HYPOGAMMAGLOBULINEMIA IN CHRONIC LYMPHOCYTIC LEUKEMIA: CLINICOBIOLOGICAL ASSOCIATIONS
Author(s): ,
Panagiotis Baliakas
Affiliations:
Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden
,
Aliki Xochelli
Affiliations:
Institute of Applied Biosciences,CERTH,Thessaloniki,Greece;Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden;Hematology Department and HCT Unit,G. Papanicolaou Hospital,Thessaloniki,Greece
,
Eva Minga
Affiliations:
Institute of Applied Biosciences,CERTH,Thessaloniki,Greece
,
George Karavalakis
Affiliations:
Hematology Department and HCT Unit,G. Papanicolaou Hospital,Thessaloniki,Greece
,
Anastasia Athanasiadou
Affiliations:
Hematology Department and HCT Unit,G. Papanicolaou Hospital,Thessaloniki,Greece
,
Evangelia Stalika
Affiliations:
Institute of Applied Biosciences,CERTH,Thessaloniki,Greece
,
Vasiliki Douka
Affiliations:
Hematology Department and HCT Unit,G. Papanicolaou Hospital,Thessaloniki,Greece
,
Maria Protopappa
Affiliations:
Hematology Department,General Hospital of Serres,Serres,Greece
,
Anastasia Mpanti
Affiliations:
Department of Hematology,Papageorgiou Hospital,Thessaloniki,Greece
,
Ioannis Kotsianidis
Affiliations:
Department of Hematology,Democritus University of Thrace,Alexandroupolis,Greece
,
Maria Papaioannou
Affiliations:
Department of Hematology,Aristotle University of Thessaloniki, 'AHEPA' Hospital,Thessaloniki,Greece
,
Niki Stavroyianni
Affiliations:
Hematology Department and HCT Unit,G. Papanicolaou Hospital,Thessaloniki,Greece
,
Achilles Anagnostopoulos
Affiliations:
Hematology Department and HCT Unit,G. Papanicolaou Hospital,Thessaloniki,Greece
,
Chrysoula Belessi
Affiliations:
Hematology Department,Nikea General Hospital,Piraeus,Greece
,
Anastasia Hadzidimitriou
Affiliations:
Institute of Applied Biosciences,CERTH,Thessaloniki,Greece
Kostas Stamatopoulos
Affiliations:
Institute of Applied Biosciences,CERTH,Thessaloniki,Greece;Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden;Hematology Department and HCT Unit,G. Papanicolaou Hospital,Thessaloniki,Greece
(Abstract release date: 05/19/16) EHA Library. Baliakas P. 06/09/16; 132614; E1065
Dr. Panagiotis Baliakas
Dr. Panagiotis Baliakas
Contributions
Abstract
Abstract: E1065

Type: Eposter Presentation

Background
A frequent feature of chronic lymphocytic leukemia (CLL) is progressive hypogammaglobulinemia that can affect one or more immunoglobulin (IG) subclasses.

Aims
To report the incidence of hypogammaglobulinemia in a large series of patients with CLL and explore associations with various clinical and biological markers.

Methods
Study group included 502 CLL patients with the following characteristics: median age: 65 years; males/females:  326/176; Binet stage A: 330/417 (79%), unmutated IGHV genes (U-CLL): 177/502 cases (35.2%); CD38 expression: 68/390 cases (17.4%); clonotypic IG of the MD or G isotype: 295 (78%) and 53 (14%) cases, respectively; isolated del(13q): 73/208 (35%); trisomy 12: 21/207 (10.1%); del(11q): 21/210 (10%); del(17p): 13/216 (6%); NOTCH1 del7544-45/p.P2514Rfs*4: 12/259 (4.6%).Within our cohort, we identified cases belonging to one of three different, major subsets with stereotyped B-cell receptor IG (BcR IG), namely: (1) subset #1 (clan I IGHV genes/IGKV1(D)-39): U-CLL, clinically aggressive, n=12; (2) subset #2 (IGHV3-21/IGLV3-21), mixed IGHV mutational status, noted clinical aggressiveness, n=6; and, (3) subset #4, mutated IGHV4-34/IGKV2-30 BcR IG, clinically indolent, n=14.

Results
 At diagnosis, decreased IG serum levels in at least one subclass were identified in 283/502 patients (56.3%), as follows: (i) decreased IgM, 224/502 cases (44.6%); (ii) decreased IgG, 105/502 cases (21%); (iii) decreased IgA, 131/502 cases (26%). In 54/502 cases (10.7%), all serum IG subclasses were decreased. Among cases with hypogammaglobulinemia, 114 (40.2%) and 31 (11%) exhibited isolated IgM and IgA subclass deficiency, respectively; isolated IgG decrease, was relatively rare (13 cases, 4.6%). Isolated IgA deficiency was significantly (p<0.05) more frequent amongst females, patients with advanced clinical stage (Binet B/C, Rai III/IV) and those with NOTCH1 mutations (p=0.01) compared to isolated IgM deficiency. Notably, all stereotyped subset #2 cases showed low levels of at least one serum subclass, while in 2/6 such cases, all three IG subclasses (IgA, IgM, IgG) were affected. No statistically significant differences were identified between patients with normal serum IG levels versus those with hypogammaglobulinemia regarding age, gender, disease burden at diagnosis, IGHV gene mutational status, CD38 expression, cytogenetic aberrations, NOTCH1 mutations and the incidence of a second malignancy. With a median follow up of 5 years, 192/413 cases [46.5%] received treatment. Patients with hypogammaglobulinemia exhibited increased need for treatment compared to those with normal serum IGs (124/234 vs 68/179 respectively, p=0.002). IgG and IgA deficiency were correlated with shorter time-to-first-treatment (TTFT) while none of the decreased IG subclasses impacted on overall survival (OS). In multivariate analysis for TTFT, IgG and IgA deficiency did not retain independent significance, with advanced clinical stage,  U-CLL, del(11q) and del(17p) remaining as independent adverse factors.

Conclusion
In conclusion, abnormalities of serum IGs at diagnosis are detected in CLL patients with heterogeneous clinicobiological profiles, including different disease burden at diagnosis, cytogenetic aberrations and IGHV gene mutational status. However, certain observations reported herein, in particular the high incidence of hypogammaglobulinemia in subset #2 and the association of NOTCH1 mutations with IgA subclass deficiency, open novel possibilities for unraveling the implicated pathophysiological mechanisms.  

Session topic: E-poster

Keyword(s): Chronic lymphocytic leukemia, Prognosis
Abstract: E1065

Type: Eposter Presentation

Background
A frequent feature of chronic lymphocytic leukemia (CLL) is progressive hypogammaglobulinemia that can affect one or more immunoglobulin (IG) subclasses.

Aims
To report the incidence of hypogammaglobulinemia in a large series of patients with CLL and explore associations with various clinical and biological markers.

Methods
Study group included 502 CLL patients with the following characteristics: median age: 65 years; males/females:  326/176; Binet stage A: 330/417 (79%), unmutated IGHV genes (U-CLL): 177/502 cases (35.2%); CD38 expression: 68/390 cases (17.4%); clonotypic IG of the MD or G isotype: 295 (78%) and 53 (14%) cases, respectively; isolated del(13q): 73/208 (35%); trisomy 12: 21/207 (10.1%); del(11q): 21/210 (10%); del(17p): 13/216 (6%); NOTCH1 del7544-45/p.P2514Rfs*4: 12/259 (4.6%).Within our cohort, we identified cases belonging to one of three different, major subsets with stereotyped B-cell receptor IG (BcR IG), namely: (1) subset #1 (clan I IGHV genes/IGKV1(D)-39): U-CLL, clinically aggressive, n=12; (2) subset #2 (IGHV3-21/IGLV3-21), mixed IGHV mutational status, noted clinical aggressiveness, n=6; and, (3) subset #4, mutated IGHV4-34/IGKV2-30 BcR IG, clinically indolent, n=14.

Results
 At diagnosis, decreased IG serum levels in at least one subclass were identified in 283/502 patients (56.3%), as follows: (i) decreased IgM, 224/502 cases (44.6%); (ii) decreased IgG, 105/502 cases (21%); (iii) decreased IgA, 131/502 cases (26%). In 54/502 cases (10.7%), all serum IG subclasses were decreased. Among cases with hypogammaglobulinemia, 114 (40.2%) and 31 (11%) exhibited isolated IgM and IgA subclass deficiency, respectively; isolated IgG decrease, was relatively rare (13 cases, 4.6%). Isolated IgA deficiency was significantly (p<0.05) more frequent amongst females, patients with advanced clinical stage (Binet B/C, Rai III/IV) and those with NOTCH1 mutations (p=0.01) compared to isolated IgM deficiency. Notably, all stereotyped subset #2 cases showed low levels of at least one serum subclass, while in 2/6 such cases, all three IG subclasses (IgA, IgM, IgG) were affected. No statistically significant differences were identified between patients with normal serum IG levels versus those with hypogammaglobulinemia regarding age, gender, disease burden at diagnosis, IGHV gene mutational status, CD38 expression, cytogenetic aberrations, NOTCH1 mutations and the incidence of a second malignancy. With a median follow up of 5 years, 192/413 cases [46.5%] received treatment. Patients with hypogammaglobulinemia exhibited increased need for treatment compared to those with normal serum IGs (124/234 vs 68/179 respectively, p=0.002). IgG and IgA deficiency were correlated with shorter time-to-first-treatment (TTFT) while none of the decreased IG subclasses impacted on overall survival (OS). In multivariate analysis for TTFT, IgG and IgA deficiency did not retain independent significance, with advanced clinical stage,  U-CLL, del(11q) and del(17p) remaining as independent adverse factors.

Conclusion
In conclusion, abnormalities of serum IGs at diagnosis are detected in CLL patients with heterogeneous clinicobiological profiles, including different disease burden at diagnosis, cytogenetic aberrations and IGHV gene mutational status. However, certain observations reported herein, in particular the high incidence of hypogammaglobulinemia in subset #2 and the association of NOTCH1 mutations with IgA subclass deficiency, open novel possibilities for unraveling the implicated pathophysiological mechanisms.  

Session topic: E-poster

Keyword(s): Chronic lymphocytic leukemia, Prognosis

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