scholarly journals Steroid Dependent Recalcitrant Well's Syndrome in a Patient with Chronic Lymphocytic Leukemia (CLL) Responding to Hydroxychloroquine (HCQS)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5579-5579
Author(s):  
Prabhsimranjot Singh ◽  
Makardhwaj S Shrivastava ◽  
Audrik Perez ◽  
Kenneth Grossman ◽  
Daniel Benasher ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Conflicts Of Interest ◽  
Oral Prednisone ◽  
Case Series ◽  
Lymphocytic Leukemia ◽  
Prolonged Treatment ◽  
Steroid Dependent ◽  
Eosinophilic Cellulitis ◽  
Granulomatous Dermatitis ◽  
Wells Syndrome

Abstract Introduction Well's syndrome is an uncommon skin condition with cosmetically unpleasant outcomes. It was initially described by Dr. GC wells in 1971 as recurrent granulomatous dermatitis with eosinophilia(1). Case A 69-years-old woman with well controlled CLL presented with pruritic, papular eruptions & ulcerations over extremities and back (Figure 1). She denied asthma or atopy, insect bite, or new medications. Skin biopsy (Figure 2) revealed perivascular & interstitial infiltrate composed of lymphocytes, histiocytes, neutrophils and eosinophils. Antibiotics, antihistamines, dapsone, steroid injection failed to control her symptoms. She responded to oral prednisone. On attempted steroid taper she experienced disease flares. She was transitioned eventually to HCQS. Prednisone was discontinued. She remained in remission on HCQS. Discussion Well's syndrome is often described as exaggerated response to insect bite; it may occur without an inciting event, commonly involves extremities, may precede or follow the diagnosis of CLL and has no association with disease course (2). The lesions range from itchy papules, plaques to edematous vesiculo-bullous lesions and panniculitis or ulcerations (3) and can result in disfiguring skin atrophy (4). Pathology reveals eosinophilic or lymphohistiocytic infiltrates (5). Use of glucocorticoids, antihistamines, immunoglobulins, dapsone, ultra violet-B therapy for treatment has been described (2, 5) and may require prolonged treatment (6). Multiple recurrences are often seen in recalcitrant cases (7). Well's syndrome should be considered in differential diagnosis of skin lesions in patients with CLL. HCQS offers an alternative to long term steroid use in its management. References 1. Wells GC. Recurrent granulomatous dermatitis with eosinophilia. Trans St Johns Hosp Dermatol Soc. 1971;57(1):46-56. 2. Bairey O, Goldschmidt N, Ruchlemer R, Tadmor T, Rahimi-Levene N, Yuklea M, et al. Insect-bite-like reaction in patients with chronic lymphocytic leukemia: a study from the Israeli Chronic Lymphocytic Leukemia Study Group. Eur J Haematol. 2012;89(6):491-6. 3. Rodriguez-Lojo R, Almagro M, Perez-varela L, et al. Eosinophilic Panniculitis and Insect Bite-Like Eruption in a Patient with Chronic Lymphocytic Leukaemia: A Spectrum of the Same Entity. Dermatology Research and Practice. 2010;2010. 4. Gilliam AE, Bruckner AL, Howard RM, Lee BP, Wu S, Frieden IJ. Bullous "cellulitis" with eosinophilia: case report and review of Wells' syndrome in childhood. Pediatrics. 2005;116(1):e149-55. 5. Davis MDP, Perniciaro C, Dahl PR, Randle HW, McEvoy MT, Leiferman KM. Exaggerated arthropod-bite lesions in patients with chronic lymphocytic leukemia: A clinical, histopathologic, and immunopathologic study of eight patients. Journal of the American Academy of Dermatology. 1998;39(1):27-35. 6. Sinno H, Lacroix JP, Lee J, Izadpanah A, Borsuk R, Watters K, et al. Diagnosis and management of eosinophilic cellulitis (Wells' syndrome): A case series and literature review. Can J Plast Surg. 2012;20(2):91-7. 7. Moossavi M, Mehregan DR. Wells' syndrome: a clinical and histopathologic review of seven cases. Int J Dermatol. 2003;42(1):62-7. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Safe Start of Ibrutinib in Patients with Chronic Lymphocytic Leukemia and Uncontrolled Autoimmune Hemolytic Anemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5560-5560 ◽  
Author(s):  
Alejandro Garcia-Horton ◽  
Rosanne St. Bernard ◽  
Alejandro Lazo-Langner ◽  
Anargyros Xenocostas ◽  
Joy Mangel ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Conflicts Of Interest ◽  
Case Reports ◽  
Laboratory Data ◽  
Case Series ◽  
Lymphocytic Leukemia ◽  
Positive Direct

Abstract It is estimated that 4-10% of patients with chronic lymphocytic leukemia (CLL) will develop autoimmune hemolytic anemia (AIHA) over the course of their disease. Ibrutinib has proven to be effective in treatment of relapsed, refractory, 17p deleted, and treatment naïve CLL. The effect of ibrutinib on AIHA in the context of CLL has not been established since patients with active hemolysis were excluded from major trials. In this abstract, we present a case series of patients that were actively hemolyzing at the start of ibrutinib therapy and in which their AIHA achieved prolonged response. Patient characteristics and laboratory data are shown in Table. Five patients (3 women, 2 men), median age 61 years (range 57 to 78), with CLL and active, uncontrolled AIHA at the time of ibrutinib initiation were identified. Uncontrolled AIHA was defined as anemia with evidence of hemolysis (at least two of the following: increased reticulocyte count, elevated lactate dehydrogenase, elevated indirect bilirubin, and reduced haptoglobin and a positive direct antiglobulin test (DAT)). Patients had a median hemoglobin of 70 g/L (range 69-96) prior to start of ibrutinib and 3 of them required transfusion support for symptomatic anemia. All patients were receiving prednisone for management of AIHA at the time of ibrutinib initiation and had been on it for a median of 10 days (range 9 - 25) without AIHA resolution. 1 patient received intravenous immunoglobulin concurrently. All patients had received at least one line of therapy for CLL in the past and 3 had experienced previous AIHA responsive to steroids. AIHA in 2 patients was related to previous fludarabine exposure but had responded to a prednisone tapering schedule and were off steroids by the time of the new AIHA flare. Median hemoglobin of 130 g/L (range 113-149) was reached at time of AIHA response. All 5 patients tolerated 420mg oral daily of ibrutinib therapy and AIHA was controlled in a median of 6.5 weeks (range 6-10). Discontinuation of steroids was achieved in all patients at a median of 10 weeks (range 6-17) without evidence of further hemolysis. All patients except one are receiving ongoing follow up and have been followed up for a median of 130 weeks (range 15-150) since ibrutinib start. Patients have not shown evidence of AIHA relapse and continue off AIHA treatment (prednisone). One patient required discontinuation of ibrutinib 6 months after starting due to neutropenia but there was no evidence of AIHA relapse in follow up. The patient has passed away from unrelated GI bleed 2 years after the initial AIHA event. This is the largest case series to our knowledge on the safe start of ibrutinib in CLL complicated by active AIHA. Hemolysis in all patients responded to a short prednisone taper with ibrutinib concurrently and obtained a sustained response at follow up without any flare ups or further AIHA treatment use. These cases suggest that it is safe to start ibrutinib during uncontrolled, active hemolysis in contrast to 2 previous case reports that suggested causal relationship between ibrutinib and onset of severe CLL-associated AIHA (Rider et al, 2015; Hodskins et al, 2014). As previously reported, AIHA occurrence or relapse once ibrutinib has been started is rare (Rogers et al, 2016). Disclosures No relevant conflicts of interest to declare.

scholarly journals Akt Inhibitors Induce Apoptosis in Chronic Lymphocytic Leukemia Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1731-1731
Author(s):  
Mercè de Frias ◽  
Daniel Iglesias-Serret ◽  
Ana M Cosialls ◽  
Llorenç Coll-Mulet ◽  
Antonio F Santidrián ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Conflicts Of Interest ◽  
Therapeutic Option ◽  
Mrna Level ◽  
Lymphocytic Leukemia ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Healthy Donors ◽  
Induced Apoptosis

Abstract Abstract 1731 Poster Board I-757 Phosphatidylinositol-3-kinase (PI3K)/Akt pathway has been described to be critical in the survival of chronic lymphocytic leukemia (CLL) cells. Here, we have analyzed the effect of two selective chemical inhibitors of Akt (Akti-1/2 and A-443654) in the survival of CLL cells. We studied by cytometric analysis the cytotoxic effects of Akt inhibitors on peripheral B and T lymphocytes from patients with CLL and from healthy donors. Both inhibitors induced apoptosis in CLL cells in a dose-dependent manner. Moreover, B cells from CLL samples were more sensitive to Akt inhibitors than T cells from CLL samples, and B or T cells from healthy donors. Survival factors for CLL cells, such as IL-4 and SDF-1a, were not able to block the apoptosis induced by both Akt inhibitors. We studied the changes induced by Akti-1/2 and A-443654 at mRNA level by performing reverse transcriptase multiplex ligation–dependent probe amplification (RT-MLPA). Akti-1/2 did not induce any change in the mRNA expression profile of genes involved in apoptosis, while A-443654 induced some changes, including an increase in NOXA and PUMA mRNA levels, suggesting the existence of additional targets for A-443654. We also studied the changes induced by both Akt inhibitors in some BCL-2 protein family members on CLL cells by Western blot. Both inhibitors induced an increase in PUMA and NOXA protein levels, and a decrease in MCL-1 protein level. Moreover, Akti-1/2 and A-443654 induced apoptosis irrespective of TP53 status. These results demonstrate that Akt inhibitors induce apoptosis of CLL cells and might be a new therapeutic option for the treatment of CLL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Epidemiology Data of Patients with Chronic Lymphocytic Leukemia in West Central Mexico

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5269-5269
Author(s):  
Virgina Campos-Cabrera ◽  
Gregorio Campos-Cabrera ◽  
Salvador Campos-Cabrera ◽  
Alicia Rivera-Trujillo ◽  
Sonia Hernandez-Rodriguez ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Conflicts Of Interest ◽  
Low Frequency ◽  
Epidemiological Data ◽  
Lymphocytic Leukemia ◽  
Female Ratio ◽  
Specific Protocol ◽  
Male Female Ratio ◽  
Epidemiology Data ◽  
International Data

Abstract Background: chronic lymphocytic leukemia (CLL) is a rare disease in Mexican mestizos (Br J Haematol 2015;169:909-911 and Int J Hematol 1999;69:253-255). No significant data on epidemiology is available. Methods: epidemiological data from samples referred to Laboratorios Fatima de Michoacan for flow cytometry immunophenotyping for neoplastic hematological disease. Results: 229 samples were received, 52 were diagnosed as CLL (22.7 %). Male 32 and female 20, ratio 1.6 a 1. Age from 33 to 89 years, average 66; 31 to 40 one, 41 to 50 two, 51 to 60 eleven, 61 to 70 twenty four, 71 to 80 ten, more than 81 four. Expression of CD 38 and ZAP-70 in three; only CD38 in 2, only ZAP-70 in three. Conclusions: similar results in male female ratio and age of presentation are noted as compared with international data. Low frequency of expression in CD38 and ZAP-70 may be due pre-analytic phase in the management of the sample. As a regional group we are trying to have epidemiology data in non-malignant and malignant hematological diseases to form specific protocol treatments. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Hodgkin lymphoma arising in patients with chronic lymphocytic leukemia: outcomes from a large multi-center collaboration

Haematologica ◽  
2020 ◽  
pp. 0-0
Author(s):  
Deborah M. Stephens ◽  
Ken Boucher ◽  
Elizabeth Kander ◽  
Sameer A. Parikh ◽  
Erin M. Parry ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Hodgkin Lymphoma ◽  
Hematopoietic Cell Transplantation ◽  
Small Sample Size ◽  
Case Series ◽  
Standard Of Care ◽  
Median Number ◽  
Small Sample ◽  
Lymphocytic Leukemia ◽  
Treatment Type

Chronic lymphocytic leukemia (CLL) patients who develop Hodgkin lymphoma (HL) have limited survival. No current therapeutic standard of care exists. We conducted a multi-center retrospective study of patients with Hodgkin Transformation (HT) of CLL. Clinicobiologic characteristics, treatment type, and survival outcomes were analyzed and compared with historic case series. Ninety-four patients were identified. Median age at HT was 67 years (range, 38-85). Median time from CLL diagnosis to HT was 5.5 years (range, 0-20.2). Prior to HT, patients received a median of 2 therapies for CLL (range, 0-12). As initial therapy for HT, 61% (n=62) received ABVD-based regimens (adriamycin, bleomycin, vinblastine, and dacarbazine). Seven (7%) patients received hematopoietic cell transplantation (HCT) while in first complete remission (CR1). The median number of treatments for HT per patient was 1 (range, 0-5) with 59 (61%) patients only receiving one line of therapy. After HT, patients had a median follow-up of 1.6 years (range, 0-15.1). Two-year overall survival (OS) after HT diagnosis was 72% (95%CI 62-83%). The patients who received standard ABVD-based therapy had a median OS of 13.2 years. Although limited by small sample size, the patients who underwent HCT for HT in CR1 had a similar 2-year OS (n=7; 67%) compared to patients who did not undergo HCT for HT in CR1 (n=87; 72%; p=0.46). In this multi-center study, HT patients treated with ABVD-based regimens had prolonged survival supporting the use of these regimens as standard of care for these patients.

Case of Wells’ syndrome: A rare association with the clinical course of chronic lymphocytic leukemia

2018 ◽  
Vol 46 (2) ◽  
pp. e57-e59 ◽  
Author(s):  
Chika Omigawa ◽  
Takeshi Namiki ◽  
Makiko Ueno ◽  
Tsukasa Ugajin ◽  
Keiko Miura ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Course ◽  
Lymphocytic Leukemia ◽  
Rare Association ◽  
Wells Syndrome

Comparative Efficacy of First-Line Chemotherapy-Free Combinations in Chronic Lymphocytic Leukemia (CLL): A Network Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 25-26
Author(s):  
Philip A Haddad ◽  
Nowell Ganey ◽  
Kevin M. Gallagher
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
English Language ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Meta Analysis ◽  
The Elderly ◽  
Lymphocytic Leukemia ◽  
First Line ◽  
Significant Difference ◽  
Anti Cd20

Introduction: Chronic Lymphocytic Leukemia (CLL) is an incurable B-cell malignancy which disproportionately affects the elderly. Although first-line chemoimmunotherapy (CIT) improved CLL clinical outcomes, recent randomized trials revealed superior outcomes with novel chemotherapy-free combinations (CFC) incorporating anti-CD20 monoclonal antibodies and inhibitors of BTK or Bcl-2. So far, these CFC have not been compared head-to-head. We conducted this network meta-analysis to evaluate their relative efficacy to each other. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language; diagnosis of CLL; trials that explored the efficacy of first-line CFC with Obinutuzumab (O), Rituximab (R), Ibrutinib (IB), Acalabrutinib (ACAL), Venetoclax (VEN) compared to standard CIT that included Chlorambucil (CHLOR) with either R or O, Bendamustine+Rituximab, or Fludarabine+ Cyclophosphamide+R; and phase 3 randomized studies reporting responses, progression, death, and adverse (AE) events. A frequentists network meta-analysis was conducted using netmeta package and random-effects model. Results: Five studies comprising a total of 2,272 participants were included. When O-based CFC data was analyzed, only ACAL-O had a significant lower relative risk (RR) of progression and death (P&D). There were no significant differences with respect to overall response rates (ORR), complete remission (CR), minimal residual disease (MRD), or grade >3 adverse events (Grd3+) among O-based CFC. When R-based CFC data was analyzed, IB and IB-R were not different with respect to RR of P&D, ORR, CR, MRD, or Grd3+. When the data was analyzed as CFC versus combined CIT, only ACAL-O was found to be significantly superior to other O- and R-based CFC with respect to RR of P&D. ORR and Grad3+ rates of O- and R-based CFC were not significantly different. While ACAL-O, IB-O, and VEN-O had superior CR and MRD rates compared to other CFC, there were no significant differences among each other. Conclusions: This network meta-analysis is the first to compare and rank first-line CFC therapies in CLL. It indicates that ACAL-O has a superior profile having the lowest RR of P&D without significant difference in Grd3+ among CFC. Disclosures No relevant conflicts of interest to declare.

Abnormal Free Light Chain Ratios in Chronic Lymphocytic Leukemia: A New Prognostic Factor?.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1237-1237 ◽  
Author(s):  
Johannes Matschke ◽  
Lewin Eisele ◽  
Ludger Sellmann ◽  
Ulrich Duehrsen ◽  
Jan Duerig ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Chronic Lymphocytic Leukemia ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Risk Groups ◽  
Typical Feature ◽  
Lymphocytic Leukemia ◽  
Al Amyloidosis ◽  
Abnormal Ratio

Abstract Abstract 1237 Poster Board I-259 Introduction Free light chains (FLC) have prognostic significance in monoclonal gammopathy of undetermined significance, solitary plasmocytoma of bone, smouldering myeloma, multiple myeloma, Waldenstroms macroglobulinaemia and AL amyloidosis. Although monoclonal protein secretion is a typical feature of plasma cell dyscrasias, it can also be detected in other B cell malignancies including chronic lymphocytic leukemia (CLL). Recent data suggest a significant correlation between abnormal ratio of FLC and outcome. Therefore, we investigated FLC in a large cohort of 120 patients in order to assess the role of FLC in CLL. Methods and Results Plasma samples which had been previously cryopreserved and collected at the time before the initiation of therapy or six months after finishing therapy were used. The levels of FLC were assessed using nephelometric immunoassays (The Binding Site) and quantified nephelometrically with the BNII analyser. A normal FLC range (κlγ) was defined as 0.26-1.65. Moreover, in all cases we evaluated the M band on immunofixation (IF). Abnormal FLC ratios were found in 71 patients (59%) whereas the IF was positive in only 32 cases (27%). In 48 cases the FLC ratio was positive while IF was negative and in only 9 cases the IF was positive while the FLC ratio was normal. In total, 23 patients had both a positive IF and an abnormal FLC ratio. Patients with an abnormal FLC ratio for γ had a significantly shorter treatment-free survival (TFS) than patients with an abnormal ratio for κ or with a normal FLC ratio (median TFS: 34 versus 78 versus 109 months, p=0.042). Evaluation of several disease characteristics in association with FLC of the patients' B-CLL cells showed no significant differences for FLC in the different risk groups (ZAP-70 status, CD38 status, cytogenetics and Binet stage) suggesting no correlation of the FLC with these already established adverse prognostic factors. Conclusion FLC can be detected in a substantial fraction of patients with CLL and the FLC technique improves detection of M-proteins. Moreover, an abnormal FLC ratio is associated with worse outcome, particularly those with a low abnormal FLC ratio. Evaluation of the prognostic significance of abnormal FLC in a larger cohort is currently under way. This data will be presented at the meeting. Future studies are warranted to elucidate the role of FLC as biomarkers of disease and as a prognostic factor for response. Disclosures No relevant conflicts of interest to declare.

Monocytes/Macrophages Are the Major Targets of the CCL3 Chemokine Produced by CD38+CD49d+ Chronic Lymphocytic Leukemia Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2350-2350
Author(s):  
Antonella Zucchetto ◽  
Dania Benedetti ◽  
Claudio Tripodo ◽  
Riccardo Bomben ◽  
Fleur Bossi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
Conflicts Of Interest ◽  
Cell Types ◽  
Lymphocytic Leukemia ◽  
Bone Marrow Biopsies ◽  
Tnf Α ◽  
Significant Difference

Abstract Abstract 2350 Poster Board II-327 Introduction: CD38 and CD49d are associated negative prognosticators in chronic lymphocytic leukemia (CLL). Recent gene expression profiling studies comparing CLL cases expressing low versus high levels of CD38 and CD49d, identified CCL3 as a gene upregulated by CD38+CD49d+ CLL. The release of CCL3 by cultured CLL cells was also demonstrated upon CD38 triggering, and CCL3 protein was found in CLL cells from bone marrow biopsies (BMB) of CD38+ cases (Zucchetto et al., Cancer Res, 2009; 69:4001-9). Given the role of CCL3 as potent chemoattractant for different cell types, we aimed at identifying the major targets of CCL3, as produced by CD38+CD49d+ CLL cells. Methods: CLL infiltrates of BMB were characterized by immunohistochemistry (IHC). Expression of the CCL3 receptors CCR1 and CCR5 by PB CLL subpopulations was evaluated by flow cytometry. T lymphocyte and monocyte migrations were performed by in-vitro transwell chemotaxis assays. Results: IHC analysis of BMB from 16 CLL cases revealed a higher number of infiltrating CD68+ cells in the context of CLL-involved areas of BMB from CD38+CD49d+CCL3+, compared to CD38−CD49d−CCL3− cases (p=0.01). CD3+ lymphocytes were interspersed in the CLL aggregates, but with no significant difference between the two subgroups. Evaluation of CCR1 and CCR5 in PB cell subpopulations from 40 CLL cases expressing or not surface CD38 and CD49d, showed the highest mean fluorescence intensity (MFI) levels for both CCR1 (624±60) and CCR5 (64±9) in the monocytic component, irrespective of CD38 and CD49d expression by CLL cells. Conversely, both CLL cells and residual T lymphocytes showed low MFI levels for CCR1 (19±4 and 14±3) and CCR5 (21±2 and 20±2). High CCR1 and CCR5 expression levels were detected in in-vitro differentiated monocytes from purified PB cells of four CD38+CD49d+ CLL. Accordingly, CCR1 expression was documented in macrophage-like cells in BMB from CD38+CD49d+ CLL. Next, we evaluated the capability of purified monocytes and T lymphocytes from 10 CLL cases to migrate in response to CCL3. In keeping with the strong expression of CCR1, monocytes migrated toward CCL3 at a concentration of 3 ng/mL (migration index, MI= 8.8±0.9, p=0.03), whereas T lymphocytes required a higher CCL3 concentration (100 ng/mL) to display slight migration capability (MI= 1.6±0.2, p=ns). The increased infiltration of macrophages in BMB from CCL3-producing CD38+CD49d+ CLL, prompted us to verify the capability of CCL3-stimulated macrophages to induce the expression by endothelial cells (EC) of the CD49d specific ligand VCAM-1. By using two different EC models (HUVEC and ADMEC), we documented a significant up-regulation of VCAM-1 by EC exposed to conditioned media (CM) collected from cultures of macrophages challenged in-vitro with CCL3 (p=0.002). Notably, increased levels of the pro-inflammatory cytokine TNF-α were detected in CCL3-CM (p=0.006), and neutralization of TNF-α by specific antibodies reverted the capability of CCL3-CM to induce VCAM-1 by EC models. In agreement with these in-vitro data, we found a more prominent meshwork of VCAM-1+ stromal/endothelial cells in lymphoid infiltrates from CD38+CD49d+ CLL compared to CD38−CD49d− cases (p=0.002), and engagement of CD49d by VCAM-1 was able to significantly delay the spontaneous apoptosis observed in cultured CLL cells. Conclusions: CD68+ monocytes/macrophages are likely the main targets for the CLL3 chemokine produced by CD38+CD49d+ CLL cells, and are active in determining, through the release of TNF-α and other yet unidentified cytokines, the overexpression of VCAM-1 by endothelial cells. Experiments aimed at investigating further roles of CD68+ monocytes/macrophage in CLL are currently matter of study. Disclosures: No relevant conflicts of interest to declare.

Plasma Circulating Caspase-3 Index as a Biomarker in Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4381-4381
Author(s):  
Jean-Marie Bruey ◽  
Zeev Estrov ◽  
Hagop Kantarjian ◽  
Susan O'Brien ◽  
Michael Keating ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Normal Control ◽  
Caspase 3 ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Surrogate Marker ◽  
Quantitative Measure ◽  
Lymphocytic Leukemia ◽  
Mutation Status ◽  
Control Subjects

Abstract Abstract 4381 Because of the accumulation of lymphocytes and relative paucity of proliferating cells characteristic of B-cell chronic lymphocytic leukemia (CLL), defective apoptosis has been proposed as a key step in the pathogenesis of this disease. Activity levels of the proapoptotic enzyme caspase-3 have been used as a simple, quantitative measure of ongoing apoptosis in various cancers. Here we explored the clinical value of assessing apoptosis levels in patients with CLL, using caspase-3 activity in plasma as a surrogate marker for apoptosis. The study included 194 patients with CLL and 96 normal control subjects. Caspase-3 activity was measured in plasma samples by incubation with the substrate DEVD. Circulating caspase-3 activity was detectable in the plasma of all CLL patients and normal control subjects, but was significantly (P=0.005) lower in CLL patients (median=7.49; range=4.2-19.68 pmol/min/μL) than in controls (median=8.27; range=4.54-34.30 pmol/min/ul. Absolute levels of caspase-3 levels in plasma in CLL did not correlate with any of the laboratory variables examined (WBC, platelets, HGB, B2M), Rai stage, or performance status. To assess the extent of apoptosis in relevance to level of the disease or tumor load, the caspase-3 index was calculated by normalizing plasma caspase-3 activity to the number of circulating lymphocytes in peripheral blood. The circulating caspase-3 index correlated negatively with bone marrow cellularity (P<0.001), spleen size (P= 0.002), and number of sites of enlarged lymph nodes (P<0.001). Interestingly, the circulating caspase-3 index correlated positively with Rai stage (P=0.03, Kruskal-Wallis) but not IgVH mutation status (P=0.74) or performance status (p=0.72). More importantly, higher circulating caspase-3 index values (>8 pmol/min/1000 lymphocytes/ul) were significantly associated with poor overall survival (P=0.005). However, in multivariate analysis incorporating caspase-3 index along with beta-2 microglobulin level and IgVH mutation status showed that caspase-3 was not predictor of survival (p=0.7). In conclusion, apoptosis as determined using plasma caspase-3 activity is low in CLL. However, high circulating caspase-3 activity index values appear to reflect more aggressive disease. Further studies are needed to explore the possibility that this circulating caspase-3 index reflects the proportion of cells that are transformed into larger cells, with consequently higher proliferation and apoptosis rates, in patients with CLL. Disclosures: No relevant conflicts of interest to declare.

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