CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease

Abstract Although the presence or absence of somatic mutations in the immunoglobulin variable region (IgVH) genes in chronic lymphocytic leukemia (B-CLL) identifies subtypes with very different prognoses, the assay is technically complex and unavailable to most laboratories. CD38 expression has been suggested as a surrogate marker for the 2 subtypes. IgVHmutations and CD38 expression in 145 patients with B-CLL with a long follow-up were compared. The 2 assays gave discordant results in 41 patients (28.3%). Multivariate analysis demonstrated that Binet stage,IgVH mutations and CD38 were independent prognostic indicators. Median survival time in patients whose cells had unmutated IgVH genes and expressed CD38 was 8 years; in those with mutated IgVHgenes not expressing CD38, it was 26 years. For those with discordant results, median survival time was 15 years. Thus, although CD38 expression does not identify the same 2 subsets as IgVHmutations in CLL, it is an independent risk factor that can be used with IgVH mutations and clinical stage to select patients with B-CLL with the worst prognoses. Using cryopreserved cells taken at intervals during the course of the disease, however, changes of CD38 expression over time were demonstrated in 10 of 41 patients. Causes of the variation of CD38 expression require further study. Additional prospective studies are required for comparing CD38 expression with other prognostic factors and for taking sequential measurements during the course of the disease.

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Bone marrow infiltration patterns and their prognostic significance in chronic lymphocytic leukemia: correlations with clinical, immunologic, phenotypic, and cytogenetic data.

Journal of Clinical Oncology ◽

10.1200/jco.1984.2.6.562 ◽

1984 ◽

Vol 2 (6) ◽

pp. 562-570 ◽

Cited By ~ 56

Author(s):

T Han ◽

M Barcos ◽

L Emrich ◽

H Ozer ◽

R Gajera ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Lymphocytic Leukemia ◽

Survival Time ◽

Median Survival ◽

Median Survival Time ◽

Clinical Stage ◽

Lymphocytic Leukemia ◽

Bone Marrow Infiltration ◽

Clinical Staging ◽

Bone Marrow Biopsies

Bone marrow biopsies were prospectively performed on 75 patients with chronic lymphocytic leukemia (CLL). There was a highly significant relationship (p less than 0.002) between clinical stages and bone marrow infiltration patterns. Ten (50%) of 20 patients with diffuse patterns died; the estimated median survival time for these patients was 87 months. In contrast, only six (11%) of 55 patients with nondiffuse patterns died; the estimated median survival time for these patients could not be computed. When both clinical stage and infiltration pattern were evaluated for survival, a highly significant association between clinical stage and survival time was still observed (p less than 0.003) whereas bone marrow infiltration pattern was no longer significant. A significant association was also observed between bone marrow infiltration patterns and absolute lymphocyte counts (p less than 0.0005), Fc-receptor-positive cells (p less than 0.002), 3H-thymidine uptake of leukocytes (p less than 0.01), serum alkaline phosphatase levels (p less than 0.05), monoclonal urinary-free light chain status (p less than 0.05), and cytogenetics of leukemic cells (p less than 0.05). These observations lead to the conclusion that in an overall prognostic evaluation of patients with CLL, although bone marrow histopathology may have no additional value over a well-established clinical staging system, as a whole, it may be of clinically predictive value in disease progression of patients with stage I and II.

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Ig V Gene Mutation Status and CD38 Expression As Novel Prognostic Indicators in Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v94.6.1840 ◽

1999 ◽

Vol 94 (6) ◽

pp. 1840-1847 ◽

Cited By ~ 1753

Author(s):

Rajendra N. Damle ◽

Tarun Wasil ◽

Franco Fais ◽

Fabio Ghiotto ◽

Angelo Valetto ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Gene Mutation ◽

Lymphocytic Leukemia ◽

Prognostic Indicators ◽

Risk Category ◽

Mutation Status ◽

Cd38 Expression ◽

Staging Systems ◽

V Genes ◽

V Gene

Abstract Cellular immunophenotypic studies were performed on a cohort of randomly selected IgM+ B-chronic lymphocytic leukemia (B-CLL) cases for which Ig VH and VL gene sequences were available. The cases were categorized based on V gene mutation status and CD38 expression and analyzed for treatment history and survival. The B-CLL cases could be divided into 2 groups. Those patients with unmutated V genes displayed higher percentages of CD38+ B-CLL cells (≥30%) than those with mutated V genes that had lower percentages of CD38+ cells (<30%). Patients in both the unmutated and the ≥30% CD38+ groups responded poorly to continuous multiregimen chemotherapy (including fludarabine) and had shorter survival. In contrast, the mutated and the <30% CD38+ groups required minimal or no chemotherapy and had prolonged survival. These observations were true also for those patients who stratified to the Rai intermediate risk category. In the mutated and the <30% CD38+ groups, males and females were virtually equally distributed, whereas in the unmutated and the ≥30% CD38+ groups, a marked male predominance was found. Thus, Ig V gene mutation status and the percentages of CD38+B-CLL cells appear to be accurate predictors of clinical outcome in B-CLL patients. These parameters, especially CD38 expression that can be analyzed conveniently in most clinical laboratories, should be valuable adjuncts to the present staging systems for predicting the clinical course in individual B-CLL cases. Future evaluations of new therapeutic strategies and drugs should take into account the different natural histories of patients categorized in these manners.

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Outcome and Prognostic Indicators in Cats Undergoing Splenectomy for Splenic Mast Cell Tumors

Journal of the American Animal Hospital Association ◽

10.5326/jaaha-ms-6280 ◽

2015 ◽

Vol 51 (4) ◽

pp. 231-238 ◽

Cited By ~ 4

Author(s):

Kelly A. Kraus ◽

Craig A. Clifford ◽

Garrett J. Davis ◽

Kristina M. Kiefer ◽

Kenneth J. Drobatz

Keyword(s):

Mast Cell ◽

Survival Time ◽

Median Survival ◽

Median Survival Time ◽

Regional Lymph Node ◽

Clinical History ◽

Prognostic Indicators ◽

Clinical Parameters ◽

Mast Cell Tumors ◽

Response To Chemotherapy

This was a multi-institutional retrospective study evaluating the outcome and clinical parameters associated with the postoperative prognosis of 36 cats with splenic mast cell tumors treated with splenectomy. Clinical parameters reviewed included signalment, clinical history, results of staging tests, surgical variables, administration of blood products, presence of metastasis, postoperative complications, administration of chemotherapy postoperatively, chemotherapy protocol, and response to chemotherapy. Overall median survival time was 390 days (range, 2–1737 days). Administration of a blood product (P < .0001), metastasis to a regional lymph node (P = .022), and evidence of either concurrent or historical neoplasia (P = .037) were negatively associated with survival. Response to chemotherapy (P = .0008) was associated with an improved median survival time. Larger-scale prospective studies evaluating different chemotherapy protocols are required to elucidate the discrepancy between lack of survival benefit with administration of chemotherapy and improvement in survival time with positive response to chemotherapy.

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Clinical Staging and Flowcytomteric CD38 and Zap 70 Prognostic Indicators in Sudanese Patients with Chronic Lymphocytic Leukemia

Sudan Journal of Medical Sciences ◽

10.18502/sjms.v15i1.6704 ◽

2020 ◽

Author(s):

Enaam Abdelrhman Abdelgader ◽

Nada Hassan Eltayeb ◽

Tasniem Ahmed Eltahir ◽

Osama Ali Altayeb ◽

Eman Abbass Fadul ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Stage Iv ◽

Cross Sectional Study ◽

Lymphocytic Leukemia ◽

Clinical Staging ◽

Prognostic Indicators ◽

P Value ◽

Cross Sectional ◽

Cd38 Expression ◽

Staging Systems

Background: The clinical course of chronic lymphocytic leukemia is highly variable. The determination of ZAP70 and CD38 is increasingly utilized as prognostic factor for chronic lymphocytic leukemia. The aim of conducting this study was to investigate the frequency of CD38 and ZAP70 expression among Sudanese Chronic lymphocytic leukemia (CLL) patients and to relate them to the Binet and Rai clinical staging systems. Method: A total of 93 patients (mean age; 62.29 ± 11.68, sd) were enrolled in this cross-sectional study. CD38 and ZAP70 expression levels were measured with four color flowcytometry using the cut-off values of 20% for ZAP70 and 30% for CD38 expression. Staging was assessed by using clinical examination and CBC for all patients. Data were analyzed using the Statistical Package for Social science for Windows (SPSS), version 22. Results: There were 93 CLL patients and the median age of the group was 63 years (36–95 years). About 71% of the patients presented with lymphadenopathy, 53.8% with splenomegaly, 73.1% with anemia, and 45.2% with thrombocytopenia. There was higher frequency of Binet stage C and Rai stage IV (62 [66.6%] patients and 34 [36.5%] patients, respectively). In addition, CD38 and ZAP70 showed higher frequency among Binet and Rai advance stages. ZAP70 and CD38 positivity were detected in 21 patients (22.6%) and 31 patients (33.3%), respectively. There was no statistically significant association between ZAP70 and CD38 and clinical staging systems (P-value > 0.05). Conclusion: No significant association was observed between Flowcytometric (CD38 and Zap70) Prognostic Indicators and clinical staging systems. Keywords: chronic lymphocytic Leukemia, Flowcytometry, ZAP70, CD38, clinical staging systems

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Efficacy of SMIP-016, a novel CD37-directed biologic therapy, in human NHL tumor xenograft models

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.2565 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 2565-2565

Author(s):

D. S. Barone ◽

C. Nilsson ◽

J. Ledbetter ◽

M. Hayden-Ledbetter ◽

K. Mohler

Keyword(s):

Survival Time ◽

Median Survival ◽

Nude Mice ◽

Median Survival Time ◽

Single Agent ◽

Human Tumor ◽

Lymphocytic Leukemia ◽

Tumor Xenograft ◽

Human Tumor Xenograft ◽

Xenograft Models

2565 Background: Small Modular Immuno-Pharmaceuticals (SMIP) biopharmaceuticals belong to a novel proprietary biologic compound class that retain Fc mediated effector functions and are smaller than monoclonal antibodies. SMIP-016 is a SMIP product candidate that binds to CD37 on human B cells and has potent ADCC and apoptotic activity in vitro. CD-37 is known to be over-expressed in non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). We have evaluated the activity of SMIP-016 in established human tumor xenograft models in nude mice. Methods: Nude mice were injected subcutaneously with either Ramos or Daudi tumor cells. At approximately 7 days post tumor inoculation the mice were randomized to groups with roughly equivalent mean tumor volumes (>200mm3) and were treated with SMIP-016 or rituximab as a comparator. Groups were evaluated for median survival time (MST), tumor volume and percentage of tumor-free animals. Results: In nude mice bearing Daudi tumors, SMIP-016 treated mice showed a significant improvement in MST compared to control mice (p < 0.0001). Nude mice bearing Ramos tumors treated with SMIP-016 also demonstrated a significant enhancement in their median survival time (MST) in comparison to control mice (p < 0.0001). In addition, mice receiving SMIP-016 administered in combination with rituximab in this model demonstrated improvements in survival time over either single agent therapy alone. Conclusions: SMIP-016 is effective in treating established tumors in these human tumor xenograft models. Addition of SMIP-016 to rituximab therapy resulted in enhanced survival times compared to animals treated with rituximab alone. [Table: see text]

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Comprehensive Assessment of Genetic and Molecular Features Predicting Outcome in Patients With Chronic Lymphocytic Leukemia: Results From the US Intergroup Phase III Trial E2997

Journal of Clinical Oncology ◽

10.1200/jco.2006.08.3089 ◽

2007 ◽

Vol 25 (7) ◽

pp. 799-804 ◽

Cited By ~ 251

Author(s):

Michael R. Grever ◽

David M. Lucas ◽

Gordon W. Dewald ◽

Donna S. Neuberg ◽

John C. Reed ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Prognostic Significance ◽

Variable Region ◽

Hazard Ratio ◽

Lymphocytic Leukemia ◽

Phase Iii ◽

Therapeutic Trial ◽

Cd38 Expression ◽

Molecular Features ◽

Mutational Status

Purpose Genomic features including unmutated immunoglobulin variable region heavy chain (IgVH) genes, del(11q22.3), del(17p13.1), and p53 mutations have been reported to predict the clinical course and overall survival of patients with chronic lymphocytic leukemia (CLL). In addition, ZAP-70 and Bcl-2 family proteins have been explored as predictors of outcome. Patients and Methods We prospectively evaluated the prognostic significance of a comprehensive panel of laboratory factors on both response and progression-free survival (PFS) using samples and data from 235 patients enrolled onto a therapeutic trial. Patients received either fludarabine (FL; n = 113) or fludarabine plus cyclophosphamide (FC; n = 122) as part of a US Intergroup randomized trial for previously untreated CLL patients. Results Complete response (CR) rates were 24.6% for patients receiving FC and 5.3% for patients receiving FL (P = .00004). PFS was statistically significantly longer in patients receiving FC (median, 33.5 months for patients receiving FC and 19.9 months for patients receiving FL; P < .0001). The occurrence of del(17p13.1) (hazard ratio, 3.428; P = .0002) or del(11q22.3) (hazard ratio, 1.904; P = .006) was associated with reduced PFS. CR and overall response rates were not significantly different based on cytogenetics, IgVH mutational status, CD38 expression, or p53 mutational status. Expression of ZAP-70, Bcl-2, Bax, Mcl-1, XIAP, Caspase-3, and Traf-1 was not associated with either clinical response or PFS. Conclusion These results support the use of interphase cytogenetic analysis, but not IgVH, CD38 expression, or ZAP-70 status, to predict outcome of FL-based chemotherapy. Patients with high-risk cytogenetic features should be considered for alternative therapies.

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Biological Prognostic Markers in Chronic Lymphocytic Leukemia

Acta Medica (Hradec Kralove Czech Republic) ◽

10.14712/18059694.2016.99 ◽

2009 ◽

Vol 52 (1) ◽

pp. 3-8 ◽

Cited By ~ 8

Author(s):

Vladimíra Vroblová ◽

Lukáš Smolej ◽

Filip Vrbacký ◽

Karolína Jankovičová ◽

Monika Hrudková ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Clinical Course ◽

Variable Region ◽

Lymphocytic Leukemia ◽

Initial Assessment ◽

Western World ◽

Cd38 Expression ◽

Cytogenetic Aberrations ◽

Mutational Status

Chronic lymphocytic leukemia (CLL) is the most frequent leukemic disease of adults in the Western world. It is remarkable by an extraordinary heterogeneity of clinical course with overall survival ranging from several months to more than 15 years. Classical staging sytems by Rai and Binet, while readily available and useful for initial assessment of prognosis, are not able to determine individual patient’s ongoing clinical course of CLL at the time of diagnosis, especially in early stages. Therefore, newer biological prognostic parameters are currently being clinically evaluated. Mutational status of variable region of immunoglobulin heavy chain genes (IgVH), cytogenetic aberrations, and both intracellular ZAP- 70 and surface CD38 expression are recognized as parameters with established prognostic value. Molecules regulating the process of angiogenesis are also considered as promising markers. The purpose of this review is to summarize in detail the specific role of these prognostic factors in chronic lymphocytic leukemia.

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Validation of IPSS criteria in more than 1,600 MDS patients

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.7079 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 7079-7079 ◽

Cited By ~ 1

Author(s):

F. Quddus ◽

A. Ahmed ◽

S. Naqvi ◽

K. Hasan ◽

M. Mumtaz ◽

...

Keyword(s):

Bone Marrow ◽

Survival Time ◽

Median Survival ◽

Scoring System ◽

Median Survival Time ◽

Bone Marrow Failure ◽

Prognostic Indicators ◽

International Prognostic Scoring System ◽

P Value ◽

Survival Difference

7079 Myelodysplastic syndromes (MDS) are a diverse group of clonal stem cell disorders characterized by bone marrow failure, dysmyelopoiesis and peripheral cytopenias and affecting predominantly an elderly population. The International Prognostic Scoring System (IPSS) incorporates the number of peripheral cytopenias, percentage of bone marrow blasts and chromosomal abnormalities and assigns a score to predict survival and risk of disease progression to AML. Using the extensive MDS database at the University of Massachusetts we analyzed survival time in relation to IPSS scoring and also its various individual components, i.e. blast percentage, number of cell lines involved and the number of karyotype abnormalities in 1,200+ patients. The overall median survival time in 1,424 MDS patients as a group was 2.9 years. IPSS low group had the longest median survival time of 7.5 years with IPSS Int-1 3.6 years. There was minimal difference in the median survival time between IPSS Int-2 and IPSS high risk group 1.2 and 1.1 years respectively. These results were significant for a P value of <0.0001. The median survival time for blasts <5% was 5.3 years and blast 5–10% was 1.7 years. Interestingly, there was minimal survival difference between median survival time for blasts 11–20% and blasts >20% showing 1.2 years and 1.3 years respectively. Again, these results were significant for a P value of <0.0001. The median survival time for the number of cytopenias involved was also calculated with 0, 1, 2 and 3 numbers of cytopenias showing 6.4 years, 4.4 years, 2.6 years and 1.8 years respectively, with P value of <0.0001. The median survival time for normal karyotype versus one or two karyotype abnormality was 4.9 years, 2.6 years and 2.4 years respectively. Three or more karyotype abnormalities showed a median survival time of 0.8 years. The P value was again significant (<0.0001). Our results not only validate the prognostic value of IPSS scoring system as a whole but also its various individual prognostic indicators. No significant financial relationships to disclose.

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