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1.
Leuk Lymphoma ; 65(5): 585-597, 2024 May.
Article En | MEDLINE | ID: mdl-38227293

Despite advances in treatment, a significant proportion of patients with chronic lymphocytic leukemia (CLL) will relapse with drug-resistant disease. The imipridones, ONC-201 and ONC-212, are effective against a range of different cancers, including acute myeloid leukemia (AML) and tumors of the brain, breast, and prostate. These drugs induce cell death through activation of the mitochondrial protease, caseinolytic protease (CIpP), and the unfolded protein response (UPR). Here we demonstrate that the novel imipridone analog, TR-57, has efficacy as a single agent and synergises with venetoclax against CLL cells under in vitro conditions that mimic the tumor microenvironment. Changes in protein expression suggest TR-57 activates the UPR, inhibits the AKT and ERK1/2 pathways and induces pro-apoptotic changes in the expression of proteins of the BCL-2 family. The study suggests that TR-57, as a single agent and in combination with venetoclax, may represent an effective treatment option for CLL.


Apoptosis , Bridged Bicyclo Compounds, Heterocyclic , Drug Synergism , Leukemia, Lymphocytic, Chronic, B-Cell , Sulfonamides , Humans , Sulfonamides/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Apoptosis/drug effects , Cell Line, Tumor , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Unfolded Protein Response/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Proto-Oncogene Proteins c-bcl-2/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Signal Transduction/drug effects
2.
Intern Med J ; 54(1): 16-25, 2024 Jan.
Article En | MEDLINE | ID: mdl-38066723

Malignancies of the B-lymphocyte lineage are among the most diagnosed haematological malignancies in clinical practice. In our community, multiple myeloma (MM) and its precursor condition monoclonal gammopathy of undetermined significance are the commonest, accounting for ~12% of diagnoses, followed by chronic lymphocytic leukaemia (CLL) and its precursor condition monoclonal B lymphocytosis, ~9%. Along with diffuse large B cell lymphoma, follicular lymphoma and marginal zone lymphoma, these conditions comprise around a third of all haematological malignancies diagnosed. Infection remains an important cause of mortality and morbidity in the management of patients with these conditions. This is in part treatment-related but also reflective of disease-related immune dysfunction. Infectious complications account for up to 50% of early mortality in patients with myeloma and up to 50% of all mortality in patients with CLL. A variety of strategies are available to decrease the morbidity and mortality of infectious complications; however, practices vary between countries and often between treating physicians. Treatment options have evolved significantly over the last decade, with the introduction of monoclonal antibodies, small molecule inhibitors, second- and third-generation immunomodulatory agents and CAR-T cell therapy. Much of the data that inform clinical practice in infection management predates current therapeutic approaches. This is in part because of the rapid development of new therapies but also reflective of the long natural history of many of these diseases and the need for prolonged periods of observation. In this article, we review the aspects of disease and treatment that contribute to immune dysfunction in MM, CLL and B-cell non-Hodgkin lymphoma and review the current strategies used to manage immune dysfunction and infection.


Hematologic Neoplasms , Leukemia, Lymphocytic, Chronic, B-Cell , Lymphoma, Follicular , Multiple Myeloma , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , B-Lymphocytes , Hematologic Neoplasms/therapy , Hematologic Neoplasms/drug therapy , Antibodies, Monoclonal/therapeutic use , Multiple Myeloma/drug therapy
3.
Intern Med J ; 53(9): 1678-1691, 2023 09.
Article En | MEDLINE | ID: mdl-37743239

Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in Australia and New Zealand (ANZ). Considerable changes to diagnostic and management algorithms have occurred within the last decade. The availability of next-generation sequencing and measurable residual disease assessment by flow cytometry allow for advanced prognostication and response assessments. Novel therapies, including inhibitors of Bruton's tyrosine kinase (BTKi) and B-cell lymphoma 2 (BCL2) inhibitors, have transformed the treatment landscape for both treatment-naïve and relapsed/refractory disease, particularly for patients with high-risk genetic aberrations. Recommendations regarding appropriate supportive management continue to evolve, and special considerations are required for patients with CLL with respect to the global SARS-CoV-2 pandemic. The unique funding and treatment environments in Australasia highlight the need for specific local guidance with respect to the investigation and management of CLL. This consensus practice statement was developed by a broadly representative group of ANZ experts in CLL with endorsement by peak haematology bodies, with a view to providing this standardised guidance.


COVID-19 , Hematologic Neoplasms , Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Consensus , SARS-CoV-2
4.
EJHaem ; 2(1): 81-93, 2021 Feb.
Article En | MEDLINE | ID: mdl-35846080

Despite advances in therapy, a significant proportion of patients with chronic lymphocytic leukemia (CLL) relapse with drug resistant disease. Novel treatment approaches are required, particularly for high risk disease. The imipridones represent a new class of cancer therapy that has been investigated in pre-clinical and clinical trials against a range of different cancers. We investigated the effects of the imipridone, ONC-212, against CLL cells cultured under conditions that mimic aspects of the tumour microenvironment and a TP53ko CLL cell line (OSU-CLL-TP53ko). ONC-212 induced dose-dependent apoptosis, cell cycle arrest and reduced the migration of CLL cells in vitro, including cells from patients with TP53 lesions and OSU-CLL-TP53ko cells. The effects of ONC-212 were associated with protein changes consistent with activation of the mitochondrial protease, CIpP, and the integrated stress response. We also observed inhibition of pathways downstream of the B-cell receptor (BCR) (AKT and MAPK-ERK1/2) and a pro-apoptotic shift in the balance of proteins of the BCL2 family of proteins (BCL2, MCL1, BCLxL, BAX and NOXA). In conclusion, the study suggests ONC-212 may represent an effective treatment for high risk CLL disease by inhibiting multiple facets of the BCR signaling pathway and the pro-survival effects of the BCL2-family proteins.

5.
Blood Adv ; 4(20): 5093-5106, 2020 10 27.
Article En | MEDLINE | ID: mdl-33085757

The B-cell receptor signaling pathway and dysregulation of the Bcl-2 family of proteins play crucial roles in the pathogenesis of chronic lymphocytic leukemia (CLL). Despite significant advances in the treatment of the disease, relapse and drug resistance are not uncommon. In the current study, we investigated the dual PI3/PIM kinase inhibitor IBL-202 in combination with venetoclax as a treatment option for CLL using both primary CLL cells and TP53-deficient OSU-CLL cells generated using the CRISPR-Cas9 system. IBL-202 and venetoclax were highly synergistic against primary CLL cells cocultured with CD40L fibroblasts (combination index [CI], 0.4, at a fractional effect of 0.9) and TP53-knockout (KO) OSU-CLL cells (CI, 0.5, at a fractional effect of 0.9). Synergy between the drugs was consistent, with a significant (P < .05) reduction in the 50% inhibitory concentration for both drugs. IBL-202 and venetoclax in combination induced cell-cycle arrest and slowed the proliferation of both wild-type and TP53-KO cell lines. The drug combination inhibited AKT phosphorylation, reduced expression of Bcl-xL and NF-κB, and increased the Noxa/Mcl-1 ratio. Downregulation of CXCR4 was consistent with inhibition of the SDF-1α-induced migratory capacity of CLL cells. Synergy between IBL-202 and venetoclax against primary CLL cells cultured under conditions that mimic the tumor microenvironment suggests this drug combination may be effective against CLL cells within the lymph nodes and bone marrow. Furthermore, the efficacy of the combination against the TP53-KO OSU-CLL cell line suggests the combination may be a highly effective treatment strategy for high-risk CLL.


Leukemia, Lymphocytic, Chronic, B-Cell , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Sulfonamides/pharmacology , Tumor Microenvironment
6.
Cancer Drug Resist ; 3(3): 532-549, 2020.
Article En | MEDLINE | ID: mdl-35582439

The treatment of chronic lymphocytic leukaemia has been revolutionised in recent years, first by the introduction of chemoimmunotherapy regimens and subsequently by the development of drugs, including ibrutinib, idelalisib and venetoclax, that target components of the B-cell receptor signalling pathway or B-cell lymphoma 2 family of proteins. Despite high initial response rates in patients treated with chemoimmunotherapy or targeted agents, a significant proportion of patients relapse with progressive and refractory disease. In a subset of these patients, drug resistance has been associated with specific genetic lesions or activation of alternate pro-survival pathways. However, the mechanisms that confer drug resistance in the remainder of the patients with refractory disease have yet to be fully elucidated. In this review, we discuss our current understanding of the mechanics of drug resistance in chronic lymphocytic leukaemia and describe how this knowledge may aid in rationalising future treatment strategies to prevent the development of refractory or aggressive transformation of the disease.

7.
Br J Haematol ; 186(5): 668-684, 2019 09.
Article En | MEDLINE | ID: mdl-31364161

Chronic lymphocytic leukaemia (CLL) is characterised by the clonal expansion of mature, CD5 positive, B lymphocytes in the blood, marrow, lymph nodes and spleen. For the majority of patients, CLL follows an indolent clinical course, while a proportion of patients experience rapid disease progression. Despite the strong correlation between certain genetic defects and prognosis, there remains no single unifying pathogenic lesion in CLL. With recent advances in therapy it is increasingly important to stratify CLL patients according to risk. This has been highlighted by two recent studies, the first showing that immunoglobulin heavy chain mutational status predicts a durable response to frontline chemoimmunotherapy and the second showing that complex karyotype is a stronger predictor of poor response to ibrutinib and venetoclax therapy than TP53 deletion. In this review we discuss the molecular features of CLL and how technological advances can identify patient subsets and stratify them according to risk.


Cytogenetics/methods , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics
8.
Leuk Lymphoma ; 60(7): 1632-1643, 2019 07.
Article En | MEDLINE | ID: mdl-30648436

Several key pathways mediate signaling via the B-cell receptor, including the mitogen-activated protein kinase-ERK1/2 pathway. However, inhibition of MEK1/2, a key component of the MAPK-ERK1/2 signaling cascade, results in paradoxical activation of AKT in chronic lymphocytic leukemia (CLL) cells. In the current study we demonstrate synergy between the MEK1/2 inhibitor binimetinib and the AKT inhibitor MK2206, which combined induce apoptosis of primary CLL cells and restrict the cell cycle progression and proliferation of the OSU-CLL cell line. The mechanisms of action of the drug combination involve dual inhibition of MAPK-ERK1/2 and AKT signaling and down-regulation of Mcl-1 expression. Collectively, these data suggest that dual inhibition of MEK1/2 and AKT may represent a therapeutic option for CLL, capable of overcoming the pro-survival effects of the lymph node and bone marrow microenvironments.


Apoptosis/drug effects , Benzimidazoles/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 2/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Coculture Techniques , Drug Therapy, Combination , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Signal Transduction , Tumor Cells, Cultured , Tumor Microenvironment/drug effects
10.
Br J Haematol ; 182(5): 654-669, 2018 09.
Article En | MEDLINE | ID: mdl-29978459

Despite significant advances in treatment, chronic lymphocytic leukaemia (CLL) remains an incurable disease. Ibrutinib and idelalisib, which inhibit Bruton Tyrosine kinase (BTK) and phosphoinositol-3 (PI3) kinase-δ respectively, have become important treatment options for the disease and demonstrate the potential of targeting components of the B-cell receptor-signalling pathway. IBL-202 is a dual inhibitor of the PIM and PI3 kinases. Synergy between the pan-PIM inhibitor, pPIMi, and idelalisib against a range of haematological cell lines and primary CLL cells supports the rationale for preclinical studies of IBL-202 in CLL. Importantly, IBL-202, but not idelalisib, was cytotoxic against CLL cells under in vitro conditions that mimic the hypoxic tumour microenvironment. The significant effects of IBL-202 on CD49d and CXCR4 expression and migration, cycle and proliferation of CLL cells suggest the drug may also interfere with the migratory and proliferative capacity of the leukaemic cells. Collectively, these data demonstrate that dual inhibition of the PIM and PI3 kinases by IBL-202 may be an effective strategy for targeting CLL cells, particularly within the environmental niches known to confer drug-resistance.


Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Protein Kinase Inhibitors/therapeutic use , Cell Movement/drug effects , Cell Proliferation/drug effects , Drug Synergism , Humans , Integrin alpha4/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Phosphoinositide-3 Kinase Inhibitors , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Purines/therapeutic use , Quinazolinones/therapeutic use , Receptors, Antigen, B-Cell/metabolism , Receptors, CXCR4/metabolism , Tumor Cells, Cultured , Tumor Microenvironment
11.
Leuk Lymphoma ; 59(12): 2917-2928, 2018 12.
Article En | MEDLINE | ID: mdl-29911936

The Raf-1 kinase inhibitory protein (RKIP) is an important regulatory element in multiple signaling pathways, including MAPK-ERK1/2. We investigated whether targeted disruption of RKIP is a therapeutic option for chronic lymphocytic leukemia (CLL). The RKIP inhibitor locostatin-induced apoptosis of CLL cells, irrespective of poor prognostic indications or treatment history. Locostatin down-regulated MAPK-ERK1/2 and AKT phosphorylation, decreased expression of the chemokine receptor CXCR4 (p = .04) and reduced the migratory capacity of CLL cells toward stroma-derived factor 1α (SDF-1α, p = .02). Immuno-blotting and immuno-precipitation showed that RKIP is constitutively phosphorylated and highly expressed in CLL cells and that the actions of locostatin may be mediated by binding of G-protein receptor kinase-2 (GRK2) to MEK1 and AKT. Collectively, our data suggest that inhibition of RKIP may be effective against CLL, reducing the survival and migratory capacity of the leukemic cells through down-regulation of MAPK-ERK1/2 and AKT-mediated signaling.


Cell Movement/drug effects , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Oxazolidinones/pharmacology , Phosphatidylethanolamine Binding Protein/antagonists & inhibitors , Receptors, CXCR4/metabolism , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Down-Regulation , Drug Screening Assays, Antitumor , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Leukocytes, Mononuclear , MAP Kinase Signaling System/drug effects , Oxazolidinones/therapeutic use , Phosphatidylethanolamine Binding Protein/metabolism , Phosphorylation/drug effects , Primary Cell Culture
12.
Br J Haematol ; 182(3): 360-372, 2018 08.
Article En | MEDLINE | ID: mdl-29767411

The survival and proliferation of chronic lymphocytic leukaemia (CLL) cells is driven by multiple signalling pathways, including those mediated by the B cell, Toll-like and chemokine receptors. Many of these pathways converge on the same signalling molecules, including those involved in the Raf-1/MEK/Erk1/2-MAPK pathway. We investigated the effects of the MEK1/2 (also termed MAP2K1/2) inhibitor, binimetinib, against CLL cells cultured under conditions that mimic aspects of the tumour microenvironment. Binimetinib blocked CLL cell survival induced by stroma-conditioned media and phorbol myristylate (PMA). Binimetinib was also significantly more toxic towards CLL cells cultured in the presence of either anti-IgM antibody or stroma-derived factor-1α (SDF-1α) and reduced CLL cell cycle progression and proliferation. Furthermore, binimetinib significantly increased the sensitivity of CLL cells co-cultured with CD40 ligand (CD40L)-expressing fibroblasts to the BH3-mimetics ABT-737 and Venetoclax (ABT-199) via a mechanism involving down-regulation of Mcl-1 (MCL1) activity and Bim (BCL2L11) and Bcl-xL (BCL2L1) expression. Collectively, these data suggest that binimetinib may have both cytotoxic and cytostatic effects on CLL cells by blocking microenvironment-derived signals known to drive survival and proliferation. The combination of binimetinib with a BH3 mimetic may be an effective treatment strategy for CLL, particularly against the proliferative fraction of the disease within the tumour microenvironment.


Antineoplastic Agents/pharmacology , Benzimidazoles/pharmacology , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 2/antagonists & inhibitors , Tumor Microenvironment/drug effects , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Biphenyl Compounds/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Cycle/drug effects , Cell Survival/drug effects , Coculture Techniques , Drug Evaluation, Preclinical/methods , Drug Synergism , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , MAP Kinase Signaling System/drug effects , Nitrophenols/pharmacology , Piperazines/pharmacology , Sulfonamides/pharmacology , Tumor Cells, Cultured
13.
Br J Haematol ; 181(1): 97-101, 2018 04.
Article En | MEDLINE | ID: mdl-29468645

Immune dysfunction attributed to hypogammaglobulinaemia is common in chronic lymphocytic leukaemia (CLL) and infection is a major contributor to morbidity and mortality. A higher incidence of multiple immunoglobulin and immunoglobulin G (IgG) subclass deficiency was associated with more advanced disease (P < 0·001 and P < 0·001, respectively) in a cohort of 147 CLL patients. Multiple immunoglobulin and IgG subclass deficiency were significantly associated with shorter treatment-free survival (TFS) (P < 0·001 and P = 0·006, respectively). The association between disease stage and immune dysfunction demonstrated by these data suggest aspects of immune deficiency correlate with disease severity and may be associated with shorter TFS in CLL.


IgG Deficiency , Immunity, Humoral , Leukemia, Lymphocytic, Chronic, B-Cell , Aged , Disease-Free Survival , Female , Humans , IgG Deficiency/blood , IgG Deficiency/immunology , IgG Deficiency/mortality , IgG Deficiency/therapy , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Male , Middle Aged , Survival Rate
14.
Leuk Lymphoma ; 58(2): 266-279, 2017 02.
Article En | MEDLINE | ID: mdl-27756161

Microenvironments within the lymph node and bone marrow promote proliferation and drug resistance in chronic lymphocytic leukemia (CLL). Successful treatment of CLL must therefore target the leukemic cells within these compartments. A better understanding of the interaction between CLL cells and the tumor microenvironment has led to the development of in vitro models that mimic the mechanisms that support leukemic cell survival and proliferation in vivo. Employing these models as part of the pre-clinical evaluation of novel therapeutic agents enables a better approximation of their potential clinical efficacy. In this review we summarize the current literature describing how different aspects of the tumor microenvironment have been modeled in vitro and detail how these models have been employed to study the biology of the disease and potential efficacy of novel therapeutic agents.


Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Tumor Microenvironment , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , B-Cell Activating Factor/metabolism , CD40 Antigens/metabolism , CD40 Ligand/metabolism , Cell Communication , Drug Resistance, Neoplasm , Humans , Hypoxia/metabolism , Interleukins/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Protein Binding , Receptors, Antigen, B-Cell/metabolism , Signal Transduction , Stromal Cells/metabolism , Toll-Like Receptors/metabolism , Tumor Microenvironment/drug effects , Tumor Necrosis Factor Ligand Superfamily Member 13/metabolism
15.
World J Clin Cases ; 3(8): 694-704, 2015 Aug 16.
Article En | MEDLINE | ID: mdl-26301230

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. Despite significant advances in therapy over the last decade CLL remains incurable. Current front-line therapy often consists of chemoimmunotherapy-based regimens, most commonly the fludarabine, cyclophosphamide plus rituximab combination, but rates of relapse and refractory disease are high among these patients. Several key signaling pathways are now known to mediate the survival and proliferation of CLL cells in vivo, the most notable of which are the pathways mediated by the B-cell receptor (BCR) and cytokine receptors. A better understanding of the pathogenesis of the disease, the underlying biology of the CLL-cell and the roles of the tumour microenvironment has provided the rationale for trials of a range of novel, more targeted therapeutic agents. In particular, clinical trials of ibrutinib and idelalisib, which target the Brutons tyrosine kinase and the delta isoform of phosphoinositol-3 kinase components of the BCR signaling pathway respectively, have shown extremely promising results. Here we review the current literature on the key signaling pathways and interactions of CLL cells that mediate the survival and proliferation of the leukemic cells. For each we describe the results of the recent clinical trials and in vitro studies of novel therapeutic agents.

16.
Leuk Lymphoma ; 56(12): 3407-17, 2015.
Article En | MEDLINE | ID: mdl-25804768

The Raf-1/MEK/ERK1/2 pathway has become a focus for novel cancer therapies. This study sought to investigate whether targeting MEK1/2 may represent a therapeutic option for chronic lymphocytic leukemia (CLL). The MEK1/2 inhibitor, MEKi-1, induced apoptosis of CLL cells and was synergistic with fludarabine under conditions that mimic the tumor microenvironment, irrespective of poor-risk characteristics. MEKi-1 down-regulated the activities of AKT and ERK1/2 and was synergistic with fludarabine through a mechanism that involved potentiation of DNA damage and attenuation of the activity of ERK1/2 and expression of Mcl-1. This study highlights the significant role of the mitogen-activated protein kinase (MAPK)-ERK1/2 pathway in mediating the effects of the CLL tumor microenvironment and suggests that targeting MEK1/2 in CLL cells may impact upon the activity of both ERK1/2 and AKT. Inhibitors of MEK1/2 as single agents or in combination with DNA-damaging agents may represent a novel therapeutic strategy for CLL.


Acrylonitrile/analogs & derivatives , Aniline Compounds/pharmacology , Antineoplastic Agents/pharmacology , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 2/antagonists & inhibitors , Tumor Microenvironment/drug effects , Vidarabine/analogs & derivatives , Acrylonitrile/pharmacology , Apoptosis/drug effects , Cell Death/drug effects , Cell Line, Tumor , Coculture Techniques , DNA Damage/drug effects , Dose-Response Relationship, Drug , Drug Synergism , Gene Expression , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , MAP Kinase Signaling System/drug effects , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Stromal Cells/drug effects , Stromal Cells/metabolism , Vidarabine/pharmacology
18.
Leuk Lymphoma ; 54(1): 99-104, 2013 Jan.
Article En | MEDLINE | ID: mdl-22738394

Hypogammaglobulinemia is a common complication of chronic lymphocytic leukemia (CLL), but the significance of immunoglobulin G (IgG) subclass deficiency is unknown. We analyzed the prevalence of immunoglobulins G, A and M, IgG subclass deficiency and infection in 150 patients with CLL. Low IgG, IgA and IgM levels were observed in 27.3%, 30.7% and 56.7% of patients, respectively. IgG subclass deficiency was frequent, with reduced IgG1, IgG2, IgG3 and IgG4 in 28%, 19.3%, 52% and 22.7% of patients, respectively. IgG subclass deficiency (total 64.6%) and hypogammaglobulinemia (27.3%) were more prevalent than clinically significant infection (16%). Recurrent or significant infections were seen in 24 patients (16%), of whom 50% had hypogammaglobulinemia but 100% had at least one IgG subclass deficiency, indicating that half the patients with infection had IgG subclass deficiency but normal total IgG level. Deficiencies of IgG3 and IgG4 were statistically associated with infection risk. Normal immunoglobulin and IgG subclass levels were seen in 26 patients (17%) and none had infections. IgG subclass deficiency is commonly observed in patients with CLL with both normal and reduced total IgG levels, and is associated with infection. Screening patients with CLL for IgG subclass deficiency may be a useful adjunct in stratifying their infection risk.


IgG Deficiency/complications , Infections/etiology , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Adult , Aged , Aged, 80 and over , Dysgammaglobulinemia/complications , Female , Humans , Immunoglobulin G/blood , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Male , Middle Aged , Young Adult
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