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Original Article

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Blood Res 2022; 57(2):

Published online June 30, 2022

https://doi.org/10.5045/br.2022.2021163

© The Korean Society of Hematology

Immunoglobulin repletion during blinatumomab therapy does not reduce the rate of secondary hypogammaglobulinemia and associated infectious risk

Stephanie Wo1*, Hannah Levavi2, John Mascarenhas2, Marina Kremyanskaya2, Shyamala Navada2*, Michal Bar-Natan2#, Sara S. Kim1#*

Author Info. +

1Department of Pharmacy, The Mount Sinai Hospital, 2Division of Hematology/Oncology, Icahn School of Medicine at The Mount Sinai Hospital, New York, NY, USA

Correspondence to : Michal Bar-Natan, M.D.
Division of Hematology/Oncology, Icahn School of Medicine at The Mount Sinai Hospital, One Gustave L. Levy Place, Box 1079, New York, NY 10029-6574, USA
E-mail: Michal.Bar-Natan@mssm.edu

#These authors contributed equally to this work.
*These authors’ affiliations are at the time of manuscript development.

Received: September 1, 2021; Revised: January 9, 2022; Accepted: April 18, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Background
Blinatumomab has demonstrated efficacy in minimal residual disease (MRD) positive and relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) by inciting rapid and sustained B-cell depletion.
Methods
Owing to its effect on B-cells, blinatumomab is associated with a higher rate of secondary hypogammaglobulinemia compared to chemotherapy. To mitigate blinatumomab-induced hypogammaglobulinemia, patients were pre-emptively repleted with intravenous immune globulin (IVIG) during blinatumomab therapy. In this retrospective study, we compared outcomes of 23 blinatumomab treated adults with ALL. Seventeen patients routinely received IVIG and 6 patients were in the control cohort.
Results
Our findings demonstrated no difference between the two cohorts in immunoglobulin G (IgG) nadir (338 mg/dL vs. 337 mg/dL, P=0.641), days to IgG nadir (120.5 vs. 85.5 days, P=0.13), infection rate (82.4% vs. 66.7%, P=0.58), infections requiring ICU admission (23.5% vs. 16.7%, P=1), and infection related mortality (17.6% vs. 16.7%, P=1).
Conclusion
Pre-emptive IVIG repletion during blinatumomab did not prevent hypogammaglobulinemia and associated infection risk.

Keywords Acute lymphoblastic leukemia, Blinatumomab, Hypogammaglobulinemia, ALL, Intravenous Immunoglobulin

Article

Original Article

Blood Res 2022; 57(2): 135-143

Published online June 30, 2022 https://doi.org/10.5045/br.2022.2021163

Copyright © The Korean Society of Hematology.

Immunoglobulin repletion during blinatumomab therapy does not reduce the rate of secondary hypogammaglobulinemia and associated infectious risk

Stephanie Wo1*, Hannah Levavi2, John Mascarenhas2, Marina Kremyanskaya2, Shyamala Navada2*, Michal Bar-Natan2#, Sara S. Kim1#*

1Department of Pharmacy, The Mount Sinai Hospital, 2Division of Hematology/Oncology, Icahn School of Medicine at The Mount Sinai Hospital, New York, NY, USA

Correspondence to:Michal Bar-Natan, M.D.
Division of Hematology/Oncology, Icahn School of Medicine at The Mount Sinai Hospital, One Gustave L. Levy Place, Box 1079, New York, NY 10029-6574, USA
E-mail: Michal.Bar-Natan@mssm.edu

#These authors contributed equally to this work.
*These authors’ affiliations are at the time of manuscript development.

Received: September 1, 2021; Revised: January 9, 2022; Accepted: April 18, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background
Blinatumomab has demonstrated efficacy in minimal residual disease (MRD) positive and relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) by inciting rapid and sustained B-cell depletion.
Methods
Owing to its effect on B-cells, blinatumomab is associated with a higher rate of secondary hypogammaglobulinemia compared to chemotherapy. To mitigate blinatumomab-induced hypogammaglobulinemia, patients were pre-emptively repleted with intravenous immune globulin (IVIG) during blinatumomab therapy. In this retrospective study, we compared outcomes of 23 blinatumomab treated adults with ALL. Seventeen patients routinely received IVIG and 6 patients were in the control cohort.
Results
Our findings demonstrated no difference between the two cohorts in immunoglobulin G (IgG) nadir (338 mg/dL vs. 337 mg/dL, P=0.641), days to IgG nadir (120.5 vs. 85.5 days, P=0.13), infection rate (82.4% vs. 66.7%, P=0.58), infections requiring ICU admission (23.5% vs. 16.7%, P=1), and infection related mortality (17.6% vs. 16.7%, P=1).
Conclusion
Pre-emptive IVIG repletion during blinatumomab did not prevent hypogammaglobulinemia and associated infection risk.

Keywords: Acute lymphoblastic leukemia, Blinatumomab, Hypogammaglobulinemia, ALL, Intravenous Immunoglobulin

Fig 1.

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Figure 1.Serum IgG levels for patients in the IVIG cohort collected at baseline and to end of follow-up.
Abbreviation: HGG, hypogamma-globulinemia.
Blood Research 2022; 57: 135-143https://doi.org/10.5045/br.2022.2021163

Fig 2.

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Figure 2.Serum IgG levels for patients in the control cohort collected at baseline and to end of follow-up.
Abbreviation: HGG, hypogamma-globulinemia.
Blood Research 2022; 57: 135-143https://doi.org/10.5045/br.2022.2021163

Table 1 . Baseline characteristics..

All (N=23)Control (N=6)IVIG (N=17)P
Demographics
Age at blinatumomab initiation, median, years (range)56 (25–74)57.5 (50–64)48 (25–74)0.32
Male9 (39.1)3 (50)6 (35.3)0.64
BMI, kg/m2, median (range)24.47 (18.48–31.89)25.49 (21.84–31.89)24.27 (18.48–29.87)0.43
Total follow up from blinatumomab initiation, days, median (range)393 (108–926)354.5 (147–453)424 (108–926)0.32
Disease characteristics
MRD (+)a)15 (75)5 (83.3)10 (71.4)1
Relapsed/refractorya)5 (25)1 (16.7)4 (28.6)1
Number lines of prior therapy, median (range)1 (1–5)2 (1–2)1 (1–5)0.76
Philadelphia chromosome (+)7 (30.4)1 (16.7)6 (35.3)0.62
HSCT prior to blinatumomab3 (13)0 (0)3 (17.6)0.54
Infectious disease history
History of MDR infection5 (22.7)2 (40)3 (17.6)0.55
ESBL1 (4.3)1 (16.7)0 (0)0.26
MRSE4 (17.4)1 (16.7)3 (17.6)1
Hypogammaglobulinemia Risk factors
Prior anti-CD20 therapy10 (43.5)2 (33.3)8 (47.1)0.66
Number of doses, median (range)3.5 (1–7)6.5 (6–7)3 (1–5)0.04
Multiple myeloma1 (4.3)0 (0)1 (5.9)1

All values listed as N (%) unless otherwise noted..

a)Excluding 3 patients who received blinatumomab for consolidation/maintenance therapy..

Abbreviations: BMI, body mass index; ESBL, extended spectrum beta-lactamase; HSCT, hematopoietic stem cell transplant; MDR, multidrug resistant organism; MRD, minimal residual disease; MRSE, methicillin-resistant staphylococcus epidermidis..

Table 2 . Immunoglobulin data..

Ref range
(mg/dL)		All (N=23)Control (N=6)IVIG (N=17)P
Baseline values (mg/dL)
Baseline IgA, mg/dL, median (range)70–400128 (40–544)117.5 (54–149)132 (40–544)0.18
Baseline IgA hypogammaglobulinemia2 (9.5)1 (16.7)1 (6.7)0.5
Baseline IgM, mg/dL, median (range)40–23041 (8–144)44 (8–117)41 (12–144)0.73
Baseline IgM hypogammaglobulinemia9 (42.9)2 (33.3)7 (46.7)0.66
Baseline IgG, mg/dL, median (range)700–1,600716 (321–1,783)836.5 (404–1,262)716 (321–1,783)0.97
Baseline IgG hypogammaglobulinemia10 (47.6)3 (50)7 (46.7)1
Nadir values (mg/dL), median (range)
IgA Nadira)70–40018 (<5–42)11 (9–33)19 (<5–42)0.4
Time to nadir-101 (35–688)82 (48–109)119 (35–688)0.14
IgM Nadira)40–2309.5 (<5–47)10 (<5–47)9 (<5–38)0.93
Time to nadir-86 (35–688)82 (48–109)93 (35–688)0.45
IgG, Nadir700–1,600338 (221–1,006)337 (221–587)338 (258–1,006)0.64
Time to nadir-103 (28–435)85.5 (48–109)120.5 (28–435)0.13
IgG <500 mg/dL, N (%)-19 (86.4) 5 (83.3)14 (87.5)1
Last available immunoglobulin follow-up data, median (range)
IgAa)70–40031 (<5–325)20 (10–325)36 (<5–313)0.5
Day from blinatumomab initiation, days-244.5 (35–912)109 (48–382)285 (35–912)0.31
IgMa)40–23027.5 (<5–211)12 (<5–90)30 (<5–211)0.53
Day from blinatumomab initiation, days-244.5 (35–912)109 (48–382)279 (35–912)0.35
IgG700–1,600591.5 (221–2,346)787 (221–1,679)547 (268–2,346)0.91
Day from blinatumomab initiation, days-243 (35–912)141.5 (48–445)276.5 (35–912)0.49
ANC <500 cells/µL at any time point, N (%)-19 (82.6)6 (100)13 (76.5)0.54
Time to ANC <500 cells/µL, days, median (range)-71 (2–249)65.5 (2–109)96 (14–249)0.35

All values listed as N (%) unless otherwise noted..

a)A value of <5 indicates a result below the detectable level..

Abbreviations: ANC, absolute neutrophil count; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M..

Table 3 . Infection outcomes..

All (N=23)Control (N=6)IVIG (N=17)P
N of patients with infection18 (78.3)4 (66.7)14 (82.4)0.58
Change in antibacterial agent or received antibiotic agente)22 (95.7)6 (100)16 (94.1)1
Change in antifungal agente)5 (21.7)1 (16.7)4 (23.5)1
Change in antiviral agente)10 (43.5)4 (66.7)6 (35.3)0.34
N of infections per patient who had ≥1 infection, median (range)4.5 (1–19)4.5 (4–7)4.5 (1–19)0.65
Time to first infection, days median (range)99.5 (15–429)89 (20–131)99.5 (15–429)0.72
Organism type, median (range)N=91N=20N=71
Virala)48 (52.7)15 (75)33 (46.5)0.33
Bacterialb)38 (41.8)4 (20)34 (47.9)0.38
Fungalc)3 (3.3)1 (5)2 (2.8)0.8
Parasited)2 (2.2)0 (0)2 (2.8)0.88
Site, N (%)N=89N=20N=69
Bloodstream33 (37.1)9 (45)24 (34.8)0.28
Upper respiratory tract20 (22.5)9 (45)11 (15.9)0.16
Lower respiratory tract11 (12.4)1 (5)10 (14.5)0.96
Urinary6 (6.7)1 (5)5 (7.2)0.8
Gastrointestinal13 (14.6)0 (0)13 (18.8)0.23
Bone1 (1.1)0 (0)1 (1.4)0.88
Intra-abdominal2 (2.2)0 (0)2 (2.9)0.72
Mouth1 (1.1)0 (0)1 (1.4)0.88
SSTI2 (2.2)0 (0)2 (2.9)0.72
Patients with infection by severity, N (%)
Grade 18 (44.4)3 (75)5 (35.7)0.28
Grade 210 (55.6)3 (75)7 (50)0.59
Grade 312 (66.7)3 (75)9 (64.3)1
Grade 46 (33.3)1 (25)5 (35.7)1
Grade 54 (22.2)1 (25)3 (21.4)1
Severe infection (grade ≥3)15 (83.3)3 (75)12 (85.7)1
Infection severity incidence, N (%)Total=88Total=20Total= 68
Grade 122 (25)8 (40)14 (20.6)1
Grade 216 (18.2)6 (30)10 (14.7)0.38
Grade 329 (33)3 (15)26 (38.2)0.21
Grade 417 (19.3)2 (10)15 (22.1)1
Grade 54 (4.5)1 (5)3 (4.4)1
Severe infection (grade ≥3)50 (56.8)6 (30)44 (64.7)0.45
Patients requiring ICU admission due to infection5 (21.7)1 (16.7)4 (23.5)1
Occurring while on blinatumomab1 (20)0 (0)1 (25)1
Patients with infection related mortality4 (17.4)1 (16.7)3 (17.6)1
Occurring while on blinatumomab0 (0)0 (0)0 (0)-

All values listed as N (%) unless otherwise noted..

a)Adenovirus, BK virus, cytomegalovirus, Epstein Barr virus, herpes simplex virus, human herpes virus 6, influenza A and B, metapneumovirus, norovirus, parainfluenza, respiratory syncytial virus, rhinovirus, rhinovirus/enterovirus, and Sars-COV-2. b)Bacteroides ovatus, Clostridioides Difficile, Enterococcus faecium, Escherichia coli, Helicobacter pylori, Klebsiella pneumonia, Lactobacillus rhamnosus, methicillin sensitive staphylococcus aureus, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus epidermidis, Staphylococcus hominis, and Stenotrophomonas. c)Candida glabrata, Rhizopus, and a probable invasive fungal infection. d)Babesia. e)To treat a known or suspected infection..

Abbreviations: ICU, intensive care unit; SSTI, skin and soft tissue infection..

Table 4 . Response to blinatumomab..

All (N=23)Control (N=6)IVIG (N=17)P
Achieved disease response to blinatumomaba),b)16 (80)5 (83.3)12 (85.7)1
Proceeded to HSCT14 (60.9)5 (83.3)9 (52.9)0.34
Time to HSCT, days, median (range)105 (58–289)1 04 (64–129)106 (58–289)0.61
Proceeded to other line of therapy4 (17.1)1 (16.7)3 (17.6)-
Time to next therapy, days, median (range)123 (108–608)123 (123–123)123 (108–608)1
If MRD (+) disease, achieved MRD (-)a),b)N=15N=5N=10
12 (80)4 (80)8 (80)1
Time to response, days, median (range)39.5 (29–83)46.5 (32–83)37 (29–85)0.65
If relapsed/refractory disease, achieved CRa)N=5N=1N=4
5 (100)1 (100)4 (100)-
CR with MRD (+)2 (40)1 (100)1 (25)0.4
Time to result, days, median (range)34 (30-89)8933 (30-35)0.5

All values listed as N (%) unless otherwise noted..

a)Excluding 3 patients who received blinatumomab for consolidation/maintenance therapy. b)One patient in the IVIG cohort achieved partial response, defined as 1–2 log reduction in BCR-ABL PCR..

Abbreviations: CR, complete response; HSCT, hematopoietic stem cell transplant; MRD, minimal residual disease..
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