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IgA levels at diagnosis predict for infections, time to treatment, and survival in chronic lymphocytic leukemia.

ABSTRACT: To better understand the relationship between baseline immunoglobulin measurements and subsequent clinical outcomes in chronic lymphocytic leukemia (CLL), we performed a retrospective analysis on 660 patients with CLL (72%), monoclonal B-cell lymphocytosis (MBL) (13%), and small lymphocytic lymphoma (SLL) (14%), diagnosed between 2005 and 2014 at CancerCare Manitoba. Of 511 patients who had their first immunoglobulin level determined within 3 months of diagnosis, abnormal (either increased or decreased) immunoglobulin M (IgM), IgG, and IgA values were observed in 58% of patients with CLL, 27% of patients with MBL, and 20% of patients with SLL. Immunoglobulin deviances were similar for MBL and CLL Rai stage 0 and for SLL and Rai stages I and II; for CLL, IgG and IgA abnormalities occurred with increasing frequency with advancing Rai stage. In contrast, the frequency of IgM abnormalities was similar in all patient groups. IgA abnormalities significantly correlated with high ?2-microglobulin (B2M) expression, whereas abnormal IgG and IgA levels were associated with the use of IGHV1-69, 3-21, and 3-49 subtypes. Increases in IgG or IgM were commonly associated with the presence of a CLL-type M-band, whereas oligoclonal bands were frequently observed with increased IgA levels. Although abnormal levels of IgG and IgA at diagnosis were independent predictors for future immunoglobulin replacement, only abnormal IgA levels were associated with shorter time to first treatment and overall survival. These findings indicate that both reduced and elevated levels of IgG and IgA at diagnosis are important and independent prognostic markers for infection in CLL, with IgA being more relevant as a marker of disease progression and survival.

SUBMITTER: Ishdorj G

PROVIDER: S-EPMC6650736 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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IgA levels at diagnosis predict for infections, time to treatment, and survival in chronic lymphocytic leukemia.

Ishdorj Ganchimeg G Streu Erin E Lambert Pascal P Dhaliwal Harbhajan S HS Mahmud Salaheddin M SM Gibson Spencer B SB Banerji Versha V Marshall Aaron J AJ Johnston James B JB

Blood advances 20190701 14

To better understand the relationship between baseline immunoglobulin measurements and subsequent clinical outcomes in chronic lymphocytic leukemia (CLL), we performed a retrospective analysis on 660 patients with CLL (72%), monoclonal B-cell lymphocytosis (MBL) (13%), and small lymphocytic lymphoma (SLL) (14%), diagnosed between 2005 and 2014 at CancerCare Manitoba. Of 511 patients who had their first immunoglobulin level determined within 3 months of diagnosis, abnormal (either increased or de ...[more]

PMID: 31324639

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Project description:BackgroundThe established clinical staging systems (Rai/Binet) of chronic lymphocytic leukemia (CLL) cannot accurately predict the appropriate treatment of patients in the earlier stages. In the past two decades, several prognostic factors have been identified to predict the outcome of patients with CLL, but only a few studies investigated more markers together. To predict the time to first treatment (TTFT) in patients of early stages, we evaluated the prognostic role of conventional markers as well as cytogenetic abnormalities and combined them together in a new prognostic scoring system, the CLL prognostic index (CLL-PI).MethodsTaking advantage of a population of 406 untreated Chinese patients with CLL at early and advanced stage of disease, we identified the strongest prognostic markers of TTFT and, subsequently, in a cohort of 173 patients who had complete data for all 3 variables, we integrated the data of traditional staging system, cytogenetic aberrations, and mutational status of immunoglobulin heavy chain variable region (IGHV) in CLL-PI. The median follow-up time was 45 months and the end point was TTFT.ResultsThe median TTFT was 38 months and the 5-year overall survival was 80%. According to univariate analysis, patients of advanced Rai stages (P < 0.001) or with 11q- (P = 0.002), 17p- (P < 0.001), unmutated IGHV (P < 0.001), negative 13q- (P = 0.007) and elevated lactate dehydrogenase levels (P = 0.001) tended to have a significantly shorter TTFT. And subsequently, based on multivariate Cox regression analysis, three independent factors for TTFT were identified: advanced clinical stage (P = 0.002), 17p- (P = 0.050) and unmutated IGHV (P = 0.049). Applying weighted grading of these independent factors, a CLL-PI was constructed based on regression parameters, which could categorize four different risk groups (low risk [score 0], intermediate low [score 1], intermediate high [score 2] and high risk [score 3-6]) with significantly different TTFT (median TTFT of not reached (NR), 65.0 months, 36.0 months and 19.0 months, respectively, P < 0.001).ConclusionsThis study developed a weighted, integrated CLL-PI prognostic system of CLL patients which combines the critical genetic prognostic markers with traditional clinical stage. This novel modified PI system could be used to discriminate among groups and may help predict the TTFT and prognosis of patients with CLL.

Project description:The immunoglobulin (Ig) variable region (V) genes expressed by IgM chronic lymphocytic leukemia (CLL) B cells display little or no somatic mutations. However, preliminary findings have shown that Ig V genes of IgA and IgG CLLs may be somatically mutated, suggesting that isotype-switched CLLs may represent a "subtype" of the disease. To investigate the degree and nature of somatic mutations and the role of antigen (Ag) in the clonal selection and expansion of isotype-switched CLLs, and to determine whether specific oncogene or tumor suppressor gene mutations are associated with isotype-switched CLLs, we analyzed the expressed Ig VH gene, bcl-1 and bcl-2 proto-oncogene, and p53 tumor suppressor gene configurations of 3 IgA-, 1 IgG-, and 1 IgA/ IgG-expressing CLLs. These isotype-switched CLL B cells expressed surface HLA-DR, CD19, CD23, and CD5, and displayed no alterations of the bcl-1 and bcl-2 oncogenes and the p53 tumor-suppressor gene. The cDNA VH-D-JH gene sequence was joined with that of the C alpha gene in the B cells of the three IgA CLLs, and with that of the C gamma gene in the IgG CLL B cells. In the IgA/IgG-coexpressing CLL B cells, identical VH-D-JH cDNA sequences were spliced to either C alpha or C gamma genes. In all five CLLs, the pattern of C mu DNA probe hybridization to the digested genomic DNAs was consistent with deletion of the C mu exon from the rearranged Ig gene locus, suggesting that these CLL B cells had undergone DNA switch recombination. In one IgA CLL, the expressed VH gene was unmutated. In all other class-switched CLLs, the Ig VH segment gene was mutated, but the point mutations were not associated with intraclonal diversification. In one IgA and in the IgA/IgG-coexpressing CLL, the nature and distribution of the mutations were consistent with Ag selection. These findings suggest that IgA- and/or IgG-expressing CLLs represent, in their VH gene structure, transformants of B cells at different stages of ontogeny. They also suggest that Ag may play a role in the clonal selection of some of these isotype-switched leukemic cells, but bcl-1 and bcl-2 oncogene rearrangements and p53 tumor suppressor gene mutation are not associated with the pathogenesis of isotype-switched CLLs.

Project description:The prognostic role of lymphocyte doubling time (LDT) in chronic lymphocytic leukemia (CLL) was recognized more than three decades ago when the neoplastic clone's biology was almost unknown. LDT was defined as the time needed for the peripheral blood lymphocyte count to double the of the initial observed value. Herein, the LDT prognostic value for time to first treatment (TTFT) was explored in our prospective O-CLL cohort and validated in in two additional CLL cohorts. Specifically, newly diagnosed Binet stage A CLL patients from 40 Italian Institutions, representative of the whole country, were prospectively enrolled into the O-CLL1-GISL protocol (clinicaltrial.gov identifier: NCT00917540). Two independent cohorts of newly diagnosed CLL patients recruited respectively at the Division of Hematology in Novara, Italy, and at the Hospital Clinic in Barcelona, Spain, were utilized as validation cohorts. In the training cohort, TTFT of patients with LDT >12 months was significantly longer related to those with a shorter LDT. At Cox multivariate regression model, LDT ≤ 12 months maintained a significant independent relationship with shorter TTFT along with IGHV unmutated (IGHVunmut) status, 11q and 17p deletions, elevated β2M, Rai stage I-II, and NOTCH1 mutations. Based on these statistics, two regression models were constructed including the same prognostic factors with or without the LDT. The model with the LTD provided a significantly better data fitting (χ2 = 8.25, P=0.0041). The risk prediction developed including LDT had better prognostic accuracy than those without LDT. Moreover, the Harrell'C index for the scores including LDT were higher than those without LDT, although the accepted 0.70 threshold exceeded in both cases. These findings were also confirmed when the same analysis was carried out according to TTFT's explained variation. When data were further analyzed based on the combination between LDT and IGHV mutational status in the training and validation cohorts, IGHVunmut and LDT>12months group showed a predominant prognostic role over IGHVmut LTD ≤ 12 months (P=0.006) in the O-CLL validation cohort. However, this predominance was of borden-line significance (P=0.06) in the Barcelona group, while the significant prognostic impact was definitely lost in the Novara group. Overall, in this study, we demonstrated that LDT could be re-utilized together with the more sophisticated prognostic factors to manage the follow-up plans for Binet stage A CLL patients.

Dataset Information

IgA levels at diagnosis predict for infections, time to treatment, and survival in chronic lymphocytic leukemia.

Publications

IgA levels at diagnosis predict for infections, time to treatment, and survival in chronic lymphocytic leukemia.

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