CLL is associated with a high rate of infections that account for up to 60% of mortality

The majority (up to 80%) of patients will experience an infectious complication. 20% of CLL patients have severe/major infections. Infectious complications account for up to 60% of deaths.

Patients are predisposed to infection due to inherent immune defects related to the primary disease, and as a result of therapy. The range of infectious complications has evolved with therapeutic advances in the treatment of CLL.

Novel targeted therapies have been recently introduced, which will likely impact the prophylaxis and management of infectious complications in these patients.

Hypogammaglobulinaemia is a key clinical parameter that correlates with infection risk. This risk further increases with disease progression.

  • Tadmor, T. et al., Expert Review of Hematology 2018; 11:1, 57-70
  • Hensel, M. et al., Br J Haematol. 2003; 122:600
  • Gale, R. P. et al., N Engl J Med. 1988; 319:902

Chronic Lymphocytic Leukaemia pathogenesis impacts differentiation and function of blood cells

CLL cells crowding the bone marrow

Proliferation of CLL cells, crowding the bone marrow and blood stream

 

 

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Lymphocytosis

Anaemia, Lymphocytosis, Lymphadenopathy, Splenomegaly, Hepatomegaly, Thrombocytopaenia, Hypogammaglobulinaemia

  • Frenzel, L. P. et al., Oncol Res Treat 2016; 39: 9
  • American Cancer Society Chronic Lymphocytic Leukemia Early Detection, Diagnosis, and
  • Staging, https://www.cancer.org/content/dam/CRC/PDF/Public/8681.00.pdf
Hypothetical model of immune regulation in CLL

Circulating CLL cells are anergic B cells with low surface IgM levels after exposure to antigen.

CLL cells express molecules with possible regulatory activity on plasma cells, resulting in lower production of serum Ig and hypogammaglobulinaemia.

Activated CLL cells produce immunosuppressive IL-10, suppressing monocytes/macrophages and reducing TNF-α.

  • Adapted from: Forconi F. et al., Blood 2015; 126: 573-581

Chronic Lymphocytic Leukaemia pathogenesis impacts differentiation and function of blood cells, a mechanism that might account for the observed hypogammaglobulinaemia

Model for PD-1 B-cell function

CLL cells have an elevated expression of PD-L1 and interact with PD-1 on activated T cells (A).

Interactions with PD-L1 high B cells increase Stat5 expression, resulting in suppressed TFH-cell development and expansion (B).

Fewer TFH cells result in limited B-cell development (C) and differentiation to plasma cells (D), a mechanism that might account for the development of hypogamma-globulinaemia.

  • Adapted from: Khan et al., Nature Communications 2019; 6:5997

Characterisation of CLL-associated immunodeficiency – extends beyond antibody deficiency

Defects in innate immunity

  • Reduced levels of several complement proteins, with specific reductions of the C1-C4 components in ~ 40% of patients - implications for opsonisation with C3b
  • Defects in neutrophils: impaired phagocytic killing of nonopsonized bacteria and a reduction in C5a-induced chemotaxis
  • Defects in monocyte cells: increased circulating monocyte count by >60% but with a gene expression profile associated with immunosuppressive properties
  • Natural killer cell defects: increased number in the circulation but with several functional defects including an impaired cytotoxic activity

Defects in adaptive immunity

  • T cells: impaired immunological synapse formation with antigen presenting cells as a result of defects in actin polymerisation
  • Hypogammaglobulinaemia with impaired antibody responses to test immunization
  • Forconi F. et al., Blood 2015; 126: 573-581

Malignant CLL cells are associated with T-cell defects

Possible link between T-cell defects and malignant CLL cells

Genes in CD4+ and CD8+ are differentially expressed in patients with CLL:

CD4+ T-cells: genes involved in cell differentiation (particularly JNK and p38 MAPK pathways; pink and yellow, respectively), and cytoskeleton formation and vesicle transportation (green).

CD8+ T-cells: genes involved in cytoskeleton formation, vesicle trafficking (green) and cytotoxicity (red).

In diagram: selected genes upregulated in CLL patients compared to healthy donors are shown in rectangular boxes and those that are downregulated in ovals.

  • Adapted from: Gorgun G. et al., J Clin Invest 2005; 115: 1797- 805
CLL pathogenesis affects differentiation and function of T-cells, B-cells, NK-cells, Monocytes, Neutrophils and Complement.-Icon

CLL pathogenesis affects differentiation and function of T-cells, B-cells, NK-cells, Monocytes, Neutrophils and Complement.

CLL results in defective innate and adaptive immunity, increasing the risk for secondary immunodeficiency.-Icon

CLL results in defective innate and adaptive immunity, increasing the risk for secondary immunodeficiency.

  • Ziegler HW et al., Int J Cancer 1981; 27: 321-7
  • Kay NE. et al., Blood. 1984; 63: 305-9
  • Burton JD. et al., Am J Hematol. 1989; 30: 61-7
  • Palmer S. et al., Br J Haematol. 2008; 141: 607-14
  • Bojarska-Junak A. et al., Oncology reports 2010; 24: 803-10
  • Zeya HI. et al., Am J Pathol. 1979; 95: 43-54
  • Sawicka-Powierza J. et al., Neoplasma 2011; 58: 45-50

CLL results in hypogammaglobulinaemia across all Immunoglobulin classes

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  • Forconi F. et al., Blood 2015; 126: 573-581
The severity of hypogammaglobulinaemia and infiltration rate of the bone marrow increase with the duration and progression of disease.-Icon

The severity of hypogammaglobulinaemia and infiltration rate of the bone marrow increase with the duration and progression of disease.

All Ig classes (Immunoglobulins IgG, IgA, IgM) are involved, leading to increased secondary immune deficiency.-Icon

All Ig classes (Immunoglobulins IgG, IgA, IgM) are involved, leading to increased secondary immune deficiency.

Protective effect of vaccines is reduced, putting CLL patients at risk (in a study with 24 CLL patients, 41.7% had an impaired antibody response to pneumococcal conjugate vaccine).-Icon

Protective effect of vaccines is reduced, putting CLL patients at risk (in a study with 24 CLL patients, 41.7% had an impaired antibody response to pneumococcal conjugate vaccine).

  • Pasiarski M. et al., PLoS One, 2014 Dec 15; 9((12)):e114966
  • Forconi F. et al., Blood 2015; 126: 573-581

Infection in CLL is associated with low Ig levels

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tabelle

In a study, 65% of patients with major infections (vs. 20% without major infections) had IgG levels below 7.44 g/L, IgA below 0.79 g/L, and/or IgM below 0.21 g/L.

  • Adapted from: Visentin, A. et al., Haematologica, 2015; 100:e515

CLL progression is associated with higher infection rates

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  • Adapted from: Freeman, J.A. et al., Leuk Lymphoma, 2013; 54:99

Low IgG subclass levels are associated with infection in CLL

IgG subclass deficiencies in CLL patients with infections (n=24)
IgG subclass deficiencies in CLL patients with infections (n=24)

In a study, all 24/150 patients with CLL and significant or recurrent infections had ≥1 IgG subclass deficiency.

  • Freeman, J.A. et al., Leuk Lymphoma, 2013; 54:99
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Low infection risk

  • Normal Ig levels
  • No history of severe or recurring infections
  • Neutropenia <7 days
  • Few co-morbidities

High infection risk

  • Hypogammaglobulinaemia
  • Severe or recurring infections
  • Neutropenia (<0.1 x 109/L) >7 days
  • Co-morbidities
  • Freifeld, A. G., et al., Clin Infect Dis. 2001; 52:427
  • Tomblyn, M. et al., Biol Blood Marrow Transplant. 2009; 15:1143
  • Lachance, S. et al., Current Oncology 2016; 23:42
  • Visentin, A. et al., Haematologica 2015;100:e515

Treatment induced secondary immune deficiency in CLL

Therapy  Immune dysfunction Infections
Chemotherapy
Alkylating agents
(e.g chlorambucil, bendamustine, cyclophosphamide)
Neutropaenia
Lymphopaenia (T cell dysfunction)
Bacterial
Purine analogues
(e.g. fludarabine, pentostatin, bendamustine, cladribine
Lymphopaenia
(T cell dysfunction +++) Neutropaenia
Bacterial, viral, fungal, if prolonged
PJP Cryptococcus
Immunotherapy
Anti-CD20 antibodies
(e.g. rituximab, ofatumumab, obinotuzumab)
Lymphopaenia B Bacterial, hepatitis B reactivation, viruses (e.g. Entero, JC)
Anti-CD22 antibodies
(moxetumomab pasudotox)
Platelet, white blood cells, neutrophil and lymphocyte count decreased Pneumonia, upper respiratory infection, febrile neutropenia 
Anti-CD52 antibody
(alemtuzumab)
Lymphopaenia
(B and T cell dysfunction)
Viruses (e.g. CMV, HSV, VZV) Fungal PJP
Small molecule inhibitors
Bruton tyrosine kinase inhibitors
(e.g. ibrutinib, acalabrutinib)
Lymphopaenia
(B cell dysfunction, possible T cell dysfunction)
Hepatitis B
reactivation, fungal (Aspergillus, Cryptococcus) PJP
Phosphatidylinositol
3-kinase inhibitors

(e.g. idelalisib, duvelisib)
Neutropaenia
Lymphopaenia (B and T cell dysfunction)
Bacterial, fungal, if prolonged Viruses (e.g. CMV, HSV) Aspergillus PJP
B-cell lymphoma inhibitors
(e.g. venetoclax)
Neutropaenia
Lymphopaenia (B cell dysfunction)
Bacterial, viruses (e.g. enterovirus)

PJP: Pneumocystis jiroveci pneumonia, JC: John Cunningham virus CMV: cytomegalo virus, HSV: herpes simplex virus, VZV: varizella zoster virus

  • HSV: herpes simplex virus, VZV: varizella zoster virus
  • Hilal T. et al., Blood Reviews 2018; 32: 387-399
  • Kreitmann et al., Leukemia 2018; 32: 1768–1777

Infections are frequent in Chronic Lymphocytic Leukaemia (CLL)

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In this study with 187 patients, 84% developed an infection.

Patients treated for CLL had a higher risk of infection.

  • Adapted from: Hensel, M. et al., Br J Haematol. 2003; 122:600

Infections remain a major cause of mortality in CLL

Cause of death in patients with CLL (n=10 455; strong colours) versus matched control population (n=508 995; soft colours)
Cause of death in patients with CLL (n=10 455; strong colours) versus matched control population (n=508 995; soft colours)
  • Adapted from: Cunha-Bang, C. et al., Blood Cancer J. 2016; 6 (11)
Significant mortality and morbidity due to infections facilitated by CLL itself and by treatment-related adverse events.-Icon

Significant mortality and morbidity due to infections facilitated by CLL itself and by treatment-related adverse events.

CLL patients have a ~50% increased risk of death due to infection (as contributory or underlying cause) compared to matched control population.-Icon

CLL patients have a ~50% increased risk of death due to infection (as contributory or underlying cause) compared to matched control population.

Infection-related deaths have not improved over time.-Icon

Infection-related deaths have not improved over time.

  • Cunha-Bang, C. et al., Blood Cancer J. 2016; 6 (11)

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