Blood Res 2022; 57(2):
Published online June 30, 2022
https://doi.org/10.5045/br.2022.2021163
© The Korean Society of Hematology
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.
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.
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
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.
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.
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.
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
Table 1 . Baseline characteristics..
All (N=23) | Control (N=6) | IVIG (N=17) | ||
---|---|---|---|---|
Demographics | ||||
Age at blinatumomab initiation, median, years (range) | 56 (25–74) | 57.5 (50–64) | 48 (25–74) | 0.32 |
Male | 9 (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 blinatumomab | 3 (13) | 0 (0) | 3 (17.6) | 0.54 |
Infectious disease history | ||||
History of MDR infection | 5 (22.7) | 2 (40) | 3 (17.6) | 0.55 |
ESBL | 1 (4.3) | 1 (16.7) | 0 (0) | 0.26 |
MRSE | 4 (17.4) | 1 (16.7) | 3 (17.6) | 1 |
Hypogammaglobulinemia Risk factors | ||||
Prior anti-CD20 therapy | 10 (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 myeloma | 1 (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) | ||
---|---|---|---|---|---|
Baseline values (mg/dL) | |||||
Baseline IgA, mg/dL, median (range) | 70–400 | 128 (40–544) | 117.5 (54–149) | 132 (40–544) | 0.18 |
Baseline IgA hypogammaglobulinemia | 2 (9.5) | 1 (16.7) | 1 (6.7) | 0.5 | |
Baseline IgM, mg/dL, median (range) | 40–230 | 41 (8–144) | 44 (8–117) | 41 (12–144) | 0.73 |
Baseline IgM hypogammaglobulinemia | 9 (42.9) | 2 (33.3) | 7 (46.7) | 0.66 | |
Baseline IgG, mg/dL, median (range) | 700–1,600 | 716 (321–1,783) | 836.5 (404–1,262) | 716 (321–1,783) | 0.97 |
Baseline IgG hypogammaglobulinemia | 10 (47.6) | 3 (50) | 7 (46.7) | 1 | |
Nadir values (mg/dL), median (range) | |||||
IgA Nadira) | 70–400 | 18 (<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) | 40–230 | 9.5 (<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, Nadir | 700–1,600 | 338 (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) | 70–400 | 31 (<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) | 40–230 | 27.5 (<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 |
IgG | 700–1,600 | 591.5 (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) | ||
---|---|---|---|---|
N of patients with infection | 18 (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=91 | N=20 | N=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=89 | N=20 | N=69 | |
Bloodstream | 33 (37.1) | 9 (45) | 24 (34.8) | 0.28 |
Upper respiratory tract | 20 (22.5) | 9 (45) | 11 (15.9) | 0.16 |
Lower respiratory tract | 11 (12.4) | 1 (5) | 10 (14.5) | 0.96 |
Urinary | 6 (6.7) | 1 (5) | 5 (7.2) | 0.8 |
Gastrointestinal | 13 (14.6) | 0 (0) | 13 (18.8) | 0.23 |
Bone | 1 (1.1) | 0 (0) | 1 (1.4) | 0.88 |
Intra-abdominal | 2 (2.2) | 0 (0) | 2 (2.9) | 0.72 |
Mouth | 1 (1.1) | 0 (0) | 1 (1.4) | 0.88 |
SSTI | 2 (2.2) | 0 (0) | 2 (2.9) | 0.72 |
Patients with infection by severity, N (%) | ||||
Grade 1 | 8 (44.4) | 3 (75) | 5 (35.7) | 0.28 |
Grade 2 | 10 (55.6) | 3 (75) | 7 (50) | 0.59 |
Grade 3 | 12 (66.7) | 3 (75) | 9 (64.3) | 1 |
Grade 4 | 6 (33.3) | 1 (25) | 5 (35.7) | 1 |
Grade 5 | 4 (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=88 | Total=20 | Total= 68 | |
Grade 1 | 22 (25) | 8 (40) | 14 (20.6) | 1 |
Grade 2 | 16 (18.2) | 6 (30) | 10 (14.7) | 0.38 |
Grade 3 | 29 (33) | 3 (15) | 26 (38.2) | 0.21 |
Grade 4 | 17 (19.3) | 2 (10) | 15 (22.1) | 1 |
Grade 5 | 4 (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 infection | 5 (21.7) | 1 (16.7) | 4 (23.5) | 1 |
Occurring while on blinatumomab | 1 (20) | 0 (0) | 1 (25) | 1 |
Patients with infection related mortality | 4 (17.4) | 1 (16.7) | 3 (17.6) | 1 |
Occurring while on blinatumomab | 0 (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) | ||
---|---|---|---|---|
Achieved disease response to blinatumomaba),b) | 16 (80) | 5 (83.3) | 12 (85.7) | 1 |
Proceeded to HSCT | 14 (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 therapy | 4 (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=15 | N=5 | N=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=5 | N=1 | N=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) | 89 | 33 (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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