0.007). Hence, contrary to our hypothesis in high-count CLLs levels of STAT3 and rate of spontaneous apoptosis are both increased. Intrigued by these
Abstracts findings we wondered whether when present at high levels STAT3 induces apoptosis of CLL cells. To test this theory we first overexpress STAT3 in MM1 cells and found that overexpression of STAT3 upregulated caspase3 levels and induced apoptosis of MM1 cells. Because sequence analysis revealed that the promoter of caspase3 harbors putative STAT3 binding sites, we sought to determine whether STAT3 activates caspase-3. Chromatin immunoprecipitation (ChIP) and an electrophoretic mobility shift essay (EMSA) confirmed that STAT3 binds the caspase-3 promoter, and a Luciferase assay validated that STAT3 activates the caspase-3 promoter in IL-6-treated MM1 cells. To assess STAT3’s binding affinity to the promoter of caspase-3, we prepared serial dilutions of CLL cell DNA and, using ChIP and EMSA, found that STAT3’s binding affinities to p21 and c-Myc were 8 and 4 times higher than STAT’s binding affinity to caspase-3, suggesting that at high levels STAT3 are required to activate caspase-3. Taken together, these findings suggest that STAT3 has a previously unknown pro-apoptotic function. When present at high levels, STAT3 activates Caspase3 and induces apoptosis rather than providing CLL cells with survival advantage.
304 Therapeutic inhibition of HAUSP-PTEN network in chronic lymphocytic leukemia Giovanna Carrà,1,5 Cristina Panuzzo,1,5 Davide Torti,1,2 Guido Parvis,2 Sabrina Crivellaro,1 Mara Brancaccio,3 Angelo Guerrasio,1 Pier Paolo Pandolfi,4 Giuseppe Saglio,1,2 Alessandro Morotti1 1
Department of Clinical and Biological Sciences, University of Turin,
San Luigi Gonzaga Hospital, Orbassano, Italy; 2Division of Internal Medicine e Hematology, San Luigi Gonzaga Hospital, Orbassano, Italy; 3Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy; 4Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Boston, MA; 5Department of Medicine and Pathology, Beth Israel Deaconess Medical Center,
in CLL. Results: most primary CD19+ CLL lymphocytes display nuclear excluded and/or predominantly cytosolic PTEN compartmentalization when compared to PTEN “diffuse” normal lymphocytes. Loss of nuclear PTEN affects CLL cell growth, apoptosis and genomic stability, while genetic restoration of nuclear PTEN in CLL cell lines promotes growth arrest and apoptosis. PTEN nuclear exclusion is mediated by aberrant HAUSP over-expression/phosphorylation by Casein Kinase II. The CKII/HAUSP/PTEN network harbors therapeutic potentials. In primary CLL lymphocytes treatment with HAUSP inhibitors restores or enriches PTEN nuclear pool, with consequent growth arrest and apoptosis induction. Notably, HAUSP is also able to regulate the stability of an additional tumor suppressors: p53. Therefore, HAUSP inhibition is associated with either PTEN nuclear accumulation and p53 stabilization. Finally, in TP53 deleted CLL HAUSP inhibitors maintains pro-apoptotic role through the re-activation of PTEN nuclear functions. Conclusion: HAUSP-PTEN network is a new therapeutic target in CLL. HAUSP inhibitors promote PTEN nuclear pool restoration with consequent CLL selective and strong apoptosis induction. Grant Acknowledgement: Giovani Ricercatori, Ricerca finalizzata, Italian Ministero della Salute. Keywords: PTEN; HAUSP; Chronic lymphocytic leukemia; P53; tumor suppressor.
305 Diagnostic Role of Lumbar Puncture (LP) for the diagnosis of Central Nervous System (CNS) Involvement by Chronic Lymphocytic Leukemia(CLL)/Richter Syndrome (RS) Paolo Strati,1 Joon H. Uhm,1 Timothy Kaufmann,1 Sameer A. Parikh,1 Curtis A. Hanson,1 Kari G. Chaffee,1 Sara J. Achenbach,1 Timothy G. Call,1 Tait D. Shanafelt1 1
The Mayo Clinic
Harvard Medical School, Boston, MA
Context: Chronic Lymphocytic Leukemia (CLL) is a B-cell malignancy for which current therapies are effective in disease control but not in disease eradication. Lack of reliable treatment options for refractory and relapsing patients represents a primary unmet clinical need. The tumor suppressor PTEN plays an essential role in CLL pathogenesis. PTEN can be functionally inactivated in cancer, upon protein down-regulation/phosphorylation/delocalization with important therapeutic implications. In particular, loss of PTEN nuclear pool is a novel and challenging mechanism of PTEN inactivation. Nuclear PTEN is indeed able to regulate in a phosphatese independent manner cell growth and genome integrity maintenance. PTEN nuclear pool is preserved by mono-ubiquitination, with the de-ubiquitinase HAUSP acting as the major regulator of PTEN nuclear loss. Objective: 1) characterization of PTEN functional inactivation in CLL; 2) development of strategies to reactivate PTEN in CLL with consequent cancer selective apoptosis induction. Design: in primary CD19+ CLL lymphocytes evaluation of PTEN expression/localization/activity and mechanisms of regulation. Development of strategies to reactivate PTEN
Introduction: The CNS is the most common site of involvement by “extra-medullary” CLL and RS. The role of LP in its diagnosis remains controversial, and only case reports are available in literature to guide its interpretation. Methods: We used the Mayo Clinic CLL database to identify all patients with CLL/small lymphocytic lymphoma who were followed at our center between 01/1995 and 11/2014. Only patients for whom adequate treatment was recommended by a Mayo hematologist were considered to have a final diagnosis of CNS CLL/RS. Descriptive statistics were gathered, and correlations between these diagnoses and LP findings were evaluated. Categorical and continuous variables were evaluated using the 2 or Fisher exact tests and the Mann-Whitney test, as appropriate. Results: Of 4317 identified patients, 176 (4%) underwent a LP because of neurological symptoms. The final diagnosis was CNS CLL in 17 (10%) patients, CNS RS in 12 (7%), infection in 40 (23%), autoimmunity in 31 (18%), other cancer in 5 (2%), and other etiology in 70 (40%). Among the 145 patients who had a negative CSF cytology for CLL/RS, 11% were diagnosed with clinically significant CNS involvement by CLL or RS on tissue biopsy. Among the 31 patients with CSF cytology demonstrating CNS CLL/RS, 18 (58%)
Clinical Lymphoma, Myeloma & Leukemia September 2015
- S25