- Email: [email protected]
Intravenous versus subcutaneous immunoglobulin replacement in secondary hypogammaglobulinemia
Intravenous versus subcutaneous immunoglobulin replacement in secondary hypogammaglobulinemia Giuseppe Spadaro, Antonio Pecoraro, Amalia De Renzo, Roberta Della Pepa, Arturo Genovese PII: DOI: Reference:
S1521-6616(16)30059-6 doi: 10.1016/j.clim.2016.04.001 YCLIM 7638
To appear in:
Clinical Immunology
Received date: Accepted date:
3 April 2016 4 April 2016
Please cite this article as: Giuseppe Spadaro, Antonio Pecoraro, Amalia De Renzo, Roberta Della Pepa, Arturo Genovese, Intravenous versus subcutaneous immunoglobulin replacement in secondary hypogammaglobulinemia, Clinical Immunology (2016), doi: 10.1016/j.clim.2016.04.001
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT LETTER TO THE EDITOR Intravenous
versus
subcutaneous
immunoglobulin
replacement
in
secondary
T
hypogammaglobulinemia
Department of Translational Medical Sciences, Allergy and Clinical Immunology, University of
SC R
a
IP
Giuseppe Spadaroa*, Antonio Pecoraroa, Amalia De Renzob, Roberta Della Pepab, Arturo Genovesea
Naples Federico II, Naples, Italy
Department of Clinical Medicine and Surgery, Haematology, University of Naples Federico II,
NU
b
MA
Naples, Italy
*Corresponding Author
D
Giuseppe Spadaro, M.D.
TE
Address: Napoli, via S. Pansini 5, C.A.P. 80131.
AC
CE P
E mail address: [email protected]; Tel: +390817462279; Mobile: +393478140542.
1
ACCEPTED MANUSCRIPT Abstract In this study, we compared intravenous immunoglobulins (IVIG) and subcutaneous
T
immunoglobulins (SCIG) in terms of serum IgG concentration and incidence of infections in
IP
patients with hypogammaglobulinemia secondary to chemo-immunotherapy regimens including
SC R
the anti-CD20 monoclonal antibody rituximab. Fourteen patients with a B-cell lymphoproliferative disease treated for at least six months with a rituximab-including chemo-immunotherapy regimen
NU
were recruited. Mean serum levels of IgG were higher during replacement therapy than at the end of rituximab treatment (p<0.001). Moreover, serum IgG level was higher during replacement
MA
therapy with SCIG than with IVIG (p<0.001). No differences in the incidence of infections were observed. Although the non-randomized design and the small number of patients do not allow
D
definitive conclusions to be drawn, study results suggest that higher mean serum IgG levels are
TE
reached when using the subcutaneous route after a switch from the intravenous regimen, and
AC
CE P
that IVIG and SCIG offer comparable protection against infections.
2
ACCEPTED MANUSCRIPT Secondary hypogammaglobulinemia (SH) can occur as a result of haematological disorders or pharmacological therapies, including anti-CD20-based chemo-immunotherapy for haematological
T
malignancies [1]. Patients with SH may be asymptomatic or may be affected by severe respiratory
IP
or gastrointestinal tract infections that can influence prognosis of the underlying disease.
SC R
Immunoglobulin-replacement therapy has been widely used over the last two decades in patients with iatrogenic or disease-related SH and recurrent infections in order to reduce the incidence and
NU
severity of infectious events and to improve quality of life and prognosis. Intravenous or subcutaneous route of administration can be safely and efficaciously used in SH, but it is not clear
MA
which route is to be preferred [2]. Moreover, information on the specific pharmacokinetic of these two regimens may help tailoring therapy [2].
D
The aim of this study was to compare intravenous immunoglobulins (IVIG) and subcutaneous
levels”
achieved)
and
incidence
of
infections
in
patients
with
CE P
“steady-state
TE
immunoglobulins (SCIG) replacement in terms of serum IgG concentration (“through-levels” and
hypogammaglobulinemia secondary to chemo-immunotherapy regimens including the anti-CD20
AC
monoclonal antibody rituximab.
Fourteen patients (7 males; mean age 61±10 years, range 46-77) with a B-cell lymphoproliferative disease (12 with non-Hodgkin lymphoma and 2 with chronic lymphoid leukaemia) treated for at least six months with a rituximab-including chemo-immunotherapy regimen were recruited. In all patients hypogammaglobulinemia was detectable for at least 12 months after discontinuation of rituximab (IgG≤400 mg/dl). Patients with protein-losing diseases (e.g. losing-protein enteropathy, intestinal lymphangiectasia, nephrophaties, etc.) were excluded. All patients provided informed consent before inclusion. The study was conducted at two specialized Haematology and Immunology Departments (University Federico II, Naples).
3
ACCEPTED MANUSCRIPT Patients were treated initially with IVIG at a mean dose of 400 (±15.7) mg/Kg/month, with an interval between each infusion of three weeks. Seven patients received IgVena® (Kedrion),
T
4patients used Kiovig® (Baxter), and 3 patients Flebogamma® (Grifols). After six months of IVIG
IP
therapy, all patients were switched to SCIG therapy at a mean dose of 100 (±4.4) mg/Kg/week,
SC R
with an interval between each infusion of one week (10 patients received Hizentra® - CSL Behring and 4 patients Subcuvia® - Baxter). Serum IgG levels were evaluated every two months for at least
NU
three times, and mean serum IgG levels during IVIG and SCIG replacement therapy were recorded. Paired t-test was used to compare mean serum IgG concentrations after rituximab treatment and
MA
during IVIG and SCIG replacement therapy. Diagnosis of infection was patient-reported with microbiological confirmation when appropriate. Data on number and type of infections
D
experienced by patients after discontinuation of rituximab and during the two treatment periods
TE
were collected. Infections were classified in: higher respiratory tract infections (HRTI), lower
CE P
respiratory tract infections (LRTI), and gastrointestinal tract infections (GTI). Descriptive statistical analysis was performed using Epiinfo ver. 3.5.4.
AC
Mean serum IgG level after discontinuation of rituximab was 251.36±105.65 mg/dl (range: 60-400 mg/dl). Mean serum levels of IgG were higher during replacement therapy than at the end of rituximab treatment (p<0.001). Moreover, serum IgG level was higher during replacement therapy with SCIG than with IVIG (p<0.001). In more details, during the 6 months of IVIG therapy, mean serum IgG level was 598.64±115.94 mg/dl (367-760 mg/dl). During SCIG therapy mean serum IgG level was 845.85±168.28 mg/dl (634-1160 mg/dl). Figure 1 summarizes individual IgG levels throughout the study. In the year before Ig-replacement therapy, the patients had experienced a mean number of infectious events equal to 11.1±3.0. Overall, the most frequent infections were HRTI (49.4%, 77/156 infections), followed by LRTI (41.7%, 65/156) and GTI (9.0%, 14/156). During IVIG and SCIG replacement therapy mean number of infectious events was 3.0±1.4 and 2.4±1.4, 4
ACCEPTED MANUSCRIPT respectively. During IVIG replacement therapy, HRTI and LRTI accounted for 66.7% (28/42 infections) and 28.6% (12/42) of all infectious events, respectively, while GTI accounted for4.8%
T
(2/42) of all infections. Similarly, during SCIG replacement therapy HRTI were 67.7% (21/31) of all
IP
infectious events, followed by LRTI (25.8%, 8/31) and GTI (6.5%, 2/31).
SC R
Although the non-randomized design and the small number of patients do not allow definitive conclusions to be drawn, our study results suggest that higher mean serum IgG levels are reached
NU
when using the subcutaneous route after a switch from the intravenous regimen, and that IVIG and SCIG offer comparable protection against infections.
MA
This preliminary finding may have some clinical implications in the treatment of SH. In fact, pharmacokinetic studies [3,4] on immunoglobulin-replacement therapy indicate that SCIG
D
administration, at the steady state, allows to achieve a lower variability of IgG serum levels than
TE
IVIG. Furthermore, SCIG have been shown to be safe, cost-effective, and greatly appreciated in
CE P
terms of Health-Related Quality of Life (HRQL) and patient compliance in primary antibody defects [5,6]. We speculate that these advantages may be extended also to SH patients.
AC
Other randomized studies on larger populations of patients are needed in order to further evaluate efficacy and safety of SCIG replacement therapy in SH. This knowledge would help establish guidelines for clinicians and policymakers that would also allow to improve HRQL of patients with SH.
Conflict of interest and financial disclosure The Authors have no conflicts of interest directly relevant to this study. Editorial assistance for the preparation of this manuscript was funded by CSL Behring
5
ACCEPTED MANUSCRIPT Acknowledgments
Editorial assistance for the preparation of this manuscript was provided by Lilia Biscaglia, PhD, and
SC R
IP
T
Luca Giacomelli, PhD, on behalf of Content Ed Net.
References
1. Compagno N, Malipiero G, Cinetto F, Agostini C. Immunoglobulin Replacement Therapy in Hypogammaglobulinemia.
Immunol.
2014;5:626.
doi:
MA
10.3389/fimmu.2014.00626.
Front
NU
Secondary
2. Lingman-Framme J, Fasth A. Subcutaneous immunoglobulin for primary and secondary
D
immunodeficiencies: an evidence-based review. Drugs. 2013;73:1307-19. doi: 10.1007/s40265-
TE
013-0094-3.
3. Berger M, Rojavin M, Kiessling P, Zenker O. Pharmacokinetics of subcutaneous
CE P
immunoglobulin and their use in dosing of replacement therapy in patients with primary immunodeficiencies. J Clin Immunol. 2011;139:133-41. doi: 10.1016/j.clim.2011.01.006.
AC
4. Jolles S, Sleasman JW. Subcutaneous Immunoglobulin Replacement Therapy with Hizentra®, the First 20% SCIG Preparation: a Practical Approach. Adv Ther. 2011;28:521-33. 5. Abolhassani H, Sadaghiani MS, Aghamohammadi A, Ochs HD, Rezaei N. Home-based subcutaneous immunoglobulin versus hospital-based intravenous immunoglobulin in treatment of primary antibody deficiencies: systematic review and meta-analysis. J Clin Immunol. 2012;32:1180-92. doi: 10.1007/s10875-012-9720-1. 6. Chapel H, Gardulf A. Subcutaneous immunoglobulin replacement therapy: the European experience.
Curr
Opin
Allergy
Clin
Immunol.
2013;13:623-9.
doi:
10.1097/ACI.0000000000000013.
6
ACCEPTED MANUSCRIPT
Figure Caption
IP
T
Figure 1. Individual and mean IgG levels throughout the study (data on IgG levels during SCIG
SC R
replacement therapy not available for patient #4). *p<0.001 for both replacement regimens vs end
AC
CE P
TE
D
MA
NU
of rituximab treatment and for SCIG vs IVIG.
7
ACCEPTED MANUSCRIPT
1400
T
1200
IP
800
*
SC R
Serum IgG (mg/dL)
1000
600
NU
400
0 1
2
3
4
5
MA
200
6
7
8
9
10
11
12
13
14
Mean values
CE P
TE
D
post-Rituximab IgG serum levels Patient #ID IgG through levels during IVIG replacement therapy IgG steady state levels during SCIG replacement therapy
AC
Note: figure captions at the end of manuscript text file
8
ACCEPTED MANUSCRIPT Highlights
T
IP
SC R NU MA D TE
CE P
Higher mean serum IgG levels are reached when using the subcutaneous route after a switch from the intravenous immunoglobulin replacement. Intravenous immunoglobulin replacement and subcutaneous immunoglobulin replacement offer comparable protection against infections. Subcutaneous immunoglobulin administration, at the steady state, allows to achieve a lower variability of IgG serum levels than Intravenous administration.
AC
9
S1521-6616(16)30059-6 doi: 10.1016/j.clim.2016.04.001 YCLIM 7638
To appear in:
Clinical Immunology
Received date: Accepted date:
3 April 2016 4 April 2016
Please cite this article as: Giuseppe Spadaro, Antonio Pecoraro, Amalia De Renzo, Roberta Della Pepa, Arturo Genovese, Intravenous versus subcutaneous immunoglobulin replacement in secondary hypogammaglobulinemia, Clinical Immunology (2016), doi: 10.1016/j.clim.2016.04.001
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT LETTER TO THE EDITOR Intravenous
versus
subcutaneous
immunoglobulin
replacement
in
secondary
T
hypogammaglobulinemia
Department of Translational Medical Sciences, Allergy and Clinical Immunology, University of
SC R
a
IP
Giuseppe Spadaroa*, Antonio Pecoraroa, Amalia De Renzob, Roberta Della Pepab, Arturo Genovesea
Naples Federico II, Naples, Italy
Department of Clinical Medicine and Surgery, Haematology, University of Naples Federico II,
NU
b
MA
Naples, Italy
*Corresponding Author
D
Giuseppe Spadaro, M.D.
TE
Address: Napoli, via S. Pansini 5, C.A.P. 80131.
AC
CE P
E mail address: [email protected]; Tel: +390817462279; Mobile: +393478140542.
1
ACCEPTED MANUSCRIPT Abstract In this study, we compared intravenous immunoglobulins (IVIG) and subcutaneous
T
immunoglobulins (SCIG) in terms of serum IgG concentration and incidence of infections in
IP
patients with hypogammaglobulinemia secondary to chemo-immunotherapy regimens including
SC R
the anti-CD20 monoclonal antibody rituximab. Fourteen patients with a B-cell lymphoproliferative disease treated for at least six months with a rituximab-including chemo-immunotherapy regimen
NU
were recruited. Mean serum levels of IgG were higher during replacement therapy than at the end of rituximab treatment (p<0.001). Moreover, serum IgG level was higher during replacement
MA
therapy with SCIG than with IVIG (p<0.001). No differences in the incidence of infections were observed. Although the non-randomized design and the small number of patients do not allow
D
definitive conclusions to be drawn, study results suggest that higher mean serum IgG levels are
TE
reached when using the subcutaneous route after a switch from the intravenous regimen, and
AC
CE P
that IVIG and SCIG offer comparable protection against infections.
2
ACCEPTED MANUSCRIPT Secondary hypogammaglobulinemia (SH) can occur as a result of haematological disorders or pharmacological therapies, including anti-CD20-based chemo-immunotherapy for haematological
T
malignancies [1]. Patients with SH may be asymptomatic or may be affected by severe respiratory
IP
or gastrointestinal tract infections that can influence prognosis of the underlying disease.
SC R
Immunoglobulin-replacement therapy has been widely used over the last two decades in patients with iatrogenic or disease-related SH and recurrent infections in order to reduce the incidence and
NU
severity of infectious events and to improve quality of life and prognosis. Intravenous or subcutaneous route of administration can be safely and efficaciously used in SH, but it is not clear
MA
which route is to be preferred [2]. Moreover, information on the specific pharmacokinetic of these two regimens may help tailoring therapy [2].
D
The aim of this study was to compare intravenous immunoglobulins (IVIG) and subcutaneous
levels”
achieved)
and
incidence
of
infections
in
patients
with
CE P
“steady-state
TE
immunoglobulins (SCIG) replacement in terms of serum IgG concentration (“through-levels” and
hypogammaglobulinemia secondary to chemo-immunotherapy regimens including the anti-CD20
AC
monoclonal antibody rituximab.
Fourteen patients (7 males; mean age 61±10 years, range 46-77) with a B-cell lymphoproliferative disease (12 with non-Hodgkin lymphoma and 2 with chronic lymphoid leukaemia) treated for at least six months with a rituximab-including chemo-immunotherapy regimen were recruited. In all patients hypogammaglobulinemia was detectable for at least 12 months after discontinuation of rituximab (IgG≤400 mg/dl). Patients with protein-losing diseases (e.g. losing-protein enteropathy, intestinal lymphangiectasia, nephrophaties, etc.) were excluded. All patients provided informed consent before inclusion. The study was conducted at two specialized Haematology and Immunology Departments (University Federico II, Naples).
3
ACCEPTED MANUSCRIPT Patients were treated initially with IVIG at a mean dose of 400 (±15.7) mg/Kg/month, with an interval between each infusion of three weeks. Seven patients received IgVena® (Kedrion),
T
4patients used Kiovig® (Baxter), and 3 patients Flebogamma® (Grifols). After six months of IVIG
IP
therapy, all patients were switched to SCIG therapy at a mean dose of 100 (±4.4) mg/Kg/week,
SC R
with an interval between each infusion of one week (10 patients received Hizentra® - CSL Behring and 4 patients Subcuvia® - Baxter). Serum IgG levels were evaluated every two months for at least
NU
three times, and mean serum IgG levels during IVIG and SCIG replacement therapy were recorded. Paired t-test was used to compare mean serum IgG concentrations after rituximab treatment and
MA
during IVIG and SCIG replacement therapy. Diagnosis of infection was patient-reported with microbiological confirmation when appropriate. Data on number and type of infections
D
experienced by patients after discontinuation of rituximab and during the two treatment periods
TE
were collected. Infections were classified in: higher respiratory tract infections (HRTI), lower
CE P
respiratory tract infections (LRTI), and gastrointestinal tract infections (GTI). Descriptive statistical analysis was performed using Epiinfo ver. 3.5.4.
AC
Mean serum IgG level after discontinuation of rituximab was 251.36±105.65 mg/dl (range: 60-400 mg/dl). Mean serum levels of IgG were higher during replacement therapy than at the end of rituximab treatment (p<0.001). Moreover, serum IgG level was higher during replacement therapy with SCIG than with IVIG (p<0.001). In more details, during the 6 months of IVIG therapy, mean serum IgG level was 598.64±115.94 mg/dl (367-760 mg/dl). During SCIG therapy mean serum IgG level was 845.85±168.28 mg/dl (634-1160 mg/dl). Figure 1 summarizes individual IgG levels throughout the study. In the year before Ig-replacement therapy, the patients had experienced a mean number of infectious events equal to 11.1±3.0. Overall, the most frequent infections were HRTI (49.4%, 77/156 infections), followed by LRTI (41.7%, 65/156) and GTI (9.0%, 14/156). During IVIG and SCIG replacement therapy mean number of infectious events was 3.0±1.4 and 2.4±1.4, 4
ACCEPTED MANUSCRIPT respectively. During IVIG replacement therapy, HRTI and LRTI accounted for 66.7% (28/42 infections) and 28.6% (12/42) of all infectious events, respectively, while GTI accounted for4.8%
T
(2/42) of all infections. Similarly, during SCIG replacement therapy HRTI were 67.7% (21/31) of all
IP
infectious events, followed by LRTI (25.8%, 8/31) and GTI (6.5%, 2/31).
SC R
Although the non-randomized design and the small number of patients do not allow definitive conclusions to be drawn, our study results suggest that higher mean serum IgG levels are reached
NU
when using the subcutaneous route after a switch from the intravenous regimen, and that IVIG and SCIG offer comparable protection against infections.
MA
This preliminary finding may have some clinical implications in the treatment of SH. In fact, pharmacokinetic studies [3,4] on immunoglobulin-replacement therapy indicate that SCIG
D
administration, at the steady state, allows to achieve a lower variability of IgG serum levels than
TE
IVIG. Furthermore, SCIG have been shown to be safe, cost-effective, and greatly appreciated in
CE P
terms of Health-Related Quality of Life (HRQL) and patient compliance in primary antibody defects [5,6]. We speculate that these advantages may be extended also to SH patients.
AC
Other randomized studies on larger populations of patients are needed in order to further evaluate efficacy and safety of SCIG replacement therapy in SH. This knowledge would help establish guidelines for clinicians and policymakers that would also allow to improve HRQL of patients with SH.
Conflict of interest and financial disclosure The Authors have no conflicts of interest directly relevant to this study. Editorial assistance for the preparation of this manuscript was funded by CSL Behring
5
ACCEPTED MANUSCRIPT Acknowledgments
Editorial assistance for the preparation of this manuscript was provided by Lilia Biscaglia, PhD, and
SC R
IP
T
Luca Giacomelli, PhD, on behalf of Content Ed Net.
References
1. Compagno N, Malipiero G, Cinetto F, Agostini C. Immunoglobulin Replacement Therapy in Hypogammaglobulinemia.
Immunol.
2014;5:626.
doi:
MA
10.3389/fimmu.2014.00626.
Front
NU
Secondary
2. Lingman-Framme J, Fasth A. Subcutaneous immunoglobulin for primary and secondary
D
immunodeficiencies: an evidence-based review. Drugs. 2013;73:1307-19. doi: 10.1007/s40265-
TE
013-0094-3.
3. Berger M, Rojavin M, Kiessling P, Zenker O. Pharmacokinetics of subcutaneous
CE P
immunoglobulin and their use in dosing of replacement therapy in patients with primary immunodeficiencies. J Clin Immunol. 2011;139:133-41. doi: 10.1016/j.clim.2011.01.006.
AC
4. Jolles S, Sleasman JW. Subcutaneous Immunoglobulin Replacement Therapy with Hizentra®, the First 20% SCIG Preparation: a Practical Approach. Adv Ther. 2011;28:521-33. 5. Abolhassani H, Sadaghiani MS, Aghamohammadi A, Ochs HD, Rezaei N. Home-based subcutaneous immunoglobulin versus hospital-based intravenous immunoglobulin in treatment of primary antibody deficiencies: systematic review and meta-analysis. J Clin Immunol. 2012;32:1180-92. doi: 10.1007/s10875-012-9720-1. 6. Chapel H, Gardulf A. Subcutaneous immunoglobulin replacement therapy: the European experience.
Curr
Opin
Allergy
Clin
Immunol.
2013;13:623-9.
doi:
10.1097/ACI.0000000000000013.
6
ACCEPTED MANUSCRIPT
Figure Caption
IP
T
Figure 1. Individual and mean IgG levels throughout the study (data on IgG levels during SCIG
SC R
replacement therapy not available for patient #4). *p<0.001 for both replacement regimens vs end
AC
CE P
TE
D
MA
NU
of rituximab treatment and for SCIG vs IVIG.
7
ACCEPTED MANUSCRIPT
1400
T
1200
IP
800
*
SC R
Serum IgG (mg/dL)
1000
600
NU
400
0 1
2
3
4
5
MA
200
6
7
8
9
10
11
12
13
14
Mean values
CE P
TE
D
post-Rituximab IgG serum levels Patient #ID IgG through levels during IVIG replacement therapy IgG steady state levels during SCIG replacement therapy
AC
Note: figure captions at the end of manuscript text file
8
ACCEPTED MANUSCRIPT Highlights
T
IP
SC R NU MA D TE
CE P
Higher mean serum IgG levels are reached when using the subcutaneous route after a switch from the intravenous immunoglobulin replacement. Intravenous immunoglobulin replacement and subcutaneous immunoglobulin replacement offer comparable protection against infections. Subcutaneous immunoglobulin administration, at the steady state, allows to achieve a lower variability of IgG serum levels than Intravenous administration.
AC
9