Prognostic Value of ZAP-70 Expression Detected by Immunohistochemistry on Bone Marrow Biopsies in Early Phase Chronic Lymphocytic Leukaemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4800-4800
Author(s):  
Achille Ambrosetti ◽  
Roberta Zanotti ◽  
Marco Chilosi ◽  
Flavia Zanetti ◽  
Maurizio Lestani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
Methodological Approach ◽  
Bone Marrow Infiltration ◽  
Leukemic Cells ◽  
Immunohistochemical Method ◽  
Bone Marrow Biopsies ◽  
Cytoplasmic Expression ◽  
Binet Stage

Abstract New biological prognostic factors have been developed over the last years with the aim of predicting at presentation the heterogeneous clinical course of B chronic lymphocytic leukaemia (B-CLL) and of planning a risk-adapted treatment strategy. Among them ZAP-70 expression on leukemic cells as evaluated by molecular analysis or flow cytometry, initially proposed as surrogate of IgVH mutational status, appears a strong prognostic marker in B-CLL. However the optimal methodological approach to immunophenotipical demonstration of ZAP-70 expression as still matter of debate. We evaluated the cytoplasmic expression of ZAP-70 protein in leukemic cells by immunohistochemical method on bone marrow trephine biopsies taken at diagnosis of 84 patients with B-CLL. We used a mouse anti-human monoclonal antibody to ZAP-70 (clone 2F3.2, 1/200, Upstate, Lake Placid NY) with a polymeric labelling two-step method (Dako cytomation EnVision+, HRP). The results were correlated with age, sex, Binet stage, pattern of bone marrow infiltration, survival and clinical outcome. They were 54 males (64%), aged 34 to 80 years (median 62.5). At presentation 69 (82%) were Binet stage A, 9 (11%) stage B and 6 (7%) stage C. Among the 60 survivors, the median follow-up period from diagnosis was 78.5 months (range 22 – 236 months) Thirty-nine cases (46%) of B-CLL patients had cytoplasmic expression of ZAP-70. This group of patients presented higher percentage of advanced Binet stage (B–C) (p= 0.001). The ZAP-70 positivity was significantly related to inferior OS (55% vs 90% at 7 years)(HR 4.67 CI 1.95–11.14) and PFS (15% vs 57% at 7 years) (HR 5.52 CI 2.57–11.86), confirmed in multivariate analysis. ZAP-70 expression was correlated to poorer outcome also when we evaluated only the 69 stage A patients and the 56 cases with non-diffuse bone marrow infiltration, whereas in patients with diffuse pattern ZAP-70 expression had no prognostic significance. In conclusion, immunohistological detection of ZAP-70 on bone marrow samples at diagnosis appears a useful methodological approach to identify patients with different prognosis in B-CLL.

Haemophagocytic Lymphohistiocytosis Following Fludarabine/Cyclophosphamide Chemotherapy for Chronic Lymphocytic Leukaemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4617-4617
Author(s):  
Deepa Ranjani Jayakody Arachchillage ◽  
Samuel Moses ◽  
Stephen O'Brien ◽  
Tobias Menne ◽  
Peter Carey ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
The Other ◽  
Whole Body ◽  
Ct Scans ◽  
Haemophagocytic Lymphohistiocytosis ◽  
Immune Disorder ◽  
Bone Marrow Biopsies ◽  
Co Morbidity

Abstract Abstract 4617 We report 3 patients who developed Haemophagocytic Lymphohistiocytosis (HLH) following treatment with Fludarabine/Cyclophosphamide (FC) chemotherapy for Chronic Lymphocytic Leukaemia (CLL). Acquired (secondary) HLH is more frequent than primary (familial) HLH and usually described in patients with an underlying immune disorder. Acquired HLH in association with haematological malignancies is well recognised. The most commonly reported associations in adults are NK/T and peripheral T cell lymphomas. There is only one previous published case report of HLH in association with CLL as a direct trigger for development of HLH where the patient developed HLH one month after FC therapy and died in spite of treatment with the HLH 2004 protocol. Our 3 patients were diagnosed with HLH using standard diagnostic criteria, fulfilling at least 5 out of 8 clinical/laboratory criteria (Table 1). There was no evidence of haemophagocytosis in the bone marrow of any of these patients prior to treatment with FC. Two patients are still alive while the other died one month after diagnosis.Table 1Patient 1Patient 2Patient 3Fever+++Splenomegaly (cm)181719Haemoglobin (g/dl)10.39.07.3Platelets (× 109/l)116319Neutrophils (× 109/l)0.81.020.6Haemophagocytosis in bone marrow+++Ferritin (ug/l)165009342>100000Triglycerides (0.5–1.7 mmol/l)1.7 mmol/l1.9 mmol/l1.8 mmo/lFibrinogen level(2.1–4.8 g/l)0.6 g/l2.0 g/l1.0 g/lDecreased/absent NK cell activityNot assessedNot assessedNot assessedSoluble CD25Not assessedNot assessedNot assessed Each had been treated with FC before they developed HLH and 2 of them had received previous treatment with chlorambucil. All 3 patients were extensively investigated for infective causes that may be associated with HLH. Multiple blood, urine and sputum cultures were negative for bacteria, fungi, mycobacteria and parasites. Polymerase chain reaction (PCR) studies for cytomegalovirus, Epstein Barr virus, herpes simplex virus, human herpes virus-6 and parvovirus B19 were all negative initially in all 3 patients. Patient 2 developed immunosuppression related HHV-6 reactivation while he was undergoing treatment with HLH 2004. This responded to brief treatment with Foscarnet. All 3 patients were treated with empirical intravenous antibiotics for neutropenic sepsis and subsequently administered antifungal therapy due to prolonged fever not responding to antibiotics. All had whole body Computerised Tomography (CT) scans looking for any evidence of infection. CT scans in each case showed splenomegaly and minor adenopathy in the abdomen and chest with no evidence of infection. Bone marrow biopsies from all 3 patients showed appearances of haemophagocytosis but no significant residual infiltration with CLL. The time interval from treatment with FC to the development of HLH ranged from 1 month to 6 months (Table 2). Patient 1 died 4 weeks following the diagnosis of HLH in spite of treatment according to HLH 2004. The remaining 2 patients are still alive and undergoing treatment as per HLH 2004. Patient 2 has been worked up for allogenic bone marrow transplant (alloBMT) as part of HLH 2004. The other patient is being treated with chemotherapy alone due to age and other co morbidity factors precluding consideration for alloBMT.Table 2:Patient 1Patient 2Patient 3Age655774SexmalemalefemaleDate of first diagnosis of CLL09/05/200931/07/200605/06/2001Previous treatmentChlorambucilNoneChlorambucilTime of treatment with FC15/09/2009 To 28/06/201003/01/2009 to 09/10/2009 and 04/04/201104/03/2010 To 10/11/2010Number of FC cycles88 and 1(FC +Rituximab)6Date of diagnosis of HLH05/01/201115/05/201106/05/2011Current statusDied on 05/02/2011Undergoing treatment with HLH2004 and awaiting alloBMTUndergoing treatment with HLH2004 To our knowledge, this is the first case series of CLL patients who developed HLH in direct association with FC treatment without evidence of an underlying infective aetiology. Therefore in CLL patients presenting with cytopenias and fever, HLH should be considered early and diagnostic tests performed. This complication of treated CLL may be more common with FC than treatment with Chlorambucil alone, with which it had not previously been reported. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CORRELATION OF TRISOMY 12 WITH CLINICAL FEATURES AND OTHER LABORTARY PARAMETERS IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKAEMIA

2021 ◽  
Vol 71 (2) ◽  
pp. 473-77
Author(s):  
Ali Ahmed ◽  
Ch Altaf Hussain ◽  
Hamid Saeed Malik ◽  
M Abdul Naeem ◽  
Rafia Mehmood ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
Bone Marrow Aspiration ◽  
Armed Forces ◽  
Cross Sectional ◽  
Course Of Illness ◽  
Pathologic Features ◽  
Trisomy 12 ◽  
Binet Stage

Objective: To determine the frequency of trisomy 12 in B-Cell chronic lymphocytic leukaemia (CLL), to correlate its association with clinico-pathologic features and to determine the role of this cytogenetic defect to the prognosis. Study Design: Cross sectional study. Place and Duration of Study: Haematology department, Armed Forces Institute of Pathology, Rawalpindi, from May 2017 to Aug 2018. Methodology: A total of 56 newly diagnosed patients of Chronic Lymphocytic Leukaemia were included in the study. Patients were diagnosed on the basis of National Cancer Institute Working Group guidelines. A detailed history and thorough clinical examination were performed and complete blood counts, biochemical profile, bone marrow examination, immunophenotyping on bone marrow/peripheral blood samples were done for the diagnosis of Chronic lymphocytic leukaemia. Interphase FISH studies were performed on blood/bone marrow aspiration for detection of Trisomy 12 were performed. Results: Out of 56 patients, trisomy was detected in 12 (10.7%) patients. Out of 7 patients with trisomy 12, five patients presented in late stages (Binet stage B and C), however this association of Trisomy 12 with Binet stage was also statistically insignificant (p=0.474). About six with trisomy 12 were positive for CD 38, however this association was also not statistically significant (p=0.124). Results revealed that patients having trisomy 12 underwent chemotherapy at diagnosis and during follow ups as compared to patients having other cytogenic abnormalities. Moreover, patient with trisomy 12 develop progression in disease during course of illness, however association was statistically insignificant (p>0.05)............

scholarly journals Colonic Involvement in a Patient with Chronic Lymphocytic Leukaemia

2008 ◽  
Vol 2008 ◽  
pp. 1-4 ◽  
Author(s):  
P. E. T. Arkkila ◽  
H. Nuutinen ◽  
F. Ebeling ◽  
E. Elonen ◽  
P. Kärkkäinen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
Lymphocytic Leukemia ◽  
Diagnostic Evaluation ◽  
Bone Marrow Infiltration ◽  
Macroscopic Finding ◽  
Colonic Involvement

Various gastrointestinal infiltrations have been described in patients with chronic lymphocytic leukaemia (CLL). Here, we report a 69-year-old man with CLL and anaemia in whom the macroscopic finding of colonoscopy was normal, but the histological specimens revealed lymphocytic leukemia in ileum and in colon. If a CLL patient has any symptoms suggesting a possible GI manifestation of the haematologic disease or anaemia not explained by bone marrow infiltration or hemolysis, the diagnostic evaluation should include endoscopies with adequate biopsies.

Chronic lymphocytic leukaemia

2020 ◽  
pp. 5302-5310
Author(s):  
Clive S. Zent ◽  
Aaron Polliack
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukaemia ◽  
B Cell ◽  
Peripheral Blood ◽  
B Lymphocyte ◽  
Lymphocytic Leukaemia ◽  
Bone Marrow Failure ◽  
Curative Therapy ◽  
Symptomatic Disease ◽  
Autoimmune Cytopenias

Chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma is the most prevalent lymphoid neoplasm in Europe and North America. The ‘cell of origin’ is a mature B lymphocyte with a rearranged immunoglobulin gene. CLL cells express modest amounts of surface immunoglobulin, and are characterized by defective apoptosis. The cause of CLL is unknown. Most patients show no specific clinical features of disease and are diagnosed during evaluation of an incidental finding of peripheral blood lymphocytosis, lymphadenopathy, or splenomegaly. A small percentage of patients (<10%) present with symptomatic disease resulting from (1) tissue accumulation of lymphocytes such as disfiguring lymphadenopathy, splenomegaly with abdominal discomfort, profound fatigue, drenching night sweats, weight loss, and fever; or (2) manifestations of marrow failure with cytopenias including anaemia and thrombocytopenia. All CLL patients have an increased risk of infection, autoimmune cytopenias, and second haematological (e.g. diffuse large B-cell lymphoma) and nonhaematological malignancies. Diagnosis is usually made by analysis of the immunophenotype of the monoclonal circulating cells in the peripheral blood. In patients with the small lymphocytic variant of CLL without a detectable circulating monoclonal B-cell population, the diagnosis is made using tissue from the bone marrow, lymph nodes, or spleen. Treatment—there is no standard curative therapy and patients should not be treated until they have progressive and symptomatic disease or develop anaemia or thrombocytopenia due to bone marrow failure. If a decision is made to treat, then the best initial treatment should be given, based on evaluation of the patient’s disease characteristics with specific attention to the integrity of TP53 (coding for p53) and patient fitness.

Correlation between TP53 Deletion and Protein Overexpression in Chronic Lymphocytic Leukaemia and Its Impact on Prognostic.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2076-2076
Author(s):  
Paloma Martin ◽  
Toon Min ◽  
Alison Morilla ◽  
Sarah Hockley ◽  
Ayoma D. Attygale ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
P53 Protein ◽  
Clinical Stage ◽  
Fish Analysis ◽  
Protein Overexpression ◽  
Purine Analogues ◽  
P53 Overexpression ◽  
Bone Marrow Biopsies ◽  
Female Ratio

Abstract B-cell chronic lymphocytic leukaemia (B-CLL) is characterized by a highly variable clinical course. TP53 abnormalities in B-CLL are strongly associated with resistance to purine analogues, short survival and large-cell transformation. Several methods can be used to investigate TP53 inactivation: FISH (gene deletion), immunohistochemistry -IHC- (protein overexpression), and DNA sequencing (mutations). The relationship between TP53 deletion and p53 protein overexpression is unclear, and it is uncertain which method is the best to assess TP53 dysfunction and which provides the most useful clinical information. In 92 CLL patients we have correlated the frequency of p53 protein overexpression by IHC, with TP53 deletion status by FISH and subsequently we have examined the response to Fludarabine in these patients. The male/female ratio was 1.35 (52M/40F), with a median age at diagnosis of 54 years (range 25–78 years). The distribution of clinical stage at diagnosis was as follows: 47% (43 cases) stage A, 16% (15 cases) stage A progressive, 14% (13 cases) stage B, 11% (10 cases) stage C, and unknown in 12% (11 cases). Fourteen cases (15%) were untreated and seventy-eight cases (85%) were previously treated. Among the latter, 66 (84%) received Fludarabine, and 9 (11%) received Campath-1H (as a first line of treatment in 5 patients). In all cases peripheral blood samples were used for FISH analysis and IHC was carried out on bone marrow biopsies. Cases were selected on the basis of whether FISH and IHC were analysed at the same time point. Deletions of TP53 (17p13) were detected by FISH (Vysis); a threshold of &gt;20% of cells with p53 deletion was considered clinically significant. For IHC detection a monoclonal antibody (clone BP53-12, Novocastra) was used. Cases were considered positive when p53 stained the majority of lymphocyte nuclei, those cases with few or weakly positive cells in proliferation centres were considered negative. Correlation with FISH (&gt;20% deleted cells) and IHC showed 69 cases (75%) negative for both assays and 6 cases (7%) positive for FISH and IHC. The remaining 17 cases (18%) showed discordant results; 6 cases showed TP53 deletion &gt;20% by FISH but showed no p53 overexpression by IHC, 4 cases had overexpression of p53 and no TP53 deletion, 3 cases had p53 overexpression with TP53 deletion between 10–20%, and 4 cases showed TP53 deletion between 10–20% but no overexpression of p53. This is compatible with a sensitivity of 50% and specificity of 91%. In order to understand the mechanism better, mutation analysis of TP53 gene will be done in discordant cases. All patients positive for both results and a minority of patients (16%) with no p53 abnormalities detected by FISH or IHC were refractory to Fludarabine. Within the discordant group, most of refractory patients (67%) were found in cases with p53 overexpression and TP53 deletion between 10–20%. In conclusion, the combination of both methods (FISH and IHC) may be useful to identify CLL cases with an adverse prognosis and non responders to Fludarabine. A large study with more cases is necessary to clarify the underlying mechanisms involved in those cases with p53 overexpression without TP53 deletion.

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