An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation
IntroductionHigh sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomi...
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| Format: | Article |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1360369/full |
| _version_ | 1797268194640003072 |
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| author | Ankit K. Desai Garima Shrivastava Christina L. Grant Raymond Y. Wang Raymond Y. Wang Trevor D. Burt Trevor D. Burt Priya S. Kishnani |
| author_facet | Ankit K. Desai Garima Shrivastava Christina L. Grant Raymond Y. Wang Raymond Y. Wang Trevor D. Burt Trevor D. Burt Priya S. Kishnani |
| author_sort | Ankit K. Desai |
| collection | DOAJ |
| description | IntroductionHigh sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT.MethodsHere, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment.ResultsIn total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week.DiscussionThese case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted. |
| first_indexed | 2024-04-25T01:28:36Z |
| format | Article |
| id | doaj.art-feaa2ff9617e4639b0282d4875ed2de3 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-25T01:28:36Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-feaa2ff9617e4639b0282d4875ed2de32024-03-08T14:42:45ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-03-011510.3389/fimmu.2024.13603691360369An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulationAnkit K. Desai0Garima Shrivastava1Christina L. Grant2Raymond Y. Wang3Raymond Y. Wang4Trevor D. Burt5Trevor D. Burt6Priya S. Kishnani7Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, United StatesDivision of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, United StatesDivision of Genetics and Metabolism, Children’s National Hospital, Washington, DC, United StatesDivision of Metabolic Disorders, Children’s Hospital of Orange County, Orange, CA, United StatesDepartment of Pediatrics, University of California-Irvine School of Medicine, Orange, CA, United StatesDivision of Neonatology, Department of Pediatrics, Duke University School of Medicine, Durham, NC, United StatesChildren’s Health and Discovery Initiative, Duke University School of Medicine, Durham, NC, United StatesDivision of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, United StatesIntroductionHigh sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT.MethodsHere, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment.ResultsIn total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week.DiscussionThese case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1360369/fullalglucosidase alfaanti-drug antibodiesentrenched immune tolerance inductionbortezomibPompe diseaseanti-rhGAA IgG antibodies |
| spellingShingle | Ankit K. Desai Garima Shrivastava Christina L. Grant Raymond Y. Wang Raymond Y. Wang Trevor D. Burt Trevor D. Burt Priya S. Kishnani An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation Frontiers in Immunology alglucosidase alfa anti-drug antibodies entrenched immune tolerance induction bortezomib Pompe disease anti-rhGAA IgG antibodies |
| title | An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation |
| title_full | An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation |
| title_fullStr | An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation |
| title_full_unstemmed | An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation |
| title_short | An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation |
| title_sort | updated management approach of pompe disease patients with high sustained anti rhgaa igg antibody titers experience with bortezomib based immunomodulation |
| topic | alglucosidase alfa anti-drug antibodies entrenched immune tolerance induction bortezomib Pompe disease anti-rhGAA IgG antibodies |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1360369/full |
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